Peter Riederer

Gerd Laux
Toshiharu Nagatsu
Weidong Le
Christian Riederer
Editors
NeuroPsychopharmacotherapy
NeuroPsychopharmacotherapy
Peter Riederer • Gerd Laux •
Toshiharu Nagatsu • Weidong Le •
Christian Riederer
Editors

NeuroPsychopharmacotherapy

With 329 Figures and 372 Tables

Editors
Peter Riederer Gerd Laux
Clinic and Policlinic for Institute of Psychological Medicine (IPM)
Psychiatry, Psychosomatics and Soyen, Germany
Psychotherapy
MVZ Waldkraiburg
University Hospital Wuerzburg
Center of Neuropsychiatry
Wuerzburg, Germany
Waldkraiburg, Germany
University of Southern Denmark Odense
Department of Psychiatry and Psychotherapy
Odense, Denmark
Ludwig-Maximilians-University (LMU)
Munich, Germany

Toshiharu Nagatsu Weidong Le

Centre for Research Promotion Center Translational Res Neurol Diseases
and Support Dalian Med Uni Shanghai Inst Health Sc Center
Fujita Health University Translational Res Neurol Diseases
Toyoake, Aichi, Japan Dalian, China

Christian Riederer
Würzburg, Germany

ISBN 978-3-030-62058-5 ISBN 978-3-030-62059-2 (eBook)

https://doi.org/10.1007/978-3-030-62059-2
© Springer Nature Switzerland AG 2022
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the
material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors
or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG.
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Preface

Psychiatric disorders are among the most common diseases worldwide, and in many
countries, neuropsychopharmaka are among the most prescribed drugs (EMA,
FDA).
Starting in the early 1990s, Peter Riederer, Gerd Laux, and Walter Pöldinger
edited, in the German language, a series of handbooks covering (1) basic aspects of
psychopharmacological drugs, (2) tranquilizers and hypnotics, (3) antidepressants,
(4) antipsychotics, (5) drugs for Parkinson’s disease and “Nootropics,” and (6) anti-
epileptics, β-blocker, and other psychopharmacological drugs. Our goal was to
provide state-of-the-art basic knowledge, current diagnostic and differential diag-
nostic methodologies, and up-to-date therapeutic strategies.
For some years, however, fundamental scientific, political, economic, and social
dynamics have substantially influenced both the development of new drugs for
neuropsychiatric disorders and their acceptance by authorities, doctors, and patients.
The reasons for it are manifold:

1. In the golden age of “neurochemistry,” drug development focused on the basic

biological principles of synapses of various neurotransmitters systems. This
resulted in new treatment strategies for depression, schizophrenia, anxiety disor-
ders, sleep disorders, ADHD, addiction, Parkinson’s disease, dementive disor-
ders, and others. Today, genes are the prime targets of research to study the
pathological basis of neuropsychiatric disorders. Molecular-biological and
molecular-genetic analyses indicate very complex pathological mechanisms
underlying neuropsychiatric disorders based on multiple triggers, multiple causal
mechanisms, multiple genetic backgrounds, and so on. While they may all be
decisive, translation of this fundamental knowledge into clinical practice is
difficult and even more so to develop new, causal acting drugs.
2. Together with a rising number of regulatory restrictions and cost-cutting mea-
sures in the national health systems, we are witnessing discussions about designs
for clinical studies. “End points” which are hard to define, “added values” which
may be tricky to prove or to meet a pathological target, and compliance issues
contribute to a more complex study environment and in some cases stop compa-
nies from doing studies and developing new drugs at all, or let them decide to

v
vi Preface

focus on areas like cancer and cardiovascular disorders which promise much
higher financial revenues.
3. We also see today a much livelier field of neuropsychopharmacotherapy than
30 years ago. In a changing social environment, more reservations toward the role
of pharmaceutical companies, their financing of clinical studies, their cooperation
with physicians, and their marketed drugs themselves, exist. The balance has
shifted from a drug-oriented therapy to psychotherapy and social psychiatry.
However, in our opinion, both poles are necessary for the optimal treatment
strategy in most patients.

All this contributes to a crisis for innovative concepts and developments in

research-oriented drug companies with the goal to develop innovative neuropsychi-
atric drugs. That is all the more regrettable as more patients with neuropsychiatric
suffering require medical treatment as cases of movement and dementive disorders
rise fast in our aging societies. Additionally, more younger people suffer from
anxiety- and stress-related disorders. Caring for these patients and providing them
with innovative drugs should be a top priority for companies, politicians, and
regulators.
Despite a slowing rate of innovation for the reasons mentioned, the overview of
the heterogeneous group of neuropsychiatric agents is still difficult and demanding.
Standard works like Stahl’s Essential Psychopharmacology, Ghaemi’s Clinical
Psychopharmacology, Schatzberg and Nemeroff’s Textbook of Psychopharmacol-
ogy, as well as World Federation of Societies of Biological Psychiatry (WFSBP)
Guidelines for biological treatments (World J Biol Psychiatry 2011–2017) exist, but
the number of individual papers published in countless scientific journals is almost
infinite, hard to keep track of, and, for physicians in clinics and practices, virtually
inaccessible and hard to apply.
Against the background of a changing era of psychopharmacology, we have
decided to publish a contemporary and more comprehensive three-volume handbook
on Neuropsychopharmacotherapy available as a print and online book with a total
238 chapters, authored by an international panel of scientists and clinicians from
33 countries. This makes it a prime example of international collaboration, and the
book is dedicated to psychiatrists, neurologists, neuroscientists, medical practi-
tioners, and clinical psychologists.
All our chapters aim to describe the current status of medication in all major
psychiatric and neurological indications and include comparisons of pharmacolog-
ical treatment strategies in in Europe, the USA, Japan, and China. We have tried to
find a balanced approach between basic science data and clinical necessities which
might be handled differently from continent to continent and from country to
country, and, additionally, we have included chapters highlighting herbal medicinal
approaches in China and Japan.
Volume 1 covers basic principles and general aspects of neuropsychopharma-
cotherapy consisting of 39 chapters dealing with neurobiological, pharmacological,
psychopathological, clinical, legal, and historical aspects.
Preface vii

Volume 2 has a strong clinical focus, and classes, drugs, and special aspects of the
role of neuropsychopharmacological substances in psychiatry and neurology in
10 major neurological and psychiatric disorders.
Volume 3 contains 34 selected overview chapters on topic of applied neuropsy-
chopharmacotherapy as well as issues related to the implementation of
neuropsychopharmacotherapy.
We would like to express our sincere gratitude to our section editors as well as to
all authors, without their support it would not have been possible to publish this
handbook. We would also like to thank Springer Nature Publishers for their ongoing
support to publish another handbook on neuropsychopharmacology. We do hope it
will find high acceptance in the scientific community and establish itself as a
standard reference work in clinical and basic science.

Wuerzburg, Germany Peter Riederer

Soyen, Germany Gerd Laux
Toyoake, Japan Toshiharu Nagatsu
Dalian, China Weidong Le
Würzburg, Germany Christian Riederer
October 2022
Acknowledgments

The Editors would like to thank the Verein zur Durchführung Neurowis-
senschaftlicher Tagungen e.V. for their financial support in organizing this
publication.

ix
Contents

Volume 1

Part I Basic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Peter Riederer

Neurobiological Principles: Neurotransmitters ................... 3

Lena Hampel and Thorsten Lau

Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology . . . 25

Norbert Müller

Pharmacokinetic and Pharmacodynamic Principles . . . . . . . . . . . . . . . 65

Gerald Zernig and Christoph Hiemke

Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Maike Scherf-Clavel

Pharmacoeconomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Richard Dodel, Christopher Kruse, Annette Conrads-Frank, and
Uwe Siebert

Compliance and Psychoeducation ............................. 235

Stefan Unterecker

Psychopathology: Rating Scales for the Assessment of Mental

Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Rolf-Dieter Stieglitz and Hans-Peter Volz

Xenobiotic Interactions in Psychopharmacotherapy: Classification

and Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Ekkehard Haen

Randomized Controlled Trials and the Efficacy of Psychotropic

Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Boadie Waid Dunlop and Carolina Medeiros Da Frota Ribeiro

xi
xii Contents

Adverse Drug Reactions, Intoxications and Interactions of

Neuropsychotropic Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Gerald Zernig, Sabine Bischinger, and Christoph Hiemke
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects
with a Focus on Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Makoto Naoi, Wakako Maruyama, and Peter Riederer
TCM Substances in Neuropsychopharmacotherapy . . . . . . . . . . . . . . . 451
Yong Wang and Jie Li
D-Serine: Basic Aspects with a Focus on Psychosis . . . . . . . . . . . . . . . . 495
Toru Nishikawa, Asami Umino, and Masakazu Umino
Amine Precursors in Depressive Disorders and the Blood-Brain
Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
Hari Shanker Sharma and Aruna Sharma
The Endocannabinoid System in the Central Nervous System:
Emphasis on the Role of the Mitochondrial Cannabinoid
Receptor 1 (mtCB1R) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
Marisol Maya-López, Cecilia Zazueta, Socorro Retana-Márquez,
Syed F. Ali, Cimen Karasu, Emmanuel S. Onaivi, Michael Aschner, and
Abel Santamaría
Experimental Psychopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
Nicola Simola

Part II General Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619

Peter Riederer
Psychopharmacology: A Brief Overview of Its History . . . . . . . . . . . . . 621
Paul Foley
Historical Overview of Psychiatric Diagnostics in Japan . . . . . . . . . . . . 661
Toshiyuki Someya and Satoshi Hoya
Neuro-psychopharmacotherapy and the Differential Diagnostic
Approaches in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Richard Musil and Peter Falkai
Neuropsychopharmacotherapy and the Differential Diagnostic
Approaches in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Jie Li and Shen Li
Ethical Issues in Neuropsychopharmacotherapy: US Perspective . . . . . 713
Michael Menconi Jr. and Veljko Dubljević
Ethics of Informed Consent: Coercive and Preventive Medication . . . . 739
Hanfried Helmchen
Contents xiii

Neuropsychopharmacotherapy: Aspects of Placebo Effects ......... 755

Petra Netter
Neuropsychopharmacotherapy: International Regulations and
Regulating Laws in Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
Akira Ishii and Yujin Natori
Health Economics for Neuropsychological Diseases in China . . . . . . . . 789
Hai-lun Cui and Gang Wang
Causal Inference Methods in Pharmacoepidemiology . . . . . . . . . . . . . . 805
Laura Pazzagli and Xiaojuan Li
Neuropsychopharmacotherapy: Guidelines . . . . . . . . . . . . . . . . . . . . . . 823
Jelena Vrublevska and Lubova Renemane
Neuropsychopharmacotherapy: Differential Dose Regimes
in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
Jie Li and Shen Li
Nutrition in Brain Aging: Its Relevance to Age-Associated
Neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869
Wakako Maruyama, Masayo Shamoto Nagai, and Makoto Naoi
Ethnopharmacology and the Development of Psychoactive Drug:
A Critical Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899
Elaine Elisabetsky
Antidepressants: Molecular Aspects of SSRIs . . . . . . . . . . . . . . . . . . . . 915
Adeline Etievant, Nasser Haddjeri, and Thorsten Lau
Neurochemical Mobile: A Heuristic Tool for Understanding
Dynamic Complexity and Treatment of Alcohol Withdrawal . . . . . . . . 933
Felix Tretter
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug
Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
Markus Karl Huber, Josef Schwitzer, Erwin Kirchler, and Peter Lepping
Hallucinogens as Therapeutic Agents: Past, Present, and Future . . . . . 975
Elena Vos, Stephen Snelders, and Toine Pieters
Lipid Metabolism Disturbances During Antipsychotic Treatment for
Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
Shin Ono and Toshiyuki Someya
Cannabinoid Drugs in Mental Health Disorders . . . . . . . . . . . . . . . . . . 1005
Stefan Kloiber, Justin Matheson, Helena K. Kim, and Bernard Le Foll
Cognitive Enhancement and American Constitutional Law . . . . . . . . . 1039
Marc Jonathan Blitz
xiv Contents

Challenges of Parkinson’s Disease Care in Southeast Asia . . . . . . . . . . 1061

Roongroj Bhidayasiri, Sasivimol Virameteekul, Banon Sukoandari,
Tai Ngoc Tran, and Thien Thien Lim

Neuropsychopharmacotherapy: Complementary Treatments . . . . . . . . 1083

Hans Moises

Volume 2a

Part III Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099

Hans-Jürgen Möller and Gerd Laux
Antidepressants: Definition, Classification, Guidelines . . . . . . . . . . . . . 1101
Gerd Laux
Antidepressants: Pharmacology and Biochemistry . . . . . . . . . . . . . . . . 1109
Vanessa Efinger, Walter E. Müller, and Kristina Friedland
Antidepressants: Indications, Contraindications, Interactions, and
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135
Filippo Corponi, Chiara Fabbri, and Alessandro Serretti
Antidepressants: Course and Duration of Therapy, Withdrawal
Syndromes, and Resistance to Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 1173
Lasse Brandt, Andreas Heinz, and Jonathan Henssler
Tricyclics: Imipramine, Clomipramine, Trimipramine
(Dibenzazepines) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
Hans-Peter Volz and Gerd Laux
Amitriptyline and Depressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1205
Mellar P. Davis
Amoxapine and Depressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225
Dan Rujescu, Stephan Röttig, and Tim Johannes Krause
Nortriptyline and Maprotiline for Depressions . . . . . . . . . . . . . . . . . . . 1233
Gerd Laux
Mianserine and Depressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1241
Frank Faltraco and Johannes Thome
Trazodone and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1247
Gerd Laux
Serotonin Reuptake Inhibitors: Citalopram, Escitalopram,
Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline . . . . . . . . . . . . . . 1257
Gerd Laux
Bupropion and Depressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1271
Dan Rujescu, Stephan Röttig, and Tim Johannes Krause
Contents xv

Mirtazapine and Depressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1281

Mellar P. Davis
Vilazodone and Depressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
Frank Faltraco and Johannes Thome
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):
Venlafaxine, Desvenlafaxine, Duloxetine, Milnacipran,
Levomilnacipran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319
Gerd Laux and Ansgar Klimke
Monoamine Oxidase Inhibitors in Depressive Disorders . . . . . . . . . . . . 1347
Jeffrey H. Meyer, Dmitriy Matveychuk, Andrew Holt,
Apitharani Santhirakumar, and Glen B. Baker
Agomelatine and Depressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1381
Gerd Laux
Hypericum and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1393
Hans-Peter Volz
Ginseng and Ginsenosides in Depression . . . . . . . . . . . . . . . . . . . . . . . . 1401
Makoto Naoi, Wakako Maruyama, and Masayo Shamoto Nagai
Vortioxetine and Depressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417
Gerd Laux

Part IV Mood Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425

Andreas Menke
Mood Stabilizer: Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1427
Andreas Menke
Mood Stabilizers: Classification, Indications and Differential
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429
Andreas Menke
Mood Stabilizers: Pharmacology and Biochemistry . . . . . . . . . . . . . . . 1437
Leif Hommers
Mood Stabilizers: Side Effects, Contraindications, and Interactions . . . 1447
Hubertus Himmerich and Amy Hamilton
Mood Stabilizers: Course and Duration of Therapy, Withdrawal
Syndromes, and Resistance to Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 1469
Georgios Schoretsanitis and Michael Paulzen
Mood Stabilizers: Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1493
Janusz K. Rybakowski
Mood Stabilizers: Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1523
Johannes M. Hennings
xvi Contents

Mood Stabilizers: Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1537

Gudrun Hefner and Andreas Menke
Mood Stabilizers: Valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1549
Maximilian Schäfer and Eva Janina Brandl
Mood Stabilizers: Olanzapin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
Stefan Kloiber
Mood Stabilizers: Asenapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1575
Frank M. Schmidt
Mood Stabilizers: Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1583
Amanda Silva de Miranda, Rodrigo Novaes Ferreira,
Antônio Lúcio Teixeira, and Aline Silva de Miranda
Mood Stabilizers: Risperidone for Treating Bipolar Disorders
in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1607
Adriana R. Vasquez and William V. Bobo
Guidelines on Mood Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1639
Johannes Gfesser and Sarah Kittel-Schneider

Volume 2b

Part V Antipsychotics/Neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . 1687

Frank Schmidt
Antipsychotics/Neuroleptics: Definition, Classification, Indications
and Differential Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1689
Yusuke Matsuzaka, Shinji Kanegae, and Hiroki Ozawa
Antipsychotics/Neuroleptics: Pharmacology and Biochemistry . . . . . . . 1699
Ken Yonezawa, Shinji Kanegae, and Hiroki Ozawa
Antipsychotics/Neuroleptics: Course and Duration of Therapy,
Withdrawal Symptoms, Resistance to Therapy, Side Effects, and
Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1709
Yoshiro Morimoto, Shinji Kanegae, and Hiroki Ozawa
History of Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1731
Ekkehardt Kumbier
Piperazine Phenothiazines: Fluphenazine and Perphenazine . . . . . . . . 1745
Gerd Laux
Flupentixol in the Treatment of Psychosis . . . . . . . . . . . . . . . . . . . . . . . 1753
Gerd Laux
Haloperidol in the Treatment of Psychosis . . . . . . . . . . . . . . . . . . . . . . . 1761
Gerd Laux
Contents xvii

Risperidone and Paliperone in the Treatment of Psychosis . . . . . . . . . . 1769

Gerd Laux

Low-Potency Antipsychotics: Levomepromazine, Melperon, and

Pipamperone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1783
Yoshiro Morimoto, Akira Imamura, Shinji Kanegae, and Hiroki Ozawa

First-Generation Antipsychotics as a Bridge to Second-Generation

Antipsychotics in the Japanese Pharmaceutical Industry:
Mosapramine, Timiperone, Zotepine, and Nemonapride . . . . . . . . . . . 1803
Ken Inada, Mitsukuni Murasaki, and Jun Ishigooka

Clozapine in the Treatment of Psychosis . . . . . . . . . . . . . . . . . . . . . . . . 1837

Gerd Laux

Olanzapine in the Treatment of Psychosis . . . . . . . . . . . . . . . . . . . . . . . 1847

Gerd Laux

Quetiapine in the Treatment of Psychosis . . . . . . . . . . . . . . . . . . . . . . . 1859

Gerd Laux

Asenapine in the Treatment of Psychosis . . . . . . . . . . . . . . . . . . . . . . . . 1871

Peter Schönknecht

Ziprasidone, Zuclopenthixole, and Fluspirilene in the Treatment of

Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1881
Daniela Rodrigues-Amorim and José Manuel Olivares

From Perospirone and Blonanserin to Lurasidone . . . . . . . . . . . . . . . . 1905

Ken Inada, Jun Ishigooka, and Mitsukuni Murasaki

Amisulpride and Sulpiride in the Treatment of Psychosis . . . . . . . . . . . 1943

Gerd Laux

Cariprazine in the Treatment of Psychosis . . . . . . . . . . . . . . . . . . . . . . . 1953

Peter Schönknecht

D-Serine in the Treatment of Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . 1963

Toru Nishikawa, Asami Umino, and Masakazu Umino

The Dopamine D2 Receptor Partial Agonist Antipsychotics,

Aripiprazole, and Brexpiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977
Tetsuro Kikuchi, Kenji Maeda, Sakiko Yamada, Mikio Suzuki,
Tsuyoshi Hirose, Takashi Futamura, and Robert D. McQuade

Evidence-Based Treatment with Antipsychotics in Schizophrenia:

S3-Guideline and Current References . . . . . . . . . . . . . . . . . . . . . . . . . . 2023
D. Wozniak and C. Rummel-Kluge
xviii Contents

Part VI Tranquilizers/Anxiolytics . . . . . . . . . . . . . . . . . . . . . . . . . . . 2035

Stefan Kloiber

Tranquilizers/Anxiolytics: Definition, Indications, Contraindications,

and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2037
Stefan Kloiber and Gerasimos Konstantinou

Tranquilizers/Anxiolytics: Pharmacology and Biochemistry of

Anxiolytic Drugs Acting via GABAergic Mechanisms . . . . . . . . . . . . . . 2053
David N. Stephens

Tranquilizer/Anxiolytics: Antidepressants . . . . . . . . . . . . . . . . . . . . . . . 2071

Gerasimos Konstantinou

Tranquilizer/Anxiolytics: Pregabalin . . . . . . . . . . . . . . . . . . . . . . . . . . . 2083

Nazanin Alavi and Callum Stephenson

Tranquilizer/Anxiolytics: Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . 2099

Heinz Grunze

Tranquilizer/Anxiolytics: Buspirone . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2115

Brett D. M. Jones and M. Ishrat Husain

Tranquilizer/Anxiolytics: Tandospirone . . . . . . . . . . . . . . . . . . . . . . . . . 2125

Jie Li

Tranquilizer/Anxiolytics: Mexazolam . . . . . . . . . . . . . . . . . . . . . . . . . . 2151

Igor Soares da Costa, Ricardo Moreira, and Hélder Fernandes

Tranquilizer/Anxiolytics: Benzodiazepines (Short-Acting) –

Etizolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2161
Peter Zwanzger

Tranquilizer/Anxiolytics: Benzodiazepines (Intermediate-Acting) –

Alprazolam, Bromazepam, Clonazepam, Lorazepam . . . . . . . . . . . . . . 2171
Brett D. M. Jones and M. Ishrat Husain

Tranquilizer/Anxiolytics: Benzodiazepines (Long-Acting) –

Chlordiazepoxide, Clorazepate, Diazepam, Ethyl Loflazepate,
Flutoprazepam, Medazepam, Mexazolam, Nitrazepam, Oxazolam . . . 2185
Yuliya Knyahnytska, Zara Abbaspour, and Tetyana Kendzerska

Tranquilizer/Anxiolytics: Lavender Oil . . . . . . . . . . . . . . . . . . . . . . . . . 2205

Davide Donelli, Michele Antonelli, and Fabio Firenzuoli

Anxiolytics: Misuse, Dependence, and Withdrawal Syndromes . . . . . . 2217

Victor M. Tang and Simon J. C. Davies
Contents xix

Augmentation of Psychotherapy with D-Cycloserine in Patients

with Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2243
Leopold Maria Lautenbacher, Lena Pyrkosch, Lea Mascarell Maricic, and
Andreas Ströhle

Part VII Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2261

Otto Dietmaier
Hypnotics: Definition, Classifications, Indications, and Differential
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2263
Otto Dietmaier
Hypnotics: Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2281
Martina Hahn
Hypnotics: Course and Duration of Therapy, Side Effects,
Contraindications, Interactions, Withdrawal Syndromes, and
Resistance to Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2311
Maria Pepe, Pierluigi Lanzotti, and Marianna Mazza
Hypnotics: Guidelines and Current References . . . . . . . . . . . . . . . . . . . 2339
Niels Bergemann
Somnologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2379
Sebastian Herberger, Eckart Ruether, and Göran Hajak

Part VIII Psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2419

Pieter Hoekstra
Stimulants: Definition, Pharmacology, Indications, Side Effects,
and Treatment Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2421
Petra Steinbuchel and Laurence Greenhill
Psychostimulants: Primary and Secondary Indications . . . . . . . . . . . . . 2451
David Coghill
Efficacy of Amphetamines, Methylphenidate, and Modafinil in the
Treatment of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2465
Wolfgang Retz
International Comparison of ADHD Clinical Practice Guidelines:
Comparing NICE, UMHS, and CADDRA Guidelines to Consider
the Latest ADHD Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2487
Atsunori Sugimoto and Toshiyuki Someya

Part IX Agents for Treatment of Withdrawal and Dependency . . . . 2503

Toshikazu Saito
Pharmacology of Alcohol and Alcohol Use Disorder . . . . . . . . . . . . . . . 2505
Naoyuki Hironaka
xx Contents

Disulfiram and Cyanamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2525

Tetsuji Cho
Topiramate, Naltrexone, and Acamprosate in the Treatment of
Alcohol Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2535
Riccardo Guglielmo, Liana Kobylinska, and Rocco de Filippis
Nalmefene in the Treatment of Alcohol Use Disorders . . . . . . . . . . . . . 2551
Jens Reimer, Ingo Schäfer, and Jürgen Gallinat
Recommendations from Current German, British, American, and
Australian Guidelines on Alcohol Treatment . . . . . . . . . . . . . . . . . . . . . 2559
Lisa Proebstl and Oliver Pogarell
Nicotine Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2569
Thomas Polak and Christian C. Jacob
Agents for Treatment of Withdrawal and Dependency: Varenicline . . . 2603
Christian C. Jacob and Thomas Polak

Volume 2c

Part X Anti-dementia Medications ......................... 2635

László Vécsei
Anti-dementia Medications: Classification, Indications, and
Differential Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2637
Frank Jessen
Anti-dementia Medications: Pharmacology and Biochemistry . . . . . . . 2649
Anne Eckert, Amandine Grimm, and Walter E. Müller
Anti-dementia Medications: Course and Duration of Therapy and
Withdrawal Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2665
Aylin Yaman and Hakan Yaman
Anti-dementia Medications: Specific Agents . . . . . . . . . . . . . . . . . . . . . 2677
Feng Zhang, Xinyao Liu, Yufei Liu, Yanjiang Wang, and Weidong Le
Acetylcholinesterase inhibitors (Galantamine, Rivastigmine, and
Donepezil) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2709
Gumpeny R. Sridhar
Memantine for Treatment of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . 2723
Thomas Müller and Wilfried Kuhn
Nootropics (Piracetam, Pyritinol, Co-dergocrine, Meclophenoxat,
Pentoxifylline, Nimodipine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2733
Zyta Beata Wojszel
Contents xxi

Anti-dementia Medications and Anti-Alzheimer’s Disease Drugs:

Side Effects, Contraindications, and Interactions . . . . . . . . . . . . . . . . . 2779
Jens Benninghoff and Robert Perneczky
Complementary Medications (Statins, Nicergoline, Naftidrofuryl) in
Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2789
Aylin Yaman and Hakan Yaman
Novel Pharmaceutical Approaches in Dementia . . . . . . . . . . . . . . . . . . 2803
Masaru Tanaka, Nóra Török, and László Vécsei

Part XI Parkinsonian Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2821

Toshiharu Nagatsu and Akira Nakashima
Definition and Classification of Parkinsonian Drugs . . . . . . . . . . . . . . . 2823
Yoshikuni Mizuno
Clinical Aspects of the Pharmacology and Biochemistry of Drugs
for the Treatment of Motor Symptoms of Parkinson’s Disease . . . . . . . 2853
Thomas Müller
Parkinsonian Drugs: Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2871
Wolfgang H. Jost
Treatment of Parkinson’s Disease: Early, Late, and Combined . . . . . . 2891
M. Beudel, R. M. A. de Bie, and K. L. Leenders
Course and Duration of Therapy with Parkinsonian Drugs and
Withdrawal Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2917
Koji Aoyama
Drugs in the Treatment of Dystonia, Multisystem Atrophy, and
Non-Parkinson Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2947
Wolfgang H. Jost and Joerg Müller
Side Effects, Contraindications, and Drug-Drug Interactions in
the Use of Antiparkinsonian Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2963
Etsuro Nakanishi and Ryosuke Takahashi
Parkinsonian Toxins: From MPTP to Endogenous Neurotoxins . . . . . . 2973
Makoto Naoi, Wakako Maruyama, and Masayo Shamoto Nagai
Guidelines for the Use of Parkinsonian Drugs (in USA) . . . . . . . . . . . . 2993
Trang N. N. Vo, Karen Frei, and Daniel D. Truong
Guidelines for the Use of Parkinsonian Drugs in Canada . . . . . . . . . . . 3015
Susan H. Fox and Sean Jeremy Udow
German Guidelines for the Use of Parkinsonian Drugs . . . . . . . . . . . . . 3025
Wolfgang H. Jost
xxii Contents

Parkinsonian Drugs: Guidelines for Japan . . . . . . . . . . . . . . . . . . . . . . 3051

Yoshikuni Mizuno
Guidelines for Therapeutic Management of Parkinson’s Disease
in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3079
Lin Lu, Shengdi Chen, Yuting Yang, Yangfu Luo, Pingyi Xu, and
Weidong Le
Parkinsonian Drugs in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3099
Shengdi Chen, Xiaojie Zhang, Yining Gao, and Weidong Le
Levodopa Therapy for the Treatment of Parkinson’s Disease . . . . . . . . 3111
Nobutaka Hattori
Levodopa/Carbidopa Intestinal Gel in Parkinson’s Disease . . . . . . . . . 3119
Jiro Fukae and Nobutaka Hattori
Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection
for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3127
Toshiharu Nagatsu and Akira Nakashima
Selegiline for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . 3149
Peter Riederer and Thomas Müller
Safinamide for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . 3159
Thomas Müller
From Anti-Parkinson’s Drug Rasagiline to Novel Multitarget Iron
Chelators with Acetylcholinesterase and Monoamine Oxidase
Inhibitory and Neuroprotective Properties for Alzheimer’s Disease . . . 3167
Hailin Zheng, Tamar Amit, Orit Bar-Am, Mati Fridkin, Silvia A. Mandel,
and Moussa B. H. Youdim
Bromocriptine for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . 3193
Reinhard Horowski
Lisuride: An 8-Alpha-Ergoline with Ergot Antagonistic Properties . . . 3199
Reinhard Horowski
Pergolide in the Treatment of Parkinson’s Disease . . . . . . . . . . . . . . . . 3243
Takashi Tsuboi, Hirohisa Watanabe, Masahisa Katsuno, and Gen Sobue
Cabergoline in the Treatment of Parkinson’s Disease . . . . . . . . . . . . . . 3253
Takashi Tsuboi, Hirohisa Watanabe, Masahisa Katsuno, and Gen Sobue
Apomorphine for the Treatment of Parkinson’s Disease . . . . . . . . . . . . 3263
Thomas Müller
Pramipexole for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . 3277
Kuni Konaka and Hideki Mochizuki
Contents xxiii

Ropinirole in the Treatment of Parkinson’s Disease . . . . . . . . . . . . . . . 3285

Kuni Konaka and Hideki Mochizuki
Rotigotine for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . 3293
Wolfgang H. Jost
Entacapone/Tolcapone/Opicapone for Treating Parkinson’s
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3309
Thomas Müller
Amantadine for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . 3327
Wilfried Kuhn and Thomas Müller
Trihexyphenidyl, Biperiden, and Other Anticholinergics in the
Treatment of Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3333
Kazuya Kawabata and Masahisa Katsuno
Mazaticol for Treating Parkinson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3341
Yoshiki Niimi and Tatsuro Mutoh
Piroheptine for Treating Parkinson . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3353
Yoshiki Niimi and Tatsuro Mutoh
Droxidopa for the Treatment of Parkinson’s Disease . . . . . . . . . . . . . . 3365
Mizuki Ito and Hirohisa Watanabe
Istradefylline for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . . 3375
Tomoyuki Kanda and Masahiro Nomoto
Zonisamide for Treating Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . 3393
Ritsuko Hanajima, Hidenori Maruyama, Osamu Konishi, and
Yoshikazu Ugawa

Volume 2d

Part XII Anti-convulsant Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3403

Christian E. Elger
Anti-convulsant Agents: Definition and Indication . . . . . . . . . . . . . . . . 3405
Tobias R. Baumgartner and Christian E. Elger
Anti-convulsant Agents: Pharmacology and Biochemistry . . . . . . . . . . 3413
Wolfgang Löscher
Anti-convulsant Agents: Beginning and Duration of Therapy,
Withdrawal, and Resistance – Children . . . . . . . . . . . . . . . . . . . . . . . . . 3441
Ingo Borggraefe
Anti-convulsant Agents: Principal Considerations on Effectiveness,
Side Effects, and Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3455
Steven C. Schachter
xxiv Contents

Anti-convulsant Agents: Beginning, Maintenance,

Pharmacoresistance, Duration of Therapy, and Withdrawal –
Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3463
Christian E. Elger and Monika Jeub
Anti-convulsant Drugs: Differential Indications – Neuropathic Pain
and Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3473
R. Baron and J. Sachau
Anti-convulsant Agents: Acute Drug Therapy Outside Status
Epilepticus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3493
Stephan Rüegg and Maria Rasenack
Anti-convulsant Drugs and Cognition . . . . . . . . . . . . . . . . . . . . . . . . . . 3517
Christoph Helmstaedter and Juri-Alexander Witt
Anti-convulsant Agents: Potassium Bromide . . . . . . . . . . . . . . . . . . . . . 3529
Thomas Bast and Bernhard J. Steinhoff
Anti-convulsant Agents: Phenobarbital and Primidone . . . . . . . . . . . . . 3537
Svein I. Johannessen and Cecilie Johannessen Landmark
Anti-convulsant Agents: Ethosuximide and Methsuximide . . . . . . . . . . 3547
Maria Tountopoulou and Angela M. Kaindl
Anti-convulsant Agents: Phenytoin and Fosphenytoin . . . . . . . . . . . . . 3555
Steven C. Schachter
Anti-convulsant Agents: Valproic Acid . . . . . . . . . . . . . . . . . . . . . . . . . 3561
Tobias R. Baumgartner and Christian E. Elger
Anti-convulsant Agents: Carbamazepine, Oxcarbazepine, and
Eslicarbazepine Acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3571
Angel Aledo-Serrano and Antonio Gil-Nagel
Anti-convulsant Agents: Vigabatrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3579
Axel Panzer
Anti-convulsant Agents: Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . 3589
Helena Janssen and Paul Boon
Anti-convulsant Agents: Gabapentin and Pregabalin . . . . . . . . . . . . . . 3605
Luigi Agró, Rita Demurtas, and Josemir W. Sander
Anti-convulsant Agents: Levetiracetam and Brivaracetam . . . . . . . . . . 3619
Bernhard J. Steinhoff
Anti-convulsant Agents: Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . 3633
Vera Dinkelacker, Maria Paola Valenti, and Edouard Hirsch
Anti-convulsant Agents: Sulthiame . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3649
Johannes Rösche
Contents xxv

Anti-convulsant Agents: Zonisamide . . . . . . . . . . . . . . . . . . . . . . . . . . . 3657

Christoph Baumgartner and Martha Britto-Arias
Anti-convulsant Agents: Rufinamide . . . . . . . . . . . . . . . . . . . . . . . . . . . 3671
Till Hartlieb and Gerhard Kluger
Anti-convulsant Agents: Stiripentol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3681
Catherine Chiron
Anti-convulsant Agents: Felbamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3691
Bassel Abou-Khalil
Anti-convulsant agents: Cortisone and Adrenocorticotropic
Hormone (ACTH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3707
Hana Kubova, Premysl Jiruska, and Vladimir Komarek
Anti-convulsant Agents: Everolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . 3721
Christoph Hertzberg and David Neal Franz
Anti-convulsant Agents: Benzodiazepines (Clobazam, Clonazepam,
Diazepam, Lorazepam, Midazolam) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3753
Francesco Brigo and Simona Lattanzi
Anti-convulsant Agents: Lacosamide and Perampanel . . . . . . . . . . . . . 3761
Christian Tilz
Anti-convulsant Agents: Cannabidiol and Fenfluramine . . . . . . . . . . . . 3781
Adam Strzelczyk, Katharina Frey, Felix Rosenow, and
Susanne Schubert-Bast
Anti-convulsant Agents: Cenobamate . . . . . . . . . . . . . . . . . . . . . . . . . . 3797
Bernhard J. Steinhoff
Anti-convulsive Drug Use in Status Therapy: Adults . . . . . . . . . . . . . . 3807
I. Beuchat and A. O. Rossetti
Anti-convulsive Drug Use in Status Treatment in Children . . . . . . . . . . 3837
Angela M. Kaindl, Alexander Gratopp, and Christine Prager
Rational Antiepileptic Treatment in Childhood . . . . . . . . . . . . . . . . . . . 3851
Alexandre N. Datta and Judith Kroell
Guidelines on Anti-convulsant Agents . . . . . . . . . . . . . . . . . . . . . . . . . . 3877
Christian E. Elger and Tobias R. Baumgartner

Volume 3
Part XIII Applied Neuropsychopharmacotherapy . . . . . . . . . . . . . . 3887
Peter Riederer and Toshiharu Nagatsu

Neuropsychopharmacotherapy: Emergency Psychiatry . . . . . . . . . . . . 3889

Thomas Messer and Frank G. Pajonk
xxvi Contents

Psychopharmacotherapy of Obsessive-Compulsive and Related

Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3935
Jacob Hoffman and Dan J. Stein
Treatment of Sleep Disorders in Specific Psychiatric Diseases . . . . . . . . 3955
Thomas C. Wetter and Axel Steiger
Pharmacotherapy of Sleep Disorders During Pregnancy and
Nursing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3985
Thorsten Mikoteit and Martin Hatzinger
Therapy of Sleep Disorders in Parkinson’s Disease . . . . . . . . . . . . . . . . 4013
F. Gandor and G. Ebersbach
Psychopharmacotherapy of Depressive Disorders . . . . . . . . . . . . . . . . . 4033
Erhan Kavakbasi and Bernhard T. Baune
Lithium in Psychiatric Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4075
Cora Schefft, Constantin Volkmann, and Stephan Köhler
Psychopharmacotherapy of Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4095
Dafin F. Muresanu, Olivia Verisezan Rosu, Codruta Birle, Livia Popa,
Diana Chira, Stefan Strilciuc, and Anca Dana Buzoianu
Use of Antipsychotics in the Treatment of Eating Disorders . . . . . . . . . 4127
Karen Borges, Yael Doreen Lewis, Jessica Bentley, and
Hubertus Himmerich
Psychopharmacotherapy of PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4141
Sarah Hassan
Pharmacotherapy of Personality Disorders . . . . . . . . . . . . . . . . . . . . . . 4153
Pierre Baumann and Sabine C. Herpertz
Psychopharmacotherapy of Sexual Disorders . . . . . . . . . . . . . . . . . . . . 4171
Leo Malandain, Abdeslam Chagraoui, and Florence Thibaut
Neuropharmacology of Dementias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4207
Gerhard N. Ransmayr
Pharmacotherapy of Psychosis in Parkinson’s Disease . . . . . . . . . . . . . 4231
Cynthia Kwan, Imane Frouni, and Philippe Huot
Psychopharmacotherapy in Patients with Tics and Other Motor
Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4271
Yijing Bai, Long Niu, Song Li, and Weidong Le
Pharmacotherapy of Alcohol Use Disorders . . . . . . . . . . . . . . . . . . . . . 4303
Michael Soyka
Psychopharmacotherapy in Forensic Psychiatry . . . . . . . . . . . . . . . . . . 4321
Peter Kalus
Contents xxvii

Part XIV Implementation of Neuropsychopharmacotherapy . . . . 4337

István Bitter

Effects of Psychopharmacological Medicines upon Driving Ability . . . 4339

Alexander Brunnauer and Gerd Laux

Psychopharmacological Agents During Pregnancy and Nursing . . . . . . 4355

Pavel Mohr

Neuropsychopharmacotherapy in Children and Adolescents . . . . . . . . 4383

Susanne Walitza, Gregor Berger, Daniel Geller, and Lukasz Smigielski

Infantile Spasms: Pharmacotherapy Challenges . . . . . . . . . . . . . . . . . . 4399

Jana Velíšková and Libor Velíšek

Psychopharmacotherapy in Aged Patients . . . . . . . . . . . . . . . . . . . . . . . 4417

Matej Stuhec and Gabriela Stoppe

Pharmacotherapy of Alzheimer’s Disease (AD) and Behavioral

and Psychological Symptoms of Dementia (BPSD) in Frail
Older Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4429
M. Seibert, J. Holbrook, and C. A. F. von Arnim

Management of Sexual Dysfunction in Neurodegenerative Diseases . . . 4439

Rocco Salvatore Calabrò and Loredana Raciti

Clinical Problems of Drugs Used to Treat Movement Disorders . . . . . . 4457

Dirk Dressler and Lizhen Pan

Post-stroke Depression: Genetics, Mechanisms, and Treatment . . . . . . 4467

Aurel Popa-Wagner, Ion Udristoiu, Andrei Gresita, Miquel Lledós, and
Israel Fernández Cadenas

Combination Therapies and Switching of Agents in Depression and

Bipolar Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4479
Thorsten Folsche, Hannah Benedictine Maier, Thomas Hillemacher, and
Helge Frieling

Pharmacotherapy of Alcohol Dependence: Treatment Readiness and

Compliance Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4497
Hans-Jürgen Rumpf, Gallus Bischof, Samantha Schlossarek, and
Stefan Borgwardt

Pharmacotherapy for Cocaine Use Disorders . . . . . . . . . . . . . . . . . . . . 4509

Boris B. Quednow, Etna J. E. Engeli, and Marcus Herdener

Therapy of Withdrawal Syndromes, Addiction Disorders, and

Substitution Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4525
Otto Lesch and Henriette Walter
xxviii Contents

Pharmacotherapy of ADHD in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . 4543

Michael Rösler, Wolfgang Retz, and Daniel Turner
Antipsychotic Drug Prescription and Behavioral Problems in
Individuals with Intellectual Disability . . . . . . . . . . . . . . . . . . . . . . . . . . 4561
Gerda Margaretha de Kuijper and Albert Willem Lenderink
Forced Migration and Mental Health Care . . . . . . . . . . . . . . . . . . . . . . 4583
Max Burger and Oliver Pogarell
Ketamine in Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4593
Lena V. Danyeli, Florian N. Götting, Zümrüt Duygu Sen, Meng Li, and
Martin Walter
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4637
About the Editors

Peter Riederer was a Professor and Head of Clinical Neurochemistry at the

Ludwig Boltzmann Institute for Clinical Neurobiology in Vienna, Austria
(1976–1986), and at the Clinic and Policlinic of Psychiatry, Psychosomatics and
Psychotherapy, University Hospital Würzburg, Germany, from 1986 to 2010. He is
currently Senior Professor at this clinic and Adjunct Professor at the Department and
Research Unit of Psychiatry, Syddansk Universitet, Odense, Denmark. His expertise
includes the pathophysiology of Parkinson’s and Alzheimer’s diseases, and he has a
special interest in treatment strategies for these disorders as well as for psychiatric
disorders. He co-developed the context of treating PD with L-deprenyl (selegiline)
from 1974 onward and elucidated the mechanism of action of memantine in 1989.
He has more than 1,100 publications in the field of neuroscience and was the most
cited chemist in the field of medicine in 2004. Together with Gerd Laux, he edited
the series of six volumes of NeuroPsychopharmacotherapy with several updated
versions.

Gerd Laux is Director of the Institute of Psychological Medicine and the Center of
Neuropsychiatry MVZ Waldkraidburg in Bavaria and a professor at the Department
of Psychiatry and Psychotherapy at the University of Munich, Germany. He has
worked as a clinician at different hospitals at the Universities of Dallas (Texas USA)
and Wuerzburg and Bonn (Germany). He has authored more than 650 articles and
book chapters and written or edited more than 40 books in the field of psychiatry and
psychopharmacology. He has been principal investigator of various clinical trials
and serves as a consultant for scientific institutions, a Geriatric Hospital and is editor-
in-chief of the journal Psychopharmakotherapie.

Toshi Nagatsu was a professor at Tokyo Institute of Technology, Nagoya Univer-

sity, and Fujita Health University. He worked in the USA at National Institutes of
Health, University of Southern California, and Roche Institute of Molecular Biology.
His work focuses on neurochemistry and molecular biology of catecholamine-
synthesizing enzymes, especially tyrosine hydroxylase and the cofactor tetra-
hydrobiopterin, and their human genes. He was co-discoverer of tyrosine hydroxy-
lase. He also worked on catecholamine-related enzymes in the molecular mechanism
of Parkinson’s disease.
xxix
xxx About the Editors

Weidong Le, M.D., Ph.D., is a neurologist/scientist. He graduated from Shanghai

2nd Medical University with a doctoral degree and completed his postdoctoral
training and became Professor of Neurology at Baylor College of Medicine. Cur-
rently he is the Director of the Center for Translational Research on Neurological
Diseases, and Vice President of 1st Affiliated Hospital, Dalian Medical University.
He is an affiliate member of Houston Methodist Research Institute and the Chinese
Academy of Science. He has published over 200 SCI papers in peer review journals
and 7 scientific books and serves as board member or associate editor for 8 interna-
tional journals.

Christian Riederer is working in the field of scientific publishing and scientific

information. He has been serving as Managing Editor of the Journal of Neural
Transmission, published by Springer Nature, since 2003, and currently directs the
scientific office of the World Association for Stress-Related and Anxiety Disorders
(WASAD). Since 2004, he has organized more than 50 medical historical projects in
neurology and psychiatry and is curating a large collection of historical material on
movement disorders and psychiatric conditions.
Section Editors

István Bitter Semmelweis University, Department of Psychiatry and Psychother-

apy, Budapest, Hungary

Otto Dietmaier Ltd. Pharm. Dir. i.R. Zentren für Psychiatrie Weinsberg, Wiesloch,
Winnenden, Aulendorf, Germany

Christian E. Elger Beta Neurologie, Bonn, Germany

Pieter Hoekstra Groningen, The Netherlands

Stefan Kloiber University of Toronto, Campbell Family Mental Health Research

Institute, Centre for Addiction and Mental Health (CAMH), Department of Psychi-
atry, Toronto, ON, Canada

Gerd Laux Institute of Psychological Medicine (IPM), Soyen, Germany

MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University
(LMU), Munich, Germany
Andreas Menke University Hospital of Wuerzburg, Department of Psychiatry,
Psychosomatics and Psychotherapy, Wuerzburg, Germany

Hans-Jürgen Möller Ludwig-Maximilians-University Munich, Department of

Psychiatry, Munich, Germany

Toshiharu Nagatsu Centre for Research Promotion and Support, Fujita Health
University, Toyoake, Aichi, Japan

Akira Nakashima Department of Physiological Chemistry, School of Medicine,

Fujita Health University, Toyoake, Aichi, Japan

xxxi
xxxii Section Editors

Peter Riederer Clinic and Policlinic for Psychiatry, Psychosomatics and Psycho-
therapy, University Hospital Wuerzburg, Wuerzburg, Germany
University of Southern Denmark Odense, Odense, Denmark
Toshikazu Saito The International College of Neuropsychopharmacology, East
Kilbride, Scotland, UK

Frank Schmidt University Hospital Leipzig, Department of Psychiatry, Leipzig,

Germany

László Vécsei MTA-SZTE, Neuroscience Research Group, Szeged, Hungary

Contributors

Zara Abbaspour CAMH, Toronto, ON, USA

Bassel Abou-Khalil Department of Neurology, Vanderbilt University Medical
Center, Nashville, TN, USA
Luigi Agró NIHR University College London Hospitals Biomedical Research
Centre, UCL Queen Square Institute of Neurology, London, UK
Chalfont Centre for Epilepsy, Chalfont St. Peter, Bucks, UK
Nazanin Alavi Department of Psychiatry, Queen’s University, Kingston, ON,
Canada
Angel Aledo-Serrano Epilepsy Program, Neurology Department, Hospital Ruber
Internacional, Madrid, Spain
Syed F. Ali Division of Neurotoxicology, National Center for Toxicological
Research, United States Food and Drug Administration, Jefferson, AR, USA
Tamar Amit Eve Topf and USA National Parkinson Foundation Centers of Excel-
lence for Neurodegenerative Diseases and Department of Pharmacology, Technion-
Rappaport Family Faculty of Medicine, Haifa, Israel
Michele Antonelli AUSL-IRCCS Reggio Emilia, Reggio Emilia, Italy
Terme di Monticelli, Parma, Italy
Koji Aoyama Department of Pharmacology, Teikyo University School of Medi-
cine, Itabashi, Tokyo, Japan
Michael Aschner Albert Einstein College of Medicine, Bronx, NY, USA
IM Sechenov First Moscow State Medical University, Moscow, Russia
Yijing Bai The First Affiliated Hospital, Dalian Medical University, Dalian, China
Glen B. Baker Neurochemical Research Unit, Department of Psychiatry, Univer-
sity of Alberta, Edmonton, AB, Canada

xxxiii
xxxiv Contributors

Orit Bar-Am Eve Topf and USA National Parkinson Foundation Centers of
Excellence for Neurodegenerative Diseases and Department of Pharmacology,
Technion-Rappaport Family Faculty of Medicine, Haifa, Israel
R. Baron Division of Neurological Pain Research and Therapy, University
Hopsital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Thomas Bast Epilepsy Center Kork, Kehl, Germany
Pierre Baumann University Hospital and University of Lausanne, Lausanne,
Switzerland
Christoph Baumgartner Department of Neurology, General Hospital Hietzing
with Neurological Center Rosenhügel, Vienna, Austria
Karl Landsteiner Institute for Clinical Epilepsy Research and Cognitive Neurology,
Vienna, Austria
Medical Faculty, Sigmund Freud University, Vienna, Austria
Tobias R. Baumgartner Department of Epileptology, University of Bonn Medical
Centre, Bonn, Germany
Bernhard T. Baune Department of Psychiatry, University Hospital Münster, Uni-
versity of Münster, Münster, Germany
Department of Psychiatry, Melbourne Medical School, The University of Mel-
bourne, Melbourne, VIC, Australia
The Florey Institute of Neuroscience and Mental Health, The University of Mel-
bourne, Parkville, VIC, Australia
Jens Benninghoff Psychiatrische LVR-Uni-Klinik Essen, Universität Duisburg-
Essen, Essen, Germany
Chefarzt Zentrum für Altersmedizin und Entwicklungsstörungen (ZfAE), kbo-Isar-
Amper-Klinikum München-Ost, Haar, Germany
Jessica Bentley Department of Psychological Medicine, King’s College London,
London, UK
Niels Bergemann Department of Biological and Clinical Psychology, University of
Trier, Trier, Germany
Gregor Berger Department of Child and Adolescent Psychiatry, Psychiatric Uni-
versity Hospital Zurich (PUK), Zurich, Switzerland
I. Beuchat Department of Clinical Neuroscience, Lausanne University Hospital
(CHUV) and University of Lausanne, Lausanne, Switzerland
M. Beudel Department of Neurology, Amsterdam Neuroscience Institute, Amster-
dam University Medical Center, Amsterdam, The Netherlands
Contributors xxxv

Roongroj Bhidayasiri Chulalongkorn Centre of Excellence for Parkinson’s Dis-

ease and Related Disorders, Department of Medicine, Faculty of Medicine,
Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red
Cross Society, Bangkok, Thailand
The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
Codruta Birle Department of Neurosciences, “Iuliu Hatieganu” University of
Medicine and Pharmacy, Cluj-Napoca, Romania
“RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca,
Romania
Sabine Bischinger Hospital Pharmacy, University Hospital of Innsbruck, Inns-
bruck, Austria
Gallus Bischof Department of Psychiatry and Psychotherapy, Translational Psy-
chiatry Unit, University of Lübeck, Lübeck, Germany
Marc Jonathan Blitz Oklahoma City University School of Law, Okahoma City,
OK, USA
William V. Bobo Department of Psychiatry and Psychology, Mayo Clinic, Jack-
sonville, FL, USA
Paul Boon Department of Neurology, Ghent University Hospital, Ghent Univer-
sity, 4Brain, Ghent, Belgium
Karen Borges Faculty of Life Sciences and Medicine, King’s College London,
London, UK
Ingo Borggraefe Comprehensive Epilepsy Program for Children, Division of
Paediatric Neurology, Developmental Medicine and Social Paediatrics, Department
of Paediatrics, University of Munich, Munich, Germany
Stefan Borgwardt Department of Psychiatry and Psychotherapy, Translational
Psychiatry Unit, University of Lübeck, Lübeck, Germany
Eva Janina Brandl Department of Psychiatry and Psychotherapy, Campus Mitte,
Charité Universitätsmedizin Berlin, Berlin, Germany
Psychiatrische Universitätsklinik der Charité im St. Hedwig-Krankenhaus, Berlin,
Germany
Lasse Brandt Department of Psychiatry and Psychotherapy, Charité Campus
Mitte, Charité Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-
Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Francesco Brigo Department of Neurology, Hospital of Merano (SABES-
ASDAA), Merano-Meran, Italy
xxxvi Contributors

Martha Britto-Arias Department of Neurology, General Hospital Hietzing with

Neurological Center Rosenhügel, Vienna, Austria
Karl Landsteiner Institute for Clinical Epilepsy Research and Cognitive Neurology,
Vienna, Austria

Alexander Brunnauer Department of Neuropsychology, kbo Inn-Salzach-

Klinikum, Wasserburg/Inn, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University
Munich, Munich, Germany
Max Burger Department of Psychiatry and Psychotherapy, University Hospital,
LMU Munich, Munich, Germany

Anca Dana Buzoianu Department of Clinical Pharmacology, “Iuliu Hatieganu”

University of Medicine and Pharmacy, Cluj-Napoca, Romania
Israel Fernández Cadenas Stroke Pharmacogenomics and Genetics group, Sant
Pau Hospital Institute of Research, Barcelona, Spain
Rocco Salvatore Calabrò IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina,
Italy

Abdeslam Chagraoui Laboratory of Neuronal and Neuroendocrine Differentiation

and Communication, Institute for Research and Innovation in Biomedicine of
Normandy (IRIB), INSERM U1239, Mont-Saint-Aignan, France
Departement of Physiology, University of Rouen, Normandie University, Rouen,
France
Department of Medical Biochemistry, CHU de Rouen, Rouen University Hospital,
Rouen, France
Shengdi Chen Department of Neurology, Ruijin Hospital Affiliated to Shanghai
Jiao Tong University School of Medicine, Shanghai, China
Diana Chira “RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-
Napoca, Romania

Catherine Chiron Neuropediatric Department, Necker-Enfants Malades Hospital,

Paris, France
Tetsuji Cho Clinical Education Center, Heartland Shigisan, General Foundation of
Shigisan Hospital, Sango, Nara, Japan
David Coghill Departments of Paediatrics and Psychiatry, Faculty of Medicine,
Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia

Annette Conrads-Frank Department of Public Health, Health Services Research

and Health Technology Assessment, UMIT – University for Health Sciences, Med-
ical Informatics and Technology, Hall, Tyrol, Austria
Contributors xxxvii

Filippo Corponi Department of Biomedical and Neuromotor Sciences, University

of Bologna, Bologna, Italy
Hai-lun Cui Department of Neurology and Neuroscience Institute, Ruijin Hospital
affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.
China
Lena V. Danyeli Department of Psychiatry and Psychotherapy, Jena University
Hospital, Jena, Germany
Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany
Alexandre N. Datta Pediatric Neurology and Developmental Medicine Depart-
ment, University of Basel Children’s Hospital, Basel, Switzerland

Simon J. C. Davies Centre for Addiction and Mental Health, Toronto, ON, Canada
Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Mellar P. Davis Department of Palliative Care, Geisinger Medical Center, Dan-

ville, PA, USA
Aline Silva de Miranda Laboratório de Neurobiologia, Departamento de
Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais,
Belo Horizonte, Brazil
Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina,
Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

Amanda Silva de Miranda Departamento de Química, Instituto de Ciências

Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Gerda Margaretha de Kuijper Centre for Intellectual Disabilities & Mental
Health, Mental health Care Drenthe, Assen, The Netherlands
R. M. A. de Bie Department of Neurology, Amsterdam Neuroscience Institute,
Amsterdam University Medical Center, Amsterdam, The Netherlands

Rocco de Filippis Institute of Psychopathology of Rome; Department of Geriatrics,

Neuroscience and Orthopedics, Institute of Psychiatry, Università Cattolica del
Sacro Cuore, Rome, Italy

Rita Demurtas NIHR University College London Hospitals Biomedical Research

Centre, UCL Queen Square Institute of Neurology, London, UK
Chalfont Centre for Epilepsy, Chalfont St. Peter, Bucks, UK

Otto Dietmaier Ltd. Pharm. Dir. i.R. Zentren für Psychiatrie Weinsberg, Wiesloch,
Winnenden, Aulendorf, Germany
Vera Dinkelacker Fondation Rothschild Paris, Paris, France
Hôpitaux Universitaires Strasbourg, Strasbourg, France
xxxviii Contributors

Richard Dodel Department of Geriatric Medicine, University Duisburg-Essen,

Essen, Germany
Davide Donelli CERFIT, Careggi University Hospital, Florence, Italy
AUSL-IRCCS Reggio Emilia, Reggio Emilia, Italy
Dirk Dressler Movement Disorders Section, Department of Neurology, Hannover
Medical School, Hannover, Germany
Veljko Dubljević Department of Philosophy and Religious Studies, and Science
Technology and Society Program, North Carolina State University, Raleigh, NC,
USA
Boadie Waid Dunlop Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, GA, USA
G. Ebersbach Movement Disorders Hospital, Kliniken Beelitz GmbH, Beelitz-
Heilstätten, Brandenburg, Germany
Anne Eckert Psychiatric University Clinics Basel, University of Basel, Basel,
Switzerland
Vanessa Efinger Institute of Pharmaceutical and Biomedical Sciences, Johannes
Gutenberg-University Mainz, Mainz, Germany
Christian E. Elger Beta Neurologie, Bonn, Germany
Elaine Elisabetsky Departamento de Bioquímica, Instituto de Ciência Básicas da
Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Etna J. E. Engeli Department of Psychiatry, Psychotherapy and Psychosomatics,
Psychiatric Hospital, University of Zurich, Zurich, Switzerland
Adeline Etievant Integrative and Clinical Neurosciences EA481, University of
Bourgogne Franche-Comté, Besançon, France
Chiara Fabbri Social, Genetic and Developmental Psychiatry Centre, Institute of
Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
Peter Falkai Klinik für Psychiatrie und Psychotherapie des Klinikums der
Universität München, Munich, Germany
Frank Faltraco Department of Psychiatry and Psychotherapy, University Medical
Centre Rostock, Rostock, Germany
Hélder Fernandes Medical Affairs Subdepartment/Development Department,
BIAL – Portela & C.ªS.A., Porto, Portugal
Rodrigo Novaes Ferreira Laboratório de Neurobiologia, Departamento de
Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais,
Belo Horizonte, Brazil
Fabio Firenzuoli CERFIT, Careggi University Hospital, Florence, Italy
Contributors xxxix

Paul Foley Medical Journal of Australia, Sydney, NSW, Australia

Thorsten Folsche Department of Psychiatry, Socialpsychiatry and Psychotherapy,
Hannover Medical School, Hannover, Lower Saxony, Germany
Susan H. Fox Division of Neurology, University of Toronto, Toronto, ON, Canada
Movement Disorder Clinic, Edmond J Safra Program in Parkinson Disease, Toronto
Western Hospital, Toronto, ON, Canada
David Neal Franz Clinical Affairs and Tuberous Sclerosis Clinic, University of
Cincinnati College of Medicine, Cincinnati, OH, USA
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Karen Frei Department of Neurology, Loma Linda University, Loma Linda, CA,
USA
Katharina Frey Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frank-
furt, Frankfurt am Main, Germany
Mati Fridkin Department of Organic Chemistry, The Weizmann Institute of Sci-
ence, Rehovot, Israel
Kristina Friedland Institute of Pharmaceutical and Biomedical Sciences, Johannes
Gutenberg-University Mainz, Mainz, Germany
Helge Frieling Department of Psychiatry, Socialpsychiatry and Psychotherapy,
Hannover Medical School, Hannover, Lower Saxony, Germany
Imane Frouni Neurodegenerative Disease Group, Montreal Neurological Institute,
Montreal, QC, Canada
Département de Pharmacologie et Physiologie, Université de Montréal, Montreal,
QC, Canada
Jiro Fukae Department of Neurology, Juntendo University Nerima Hospital,
Tokyo, Japan
Takashi Futamura Department of CNS Research, New Drug Research Division,
Pharmaceutical Business Division, Otsuka Pharmaceutical Co., Ltd., Tokushima,
Japan
Jürgen Gallinat Department of Psychiatry and Psychotherapy, Center for Interdis-
ciplinary Addiction Research, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany
F. Gandor Movement Disorders Hospital, Kliniken Beelitz GmbH, Beelitz-
Heilstätten, Brandenburg, Germany
Department of Neurology, Otto-von-Guericke University, Magdeburg, Saxony-
Anhalt, Germany
Yining Gao Department of Neurology, Ruijin Hospital, Shanghai Jiaotong Univer-
sity School of Medicine, Shanghai, China
xl Contributors

Daniel Geller Department of Child and Adolescent Psychiatry, Psychiatric Univer-

sity Hospital Zurich (PUK), Zurich, Switzerland
Johannes Gfesser Department of Psychiatry, Psychotherapy and Psychosomatic
Medicine, University Hospital of Frankfurt, Goethe University, Frankfurt am Main,
Germany
Antonio Gil-Nagel Epilepsy Program, Neurology Department, Hospital Ruber
Internacional, Madrid, Spain
Florian N. Götting Department of Psychiatry and Psychotherapy, Jena University
Hospital, Jena, Germany
Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany
Alexander Gratopp Department of Pediatric Pneumonology, Immunology and
Intensive Care, Charité – Universitätsmedizin Berlin, Berlin, Germany
Laurence Greenhill Department of Psychiatry, University of California San
Francisco, San Francisco, CA, USA
Andrei Gresita Department of Psychiatry, University of Medicine and Pharmacy
Craiova, Craiova, Romania
Amandine Grimm Psychiatric University Clinics Basel, University of Basel,
Basel, Switzerland
Heinz Grunze Klinik für Allgemeine Psychiatrie und Psychotherapie Ost,
Psychiatrie Schwäbisch Hall & Paracelsus Medical University, Nuremberg,
Germany
Riccardo Guglielmo Department of Geriatrics, Neuroscience and Orthopedics,
Institute of Psychiatry, Università Cattolica del Sacro Cuore, Rome, Italy
Nasser Haddjeri Stem Cell and Brain Research Institute, INSERM, U1208, Bron,
France
Université de Lyon, Université Lyon 1, Lyon, France
Ekkehard Haen Clinical Pharmacology, Institut AGATE gGmbH Pentling,
Pentling, Germany
Department of Psychiatry and Psychotherapy, Department of Pharmacology and
Toxicology, University of Regensburg, Regensburg, Germany
Martina Hahn Department of Psychiatry, Psychosomatics and Psychotherapy,
University Hospital Frankfurt am Main – Goethe University, Frankfurt, Hessia,
Germany
Göran Hajak Clinic for Psychiatry and Psychotherapy, Bamberg, Germany
Contributors xli

Amy Hamilton Bethlem Royal Hospital, South London and Maudsley NHS Foun-
dation Trust, London, UK
Lena Hampel Central Institute of Mental Health, Department of Translational
Brain Research, Medical Faculty Mannheim; Heidelberg University, Hector Institute
for Translational Brain Research, Mannheim, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
Ritsuko Hanajima Division of Neurology, Department of Brain and Neurosci-
ences, Faculty of Medicine, Tottori University, Yonago/Tottori, Japan
Till Hartlieb Fachzentrum für pädiatrische Neurologie, Neuro-Rehabilitation und
Epileptologie, Schön Klinik Vogtareuth, Vogtareuth, Germany
Sarah Hassan Department of Psychology, University of Illinois at Urbana-Cham-
paign, Urbana, IL, USA
Nobutaka Hattori Department of Neurology, Juntendo University School of Med-
icine, Bunkyo, Tokyo, Japan
Martin Hatzinger Psychiatric Services Solothurn and Medical Faculty of the
University of Basel, Solothurn, Switzerland
Gudrun Hefner Psychiatric Hospital, Vitos Klinik Hochtaunus, Friedrichsdorf,
Germany
Andreas Heinz Department of Psychiatry and Psychotherapy, Charité Campus
Mitte, Charité Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-
Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Hanfried Helmchen Department of Psychiatry & Psychotherapy, CBF, Charité –
University Medicine Berlin, Berlin, Germany
Christoph Helmstaedter Department of Epileptology, University Hospital Bonn
(UKB), Bonn, Germany
Johannes M. Hennings kbo Isar-Amper-Klinikum Munich, Haar/Munich,
Bavaria, Germany
Jonathan Henssler Department of Psychiatry and Psychotherapy, Charité Campus
Mitte, Charité Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-
Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Sebastian Herberger ProSomno Clinic for Sleep Medicine, Munich, Germany
Charité Interdisciplinary Centre of Sleep Medicine, Berlin, Germany
Marcus Herdener Department of Psychiatry, Psychotherapy and Psychosomatics,
Psychiatric Hospital, University of Zurich, Zurich, Switzerland
xlii Contributors

Sabine C. Herpertz Department of General Psychiatry, University of Heidelberg,

Heidelberg, Germany
Christoph Hertzberg Klinik für Neuropädiatrie und Sozialpädiatrie (DBZ),
Vivantes-Klinikum Neukölln, Berlin, Germany
Christoph Hiemke Department of Psychiatry and Psychotherapy, University Med-
ical Center Mainz, Mainz, Germany
Thomas Hillemacher Department of Psychiatry and Psychotherapy, Paracelsus
Medical University, Nuremberg, Bavaria, Germany
Hubertus Himmerich Department of Psychological Medicine, King’s College
London, London, UK
Naoyuki Hironaka Department of Pharmacology, Drug Development Service
Segment, LSI Medience Corporation (Panasonic Health Care), Kanazawa-ku, Yoko-
hama, Japan
Tsuyoshi Hirose New Drug Research Division, Pharmaceutical Business Division,
Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan
Edouard Hirsch Hôpitaux Universitaires Strasbourg, Strasbourg, France
Jacob Hoffman South African Medical Research Council (SAMRC) Unit on Risk
and Resilience in Mental Disorders, Department of Psychiatry & Mental Health,
Neuroscience Institute, University of Cape Town, Cape Town, South Africa
J. Holbrook Department of Neurology, University Clinic Ulm, Ulm, Germany
Andrew Holt Neurochemical Research Unit, Department of Psychiatry, University
of Alberta, Edmonton, AB, Canada
Leif Hommers Zentrum für Psychische Gesundheit, Universitätsklinikum
Würzburg, Würzburg, Germany
Reinhard Horowski Antaxios GmbH, Michendorf, Germany
Satoshi Hoya Department of Psychiatry, Niigata University Graduates School of
Medicine and Dental Science, Niigata, Japan
Markus Karl Huber Department of Psychiatry, General Hospital Bruneck, South
Tyrol, Italy
Philippe Huot Neurodegenerative Disease Group, Montreal Neurological Institute,
Montreal, QC, Canada
Département de Pharmacologie et Physiologie, Université de Montréal, Montreal,
QC, Canada
Department of Neurology and Neurosurgery, McGill University, Montreal, QC,
Canada
Movement Disorder Clinic, Division of Neurology, Department of Neuroscience,
McGill University Health Centre, Montreal, QC, Canada
Contributors xliii

M. Ishrat Husain Department of Psychiatry, Centre for Addiction and Mental

Health, University of Toronto, Toronto, ON, Canada
Akira Imamura Child and Adolescent Psychiatry Community Partnership Unit,
Nagasaki University Hospital, Nagasaki, Japan
Department of Neuropsychiatry, Unit of Translation Medicine, Nagasaki University
Graduate School of Biomedical Sciences, Nagasaki, Japan
Ken Inada Department of Psychiatry, Tokyo Women’s Medical University, Tokyo,
Japan
Jun Ishigooka Institute of CNS Pharmacology, Tokyo, Japan
Akira Ishii Department of Legal Medicine and Bioethics, Nagoya University
Graduate School of Medicine, Nagoya, Japan
Mizuki Ito Department of Neurology and Neuroscience, School of Medicine,
Fujita Health University, Toyoake, Aichi, Japan
Christian C. Jacob Clinic for Psychiatry and Psychotherapy, medius KLINIK
Kirchheim, Kirchheim unter Teck, Germany
Helena Janssen Department of Neurology, Ghent University Hospital, Ghent,
Belgium
Frank Jessen Department of Psychiatry and Psychotherapy, University of
Cologne, Köln, Germany
Monika Jeub Beta Neurologie, Bonn, Germany
Premysl Jiruska Department of Developmental Epileptology, Institute of Physiol-
ogy of the Czech Academy of Sciences, Prague, Czech Republic
Department of Physiology, Second Faculty of Medicine, Charles University, Prague,
Czech Republic
Svein I. Johannessen The National Center for Epilepsy and Dept of Pharmacology,
Oslo University Hospital, Oslo, Norway
Cecilie Johannessen Landmark The National Center for Epilepsy and Dept of
Pharmacology, Oslo University Hospital, Oslo, Norway
Programme for Pharmacy, Oslo Metropolitan University, Oslo, Norway
Brett D. M. Jones Department of Psychiatry, University of Toronto, Toronto, ON,
Canada
Wolfgang H. Jost Parkinson-Klinik Ortenau, Wolfach, Germany
Angela M. Kaindl Department of Pediatric Neurology, Center for Chronically Sick
Children and Institute of Cell Biology and Neurobiology, Charité –
Universitätsmedizin Berlin, Berlin, Germany
Peter Kalus Zentrum für Forensisch-Psychiatrische Begutachtung Berlin (ZFPB),
Berlin, Germany
xliv Contributors

Tomoyuki Kanda Translational Research Unit, Research and Development Divi-

sion, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan
Shinji Kanegae Department of Neuropsychiatry, Unit of Translation Medicine,
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Cimen Karasu Cellular Stress Response and Signal Transduction Research Labo-
ratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University,
Ankara, Turkey
Masahisa Katsuno Department of Neurology, Nagoya University Graduate School
of Medicine, Nagoya, Aichi, Japan
Erhan Kavakbasi Department of Psychiatry, University Hospital Münster, Uni-
versity of Münster, Münster, Germany
Kazuya Kawabata Department of Neurology, Nagoya University Graduate School
of Medicine, Nagoya, Aichi, Japan
Tetyana Kendzerska The Ottawa Hospital Research Institute, Ottawa, ON,
Canada
Division of Respirology, Department of Medicine, The University of Ottawa,
Ottawa, ON, Canada
The Ottawa Hospital Sleep Center, Civic Campus, The Ottawa Hospital, Ottawa,
ON, Canada
Tetsuro Kikuchi New Drug Research Division, Pharmaceutical Business Division,
Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan
Helena K. Kim Department of Psychiatry, University of Toronto, Toronto, ON,
Canada
Erwin Kirchler Department of Psychiatry, General Hospital Bruneck, South Tyrol,
Italy
Sarah Kittel-Schneider Klinik für Psychiatrie, Psychosomatik und
Psychotherapie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main,
Germany
Ansgar Klimke Vitos Waldkrankenhaus Köppern, Friedrichsdorf, Germany
Stefan Kloiber Campbell Family Mental Health Research Institute, Centre for
Addiction and Mental Health (CAMH), Department of Psychiatry, University of
Toronto, Toronto, ON, Canada
Gerhard Kluger Fachzentrum für pädiatrische Neurologie, Neuro-Rehabilitation
und Epileptologie, Schön Klinik Vogtareuth, Vogtareuth, Germany
Yuliya Knyahnytska Department of Psychiatry, University of Toronto, Toronto,
ON, USA
Temerty Centre for Theraputic Brain Intervention, Centre for Addiction and Mental
Health, Toronto, ON, USA
Contributors xlv

Liana Kobylinska Centre Hospitalier de la Savoie, Bassens, France

Stephan Köhler Charité – Universitätsmedizin Berlin, corporate member of Freie
Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health,
Department of Psychiatry and Neurosciences, CCM, Berlin, Germany
Vladimir Komarek Department of Paediatric Neurology, Second Faculty of Med-
icine, Charles University and Motol University Hospital, Prague, Czech Republic
Kuni Konaka Department of Physical Therapy, Faculty of Health Science, Osaka
Yukioka College of Health Science, Ibaraki City, Osaka, Japan
Department of Neurology, Osaka University Graduate School of Medicine, Suita
City, Osaka, Japan
Osamu Konishi Medical Affairs, Sumitomo Dainippon Pharma Co., Ltd., Tokyo,
Japan
Gerasimos Konstantinou Department of Psychiatry, University of Toronto,
Toronto, ON, Canada
Centre for Addiction and Mental Health, Toronto, ON, Canada
Tim Johannes Krause Department of Psychiatry, Psychotherapy and Psychoso-
matics, Martin Luther University of Halle-Wittenberg, Halle/Saale, Germany
Judith Kroell Paediatric Deptartment, Swiss Epilepsy Clinic, Lengg Clinic,
Zurich, Switzerland
Christopher Kruse Uniklinik Essen, Essen, Germany
Hana Kubova Department of Developmental Epileptology, Institute of Physiology
of the Czech Academy of Sciences, Prague, Czech Republic
Wilfried Kuhn Department of Neurology, Leopoldina Hospital Schweinfurt,
Schweinfurt, Germany
Ekkehardt Kumbier Institute of History of Medicine, University Medicine Ros-
tock, Rostock, Germany
Cynthia Kwan Neurodegenerative Disease Group, Montreal Neurological Insti-
tute, Montreal, QC, Canada
Pierluigi Lanzotti Institute of Psychiatry and Psychology, Department of Geriat-
rics, Neuroscience and Orthopedics, Fondazione Policlinico Universitario A.
Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
Simona Lattanzi Neurological Clinic, Department of Experimental and Clinical
Medicine, Marche Polytechnic University, Ancona, Italy
Thorsten Lau Central Institute of Mental Health, Department of Translational
Brain Research, Medical Faculty Mannheim; Heidelberg University, Hector Institute
for Translational Brain Research, Mannheim, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
xlvi Contributors

Leopold Maria Lautenbacher Department of Psychiatry and Psychotherapy,

Charité – Universitätsmedizin Berlin, Berlin, Germany
Gerd Laux Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University
(LMU), Munich, Germany
Weidong Le Liaoning Provincial Key Laboratory for Research on the Pathogenic
Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical
University, Dalian, China
Liaoning Provincial Center for Clinical Research on Neurological Diseases, The
First Affiliated Hospital, Dalian Medical University, Dalian, China
Bernard Le Foll Translational Addiction Research Laboratory, Acute Care Pro-
gram, and Campbell Family Mental Health Research Institute, CAMH, Departments
of Family and Community Medicine, Pharmacology and Toxicology, Psychiatry,
and Institute of Medical Science, University of Toronto, Toronto, ON, Canada
K. L. Leenders Department of Neurology, University Medical Center Groningen,
Groningen, The Netherlands
Department of Nuclear Medicine, University Medical Center Groningen, Gro-
ningen, The Netherlands
Albert Willem Lenderink Dutch Association Pharmacists for Intellectual Dis-
abled, Loon op Zand, The Netherlands
Peter Lepping Wrexham Academic Unit, Bangor University, Bangor, Wales, UK
Heddfan Psychiatric Unit, Betsi Cadwaladr University Health Board, Wrexham,
Wales, UK
Mysore Medical College/Research Institute, Honorary Professor Bangor University,
Mysore, India
Otto Lesch Clinical Department of Social Psychiatry, Medical University Vienna,
Vienna, Austria
Yael Doreen Lewis Hadarim Eating Disorders Unit, Shalvata Mental Health Cen-
ter, Hod Hasharon, Israel
Jie Li Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China
Meng Li Department of Psychiatry and Psychotherapy, Jena University Hospital,
Jena, Germany
Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany
Shen Li Department of Psychiatry, Tianjin Medical University, Tianjin, China
Song Li The First Affiliated Hospital, Dalian Medical University, Dalian, China
Contributors xlvii

Xiaojuan Li Department of Population Medicine, Harvard Medical School and

Harvard Pilgrim Health Care Institute, Boston, MA, USA
Thien Thien Lim Island Hospital, Penang, Malaysia
Yufei Liu The First Affiliated Hospital, Dalian Medical University, Dalian, China
Xinyao Liu The First Affiliated Hospital, Dalian Medical University, Dalian, China
Miquel Lledós Stroke Pharmacogenomics and Genetics group, Sant Pau Hospital
Institute of Research, Barcelona, Spain
Wolfgang Löscher Department of Pharmacology, Toxicology, and Pharmacy, Uni-
versity of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Lin Lu Department of Neurology, The First Affiliated Hospital of Guangzhou
Medical University, Guangzhou, China
Yangfu Luo Department of Neurology, The First Affiliated Hospital of Guangzhou
Medical University, Guangzhou, China
Kenji Maeda Department of Lead Discovery Research, New Drug Research Divi-
sion, Pharmaceutical Business Division, Otsuka Pharmaceutical Co., Ltd.,
Tokushima, Japan
Hannah Benedictine Maier Department of Psychiatry, Socialpsychiatry and Psy-
chotherapy, Hannover Medical School, Hannover, Lower Saxony, Germany
Leo Malandain University Hospital Cochin, Paris, France
Silvia A. Mandel Eve Topf and USA National Parkinson Foundation Centers of
Excellence for Neurodegenerative Diseases and Department of Pharmacology,
Technion-Rappaport Family Faculty of Medicine, Haifa, Israel
Lea Mascarell Maricic Department of Psychiatry and Psychotherapy, Charité –
Universitätsmedizin Berlin, Berlin, Germany
Hidenori Maruyama Medical Affairs, Sumitomo Dainippon Pharma Co., Ltd.,
Tokyo, Japan
Wakako Maruyama Department of Health and Nutrition, Faculty of Psychologi-
cal and Physical Science, Aichi Gakuin University, Nisshin, Aichi, Japan
Justin Matheson Translational Addiction Research Laboratory, CAMH, Toronto,
ON, Canada
Yusuke Matsuzaka Department of Neuropsychiatry, Nagasaki University Hospi-
tal, Nagasaki, Japan
Dmitriy Matveychuk Neurochemical Research Unit, Department of Psychiatry,
University of Alberta, Edmonton, AB, Canada
xlviii Contributors

Marisol Maya-López Posgrado en Ciencias Biológicas y de la Salud, DCBS,

Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, Mexico
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y
Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
Marianna Mazza Institute of Psychiatry and Psychology, Department of Geriat-
rics, Neuroscience and Orthopedics, Fondazione Policlinico Universitario A.
Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
Robert D. McQuade Otsuka Pharmaceutical Development & Commercialization,
Inc., Princeton, NJ, USA
Carolina Medeiros Da Frota Ribeiro Department of Psychiatry and Behavioral
Sciences, Emory University School of Medicine, Atlanta, GA, USA
Michael Menconi Jr. Bioethics and Public Health, Columbia University, New
York, NY, USA
Andreas Menke Department of Psychiatry, Psychosomatics and Psychotherapy,
University Hospital of Würzburg, Würzburg, Germany
Thomas Messer Danuviusklinik Pfaffenhofen, Pfaffenhofen, Germany
Jeffrey H. Meyer Centre for Addiction and Mental Health (CAMH) and Depart-
ment of Psychiatry, University of Toronto, Toronto, ON, Canada
Thorsten Mikoteit Psychiatric Services Solothurn and Medical Faculty of the
University of Basel, Solothurn, Switzerland
Yoshikuni Mizuno Juntendo University School of Medicine, Tokyo, Japan
Hideki Mochizuki Department of Neurology, Osaka University Graduate School
of Medicine, Suita City, Osaka, Japan
Pavel Mohr National Institute of Mental Health, Klecany, Czechia
Third faculty of Medicine, Charles University, Prague, Czechia
Hans Moises Department of Psychiatry and Psychotherapy, Kiel University Hos-
pital, Kiel, Germany
Ricardo Moreira Clinic of Psychiatry and Mental Health, Centro Hospitalar e
Universitário de São João, Porto, Portugal
Yoshiro Morimoto Department of Neuropsychiatry, Unit of Translation Medicine,
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Joerg Müller Klinik für Neurologie, Vivantes Klinikum Spandau, Berlin, Germany

Hans Moises has retired.

Contributors xlix

Norbert Müller Department of Psychiatry and Psychotherapy, Ludwig-

Maximilians-Universität Munich, Munich, Germany
Thomas Müller Department of Neurology, St. Joseph Hospital Berlin-Weißensee,
Berlin, Germany
Walter E. Müller Institute of Pharmacology and Clinical Pharmacy, Goehte Uni-
versity Frankfurt, Frankfurt, Germany
Mitsukuni Murasaki Institute of CNS Pharmacology, Tokyo, Japan
Dafin F. Muresanu Department of Neurosciences, “Iuliu Hatieganu” University of
Medicine and Pharmacy, Cluj-Napoca, Romania
“RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca,
Romania
Richard Musil Klinik für Psychiatrie und Psychotherapie des Klinikums der
Universität München, Munich, Germany
Tatsuro Mutoh Department of Neurology and Neuroscience, School of Medicine,
Fujita Health University, Toyoake, Aichi, Japan
Masayo Shamoto Nagai Department of Health and Nutrition, Faculty of Psycho-
logical and Physical Science, Aichi Gakuin University, Nisshin, Aichi, Japan
Toshiharu Nagatsu Centre for Research Promotion and Support, Fujita Health
University, Toyoake, Aichi, Japan
Etsuro Nakanishi Department of Neurology, Kyoto University Graduate School of
Medicine, Kyoto, Japan
Akira Nakashima Department of Physiological Chemistry, School of Medicine,
Fujita Health University, Toyoake, Aichi, Japan
Makoto Naoi Department of Health and Nutrition, Faculty of Psychological and
Physical Science, Aichi Gakuin University, Nisshin, Aichi, Japan
Yujin Natori Department of Legal Medicine and Bioethics, Nagoya University
Graduate School of Medicine, Nagoya, Japan
Petra Netter Department of Psychology, University of Giessen, Giessen, Germany
Yoshiki Niimi Department of Neurology and Neuroscience, School of Medicine,
Fujita Health University, Toyoake, Aichi, Japan
Toru Nishikawa Department of Pharmacology, School of Medicine, and Pharma-
cological Research Center, Showa University, Tokyo, Japan
Long Niu The First Affiliated Hospital, Dalian Medical University, Dalian, China
l Contributors

Masahiro Nomoto Department of Neurology and Clinical Pharmacology, Ehime

University Graduate School of Medicine, Tohon, Japan
José Manuel Olivares Department of Psychiatry, Hospital Álvaro Cunqueiro,
Vigo, Spain
Research Area of Translational Neuroscience, Galicia Sur Health Research Institute
(IISGS), CIBERSAM, Vigo, Spain
Emmanuel S. Onaivi Department of Biology, William Paterson University,
Wayne, NJ, USA
Shin Ono Department of Community Psychiatric Medicine, Niigata University
Graduate School of Medical and Dental Sciences, Niigata, Japan
Hiroki Ozawa Department of Neuropsychiatry, Unit of Translation Medicine,
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Frank G. Pajonk Praxis Isartal, Kloster Schäftlarn, Germany
Lizhen Pan Department of Neurology, Shanghai Tongji Hospital, Tongji Univer-
sity School of Medicine, Shanghai, People’s Republic of China
Axel Panzer Center for Epilepsy/Neuropediatrics, Berlin, Germany
Michael Paulzen Department of Psychiatry, Psychotherapy and Psychosomatics
and JARA – Translational Brain Medicine, RWTH Aachen University, Aachen,
Germany
Alexianer Hospital Aachen, Aachen, Germany
Laura Pazzagli Centre for Pharmacoepidemiology, Department of Medicine,
Karolinska Institutet, Stockholm, Sweden
Maria Pepe Institute of Psychiatry and Psychology, Department of Geriatrics,
Neuroscience and Orthopedics, Fondazione Policlinico Universitario A. Gemelli
IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
Robert Perneczky Klinik für Psychiatrie und Psychotherapie, Klinikum der
Universität München (KUM), Ludwig-Maximilians-Universität (LMU) München,
Munich, Germany
Toine Pieters Department of Pharmaceutical Sciences, Utrecht University, Utrecht,
The Netherlands
Oliver Pogarell Department of Psychiatry and Psychotherapy, University Hospital,
LMU Munich, Munich, Germany
Thomas Polak Department of Psychiatry, Psychosomatics and Psychotherapy,
University Clinic Würzburg, Würzburg, Germany
Contributors li

Livia Popa Department of Neurosciences, “Iuliu Hatieganu” University of Medi-

cine and Pharmacy, Cluj-Napoca, Romania
“RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca,
Romania
Aurel Popa-Wagner Department of Neurology, University Hospital Essen, Uni-
versity of Duisburg-Essen, Essen, Germany
Experimental Research Centre for Normal and Pathological Aging, University of
Medicine and Pharmacy of Craiova, Craiova, Romania
Christine Prager Department of Pediatric Neurology, Center for Chronically Sick
Children, Charité – Universitätsmedizin Berlin, Berlin, Germany
Lisa Proebstl Department of Psychiatry and Psychotherapy, University Hospital,
LMU Munich, Munich, Germany
Lena Pyrkosch Department of Psychiatry and Psychotherapy, Charité –
Universitätsmedizin Berlin, Berlin, Germany
Boris B. Quednow Department of Psychiatry, Psychotherapy and Psychosomatics,
Psychiatric Hospital, University of Zurich, Zurich, Switzerland
Neuroscience Centre Zurich, Joint Institute of the University of Zurich and the Swiss
Federal Institute of Technology (ETH), Zurich, Switzerland
Loredana Raciti U.O.S.D. Stroke Unit, A.O.U. Policlinico “G. Martino”, Messina,
Italy
Gerhard N. Ransmayr Department of Neurology 2, Kepler-University-Hospital,
Medical Faculty, Johannes-Kepler-University, Linz, Austria
Maria Rasenack Spinal Cord Injury Center, University Hospital Balgrist, Zurich,
Switzerland
Jens Reimer Department of Psychiatry and Psychotherapy, Center for Interdisci-
plinary Addiction Research, University Medical Center Hamburg-Eppendorf, Ham-
burg, Germany
Lubova Renemane Department of Psychiatry and Narcology, Riga Stradins Uni-
versity, Riga, Latvia
Socorro Retana-Márquez Departamento de Biología de Reproducción,
Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, Mexico
Wolfgang Retz University of the Saarland, Neurocentre, ADHD Research Group,
Homburg, Germany
Department of Psychiatry and Psychotherapy, University Medical Center Mainz,
Mainz, Germany
lii Contributors

Peter Riederer Clinic and Policlinic for Psychiatry, Psychosomatics and Psycho-
therapy, University Hospital Wuerzburg, Wuerzburg, Germany
University of Southern Denmark Odense, Odense, Denmark
Daniela Rodrigues-Amorim Translational Neuroscience Research Group, Galicia
Sur Health Research Institute (IISGS), CIBERSAM, Vigo, Spain
Johannes Rösche Klinik und Poliklinik für Neurologie, Universitätsmedizin Ros-
tock, Rostock, Germany
Hephata Klinik, Schwalmstadt, Germany
Felix Rosenow Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frank-
furt, Frankfurt am Main, Germany
Michael Rösler University of the Saarland, Neurocentre, ADHD Research Group,
Homburg/Saar, Germany
A. O. Rossetti Department of Clinical Neuroscience, Lausanne University Hospital
(CHUV) and University of Lausanne, Lausanne, Switzerland
Stephan Röttig Department of Psychiatry, Psychotherapy and Psychosomatics,
Martin Luther University of Halle-Wittenberg, Halle/Saale, Germany
Stephan Rüegg Department of Neurology, Basel University Hospital, Basel,
Switzerland
Eckart Ruether ProSomno Clinic for Sleep Medicine, Munich, Germany
Dan Rujescu Department of Psychiatry, Psychotherapy and Psychosomatics, Mar-
tin Luther University of Halle-Wittenberg, Halle/Saale, Germany
C. Rummel-Kluge Klinik und Poliklinik für Psychiatrie und Psychotherapie,
Universitätsklinikum Leipzig, Leipzig, Germany
Hans-Jürgen Rumpf Department of Psychiatry and Psychotherapy, Translational
Psychiatry Unit, University of Lübeck, Lübeck, Germany
Janusz K. Rybakowski Department of Adult Psychiatry, Poznan University of
Medical Sciences, Poznan, Poland
J. Sachau Division of Neurological Pain Research and Therapy, University
Hopsital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Josemir W. Sander NIHR University College London Hospitals Biomedical
Research Centre, UCL Queen Square Institute of Neurology, London, UK
Chalfont Centre for Epilepsy, Chalfont St. Peter, Bucks, UK
Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands
Abel Santamaría Laboratorio de Aminoácidos Excitadores, Instituto Nacional de
Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
Contributors liii

Apitharani Santhirakumar Centre for Addiction and Mental Health (CAMH) and
Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Steven C. Schachter Departments of Neurology, Beth Israel Deaconess Medical
Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA,
USA
Ingo Schäfer Department of Psychiatry and Psychotherapy, Center for Interdisci-
plinary Addiction Research, University Medical Center Hamburg-Eppendorf, Ham-
burg, Germany
Maximilian Schäfer Department of Psychiatry and Psychotherapy, Campus Mitte,
Charité Universitätsmedizin Berlin, Berlin, Germany
Cora Schefft Charité – Universitätsmedizin Berlin, corporate member of Freie
Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health,
Department of Psychiatry and Neurosciences, CCM, Berlin, Germany
Maike Scherf-Clavel Department of Psychiatry, Psychosomatics and Psychother-
apy, University Hospital of Würzburg, Würzburg, Germany
Samantha Schlossarek Department of Psychiatry and Psychotherapy, Transla-
tional Psychiatry Unit, University of Lübeck, Lübeck, Germany
Frank M. Schmidt Department of Psychiatry, University Hospital Leipzig, Leip-
zig, Germany
Peter Schönknecht University Hospital Leipzig and Academic Hospital Arnsdorf,
Leipzig/Arnsdorf, Germany
Georgios Schoretsanitis Psychiatry Research, The Zucker Hillside Hospital, New
York, USA
Susanne Schubert-Bast Epilepsy Center Frankfurt Rhine-Main, Goethe-Univer-
sity Frankfurt, Frankfurt am Main, Germany
Josef Schwitzer Department of Psychiatry, General Hospital Brixen, South Tyrol,
Italy
M. Seibert Department of Neurology, University Clinic Ulm, Ulm, Germany
Geriatric Center Ulm/Alb-Donau, Ulm, Germany
Zümrüt Duygu Sen Department of Psychiatry and Psychotherapy, Jena University
Hospital, Jena, Germany
Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany
Department of Psychiatry and Psychotherapy, University Tuebingen, Tuebingen,
Germany
Alessandro Serretti Department of Biomedical and Neuromotor Sciences, Univer-
sity of Bologna, Bologna, Italy
liv Contributors

Hari Shanker Sharma International Experimental Central Nervous System Injury

& Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive
Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
Aruna Sharma International Experimental Central Nervous System Injury &
Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive
Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
Uwe Siebert Department of Public Health, Health Services Research and Health
Technology Assessment, UMIT – University for Health Sciences, Medical Infor-
matics and Technology, Hall, Tyrol, Austria
Nicola Simola Department of Biomedical Sciences, University of Cagliari,
Monserrato University Campus, Monserrato, Italy
Lukasz Smigielski Department of Child and Adolescent Psychiatry, Psychiatric
University Hospital Zurich (PUK), Zurich, Switzerland
Stephen Snelders Freudenthal Institute, Utrecht University, Utrecht, The
Netherlands
Igor Soares da Costa Clinic of Psychiatry and Mental Health, Centro Hospitalar e
Universitário de São João, Porto, Portugal
Gen Sobue Brain and Mind Research Center, Nagoya University, Nagoya, Japan
Toshiyuki Someya Department of Psychiatry, Niigata University Graduates School
of Medicine and Dental Science, Niigata, Japan
Michael Soyka Psychiatric Hospital, University of Munich, Munich, Germany
Gumpeny R. Sridhar Endocrine and Diabetes Centre, Visakhapatnam, Andhra
Pradesh, India
Axel Steiger Max-Planck-Institut für Psychiatrie (MPI-PSY) Psychiatrische Klinik,
München, Germany
Dan J. Stein South African Medical Research Council (SAMRC) Unit on Risk and
Resilience in Mental Disorders, Department of Psychiatry & Mental Health, Neu-
roscience Institute, University of Cape Town, Cape Town, South Africa
Petra Steinbuchel Department of Psychiatry, University of California San
Francisco, San Francisco, CA, USA
Bernhard J. Steinhoff Kork Epilepsy Center, Kehl-Kork, Germany
David N. Stephens School of Psychology, University of Sussex, Brighton, UK
Callum Stephenson Centre for Neuroscience Studies, Queen’s University, Kings-
ton, ON, Canada
Rolf-Dieter Stieglitz Emeritus (Klinische Psychologie und Psychiatrie) Klinische
Psychologie und Psychotherapie, Basel, Switzerland
Contributors lv

Gabriela Stoppe MentAge, Basel, Switzerland

Medical Faculty, University of Basel, Basel, Switzerland
Stefan Strilciuc Department of Neurosciences, “Iuliu Hatieganu” University of
Medicine and Pharmacy, Cluj-Napoca, Romania
“RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca,
Romania
Andreas Ströhle Department of Psychiatry and Psychotherapy, Charité –
Universitätsmedizin Berlin, Berlin, Germany
Adam Strzelczyk Epilepsy Center Frankfurt Rhine-Main, Goethe-University
Frankfurt, Frankfurt am Main, Germany
Matej Stuhec Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Department of Pharmacology, Faculty of Medicine Maribor, University of Maribor,
Maribor, Slovenia
Department for Clinical Pharmacy, Psychiatric Hospital Ormoz, Ormoz, Slovenia
Atsunori Sugimoto Department of Community Psychiatric Medicine, Niigata Uni-
versity Graduate School of Medical and Dental Sciences, Niigata, Japan
Banon Sukoandari Red Cross Hospital, Bogor, West Java, Indonesia
Mikio Suzuki Department of CNS Research, New Drug Research Division, Phar-
maceutical Business Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
Ryosuke Takahashi Department of Neurology, Kyoto University Graduate School
of Medicine, Kyoto, Japan
Masaru Tanaka MTA-SZTE, Neuroscience Research Group, Szeged, Hungary
Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine,
University of Szeged, Szeged, Hungary
Victor M. Tang Centre for Addiction and Mental Health, Toronto, ON, Canada
Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Antônio Lúcio Teixeira Neuropsychiatry Program, Department of Psychiatry &
Behavioral Sciences, McGovern Medical School, University of Texas Health Sci-
ence Center at Houston, Houston, TX, USA
Florence Thibaut University of Paris, INSERM U1266, Institute of Psychiatry and
Neurosciences, Paris, France
Department of Psychiatry and Addictive Disorders, University Hospital Cochin,
Paris, France
Johannes Thome Department of Psychiatry and Psychotherapy, University Med-
ical Centre Rostock, Rostock, Germany
lvi Contributors

Christian Tilz Epilepsy Unit, Department of Neurology, Hospital of Barmherzige

Brüder, Regensburg, Germany
Nóra Török MTA-SZTE, Neuroscience Research Group, Szeged, Hungary
Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine,
University of Szeged, Szeged, Hungary
Maria Tountopoulou Department of Pediatric Neurology, Center for Chronically
Sick Children, Charité – Universitätsmedizin Berlin, Berlin, Germany
Tai Ngoc Tran Movement Disorder Unit, Department of Neurology, University
Medical Center, University of Medicine and Pharmacy, Ho Chi Minh, Vietnam
Felix Tretter Bertalanffy Center for the Study of Systems Science, Vienna, Austria
Daniel D. Truong The Truong Neuroscience Institute, Orange Coast Memorial
Medical Center, Fountain Valley, CA, USA
Department of Psychiatry and Neuroscience, UC Riverside, Riverside, CA, USA
Takashi Tsuboi Department of Neurology, Nagoya University Graduate School of
Medicine, Nagoya, Japan
Daniel Turner Department of Psychiatry and Psychotherapy, University Medical
Center Mainz, Mainz, Germany
Sean Jeremy Udow Section of Neurology, Division of Internal Medicine, Univer-
sity of Manitoba Rady Faculty of Health Sciences, Winnipeg, MB, Canada
Movement Disorders Clinic, Deer Lodge Hospital, Winnipeg, MB, Canada
Ion Udristoiu Department of Psychiatry, University of Medicine and Pharmacy
Craiova, Craiova, Romania
Yoshikazu Ugawa Department of Human Neurophysiology, Faculty of Medicine,
Fukushima Medical University, Fukushima, Japan
Asami Umino Department of Pharmacology, School of Medicine, and Pharmaco-
logical Research Center, Showa University, Tokyo, Japan
Masakazu Umino Department of Pharmacology, School of Medicine, and Phar-
macological Research Center, Showa University, Tokyo, Japan
Stefan Unterecker Center of Mental Health, Department of Psychiatry, Psychoso-
matics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
Maria Paola Valenti Hôpitaux Universitaires Strasbourg, Strasbourg, France
Adriana R. Vasquez Department of Psychiatry and Psychology, Mayo Clinic,
Jacksonville, FL, USA
László Vécsei MTA-SZTE, Neuroscience Research Group, Szeged, Hungary
Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine,
University of Szeged, Szeged, Hungary
Contributors lvii

Libor Velíšek Departments of Cell Biology & Anatomy, Pediatrics, and Neurology,
New York Medical College, Valhalla, NY, USA
Jana Velíšková Departments of Cell Biology & Anatomy, Obstetrics & Gynecol-
ogy, and Neurology, New York Medical College, Valhalla, NY, USA
Olivia Verisezan Rosu Department of Neurosciences, “Iuliu Hatieganu” Univer-
sity of Medicine and Pharmacy, Cluj-Napoca, Romania
“RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca,
Romania
Sasivimol Virameteekul Chulalongkorn Centre of Excellence for Parkinson’s
Disease and Related Disorders, Department of Medicine, Faculty of Medicine,
Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red
Cross Society, Bangkok, Thailand
Trang N. N. Vo Neurology Department, International Neurosurgery Hospital, Ho
Chi Minh City, Vietnam
Constantin Volkmann Charité – Universitätsmedizin Berlin, corporate member of
Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of
Health, Department of Psychiatry and Neurosciences, CCM, Berlin, Germany
Hans-Peter Volz Krankenhaus für Psychiatrie, Psychotherapie und Psychoso-
matische Medizin Schloss Werneck, Werneck, Germany
C. A. F. von Arnim Division of Geriatrics, University Medical Centre, Georg
August University, Göttingen, Germany
Elena Vos University of Amsterdam, Amsterdam, The Netherlands
Jelena Vrublevska Department of Psychiatry and Narcology, Riga Stradins Uni-
versity, Riga, Latvia
Susanne Walitza Department of Child and Adolescent Psychiatry, Psychiatric
University Hospital Zurich (PUK), Zurich, Switzerland
Henriette Walter Clinical Department of Social Psychiatry, Medical University
Vienna, Vienna, Austria
Martin Walter Department of Psychiatry and Psychotherapy, Jena University
Hospital, Jena, Germany
Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany
Department of Psychiatry and Psychotherapy, University Tuebingen, Tuebingen,
Germany
Leibniz Institute for Neurobiology, Magdeburg, Germany
Gang Wang Department of Neurology and Neuroscience Institute, Ruijin Hospital
affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.
China
lviii Contributors

Yanjiang Wang Daping Hospital, Third Military Medical University, Chongqing,

China
Yong Wang Tianjin Mental Health Institute, Tianjin Anding Hospital, Tianjin,
China
Hirohisa Watanabe Department of Neurology and Neuroscience, School of Med-
icine, Fujita Health University, Toyoake, Aichi, Japan
Thomas C. Wetter Department of Psychiatry and Psychotherapy, University of
Regensburg, Regensburg, Germany
Juri-Alexander Witt Department of Epileptology, University Hospital Bonn
(UKB), Bonn, Germany
Zyta Beata Wojszel Department of Geriatrics, The Medical University of
Bialystok, Bialystok, Poland
D. Wozniak Klinik und Poliklinik für Psychiatrie und Psychotherapie,
Universitätsklinikum Leipzig, Leipzig, Germany
Pingyi Xu Department of Neurology, The First Affiliated Hospital of Guangzhou
Medical University, Guangzhou, China
Sakiko Yamada Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
Aylin Yaman Department of Neurology, Antalya Training and Research Hospital,
Antalya, Turkey
Hakan Yaman Independent Scholar, Family Physician, Antalya, Turkey
Yuting Yang Liaoning Provincial Key Laboratory for Research on the Pathogenic
Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical
University, Dalian, China
Liaoning Provincial Center for Clinical Research on Neurological Diseases, The
First Affiliated Hospital, Dalian Medical University, Dalian, China
Ken Yonezawa Department of Neuropsychiatry, Unit of Translation Medicine,
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Moussa B. H. Youdim Eve Topf and USA National Parkinson Foundation Centers
of Excellence for Neurodegenerative Diseases and Department of Pharmacology,
Technion-Rappaport Family Faculty of Medicine, Haifa, Israel
Department of Biology, Yonsei World Central University, Seoul, South Korea
Cecilia Zazueta Departamento de Biomedicina Cardiovascular, Instituto Nacional
de Cardiología Ignacio Chávez, Ciudad de México, Mexico
Gerald Zernig Department of Psychiatry 1, Medical University of Innsbruck,
Innsbruck, Tirol, Austria
Contributors lix

Feng Zhang The First Affiliated Hospital, Dalian Medical University, Dalian,
China
Xiaojie Zhang Department of Neurology, Shanghai 6th People’s Hospital, Shang-
hai Jiaotong University School of Medicine, Shanghai, China
Hailin Zheng Department of Medicinal Chemistry, Intra-cellular Therapies Inc.,
New York, NY, USA
Peter Zwanzger Clinical Center for Psychiatry, Psychotherapy, Psychosomatic
Medicine and Neurology, Wasserburg am Inn, Germany
 Part I
Basic Principles

Peter Riederer
Neurobiological Principles:
Neurotransmitters

Lena Hampel and Thorsten Lau

Contents
Neurotransmitters: More than Crossing the Synaptic Cleft . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
One Neuron: Two Messengers – Neurotransmission Beyond Dale’s Principle . . . . . . . . . . . . . . . . 7
Dopamine Neurons: A Versatile Model for Joint Neurotransmitter Release . . . . . . . . . . . . . . . . . . . . 10
Maintenance of Neuronal Network Activity: A Small Insight into Giant Domains . . . . . . . . . . . . 13
A New Frontier: Serotonylation of Histones – Neurotransmitter Activity Inside the Nucleus . . . 15
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Abstract
To integrate sensory and memory information, to control behavior, and to regulate
various metabolic processes in favor of homeostasis, the central nervous system
has to perform a huge amount of computations at once. This task is fulfilled by
intra- and intercellular signaling cascades driven by a sophisticated network of
highly connected neural cells. Most prominently, the release of neurotransmitters
into the synaptic cleft is considered to be the key element core of neuronal
intercellular communication. This core process of neuronal communication
makes the synapse the substantial unit of neurotransmission. Consequently,
neurons are thought to establish the foundation of efficient communication within
their networks by strengthening and promoting the molecular structures of this
functional unit. In the classic view of chemical neurotransmission, the synapse
requires (1) the availability for synthesis of the respective neurotransmitter; (2) an
activity-responsive, tightly regulated vesicular release machinery on the

L. Hampel · T. Lau (*)

Central Institute of Mental Health, Department of Translational Brain Research, Medical Faculty
Mannheim; Heidelberg University, Hector Institute for Translational Brain Research, Mannheim,
Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
e-mail: lenahampel@gmx.de; thorsten.lau@zi-mannheim.de

© Springer Nature Switzerland AG 2022 3

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_365
4 L. Hampel and T. Lau

presynaptic side; (3) postsynaptic receptors, which are selectively activated upon
binding by neurotransmitters and subsequently trigger intracellular signaling
cascades; and (4) mechanisms to successfully terminate neurotransmission by
removal of neurotransmitters from their site of action. With advanced experimen-
tal methods and interdisciplinary research approaches, our knowledge on neuro-
transmission is constantly growing. As a result, the once classical view on
neurotransmission is changing in the light of new insights into regulation and
organization of synaptic activity. The following sections first give a brief over-
view on elements determining neurotransmission, the axon initial segment, and
presynaptic cytomatrix active zone, before focusing on simultaneous release of
two chemically distinct neurotransmitters and neurotransmitter activity beyond
synaptic structures (Fig. 1).

Neurotransmitters: More than Crossing the Synaptic Cleft

A broad variety of molecules were identified to act as neurotransmitters, chemical

messengers transmitting information at synaptic connections between neurons. The
chemical profile of neurotransmitters is highly diverse. The majority of neurotrans-
mitters are amino acids or amino acid derivatives, for example, glutamate, glycine, γ-
amino-butyric acid (GABA), or monoamine neurotransmitters, including dopamine,
serotonin, and norepinephrine. Neuropeptides also constitute a huge class of neuro-
transmitters originating from amino acids (Lodish et al. 2000; Russo 2017; Wang
et al. 2015). In addition to these molecules, other chemical substances have been
shown to function as neurotransmitters, too. Among these, chemically diverse
substance as endocannabinoids, nitric oxide, or adenosine triphosphate can be
found. All types of neurotransmitters are made available at the presynapse in defined
synaptic vesicle pools. Synaptic vesicles undergo activity- and calcium-dependent
exocytosis and release neurotransmitters into the synaptic cleft upon fusion with the
synaptic plasma membrane. The small signaling molecules, for example, glutamate,
are considered neurotransmitters in their classical meaning, transmitting the infor-
mation from pre- to postsynapse. Neuropeptides are the neuronal equivalent of
peptide hormones – resembling them not only in their metabolism but also in their
autocrine, paracrine, or even endocrine mode of action. Neuropeptides may be
released simultaneously with or slightly delayed after vesicular exocytosis of clas-
sical neurotransmitters (van den Pol 2012). The high variety of chemically distinct
signaling molecules as well as the diversity of neurotransmitter receptors constitutes
the framework for neuronal activity.
Neuronal communication and data processing require networks of cells that are
highly specialized in signal processing and forwarding information. At the very
beginning of activity-dependent vesicular neurotransmitter release, electrical excit-
atory and inhibitory potentials are finely processed at the axon initial segment (AIS),
the site of action potential generation (Fig. 1). This unique segment separates the
somatodendritic (input) compartment of a neuron from the axonal (output) compart-
ment. It thereby not only maintains neuronal polarity by spatial separation and
Neurobiological Principles: Neurotransmitters 5

synaptic
transmission axo-axonic synaptic transmission
at the axon initial segment

extrasynaptic volume transmission

transamidation of proteins

Fig. 1 Overview on neurotransmitters’ sites of action in mammalian brain. The overview intro-
duces four sites of action for neurotransmitters: (a) Neurotransmitters act at synaptic connections
between two neurons, for example, synaptic transmission between pre- and postsynapse at nerve
terminals that connect to dendrites. After crossing the synaptic cleft, neurotransmitters bind their
respective ionotropic or metabotropic receptors to trigger cellular responses. (b) An alternative
synaptic transmission occurs at axo-axonic synapses located at the axon initial segment, the site of
action potential generation. Here, the neurotransmitters dopamine, GABA, and serotonin are able to
positively or negatively interfere with action potential generation. (c) Extrasynaptic volume trans-
mission, especially for the monoamines dopamine and serotonin, was shown to occur at
somatodendritic structures as well as along the axon. These extrasynaptic release sites do not
depend on establishing connection to an opposing postsynapse. (d) Beyond neurotransmission,
monoamine neurotransmitters are substrates for transamidation of proteins, including extracellular
matrix proteins, which affect the scaffolding of these proteins, and intracellular GTPases, directly
changing the activity of small GTPases. Recently serotonin was shown to be transamidated to
histones, which influences permissive gene expression

regulation of protein trafficking but is also the critical intracellular gate of signal
transduction that determines neuronal output. The threshold for the initiation of
action potentials depends on the variable AIS position relative to the neuron’s soma,
length, and highly adaptive ion channel composition (Leterrier 2018; Petersen et al.
2017). These characteristics make the AIS a key player in fine-tuning neuronal
excitability and thereby a crucial element of neuronal plasticity. Its structural and
biophysical properties were shown to be altered in an activity-dependent manner as
well as by neurotransmitter actions, both from the surrounding extracellular space
and from direct axo-axonic synaptic innervation by GABAergic and dopaminergic
interneurons (Jamann et al. 2018; Khirug et al. 2008; Wefelmeyer et al. 2015;
Yamada and Kuba 2016). According to its central role in generating and shaping
action potentials, it is not surprising that disruptions of AIS components and
alterations in their formation are emerging as critical factors in the pathogenesis of
several important mental and neurological disorders. For example, dysregulations of
the AIS scaffold protein ankyrin-G have been associated with schizophrenia as well
as bipolar disorder, while genetic mutations of AIS voltage-dependent sodium
6 L. Hampel and T. Lau

channels are correlated with the occurrence of autism spectrum disorders (reviewed
in Hsu et al. 2014). Given that the AIS is a key structure in maintenance of neuronal
structural and functional organization, therefore AIS components and their protein-
protein interactions are promising future targets for pharmacological treatments.
Along the axon, differences in electrical charges between the extra- and intracel-
lular side of the plasma membrane are exploited to generate currents that drive
depolarization and propagation of the action potential. Axons are highly specialized
for fast and efficient conduction. In myelinated neurons the increased electrical
isolation and clustered distribution of voltage-dependent sodium channels at
the Nodes of Ranvier allow conduction of super-threshold electrical signals to the
synapses at velocities up to 150 m/s (Purves et al. 2001). Upon arrival of the
electrical signals at the presynaptic side, a tightly regulated release machinery is
activated, which is organized by a highly specialized cytoskeleton region: the
cytomatrix active zone. The cytomatrix active zone builds the framework for storage
and regulated release of synaptic vesicles at the presynapse. Its evolutionary con-
served protein complex primes and sorts neurotransmitter vesicles ready for synaptic
exocytosis, recruits voltage-gated calcium channels, and tethers them to trans-
synaptic cell adhesion molecules. In addition, its components interact in a differen-
tiated way in response to distinct bursts or trains of action potentials. Soluble matrix
proteins of the active zone initiate exocytosis in a very fast and finely tuned manner
by interacting with proteins of the presynaptic fusion machinery, consisting of
vesicular and membrane SNARE as well as calcium-sensitive proteins, which are
obligatory for all eukaryotic synaptic exocytosis events (Chia et al. 2013; Dresbach
et al. 2001; Lazarevic et al. 2013; Südhof 2012).
Incoming action potentials result in a calcium ion influx by opening voltage-
dependent calcium channels, which provides the calcium ions required for activity-
dependent exocytotic neurotransmitter release into the synaptic cleft (Nanou and
Catterall 2018). Regarding the temporal sequence and the coupling of incoming
action potentials to synaptic neurotransmitter release, three functionally different
exocytosis modes can be described. There are two different types of
stimulation-dependent neurotransmitter release and one based on spontaneous syn-
aptic exocytosis. The two stimulation-dependent release modes are based on highly
synchronized vesicular fusion within hundreds of microseconds after arrival of an
action potential at the synapse. This event is followed by a phase of asynchronous
neurotransmitter release, which complements the synchronous vesicle fusion in
order to maintain synaptic signaling strength. Synchronous neurotransmitter release
is thought to be the pacemaker in neuronal networks, while asynchronous neuro-
transmitter release may drive prolonged synaptic transmission (Bartos et al. 2002;
Chamberland and Tóth 2016; Plenz and Kitai 1998; Volman and Gerkin 2011). In
contrast to stimulation-driven synaptic release, the third mode is constituted by
neurotransmitter-containing synaptic vesicles, which undergo spontaneous exocyto-
sis. Spontaneous neurotransmitter release was shown to play a central role in
synaptic plasticity, especially since spontaneously released neurotransmitters seem
to activate a postsynaptic receptor population not targeted by stimulation-dependent
release. In this way neurons employ differential neurotransmitter signaling of
Neurobiological Principles: Neurotransmitters 7

spontaneous and stimulation-dependent release to fine-tune homeostatic regulation

of synaptic inputs (Kavalali 2015; Sutton and Schuman 2009; Sutton 2010).
Apart from the classical well-known synaptic transmission modes, there are also
axonal boutons without corresponding postsynaptic densities at which neurotrans-
mitters are released into the extracellular space (Fig. 1). In contrast to the synaptic
transmission mode, these transmitters diffuse over further distances – the so-called
volume transmission – and finally bind to extrasynaptic receptors. These receptors
do not receive the same concentrations of neurotransmitters in the mM range as their
synaptic counterparts and are therefore characterized by a particularly high substrate
affinity. The same applies to extrasynaptic transporters, which also display high
substrate affinities in order to regulate the extracellular concentrations of neurotrans-
mitters and also are affected by pharmacotherapies aiming to regulate synaptic
transmission. This is of particular interest in terms of pharmacotherapies because
here, successful therapeutic responses are sometimes judged by peripheral micro-
molar concentrations of applicated drugs. In this context, it has to be considered that
the cellular transmitter effects of extrasynaptic neurotransmission may in part be
completely different from those of their synaptic counterparts. Accumulating evi-
dence suggests that volume transmission seems to have its own physiological
function and enables a longer, more comprehensive and tonic interaction between
neurons and entire neuronal networks. Thus, it may be the basis of behavioral and
consciousness conditions and possible biochemical rationale for the slow and endur-
ing changes involved in altered states of, e.g., attention and motivation (Fuxe et al.
2015; Taber and Hurley 2014; Quentin et al. 2018; Vizi et al. 2004).

One Neuron: Two Messengers – Neurotransmission Beyond Dale’s

Principle

Our general understanding of neuronal identity is closely associated with the bio-
chemical identity of its neurotransmitter. A neuron is thought to only express the
enzymes needed for the synthesis of its own set of transmitters. Consequently, the
detection of the particular enzymes allows conclusions regarding the neuron’s
signaling characteristics. The expression of tryptophan hydroxylase 2 as synthesiz-
ing enzyme of serotonin defines a neuron as “serotonergic,” while the presence of
glutamic acid decarboxylase categorizes the respective neuron as GABAergic.
Based on these biochemical features, our general view on neurotransmission is
that a genetically-biochemically defined neuron releases the same neurotransmitters
at every synapse, as stated in Dale’s principle (Strata and Harvey 1999). Therefore,
the mode of action of a presynaptic neuron on its postsynaptic counterpart is
considered to depend on the type of neurotransmitter released. For example, gluta-
mate-releasing neurons are considered as excitatory neurons, GABA-releasing neu-
rons as inhibitory neurons, and monoamine-releasing neurons, for example,
dopamine or serotonin, as neuromodulatory neurons. This view denies the potential
of a more sophisticated mode of action by the combined release of two or more
neurotransmitter molecules. In 1979 Jan and colleagues monitored the release of two
8 L. Hampel and T. Lau

chemically different transmitters from frog ganglia. In addition to the cholinergic

neurotransmission, a neuropeptide was released that on its own was capable to evoke
a slow synaptic potential (Jan et al. 1979; Jan et al. 1980). Since then, a growing
number of studies provided experimental data for a combined synaptic release of
signaling molecules. This release mode was observed not only for the combination
of classical neurotransmitters and neuropeptides but also for the joint release of fast-
acting neurotransmitters and slow-acting neuromodulators, for example, the combi-
nation of glutamate and GABA, respectively, glutamate and dopamine or serotonin
(Broussard 2011; Granger et al. 2017; Johnson 1994; Seal and Edwards 2006;
Svensson et al. 2019; Vaaga et al. 2014).
The combined release of neurotransmitters from one presynaptic neuron opens up
a complex tool for fine-tuning neuronal communication in neuronal circuits (Fig. 2b
and c). First of all, neurotransmitters may be co-released or co-transmitted. Co-
release requires packing two chemically distinct neurotransmitters into one synaptic
vesicle. To do so, synaptic vesicles need to express the respective vesicular trans-
porters or rely on non-specific uptake by transporters located in the synaptic vesicle
membrane (see next section; Tritsch et al. 2012; Wojcik et al. 2006). Once loaded,
the synaptic vesicle pool contains at least two different types of neurotransmitters,
which are released simultaneously upon stimulation of the presynaptic neuron.
Regarding neuronal communication, co-release of two fast-acting neurotransmitters
is thought to mainly affect dynamics of the postsynaptic density. Here they directly
affect postsynaptic excitability and may also contribute to the composition and
function of the postsynapse, for example, neurotransmitter receptor activity and
trafficking (Choquet and Triller 2013; Dugué et al. 2005; Jonas et al. 1998). Co-
transmission on the other hand is maintained by differentially packed and therefore
spatially and chemically separated vesicles of the presynaptic vesicle pool. There-
fore, co-transmission provides the basis for temporal and mechanically regulated
exocytosis of the different vesicles types, constituting a more complex tool for fine-
tuning synaptic communication. In addition to the input given to postsynaptic
neurons by fast-acting excitatory or inhibitory neurotransmitters, co-transmission
is also considered to provide autoregulatory feedback on neurotransmitter release via
the slow-acting neuromodulators as well as modulation of postsynaptic receptor and
ion channel activity (Svensson et al. 2019; Vaaga et al. 2014). Both modes of joint
neurotransmitter release are a source for fine-tuning neuronal communication, espe-
cially in complex neuronal circuits of the mammalian brain. However, although co-
release and co-transmission have the potential to differentially impact signal trans-
duction at the synapse, the relevance for neuronal communication modes simulta-
neously involving two or even more neurotransmitters is not fully understood
(Hnasko and Edwards 2012). The following chapter will have a closer look at
dopamine neurons, which have been shown to perform co-release and co-transmis-
sion of fast-acting neurotransmitters, GABA or glutamate, and their own neurotrans-
mitter, the slow-acting neuromodulator dopamine.
Neurobiological Principles: Neurotransmitters 9

A B 1
Target neurons (striatum)
dopamine Nucleus accumbens dorsal striatum
medial shell core
glutamate
+ 2
GABA + +
+ + + + + +
+

Dopamine neurons (substantia nigra) t2

3
t1

Striatum Cortex
C 1

External Internal Thalamus

globus globus
pallidus pallidus 2
Subthalamic nucleus

t2
3
Substantia t1
nigra

Fig. 2 Dopamine neurons as a model for joint neurotransmitter release. (a) As part of the motor
system, the basal ganglia (striatum, globus pallidus, substantia nigra, and subthalamic nucleus)
control initiation, extent, direction, force, and speed of movements, among other things. The basal
ganglia are connected to each other by complex control loops. Initially they are activated by the
cortex and then process the signal via main and branch loops (including feedback projections) and
finally project via the thalamus to the motor cortex, which finally executes the movement. In the
overview scheme green and red arrows indicate stimulating, respectively inhibitory input. Here, a
special focus lies on the highly differentiated connection between dopamine neurons of the
substantia nigra and their target neurons in the striatum. Inside this brain region, dopamine neurons
are capable to co-transmit dopamine, GABA, and glutamate in area-specific quantities. (b and c)
Dopamine neurons have the potential to create a unique neuronal input on a postsynaptic neuron by
using combined neurotransmitter release. (b) Co-release of neurotransmitters from dopamine
neurons. (1) Dopamine and a second neurotransmitter are packed into identical synaptic vesicles
yet in different concentrations. (2) Both neurotransmitters are released simultaneously into the
synaptic cleft and bind to corresponding postsynaptic receptors. (3) The cellular response of a
dopamine target neuron is influenced by the concentrations of the second neurotransmitter at
different time points (t1, t2) during dopaminergic neurotransmission. (c) Co-transmission by
dopamine neurons: (1) the dopamine synapse contains synaptic vesicles with different neurochem-
ical identities, for example, either dopaminergic or glutamatergic. (2–3) Co-transmission features
the benefit of spatial and temporal resolution, which enables the synapse to fine-tune neurotrans-
mitter release by releasing the second neurotransmitter in a short pulse, similar duration, or
recurring during dopamine release (2). For example, the second neurotransmitter modulates the
cellular response by a short availability (t1) or a repeated exposure to itself (t2). Both ways of joint
neurotransmission enable dopamine neurons to maintain brain region-specific neurotransmitter
release patterns
10 L. Hampel and T. Lau

Dopamine Neurons: A Versatile Model for Joint Neurotransmitter

Release

Dopamine neurons are well known for their responses to reward, their role in
positive motivation, and their reinforcing effect on self-harming behavior in the
development of addiction. Here, the neuronal signaling pathway constituted by
midbrain dopamine neurons that project from the ventral tegmental area to the
striatum is pivotal for mechanisms underlying associative and reward learning and,
as a component of basal ganglia, also contributes to movement generation. Based on
these exemplary essential physiological processes, it is hardly surprising that
dysregulations in dopamine signaling are assumed to contribute critically to the
pathogenesis of psychiatric and neurologic disorders. Among other psychiatric
diseases, the midbrain to striatum signaling pathway is a key factor in the emergence
of schizophrenia as well as in the onset of dysfunctional behavior in addiction. With
regard to neurodegenerative diseases, the continuous loss of dopaminergic midbrain
neurons is observed in Parkinson’s disease (Chinta and Andersen 2005).
Dopamine neurons located to the ventral tegmental area and targeting striatal
spiny neurons were shown to be capable of performing neurotransmitter co-release
(Fig. 2a). In studies, which employed electrophysiological recordings, Tritsch and
colleagues demonstrated that these neurons co-released dopamine and the fast-acting
neurotransmitter GABA (Tritsch et al. 2012, 2014). Interestingly, their studies also
provided evidence that dopamine neurons recruited GABA by active uptake via
plasma membrane-bound GABA transporter (GAT) molecules rather than de novo
synthesis of the neurotransmitter (Tritsch et al. 2012). Surprisingly, experimental
evidence shows that GABA release from dopamine neurons was diminished by
inhibition of GAT-dependent GABA uptake rather than expression of a functional
vesicular GABA transporter. Here, experimental data provided evidence for vesic-
ular monoamine transporter 2 (VMAT2)-dependent uptake of GABA into the syn-
aptic vesicles of dopamine neurons (Tritsch et al. 2014). The potential of the latter
observation implies that all types of monoamine neurons may have the potential for
GABA co-release by loading their synaptic vesicles without de novo GABA syn-
thesis via plasma membrane GAT and non-canonical VMAT2 uptake (discussed in
Granger et al. 2017; Vaaga et al. 2014). Regarding the effect of GABA co-release,
Tritsch and colleagues were able to show that GABAA receptor-evoked postsynaptic
currents in neurons, targeted by the dopamine presynapse, were diminished once
GABA uptake into the dopamine neurons was prevented (Tritsch et al. 2014).
Interestingly, the functional analysis of midbrain dopamine neurons revealed that
they are capable to simultaneously release dopamine and either glutamate or GABA
in the nucleus accumbens yet not in the dorsal striatum (Stuber et al. 2010). Based on
these observations, dopamine neurons seem to be capable to differentially control
striatal circuit function. Here, single dopamine release is viewed to affect the
neuronal activity of all striatal neurons targeted by dopamine neurons. In contrast,
simultaneous release modes comprised of dopamine-glutamate or dopamine-GABA
release, occurring exclusively at the shell and core of the nucleus accumbens,
respectively, are considered a manifold way for dopamine neurons to transmit fast,
Neurobiological Principles: Neurotransmitters 11

distinct signals to differentially affect their target neurons in defined striatal areas
(Fig. 2b and c). Furthermore, dopamine neurons may complement their own neuro-
transmission by directly modulating the activity of striatal cholinergic interneurons.
Thereby dopamine neurons have the potential to create a unique neuronal input on
general striatal function via a specific link to their target neurons and via cholinergic
interneurons (Chuhma et al. 2014). This distinctive dopaminergic neurotransmission
feature, which combines differential temporal joint neurotransmitter release and
modulation of interneuron activity, is thought to be specifically involved in
reward-related learning and the development of addictive disorders (Stuber et al.
2010; Chuhma et al. 2014).
Prior to these studies, immunofluorescence analysis as well as electrophysiolog-
ical recordings of the dopamine synapse in cultured dopamine neurons already
provided first evidence for combined synaptic dopamine-glutamate release. On the
molecular level, the expression of the vesicular glutamate transporter 2 (vGLUT2)
gene was verified in cultured dopamine neurons. Immunofluorescence analysis
revealed that vGLUT2 was localized in synaptic vesicle pools of dopamine synap-
ses. Further functional evidence was provided by electrical stimulation of dopamine
neurons, which evoked fast glutamate-dependent excitatory postsynaptic currents
(Dal Bo et al. 2004; Joyce and Rayport 2000; Onoa et al. 2010; Sulzer et al. 1998).
Evidence for dopamine-glutamate co-transmission was also found by corresponding
in vivo data: for example, vGLUT2 expression in dopamine neurons of rodent brain,
a prerequisite for specific glutamate uptake by synaptic vesicles, was verified in
midbrain dopamine neurons (Kawano et al. 2006). Interestingly, a dopamine neuron-
specific knockout of the vGLUT2 gene impaired axonal growth of dopamine
neurons and resulted in a diminished innervation of the nucleus accumbens and
even reduced dopamine neuron survival. Consequently, a diminished dopamine
signaling led to impaired motor behavior (Fortin et al. 2012). A thorough combined
immunofluorescence and electron microscopy analysis of dopamine synapses
showed that dopamine synapses in the nucleus accumbens display differentially
organized cytomatrix active zones hosting microdomains with either vGLUT2- or
VMAT2-containing synaptic vesicles (Zhang et al. 2015). Furthermore, these studies
provided evidence for an age-dependent vGLUT2 expression, with a declining
ability of combined dopamine-glutamate neurotransmission in adult rodent brain
(Mendez et al. 2008; Bérubé-Carrière et al. 2009). Optogenetic approaches
performed in nucleus accumbens brain sections provided further insight into the
characteristics of dopamine-glutamate co-transmission. One study successfully dem-
onstrated glutamate release by mesolimbic dopamine neurons in the nucleus
accumbens, which resulted in postsynaptic excitation (Tecuapetla et al. 2010).
Furthermore, the glutamatergic input could be linked to mesolimbic reward-related
dopamine signaling circuits, a first indication that synaptic glutamate release by
dopamine neurons may contribute to mesolimbic reward signaling. In addition,
optogenetic approaches verified the findings of microscopic localization analysis
of the dopamine synaptic vesicle pools. Dopamine- and glutamate-mediated post-
synaptic responses are based on similar neurotransmitter release probabilities, yet
dopamine and glutamate signaling was shown to be differentially affected by drugs
12 L. Hampel and T. Lau

targeting dopamine signaling (Adrover et al. 2014). This observation and previous
findings provide evidence for independent vesicle pools localized to the cytomatrix
active zone of dopamine synapses, which contain either dopamine or glutamate
(Adrover et al. 2014; Barker et al. 2016; Hnasko et al. 2010).
Although the relevance for joint neurotransmitter release is not fully understood
(discussed in Hnasko and Edwards 2012), the experimental data obtained by studies
covering mechanisms and structural organization of dopamine synapses provide a
constantly growing insight into co-release and co-transmission by dopamine neu-
rons. Due to their different postsynaptic or autoregulatory effects, co-transmission of
dopamine and glutamate or co-release with GABA can have versatile outcomes.
Regarding glutamate neurotransmission, dopamine may modulate glutamatergic
signaling either by strengthening or by weakening glutamate transmission,
depending on the postsynaptic dopamine receptor profile. Glutamate on the other
hand may enhance dopamine signaling by providing additional excitatory input.
Similarly, by dopamine-GABA co-release, GABA signaling may be directly mod-
ulated due to the presence of dopamine, while dopamine signaling may be dimin-
ished by simultaneous GABA release. In contrast to dopamine-glutamate co-
transmission, dopamine-GABA co-release lacks the spatial and temporal resolution
displayed by co-transmission (Barker et al. 2016; Granger et al. 2017; Svensson et al.
2019).
Due to their different postsynaptic or autoregulatory effects, co-transmission of
dopamine and glutamate or co-release with GABA can have versatile outcomes.
Regarding glutamate neurotransmission, dopamine may modulate glutamatergic
signaling either by strengthen or by weaken glutamate signaling, depending on the
postsynaptic dopamine receptor profile. Glutamate on the other hand may enhance
dopamine signaling by providing additional excitatory input. Similarly, by dopa-
mine-GABA co-release, GABA signaling may be directly modulated due to the
presence of dopamine, while dopamine signaling may be diminished by simulta-
neous GABA release. In contrast to dopamine-glutamate co-transmission, dopa-
mine-GABA co-release lacks the spatial and temporal resolution displayed by co-
transmission (Barker et al. 2016; Granger et al. 2017; Svensson et al. 2019).
Regarding neurotransmitter activity at the AIS, where dopamine and GABAergic
neurons maintain axo-axonic synapses and were shown to modulate action potential
generation, the occurance of dopamine-GABA co-release provides a highly inter-
esting synaptic input beyond singular, independent dopamine or GABA signaling.
This is especially interesting since dopamine was shown to be able to inhibit
GABAA-receptors (Hoerbelt et al. 2015).
In summary, our example for joint neurotransmitter release by dopamine neurons
shows that neurons are capable to maintain brain region-specific neurotransmitter
release patterns. This enables neurons to fine-tune synaptic communication within
well-defined neuronal circuits. Regarding psychiatric as well as neurodegenerative
diseases, established pharmacotherapies may cause additional disruptive signaling in
synapse maintaining joint neurotransmitter release if only one of multiple neuro-
transmitter signals is either enhanced or inhibited. Consequently, already impaired
signaling pathways may be further disrupted and disease conditions promoted.
Neurobiological Principles: Neurotransmitters 13

Therefore, to better understand the relevance and impact of co-neurotransmission,

one has to better understand key structures of neuronal communication, such as the
axon initial segment or the presynaptic cytomatrix active zone, and their role in
neuronal activity under physiological as well as pathological conditions. It is con-
ceivable that a better understanding of this phenomenon is also a starting point for
more specific pharmacotherapies and better therapeutic effects, since so far our focus
lied on repairing dopaminergic signaling without taking into account simultaneous
release modes.

Maintenance of Neuronal Network Activity: A Small Insight into

Giant Domains

Communication between neurons relies on maintenance of persistent neuronal

activity. This requires the interaction of various cellular structures, including,
among others, the axon hillock as well as pre- and postsynatpic densities. Each of
these key structures represents a finely adjustable screw set into an extensive
network of neuronal communication and is able to undergo constant change within
the scope of all our central nervous processes. Some structures have already been
discussed in this chapter, which may be simplified into (1) signal generators, the
presynaptic active zone, where action potentials are translated into neurotransmitter
release; (2) signal processors, membrane channels in general, and the AIS as a fine-
tuning structure between input and output signals that determines action potential
generation; and (3) signal receivers, for example, postsynaptic receptors in their role
as receivers of neuronal communication and initiators of cellular responses. Similar
to constant changes that develop and shape neuronal networks, these cellular
elements are continuously modified and adapted in order to fulfill the requirements
imposed on a neuron by its network environment. In 1973 Timothy Bliss and Terje
Lomo were the first to describe long-term changes of synaptic plasticity by
demonstrating long-term potentiation (LTP) in rabbit brain (Bliss and Lømo 1973).
Long-term synaptic plasticity comprises not only LTP but also its opposite-acting
long-term depression (LTD), and both are crucial factors in learning and memory
formation. Here, high-frequency stimuli lead to strengthening of synaptic connec-
tions by increasing the density and function of both the signal generators and signal
receivers (Abraham 2003; Caroni et al. 2012; Reymann and Frey 2007).
A very strong focus on dissecting these processes is on glutamate neurotransmis-
sion and the role of the N-methyl d-aspartate receptors (NMDARs) and calcium-/
calmodulin-dependent protein kinase II (CAMKII). In addition to this signaling
pathway, a large number of studies also demonstrated that the activation of G-
protein-coupled receptors (GPCRs) also underlies the dynamic processes of long-
term synaptic plasticity. Accordingly, long-term synaptic plasticity is considered to
be maintained by NMDAR-dependent and NMDAR-independent signaling cas-
cades (Bazzari and Parri 2019; Citri and Malenka 2008; Pfeiffer and Huber 2006).
Regarding NMDAR dependency, long-term synaptic plasticity involves postsynap-
tic protein synthesis, which provides an immediate cellular response prior to
14 L. Hampel and T. Lau

establishing nuclear gene expression. Interestingly, there is experimental evidence

that, although playing an essential role in synaptic plasticity, the NMDAR-CAMKII-
signaling cascade on its own seems not sufficient enough to initiate and maintain
LTP. Rather non-NMDAR-dependent pathways, including BDNF signaling or meta-
botropic dopamine and glutamate receptor activation, are thought to support long-
term plasticity by switching on local dendritic transcription as well as nuclear gene
expression (discussed in Bazzari and Parri 2019; Bramham 2008). Regarding the
essential role of local transcription within dendritic structures, well-controlled
mRNA transport to and localization at active synapses are a critical feature in
formation and maintenance of long-term synaptic plasticity. To ensure this, neuronal
mRNA is organized in ribonucleoprotein particles that are primed for bidirectional
transport along dendritic microtubules. An activated postsynapse may then recruit
dynamic microtubules and thereby guide these particles for specific activity-depen-
dent mRNA for activity-dependent local transcription at individual postsynaptic
densities. Based on the hypothesis of continuous back-and-forth transport of ribo-
nucleoprotein particles along dendritic microtubules, this transport pattern was
termed “synaptic sushi belt” (Doyle and Kiebler 2011).
In addition to glutamate neurotransmission, long-term synaptic plasticity is also
defined by different GPCR-dependent as well as neurotrophin receptor signaling
cascades, which are triggered by binding their respective ligands, including neuro-
transmitters and neuromodulators such as dopamine, serotonin, or BDNF (reviewed
in Bazzari and Parri 2019). Such receptor activities were shown to contribute to early
and late stages of long-term plasticity and also to act either independently or
synergistically to form and maintain synaptic plasticity. A broad number of kinases
were identified to be involved in the intracellular signaling cascades, including
protein kinase A and C, mammalian target of rapamycin (mTOR), phosphoinositide
3-kinase (PI3K), and mitogen-activated protein kinases (MAPK). Together, these
kinases orchestrate signaling pathways, which shape long-term synaptic plasticity
events: (1) the modulation of neuronal excitability, (2) recruitment of neurotrans-
mitter receptors for synaptic insertion, and (3) adaption of gene expression in order
to secure the maintenance of long-term synaptic plasticity (Sossin 2007; Hoeffer and
Klann 2010; Horwood et al. 2006; Sweatt 2004, reviewed in Bazzari and Parri
2019).
Next to understanding the neuronal mechanisms discussed above, our awareness
grew that astrocytes are able to significantly contribute to neuronal excitability and
that there is actually active communication between astrocytes and neurons. Thereby
astrocytes display the potential to act as essential regulators of neuronal transmission
(Araque et al. 2014; De Pittà et al. 2016; Pirttimaki et al. 2017). With regard to their
ability to modulate neuronal network activity, for example, astrocytes were shown to
be involved in the regulation of synchronous neuronal activity via modulation of
calcium signaling within a neuronal network (Bekar et al. 2008; Brockett et al. 2018)
or by stimulation of interneurons as a response to neuronal acetylcholine release
(Pabst et al. 2016). These few examples already highlight that astrocytes are active
signaling elements within neuronal networks. They respond to presynaptic neuro-
transmitter release by releasing their own neurotransmitters (gliotransmitters), for
Neurobiological Principles: Neurotransmitters 15

example, glutamate, which signal back to the presynapse or interneurons to either

enhance or diminish synaptic activity.
All these processes contribute to the enormous adaptability of our brain’s network
activities. But which is it that provides stability within our highly dynamic neuronal
circuits? Considering (rapid) adaption and the self-reinforcing synaptic plasticity of
LTP and LTD, it is astonishing that usually no runaway excitations occur. Thus, there
must be negative feedback mechanisms that maintain firing rates within distinctly
defined boundaries. On one hand, the intrinsic firing properties of each neuron,
including ion channel densities or the plasticity of the AIS, are able to regulate
signaling by shifting input-output relations (Grubb and Burrone 2010; Hamada et al.
2016; Jamann et al. 2018). On the other hand, there are synaptic regulatory processes
such as the extensively studied synaptic scaling, which keeps synaptic inputs in
check. Elevated activity leads to a global downscaling of a neuron’s synapses in a
multiplicative manner, whereas chronically inhibited neurons undergo synaptic
upscaling. At the presynapse, synaptic scaling is reflected by mechanisms which
regulate the release probability by alteration of synaptic vesicle recycling and
adjusting the number of readily releasable synaptic vesicles. On the side of the
postsynapse, neurons compensate for altered activity levels by adapting their neu-
rotransmitter receptor properties. For example, an extensively excited neuron
reduces its postsynaptic receptor density; a chronically inhibited one increases it
by lateral diffusion of receptors in the postsynaptic membrane and recruitment of
receptors from intracellular pools (reviewed in Pozo and Goda 2010).
In summary, learning and memory depend on synaptic plasticity, which in turn
depend on rapid adaptation of existing and establishing of new neuronal connectiv-
ity. Here, several cellular structures, such as the axon initial segment, dendritic
spines, and synapse, are to respond in appropriate, highly flexible ways to various
inputs from neurons and glia cells alike. At the same time, these elements have to
secure network stability, which indicates robust underlying homeostatic regulators.
These regulators orchestrate neurotransmission within defined boundaries, which,
when broken, open the way toward pathogenesis. Given this, it is of utmost interest
to understand not only one of these essential regulators on its own but also its
interaction with other homeostatic regulators.

A New Frontier: Serotonylation of Histones – Neurotransmitter

Activity Inside the Nucleus

Synaptic plasticity is the cornerstone of neuronal communication: memory forma-

tion depends on how specific synaptic connections are strengthened or weakened
and how this affects the way neuronal information is transmitted and processed. As
described in the chapter before, long-term synaptic plasticity is a persistent
activity-dependent strengthening of synaptic connections between two neurons,
which results in a long-lasting enhanced synaptic transmission reflected by an
increase of pre- and postsynaptic structures. The underlying mechanisms of long-
term synaptic plasticity were and still are extensively researched in a variety of brain
16 L. Hampel and T. Lau

serotonin release MATs

and re-uptake
OCTs

SERT

extracellular
histones matrix proteins

GTPases

Fig. 3 Serotonin as a substrate for transamidation of proteins. Serotonin signaling is a circuit of

tonic serotonin release at synaptic and extrasynaptic release sites and clearance of extracellular
serotonin back into neurons via SERT. Beyond neurotransmission, serotonin is recruited to enzy-
matic transamidation of proteins by transglutaminase-2 (serotonylation). Serotonin may be cova-
lently bound to extracellular matrix proteins. Regarding intracellular proteins, serotonin is used as a
substrate to transamidate GTPases, directly affecting their activity, or to histone H3, which
contributes to permissive gene expression. Intracellular serotonylation is not restricted to serotonin
neurons. Neurons of a different phenotype may take up serotonin via monoamine transporters
(MATs), organic cation transporters (OCTs) or, depending on their developmental stage, SERT.
How serotonin is transported into the nucleus is yet unknown

regions, and some studies provided evidence for activity-dependent gene expression
to maintain dendritic spine formation (Bosch et al. 2014; Govindarajan et al. 2011).
In this scenario, neurotransmitters are able to affect gene expression by interaction
with their respective receptors and subsequent stimulation of intracellular signaling
cascades. In contrast to this, a very recent study provided first evidence for a
neurotransmitter to directly participate in gene transcription. The covalent binding
of serotonin to glutamine residues of histone H3 was shown to mediate permissive
gene expression and represents a new nonsynaptic signaling function for the neuro-
transmitter serotonin (Farrelly et al. 2019; Fig. 3).
The enzymatic covalent binding of primary amines to glutamine residues of
proteins was discovered several decades ago by Heinrich Waelsch and colleagues
(Sarkar et al. 1957). The proteins mediating this reaction were termed trans-
glutaminases, and substrates include the neurotransmitters serotonin and norepi-
nephrine among others. The transamidation of proteins with monoamines was
termed monoaminylation and specifically serotonylation for the covalent binding
of the neurotransmitter serotonin to glutamine residues (Berger et al. 2009; Bader
2019). Initially, serotonylation was shown in platelets, where serotonin was cova-
lently bound to extracellular matrix proteins as well as small cytoplasmic GTPases.
In both cases serotonylation resulted in enhanced metabolism activity of platelets
(Walther et al. 2003; Dale et al. 2002). In the context of neuronal cells, serotonylation
was first confirmed in a glia cell line, where radioactive serotonin was bound to
Neurobiological Principles: Neurotransmitters 17

extracellular fibronectin and thereby increased protein accumulation in the extracel-

lular matrix (Hummerich et al. 2012, 2015). Further evidence for neuronal
serotonylation was provided by an analysis of 5-HT receptor signaling in primary
cortical neurons. Here, the activation of serotonin receptors 2A and 2C stimulates
neuronal transglutaminase 2, which in turn results in serotonylation of the small G-
proteins Rac1 and CDC42. In their transamidated state, both GTPases are constitu-
tively active and promote dendritic spine size (Mi et al. 2017). Although
serotonylation has been demonstrated to occur in various tissues and its outcome
has significant changes in protein activity, up to date, it is not fully understood how
glutamine residues for serotonylation are selected and substrate specificity is secured
(Lai et al. 2017).
Posttranslational modifications of histones play an important role in the epige-
netic regulation of gene transcription during brain development and maintenance of
neurophysiological processes (Graff et al. 2011). Recently, Lorna Farrelly and
colleagues demonstrated for the very first time that transglutaminase 2-dependent
serotonylation of histone H3 occurs in dorsal raphe nucleus of rodent brains as well
as in human serotonin neurons derived from induced pluripotent stem cells (Farrelly
et al. 2019). In addition, this study showed that histone serotonylation seems to be a
specific posttranslational modification for histone H3 but not for other histones, even
though transglutaminase 2 may covalently bind the in vitro substrate mono-
dansylcadaverine to chicken erythrocyte core histone glutamine residues (Ballestar
et al. 1996). Regarding posttranslational histone modifications, methylation of
histone 3 is considered to play a crucial role in gene transcription. This essential
regulatory histone modification seems not to be affected by serotonylation of histone
H3 and vice versa. Furthermore, histone H3 serotonylation displayed a wide distri-
bution pattern and was found in non-serotonin neurons as well as non-neuronal cell
types, including astrocytes, cells of blood, and cardiac and colon tissue. Based on
this observation, one may conclude that histone serotonylation patterns represent a
novel epigenetic modulation of gene expression. Within this scope, a histone-
associated protein, which is able to identify serotonylated histones or communicate
histone-serotonin signals to the transcription machinery, remains to be identified.
Aside from this, a histone serotonylation-dependent enhanced gene expression in
developing rodent brain and human in vitro neurons was already demonstrated
(Farrelly et al. 2019; discussed in Bader 2019; Fu and Zhang 2019).
There is already experimental evidence that the phenomenon of intracellular
serotonylation, either of cytoplasmatic or nuclear proteins, is not exclusively limited
to serotonin neurons in mammalian brain. In the case of serotonin neurons or
enterochromaffin cells, the enzymatic activity of the respective serotonin-synthesiz-
ing tryptophan hydroxylase isoform seems to meet all prerequisites to provide
serotonin for histone H3 serotonylation (Berger et al. 2009; discussed in Anastas
and Shi 2019). It stands to reason that serotonin-synthesizing cells may easily
employ serotonin for epigenetic regulation of their gene activity, while non-seroto-
nin-synthesizing cells depend on serotonin uptake to perform intracellular
serotonylation. Serotonin uptake can be maintained in two ways: either by the
high affinity, low capacity serotonin transporter SERT or by low affinity, high
capacity monoamine transporters, including plasma membrane monoamine
18 L. Hampel and T. Lau

transporters or organic cation transporters (Chen et al. 2004; Daws 2009). SERT
expression was recently shown to depend on temporally and spatially defined
expression in non-serotonin neurons during cortical development (Chen et al.
2016), and one may assume that intracellular serotonylation may be linked to
developmental SERT expression patterns. Independent of SERT expression, intra-
cellular serotonylation may be maintained via serotonin taken up into non-serotonin
cells by non-specific monoamine transporters (discussed in Anastas and Shi 2019;
Bader 2019; Fu and Zhang 2019). For both uptake scenarios, either the spatiotem-
poral availability of SERT or a putative constitutional uptake by PMAT and/or OCT,
serotonin uptake may clearly benefit from serotonin volume transmission without
the need to establish a synaptic connection with serotonin neurons.
In conclusion, the experimental proof of histone serotonylation reveals a new way
how a neurotransmitter may directly and independently of its neurotransmitter
receptor pathways affect gene expression. Serotonin’s covalent binding to histone
3 changes the posttranslational modification of histone and subsequently influences
transcription activity in a variety of cell types. This circumstance raises the question
to which extent other neurotransmitters may directly affect gene expression. For
example, dopamine, norepinephrine, and histamine are substrates for transamidation
of glutamine residues, too, and thereby display the potential for histone mono-
aminylation (Hummerich et al. 2012, 2015; Muma and Mi 2015; Walther et al.
2011). Monoaminylation of histones by neurotransmitters crosses a new frontier of
how we perceived neurotransmitters’ mode of action in recent years. Upcoming
research will tell us whether our view on brain diseases as axono- or synaptopathies
has to be extended to including neurotransmitter-dependent chromatin modifica-
tions. Future research will unravel whether monoaminylation crucially contributes to
the onset of psychiatric diseases or efficacy of established therapeutic treatment or
whether this fascinating mechanism is a new starting point for the discovery of novel
therapeutic approaches.

Cross-References

▶ Experimental Psychopharmacology
▶ Mood Stabilizers: Pharmacology and Biochemistry
▶ Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology
▶ Pharmacokinetic and Pharmacodynamic Principles

References
Abraham WC. How long will long-term potentiation last? Phil Trans R Soc Lond B. 2003;358:735–44.
Adrover MF, Shin JH, Alvarez VA. Glutamate and dopamine transmission from midbrain dopamine
neurons share similar release properties but are differentially affected by cocaine. J Neurosci.
2014;34:3183–92.
Anastas JN, Shi Y. Histone Serotonylation: can the brain have “happy” chromatin? Mol Cell.
2019;74(3):418–20.
Neurobiological Principles: Neurotransmitters 19

Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A. Gliotransmitters travel in
time and space. Neuron. 2014;81:728–39.
Bader M. Serotonylation: serotonin signaling and epigenetics. Front Mol Neurosci. 2019;12:288.
Ballestar E, Abad C, Franco L. Core histones are glutaminyl substrates for tissue transglutaminase. J
Biol Chem. 1996;271:18817–24.
Barker DJ, Root DH, Zhang S, Morales M. Multiplexed neurochemical signaling by neurons of the
ventral tegmental area. J Chem Neuroanat. 2016;73:33–42.
Bartos M, Vida I, Frotscher M, Meyer A, Monyer H, Geiger JR, Jonas P. Fast synaptic inhibition
promotes synchronized gamma oscillations in hippocampal interneuron networks. Proc Natl
Acad Sci U S A. 2002;99(20):13222–7.
Bazzari AH, Parri HR. Neuromodulators and long-term synaptic plasticity in learning and memory:
a steered-glutamatergic perspective. Brain Sci. 2019;9(11):300.
Bekar LK, He W, Nedergaard M. Locus coeruleus α-adrenergic–mediated activation of cortical
astrocytes in vivo. Cereb Cortex. 2008;18(12):2789–95.
Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–66.
Bérubé-Carrière N, Riad M, Dal Bo G, Lévesque D, Trudeau LE, Descarries L. The dual dopamine-
glutamate phenotype of growing mesencephalic neurons regresses in mature rat brain. J Comp
Neurol. 2009;517:873–91.
Bliss TVP, Lømo T. Long-lasting potentiation of synaptic transmission in the dentate area of the
anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973;232:331–56.
Bosch M, Castro J, Saneyoshi T, Matsuno H, Sur M, Hayashi Y. Structural and molecular
remodeling of dendritic spine substructures during long-term potentiation. Neuron.
2014;82:444–59.
Bramham CR. Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin
Neurobiol. 2008;18:524–31.
Brockett AT, Kane GA, Monari PK, Briones BA, Vigneron P-A, Barber GA, Bermudez A,
Dieffenbach U, Kloth AD, Buschman TJ, Gould E. Evidence supporting a role for astrocytes
in the regulation of cognitive flexibility and neuronal oscillations through the Ca2+ binding
protein S100β. PLoS One. 2018;13(4):e0195726.
Broussard J. Co-transmission of dopamine and glutamate. J Gen Physiol. 2011;139:93–6.
Caroni P, Donato F, Muller D. Structural plasticity upon learning: regulation and functions. Nat Rev
Neurosci. 2012;13:478–90.
Chamberland S, Tóth K. Functionally heterogeneous synaptic vesicle pools support diverse syn-
aptic signalling. The Journal of Physiology 2016;594 (4):825–835.
Chen NH, Reith ME, Quick MW. Synaptic uptake and beyond: the sodium- and chloride-dependent
neurotransmitter transporter family SLC6. Pflugers Arch. 2004;447(5):519–31.
Chen X, Petit EI, Dobrenis K, Sze JY. Spatiotemporal SERT expression in cortical map develop-
ment. Neurochem Int. 2016;98:129–37.
Chia PH, Li P, Shen K. Cell biology in neuroscience: cellular and molecular mechanisms underlying
presynapse formation. J Cell Biol. 2013;203(1):11–22.
Chinta SJ, Andersen JK. Dopaminergic neurons. Int J Biochem Cell Biol. 2005;37(5):942–6.
Choquet D, Triller A. The dynamic synapse. Neuron. 2013;80(3):691–703.
Chuhma N, Mingote S, Moore H, Rayport S. Dopamine neurons control striatal cholinergic neurons
via regionally heterogeneous dopamine and glutamate signaling. Neuron. 2014;81:901–12.
Citri A, Malenka RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsy-
chopharmacology. 2008;33:18–41.
Dal Bo G, St-Gelais F, Danik M, Williams S, Cotton M, Trudeau LE. Dopamine neurons in culture
express VGLUT2 explaining their capacity to release glutamate at synapses in addition to
dopamine. J Neurochem. 2004;88:1398–405.
Dale GL, Friese P, Batar P, Hamilton SF, Reed GL, Jackson KW, Clemetson KJ, Alberio L.
Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the
cell surface. Nature. 2002;415:175–9.
Daws LC. Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for
antidepressant efficacy. Pharmacol Ther. 2009;121(1):89–99.
20 L. Hampel and T. Lau

De Pittà M, Brunel N, Volterra A. Astrocytes: orchestrating synaptic plasticity? Neuroscience.

2016;323:43–61.
Doyle M, Kiebler MA. Mechanisms of dendritic mRNA transport and its role in synaptic tagging.
EMBO J. 2011;30(17):3540–52.
Dresbach T, Qualmann B, Kessels MM, Garner CC, Gundelfinger ED. The presynaptic cytomatrix
of brain synapses. Cell Mol Life Sci. 2001;58(1):94–116.
Dugué GP, Dumoulin A, Triller A, Diedonné S. Target-dependent use of co-released inhibitory
transmitters at central synapses. J Neurosci. 2005;25:6490–8.
Farrelly LA, Robert E. Thompson, Shuai Zhao, Ashley E. Lepack, Yang Lyu, Natarajan V. Bhanu,
Baichao Zhang, Yong-Hwee E. Loh, Aarthi Ramakrishnan, Krishna C. Vadodaria, Kelly J.
Heard, Galina Erikson, Tomoyoshi Nakadai, Ryan M. Bastle, Bradley J. Lukasak, Henry
Zebroski, Natalia Alenina, Michael Bader, Olivier Berton, Robert G. Roeder, Henrik Molina,
Fred H. Gage, Li Shen, Benjamin A. Garcia, Haitao Li, Tom W. Muir, Ian Maze Histone
serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature
2019;567 (7749):535–539.
Fortin GM, Bourque MJ, Mendez JA, Leo D, Nordenankar K, Birgner C, Arvidsson E, Rymar VV,
Bérubé-Carrière N, Claveau AM, et al. Glutamate corelease promotes growth and survival of
midbrain dopamine neurons. J Neurosci. 2012;32:17477–91.
Fu L, Zhang L. Serotonylation: a novel histone H3 marker. Signal Transduct Target Ther. 2019;4:15.
Fuxe K, Agnati LF, Marcoli M, Borroto-Escuela DO. Volume transmission in central dopamine and
noradrenaline neurons and its astroglial targets. Neurochem Res. 2015;40(12):2600–14.
Govindarajan A, Israely I, Huang SY, Tonegawa S. The dendritic branch is the preferred integrative
unit for protein synthesis- dependent LTP. Neuron. 2011;69:132–46.
Graff J, Kim D, Dobbin MM, Tsai LH. Epigenetic regulation of gene expression in physiological
and pathological brain processes. Physiol Rev. 2011;91:603–49.
Granger AJ, Wallace ML, Sabatini BL. Multi-transmitter neurons in the mammalian central nervous
system. Curr Opin Neurobiol. 2017;45:85–91.
Grubb MS, Burrone J. Activity-dependent relocation of the axon initial segment fine-tunes neuronal
excitability. Nature. 2010;465(7301):1070–4.
Hamada MS, Goethals S, de Vries SI, Brette R, Kole MH. Covariation of axon initial segment
location and dendritic tree normalizes the somatic action potential. Proc Natl Acad Sci U S A.
2016;113(51):14841–6.
Hnasko TS, Edwards RH. Neurotransmitter corelease: mechanism and physiological role. Annu
Rev Physiol. 2012;74:225–43.
Hnasko TS, Chuhma N, Zhang H, Goh GY, Sulzer D, Palmiter RD, Rayport S, Edwards RH.
Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo.
Neuron. 2010;65:643–56.
Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends
Neurosci. 2010;33:67–75.
Hoerbelt P, Lindsley TA, Fleck MW. Dopamine directly modulates GABAA receptors. J Neurosci.
2015;35(8):3525–36.
Horwood JM, Dufour F, Laroche S, Davis S. Signalling mechanisms mediated by the phosphoi-
nositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat. Eur J Neurosci.
2006;23:3375–84.
Hsu WC, Nilsson CL, Laezza F. Role of the axonal initial segment in psychiatric disorders:
function, dysfunction, and intervention. Front Psych. 2014;5:109.
Hummerich R, Thumfart JO, Findeisen P, Bartsch D, Schloss P. Transglutaminase-mediated
transamidation of serotonin, dopamine and noradrenaline to fibronectin: evidence for a general
mechanism of monoaminylation. FEBS Lett. 2012;586:3421–8.
Hummerich R, Costina V, Findeisen P, Schloss P. Monoaminylation of fibrinogen and glia-derived
proteins: indication for similar mechanisms in posttranslational protein modification in blood
and brain. ACS Chem Neurosci. 2015;6:1130–6.
Neurobiological Principles: Neurotransmitters 21

Jamann N, Jordan M, Engelhardt M. Activity-dependent axonal plasticity in sensory systems.

Neuroscience. 2018;368:268–82.
Jan LY, Jan YN, Brownfield MS Peptidergic transmitters in synaptic boutons of sympathetic
ganglia. Nature 1980;288 (5789):380–382.
Jan YN, Jan LY, Kuffler SW. A peptide as a possible transmitter in sympathetic ganglia of the frog.
Proc Natl Acad Sci U S A. 1979;76:1501–5.
Johnson MD. Synaptic glutamate release by postnatal rat serotonergic neurons in microculture.
Neuron. 1994;12:433–42.
Jonas P, Bischofberger J, Sandkühler J. Corelease of two fast neurotransmitters at a central synapse.
Science. 1998;281:419–24.
Joyce MP, Rayport S. Mesoaccumbens dopamine neuron synapses reconstructed in vitro are
glutamatergic. Neuroscience. 2000;99:445–56.
Kavalali ET. The mechanisms and functions of spontaneous neurotransmitter release. Nat Rev
Neurosci. 2015 Jan;16(1):5–16.
Kawano M, Kawasaki A, Sakata-Haga H, Fukui Y, Kawano H, Nogami H, Hisano S. Particular
subpopulations of midbrain and hypothalamic dopamine neurons express vesicular glutamate
transporter 2 in the rat brain. J Comp Neurol. 2006;498:581–92.
Khirug S, Yamada J, Afzalov R, Voipio J, Khiroug L, Kaila K. GABAergic depolarization of the
axon initial segment in cortical principal neurons is caused by the Na-K-2Cl cotransporter
NKCC1. J Neurosci. 2008;28(18):4635–9.
Lai TS, Lin CJ, Greenberg CS. Role of tissue transglutaminase-2 (TG2)-mediated aminylation in
biological processes. Amino Acids. 2017;49:501–15.
Lazarevic V, Pothula S, Andres-Alonso M, Fejtova A. Molecular mechanisms driving homeostatic
plasticity of neurotransmitter release. Front Cell Neurosci. 2013;7:244.
Leterrier C. The axon initial segment: an updated viewpoint. J Neurosci. 2018;38(9):2135–45.
Lodish H, Berk A, Zipursky SL. Molecular cell biology: section 21.4. Neurotransmitters, synapses,
and impulse transmission. 4th ed. New York: W. H. Freeman; 2000.
Mendez JA, Bourque MJ, Dal Bo G, Bourdeau ML, Danik M, Williams S, Lacaille JC, Trudeau LE.
Developmental and target-dependent regulation of vesicular glutamate transporter expression by
dopamine neurons. J Neurosci. 2008;28:6309–18.
Mi Z, Si T, Kapadia K, Li Q, Muma NA. Receptor-stimulated transamidation induces activation
of Rac1 and Cdc42 and the regulation of dendritic spines. Neuropharmacology.
2017;117:93–105.
Muma NA, Mi Z. Serotonylation and transamidation of other monoamines. ACS Chem Neurosci.
2015;6(7):961–9.
Nanou E, Catterall WA. Calcium channels, synaptic plasticity, and neuropsychiatric disease.
Neuron. 2018;98(3):466–81.
Onoa B, Li H, Gagnon-Bartsch JA, Elias LA, Edwards RH. Vesicular monoamine and glutamate
transporters select distinct synaptic vesicle recycling pathways. J Neurosci. 2010;30:7917–27.
Pabst M, Braganza O, Dannenberg H, Hu W, Pothmann L, Rosen J, Mody I, van Loo K, Deisseroth
K, Becker AJ, Schoch S, Beck H. Astrocyte intermediaries of septal cholinergic modulation in
the hippocampus. Neuron. 2016;90:853–65.
Petersen AV, et al. Plasticity of the axon initial segment: fast and slow processes with multiple
functional roles. Neuroscientist. 2017;23(4):364–73.
Pfeiffer BE, Huber KM. Current advances in local protein synthesis and synaptic plasticity. J
Neurosci. 2006;26:7147–50.
Pirttimaki TM, Sims RE, Saunders G, Antonio SA, Codadu NK, Parri HR. Astrocyte-mediated
neuronal synchronization properties revealed by false gliotransmitter release. J Neurosci.
2017;37:9859–70.
Plenz D, Kitai ST. Up and down states in striatal medium spiny neurons simultaneously recorded
with spontaneous activity in fast-spiking interneurons studied in cortex-striatum-substantia
nigra organotypic cultures. J Neurosci. 1998;18(1):266–83.
22 L. Hampel and T. Lau

Pozo K, Goda Y. Unraveling mechanisms of homeostatic synaptic plasticity. Neuron. 2010;66

(3):337–51.
Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd ed. Sunderland: Sinauer
Associates; 2001. Increased Conduction Velocity as a Result of Myelination.
Quentin E, Belmer A, Maroteaux L. Somato-dendritic regulation of raphe serotonin neurons; a key
to antidepressant action. Front Neurosci. 2018;12:982.
Reymann KG, Frey JU. The late maintenance of hippocampal LTP: requirements, phases, ‘synaptic
tagging’, ‘late-associativity’ and implications. Neuropharmacology. 2007;52:24–40.
Russo AF. Overview of neuropeptides: awakening the senses? Headache. 2017;57(Suppl 2):37–46.
Sarkar NK, Clarke DD, Waelsch H. An enzymically catalyzed incorporation of amines into pro-
teins. Biochim Biophys Acta. 1957;25:451–2.
Seal RP, Edwards RH. Functional implications of neurotransmitter co-release: glutamate and
GABA share the load. Curr Opin Pharmacol. 2006;6:114–9.
Sossin WS. Isoform specificity of protein kinase Cs in synaptic plasticity. Learn Mem.
2007;14:236–46.
Strata P, Harvey R. Dale’s principle. Brain Res Bull. 1999;50(5–6):349–50.
Stuber GD, Hnasko TS, Britt JP, Edwards RH, Bonci A. Dopaminergic terminals in the nucleus
accumbens but not the dorsal striatum corelease glutamate. J Neurosci. 2010;30:8229–33.
Südhof TC. The presynaptic active zone. Neuron. 2012;75(1):11–25.
Sulzer D, Joyce MP, Lin L, Geldwert D, Haber SN, Hattori T, Rayport S. Dopamine neurons make
glutamatergic synapses in vitro. J Neurosci. 1998;18:4588–602.
Sutton MA. Homeostatic plasticity: single hippocampal neurons see the light. Neuron. 2010;68
(3):326–8.
Sutton MA, Schuman EM. Partitioning the synaptic landscape: distinct microdomains for sponta-
neous and spike-triggered neurotransmission. Sci Signal. 2009;2(65):pe19.
Svensson E, Apergis-Schoute J, Burnstock G, Nusbaum MP, Parker D, Schiöth HB. General
principles of neuronal co-transmission: insights from multiple model systems. Front Neural
Circuits. 2019;12:117.
Sweatt JD. Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin
Neurobiol. 2004;14:311–7.
Taber KH, Hurley RA. Volume transmission in the brain: beyond the synapse. J Neuropsychiatry
Clin Neurosci. 2014;26(1):iv, 1–4.
Tecuapetla F, Patel JC, Xenias H, English D, Tadros I, Shah F, Berlin J, Deisseroth K, Rice ME,
Tepper JM, et al. Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus
accumbens. J Neurosci. 2010;30:7105–10.
Tritsch NX, Ding JB, Sabatini BL. Dopaminergic neurons inhibit striatal output through non-
canonical release of GABA. Nature. 2012;490:262–6.
Tritsch NX, Oh W-J, Gu C, Sabatini BL. Midbrain dopamine neurons sustain inhibitory transmis-
sion using plasma membrane uptake of GABA, not synthesis. Elife. 2014;3:e01936.
Vaaga CE, Borisovska M, Westbrook GL. Dual-transmitter neurons: functional implications of co-
release and co-transmission. Curr Opin Neurobiol. 2014;29:25–32.
van den Pol AN. Neuropeptide transmission in brain circuits. Neuron. 2012;76(1):98–115.
Vizi ES, Kiss JP, Lendvai B. Nonsynaptic communication in the central nervous system.
Neurochem Int. 2004;45(4):443–51.
Volman V, Gerkin RC. Synaptic scaling stabilizes persistent activity driven by asynchronous
neurotransmitter release. Neural Comput. 2011;23(4):927–57.
Walther DJ, Peter JU, Winter S, Höltje M, Paulmann N, Grohmann M, Vowinckel J, Alamo-
Bethencourt V, Wilhelm CS, Ahnert-Hilger G, Bader M. Serotonylation of small GTPases is a
signal transduction pathway that triggers platelet α-granule release. Cell. 2003;115:851–62.
Walther DJ, Stahlberg S, Vowinkel J. Novel roles for biogenic monoamines: from monoamines in
transglutaminase-mediated post-translational protein modifications to monoaminylation dereg-
ulation diseases. FEBS J. 2011;278:470–4755.
Neurobiological Principles: Neurotransmitters 23

Wang Y, Wang M, Yin S, Jang R, Wang J, Xue Z, Xu T. NeuroPep: a comprehensive resource of

neuropeptides. Database (Oxford). 2015;2015:bav038. https://doi.org/10.1093/database/bav038
Wefelmeyer W, Cattaert D, Burrone J. Activity-dependent mismatch between axo-axonic synapses
and the axon initial segment controls neuronal output. Proc Natl Acad Sci U S A. 2015;112
(31):9757–62.
Wojcik SM, Katsurabayashi S, Guillemin I, Friauf E, Rosenmund C, Brose N, Rhee JS. A shared
vesicular carrier allows synaptic corelease of GABA and glycine. Neuron. 2006;50(4):575–87.
Yamada R, Kuba H. Structural and functional plasticity at the axon initial segment. Front Cell
Neurosci. 2016;10:250. eCollection 2016.
Zhang S, Qi J, Li X, Wang H-L, Britt JP, Hoffman AF, Bonci A, Lupica CR, Morales M.
Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons.
Nat Neurosci. 2015;18:386–92.
Neurobiological Principles: Psycho-Neuro-
Immuno-Endocrinology

Norbert Müller

Contents
Immunological Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Immunological Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Definition of Psycho-neuro-immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Methodological Aspects of Psycho-neuro-immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Interaction Between the Immune, Endocrine, and Central Nervous Systems . . . . . . . . . . . . . . . . . . . 29
The Cytokine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Stimulation of Cells in the CNS by Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Cytokine Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Kindling and Sensitization of the Immune Response: The Basis for a Stress-Induced
Inflammatory Immune Response in Mental Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Interaction of Cytokines and Neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Interleukin-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Interleukin-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Interleukin-6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
TNF-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Blood-Brain Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Immune Genetics, the HLA System, and Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Cellular Immune System and Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Lymphocyte Population and Cytokine Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Tryptophan-Kynurenine Metabolism in Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
The Role of the Immune System in Cognition and Cognitive Disorders . . . . . . . . . . . . . . . . . . . . . . . 38
Mental Disorders and Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Treatment with Interferon-α and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Schizophrenia and the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Disturbances of Neurotransmitters as a Result of Pre- or Postnatal Infections . . . . . . . . . . . . . . 40

N. Müller (*)
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität Munich,
Munich, Germany
e-mail: norbert.mueller@med.uni-muenchen.de

© Springer Nature Switzerland AG 2022 25

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_2
26 N. Müller

Lymphocyte Status in Schizophrenic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Cytokines and Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
CSF Diagnostic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Stimulation of Catecholamine Neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Anti-inflammatory Substances as a Therapeutic Approach in Schizophrenia . . . . . . . . . . . . . . . . . . 44
Anti-inflammatory Treatment in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Other Immune-Related Substances in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Depression and the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Interleukin-6 and Depressive Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Major Depression and Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Cellular Immune System and Depressive Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Anti-inflammatory Treatment of Depressive Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Cyclooxygenase-2 (COX-2) Inhibition as an Example for an Anti-inflammatory
Therapeutic Approach in Major Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Methodological Issues Regarding Anti-inflammatory Treatment in Major Depression . . . . . 50
Anti-inflammatory Compounds Other than NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Anti-IL-6 Complex as a Therapeutic Target in Major Depression . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Other Immune-Related Substances in the Treatment of Major Depression . . . . . . . . . . . . . . . . . 52
Immunological Effects of Psychopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Abstract
Mental disorders have a complex pathophysiology that remains only partially
understood. In addition to changes in neurotransmitter systems and receptors –
the effector systems that act on downstream signal transduction processes – there
is increasing evidence that immunological mechanisms play an important role in
the pathophysiology of mental disorders. In recent decades, psycho-neuro-
immuno-endocrinology, which is concerned with the relationships between men-
tal functions, psychiatric disorders, the immune system, and endocrine mecha-
nisms, has become an important topic in psychiatry. Meanwhile, initial attempts
have been made to make use of such psycho-neuro-immunological mechanisms
as novel treatment strategies.

Immunological Principles

The first barrier of the immune system is monocytes which, when activated, differ-
entiate into macrophages; macrophages phagocytize foreign antigens and present
antigens on the cell surface. Monocytes are part of the non-specific, or innate,
immune system, which activates the specific immune response via the adaptive
immune system. Natural killer (NK) cells, a type of lymphocyte, are also part of
the innate immune system and play a major role in killing tumor cells and cells
infected with viruses.
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 27

Other lymphocytes, the B and T cells, are also crucial for the immune response.
B cells develop in the bone marrow, whereas T lymphocyte maturation and imprint-
ing take place in the thymic cortex. Both B and T cells then migrate to the other
lymphatic organs (tonsils, lymph follicles, lymph nodes, and spleen).
In an immune response, some T cells are directly involved in cytolytic cell-cell
interactions, such as in transplant rejection or graft-versus-host reactions after bone
marrow transplants. T lymphocytes are therefore referred to as facilitators of cell-
mediated immunity. They are activated when the respective specific antigen is
presented on the surface of an “accessory” cell, a so-called antigen-presenting cell
(e.g., macrophages or certain types of lymphocytes), together with a histocompati-
bility antigen (human leukocyte antigen, HLA); T-cell activation and proliferation
also require a non-antigen-specific signal from the accessory cell.
The HLA system helps differentiate between self and nonself, an essential
function of the immune system. Immune system function is critically dependent
on the HLA system in that, after antigens have been processed inside the cell, the
HLA system determines which specific parts (peptides) of them are presented to the
T lymphocytes. This system comprises about one thousandth of the human genome
and contains a number of tightly linked loci on the short arm of chromosome 6. A
number of genetic diseases of the nervous system, e.g., multiple sclerosis (MS) and
narcolepsy, are associated with HLA genes. Natural killer cells (NK cells) kill cells
non-specifically and are not restricted by the HLA system.
Antigen-presenting cells release activating cytokines, a group of proteins that
activate B lymphocytes (CD19+) and T lymphocytes. B lymphocytes differentiate
into plasma cells that produce antibodies. The cells of the immune system are defined
by their surface marker molecules and the pattern of cytokines they secrete. Thus, CD3
is a marker for the total number of T lymphocytes. T lymphocytes can be divided into
several, functionally different subpopulations that can be defined with the help of
monoclonal antibodies. The most important subpopulations are the T helper/inducer
cells (CD4+), which induce an immune response, and the cytotoxic T cells/T suppres-
sor cells (CD8+), which regulate an organism’s immune response and also have
cytotoxic effects and lyse cells. CD14+ is a surface marker for monocytes and
macrophages, CD16+/56+ for NK cells, and CD5+/ CD19+ for B lymphocytes. NK
cells are primarily activated by interferon-(INF-)γ. The function of CD4+ and CD8+
cells, which in turn are activated by CD3+ T lymphocytes, is usually balanced.
The T helper 1 (TH-1) system, which initiates the rapid immune response and
consists primarily of elements of the cellular immune system, becomes active in acute
inflammation. Characteristic cytokines of this system are INF-γ, interleukin-(IL-)2,
and IL-12. Because not only T helper cells (CD4+ cells) but also monocytes/macro-
phages and other cell types produce these cytokines, this type of immune response is
called the type 1 immune response. The T helper 2 (TH-2) system or type 2 immune
response is the humoral arm of the immune system and is activated in chronic
inflammatory processes and also in allergic reactions. T helper 2 cells (TH-2) or
type 2 monocytes/macrophages (M2) produce mainly IL-4, IL-10, and IL-13. The
differentiation to T helper 1 and T helper 2 lymphocytes (which is also defined by their
pattern of cytokine release) appears to be relevant in chronic inflammatory diseases.
28 N. Müller

(Monocytic) pro-inflammatory cytokines, such as tumor necrosis factor-(TNF-)α,

IL-1, and IL-6, are released primarily by monocytes/macrophages. TNF-α mainly
activates the type 1 immune response, whereas IL-6 activates the type 2 immune
response and promotes antibody production by B cells. The activation of the
monocyte/macrophage system is usually followed by the specific activation of the
TH-1 or TH-2 system. The type 1 and type 2 immune responses are normally
functionally balanced.

Immunological Memory

The immune system is the only human system besides the central nervous system
(CNS) that has a memory. The T memory cells (CD45+) are responsible for this
function in that they “remember” a specific antigen and initiate a strong specific
immune response if re-exposed to it.
One of the historical starting points for psycho-neuro-immunology was an
immune conditioning in animals: In mice and rats, immune suppression mediated
by cyclophosphamide (unconditioned stimulus) can be conditioned by simultaneous
administration of saccharin (conditioned stimulus) (Ader and Felten 1991). The
conditioned immune response is now well elaborated in different animal models
and is an interesting approach for treatment in humans. T memory cells and other
molecules of the immunological memory may be involved in this therapeutic
approach, but so far results in humans are not convincing.

Definition of Psycho-neuro-immunology

The field of psycho-neuro-immunology has developed rapidly in recent years.

Psycho-neuro-immunology is the study of the influence of the nervous system on
the immune system and vice versa and the associated effects on people’s behavior
and state of health. Work in this field involves a range of research fields, including
in vitro studies on tissue and lymphocytes; studies on the influence of stress, stress
processing, and personality traits on immune system function; the role of psychiatric
factors in infectious diseases and tumors, including the effects of psychotherapeutic
interventions; and behavioral medicine and animal studies, e.g., the conditioning of
an immune response.

Methodological Aspects of Psycho-neuro-immunology

Studies of the human immune system are known to have a range of methodolog-
ical problems because different components of the immune system are influenced
by variables that are difficult to control in human studies, including sleep, alcohol
and drug consumption, medicines, eating habits, daily rhythms, stress, smoking,
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 29

physical activity, infections, tumors, etc. Clinical illness factors, such as acute-
ness, course, severity, and psychopathology, also appear to influence the immune
system. These examples show that the immune system is very sensitive to various
influences; on the other hand, however, thanks to its high complexity and
variability, it is able to functionally overcome many influences and maintain a
functional homeostasis.

Interaction Between the Immune, Endocrine, and Central Nervous

Systems

In recent years, numerous interactions have been described between the immune
system and the CNS. There are two main reasons for the great interest in research in
this field:

– Influences of the CNS (including the neuroendocrine system), such as mental

processes and psychopathological abnormalities, modulate the vulnerability for
somatic illnesses, e.g., infections, via effects on the activity of the immune
system.
– (Direct or indirect) impairments in the immune system probably predispose to the
development of mental disorders, including psychoses, depressive syndromes,
and neurodegenerative disorders.

The hypothesis that immune processes are involved in the pathogenesis of

mental disorders has been discussed for a long time. It was first proposed on the
basis of findings of immune abnormalities. These were particularly pronounced
in catatonic schizophrenia and had been identified by various researchers in the
blood and cerebrospinal fluid (CSF) of patients with schizophrenia long before
the era of antipsychotics (Bruce and Peebles 1903; Dameshek 1930; Lehmann-
Facius 1939). In the 1950s, in patients with schizophrenia, serum components
were described that showed autoaggressive behavior toward brain tissue. Knight
(1982) tried to reconcile the key role of the dopamine system with the autoim-
mune hypothesis of schizophrenia by postulating that autoantibodies that stimu-
lated the dopamine receptor were involved in the pathogenesis of schizophrenic
disorders.
Modern methods now allow researchers to assess the various subgroups of the
cellular immune system separately from the components of the humoral immune
system, such as cytokines, antibodies, acute phase proteins (APPs), etc., so that they
can describe the functional relationship of the immune parameters and their effects
on immune pathology.
Much is now also known about the interaction of the CNS and immune system
with the endocrine system. For example, cytokines are known to communicate with
receptors expressed in the CNS and influence various functions, e.g., IL-1 stimulates
the release of adrenocorticotropic hormone (ACTH) and induces sleep. Glucocorti-
coids inhibit cytokine production and suppress the immune response in vivo.
30 N. Müller

Androgens have also been shown to suppress the immune response, whereas
thyroxin, growth hormone (GH) and insulin stimulate it. At higher doses, estrogens
suppress the cellular immune response, but lower doses have a stimulatory effect.
The higher rate of autoimmune diseases such as scleroderma, rheumatoid arthritis,
and systemic lupus erythematosus in women indicates a possible involvement of sex
hormones in immune dysregulation.
Not only is the immune system influenced by the endocrine system, but it can also
regulate the endocrine system and peripheral immune processes impact the CNS in
the form of afferent effects. Thus, in experimental animals, the maximum antibody
production after an antigen injection is accompanied by a two- to threefold increase
in the blood concentration of glucocorticoids, and an immunosuppressive effect is
achieved; at the same time, the firing rate of hypothalamic nuclei reaches its
maximum (Besedovsky et al. 1986). On the basis of these findings, the immune
modulatory effect of cortisol is hypothesized to be one of the most important
physiological effects of this hormone.
On the other hand, findings indicate that an overstimulation of the hypothalamic-
pituitary-adrenal (HPA) axis through release of cytokines that stimulate corticotro-
phin-releasing factor (CRF) results in immune suppression, seen, for example, in
decreased effectiveness of hepatitis or influenza vaccinations (Pennisi 1997). Fur-
thermore, lymphocytes of the peripheral immune system were found to produce
hormones, i.e., ACTH, β-endorphins, thyroid-stimulating hormone (TSH), GH, and
prolactin. The immune system thus seems to also take over some functions of the
endocrine system.
Peptide signals of the immune and endocrine systems appear to have some joint
functions, and functions and signals of both systems appear to have many
similarities.

The Cytokine System

Cytokines convey information between cells of the peripheral immune system and
the CNS. In part, they are actively transported across the blood-brain barrier, but they
are also formed in the CNS by activated astrocytes and microglia. IL-1, IL-2, IL-6,
and TNF-α are the most important activating cytokines and have a variety of known
functions in the CNS. Findings from recent years show that the effects of cytokines
are also relevant for mental illnesses.
Cytokines in the CNS are involved in various regulatory mechanisms, including
the following:

– Initiation of an immune process in the CNS in inflammatory diseases

– Regulation of the blood-brain barrier
– Regulation of the hormones of the HPA axis
– Different stimulatory and inhibitory effects on dopaminergic, serotonergic, nor-
adrenergic, and cholinergic neurotransmission
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 31

Stimulation of Cells in the CNS by Cytokines

CNS cells can be activated by cytokines in various ways: First, at least some
cytokines, e.g., IL-1, IL-2, IL-6, and TNF-α, are transported from the blood into
the CNS by active transport mechanisms; second, glia cells secrete cytokines after
being activated by antigen stimuli; and, last, cytokine secretion in the CNS can be
triggered by neurotransmitters. For example, noradrenalin was shown to stimulate
IL-6 production in astrocytes in a dose-dependent way (Norris and Benveniste
1993). Because IL-6 is closely functionally related to other cytokines, such as
IL-1, IL-2, and TNF-α, this finding indicates that the cytokine cascade can possibly
also be stimulated by neurotransmitters. This may represent an important link
between (auto)immune disorders, susceptibility to infections, state of health, and
mental disorders.
Furthermore, cytokines of course also pass through a disturbed blood-brain
barrier into the CNS.

Cytokine Production

Once activated, both astrocytes and microglia can produce and secrete cytokines.
Interestingly, the ways in which these cell types are stimulated to produce cyto-
kines and the pattern of cytokine release differ, suggesting that they have different
functions in the CNS immune response. Astrocytes, which are closely associated
with neuronal synapses, store neurotransmitters and release them when needed.
Astrocyte dysfunction, e.g., as a result of activation by cytokines, can thus easily
affect neurotransmitter balance. Microglia are stimulated by viruses to produce
cytokines, which – together with the expression of cellular surface structures –
initiates an immune reaction in the CNS in case of viral infections (Lieberman
et al. 1989).

Mode of Action

The fact that neurons have cytokine receptors suggests that cytokines have a direct
effect on neuronal functions. Neurons containing IL-1 are found in various regions
of the CNS, including the hypothalamus and hippocampus. IL-2-receptor mRNA
(the genetic information of the IL-2 receptor) has been demonstrated in neurons,
suggesting that IL-2 also has direct effects on neurons. Furthermore, in animal
studies stimuli were shown to be conducted from IL-1, i.e., from the immune
system, via the vagus nerve to critical regions in the CNS without IL-1 itself
entering the CNS. Thus, the vagus nerve is clearly a link between the immune
system and the CNS.
Physiological development of the CNS can also be significantly impaired by an
over- or underproduction of cytokines (Merrill 1992) because cytokines also func-
tion as growth factors in the CNS. This may represent a link between pre- or
32 N. Müller

perinatal damage, e.g., through birth trauma or a prenatal virus infection, and a
disturbance of brain maturation, as is postulated in schizophrenic disorders.

Kindling and Sensitization of the Immune Response: The Basis

for a Stress-Induced Inflammatory Immune Response in Mental
Illness

The immune response and the release of cytokines in response to immune-activating

stimuli can be sensitized by a kindling process. First, exposure to a new, immune-
activating stimulus produces an immune response, i.e., the release of cytokines and
other mediators of immune activation. Thereafter, re-exposure to the same stimulus,
whether, for example, through stress or infection, leads either to an increased release
of cytokines or to the same activation process in response to a weaker stimulus. This
“sensitization” or “kindling” phenomenon is probably based on the memory function
of the immune system (Furukawa et al. 1998; Sparkman and Johnson 2008). For
example, studies showed that the stress-related release of IL-6 reactivated condi-
tioned (prenatal) processes (Zhou et al. 1993). In healthy individuals, a second
stimulus (e.g., systemic inflammation or stress) caused an immune activation in
the form of cellular proliferation and increased formation and release of
pro-inflammatory cytokines (Frank et al. 2007). This is a key mechanism for
triggering an immune activation and inflammation; it is probably also behind
stress-induced immune activation, which then results in psychopathological symp-
toms. The assumption of a sensitization process in the immune system could also
explain the hypothesis that after an infection in early childhood, a reinfection or other
stimulation of the immune system in later life is accompanied by an increased release
of these sensitized cytokines, which ultimately results in neurotransmitter disorders
(e.g., in the context of the two-hit hypothesis) (Müller 2013).
Sensitization phenomena play a role in stress-related, cytokine-induced, and
neurotransmitter-mediated behavior, i.e., the cytokine response to a stimulus
increases and the intensity of the associated stimulus decreases (Sparkman and
Johnson 2008). In basic research experiments in animal models, cytokines elicited
stronger neurotransmitter responses when the study animals were re-exposed to
these cytokines, e.g., TNF-α (Hayley et al. 2002). In the CNS, the stress-induced
activation and proliferation of microglia mediate these cytokine effects (Nair and
Bonneau 2006).

Interaction of Cytokines and Neurotransmitters

The effects of cytokines on neurotransmitters of the catecholamine system are

probably of particular importance in psychiatric disorders. However, systematic
studies of the effects of chronic versus acute administration of cytokines, which
are highly relevant for questions related to psychiatric disorders, are still lacking for
most cytokines (Table 1).
Table 1 Presumed function, localization, biological effects, and relevance of some cytokines in the CNS
Localization of Influence
Function in the receptors in the Production Neurotransmitter on mental
Function in the peripheral immune system CNS CNS in the CNS effects functions
IL-1 Pleiotropic activation; proliferation of T and Stimulation of Hippocampus; Astrocytes; Serotonin, dopamine, Sleep,
B cells, cytolytic activity of natural killer the HPA axis; hypothalamus; microglia noradrenaline; drive,
cells fever, sleep brain stem neuroendocrine stress,
stimulation malaise
IL-2 Activation of T, T helper, natural killer, and Barrier Pyramidal cells of Astrocytes; Dopamine; Memory,
B cells and cytokine production, e.g., IL-6 in disturbances; the hippocampus; microglia noradrenaline; cognition
helper cells dopamine locus coeruleus acetylcholine
metabolism
IL-6 Mediator of inflammation, B-cell Barrier Hippocampus; Astrocytes; Noradrenaline; Stress?
stimulation, synthesis of antibodies and disturbances; prefrontal cortex microglia serotonin; dopamine
acute-phase proteins; synergism with IL-1 intrathecal IgG
production
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology

TNF-α Endogenous pyrogens; release of IL-1, Cytotoxic; Ubiquitous? Astrocytes; Acute: catecholamines Cognition?
activation of macrophages, cytotoxicity demyelination; microglia
fever
33
34 N. Müller

Interleukin-1

IL-1 stimulates catecholamine release both outside and within the CNS, particularly
in the brain stem and hypothalamus. Increased levels of noradrenaline and serotonin
and their metabolites were found in these regions after both intraventricular and
peripheral administration of IL-1 (Zalcman et al. 1994).

Interleukin-2

Studies have shown that stimulation of dopaminergic neurotransmission is an

important neuromodulatory effect of IL-2. IL-2 stimulates dopamine release
in vitro (Lapchak 1992). Because this happens at physiological concentrations of
IL-2, IL-2 is postulated to have an important physiological role in dopamine
metabolism in the CNS (Alonso et al. 1993). In animal experiments, peripheral
administration of IL-2 increased noradrenaline metabolism in the hippocampus and
dopamine metabolism in the prefrontal cortex (Zalcman et al. 1994).
The density of IL-2 receptors in the pyramidal cells of the hippocampus is
particularly high, indicating that IL-2 is probably involved in the regulation of
neurotransmission in the pyramidal tract of the hippocampus (Plata-Salaman
1991). In animal studies, IL-2 was shown to selectively inhibit acetylcholine
release in the hippocampus and frontal cortex (Araujo et al. 1989). In line with
this finding, in animal studies longer administration of IL-2 led to a decrease in
neurons, degenerative changes in the hippocampus, and a marked impairment
of memory function (Nemni et al. 1992). The stimulation of dopamine and
inhibition of acetylcholine seem to be two important effects of IL-2 in
the CNS.
So far, a regulatory role of cytokines in memory function has received little
attention. The involvement of IL-2 in the regulation of striatal dopaminergic func-
tions could explain the motor effects (on posture) that have been described for IL-2.
Furthermore, a sedative effect of IL-2 has been reported. These effects of IL-2 are
probably mediated through the locus coeruleus and caudate nucleus (Nistico and De
Sarro 1991).

Interleukin-6

In vitro, IL-6 can stimulate neurons to secrete dopamine and possibly also other
catecholamines. In animal experiments, the peripheral administration of IL-6
increases dopamine and serotonin turnover in the hippocampus and frontal cortex,
without affecting noradrenaline metabolism (Zalcman et al. 1994). Conversely,
noradrenaline can stimulate IL-6 production in activated astrocytes (Norris and
Benveniste 1993).
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 35

TNF-a

TNF-α also affects the neurotransmitter balance, whereby these effects appear to
depend on the duration of administration of TNF-α: Whereas acute administration of
TNF-α was found to stimulate the catecholamine system via mechanisms in the
CNS, chronic administration diminished catecholamine secretion (Soliven and
Albert 1992). TNF-α is proposed to play a key role in dementia and also in the
cognitive impairments associated with HIV.

Blood-Brain Barrier

About 20–30% of psychiatric patients show “unspecific” abnormalities in the

CSF, e.g., indicating disturbances of the blood-brain barrier. Studies on
patients with schizophrenia at the Department of Psychiatry of the University
Hospital Munich found that the blood-brain barrier was disturbed in 27% of
patients and that IgG was produced intrathecally in 15% (Muller and
Ackenheil 1995b). However, the amount of IgG in the CSF did not correlate
significantly with psychopathology, in particular negative symptoms.
Increased levels of immunoglobulins and disturbances of the blood-brain
barrier are part of an immune process, probably a mild inflammatory
process. Much more severe disturbances of the blood-brain barrier are seen in
acute, fulminant inflammatory processes, e.g., bacterial or viral meningitis or
encephalitis. The signs of a mild inflammatory process in a range of mental
disorders prompted Bechter to formulate the “mild encephalitis hypothesis”
(Müller and Bechter 2013). The significant correlation between psychopathology
and IgG levels indicates close links between the immune process and the disease
process.
A disturbance of the blood-brain barrier is associated with activation of astro-
cytes, which almost completely surround the capillary endothelial cells that make up
the blood-brain barrier and modulate the barrier via effects on these cells (Benveniste
1992). A disturbance presumably in turn leads to secondary activation of the
cytokinin cascade in the CNS. The physiological purpose of this process is to deal
with antigens in the CNS. For example, the course of infections with herpes viruses
that cannot activate glial cells is considerably more unfavorable than that of infec-
tions with herpes viruses in which astrocytes are involved in the immune response
(Lewandowski et al. 1994).
As a result of the bidirectional relationship between the CNS and peripheral
immune system, after the blood-brain barrier is opened, a process that is initially
limited to the CNS can activate both the peripheral immune system and counter-
regulatory processes and thus ultimately control an inflammatory process in
the CNS.
36 N. Müller

Immune Genetics, the HLA System, and Schizophrenia

Genetic data from multiple, large patient cohorts found the most evidence for suscep-
tibility genes for schizophrenia on chromosome 6p22.1 (Muller et al. 2012a, b; Muller
and Schwarz 2010). This region includes various interesting genes relevant for
immune functions. The strongest evidence for an association was found in or near a
cluster of histone protein genes, which are important because of their role in regulating
DNA transcription or repair, i.e., for epigenetics (Purcell et al. 2009), or their direct
role in microbe defense (Shi et al. 2009). Furthermore, various genes of the HLA
complex are located in this region. HLA genes regulate immune function and have
been discussed as being involved in the pathophysiology of schizophrenia (Stefansson
et al. 2009). A meta-analysis showed the by far most significant association with
schizophrenia risk in this region (Schizophrenia Working Group of the Psychiatric
Genomics 2014).
Since the mid-1970s, numerous studies have evaluated the association between
HLA class I antigens (HLA-A, HLA-B, HLA-C) and schizophrenia. The results are
inconsistent, however, and a range of described associations could not be replicated.
On the other hand, several methodological factors may explain the discrepancies in
the results, e.g., ethnic and local differences, influences on “linkage disequilibrium,”
diagnostic criteria, and small sample sizes.
In various autoimmune diseases, clearer associations have been found with the
HLA class II system (HLA-DR, HLA-DQ, HLA-DP) than with the class I system.
Only a few studies have considered the class II system in schizophrenia, however.
Both a German study and a small American study found a slight increase in
HLA-DQB1 0602. This finding is particularly interesting because HLA-DQB1
0602 is also associated with narcolepsy and MS and thus may be a joint vulnera-
bility gene for several CNS diseases (Grosskopf et al. 1998).

Cellular Immune System and Mental Disorders

After the development of modern immunological methods, researchers first focused

on cellular immunology. Analyses of the cellular immune system in mental disorders
assumed that changes in the CNS are reflected in the composition of various
functional groups of lymphocytes in the blood. Psycho-neuro-immunological
research is based on neurological CNS diseases, e.g., MS, in which changes in the
composition of lymphocyte populations are found in blood.
These days, one assumes that to maintain a healthy homeostasis, certain lympho-
cyte populations permanently “patrol” the CNS and that there is a limited but
constant exchange of lymphocytes between the CNS and the blood. Signals from
CNS cells, which are probably a result of antigen presentation, e.g., by microglial
cells, and the subsequent recognition of the antigen by lymphocytes, result in an
invasion combined with the rapid proliferation of certain cell clones that are prob-
ably transported via peripheral blood. This process is associated with increased
permeability of the blood-brain barrier, whereby adhesion molecules appear to
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 37

play a key role (Hampel et al. 1996). Studies have found indications of an opening of
the blood-brain barrier in schizophrenia, depression, and dementia (Hampel et al.
1999; Muller 2019; Muller and Ackenheil 1995b; Schwarz et al. 1998).

Lymphocyte Population and Cytokine Production

Cytokine production differs between the various functional groups of lymphocytes.

Modern immunological methods, including the analysis of a few CSF cells, allow
conclusions to be made about changes in cytokine production or the composition of
the lymphocyte population. Besides NK cells, most studies in psychiatric patients
have investigated overall T lymphocytes (CD3+), T helper/inducer cells (CD4+), and
T suppressor cells/cytotoxic T cells (CD8+). This topic is discussed in greater detail
in the section on schizophrenia below.

Tryptophan-Kynurenine Metabolism in Mental Disorders

Tryptophan-kynurenine metabolism is one of the mechanisms involved in the

interaction between the immune system and neurotransmitter systems (see Fig. 1).
Activation of one of the enzymes of this metabolic pathway, indoleamine-2,3-
dioxygenase (IDO), catalyzes the production of kynurenic acid (KYNA). IDO is
activated by pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, and
inhibited by anti-inflammatory cytokines, such as IL-10 (Bohar et al. 2015; Boros
et al. 2018; Vecsei et al. 2013).

COX-2 inhibition
Tryptophan
+ IDO - Type 2
Type 1
TDO Present in astrocytes
Kynurenic Kynurenine (KYN)
acid (KYNA) Not present
(NMDA receptor antagonist) Type 1 + - Type 2 in astrocytes
KMO

3-hydroxykynurenine (3-
HK)

Quinolinic acid (QUIN)

Fig. 1 Metabolism pathways from tryptophan/kynurenine to kynurenic acid and quinolinic acid.
IDO, indoleamine-2,3-dioxygenase; KMO, kynurenine 3-monooxygenase; TDO, tryptophan-2,3-
dioxygenase
38 N. Müller

Astrocytes play a key role in the production of KYNA in the CNS and are its main
source (Maes et al. 1997). Kynurenine (KYN) is predominantly metabolized in
macrophages and microglia, but also in astrocytes. Kynurenine 3-monooxygenase
(KMO; also referred to as kynurenine hydroxylase, among other names) is an
important enzyme in kynurenine metabolism that is not found in human astrocytes
(Muller et al. 1999). Consequently, astrocytes are unable to produce
3-hydroxykynurenine (3-HK) or quinolinic acid (QUIN), although they can produce
larger amounts of the earlier metabolites, such as KYN and KYNA (Muller et al.
1999). This finding is in line with the observation in animal models that inhibition of
KMO results in an increase in KYNA production in the CNS (Pollmacher et al.
2001). The complete metabolism of KNY to QUIN is mainly observed in microglia,
whereas only small amounts of QUIN are synthesized in astrocytes via a side arm of
kynurenine metabolism. Because of the lack of KMO, increased tryptophan metab-
olism to KYN can result in an accumulation of KYNA in astrocytes. Monocytic cells
that infiltrate the CNS are a second key in the metabolism of 3-HK in that they help
astrocytes in the metabolization of 3-HK to QUIN (Muller et al. 1999).
Thus, depending on the immune status, there is a preponderance either of the N-
methyl-D-aspartate (NMDA) antagonist KYNA or the NMDA agonist QUIN.
Because KYNA interferes with glutamatergic metabolism, a pro-inflammatory
immune status could explain the glutamatergic hyperfunction that has been fre-
quently described in schizophrenia. In contrast, a lack of glutamatergic neurotrans-
mission is discussed in depressive disorders (Plangar et al. 2012), which may be the
result of a preponderance of QUIN. KYNA is also an antagonist at the α7 nicotine
receptor, which is highly relevant for cognitive function; antagonism at this receptor
is associated with cognitive impairment.
QUIN and 3-HK also have neurotoxic effects, whereas KYNA has
neuroprotective properties. Because tryptophan is the starting point for the produc-
tion of serotonin and is also involved in melatonin metabolism, changes in trypto-
phan metabolism affect not only glutamatergic but also serotonergic and melatonin
metabolism. Thus, tryptophan/KYN metabolism is an important link with regard to
changes in the immune system and their effects on neurotransmitters that play a
major role in mental disorders.

The Role of the Immune System in Cognition and Cognitive

Disorders

A study that evaluated the association between the T-cell immune system and
cognitive ability in animals provided a clear indication that the immune system is
closely involved in cognitive processes. Mice with a severe combined immune
deficiency were compared with healthy wild-type mice by using the Morris water
maze test, which represents memory and learning. The study found that learning
behavior was worse in the T-cell-deficient study mice than in the wild-type mice, i.e.,
they learned more slowly and also more quickly forgot what they had learned. If the
study mice were substituted with T cells from other mice, they showed
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 39

improvements in both learning and memory, but if they were treated with the NMDA
antagonist MK801 or other substances with similar effects, their cognitive perfor-
mance deteriorated further. However, if Copaxone, a T-cell stimulator, was admin-
istered at the same time as the other substances, the study mice showed the same
learning and memory performance as the wild-type mice. This study shows that an
intact T-cell immune response is required for intact cognitive performance (Kipnis
et al. 2004). Considering that the T-cell immune response is subject to an aging
process from age 55 onward (“immunosenescence”), the immune deficiency in old
age may also explain cognitive deficits in old age. The Maastricht Aging Study
examined this hypothesis and prospectively evaluated 100 healthy participants with
a mean age of 57 years with respect to inflammatory markers and cognitive tests
(Teunissen et al. 2003). The study found a significant negative correlation between
levels of haptoglobin (an APP) and the course of cognitive abilities, measured with
the Stroop Test and the Auditory Verbal Learning Test. It also found a significant
negative correlation between high levels of C-reactive protein (CRP) and cognitive
abilities (Auditory Verbal Learning Test) after 3 and 6 years, i.e., worse cognitive
abilities were associated with higher concentrations of CRP and haptoglobin.
A similarly designed prospective study assessed the inflammatory markers CRP
and IL-6 in 4200 people and performed cognitive tests after about 7 and 12 years.
CRP and IL-6 were significantly associated with cognitive performance, particularly
in men. Higher levels of pro-inflammatory markers in midlife were moderately
correlated with poor cognitive performance and weakly correlated with the decline
in cognitive abilities (Gimeno et al. 2008). Animal studies showed that increased
release of IL-6 leads to learning and memory deficits (Heyser et al. 1997), and IL-6
knockout mice had a lower risk of forgetting what they had learned and showed
better cognitive performance overall than wild-type mice (Braida et al. 2004).
Interestingly, the intravenous administration of anti-IL-6 antibodies also improved
memory function (Balschun et al. 2004).
The impact of inflammation on cognition led to ongoing research on the role of
the immune system in cognitive decline and cognition-related disorders, such as
Alzheimer’s disease (Blum-Degen et al. 1995; Eikelenboom et al. 1991; McGeer
et al. 2016) and Parkinson’s disease (Mogi et al. 1994a, b, 1995a, b).

Mental Disorders and Autoimmune Diseases

The fact that psychoses can result from immune processes is shown by the occur-
rence of psychotic phenomena in various autoimmune diseases in which CNS
immune processes can be demonstrated, such as lupus erythematosus, scleroderma,
Sjögren syndrome, and antiphospholipid syndrome (Kurtz and Muller 1994).
From a clinical perspective, similarities exist between autoimmune diseases and
in particular schizophrenia and affective disorders. These include the often early
onset of the disease, the genetic vulnerability, and the relapsing or phasic course.
Authors have drawn parallels between MS and the increased occurrence of both
schizophreniform syndromes (Stevens 1988) and affective disorders (Berrios and
40 N. Müller

Quemada 1990) to draw attention to a possible immune pathogenesis or similar

pathogenetic mechanisms of these disorders. Conversely, a groundbreaking epide-
miological study from Denmark not only demonstrated a clear link between infec-
tious diseases and an increased risk for both depression and schizophrenia but also
showed that the diagnosis of an autoimmune disease significantly increased the risk
of later developing schizophrenia or depression; the type or localization of the
autoimmune disease was thereby irrelevant (Benros et al. 2012; see also section
“Schizophrenia and the Immune System” below).
These findings underline the clear link between the activation of the immune
system and mental disorders.

Treatment with Interferon-a and Depression

Activation of the immune system by clinical use of interferon-α has been shown to
be associated with the occurrence of depressive symptoms and even clinical depres-
sion, including suicidality. Interferon-α is part of the standard treatment for chronic
hepatitis C and various malignant diseases, such as malignant melanoma and renal
cell carcinoma. The prevalence rates for the occurrence of a depressive syndrome
vary greatly, from 16% to 58% of treated patients. The risk of developing a
depression requiring treatment increases with higher doses of interferon-α and a
longer treatment duration. If fatigue is considered to be a symptom of depression, the
prevalence of a depressive syndrome during interferon-α treatment increases up to
80% (Capuron et al. 2002). Besides depressive mood, fatigue, insomnia, weight loss,
loss of appetite, and cognitive impairment have been described during interferon-α
treatment. Antidepressants, e.g., selective serotonin reuptake inhibitors (SSRIs),
have therapeutic and prophylactic effects in interferon-α-induced depressive
syndromes.

Schizophrenia and the Immune System

Disturbances of Neurotransmitters as a Result of Pre- or Postnatal

Infections

An infection during pregnancy, especially in the second trimester, has been repeat-
edly described in mothers of offspring with schizophrenia. The maternal immune
response, e.g., to a pathogen, appears to be responsible for the increased risk for
schizophrenia in the offspring, and a link has been shown between an increased
maternal level of the pro-inflammatory cytokine IL-8 during the second trimester of
pregnancy and the later risk for schizophrenia in the offspring (Brown et al. 2004). A
link was also shown between the increased level of IL-8 in the mother and morpho-
logical changes typical of schizophrenia in the CNS of offspring who later developed
schizophrenia (Ellman et al. 2010).
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 41

Interestingly, the risk for schizophrenia is not only increased as a result of an

infection in the mother during pregnancy, but infections and autoimmune diseases
also increase the risk for schizophrenia not only prenatally and in the first years of
life but also in later life (Benros et al. 2012). The increased risk for schizophrenia is
thereby “dose dependent”: The more often someone was treated in hospital for an
infection and/or autoimmune disease, the greater the risk of later developing schizo-
phrenia. There was also a temporal link in that the more recent the hospital treatment,
the higher the risk for schizophrenia (Benros et al. 2012). A fivefold higher risk for
later psychosis has been described in people with a CNS infection in early childhood
(Muller and Schwarz 2007; Swerdlow et al. 2009; Mills et al. 2000, 2011; Spellberg
and Edwards 2001).

Lymphocyte Status in Schizophrenic Disorders

The findings of studies on the cellular immune system in schizophrenia are incon-
sistent (Muller and Ackenheil 1995a). A great number of researchers, however,
found increases in CD4+ T lymphocytes (Henneberg et al. 1990; Muller et al.
1991). Increases in the total number of T lymphocytes (CD3+) were also described
(DeLisi et al. 1982), which is probably due mainly to the increased number of CD4+
cells. Increased levels of CD5+ B cells have also been observed (McAllister et al.
1989b). These findings were considered to indicate that the immune system was
activated. It should be noted, however, that many of the patients were being treated
with antipsychotics, which have marked effects on the immune system. Treatment
with antipsychotics is presumed to cause an increase in certain subgroups of CD4+
and B cells.

Cytokines and Schizophrenia

Recently, immunological research in mental disorders has placed more emphasis

on the cytokines. The hypothesis that excessive IL-2 production plays an impor-
tant role in the pathogenesis of schizophrenia is supported primarily by the finding
that IL-2 can cause schizophrenia-like symptoms in a dose-dependent manner
(Denicoff et al. 1987).
A recently published meta-analysis on cytokine changes in schizophrenia differ-
entiated between patients with a first episode of schizophrenia and those with an
acute relapse (Miller et al. 2011). Patients with an acute relapse had significantly
higher levels of IL-1, TNF-α, IL-8, TGF-ß, IL-1RA, and IFN-γ compared with the
controls. In contrast, levels of IL-6, IL-12, TNF-α, IL-1β, TGF-β, soluble IL-2
receptors (sIL-2R), and IFN-γ were higher in the patients with first-episode schizo-
phrenia than in the controls, whereas the anti-inflammatory cytokine IL-10 was
lower in patients with an acute relapse. The authors concluded that some cytokines
depend on the respective acute status and should thus be viewed as “state markers”
(IL-6, IL-1-β, TGF-β), whereas others represent “trait markers” of schizophrenia
42 N. Müller

(IFN-γ, IL-12, TNF-α, sIL-2R). One must consider, however, that the cytokines
IL-12, IL-1-β, TGF-β, and IFN-γ have only paracrine effects through cell-cell
contact and no endocrine effects, so that levels of these cytokines in circulating
blood may not actually reflect the function of the immune system. Furthermore, the
meta-analysis did not consider the time of blood sampling or the medication status of
the patients (medicated vs. not medicated), even though antipsychotic medication is
known to affect cytokine levels in schizophrenia (Potvin et al. 2008). For example,
levels of sIL-2R have been shown to increase with antipsychotic medication (Muller
et al. 1997; Potvin et al. 2008).
IFN-γ is the key cytokine of the type 1 immune response. As mentioned above,
IFN-γ is a paracrine cytokine that has effects through cell-cell contact. Thus, the
in vitro stimulation of cytokine production measured by the enzyme-linked
immunospot (ELISpot) or ELISA methods are more valid approaches to demonstrate
the response of this cytokine than measuring plasma or serum levels. The ELISpot
method allows the (unstimulated) IFN-γ content of individual immune cells to be
measured. Studies on the in vitro production of IFN-γ after stimulation in whole
blood repeatedly using ELISA showed lower IFN-γ production in patients with
schizophrenia compared with health controls (Arolt et al. 2000; Wilke et al. 1996).
Avgustin et al. (2005) stimulated peripheral blood mononuclear cells (PBMC) and
found a greater production of IFN-γ in medicated schizophrenia patients than in
healthy controls. However, stimulated PBMC did not appear to reflect the in vivo
production of IFN-γ as well as the whole blood method.
A study in unmedicated patients with schizophrenia found lower serum levels of IFN-γ
and neopterin, a product of activated monocytes/macrophages, than in healthy controls;
this finding was interpreted as indicating a reduced activation of the type 1 immune
response (Sperner-Unterweger et al. 1999). Lower neopterin levels in body fluids such as
the CSF, blood, and urine directly reflect the activation of guanosine triphosphate
cyclohydrolase, which is induced by IFN-γ but not by other pro-inflammatory factors,
such as TNF-α and IL-1-β (Schennach et al. 2002). Neopterin thus reflects the
IFN-γ-induced immune status and in clinical studies is a marker for the activation of
the cellular immune system (Murr et al. 2002). The findings on neopterin are inconsistent,
however. Higher levels were also described in schizophrenia (Chittiprol et al. 2010), and
an earlier study found no difference in the urine concentration of neopterin between
unmedicated patients with schizophrenia and controls (Duch et al. 1984). Bechter et al.
(2010) found higher neopterin levels in the CSF in about one third of a mixed sample of
patients (schizophrenia or affective disorders) being treated with multiple medications. In
another study, the neopterin concentration in the CSF of ten unmedicated schizophrenia
patients did not differ significantly from controls (Nikkila et al. 2001). An increase in
neopterin has been described during antipsychotic treatment (Korte et al. 1998; Sperner-
Unterweger et al. 1999), which underlines that medication status is an important factor
when interpreting study results.
A study that found a reduced lymphocyte response after stimulation with specific
antigens provides further support for a decreased type 1 response in schizophrenia
(Muller et al. 1991).
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 43

Intercellular adhesion molecule-1 (ICAM-1) is a type 1-dependent protein and

cell adhesion molecule that is expressed on macrophages and lymphocytes, and
lower levels of soluble ICAM-1 (sICAM-1) were found in schizophrenia (Schwarz
et al. 2000). ICAM-1 levels are hypothesized to reflect the type 1 immune
response. This hypothesis is supported among other things by the finding that a
lack of ICAM-1 results in less recruiting and migration of Th1 cells (Ogawa et al.
2010; Varga et al. 2010).
The key cytokine of the type 2 immune response is IL-4. Higher concentrations of
IL-4 were found in the CSF of children with schizophrenia (Mittleman et al. 1997),
which can be interpreted as an indication that a greater type 2 response in schizo-
phrenia is reflected not only in the peripheral immune response but also in the CNS
immune system.
The meta-analysis by Potvin et al. mentioned above also showed pronounced
pro-inflammatory changes in schizophrenia (higher levels of IL-6, IL-1RA, and
sIL-2R) but no major changes in the Th2 cytokines (Potvin et al. 2008). When the
effects of antipsychotic medication were included in the analysis, however, signif-
icant changes were found only in the serum levels of IL-1RA and IL-6.
A lower concentration of the soluble TNF receptor p55 – which is usually lower
when TNF-α is lower – was described in schizophrenia (Haack et al. 1999).
Even before the era of antipsychotics, a reduced skin reaction to various antigens
was observed in schizophrenia (Molholm 1942). This finding was confirmed in a
sample of unmedicated patients with schizophrenia by using a skin test for the
cellular immune response (Riedel et al. 2007). The findings here, however, are
also inconsistent, and other researchers found higher levels of type 1 cytokines in
schizophrenia (Bresee and Rapaport 2009).

CSF Diagnostic Procedures

Two studies that determined IL-2 in the CSF provided interesting results. One of
them described higher IL-2 levels in the CSF of untreated schizophrenia patients
than in controls (Licinio et al. 1993). This finding attracted a good deal of attention
because IL-2 can cause schizophrenia-like symptoms in a dose-dependent manner
(Denicoff et al. 1987). The other, carefully designed study found that IL-2 in the
CSF was the only predictor for a relapse in patients with schizophrenia after
discontinuation of haloperidol; 5-HIAA and HVA in CSF and psychopathological
variables, such as anxiety, were not significant predictors. Only when the variable
IL-2 was removed from the logistic regression model did products of catechol-
amine metabolism and early symptoms of anxiety become significant predictors
(McAllister et al. 1995).
Interestingly, higher IL-6 levels were found in the CSF of patients with chronic
schizophrenia than in healthy controls (Schwieler et al. 2015). This finding has been
frequently replicated in the serum of patients with schizophrenia and underlines the
role of inflammatory components.
44 N. Müller

A recent meta-analysis of cytokine studies in psychiatric disorders showed

similar patterns of higher levels of pro-inflammatory cytokines and lower levels of
anti-inflammatory cytokines in the CSF of patients with schizophrenia, major
depression, and bipolar disorder (Wang and Miller 2018). This indicates that an
inflammatory state might play a role in different diagnostic groups in psychiatry.

Stimulation of Catecholamine Neurotransmitters

A number of findings suggest that in the CNS of patients with schizophrenia, there is
an increased release of activating cytokines, which is associated with a stimulation of
the catecholaminergic neurotransmitter system. A possible explanation may be that
the peripheral immune system is initially not adequately activated, so that there is
insufficient counter-regulation and associated communication between the CNS and
peripheral immune system. This could be related to a defect in antigen recognition or
presentation. Treatment with neuroleptics appears to activate the peripheral immune
system and may thus counter-regulate cytokine release in the CNS.

Anti-inflammatory Substances as a Therapeutic Approach

in Schizophrenia

Immune-based treatment for schizophrenia was first proposed many decades ago: In
the 1920s, the Nobel laureate Julius Ritter Wagner von Jauregg developed a vacci-
nation treatment for psychoses (the term schizophrenia had not yet been introduced)
(Wagner-Jauregg 1926). He successfully treated patients with vaccines for tubercu-
losis, malaria, and typhoid salmonella by stimulating the type 1 immune response
(Muller et al. 2005b). Although promising, this immune-based vaccination treatment
did not become established outside German-speaking countries, especially after
introduction of electroconvulsive therapy and then antipsychotics. Except for anti-
inflammatory drugs – specifically the cyclooxygenase-2 (COX-2) inhibitors, which
are discussed below – only preliminary data exist for other immune-based therapies.

Anti-inflammatory Treatment in Schizophrenia

The finding that anti-inflammatory medication is beneficial in schizophrenia pro-

vides perhaps the most convincing evidence for an involvement of inflammation in
schizophrenia. One such anti-inflammatory agent is the cyclooxygenase-2 (COX-2)
inhibitor celecoxib. A 6-week prospective randomized controlled trial (RCT) in
patients with an acute exacerbation of schizophrenia compared celecoxib as an
add-on to risperidone with risperidone and a placebo add-on (Muller et al. 2002).
Outcome was significantly better in the celecoxib add-on group (n = 25) than in the
group receiving only the antipsychotic (n = 25), whereby the effects on cognition
were especially pronounced (Muller et al. 2005a). Data from this study were pooled
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 45

with data from another 6-week study of risperidone and celecoxib add-on, and the
resulting group of n = 90 cases was analyzed. The analysis found that patients who
had been ill for 2 years or less benefited from the celecoxib add-on, whereas patients
with a longer disease duration showed no benefit compared with the placebo add-on
group.
These findings are in line with animal studies showing that the effects of COX-2
inhibition on cytokines, hormones, and in particular abnormal behavior depend on
both the duration of the changes and the duration of administration of the COX-2
inhibitor (Casolini et al. 2002). Thus, treatment of schizophrenia patients with a
COX-2 inhibitor appears to be most beneficial in the initial period of the disease
process. Support for this hypothesis is provided by a study that found no benefit of
celecoxib in chronic schizophrenia (Rapaport et al. 2005). To further test this
hypothesis, my group studied celecoxib as an add-on to amisulpride in first-
manifestation schizophrenia (Muller et al. 2010). We found positive effects of
celecoxib add-on treatment on the Positive and Negative Syndrome Scale
(PANSS) positive, negative, and total scores and on the general psychopathology
score (Muller 2010; Muller et al. 2010). An effect on cognition could be expected on
the basis of animal experiments with COX-2 inhibitors, which found that COX-2
inhibition has a direct effect on inflammation-inducted inhibition of long-term
potentiation (LTP), an animal model for cognition (Cumiskey et al. 2007; Muller
et al. 2005a). Another study found that the more pronounced effects on cognition in
an animal model with a genetic overexpression of COX-2 could be improved by
administration of a selective COX-2 inhibitor (Melnikova et al. 2006).
Meta-analyses corroborate findings that COX-2 inhibition has clear therapeutic
effects, especially in the early stages of a schizophrenic disorder (Nitta et al. 2013;
Sommer et al. 2012). The data on chronic schizophrenia are controversial, but brief
anti-inflammatory treatment cannot usually be expected to have an effect in chronic
inflammatory clinical processes.
Acetylsalicylic acid (ASA), another anti-inflammatory agent, has also shown
positive effects in schizophrenia spectrum disorders (Laan et al. 2010). A meta-
analysis of five double-blind studies of nonsteroidal anti-inflammatory drugs
(NSAIDs) in schizophrenia (four studies of celecoxib and one of ASS) found
significant effects of the drugs on overall symptoms and both positive and negative
symptoms (Sommer et al. 2012). However, a meta-analysis of eight studies (six of
celecoxib and two of ASS) in schizophrenia found significant effects in first-episode
but not chronic patients and in inpatients but not outpatients (Nitta et al. 2013). Some
studies have evaluated omega-3 fatty acids in schizophrenia, but results are incon-
sistent and the effect size is small (Ross et al. 2007). The results of a study by
Amminger and colleagues, however, are highly interesting (Amminger et al. 2010):
In a 12-month study on individuals with prodromal symptoms, i.e., a high-risk
population for schizophrenia, the group found a significantly lower rate of transition
to psychosis in the omega-3 fatty acid group than in the control group.
The studies described above indicate that the efficacy of anti-inflammatory
treatment is associated with the disease stage, i.e., such treatment shows less efficacy
in chronic schizophrenia (which may be related to the degree of neuroprogression).
46 N. Müller

The negative impact of chronification on the outcome of schizophrenia in general is

well-known from studies of first- and second-generation antipsychotics. Neverthe-
less, to date anti-inflammatory treatment has been evaluated in schizophrenia only in
short-term studies lasting a few weeks at the most. Of relevance in this context is that
short-term anti-inflammatory treatment also shows only weak effects in chronic
inflammatory diseases. Longer-term anti-inflammatory treatment may have more
positive effects in chronic schizophrenia (Akhondzadeh et al. 2007).

Other Immune-Related Substances in Schizophrenia

As described above, microglia activation is involved in inflammatory processes in

the CNS. The antibiotic minocycline crosses the blood-brain barrier, is known to
inhibit microglia activation, and, consequently, is of interest in schizophrenia. In
animal models of schizophrenia, it has been shown to improve cognition (Mizoguchi
et al. 2008). In patients with schizophrenia, a double-blind placebo-controlled
add-on study also found positive effects of minocycline on negative symptoms
(Chaudhry et al. 2012; Levkovitz et al. 2010). Case reports have described positive
effects of minocycline on the overall symptom spectrum in schizophrenia (Ahuja
and Carroll 2007).
Substances with anti-inflammatory and other effects, including acetylcysteine
(ACC) and omega-3 fatty acids, have been found to have some beneficial effects
in schizophrenia (Sommer et al. 2014). The cytokine interferon-gamma (IFN-γ)
stimulates the monocytic type 1 immune response and has shown encouraging,
although preliminary, results in schizophrenia (Gruber et al. 2014). Treatment with
IFN-γ requires careful monitoring of side effects, including unwanted immune
effects.
Because the immune system and in particular cytokines appear to be involved in
schizophrenia, monoclonal antibodies against pro-inflammatory cytokines may be
expected to show positive effects in schizophrenia (Miller and Buckley 2016). The
data from the few studies performed to date indicate that treatment with monoclonal
antibodies is feasible and may show efficacy, but further research is needed (Miller
and Buckley 2016).
COX inhibition has different effects on KYN metabolism: Whereas COX-1
inhibition increases the concentration of KYNA, COX-2 inhibition decreases it
(see Fig. 1) (Schwieler et al. 2005).

Depression and the Immune System

Interleukin-6 and Depressive Disorders

Recently, changes in the cytokine system have become a focus of interest also in
depressive disorders.
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 47

Maes (1995) proposed that IL-6 hypersecretion plays a role in depressive disor-
ders. In depressed patients, he found both increased serum levels of IL-6 and soluble
IL-6 receptors (sIL-6R) and other signs of immune activation, in particular APPs,
which are stimulated by IL-6. The simultaneous increase in IL-6 and sIL-6R, which
congregate as a complex and may increase the biological activity of IL-6 through an
association with a signaling protein, underlines the important role of IL-6 in major
depressive disorder.
A significant correlation between high IL-6 levels and cortisol plasma levels was
also described in depressed patients (Maes et al. 1995b). This finding could be
expected because of the known stimulatory effect of IL-6 on the HPA axis, although
suppression of IL-6 could be expected in the peripheral immune system as a counter-
regulation. In the authors’ opinion, the correlation of the higher in vitro IL-6
production from the lymphocytes of depressed patients with the lower tryptophan
plasma levels in these patients was related to the influence of IL-6 on serotonin
metabolism (Maes et al. 1995b). Serotonin synthesis in the CNS is at least partially
regulated by the availability of tryptophan in blood, so that lower tryptophan levels
in blood can result in reduced serotonin synthesis in the CNS.
The following are characteristics for immune activation in depression: a high
number of circulating lymphocytes and phagocytic cells; highly regulated serum
levels of molecules that indicate an immune activation (neopterin, sIL-2R); higher
concentrations of positive APPs and lower levels of negative APPs; and increased
production of pro-inflammatory cytokines, such as IL-1, IL-2, TNF-α, and IL-6 by
activated macrophages and INF-γ by activated T lymphocytes. Several researchers
have also described a higher number of peripheral mononuclear cells in depression
(Herbert and Cohen 1993; Rothermundt et al. 2001; Seidel et al. 1996).
CRP is the most common marker for an inflammatory process. Studies on the
inflammatory hypothesis of depression found significantly higher CRP levels in
severely depressed patients; CRP levels decreased with antidepressant treatment
(Lanquillon et al. 2000). Another study showed a significant association between
CRP levels and the severity of depression (Hafner et al. 2008). An increase in CRP is
known to be caused by many other factors that also play a role in depressive
disorders, e.g., body mass index, nicotine abuse, and aging processes. Studies
show, however, that even after controlling for these factors, the association between
depression and increased CRP levels remains statistically significant.

Major Depression and Cytokines

Higher levels of sIL-2R and IL-1 in patients with major depression than in healthy
controls were described more than 20 years ago (Maes 1995). In the meantime, many
other studies of cytokines in major depression have been published. Meta-analyses
of cytokine studies in major depression have shown higher levels of
pro-inflammatory cytokines in peripheral blood (Goldsmith et al. 2016). This find-
ing, however, is not restricted to major depression but is also found in other
diagnostic groups. Moreover, similar patterns of higher levels of pro-inflammatory
48 N. Müller

cytokines and lower levels of anti-inflammatory cytokines in the CSF have been
described in major depression, and bipolar disorder, and schizophrenia (Wang and
Miller 2018).
Autoantibodies appear to be present in a subgroup of depressed patients. For
example, “antibrain antibodies” were found in 2 of 11 patients with an affective
disorder (DeLisi et al. 1985). Findings from the Department of Psychiatry at the
University Hospital Munich of anti-DNA autoantibodies in the CSF of a depressed
patient with scleroderma (Muller et al. 1992) also indicate that autoantibodies may
be involved in the development of depressive symptoms.

Cellular Immune System and Depressive Disorders

The findings on the cellular immune system are also inconsistent in depressive
disorders. However, the vast majority of researchers also found signs of an activation
of the peripheral immune system, such as increased levels of CD4+ cells. An increase
in the ratio of CD4+ to CD8+ has been described more often (Syvalahti et al. 1985),
although a few researchers found no changes or even a reduction in CD4+ cells
(Denney et al. 1988). One study found interesting evidence for a positive correlation
of the Hamilton Depression Scale with the number of CD4+ cells: The more severe
the depression, the higher the number of CD4+ cells (Levy et al. 1991). This was in
line with earlier findings of a positive correlation between scores on the Hamilton
Depression Scale and the number of CD4+ cells (Irwin et al. 1987).

Anti-inflammatory Treatment of Depressive Disorders

On the basis of the increased concentration of pro-inflammatory cytokines and PGE2 in

patients with depression and the association with depressive symptoms, one could
expect that anti-inflammatory treatment would have antidepressant effects. The COX-2
inhibitors in particular appear to be promising because animal studies have shown that
COX-2 inhibition inhibits the increase in the pro-inflammatory cytokines IL-1β,
TNF-α, and PGE2 and also prevents the clinical symptoms that are associated with
an increase in pro-inflammatory cytokines, e.g., anxiety and cognitive impairment.

Cyclooxygenase-2 (COX-2) Inhibition as an Example for an Anti-

inflammatory Therapeutic Approach in Major Depression

In addition to inhibiting IL-1 and IL-6 release, COX-2 inhibitors influence the
serotonergic system in the CNS, either directly or via CNS immune mechanisms.
In a rat model, treatment with rofecoxib was followed by an increase of serotonin in
the frontal and the temporoparietal cortex (Sandrini et al. 2002), so that COX-2
inhibitors would be expected to show a clinical antidepressant effect. In the depres-
sion animal model of the bulbectomized rat, a decrease in hypothalamic cytokine
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 49

levels and a change in behavior have been observed after chronic celecoxib treat-
ment (Myint et al. 2007). In another animal model of depression, however, the mixed
COX-1/COX-2 inhibitor ASA showed an additional antidepressant effect by accel-
erating the antidepressant effect of fluoxetine (Brunello et al. 2006). A significant
therapeutic effect of the COX-2 inhibitor celecoxib in major depression was also
found in a randomized, double-blind add-on pilot study of reboxetine and celecoxib
versus reboxetine versus placebo (Muller et al. 2006). Interestingly, the ratio of KYN
to tryptophan, which represents the activity of the pro-inflammatory cytokine-driven
enzyme IDO, predicted the antidepressant response to the celecoxib therapy. Patients
with high activity of IDO, i.e., high pro-inflammatory activity, responded better to
celecoxib. Another RCT in 50 patients with major depression also showed a
significantly better outcome with the COX-2 inhibitor celecoxib plus fluoxetine
than with fluoxetine alone (Akhondzadeh et al. 2008). This finding was recently
replicated in a study that used a combination of sertraline and celecoxib in 40 patients
with depression (Abbasi et al. 2012). Interestingly, the blood levels of IL-6 predicted
the antidepressant response in both the sertraline (plus placebo) and the celecoxib
(plus sertraline) groups.
A meta-analysis on the efficacy of adjunctive celecoxib treatment for patients
with major depression included 150 patients and concluded that adjunctive treatment
with NSAIDs, particularly celecoxib, can be a promising strategy for patients with
depressive disorders. However, future studies with larger sample sizes and longer
study durations are needed to confirm the efficacy and tolerability of NSAIDs in
depression (Na et al. 2014).
The results of an international multicenter add-on RCT of the selective COX-2
inhibitor cimicoxib to sertraline in patients with major depression were also inter-
esting: Although there was no benefit of cimicoxib over sertraline and placebo in the
whole group of depressed patients, there was a significantly better outcome of
cimicoxib and sertraline in the subgroup of severely depressed patients (Hamilton
Depression Score < 25 at baseline) (Müller et al., manuscript in preparation). As
discussed below, because the placebo response in depression studies is generally
very high, and even higher in mild to moderately depressed patients, a therapeutic
benefit can be shown more easily in severely depressed patients, particularly if
sample sizes are small.
In the European-wide study of the role of inflammation in mood disorders
(MOODINFLAME), a therapeutic multicenter RCT of celecoxib add-on to sertraline
compared with sertraline and placebo was performed in a subgroup of patients with
major depression (n = 53). This study found a statistically significant benefit of
COX-2 treatment only in the group of patients who completed the study (completer
analysis) and not in the last observation carried forward (LOCF) analysis (Leitner B.,
Müller N. et al., manuscript in preparation).
Although the abovementioned studies have some limitations, they represent
further small pieces in the puzzle of the effects of anti-inflammatory treatment and
in particular of COX-2 inhibition in major depression. Future studies should place
more emphasis on sample size; the high rate of placebo response, especially in
studies of an add-on to an effective antidepressant; and the severity of depression.
50 N. Müller

Methodological Issues Regarding Anti-inflammatory Treatment

in Major Depression

Several methodological issues are relevant regarding anti-inflammatory treatment in

major depression. From a scientific point of view, the gold standard of clinical
studies would be a randomized, controlled, head-to-head comparison of an anti-
inflammatory compound, such as a COX-2 inhibitor or an anti-cytokine antibody,
with an appropriate placebo. However, for ethical reasons, a patient with depression
cannot be treated only with an anti-inflammatory substance (or placebo) without any
antidepressant medication. Therefore, nearly all the studies are performed with an
anti-inflammatory substance as an add-on to an antidepressant. The consequence of
this approach is that the anti-inflammatory drug has to have large effects to prove an
additional benefit over the antidepressant alone and over the antidepressant com-
bined with placebo.
One must also consider that in the last few years, there has been a dramatic
increase in the number of “failed studies,” i.e., studies of antidepressants that showed
no benefit over placebo. This is partly due to methodological issues, such as sample
size, lack of statistical power, and others, but also to the high placebo response rate of
up to 40%. This high placebo response may also contribute to the difficulties in
proving an advantage of anti-inflammatory substances over placebo (as an add-on to
an antidepressant).
The benefit of an antidepressant compound over placebo is well-known to
increase with the severity of depression. Therefore, if possible clinical trials should
include more severely depressed patients. It might also be easier to show an
antidepressant effect of anti-inflammatory compounds in more severely depressed
patients, as we could show in a study with the COX-2 inhibitor cimicoxib.
A very important point discussed in most of the studies with anti-inflammatory
substances in depression is the fact that different pathologies might play a role in
depression. An inflammatory process is unlikely to be involved in all cases of
depression, although that cannot yet be ruled out. Treatment resistance to monoam-
inergic antidepressants, such as SSRIs, might indicate an inflammatory origin of the
depressive syndrome because increased pro-inflammatory cytokines have been
found in patients with treatment-resistant depression (Lanquillon et al. 2000). The
more patients with an inflammatory pathology who are included in clinical trials
testing anti-inflammatory compounds, the higher the probability of seeing an effect
of anti-inflammatory treatment. Until now, however, no valid and reliable (biological
or psychopathological) marker exists to identify the subgroup of patients in whom
inflammation is involved in the pathological process.

Anti-inflammatory Compounds Other than NSAIDs

In a first study, the anti-TNF-α antibody infliximab, which blocks the interaction of
TNF-α with cell-surface receptors and was developed for the treatment of inflam-
matory joint disorders and psoriasis, showed a highly significant effect on
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 51

symptoms of depression in psoriasis patients (Tyring et al. 2006). Further studies

with anti-TNF-α antibodies also showed antidepressant effects (overview in
Kappelmann et al. 2018).
A random-effect meta-analysis of seven RCTs involving 2,370 participants
showed a significant antidepressant effect of anti-cytokine treatment compared
with placebo. Anti-TNF-α drugs (adalimumab, etanercept, infliximab) were the
most commonly studied (five RCTs). Separate meta-analyses of two RCTs of
adjunctive treatment with anti-cytokine therapy and eight non-randomized and/or
non-placebo studies yielded similar small-to-medium effect estimates favoring anti-
cytokine therapy. The anti-TNF-α antibodies adalimumab, etanercept, and
infliximab and the anti-IL-6 antibody tocilizumab all showed statistically significant
improvements in depressive symptoms. Meta-regression exploring predictors of
response found that the antidepressant effect was associated with baseline symptom
severity but not with improvement in primary physical illness, sex, age, or study
duration (Kappelmann et al. 2018). An important limitation of these studies is that
these patient samples exhibited concomitant symptoms of anxiety and/or depression
in addition to their (primary) diagnosis of an inflammatory disease, such as rheuma-
toid arthritis, Crohn’s disease, and psoriasis. Moreover, overall the symptoms of
depression were mild to moderate and no diagnosis of depression or major depres-
sion was performed.
So far, only one study has evaluated an anti-TNF-α antibody in patients with
major depression: The placebo-controlled add-on study of infliximab found no
overall antidepressant effect in patients with treatment-resistant depression (Raison
et al. 2013). Three infusions of infliximab or placebo were given in a 12-week trial in
partly medication-free non-responders to antidepressant therapy; no overall better
outcome of infliximab vs. placebo could be shown. There was, however, a significant
interaction between treatment, time, and baseline CRP (5 mg/L): Patients with
higher baseline CRP levels had a higher response rate to infliximab (62%)
vs. placebo (33%). Moreover, the baseline concentrations of TNF-α, sTNFR1, and
sTNFR2 were significantly higher in infliximab responders ( p  0.01). Additionally,
infliximab responders exhibited a significantly higher decrease in CRP levels
( p  0.01) than non-responders (Raison et al. 2013). This result is promising,
particularly because patients with treatment-resistant depression reflect a negative
selection for treatment outcome. The CRP level might be a possible biological
marker for the outcome of treatment with anti-TNF-α antibodies.

Anti-IL-6 Complex as a Therapeutic Target in Major Depression

As mentioned above, elevated levels of IL-6 have been reported in the peripheral
blood and CSF of patients with depression. Therefore, the IL-6 complex is also an
interesting target for anti-cytokine treatment. Two studies of the anti-IL-6 antibody
tocilizumab (Gossec et al. 2015; Traki et al. 2014) were included in the meta-analysis
mentioned above (Kappelmann et al. 2018). In both open-labeled studies, the
concomitant symptoms of anxiety and depression improved. However, valid and
52 N. Müller

reliable data of anti-IL-6 treatment in patients with major depression are still
missing, and the correct target for anti-IL-6 treatment is a matter of discussion.
IL-6 levels are well-known to be higher in the CSF than in peripheral blood, and
patients with depression have higher IL-6 CSF levels than controls; therefore, CNS
IL-6 was postulated to be the most promising therapeutic target. Moreover, the
preclinical model of chronically stressed rats shows an overexpression of IL-6 in
the cortex. On the other hand, CSF IL-6 levels cannot be seen as completely distinct
from the IL-6 concentration in the CSF or IL-6 expression in the brain because there
are many interconnections between central and peripheral IL-6 concentrations.
Therefore, peripheral IL-6 might be a promising target to treat depressive symptoms
(Yang and Hashimoto 2015). This view is supported by the findings that peripheral
IL-6 promotes resilience versus susceptibility to chronic inescapable electric stress in
an animal model of depression (Yang et al. 2015a) and serum IL-6 predicts the
antidepressant response to ketamine (Yang et al. 2015b) in depressed patients. Maes
et al. (2014) propose, however, that a more promising strategy to inhibit IL-6 might
be to increase inhibition of IL-6 trans-signaling by increasing the soluble glycopro-
tein 130 (sgp 130), part of the IL-6 complex, while allowing maintenance of IL-6R
signaling. Sirukumab, a monoclonal antibody against IL-6 distinct from tocilizumab,
has also been proposed for use in depression (Zhou et al. 2017). Sirukumab targets
the IL-6 signaling pathway, inhibiting both the pro- and anti-inflammatory effects of
the pleiotropic cytokine IL-6 (Zhou et al. 2017). Beneficial effects of sirukumab have
been shown in other inflammatory diseases, such as lupus erythematosus and
rheumatoid arthritis.

Other Immune-Related Substances in the Treatment of Major

Depression

Interestingly, there are also preliminary findings that angiotensin II AT1 receptor
blockade has anti-inflammatory effects in the CNS and ameliorates stress, anxiety,
and CNS inflammation (Saavedra et al. 2011; Benicky et al. 2011).
A recently published broader meta-analysis of inflammation-related therapeutic
approaches included ten publications reporting on 14 trials (6,262 participants). It
showed very interesting results of anti-inflammatory treatment in major depression:
ten trials evaluated the use of NSAIDs (n = 4,258) and four investigated cytokine
inhibitors (n = 2,004). The pooled effect estimate suggested that anti-inflammatory
treatment reduced depressive symptoms compared with placebo. This effect was
observed in studies including patients with depression and depressive symptoms.
The heterogeneity of the studies was not explained by differences in inclusion of
clinical depression vs. depressive symptoms or use of NSAIDs vs. cytokine inhib-
itors. Sub-analyses emphasized the antidepressant properties of celecoxib on remis-
sion and response. Among the six studies reporting on adverse effects, no evidence
was found of an increased number of gastrointestinal or cardiovascular events after
6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with
placebo. All trials were associated with a high risk of bias because of potentially
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 53

compromised internal validity. The analysis suggests that anti-inflammatory treat-

ment, in particular celecoxib, decreases depressive symptoms without increased
risks of adverse effects. This study supports a proof of concept concerning the use
of anti-inflammatory treatment in depression (Kohler et al. 2014).
Despite being used primarily for their lipid-lowering properties, statins have
direct anti-inflammatory effects that are not mediated by their hypocholesterolemic
activity (Kohler et al. 2016; Weitz-Schmidt 2002). Therefore, a large population-
based study was performed in nearly 900,000 people using SSRIs, of whom more
than 110,000 used a statin concomitantly, to evaluate a possible anti-depressant
effect of statins. The concomitant treatment of SSRI and statins resulted in a robust
advantage regarding the risk for (a relapse to) depression compared with a SSRI
alone (Kohler et al. 2016).

Immunological Effects of Psychopharmaceuticals

Antipsychotics

If an increased concentration of activating cytokines in the CNS plays a role in

schizophrenia, one would expect antipsychotic treatment to inhibit these cytokines;
indeed, ex vivo, in vitro, and animal studies have shown that antipsychotics have
inhibitory effects on the production and/or release of activating cytokines. Early
studies indicated an immunosuppressive effect of antipsychotics (Baker et al. 1977),
although other studies found no suppression of the immune system. However, the
term “immunosuppressive” is vague and these effects need to be more clearly
defined. Some in vitro studies have even reported an immune-activating function
of antipsychotics (Zarrabi et al. 1979).
The contradictory results suggest that we need to differentiate between in vitro
and in vivo effects and short- and long-term effects. Neither short-term treatment nor
a single dose of antipsychotics appeared to have a demonstrable effect in ex vivo
studies (McAllister et al. 1989a), but this in no way precludes immunomodulatory
effects of longer-term antipsychotic treatment in naturalistic conditions.
Because the immune system is composed of complex regulatory mechanisms, the
effects of the various components have to be specified. To date, a number of studies
have been performed that indicate inhibitory effects of antipsychotic treatment on
activating cytokines. Studies consistently found that antipsychotic treatment is
associated with low levels of the sIL-6R and high levels of the sIL-2R (Maes et al.
1995a; Muller et al. 1997; Pollmacher et al. 1995). The fact that sIL-2R reflect effects
on the T helper 1 system, but sIL-6R rather reflect the activity of the monocytic or T
helper 2 system, suggests that antipsychotic effects should be interpreted as differ-
ential effects on the T helper 1 and T helper 2 systems. It appears that the T helper
1 system is activated, whereas the monocytic or T helper 2 system is rather
downregulated.
Inhibitory effects of chlorpromazine – and weaker inhibitory effects of haloper-
idol and fluphenazine – on TNF-α production were observed in animal studies
54 N. Müller

(Bertini et al. 1993). In mice, chlorpromazine also protects from the toxic effects of
IL-1 and from endotoxin-induced toxic effects of TNF.
Particular attention has been paid to the immunological effects of clozapine
because such effects were implicated in its increased risk for agranulocytosis.
Clozapine was shown to have an inhibitory effect on granulocyte-macrophage
colony-stimulating factor (GM-CSF) (Sperner-Unterweger et al. 1993).

Antidepressants

In contrast to antipsychotics, hardly any studies have been performed on the

immunological effects of antidepressants (Miller and Lackner 1989). The only
available findings are on the relationship between the serotonin and immune systems
and on the immunological effects of drugs with serotonergic effects. Because studies
have found indications in depression for an overproduction of activating cytokines,
mainly of the monocytic system, one would expect antidepressants to have inhibi-
tory effects on monocyte cytokines. Animal studies showed modulatory, mainly
inhibitory, effects of SSRIs on activating immune parameters (Zhu et al. 1994) and
APPs (Song and Leonard 1994). In patients with depression, decreased levels of IL-6
were found during treatment with the SSRI fluoxetine (Sluzewska et al. 1995). These
preliminary results indicate inhibitory effects of antidepressants; however, overall
the immunological activity and effects on cytokine productions have not been
sufficiently studied to date.

Outlook

Thanks to rapid progress in the understanding of the functional relationships

between immune processes and neurotransmitters, older findings can now be better
classified. The disturbances of the blood-brain barrier in some patients and the
autochthonous production of IgG indicate an immune process in the CNS or an
interaction between the CNS and peripheral immune system. A model based on the
function of the CNS cytokine network can explain how an autochthonous process
can initiate a disease process through the immune system. Initially, this takes place
largely independent of peripheral immune processes, but in a second step, the
disease process itself may activate the peripheral immune system, which then
gains momentum and results in chronification (Muller and Ackenheil 1998). Mech-
anisms of the cellular immune system can now also be better classified because the
increased knowledge about the function of subgroups of lymphocytes and method-
ological advances allow a differential functional analysis.
Immunology is currently advancing faster than any other field of medicine.
Knowledge on peripheral immunology is much more developed than on neuro-
immunology – and especially on psycho-neuro-immunology – because the periph-
eral immune system is easier to study, animal models exist for many diseases, and
the peripheral immune system is relevant for many specialties, e.g., infectious
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 55

diseases, tumor immunology, and transplantation medicine. For example, the rele-
vance for processes in the CNS and in particular for neuronal processes of many of
the newly discovered cytokines, some of which are expressed in the CNS, remains
completely unknown.
A model of the immunopathogenesis of mental disorders must consider the
effects of cytokines in the CNS and the functions of both the peripheral cellular
immune system and the blood-brain barrier as well as immunogenetics, which may
contribute to an increased susceptibility. Such a model is not only a fascinating
hypothesis – an increasing number of findings support the assumption that cyto-
kines, perhaps through their regulatory effects on neurotransmitters, play an impor-
tant role in the pathogenesis of mental disorders. Immunological effects of
psychopharmaceuticals may not only be a side effect but may also contribute to
the therapeutic efficacy. This may have far-reaching effects on immuno-
psychopharmacology (Müller 1995).

Cross-References

▶ Antidepressants: Molecular Aspects of SSRIs

▶ Experimental Psychopharmacology
▶ Neurobiological Principles: Neurotransmitters

Acknowledgments The author thanks the foundation ‘Immunität & Seele’ for its support

References
Abbasi SH, Hosseini F, Modabbernia A, Ashrafi M, Akhondzadeh S. Effect of celecoxib add-on
treatment on symptoms and serum IL-6 concentrations in patients with major depressive
disorder: randomized double-blind placebo-controlled study. J Affect Disord. 2012;141:308–14.
Ader R, Felten DL. Psychoneuroimmunology. San Diego/New York/Toronto: Academic
Press; 1991.
Ahuja N, Carroll BT. Possible anti-catatonic effects of minocycline in patients with schizophrenia.
Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31:968–9.
Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B. Celecoxib as
adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial.
Schizophr Res. 2007;90:179–85.
Akhondzadeh S, Jafari S, Raisi F, Ghoreishi A. A clinical trial of adjunctive celecoxib treatment in
patients with major depression: a double blind and placebo controlled trial. Paper presented at
the WPA Section on Immunology and psychiatry – psychoneuroimmunology training work-
shop, Seeon, Munich, 11–13 July 2008.
Alonso R, Chaudieu I, Diorio J, Krishnamurthy A, Quirion R, Boksa P. Interleukin-2 modulates
evoked release of [3H]dopamine in rat cultured mesencephalic cells. J Neurochem.
1993;61:1284–90.
Amminger GP, Schafer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, et al. Long-
chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized,
placebo-controlled trial. Arch Gen Psychiatry. 2010;67:146–54.
56 N. Müller

Araujo DM, Lapchak PA, Chabot JG, Nair NP, Quirion R. Characterization and possible role of
growth factor and lymphokine receptors in the regulation of cholinergic function in the
mammalian brain. Prog Clin Biol Res. 1989;317:423–36.
Arolt V, Rothermundt M, Wandinger KP, Kirchner H. Decreased in vitro production of interferon-
gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment. Mol
Psychiatry. 2000;5:150–8.
Avgustin B, Wraber B, Tavcar R. Increased Th1 and Th2 immune reactivity with relative Th2
dominance in patients with acute exacerbation of schizophrenia. Croat Med J. 2005;46:268–74.
Baker GA, Santalo R, Blumenstein J. Effect of psychotropic agents upon the blastogenic response
of human t-lymphocytes. Biol Psychiatry. 1977;12:159–69.
Balschun D, Wetzel W, Del Rey A, Pitossi F, Schneider H, Zuschratter W, et al. Interleukin-6: a
cytokine to forget. FASEB J. 2004;18:1788–90.
Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG. Cerebrospinal fluid analysis in
affective and schizophrenic spectrum disorders: identification of subgroups with immune
responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44:321–30.
Benicky J, Sanchez-Lemus E, Honda M, Pang T, Orecna M, Wang J, et al. Angiotensin II AT1
receptor blockade ameliorates brain inflammation. Neuropsychopharmacology.
2011;36:857–70.
Benros ME, Mortensen PB, Eaton WW. Autoimmune diseases and infections as risk factors for
schizophrenia. Ann N Y Acad Sci. 2012;1262:56–66.
Benveniste EN. Inflammatory cytokines within the central nervous system: sources, function, and
mechanism of action. Am J Phys. 1992;263:C1–16.
Berrios GE, Quemada JI. Depressive illness in multiple sclerosis. Clinical and theoretical aspects of
the association. Br J Psychiatry. 1990;156:10–6.
Bertini R, Garattini S, Delgado R, Ghezzi P. Pharmacological activities of chlorpromazine involved
in the inhibition of tumour necrosis factor production in vivo in mice. Immunology.
1993;79:217–9.
Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between
interleukin-1 and glucocorticoid hormones. Science. 1986;233:652–4.
Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 beta and
interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s
disease patients. Neurosci Lett. 1995;202:17–20.
Bohar Z, Toldi J, Fulop F, Vecsei L. Changing the face of kynurenines and neurotoxicity:
therapeutic considerations. Int J Mol Sci. 2015;16:9772–93.
Boros FA, Bohar Z, Vecsei L. Genetic alterations affecting the genes encoding the enzymes of
the kynurenine pathway and their association with human diseases. Mutat Res.
2018;776:32–45.
Braida D, Sacerdote P, Panerai AE, Bianchi M, Aloisi AM, Iosue S, et al. Cognitive function in
young and adult IL (interleukin)-6 deficient mice. Behav Brain Res. 2004;153:423–9.
Bresee C, Rapaport MH. Persistently increased serum soluble interleukin-2 receptors in continu-
ously ill patients with schizophrenia. Int J Neuropsychopharmacol. 2009;12:861–5.
Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, et al. Elevated maternal
interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry.
2004;161:889–95.
Bruce LC, Peebles AMS. Clinical and experimental observations in catatonia. J Ment Sci.
1903;49:614–28.
Brunello N, Alboni S, Capone G, Benatti C, Blom JM, Tascedda F, et al. Acetylsalicylic acid
accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of
depression. Int Clin Psychopharmacol. 2006;21:219–25.
Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al.
Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine
responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26:643–52.
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 57

Casolini P, Catalani A, Zuena AR, Angelucci L. Inhibition of COX-2 reduces the age-dependent
increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impair-
ments in the rat. J Neurosci Res. 2002;68:337–43.
Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, et al. Minocycline benefits
negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled
clinical trial in patients on standard treatment. J Psychopharmacol. 2012;26:1185–93.
Chittiprol S, Venkatasubramanian G, Neelakantachar N, Babu SV, Reddy NA, Shetty KT, et al.
Oxidative stress and neopterin abnormalities in schizophrenia: a longitudinal study. J Psychiatr
Res. 2010;44:310–3.
Cumiskey D, Curran BP, Herron CE, O’Connor JJ. A role for inflammatory mediators in the IL-18
mediated attenuation of LTP in the rat dentate gyrus. Neuropharmacology. 2007;52:1616–23.
Dameshek W. White blood cells in dementia praecox and dementia paralytica. Arch Neurol
Psychiatr. 1930;24:855.
DeLisi LE, Goodman S, Neckers LM, Wyatt RJ. An analysis of lymphocyte subpopulations in
schizophrenic patients. Biol Psychiatry. 1982;17:1003–9.
DeLisi LE, Weber RJ, Pert CB. Are there antibodies against brain in sera from schizophrenic
patients? Review and prospectus. Biol Psychiatry. 1985;20:110–5.
Denicoff KD, Rubinow DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, et al. The neuropsychiatric
effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med.
1987;107:293–300.
Denney DR, Stephenson LA, Penick EC, Weller RA. Lymphocyte subclasses and depression.
J Abnorm Psychol. 1988;97:499–502.
Duch DS, Woolf JH, Nichol CA, Davidson JR, Garbutt JC. Urinary excretion of biopterin and
neopterin in psychiatric disorders. Psychiatry Res. 1984;11:83–9.
Ellman LM, Deicken RF, Vinogradov S, Kremen WS, Poole JH, Kern DM, Tsai WY, Schaefer CA,
Brown AS.Structural brain alterations in schizophrenia following fetal exposure to the inflam-
matory cytokine interleukin-8.Schizophr Res. 2010;121(1–3):46–54. https://doi.org/10.1016/j.
schres.2010.05.014. Epub 2010 Jun 9
Eikelenboom P, Rozemuller JM, Kraal G, Stam FC, McBride PA, Bruce ME, et al. Cerebral amyloid
plaques in Alzheimer’s disease but not in scrapie-affected mice are closely associated with a
local inflammatory process. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60:329–36.
Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF. Microglia serve as a neuroimmune
substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain
Behav Immun. 2007;21:47–59.
Furukawa H, del Rey A, Monge-Arditi G, Besedovsky HO. Interleukin-1, but not stress, stimulates
glucocorticoid output during early postnatal life in mice. Ann N Y Acad Sci. 1998;840:117–22.
Gimeno D, Marmot MG, Singh-Manoux A. Inflammatory markers and cognitive function in
middle-aged adults: the Whitehall II study. Psychoneuroendocrinology. 2008;33:1322–34.
Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in
psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol
Psychiatry. 2016;21:1696–709.
Gossec L, Steinberg G, Rouanet S, Combe B. Fatigue in rheumatoid arthritis: quantitative findings
on the efficacy of tocilizumab and on factors associated with fatigue. The French multicentre
prospective PEPS study. Clin Exp Rheumatol. 2015;33:664–70.
Grosskopf A, Muller N, Malo A, Wank R. Potential role for the narcolepsy- and multiple sclerosis-
associated HLA allele DQB10602 in schizophrenia subtypes. Schizophr Res. 1998;30:187–9.
Gruber L, Bunse T, Weidinger E, Reichard H, Muller N. Adjunctive recombinant human interferon
gamma-1b for treatment-resistant schizophrenia in 2 patients. J Clin Psychiatry.
2014;75:1266–7.
Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kuhn M, Schuld A, et al. Plasma levels of cytokines
and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of
confounding factors and diagnosis. J Psychiatr Res. 1999;33:407–18.
58 N. Müller

Hafner S, Baghai TC, Eser D, Schule C, Rupprecht R, Bondy B, et al. C-reactive protein is
associated with polymorphisms of the angiotensin-converting enzyme gene in major depressed
patients. J Psychiatr Res. 2008;42:163–5.
Hampel H, Schwarz MJ, Kötter HU, Schneider C, Müller N. Cell adhesion molecules in the central
nervous system: significance and therapeutic perspectives in neuropsychiatric disorders. Drug
News Perspect. 1996;9:69–81.
Hampel H, Kotter HU, Padberg F, Korschenhausen DA, Moller HJ. Oligoclonal bands and blood–
cerebrospinal-fluid barrier dysfunction in a subset of patients with Alzheimer disease: compar-
ison with vascular dementia, major depression, and multiple sclerosis. Alzheimer Dis Assoc
Disord. 1999;13:9–19.
Hayley S, Wall P, Anisman H. Sensitization to the neuroendocrine, central monoamine and
behavioural effects of murine tumor necrosis factor-alpha: peripheral and central mechanisms.
Eur J Neurosci. 2002;15:1061–76.
Henneberg A, Riedl B, Dumke HO, Kornhuber HH. T-lymphocyte subpopulations in schizophrenic
patients. Eur Arch Psychiatry Neurol Sci. 1990;239:283–4.
Herbert TB, Cohen S. Depression and immunity: a meta-analytic review. Psychol Bull.
1993;113:472–86.
Heyser CJ, Masliah E, Samimi A, Campbell IL, Gold LH. Progressive decline in avoidance learning
paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the
brain. Proc Natl Acad Sci U S A. 1997;94:1500–5.
Irwin M, Smith TL, Gillin JC. Low natural killer cytotoxicity in major depression. Life Sci.
1987;41:2127–33.
Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-
cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflam-
matory conditions. Mol Psychiatry. 2018;23:335–43.
Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction:
implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc
Natl Acad Sci U S A. 2004;101:8180–5.
Knight JG. Dopamine-receptor-stimulating autoantibodies: a possible cause of schizophrenia.
Lancet. 1982;2:1073–6.
Kohler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, et al. Effect of anti-
inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic
review and meta-analysis of randomized clinical trials. JAMA Psychiat. 2014;71:1381–91.
Kohler O, Gasse C, Petersen L, Ingstrup KG, Nierenberg AA, Mors O, et al. The effect of
concomitant treatment with SSRIs and statins: a population-based study. Am J Psychiatry.
2016;173:807–15.
Korte S, Arolt V, Peters M, Weitzsch C, Rothermundt M, Kirchner H. Increased serum neopterin
levels in acutely ill and recovered schizophrenic patients. Schizophr Res. 1998;32:63–7.
Kurtz G, Muller N. The antiphospholipid syndrome and psychosis. Am J Psychiatry.
1994;151:1841–2.
Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces
symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind,
placebo-controlled trial. J Clin Psychiatry. 2010;71:520–7.
Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment
response in major depressive disorder. Neuropsychopharmacology. 2000;22:370–9.
Lapchak PA. A role for interleukin-2 in the regulation of striatal dopaminergic function.
Neuroreport. 1992;3:165–8.
Lehmann-Facius H. Serologisch-analytische Versuche mit Liquores und Seren von Schizophrenen.
Allg Z Psychiatrie. 1939;110:232–43.
Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, et al. A double-blind,
randomized study of minocycline for the treatment of negative and cognitive symptoms in early-
phase schizophrenia. J Clin Psychiatry. 2010;71:138–49.
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 59

Levy EM, Borrelli DJ, Mirin SM, Salt P, Knapp PH, Peirce C, et al. Biological measures and
cellular immunological function in depressed psychiatric inpatients. Psychiatry Res.
1991;36:157–67.
Lewandowski G, Hobbs MV, Bloom FE. Alteration of intracerebral cytokine production in mice
infected with herpes simplex virus types 1 and 2. J Neuroimmunol. 1994;55:23–34.
Licinio J, Seibyl JP, Altemus M, Charney DS, Krystal JH. Elevated CSF levels of interleukin-2 in
neuroleptic-free schizophrenic patients. Am J Psychiatry. 1993;150:1408–10.
Lieberman AP, Pitha PM, Shin HS, Shin ML. Production of tumor necrosis factor and other
cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl
Acad Sci U S A. 1989;86:6348–52.
Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog
Neuro-Psychopharmacol Biol Psychiatry. 1995;19:11–38.
Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY. Interleukin-2 and interleukin-6 in
schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res.
1995a;29:141–52.
Maes M, Bosmans E, Meltzer HY. Immunoendocrine aspects of major depression. Relationships
between plasma interleukin-6 and soluble interleukin-2 receptor, prolactin and cortisol. Eur
Arch Psychiatry Clin Neurosci. 1995b;245:172–8.
Maes M, Bosmans E, Kenis G, De Jong R, Smith RS, Meltzer HY. In vivo immunomodulatory
effects of clozapine in schizophrenia. Schizophr Res. 1997;26:221–5.
Maes M, Anderson G, Kubera M, Berk M. Targeting classical IL-6 signalling or IL-6 trans-
signalling in depression? Expert Opin Ther Targets. 2014;18:495–512.
McAllister CG, Rapaport MH, Pickar D, Paul SM. Effects of short-term administration of antipsy-
chotic drugs on lymphocyte subsets in schizophrenic patients. Arch Gen Psychiatry.
1989a;46:956–7.
McAllister CG, Rapaport MH, Pickar D, Podruchny TA, Christison G, Alphs LD, et al. Increased
numbers of CD5+ B lymphocytes in schizophrenic patients. Arch Gen Psychiatry.
1989b;46:890–4.
McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME, et al. Increases in CSF
levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication
status. Am J Psychiatry. 1995;152:1291–7.
McGeer PL, Rogers J, McGeer EG. Inflammation, antiinflammatory agents, and Alzheimer’s
disease: the last 22 years. J Alzheimers Dis. 2016;54:853–7.
Melnikova T, Savonenko A, Wang Q, Liang X, Hand T, Wu L, et al. Cycloxygenase-2 activity
promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer’s disease
in a sex-dimorphic pattern. Neuroscience. 2006;141:1149–62.
Merrill JE. Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development:
normal and pathological. Dev Neurosci. 1992;14:1–10.
Miller BJ, Buckley PF. The case for adjunctive monoclonal antibody immunotherapy in schizo-
phrenia. Psychiatr Clin North Am. 2016;39:187–98.
Miller AH, Lackner C. Tricyclic antidepressants and immunity. In: Miller AH, editor. Depressive
disorders and immunity. Washington: American Psychiatric Press; 1989.
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine
alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry.
2011;70:663–71.
Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2
paradigm. J Immunol. 2000;164:6166–73.
Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM. Cerebrospinal
fluid cytokines in pediatric neuropsychiatric disease. J Immunol. 1997;159:2994–9.
Mizoguchi H, Takuma K, Fukakusa A, Ito Y, Nakatani A, Ibi D, et al. Improvement by minocycline
of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacol-
ogy. 2008;196:233–41.
60 N. Müller

Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, et al. Interleukin-1 beta,

interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in
the brain from parkinsonian patients. Neurosci Lett. 1994a;180:147–50.
Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T. Tumor necrosis factor-alpha
(TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian
patients. Neurosci Lett. 1994b;165:208–10.
Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P, Nagatsu T. Transforming growth factor-
beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson’s
disease. Neurosci Lett. 1995a;193:129–32.
Mogi M, Harada M, Kondo T, Riederer P, Nagatsu T. Brain beta 2-microglobulin levels are elevated
in the striatum in Parkinson’s disease. J Neural Transm Park Dis Dement Sect. 1995b;9:87–92.
Molholm HB. Hyposensitivity to foreign protein in schizophrenic patients. Psychiatr
Q. 1942;16:565–71.
Müller N. Psychoneuroimmunology: implications for the drug treatment of psychiatric disorders.
CNS Drugs. 1995;4:125–40.
Muller N. COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr Opin
Investig Drugs. 2010;11:31–42.
Müller N. Immunologische Behandlungsoptionen bei schizophrenen Störungen. Fortschr Neurol
Psychiatr. 2013;82:210–9.
Muller N. The role of intercellular adhesion molecule-1 in the pathogenesis of psychiatric disorders.
Front Pharmacol. 2019;10:1251.
Muller N, Ackenheil M. The immune system and schizophrenia. In: Leonard BE, Miller K, editors.
Stress, the immune system and psychiatry. New York/Chichester: Wiley; 1995a. p. 137–64.
Muller N, Ackenheil M. Immunoglobulin and albumin content of cerebrospinal fluid in schizo-
phrenic patients: relationship to negative symptomatology. Schizophr Res. 1995b;14:223–8.
Muller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications
for psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 1998;22:1–33.
Müller N, Bechter K. The mild encephalitis concept for psychiatric disorders revisited in the light of
current psychoneuroimmunological findings. Neurol Psychiatry Brain Res. 2013;19:87–101.
Muller N, Schwarz MJ. The immunological basis of glutamatergic disturbance in schizophrenia:
towards an integrated view. J Neural Transm. 2007;(Suppl 72):269–80.
Muller N, Schwarz MJ. Immune system and Schizophrenia. Curr Immunol Rev. 2010;6:213–20.
Muller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R. Cellular immunity in schizophrenic
patients before and during neuroleptic treatment. Psychiatry Res. 1991;37:147–60.
Muller N, Gizycki-Nienhaus B, Gunther W, Meurer M. Depression as a cerebral manifestation of
scleroderma: immunological findings in serum and cerebrospinal fluid. Biol Psychiatry.
1992;31:1151–6.
Muller N, Empl M, Riedel M, Schwarz M, Ackenheil M. Neuroleptic treatment increases soluble
IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur Arch Psychiatry Clin
Neurosci. 1997;247:308–13.
Muller N, Riedel M, Hadjamu M, Schwarz MJ, Ackenheil M, Gruber R. Increase in expression of
adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to
blood-brain barrier permeability in schizophrenia. Am J Psychiatry. 1999;156:634–6.
Muller N, Riedel M, Scheppach C, Brandstatter B, Sokullu S, Krampe K, et al. Beneficial
antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophre-
nia. Am J Psychiatry. 2002;159:1029–34.
Muller N, Riedel M, Schwarz MJ, Engel RR. Clinical effects of COX-2 inhibitors on cognition in
schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2005a;255:149–51.
Muller N, Schwarz MJ, Riedel M. COX-2 inhibition in schizophrenia: focus on clinical effects of
celecoxib therapy and the role of TNF-alpha. In: Eaton WW, editor. Medical and psychiatric
comorbidity over the course of life. Washington, DC: American Psychiatric Publishing; 2005b.
p. 265–76.
Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, et al. The
cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 61

double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry.
2006;11:680–4.
Muller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, et al. Celecoxib
treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-
controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res.
2010;121:118–24.
Muller N, Myint AM, Schwarz MJ. Immunological treatment options for schizophrenia. Curr
Pharm Biotechnol. 2012a;13:1606–13.
Muller N, Myint AM, Schwarz MJ. Inflammation in schizophrenia. Adv Protein Chem Struct Biol.
2012b;88:49–68.
Murr C, Widner B, Wirleitner B, Fuchs D. Neopterin as a marker for immune system activation.
Curr Drug Metab. 2002;3:175–87.
Myint AM, Steinbusch HW, Goeghegan L, Luchtman D, Kim YK, Leonard BE. Effect of the
COX-2 inhibitor celecoxib on behavioural and immune changes in an olfactory bulbectomised
rat model of depression. Neuroimmunomodulation. 2007;14:65–71.
Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Efficacy of adjunctive celecoxib treatment for patients
with major depressive disorder: a meta-analysis. Prog Neuro-Psychopharmacol Biol Psychiatry.
2014;48:79–85.
Nair A, Bonneau RH. Stress-induced elevation of glucocorticoids increases microglia proliferation
through NMDA receptor activation. J Neuroimmunol. 2006;171:72–85.
Nemni R, Iannaccone S, Quattrini A, Smirne S, Sessa M, Lodi M, et al. Effect of chronic treatment
with recombinant interleukin-2 on the central nervous system of adult and old mice. Brain Res.
1992;591:248–52.
Nikkila HV, Muller K, Ahokas A, Rimon R, Andersson LC. Increased frequency of activated
lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res.
2001;49:99–105.
Nistico G, De Sarro G. Is interleukin 2 a neuromodulator in the brain? Trends Neurosci.
1991;14:146–50.
Nitta M, Kishimoto T, Muller N, Weiser M, Davidson M, Kane JM, et al. Adjunctive use of
nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of ran-
domized controlled trials. Schizophr Bull. 2013;39:1230–41.
Norris JG, Benveniste EN. Interleukin-6 production by astrocytes: induction by the neurotransmit-
ter norepinephrine. J Neuroimmunol. 1993;45:137–45.
Ogawa A, Yoshizaki A, Yanaba K, Ogawa F, Hara T, Muroi E, et al. The differential role of
L-selectin and ICAM-1 in Th1-type and Th2-type contact hypersensitivity. J Invest Dermatol.
2010;130:1558–70.
Pennisi E. Neuroimmunology. Tracing molecules that make the brain-body connection. Science.
1997;275:930–1.
Plangar I, Majlath Z, Vecsei L. Kynurenines in cognitive functions: their possible role in depression.
Neuropsychopharmacol Hung. 2012;14:239–44.
Plata-Salaman CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev.
1991;15:185–215.
Pollmacher T, Hinze-Selch D, Mullington J, Holsboer F. Clozapine-induced increase in plasma
levels of soluble interleukin-2 receptors. Arch Gen Psychiatry. 1995;52:877–8.
Pollmacher T, Schuld A, Kraus T, Haack M, Hinze-Selch D. On the clinical relevance of clozapine-
triggered release of cytokines and soluble cytokine-receptors. Fortschr Neurol Psychiatr.
2001;69(Suppl 2):S65–74.
Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in
schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63:801–8.
Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, et al. Common polygenic
variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized
controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depres-
sion: the role of baseline inflammatory biomarkers. JAMA Psychiat. 2013;70:31–41.
62 N. Müller

Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Celecoxib
augmentation of continuously ill patients with schizophrenia. Biol Psychiatry. 2005;57:1594–6.
Riedel M, Spellmann I, Schwarz MJ, Strassnig M, Sikorski C, Moller HJ, et al. Decreased T cellular
immune response in schizophrenic patients. J Psychiatr Res. 2007;41:3–7.
Ross BM, Seguin J, Sieswerda LE. Omega-3 fatty acids as treatments for mental illness: which
disorder and which fatty acid? Lipids Health Dis. 2007;6:21.
Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H. Different immune patterns in
melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci.
2001;251:90–7.
Saavedra JM, Sanchez-Lemus E, Benicky J. Blockade of brain angiotensin II AT1 receptors
ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications.
Psychoneuroendocrinology. 2011;36:1–18.
Sandrini M, Vitale G, Pini LA. Effect of rofecoxib on nociception and the serotonin system in the rat
brain. Inflamm Res. 2002;51:154–9.
Schennach H, Murr C, Gachter E, Mayersbach P, Schonitzer D, Fuchs D. Factors influencing serum
neopterin concentrations in a population of blood donors. Clin Chem. 2002;48:643–5.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from
108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
Schwarz MJ, Ackenheil M, Riedel M, Muller N. Blood-cerebrospinal fluid barrier impairment as
indicator for an immune process in schizophrenia. Neurosci Lett. 1998;253:201–3.
Schwarz MJ, Riedel M, Ackenheil M, Muller N. Decreased levels of soluble intercellular adhesion
molecule-1 (sICAM-1) in unmedicated and medicated schizophrenic patients. Biol Psychiatry.
2000;47:29–33.
Schwieler L, Erhardt S, Erhardt C, Engberg G. Prostaglandin-mediated control of rat brain
kynurenic acid synthesis–opposite actions by COX-1 and COX-2 isoforms. J Neural Transm
(Vienna). 2005;112:863–72.
Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, et al. Increased levels of
IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia – significance for activa-
tion of the kynurenine pathway. J Psychiatry Neurosci. 2015;40:126–33.
Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H. Major depressive disorder is
associated with elevated monocyte counts. Acta Psychiatr Scand. 1996;94:198–204.
Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, et al. Common variants on chromosome
6p22.1 are associated with schizophrenia. Nature. 2009;460:753–7.
Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska M, Wiktorowicz K. Interleukin-
6 serum levels in depressed patients before and after treatment with fluoxetine. Ann N Y Acad
Sci. 1995;762:474–6.
Soliven B, Albert J. Tumor necrosis factor modulates the inactivation of catecholamine secretion in
cultured sympathetic neurons. J Neurochem. 1992;58:1073–8.
Sommer IE, de Witte L, Begemann M, Kahn RS. Nonsteroidal anti-inflammatory drugs in schizo-
phrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73:414–9.
Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-
inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr
Bull. 2014;40:181–91.
Song C, Leonard BE. An acute phase protein response in the olfactory bulbectomised rat: effect of
sertraline treatment. Med Sci Res. 1994;22:313–4.
Sparkman NL, Johnson RW. Neuroinflammation associated with aging sensitizes the brain to the
effects of infection or stress. Neuroimmunomodulation. 2008;15:323–30.
Spellberg B, Edwards JE Jr. Type 1/Type 2 immunity in infectious diseases. Clin Infect Dis.
2001;32:76–102.
Sperner-Unterweger B, Gaggl S, Fleischhacker WW, Barnas C, Herold M, Geissler D. Effects of
clozapine on hematopoiesis and the cytokine system. Biol Psychiatry. 1993;34:536–43.
Sperner-Unterweger B, Miller C, Holzner B, Widner B, Fleischhacker WW, Fuchs D. Measurement
of neopterin, kynurenine and tryptophan in sera of schizophrenic patients. In: Müller N, editor.
Psychiatry, psychoimmunology, and viruses. Vienna/New York: Springer; 1999. p. 115–9.
Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology 63

Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common
variants conferring risk of schizophrenia. Nature. 2009;460:744–7.
Stevens JR. Schizophrenia and multiple sclerosis. Schizophr Bull. 1988;14:231–41.
Swerdlow NR, van Bergeijk DP, Bergsma F, Weber E, Talledo J. The effects of memantine on
prepulse inhibition. Neuropsychopharmacology. 2009;34:1854–64.
Syvalahti E, Eskola J, Ruuskanen O, Laine T. Nonsuppression of cortisol in depression and immune
function. Prog Neuro-Psychopharmacol Biol Psychiatry. 1985;9:413–22.
Teunissen CE, van Boxtel MP, Bosma H, Bosmans E, Delanghe J, De Bruijn C, et al. Inflammation
markers in relation to cognition in a healthy aging population. J Neuroimmunol.
2003;134:142–50.
Traki L, Rostom S, Tahiri L, Bahiri R, Harzy T, Abouqal R, et al. Responsiveness of the EuroQol
EQ-5D and Hospital Anxiety and Depression Scale (HADS) in rheumatoid arthritis patients
receiving tocilizumab. Clin Rheumatol. 2014;33:1055–60.
Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, et al. Etanercept and clinical
outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised
phase III trial. Lancet. 2006;367:29–35.
Varga G, Nippe N, Balkow S, Peters T, Wild MK, Seeliger S, et al. LFA-1 contributes to signal I of
T-cell activation and to the production of T(h)1 cytokines. J Invest Dermatol.
2010;130:1005–12.
Vecsei L, Szalardy L, Fulop F, Toldi J. Kynurenines in the CNS: recent advances and new questions.
Nat Rev Drug Discov. 2013;12:64–82.
Wagner-Jauregg J. Fieberbehandlung bei Psychosen. Wien Med Wochenschr. 1926;76:79–82.
Wang AK, Miller BJ. Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite
alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder, and
depression. Schizophr Bull. 2018;44:75–83.
Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci. 2002;23:482–6.
Wilke I, Arolt V, Rothermundt M, Weitzsch C, Hornberg M, Kirchner H. Investigations of cytokine
production in whole blood cultures of paranoid and residual schizophrenic patients. Eur Arch
Psychiatry Clin Neurosci. 1996;246:279–84.
Yang C, Hashimoto K. Peripheral IL-6 signaling: a promising therapeutic target for depression?
Expert Opin Investig Drugs. 2015;24:989–90.
Yang C, Shirayama Y, Zhang JC, Ren Q, Hashimoto K. Peripheral interleukin-6 promotes resilience
versus susceptibility to inescapable electric stress. Acta Neuropsychiatr. 2015a;27:312–6.
Yang JJ, Wang N, Yang C, Shi JY, Yu HY, Hashimoto K. Serum interleukin-6 is a predictive
biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depres-
sion. Biol Psychiatry. 2015b;77:e19–20.
Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, et al. Cytokine-specific
central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res. 1994;643:40–9.
Zarrabi MH, Zucker S, Miller F, Derman RM, Romano GS, Hartnett JA, et al. Immunologic and
coagulation disorders in chlorpromazine-treated patients. Ann Intern Med. 1979;91:194–9.
Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure to physical and psychological
stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-
adrenal axis. Endocrinology. 1993;133:2523–30.
Zhou AJ, Lee Y, Salvadore G, Hsu B, Fonseka TM, Kennedy SH, et al. Sirukumab: a potential
treatment for mood disorders? Adv Ther. 2017;34:78–90.
Zhu J, Bengtsson BO, Mix E, Thorell LH, Olsson T, Link H. Effect of monoamine reuptake
inhibiting antidepressants on major histocompatibility complex expression on macrophages in
normal rats and rats with experimental allergic neuritis (EAN). Immunopharmacology.
1994;27:225–44.
Pharmacokinetic and Pharmacodynamic
Principles

Gerald Zernig and Christoph Hiemke

Contents
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
“Dose-Response Curve”: Concentration-Effect Relationships Explained . . . . . . . . . . . . . . . . . . . . . . . 70
Difficulties Encountered in Clinical Trials Aimed at Demonstrating Concentration-Effect
Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Why Single Center Trials Still Can Go Wrong . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Variability of the Medication’s Concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Other Examples for Clear-Cut Concentration-Effect Relationships Obtained
with Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Clear-Cut Concentration-Effect Relationships Obtained with Antidepressants . . . . . . . . . . . . . . . . . 77
The Problem of the Placebo Responders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
A Checklist to Improve Trials Investigating Concentration Effect Relationships . . . . . . . . . . . . . . 80
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Abstract
This chapter summarizes the pharmacokinetic principles that are essential in everyday
clinical practice: Whenever initiating a dosage, changing a dosage, or upon cessation
of a treatment, the new steady state of the medication (including its de facto
elimination) is not reached before 4 elimination half-lives. Many neuropsychiatric
medications have elimination half-lives around 24 h, so the clinician has to wait at
least 4 days until the new effect intensity can be expected. On pharmacologic
principle, medications with longer elimination half-lives should be preferred because
their concentrations fluctuate less, producing less variation in effect strength and

G. Zernig (*)
Department of Psychiatry 1, Medical University of Innsbruck, Innsbruck, Tirol, Austria
e-mail: gerald.zernig@i-med.ac.at
C. Hiemke
Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany
e-mail: hiemke@uni-mainz.de

© Springer Nature Switzerland AG 2022 65

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_1
66 G. Zernig and C. Hiemke

carrying a lower risk of adverse drug reactions (ADRs). With respect to pharmaco-
dynamics, clinical studies in psychiatric institutions have been notoriously poor in
demonstrating a relationship between the concentration of the prescribed medication
and its effect on psychiatric symptoms. This chapter identifies the very likely reasons
for this shortcoming of clinical trials: Concentration-effect relationships becomes less
and less clear-cut as one proceeds from simple outcomes that are very much upstream
in the biologic chain of events, for example, receptor occupancy or prolactin blood
concentration, to a multifactored outcome such as symptom improvement. Investi-
gators have to contend with “signal noise” contributed by placebo responders,
placebo deteriorators, and nonresponders, especially as one moves from single center
to multicenter trials. This chapter ends with a study design checklist to improve
clinical trials investigating concentration-effect relationships of neuropsychiatric
medications. With respect to the pharmacologic targets of neuropsychotropic medi-
cations (receptors, monoamine transporters, etc.), the reader is referred to the chapter
▶ “Adverse Drug Reactions, Intoxications and Interactions of Neuropsychotropic
Medications”

Abbreviations
▮ For reasons of easier accessibility through the search function of
softwares, hyphens or subscripts are given in the text. Therefore,
the 5HT1A receptor is given as “5HT1A receptor, or the com-
pound “MK-801” simply as “MK801.”
5HT 5-hydroxytryptamine ¼ serotonin
5HT2A Serotonin receptor, subtype 2A ¼ 5HT1A receptor ¼ 5HT2A
receptor
5HTT Serotonin transporter
ADR Adverse drug reaction
BPRS Brief psychiatric rating scale
CGI-I Clinical global impressions, improvement scale
D1, D2, etc. Dopamine receptor, subtype 1 ¼ D1 receptor ¼ D1 receptor
DAT Dopamine transporter
HAMD Hamilton depression rating scale
HRSD Hamilton rating scale for depression
NARI Noradrenaline reuptake inhibitor (reboxetine)
NaSSA Noradrenergic and specific serotonergic antidepressant
(mirtazapine, mianserin)
NAT Noradrenaline transporter, same as NET
PANSS Positive and negative syndrome scale
SERT Serotonin transporter
SERTI Serotonin transporter inhibitor, see also SSRI
SGA Second generation antipsychotic
SPC Summary of product characteristics
SNRI Serotonin norepinephrine reuptake inhibitor (e.g., duloxetine,
venlafaxine)
SSRI Selective serotonin reuptake inhibitor (e.g., escitalopram)
Pharmacokinetic and Pharmacodynamic Principles 67

Pharmacokinetics

Some pharmacologists like the following quip to sum up the difference between
pharmacokinetics and pharmacodynamics: “Pharmacokinetics is what the body does
to the drug and pharmacodynamics what the drug does to the body.” In the follow-
ing, we try to give a very concise overview of pharmacokinetics as relevant in
everyday clinical practice. Further readings are given at the end of this section.
When a compound is introduced into the body, be that through the mouth (“per
os,” po), by inhalation, injection, infusion, rubbing onto the skin, transdermal
patches, rectal or vaginal suppositories or enemas, it is absorbed at a speed and
completeness according to the route of administration, with the body starting to
metabolize and/or excrete the compound right away. Absorption is good for most of
the neuropsychotropic medications and independent of concomitant food intake,
with the notable exception of ziprasidone (Hiemke et al. 2018). For the oral route of
administration, a useful measure is the (oral) bioavailability, that is, the fraction
absorbed (F) of the active unmetabolized medication that can be found (usually over
the first 24 h) after oral intake as compared to an intravenous injection. Most
neuropsychotropic medications are well absorbed, so their bioavailability, F,
approaches 1 (i.e., 100%), for example, escitalopram or olanzapine with an F of
0.8 (i.e., 80% Hiemke et al. 2018). Some medications, however, are extensively
metabolized even during their first passage through the liver (“first pass effect”) so
that only a small fraction can exert its effect, for example, venlafaxine (F ¼ 0.4 or
40%) or quetiapine (F ¼ 0.09 or 9%) (Hiemke et al. 2018). Metabolism, broadly
speaking, occurs in two steps: First, the medication molecule is enzymatically
changed in its structure (phase 1 reactions: oxidation, reduction, hydrolysis), pre-
dominantly in reactions involving the cytochrome P450 (CYP) system. Often, the
medication loses its efficacy with the enzymatic change. Quite a number of psycho-
pharmacologic medications, however, retain their efficacy after enzymatic modifi-
cation, that is, become active metabolites, for example, 9-hydroxyrisperidone (also
called paliperidone (Hiemke et al. 2018)). More information on CYP isoforms
(pharmacogenetic variation) and drug-drug interactions involving the CYP system
can be found in our chapter on adverse drug reactions (ADRs) and in Hiemke et al.
(2018). Phase 1 reactions introduce a polar functional group that enables a phase
2 conjugation reaction with highly polar molecules such as glucuronic acid (forming
a glucuronide) or sulfuric acid (forming a sulfate). Both phase 1 and phase 2 reactions
take place in the liver, which has a much greater capacity for phase 2 than phase
1 reactions. These highly polar molecules are readily excreted in the liver or kidney
(Hiemke et al. 2018). Medications can also be excreted unchanged in the kidney, or
excreted through the bile and/or feces, or exhaled.
Medications can also be redistributed between different compartments of the
body (blood, muscle, fat, brain). Generally speaking, the more lipophilic a medica-
tion is (and most neuropsychotropic compounds are highly lipophilic), the more
readily it enters and “hides” in fatty compartments (including the brain), and the
larger its volume of distribution, Vd, becomes. If a medication distributes equally in
the water and tissues of the body, its Vd is 0.7 L/kg (as our bodies consist of 70%
water).
68 G. Zernig and C. Hiemke

In everyday clinical practice, it is important to know at what time after oral intake
(ingestion) a medication reaches it maximal concentration. The respective measure is
called tmax. Extended release formulations (in marketing lingo: “ER,” “XR,” “LA”
(“long acting”) or, an especially unlucky term, “retard”) have a longer tmax than the
respective “immediate release” (“IR”) formulation (sometimes not labeled as such).
For example, tmax is 6 h for Seroquel ® XR “Retardtabletten” but only 1–1.8 h in the
“normal,” that is, IR formulation of quetiapine (unfortunately, this is not explicitly
stated in the respective SPC for Seroquel ®, only in the very useful pharmacokinetics
tables in (Brunton et al. 2017) or (Hiemke et al. 2018)). Interestingly, the elimination
half-life for both Seroquel ® formulations is 7 h (respective SPC). Thus, the only
difference between the two formulations (ER ¼ XR vs IR) is that the IR formulation
peaks faster (i.e., at 1.8 h at the latest vs at 6 h; useful if quetiapine is used as a
hypnotic) than the ER formulation.
Almost all neuropsychotropic compounds are eliminated exponentially, mean-
ing that if a medication is stopped, has reached its peak concentration, and is then
eliminated from the body, at the end of the first elimination half-life (i.e., a time
span), t1/2, 50% of the medication remains. At the end of a time span of 2 elimi-
nation half-lives, 50% of 50%, that is, 25% of the original concentration remains.
After 3 t1/2, 12.5% remain, after 4 t1/2, only 6.25% remain, that is, the medication is
de facto eliminated. As Fig. 1 (corresponding to Fig. 2 of Hiemke et al. 2018)

Fig. 1 Fluctuation of the concentration of a medication based on elimination half-life and

dosing. In this schematic diagram, the following scenarios are illustrated: A, initiation of pharma-
cotherapy at a dosing interval that is equal to the elimination half-life, t1/2, of the medication (many
neuropsychiatric medications have been developed to have a t1/2 in the range of 24 h, allowing for
once daily dosing). B, upon changing the dosage, it takes 4 t1/2 to reach a new steady state. C,
fluctuations of the drug concentration if the dosing interval is twice the t1/2. D, fluctuations if the
dosing interval is half the t1/2. E, time-dependent concentration changes after a depot administration.
Reproduced with the publisher’s permission from Fig. 2 of Hiemke et al. (2018)
Pharmacokinetic and Pharmacodynamic Principles 69

Fig. 2 Different dose/

dosage/concentration-effect
relationships. For the purpose
of the present chapter, unit
dose (i.e., dose per
administration) can also be
regarded as “dosage”
(i.e., doses per time, ideally
the daily dose given once
daily) and should, ideally,
correspond to “concentration”
(blood plasma/serum level).
Please see the text for a
discussion of the different
curve shapes. Reproduced
with the publisher’s
permission from Fig. 4 of
Zernig et al. (2007)

shows, the same 4-elimination half-lives principle holds when initiating a

dosage (scenario A in Fig. 1), changing a dosage (scenario B in Fig. 1), or
upon cessation of a treatment (also scenario B in Fig. 1): The new steady state
of the medication (its de facto elimination can also be considered a form of
“steady state”) is not reached before 4 elimination half-lives have passed. Many
neuropsychiatric medications have elimination half-lives around 24 h, so the
clinician has to wait at least 4 days until the new effect intensity can be
expected. This is also essential for the design of clinical trials investigating
dose-response relationships in psychiatry (more precise, concentration-
response relationships): If the steady state of the medication has not been
reached, the clinician risks underestimating a medications efficacy and, there-
fore, overdosing the patient. On pharmacologic principle, in clinical practice,
medications with longer elimination half-lives should be preferred because their
concentrations fluctuate less, producing less variation in effect strength and
carrying a lower risk of adverse drug reactions (ADRs) (compare scenario C vs
D in Fig. 1).
70 G. Zernig and C. Hiemke

The reader who is interested in a more detailed presentation of pharmacokinetic

principles may consult, for example, the following references: (Welling 1986;
Wagner 1993; Bauer 2008; Brunton et al. 2017).

Pharmacodynamics

Clinical studies in psychiatric institutions have been notoriously poor in demonstrat-

ing a relationship between the concentration of the prescribed medication and its
effect on psychiatric symptoms. This unfortunate situation is not improved by the
fact that, by law, no proof of a concentration-effect relationship is required for the
approval of a medication. This section identifies the very likely reasons for this
shortcoming of clinical trials: Concentration-effect relationships become less and
less clear-cut as one proceeds from simple outcomes that are very much upstream in
the biologic chain of events, for example, receptor occupancy or prolactin blood
concentration, to a multifactored outcome such as symptom improvement. Investi-
gators have to contend with “signal noise” contributed by placebo responders,
placebo deteriorators, and nonresponders, especially as one moves from single
center to multicenter trials. This section ends with a study design checklist to
improve clinical trials investigating concentration-effect relationships of neuropsy-
chiatric medications.

“Dose-Response Curve”: Concentration-Effect Relationships

Explained

If one accepts that neuropsychotropic medications exert their effects in psychiatric

patients by interacting with biologically defined target structures (Eggart et al. 2011;
Stahl 2013; Brunton et al. 2017), then one has to recognize that these interactions are
governed by natural laws that have been defined in a quantitatively precise manner
(i.e., by equations) in the field of pharmacology (see, e.g., Zernig et al. 1996, 2007;
Kenakin 2009).
Such a systematic relationship between dose/dosage/concentration and effect is
implicitly acknowledged by almost all of us: Every time you put more sugar or
sweetener into your coffee or tea to make it sweeter, every time you swallow the
second pill because your headache has not improved enough after the first pill, every
time the prescribing physician increases the dose of a medication because of a
hitherto unsatisfactory response of the patient, every time we do that we acknowl-
edge the natural laws governing the relationship between a substance’s concentration
and its effect size.
Figure 2 provides an overview of the type of dose/concentration-response rela-
tionships that can be expected when analyzing the effects of neuropsychiatric
medications. If the effect is based on the interaction (i.e., binding) of the medication
(called a ligand when viewed from the perspective of binding) with a finite amount/
concentration of receptors (e.g., dopamine D2 receptors or serotonin transporters,
Pharmacokinetic and Pharmacodynamic Principles 71

SERTs), then the effect is saturable (solid curve in Fig. 2): Regardless of how high
the concentration of the medication (ligand) is pushed, the medication (ligand)
cannot produce an effect that exceeds a maximum that is defined by the system
under investigation. In the left panel (a) of Fig. 2, this is shown as a continuously
decreasing slope and, finally, a flattening of the curve describing this relationship
(called a “curvilinear” one). A pharmacologist would describe that the function
reaches its asymptote (ceiling). To emphasize, even in a plot in which the values
both of the ordinate (y axis) an abscissa (x axis) are expressed in linear (and not
logarithmic) form (panel a on the left side of Fig. 2) – a so-called “linear” plot – this
relationship is represented by a curve (solid) and not a line (small dashes). Such a
linear plot is most commonly used to describe concentration-effect relationships in
psychiatry. The saturability of the target system becomes more clearly visible if the
dose/concentration data on the abscissa (x axis) are transformed to their decadic
logarithm (panel b on the right side of Fig. 2). This type of plot is called a
semilogarithmic or “semilog” plot.
The relationship linking drug concentration to effect can be fitted to a logistic
function of the following form (see, e.g., Eq. 11.27 on p. 269 of (Kenakin 2009) or,
e.g., (Zernig et al. 1996) for a discussion):

Emax  concentrationslope
E¼ ð1Þ
EC50slope þ concentrationslope

where E is an effect and Emax the maximal effect of the drug, EC50 is the agonist
concentration producing a half-maximal effect, and “slope” is the slope factor
(sometimes called “Hill coefficient” (Walker et al. 1995; Kenakin 2009)). To account
for a baseline response (e.g., placebo responders), this equation should be extended
by a factor c (for baseline “constant”; see, e.g., Zernig et al. 1995, 1996, 1997;
Walker et al. 1998):

Emax  concentrationslope
E¼ þc ð2Þ
EC50slope þ concentrationslope

When the medication’s effects (e.g., alleviation of positive symptoms in schizo-

phrenic patients) is the result of the medication binding to only one group of
structurally identical binding sites (in our example, D2 receptor antagonists or
“blockers”) which are linked to a homogeneous signal transduction system, that is,
one receptor system (e.g., dopamine D2 receptors coupled to guanine nucleotide
binding proteins containing Gialpha subunits), the slope factor (or “Hill coefficient”
(Kenakin 2009)) becomes 1 (unity). In that case, the general logistic relationship
simplifies to that of a rectangular hyperbola (solid curve in panel a of Fig. 2). In a
semilog plot, this function becomes sigmoid function (panel b of Fig. 2), the typical
shape of what pharmacologists loosely call a “dose-response curve.” To repeat, a
rectangular hyperbola is the simplest form of the logistic equation (see, e.g., Zernig
et al. 1996; Kenakin 2009 for the underlying mathematical models). Examples for
72 G. Zernig and C. Hiemke

such a simple concentration-effect relationships are Fig. 5 below for D2 receptor

occupancy by olanzpaine or Fig. 17 below for SERT occupancy by the SSRI
paroxetine.
However, most concentration behavior relationships – including those in the field
of psychiatry, that is, the relationship between the concentration of a psychophar-
macologic medication and the clinical improvement of the patient – are characterized
by steep concentration-effect curves (see below). In mathematical terms, the slope
factor (or simply “slope”) of the logistic equation in these cases is larger than 1. In
the models illustrated in Fig. 2, the slope was set at 5 (long dashes). Consequently,
the full range of no effect to almost maximal effect is covered by changing the dose/
dosage/concentration of the medication only about three- to five-fold. Such a short
range was indeed found to be the orienting therapeutic range (“therapeutic reference
range”) of neuropsychiatric medications (Hiemke et al. 2018).
To complicate matters, many psychopharmacologic medications seem to have an
ascending concentration-response relationship at lower doses/dosages/concentra-
tions (covering the desired effects) and, at higher concentrations, a descending
concentration-response relationship, most likely because the adverse drug effects
at these high concentrations (e.g., sedation, psychomotor impairment or hyper-
prolactinemia) increasingly impair the clinical benefit for the patient. Therefore,
the best approach to quantitatively explain the clinical data without violating the
natural laws explained by pharmacology would be to fit the data to two logistic
equations, an ascending one at the lower concentration range and a descending one
at higher concentrations.
In the clinical literature given below, this biphasic concentration-effect relation-
ship has been crudely and wrongly approximated by a function of the general form
y ¼ a + b*x  c*x (Mauri et al. 2005), or y ¼ a + b*x  c*x2 (Perry et al. 1997;
Florio et al. 2017; De Donatis et al. 2019) (or forms with reverse signs, depending on
how clinical improvement is expressed, i.e., either as a decrease in the score of a test
or after transformation of the decrease into to a positive value, i.e., “improvement”)
which has no pharmacologic basis, that is, does not obey the natural laws discovered
and defined by the field of pharmacology. In other word, these functions do not
correspond to the underlying ligand-receptor interactions and signal transduction
amplification processes, that is, are logistic functions (see detailed discussion above).
As a methodologic note, the software package prism ® (www.graphpad.com) allows
even relatively inexperienced users to perform the analysis by using predefined
equations for the fits (the authors have no financial interest in this company or this
product).
A word of caution: Most neuropsychotropic medications show a large
interindividual variation in their pharmacokinetic parameters (see, e.g., Brunton
et al. 2017; Hiemke et al. 2018 or the respective SPCs). When these differences
were systematically studied (see, e.g., (Tanum et al. 2010) for citalopram or (Grunder
et al. 2008) for aripiprazol), it was found that for each dosage (i.e., daily dose), actual
concentrations varied mostly at least five-fold between individual patients, in some
individuals much more, that is, up to approximately 20-fold. It can be assumed that
in these studies, medication compliance/adherence was controlled, and that the
Pharmacokinetic and Pharmacodynamic Principles 73

Fig. 3 Relationship between duloxetine plasma concentration and antidepressant effect in a

single center trial. AR month 3, antidepressant response after 3 months of treatment. SCD, serum
concentration of duloxetin. See text for a detailed discussion. Reproduced with the publisher’s
permission from Fig. 1 of De Donatis et al. (2019)

documented differences were due to pharmacokinetic variation only. To further

illustrate the large interindividual differences in pharmacokinetic parameters, in the
well-controlled study by Conca and coworkers (De Donatis et al. 2019) detailed
below (Fig. 3), individual duloxetine concentrations ranged from approximately
10 to 175 ng/mL after a fixed dosage of 60 mg/day had been administered to all
patients as a monotherapy.
Therefore, basing any “dose-response relationship” analysis only on the dose/
dosage of the medication and not on the actual concentration of this medication in
blood (usually plasma or serum) will introduce an unacceptably high level of
uncertainty that can be avoided when focusing on the concentration of the
medication.

Difficulties Encountered in Clinical Trials Aimed at Demonstrating

Concentration-Effect Curves

As already stated above, clinical studies in psychiatric institutions have been

notoriously poor in demonstrating a relationship between the concentration of
the prescribed medication and its effect on psychiatric symptoms. Concentration-
effect relationship becomes harder and harder to demonstrate as one proceeds from
74 G. Zernig and C. Hiemke

simple outcomes that are very much upstream in the biologic chain of events, for
example, receptor occupancy or prolactin blood concentration, to a multifactored
outcome such as symptom improvement and as investigators have to contend with
“signal noise” contributed by placebo responders, placebo deteriorators, and non-
responders. We will argue that clinical improvement as rated by different observers
may be jeopardized by such a high degree of variability that it has very often been
impossible, especially in multicenter trials, to demonstrate the meaningful
concentration-effect relationships that the natural laws as described by pharma-
cology predict.
In other words, concentration-effect relationships become less and less clear-cut
as one proceeds from outcomes that, with respect to cause-effect relationships, are
most upstream, such as binding and occupancy of dopamine D2 receptors, to
biologic events that immediately follow D2 receptor occupancy, that is, changes in
the prolactin blood concentration, to psychiatric symptom improvement, which is
very much downstream in the chain of events and which is influenced by other
factors than the pharmacologic effect of the investigated medication. The decreasing
relationship between concentration and effect is exemplified here for olanzapine.
In a positron emission tomography (PET) study (Kapur et al. 1998), the binding
of the antipsychotic olanzapine to serotonin 5HT2 and dopamine D2 receptors at
different olanzapine (blood) plasma levels (concentrations) was analyzed. Assuming
binding to a single population of D2 receptors, the data were fitted to a saturating
function, that is, a rectangular hyperbola or, in other words, to a logistic equation
with a slope of 1 (see above) with very limited “noise” (i.e., the small variability) of
the D2 receptor binding data, that is, with actual PET data points that were very close
to the fitted curve (see Fig. 1 of Kapur et al. 1998).
A similar clear-cut and statistically significant correlation can be found for
olanzapine concentrations in plasma and a laboratory parameter, that is, the prolactin
level (see Fig. 2 of Citrome et al. 2009). Prolactin is a hormone synthesized in
lactotrophs of the anterior pituitary gland. Synthesis and secretion of this hormone
are mainly under the inhibitory control of hypothalamic dopamine. Inhibition of
hypophyseal dopamine D2 receptors enhances the release of prolactin.
Going more downstream and correlating olanzapine concentrations with the
improvement of psychiatric symptoms a poor relationship is obtained at best. In a
single center clinical trial on 54 inpatients the improvement after 2 weeks of the
same dosage (Mauri et al. 2005) weak, nevertheless still significant relationship was
observed by Mauri and coworkers (see Fig. 3 of Mauri et al. 2005). An ascending
concentration-effect curve and a few data points at very high olanzapine concentra-
tions suggest a descending part of a biphasic relationship as well (please see above
for an explanation of biphasic concentration-response relationships). As detailed
above, these authors have chosen to fit the data to a mathematical function that that
does not have a pharmacologic justification, that is, does not obey the underlying
ligand-receptor interactions and signal transduction amplification processes. How-
ever, when compared to the PET binding data above, the data points are scattered to a
visibly higher degree, also depending on the psychometric test used. The olanzapine
concentration-effect relationship obtained in a multicenter trial conducted in
Pharmacokinetic and Pharmacodynamic Principles 75

12 different investigative sites (Beasley et al. 1996a) exhibited markedly increased

variability compared to the abovementioned single center trial.
Finally, in the most recent analysis (Citrome et al. 2009) of the olanzapine
concentration-effect relationship obtained in a multicenter trial (Kinon et al.
2008) that we are aware of no relationship between olanzapine concentration and
improvement of psychiatric symptoms could be demonstrated, whereas a statisti-
cally significant correlation was found between olanzapine concentration and
prolactin level (see Fig. 2 of (Citrome et al. 2009). Even simple inspection of the
figure indicates that experimenters’ ratings of clinical improvement (i.e., percent
change in the total PANSS score) are jeopardized by a much higher variation than the
laboratory parameter prolactin.

Why Single Center Trials Still Can Go Wrong

The discussion of the above findings should not mislead the reader in believing that
every single center trial will yield a clear-cut concentration-effect relationship. The
following example may serve as a cautionary case, especially as one of us
(gz) contributed to that study as a coauthor (and could neither convince the other
authors to retract the paper nor retract his coauthorship once the study was published):
In a “naturalistic” treatment setting, that is, among in- and outpatients treated at a
university hospital psychiatric department, plasma concentrations of several
new-generation antipsychotics were correlated to clinical improvement, expressed
as percent change in PANSS scores (Kaufmann et al. 2016). As several different
antipsychotics were administered, their plasma concentrations were normalized to
the lower limit of their respective orienting therapeutic range (OTR, “therapeutic
reference range”) (Hiemke et al. 2018). This study demonstrated a significant effect
of treatment but did not reveal any significant relationship between concentration
and effect (see Fig. 2b of Kaufmann et al. 2016). If anything, the most pronounced
improvement occurred at concentrations that were below the lower limit of the OTR.
After publication, it turned out that steady state may not have been reached in some
cases. This meant that – also depending on the time span between the plasma level
determination and the PANSS symptom scoring relative to the antipsychotic’s
elimination half-life – overreporting or underreporting of the antipsychotic’s efficacy
may have occurred. More importantly, 14 of the 67 patients were treated with two
antipsychotics and 3 patients were treated with three antipsychotics consecutively, a
fact that had not been declared explicitly in the original article (Kaufmann et al.
2016). This mistake was corrected later (Kaufmann et al. 2020). Of importance for
the analysis of the concentration-effect relationship, 14 of the 67 patients did not
respond to the first antipsychotic or suffered from intolerable adverse drug reactions
(ADRs) and had thus to be switched to a second antipsychotic. Three of the
67 patients even had to be switched twice. Thus, underresponders or nonresponders
with respect to the desired antipsychotic effects and/or overresponders with respect
to ADRs are overrepresented – while not being declared as such – in the published
data set. With respect to interrater- and test-retest reliability, that is, the variability of
76 G. Zernig and C. Hiemke

the score of clinical response, the original article only stated that “... At each visit, a
psychiatrist belonging to a trained schizophrenia research team rated psychopathol-
ogy ...” (p. 718 of Kaufmann et al. 2016)).

Variability of the Medication’s Concentration

After commenting critically on the variability of the assessment of the change in

psychiatric symptoms, we should not forget that the determination of the medica-
tion’s concentration is also subject to considerable variability. As stated on p. 55 of
Hiemke et al. (2018): “Within the therapeutic reference range, intraday- and interday
precision should not exceed 15% (coefficient of variation) and accuracy should not
deviate more than 15% for the nominal value . . .” The coefficient of variation is the
standard deviation expressed as percent of the mean value. With respect to intraday
precision, this translates to the true value lying within 4*15% (i.e., 2 standard
deviations in each direction) of the measured value. For example, for a measured
value of 10 ng/mL, the true value may range from 7 ng/mL to 13 ng/mL, that is,
differ by almost a factor of 2. The true concentration could be more precisely
captured by performing more than one measurement, for example, do duplicate or
triplicate determinations of each blood sample. This, however, is to our knowledge
not done under routine clinical conditions, even if these measurements are subse-
quently used for clinical trials.

Other Examples for Clear-Cut Concentration-Effect Relationships

Obtained with Antipsychotics

Another example that a laboratory parameter, that is, prolactin concentration, is less
variable that the rating of the clinical improvement of the patient comes from a single
center trial by (Kapur et al. 2000): The prolactin concentrations of the very same
patients followed a much more orderly relationship to dopamine D2 receptor
occupancy by haloperidol than their CGI-I ratings (see Fig. 1 of (Kapur et al. 2000).
The clear-cut receptor occupancy data obtained with the PET ligand [11C]
raclopride for the D2 receptor antagonist (or “blocker”) olanzapine (see Fig. 1 of
Kapur et al. 1998) can be generalized to the partial D2 receptor partial agonist
aripiprazole as obtained in a [18F]fallypride PET study as well (see Fig. 1 of Grunder
et al. 2008).
To provide the reader with a pharmacodynamic orientation with respect to the all
these different dopamine receptor ligands: According to the International Union of
Basic and Clinical Pharmacology (IUPHAR) Subcommittee on Dopamine Recep-
tors (www.guidetopharmacology.org), dopamine receptors can be divided in two
families: a D1-like family (D1 and D5) and a D2-like family (D2, D3 and D4). The
affinities of the various dopamine receptor ligands (agonists or antagonists/blockers)
can be expressed as the negative decadic logarithm (“p”) of the concentration
(in mol/L) at which 50% of the receptors are occupied (usually quantified in
Pharmacokinetic and Pharmacodynamic Principles 77

competition binding experiments and therefore termed “pKi” or “dissociation con-

stant of the inhibitor”). To illustrate, a pKi of 9 corresponds to 1 nanomol/liter and a
pKi of 7 to 100 nanomol/liter, that is, a concentration that is 100-fold higher, thus
indicating a 100-fold lower affinity of ligand with a pKi of 7 than a ligand with a pKi
of 9. In other words, the higher the pKi, the higher the affinity of the ligand for the
receptor under investigation.
According to the IUPHAR data base (www.guidetopharmacology.org, accessed
20,200,609), haloperidol displays a pKi of 7.6–8.2 at the human D1 receptor, 7.4–
8.8 at D2, 7.5–8.6 at D3, 8.7–8.8 at D4, 6.3 at D5, and 6.7–7.3 at the 5HT2A
receptor and acts as an antagonist/blocker at all these receptors. To summarize,
haloperidol does not seem to differentiate well between D1 and D2/D3/D4 receptors.
Olanzapine has a pKi of 8.7 at the human D2 receptor (no data for the D1, D3, or D5
receptor available) and a pKi of 8.6–8.9 at 5HT2A receptor and acts as an antagonist/
blocker at all these receptors with similar affinity for both D2 and 5HT2A receptors.
Aripiprazole acts as partial agonist with a pKi of 9.1 at the human D2 receptor and
of 9.7 at the rat D2 receptor and of 7.3 for the rat D4 receptor (no human D4 and no
D1, D3, or D5 receptor data available). To summarize, aripiprazole seems to be a
partial agonist with high selectivity for D2 over D4 receptors. S-()-raclopride acts
as an antagonist/blocker with the following pKi at the following dopamine receptors:
8.0 at D2 (human), 7.9 at D3 (human), 7.5 D3 (rat), and 5.7 at D4 (rat; no other data
on DA or 5HT2A receptors available). To summarize, S-()-raclopride binds with
equal and preferential affinity to D2- and D3 receptors. Binding affinities for
fallypride were not available in the IUPHAR database or the PET study itself
(Grunder et al. 2008).

Clear-Cut Concentration-Effect Relationships Obtained

with Antidepressants

As another example why rater homogeneity – which by definition is greater in a

single center study than in a multicenter one – is beneficial for demonstrating a
systematic relationship between concentration and effect of a neuropsychiatric
medication is the study by De Donatis et al. (2019). Figure 3 (corresponding to
Fig. 1 of De Donatis et al. 2019 shows the effect of the antidepressant duloxetine
given (after an initial titration) at a fixed oral dosage of 60 mg/day for 3 months.
Clinical improvement (on the ordinate or y-axis) was quantified as percent improve-
ment in the 21-item Hamilton Depression (HAMD-21) score (25  3 for N ¼ 66
(26 males); type of variance not given). The patients were rated in an outpatient
setting by two psychiatrists with more than 10 years’ experience as close collabo-
rators, rendering very similar HAMD ratings very likely. Interrater- or test-retest
reliability, however, was not explicitly examined. Each assessment was done by one
of these two psychiatrists independently (Conca, personal communication). Please
note how much the individual duloxetine concentrations differed, that is, ranged
from approximately 10 to 175 ng/mL, after one and the same dosage of 60 mg/d.
Please also note that the authors fitted the concentration-effect relationship to a
78 G. Zernig and C. Hiemke

Fig. 4 Relationship between escitalopram plasma concentration and antidepressant effect in

a single center trial. AR month 3, antidepressant response after 3 months of treatment. SCE, serum
concentration of escitalopram. See text for a detailed discussion. Reproduced with the publisher’s
permission from Fig. 3B of Florio et al. (2017)

function (i.e., y ¼ a + b*x - c*x2) that has no pharmacologic basis, that is, does not
obey the underlying ligand-receptor interactions and signal transduction amplifica-
tion processes, that is, are logistic functions (see detailed discussion above).
A similarly clear-cut concentration-effect relationship could be demonstrated by
Conca and coworkers for escitalopram (Fig. 4):

The Problem of the Placebo Responders

In a 2014 position paper, Preskorn explained “why standard antidepression registra-

tion trials are not able to establish a correlation between antidepressant response and
the plasma concentration of biogenic amine antidepressants, such as selective
serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors”
(p. 133 of (Preskorn 2014)). Regardless of the fact that clear-cut concentration-effect
relationships could indeed be demonstrated for the serotonin-norepinephrine reup-
take inhibitor (SNRI) duloxetine (De Donatis et al. 2019) and the SSRI escitalopram
in single center trials (Florio et al. 2017), Preskorn pointed out an important reason
for his claim; he asserted that about one-third of the patients do not respond to SSRIs
or SNRIs, about one-third do respond specifically to the medication, and about
one-third respond to the “placebo” effect (Preskorn 2014). Figure 5 (corresponding
to Fig. 2 of Hiemke 2019) illustrates how nonresponders and placebo responders
Pharmacokinetic and Pharmacodynamic Principles 79

Fig. 5 Masking of a clear-cut concentration-effect relationship because of nonresponders and

placebo responders in a clinical trial. In this example, a response is defined as 50% of the
maximum possible response. The total sample of 30 patients consists of 10 serum responders
(i.e., patients responding to the medication), 10 placebo responder (i.e., patients profiting from the
sum on non-medication interventions in a clinical trial), and 10 nonresponders (i.e., patients
profiting neither from pharmacotherapy or non-medication interventions). Reproduced with the
publisher’s permission from Fig. 2 of (Hiemke 2019). Under flexible dose conditions placebo
responders will stay on low doses associated with low drug concentrations and nonresponders will
receive maximal doses and high drug concentrations to attain the maximal drug effect. This will
even lead to a negative relation between drug concentration and clinical improvement
(Hiemke 2019)

muddy the concentration effect relationship and illustrates by which type of analysis
this can be overcome, that is, by constructing bins of drug concentrations and
expressing the response as percent responders for each given bin.
We could demonstrate that this type of analysis is able to unmask hidden
concentration-effect relationships (Eggart et al. 2011) by reanalyzing data that had
been interpreted as demonstrating a “lack of correlation [of paroxetine plasma levels]
with efficacy or adverse events” (i.e., the title of (Tasker et al. 1989)). In the original
multicenter analysis, steady state paroxetine plasma concentrations were obtained
with “the timing of the blood sampled varied according to the study design,” p. 152
of (Tasker et al. 1989)) and correlated with the antidepressant response. Unfortu-
nately, no quantitative definition of the Clinical Global Impression (CGI)-based
response was given in that analysis. When paroxetine concentrations were
arranged in increasing bins of 10 ng/mL and the respective number of responders
was given for each bin, no clear-cut concentration-effect relationship was obtained
80 G. Zernig and C. Hiemke

Fig. 6 Relationship
between paroxetine plasma
concentration, serotonin
transporter occupancy, and
antidepressant effect. SERT,
serotonin transporter (5HTT).
See text for details.
Reproduced with the
publisher’s permission from
Fig. 6 of Eggart et al. (2011)

(Tasker et al. 1989)). In our analysis, we kept the original 10 ng/mL bin order but
expressed the effect as percent of responders by 10 ng/mL (Eggart et al. 2011)).
After this modest data transformation, a clear-cut and meaningful relationship
emerged (Fig. 17). We also compared the clinical response data to serotonin trans-
porter occupancy data obtained in a PET study (Meyer et al. 2004) and found that the
clinical response data corresponded well to the binding data, that is, the respective
concentration-effect relationships overlapped to a considerable degree (Fig. 6
corresponding to Fig. 6 of Eggart et al. 2011).
At the level of the study design, a placebo lead-in phase of 4–7 days had been
employed in the olanzapine trials discussed above (Beasley et al. 1996a, b; Perry
et al. 1997; Callaghan et al. 1999). We opine that this is a very commendable
approach. However, inspection of Fig. 8 above (corresponding to Fig. 10 of Calla-
ghan et al. 1999) reveals that at olanzapine concentrations below approximately
3 ng/mL (i.e., levels that are close to placebo), the BPRS change still ranges from
approximately 70% (quasi-placebo responders) to +80% (quasi-placebo
deteriorators). Still, the placebo lead-in may have improved the data (i.e., lowered
the noise of the response); we are not aware of any study that compared data
obtained without versus with the placebo lead-in.
A final note on data analysis using the receiver operating characteristic (ROC)
relationship: This type of analysis has successfully been used to derive a threshold
concentration for a significant clinical response (see, e.g., Perry et al. 1997; Spina
et al. 2000; Perry et al. 2001; Muller et al. 2007; Fellows et al. 2003) and may be
successful in cases in which the fitting of the concentration effect data to the logistic
function (see above for a detailed description) has failed. A good description of the
ROC method can be found in Fellows et al. (2003).

A Checklist to Improve Trials Investigating Concentration Effect

Relationships

Based on the published studies discussed above, the following is a (most likely
incomplete) checklist for the design of clinical trials investigating concentration-
effect curves and for the analysis of such relationships:
Pharmacokinetic and Pharmacodynamic Principles 81

1. Use a placebo lead-in phase to eliminate placebo responders

2. Avoid flexible dosage during trial (initial titration is OK for first 2 weeks) but
should be of the same duration for all patients
3. Predefine the sufficient length of fixed dosage for the effect to stabilize
4. Steady state must be reached
5. Sample blood at the minimal (i.e., trough) concentration
6. When blood is not taken at trough, expected minimal concentrations should be
calculated by extrapolation (Hiemke et al. 2018)
7. Design study to include treatment at concentrations below the orienting thera-
peutic range as well to capture the lower and ascending part of the concentration-
effect relationship, that is, avoid sampling only at the ceiling of the concentration-
effect relationship
8. Allow for the concentration-effect relationship to start at placebo responder level
(i.e., do not force the fitting through zero but introduce a baseline response in the
fitting model)

Cross-References

▶ Adverse Drug Reactions, Intoxications and Interactions of Neuropsychotropic

Medications

References
Bauer LA. Applied clinical pharmacokinetics. New York: McGraw Hill; 2008.
Beasley CM Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo:
results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology. 1996a;124:159–67.
Beasley CM Jr, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S. Olanzapine versus placebo
and haloperidol: acute phase results of the north American double-blind olanzapine trial.
Neuropsychopharmacology. 1996b;14:111–23.
Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman and Gilman’s the pharmacological basis of
therapeutics. 13th ed. New York: McGraw-Hill; 2017.
Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine. Pharmacokinetic and pharmaco-
dynamic profile. Clin Pharmacokinet. 1999;37:177–93.
Citrome L, Stauffer VL, Chen L, Kinon BJ, Kurtz DL, Jacobson JG, Bergstrom RF. Olanzapine
plasma concentrations after treatment with 10, 20, and 40 mg/d in patients with schizophrenia:
an analysis of correlations with efficacy, weight gain, and prolactin concentration. J Clin
Psychopharmacol. 2009;29:278–83.
De Donatis D, Florio V, Porcelli S, Saria A, Mercolini L, Serretti A, Conca A. Duloxetine plasma level
and antidepressant response. Prog Neuro-Psychopharmacol Biol Psychiatry. 2019;92:127–32.
Eggart V, Hiemke C, Zernig G. “There is no dose-response relationship in psychopharmacotherapy”
vs “pharmacotherapy in psychiatry is based on ligand-receptor interaction”: a unifying hypoth-
esis and the need for plasma concentration based clinical trials. Psychopharmacology.
2011;217:297–300.
Fellows L, Ahmad F, Castle DJ, Dusci LJ, Bulsara MK, Ilett KF. Investigation of target plasma
concentration-effect relationships for olanzapine in schizophrenia. Ther Drug Monit.
2003;25:682–9.
Florio V, Porcelli S, Saria A, Serretti A, Conca A. Escitalopram plasma levels and antidepressant
response. Eur Neuropsychopharmacol. 2017;27:940–4.
82 G. Zernig and C. Hiemke

Grunder G, Fellows C, Janouschek H, Veselinovic T, Boy C, Brocheler A, Kirschbaum KM,

Hellmann S, Spreckelmeyer KM, Hiemke C, Rosch F, Schaefer WM, Vernaleken I. Brain and
plasma pharmacokinetics of aripiprazole in patients with schizophrenia: an [18F]fallypride PET
study. Am J Psychiatry. 2008;165:988–95.
Hiemke C. Concentration-effect relationships of psychoactive drugs and the problem to calculate
therapeutic reference ranges. Ther Drug Monit. 2019;41:174–9.
Hiemke C, Bergemann N, Broich K, Clement HW, Conca A, Deckert J, Dietmaier O, Domschke K,
Eckermann G, Egberts K, Fric M, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-
Reinecke U, Janssen G, Jaquenoud Sirot E, Laux G, Messer T, Mossner R, Muller MJ,
Paulzen M, Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schwarz M, Stegmann B,
Steimer W, Stingl J, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G, Baumann
P. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry and neurology:
update 2017. Pharmacopsychiatry. 2018;51:9–62.
Kapur S, Zipursky RB, Remington G, Jones C, Dasilva J, Wilson AA, Houle S. 5-HT2 and D2
receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry.
1998;155:921–8.
Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occu-
pancy, clinical response, and side effects: a double-blind PET study of first-episode schizophre-
nia. Am J Psychiatry. 2000;157:514–20.
Kaufmann A, Wartelsteiner F, Yalcin-Siedentopf N, Baumgartner S, Biedermann F, Edlinger M,
Kemmler G, Rettenbacher MA, Rissanen TT, Widschwendter CG, Zernig G, Fleischhacker
WW, Hofer A. Changes in psychopathology in schizophrenia patients starting treatment with
new-generation antipsychotics: therapeutic drug monitoring in a naturalistic treatment setting.
Eur Neuropsychopharmacol. 2016;26:717–28.
Kaufmann A, Post F, Yalcin-Siedentopf N, Baumgartner S, Biedermann F, Edlinger M, Kemmler G,
Rettenbacher MA, Widschwendter CG, Zernig G, Fleischhacker WW, Hofer A. Corrigendum to
“Changes in psychopathology in schizophrenia patients starting treatment with new-generation
antipsychotics: therapeutic drug monitoring in a naturalistic treatment setting” [Eur. Neuropsy-
chopharmacol. 26 (2016) 717–728]. Eur Neuropsychopharmacol. 2020;31:162–3.
Kenakin TP. A pharmacology primer. Theory, applications, and methods. Amsterdam: Elsevier;
2009.
Kinon BJ, Volavka J, Stauffer V, Edwards SE, Liu-Seifert H, Chen L, Adams DH, Lindenmayer JP,
Mcevoy JP, Buckley PF, Lieberman JA, Meltzer HY, Wilson DR, Citrome L. Standard and
higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a random-
ized, double-blind, fixed-dose study. J Clin Psychopharmacol. 2008;28:392–400.
Mauri MC, Steinhilber CP, Marino R, Invernizzi E, Fiorentini A, Cerveri G, Baldi ML, Barale
F. Clinical outcome and olanzapine plasma levels in acute schizophrenia. Eur Psychiatry.
2005;20:55–60.
Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP,
Cheok A, Houle S. Serotonin transporter occupancy of five selective serotonin reuptake
inhibitors at different doses: an [11C]DASB positron emission tomography study. Am
J Psychiatry. 2004;161:826–35.
Muller MJ, Regenbogen B, Hartter S, Eich FX, Hiemke C. Therapeutic drug monitoring for
optimizing amisulpride therapy in patients with schizophrenia. J Psychiatr Res. 2007;41:673–9.
Perry PJ, Sanger T, Beasley C. Olanzapine plasma concentrations and clinical response in acutely ill
schizophrenic patients. J Clin Psychopharmacol. 1997;17:472–7.
Perry PJ, Lund BC, Sanger T, Beasley C. Olanzapine plasma concentrations and clinical response:
acute phase results of the North American olanzapine trial. J Clin Psychopharmacol.
2001;21:14–20.
Preskorn SH. Therapeutic drug monitoring (TDM) in psychiatry (part I): why studies attempting to
correlate drug concentration and antidepressant response don’t work. J Psychiatr Pract.
2014;20:133–7.
Pharmacokinetic and Pharmacodynamic Principles 83

Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia AG, Ventimiglia A, Perucca
E. Relationship between plasma concentrations of clozapine and norclozapine and therapeutic
response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharma-
cology. 2000;148:83–9.
Stahl SM. Stahl’s essential psychopharmacology: neuroscientific basis and practical application.
Cambridge: Cambridge University Press; 2013.
Tanum L, Strand LP, Refsum H. Serum concentrations of citalopram – dose-dependent variation in
R- and S-enantiomer ratios. Pharmacopsychiatry. 2010;43:190–3.
Tasker TC, Kaye CM, Zussman BD, Link CG. Paroxetine plasma levels: lack of correlation with
efficacy or adverse events. Acta Psychiatr Scand Suppl. 1989;350:152–5.
Wagner JG. Pharmacokinetics for the pharmaceutical scientist. Missionsstrasse 44, CH-4055.
Basel: Technomic Publishing AG; 1993.
Walker EA, Zernig G, Woods JH. Buprenorphine antagonism of mu opioids in the rhesus monkey
tail-withdrawal procedure. J Pharmacol Exp Ther. 1995;273:1345–52.
Walker EA, Zernig G, Young AM. In vivo apparent affinity and efficacy estimates for mu opiates in
a rat tail-withdrawal assay. Psychopharmacology. 1998;136:15–23.
Welling PG. Pharmacokinetics. Processes and mathematics. Washington, DC: American Chemical
Society; 1986.
Zernig G, Issaevitch T, Broadbear J, Burke T, Lewis JW, Brine GA, Woods JH. Receptor reserve
and affinity of mu opioid agonists in mouse antinociception: correlation with receptor binding.
Life Sci. 1995;57:2113–25.
Zernig G, Issaevitch T, Woods JH. Calculation of agonist efficacy, apparent affinity and receptor
population changes after administration of insurmountable antagonists: comparison of different
analytical approaches. J Pharmacol Toxicol Methods. 1996;35:223–37.
Zernig G, Lewis JW, Woods JH. Clocinnamox inhibits the intravenous self-administration of opioid
agonists in rhesus monkeys: comparison with effects on opioid agonist-mediated anti-
nociception. Psychopharmacology. 1997;129(3):233–42.
Zernig G, Ahmed SH, Cardinal RN, Morgan D, Acquas E, Foltin RW, Vezina P, Negus SS, Crespo
JA, Stoeckl P, Grubinger P, Madlung E, Haring C, Kurz M, Saria A. Explaining the escalation of
drug use in substance dependence: models and appropriate animal laboratory tests. Pharmacol-
ogy. 2007;80:65–119.
Pharmacovigilance

Maike Scherf-Clavel

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Core Functions of Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
How Pharmacovigilance Works . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Pharmacovigilance in Different Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Adverse Drug Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Pharmacovigilance in Psychiatry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Prevention and Management of Adverse Drug Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Prevention of ADE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Therapeutic Drug Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Managing Adverse Drug Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Abstract
Fatal outcomes related to the use of drugs in the past, for example, most
prominently, the thalidomide tragedy, has caused the development of systematic,
structured and regulated pharmacovigilance system in the 1960s. Pharmacov-
igilance includes processes for monitoring and evaluating adverse drug effects
with the aim to improve the safety of a drug therapy. Core functions of
pharmacovigilance are case management, signal management, and benefit-risk
management. They cover the early stages in a drug’s life cycle, but also, as it is
impossible to identify all safety concerns during clinical trials, post-marketing
observational analyses. In later stages of a drug’s life cycle safety monitoring is
based on spontaneous reporting of ADEs. In the EU and the USA, good
pharmacovigilance systems are established; however, in some middle- and low-
income countries, pharmacovigilance is still at its beginning or not available.

M. Scherf-Clavel (*)
Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg,
Würzburg, Germany
e-mail: Scherf_M@ukw.de

© Springer Nature Switzerland AG 2022 85

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_9
86 M. Scherf-Clavel

This chapter focusses on pharmacovigilance, describing how it works, what

methods are used, describing more or less advanced pharmacovigilance systems
in different countries, what an adverse drug effect and an adverse drug event is,
and how to prevent and to manage adverse drug effects, especially in the field of
neuropsychopharmacology.

Introduction

Fatal outcomes related to the use of drugs in the past have caused the development of
pharmacovigilance systems (Beninger 2018). The World Health Organization
(WHO) defines pharmacovigilance as the “science and activities relating to the
detection, assessment, understanding and prevention of adverse effects or any
other possible drug-related problem” (WHO 2004). In short, pharmacovigilance
describes processes for monitoring and evaluating adverse drug effects (WHO
2004). An adverse drug effect can be caused by every substance that produces a
therapeutic effect; however, different drugs showed different risks of producing
adverse effects (Edwards and Aronson 2000).
The thalidomide tragedy, described as the “largest men-made medical disaster in
history,” causing congenital malformation in newborns, triggered the establishment
of a systematic, structured, and regulated spontaneous reporting system (Fornasier
et al. 2018; Vargesson 2015). Probably the first pharmacovigilance program was a
careful systematic review of case reports considering adverse effects of chloram-
phenicol in 1962 (Beninger 2018). In 2001 EudraVigilance, the official European
database to manage and analyze information regarding adverse drug effects, was
founded (Fornasier et al. 2018). In 2012, a new legislation changed the pharmacov-
igilance program in Europe; in consequence, proactive strategies of risk manage-
ment replaced reactive strategies (Coleman and Pontefract 2016; Fornasier et al.
2018). Nowadays, an ADE defines any adverse event following the use of a drug,
and patients were involved in pharmacovigilance activities (Fornasier et al. 2018).

Core Functions of Pharmacovigilance

Pharmacovigilance is “a key component of effective drug regulation systems,

clinical practice and public health programs” (WHO 2004). Core functions of
pharmacovigilance are case management, signal management, and benefit-risk man-
agement, but also safety-related activities in pharmaceutical companies are included
(Beninger 2018). “Case management” describes the input and process of adverse
events in a safety database, including the observation of a clinical finding probably
related to drug administration (Beninger 2018; Ralph 2017). “Signal management”
describes standardized signal detection activities to find drug-associated reported
adverse events (Beninger 2018; Ralph 2017), and “benefit-risk management”
describes the overall process, including all of a product’s risk-related knowledge
Pharmacovigilance 87

and the resulting benefit (Beninger 2018). To manage pharmacovigilance programs,

a close collaboration between the industry, government, hospitals, academia, med-
ical and pharmaceutical associations, poison control centers and medicine informa-
tion centers, health professionals, patients, consumers, the media, and the WHO is
mandatory (WHO 2004).

How Pharmacovigilance Works

Pharmacovigilance activities can be divided into regulatory, industry, and academia

activity (Harmark and van Grootheest 2008).
Pharmacovigilance activities in the early stage of a drug’s life cycle covers the
protection of humans participating in clinical trials including, for example, informed
consent forms for clinical studies, institutional review board documentation and data
monitoring committee deliberations (Beninger 2018). Today, these documents and
information are mostly standardized receiving periodic updates; pharmacovigilance
professionals therefore play a critical role in keeping stakeholders informed about
developments (Beninger 2018).
During clinical development, only a limited number of individuals receive the
drug, and only short-time safety and efficacy is investigated (WHO 2004). Even
phase III studies, determining the cause-effect relationship, are not ideal for moni-
toring the safety of a drug (Harmark and van Grootheest 2008); however in the early
stage of a drug’s life cycle, clinical pre- and post-approval studies are the primary
source of ADEs (Martin et al. 2018) (Fig. 1). Long-term effectiveness and safety, as
well as safety under real-life conditions, preferably in an inhomogeneous patient
group or vulnerable patient groups (pregnant women, children, elderly, people

Fig. 1 Pharmacovigilance and safety concerns during clinical development of a drug. (Modified
according to WHO 2004)
88 M. Scherf-Clavel

belonging to an ethnic minority, patients with comedication, or confounding dis-

eases) are unknown at this time (Awada and Zgheib 2014; Bigi and Bocci 2017;
Harmark and van Grootheest 2008; WHO 2004). As it is impossible to identify all
safety concerns during clinical trials, post-marketing observational data are critical
for risk minimization and to improve therapy (FDA 2005; Harmark and van
Grootheest 2008; WHO 2004).
In this later stage, safety monitoring is based on spontaneous reporting of
adverse drug events (Fig. 1) (Bigi and Bocci 2017; Hadi et al. 2017; Martin et al.
2018). Post-marketing pharmacovigilance studies are either descriptive (hypotheses
generating studies) or analytical (e.g., validate generated hypotheses, detect causal
relationships, estimate proportion of these events) (Awada and Zgheib 2014).
Descriptive studies cover spontaneous or anecdotal (e.g., case reports in journals)
reporting or intensive monitoring; for analytical studies various approaches, for
example, case-control studies, cohort studies, and clinical trials, can be used
(Edwards and Aronson 2000; Harmark and van Grootheest 2008). Both types of
studies (descriptive and analytical) do not classify patients into subpopulations or
low- and high-risk groups and do not ascertain a causal relationship between an
event and the drug as these studies do not assess the underlying mechanism of an
ADE (Awada and Zgheib 2014).
Spontaneous reporting systems are considered as the most cost-effective method to
monitor drug safety (Hadi et al. 2017). The main function of spontaneous reporting
systems, applied to all drugs during their lifetime, is detecting signals of new, rare, and/
or serious ADEs (Hadi et al. 2017; Harmark and van Grootheest 2008). Nurses,
constantly monitoring patients’ drug responses, medical doctors, and pharmacists
should be proactive in pharmacovigilance activities (Bigi and Bocci 2017; Meyboom
et al. 1999). However, about 95% of all healthcare professionals do not report adverse
drug events, and less than 5% of all ADEs were reported (Bigi and Bocci 2017;
Coleman and Pontefract 2016). Another option is that patients themselves report their
ADEs (Inacio et al. 2017). This might be advantageous, as patients describe their
ADEs in more detail than healthcare professionals (Inacio et al. 2017); however,
patient-reported outcomes always include an emotional component. For evaluation
of the relationship between the drug and the ADE the quality of the report is critical
(FDA 2005). For a valid report, only four items are necessary: an identifiable patient, a
reaction, a medical product, and an identifiable reporter (Coleman and Pontefract
2016). Poor quality reports, also reports on known adverse effects, underreporting,
or selective reporting, are limitations of spontaneous reporting systems (Hadi et al.
2017; Harmark and van Grootheest 2008). Moreover, spontaneous reporting systems
cannot prove cause-effect relationships, establish accurate incidence rates, and identify
risk factors for ADEs (Harmark and van Grootheest 2008).
The major systems of pharmacovigilance are VigiBase, the WHO Programme for
International Drug Monitoring; EudraVigilance, the EMA system for European
Economic Area members; and FAERS/VAERS, the FDA Pharmacovigilance
Reporting Systems (Martin et al. 2018). To analyze the spontaneous reporting
databases, data mining becomes more and more important (Harmark and van
Grootheest 2008). Data mining uses different algorithms to analyze how the number
of observed cases differs from the number of expected cases (Harmark and van
Pharmacovigilance 89

Grootheest 2008). One example is the sequence symmetry analysis, which compares
initiation of a drug (A) after another drug (B) with initiation of B after A (Lai et al.
2017). If there is a difference, it may indicate on an ADE of one of the two drugs (Lai
et al. 2017).
Intensive monitoring uses prescription data to identify users of a drug and asking
the prescriber about adverse events (Harmark and van Grootheest 2008). Only
selected drugs during a specified time period were monitored; however, the method
can identify events that were not suspected as ADE of the studied drug and quantify
the risk of an ADE (Harmark and van Grootheest 2008).

Pharmacovigilance in Different Countries

In middle- and low-income countries, pharmacovigilance was absent in the early

years (Olsson et al. 2015). In these countries improving the access to drugs was more
important than reporting adverse events of drugs not available to the majority of the
population (Olsson et al. 2015). Recently, the access to medicines has enhanced, and
therefore the need for pharmacovigilance also in middle- and low-income countries
is existent (Olsson et al. 2015). Thus, most middle- and low-income countries begin
to establish pharmacovigilance systems with the help of the WHO (Olsson et al.
2015). However, as the healthcare systems in these countries are more complex and
fragmented compared to industrial countries, establishing pharmacovigilance
involves new challenges. For example, the limited number of healthcare profes-
sionals, their general fear of reporting ADEs as they do not trust in the integrity of
authorities, the limited electronic or postal network, and the numerous local lan-
guages hamper the establishment of pharmacovigilance systems (Olsson et al. 2015).
Regarding most of the Asian countries, the pharmaceutical market is dominated by
generic drugs; however, more advanced countries, as Singapore, have a strong
patented drug market (Biswas 2013). As the volume of clinical trials conducted in
Asia increased, higher-quality requirements and a focus on pharmacovigilance were
necessary (Biswas 2013). In India, exporting about 40% of the generic drugs
worldwide, several approaches to establish a pharmacovigilance system failed
even though India joined the WHO program in 1997 (Biswas 2013). However,
with the financial help of their governments, India and China set good examples
and established proper pharmacovigilance systems recently (Olsson et al. 2015).
Nowadays, in India in all medical colleges, pharmacovigilance training is included
in the undergraduate curriculum (Olsson et al. 2015). Also in Japan, Korea,
Morocco, Tunisia, and Egypt, a progressive pharmacovigilance system is present,
whereas in Libya or Yemen, pharmacovigilance is just in statu nascendi, and in
countries as Somalia and Mauritania, no pharmacovigilance system is available
(Alshammari et al. 2019; Biswas 2013). However, compared to high-income coun-
tries, in very few middle- and low-income countries, a full set of pharmacovigilance
requirements for marketing authorization holders is introduced, and the regulatory
basis of a pharmacovigilance is weak or nonexistent (Olsson et al. 2015). To further
expand pharmacovigilance systems in middle- and low-income countries, annual
meetings of representatives of national pharmacovigilance centers are organized
90 M. Scherf-Clavel

from the WHO, and additional WHO collaboration centers were established in
Ghana and Morocco (Olsson et al. 2015).
In Europe, countries have moved toward greater harmonization of pharmacov-
igilance (Pitts et al. 2016). Since the renewal of the pharmacovigilance program in
2012, in the EU over 26,000 potential signals were reviewed resulting in 453 signals
assessed by the Pharmacovigilance Risk Assessment Committee (PRAC), and about
200 signals resulted in updates of the product information (Potts et al. 2019). Signal
detection, following the reporting of ADEs, is a collaboration between different
officials (National Competent Authorities (NCAs), European Medicines Agency
(EMA), and marketing authorization holders (MAHs)) (Potts et al. 2019). A con-
firmed signal is then reported to the PRAC for prioritization and assessment (Potts
et al. 2019). In the USA, the pharmacovigilance system is stricter than in the EU,
showing that pharmacovigilance in the twenty-first century is “the systematic mon-
itoring of the process of pre-market review and post-market surveillance, which are
linked through study design, product labelling, therapeutic outcomes, adverse
events, hospital and clinician reporting systems, the pharmacy interface, compliance,
and a complete understanding of real-world evidence” (Pitts et al. 2016).
However, as every country is individual, there is no general way to establish
pharmacovigilance in one country (Olsson et al. 2015). Moreover, no country has a
perfect pharmacovigilance system, but every country needs clear and published
national policies for pharmacovigilance (Martin et al. 2018; Olsson et al. 2015).

Adverse Drug Effects

Pharmacovigilance includes detection and reporting of adverse drug effects, medi-

cation errors, counterfeit and substandard drugs, lack of efficacy, and misuse/abuse
of drugs, drug-drug interactions (Hadi et al. 2017). However, adverse drug effects
remain the prime focus of pharmacovigilance, as they are a major reason for therapy
discontinuation and consequently of potentially poor treatment outcomes and are
ranked among the top ten mortality reasons in some countries, even if they are often
preventable (Dodd et al. 2018; Hadi et al. 2017; WHO 2004). In general, an adverse
effect is a harmful or unpleasant reaction due to the administration of a medicinal
product, predicting a risk for future administrations and warranting prevention,
specific treatment or withdrawal of the drug (Edwards and Aronson 2000). The
terms “adverse effect” and “adverse reaction” are substitutable and describe an
adverse outcome that is caused by the drug, whereas an “adverse event” defines an
outcome occurring while taking a drug, but not necessarily associable to it (Edwards
and Aronson 2000). Adverse drug reactions can be classified with different
classification systems. Most prominently, type A adverse drug reactions are dose-
dependent and pharmacologically predictable, and type B reactions are not predict-
able and idiosyncratic (Coleman and Pontefract 2016). Type A reactions accounted
for >80% of all reactions and are more common than type B reactions (Jaquenoud
Sirot et al. 2006). Off-target adverse effects are not predictable based on their
therapeutic pharmacological action but are associated with significant morbidity
and costs (Garon et al. 2017). Adverse effects can also be classified into six types:
Pharmacovigilance 91

dose-related (augmented), non-dose-related (bizarre), dose-related and time-related

(chronic), time-related (delayed), withdrawal (end-of-use), and failure of therapy
(failure) (Edwards and Aronson 2000). DoTS is another classification system, which
was proposed as the terms type A and B reaction do not work for every adverse
effect, classifying reactions depending on the dose, the time course of the reaction,
and relevant susceptibility factors (Coleman and Pontefract 2016). Suspected
adverse effects can be attributed to various causalities describing the association
with the drug (Edwards and Aronson 2000). The WHO Uppsala Monitoring Centre
(WHO-UMC) classifies ADE into groups with “certain,” “probably/likely,” “possi-
ble,” “unlikely,” “conditional/unclassified,” and “unassessable/unclassifiable” cau-
sality (Edwards and Aronson 2000; WHO-UMC).

Pharmacovigilance in Psychiatry

As psychiatric disorders are of chronic and relapsing nature pharmacotherapy should

be continued for months or even years (Gaitatzis and Sander 2013; Huhn et al. 2019;
Rajkumar and Melvin 2014). Therefore, the risk for ADEs increases (Rajkumar and
Melvin 2014). The FDA-reported drugs associated with serious adverse effects
between 1998 and 2005 including a number of psychoactive drugs, for example,
venlafaxine, clozapine, risperidone, or olanzapine (Moore et al. 2007). Additionally,
seizures with bupropion and suicidality in children taking SSRIs were two of the
major ADEs reported in Europe between 1995 and 2008 (Harmark and van
Grootheest 2008). The ADE of bupropion was identified through physician reports
(Rajkumar and Melvin 2014). Thus, for clinicians it is important to take responsive-
ness in identifying and reporting ADEs.
Especially in psychiatry, pharmacovigilance is of special importance due to
different reasons. Most of the drugs used for psychiatric diseases are frequently
associated to ADEs, and polypharmacy is frequently observed (Rajkumar and
Melvin 2014). Moreover, patients were often comorbid and need to take their
medications for years (Rajkumar and Melvin 2014).
In general, patients should not be treated longer than necessary with a drug
(Edwards and Aronson 2000), and careful pretreatment as well as monitoring of
the patients during drug therapy can minimize adverse events. However, untreated
mental illness itself is associated to a number of risks and adverse outcomes, which
often are underappreciated (Dodd et al. 2018).

Prevention and Management of Adverse Drug Effects

Prevention of ADE

In general, knowledge of patient susceptibilities, for example, pharmacogenetic

markers, age, pregnancy, and ethnicity, can reduce the risk of adverse drug effects
(Coleman and Pontefract 2016). To prevent known adverse drug effects, a health
check should be undertaken before initiating pharmacotherapy (Lader 1999).
92 M. Scherf-Clavel

This check should include information about comorbid conditions, drug misuse,
self-harm, self-neglect, poor nutrition, alcohol/smoking, accidents, chaotic lifestyle,
social circumstances, isolation, lack of caregiver, inappropriate accommodation, and
delusional conduct (Lader 1999). Additionally, the patient should accept the risks
and benefits of the treatment option (Dodd et al. 2018). Considering specific drug
classes, pretreatment evaluation, individualization of the therapy, and regular patient
monitoring can prevent predictable adverse effects (Lader 1999). Also cotreatment
with other drugs, but also monitoring electrolytes or renal function, can also reduce
the risk for ADEs (Coleman and Pontefract 2016).
Common adverse effects and handling them during neuropsychopharma-
cotherapy are shown in Table 1 (Ables and Nagubilli 2010; Dodd et al. 2018;
Lader 1999; Toledano and Gil-Nagel 2008).
Different antipsychotic drugs show different side effect profiles (Huhn et al.
2019). In general, older antipsychotics are associated with EPS and prolactin
elevation, whereas newer antipsychotics are associated with weight gain and seda-
tion (Huhn et al. 2019).
Most of the ADEs of antiepileptic drugs are predictable and occur early after
onset of therapy, but others occur after months or years of treatment (Gaitatzis and
Sander 2013). Due to the comparable efficacy of the antiepileptic drugs, the differ-
ences in ADEs are an important factor while initiating individual therapies (Toledano
and Gil-Nagel 2008). ADEs were reported to affect the quality of life at least as much
as repetitive seizures (Toledano and Gil-Nagel 2008). However, in everyday clinical
practice, screening for ADEs is not systematically included; therefore, the preva-
lence of ADEs in antiepileptic drug treatment potentially remains underestimated
(Toledano and Gil-Nagel 2008). In general, before treatment initiation, potential
individual risks, described by age, sex, childbearing potential, comorbidities,
comedications, and individual wishes, should be taken into account (Gaitatzis and
Sander 2013). Avoiding overtreatment reduces the risk of ADEs, as most of the
reported adverse effects of antiepileptic drugs are dose-dependent (Gaitatzis and
Sander 2013).
Anticholinergic drugs include many different classes of drugs, for example,
antipsychotics, antidepressants, but also drugs for the treatment of the Parkinson’s
disease and anxiolytics (Collamati et al. 2016). Peripheral side effects of anticholin-
ergic drugs are dry mouth, nausea, vomiting, constipation, bloated feeling, abdom-
inal pain, loss of taste, and anorexia, and also ophthalmic side effects occur (blurred
vison, diplopia, mydriasis, increased ocular tension); central side effects are dizzi-
ness, lightheadedness, tingling, headache, drowsiness, weakness, nervousness,
numbness, mental confusion, excitement, dyskinesia, lethargy, syncope, speech
disturbance, and insomnia (Collamati et al. 2016). To predict the risk of known
ADEs in the treatment with anticholinergic drugs, in vitro methods and anticholin-
ergic scales have been developed (Cantudo Cuenca et al.; Villalba-Moreno et al.
2016), but none of these methods have been standardized, and there is no consensus
on how to define drug exposure (Collamati et al. 2016).
Psychoactive drugs in general affect the cardiovascular system (Brouillette and
Nattel 2017). To minimize the risk of negative cardiovascular consequences, patient-
Pharmacovigilance 93

Table 1 Common adverse drug effects, pretreatment before initiating therapy and treatment during
therapy of the most important neuropsychopharmacological drugs
Adverse effect Comments Pretreatment procedure Monitoring/treatment
Antipsychotics (Lader 1999)
Weight gain Increased risk Establish baseline Monitor weight
for weight Exercise regularly
cardiovascular Dietary advice Diet
disease,
diabetes,
osteoarthritis
Psychological
impact
Hyperprolactinemia Evaluate symptoms of Monitor symptoms
prolactinemia
Sedation Tolerance Advise patients on Take the drug as
development additive effects of nighttime dose
alcohol, risk of driving, Check if persisting for
and accidents >6 months
Anticholinergic effects Dry mouth, Exclude severe Dental hygiene
blurred vision, constipation, urologic Regular dental checks
constipation, difficulties, visual
urinary problems
retention
Hypotension Increased risk Supine and standing Monitor blood
for falls, bone blood pressure pressure
fractures, and measurement Start with a low dose
considerable and increase slowly
morbidity
Extrapyramidal Acute EPS, Assessment of Treat appropriately
symptoms (EPS) parkinsonism, preexisting EPS
akathisia,
tardive
dyskinesia
Seizures Dose-related Identify high-risk Avoid high doses and
seizure patients (family history rapid dose titration
potential of epilepsy, substantial Prophylactic use of
brain damage) anti-convulsants
Cardiac toxicity QT Check for cardiac Regular ECGs
prolongation history, irregular pulse,
undertake an ECG
Antidepressants (Ables and Nagubilli 2010; Dodd et al. 2018)
Headache, nausea, Diagnostic work up, e.g., organic causes of Monitor weight and
agitation, sedation, depression, personal and family history, waist circumference,
sexual dysfunction, physical health (weight, metabolic assess metabolic
diminished mental disorders, sexual health, alcohol, tobacco, parameters and sexual
acuity and memory, substance use/dependence, pregnancy, dysfunction, check for
weight gain, metabolic liver function), EGC, electrolytes suicidal ideation,
abnormalities, cardiac monitor renal and
toxicity, neurological hepatic function,
toxicity, hepatic electrolytes and blood
pressure, monitor
(continued)
94 M. Scherf-Clavel

Table 1 (continued)
Adverse effect Comments Pretreatment procedure Monitoring/treatment
toxicity, increased cardiac function,
suicidality therapeutic drug
monitoring
Serotonin syndrome Elucidate on symptoms of serotonin Appropriate treatment
syndrome, avoid combined use of and withdrawal of
serotonergic drugs serotonergic drugs
Antiepileptic drugs (Gaitatzis and Sander 2013; Toledano and Gil-Nagel 2008)
Somnolence Fluctuations in Tolerance development Avoid high doses,
Dizziness serum level ➔ rapid dose titration,
Ataxia exacerbation of and coadministration
Diplopia ADEs with other drugs
Blurring of vision “Start low, go slow”
Fatigue Therapeutic drug
Vertigo monitoring
Cognitive dysfunction Lower doses, if drugs
are used in
combination
Skin rush Resolved after “Start low, go slow”
discontinuation Immediate
discontinuation
Steven-Johnson- Infrequently “Start low, go slow”
Syndrome, toxic within the first Monitor: painful rash,
epidermal necrolysis 2 month of systemic
treatment inflammation, mucosal
involvement
Immediate
discontinuation
Acute hepatitis Within the first Screen for previous
3 months (drug hepatic diseases,
induced liver inborn errors of
injuries) metabolism, mental
No retardation
concentration-
dependence
Aplastic anemia
Agranulocytosis
Psychiatric adverse Common in all Screen for patient’s “Start low, go slow”
effects antiepileptic individual and family
drugs history on existing
psychiatric or
neurological disorders,
refractory epilepsy
Paradoxical Pharmacological
Aggravation of treatment should not be
Seizures based solely on the
type of seizure but
rather on the epilepsy
syndrome.
(continued)
Pharmacovigilance 95

Table 1 (continued)
Adverse effect Comments Pretreatment procedure Monitoring/treatment
Change in body weight Weight gain Establish baseline
and weight loss weight
possible
(depending on
the drugs)
Fractures, osteoporosis, No uniform consensus
rickets how to monitor and
prevent osteoporosis
periodic bone health
screening
Supplements:
bisphosphonates,
calcium, vitamin D
Sexual dysfunction,
altered sperm
morphology, motility,
concentration,
reproductive endocrine
dysfunction in women
Visual field defects

specific risk factors and the risk profile of drugs should be considered (Brouillette
and Nattel 2017). Following the low-dose treatment initiation, the applied dose
should carefully be increased according to the clinical signs (Brouillette and Nattel
2017). It is good to know that QT-prolonging drugs can be used safely, if appropriate
precautions are taken (Brouillette and Nattel 2017). Therefore, the risk of QT
prolongation should not dissuade patients from the necessary psychiatric therapy
(Brouillette and Nattel 2017).

Pharmacogenetics

Searching for genetic predictors for adverse drug reactions is another approach to
prevent ADEs (Brandl et al. 2014; Guerrini and Perucca 2018; Jaquenoud Sirot et al.
2006). Currently, for antiepileptic drugs genetic predictors were established
(Guerrini and Perucca 2018). For example, the human leukocyte antigen (HLA)-
B15:02 allele is strongly associated to carbamazepine-induced Steven-Johnson
syndrome in the Chinese Han population and other South Asian ethnic groups
(Guerrini and Perucca 2018). Also regarding antipsychotic drugs, different genetic
factors were associated with adverse effects (Brandl et al. 2014). It is recommended
to reduce doses in CYP2D6 poor metabolizers (Dean 2012), two polymorphisms in
dopamine receptor 2 were associated with a higher risk for tardive dyskinesia and the
Met allele in COMT (Val(108/158)Met) was protective against tardive dyskinesia
(Brandl et al. 2014).
96 M. Scherf-Clavel

Clinical consequences from pharmacogenetic findings are just now being

introduced, for example, the metabolizer status, but the widespread use of
pharmacogenetics will still take several years of investigation as most of the
studies are far from reliable results (Brandl et al. 2014; Osanlou et al. 2018;
Perroud 2011). However, as the significant interindividual variation in drug
exposure is explained by, for example, organ function and disease state,
pharmacogenetic testing does not replace drug monitoring to guide clinical
decisions (Garon et al. 2017), but has the potential to add significant information
to the drug monitoring result.

Therapeutic Drug Monitoring

Therapeutic drug monitoring is also a tool to prevent adverse drug effects, as the
upper limit of the therapeutic reference range is defined by the increased risk of
adverse drug reactions (Baumann 2008; Gentry and Rodvold 1995; Gerlach et al.
2016; Haen 2011; Hiemke et al. 2018; Jaquenoud Sirot et al. 2006; Schütze and
Schwarz 2016). In contrast, others argue that TDM is only of limited use for
therapy safety, as the same serum concentration in different patients can lead to
an ADE in one patient but not in the second (Dodd et al. 2018; Jaquenoud Sirot
et al. 2006).
In psychiatry the association between serum drug levels and clinical effects has
been investigated mainly for lithium and tricyclic drugs (Jaquenoud Sirot et al.
2006). In other areas, for example, immunosuppressant drugs, TDM is an
established tool to prevent ADEs (Jaquenoud Sirot et al. 2006). In epilepsy, TDM
has shown its clinical utility and in oncology, TDM is increasingly used for therapy
safety reasons (Jaquenoud Sirot et al. 2006; Verheijen et al. 2017; Westerdijk et al.
2019).

Managing Adverse Drug Effects

Due to the nature of the different adverse effects, various strategies for their
management were suggested. In case of serious ADEs, rapid action, for exam-
ple, emergency treatment and withdrawal of the medicine, is essential (Edwards
and Aronson 2000). Clinical benefit-risk assessment can be used to decide
which medicine should be withdrawn and which not, and a benefit-risk deci-
sion should be made whether or not the medicine is crucial to the patient
(Edwards and Aronson 2000). If it is not clear which drug was causative for
the reaction, the nonessential should be withdrawn first, and if it is a dose-
related ADR, dose reduction should be considered, rather than withdrawal of
the drug (Edwards and Aronson 2000). If a drug, causing ADR is absolutely
necessary for a patient, symptomatic treatment is obligatory (Edwards and
Aronson 2000).
Pharmacovigilance 97

References
Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam
Physician. 2010;81:1139–42.
Alshammari TM, Mendi N, Alenzi KA, Alsowaida Y. Pharmacovigilance systems in Arab coun-
tries: overview of 22 Arab countries. Drug Saf. 2019;42:849–68.
Awada Z, Zgheib NK. Pharmacogenovigilance: a pharmacogenomics pharmacovigilance program.
Pharmacogenomics. 2014;15:845–56.
Baumann P. Pharmacovigilance in psychiatry: pharmacogenetic tests and therapeutic drug moni-
toring are promising tools. Expert Rev Clin Pharmacol. 2008;1:183–5.
Beninger P. Pharmacovigilance: an overview. Clin Ther. 2018;40:1991–2004.
Bigi C, Bocci G. The key role of clinical and community health nurses in pharmacovigilance. Eur J
Clin Pharmacol. 2017;73:1379–87.
Biswas P. Pharmacovigilance in Asia. J Pharmacol Pharmacother. 2013;4:S7–s19.
Brandl EJ, Kennedy JL, Muller DJ. Pharmacogenetics of antipsychotics. Can J Psychiatr.
2014;59:76–88.
Brouillette J, Nattel S. A practical approach to avoiding cardiovascular adverse effects of psycho-
active medications. Can J Cardiol. 2017;33:1577–86.
Cantudo Cuenca M, Munoz Cejudo B, Mora Mora M, Fernandez Martinez G, Cantal Sanchez M.
Applying different scales for calculating the anticholinergic burden in older patients. European
Association of Hospital Pharmacists. https://www.eahp.eu/sites/default/files/4cps-180.pdf
Accessed 16 Dec 2019.
Coleman JJ, Pontefract SK. Adverse drug reactions. Clin Med (Lond). 2016;16:481–5.
Collamati A, Martone AM, Poscia A, Brandi V, Celi M, Marzetti E, Cherubini A, Landi F.
Anticholinergic drugs and negative outcomes in the older population: from biological plausi-
bility to clinical evidence. Aging Clin Exp Res. 2016;28:25–35.
Dean L. Clozapine therapy and CYP2D6, CYP1A2, and CYP3A4 genotypes. In: Pratt V, McLeod
H, Rubinstein W, Dean L, Kattman B, Malheiro A, editors. Medical genetics summaries.
Bethesda: National Center for Biotechnology Information (US); 2012.
Dodd S, Mitchell PB, Bauer M, Yatham L, Young AH, Kennedy SH, Williams L, Suppes T, Lopez
Jaramillo C, Trivedi MH, Fava M, Rush AJ, McIntyre RS, Thase ME, Lam RW, Severus E,
Kasper S, Berk M. Monitoring for antidepressant-associated adverse events in the treatment of
patients with major depressive disorder: an international consensus statement. World J Biol
Psychiatry. 2018;19:330–48.
Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet.
2000;356:1255–9.
FDA. Guidance for industry – good pharmacovigilance practices and pharmacoepidemiologic
assessment. Food and Drug Administration. 2005. https://www.fda.gov/regulatory-informa
tion/search-fda-guidance-documents Accessed 21 Nov 2019.
Fornasier G, Francescon S, Leone R, Baldo P. An historical overview over pharmacovigilance. Int J
Clin Pharm. 2018;40:744–7.
Gaitatzis A, Sander JW. The long-term safety of antiepileptic drugs. CNS Drugs. 2013;27:435–55.
Garon SL, Pavlos RK, White KD, Brown NJ, Stone CA Jr, Phillips EJ. Pharmacogenomics of off-
target adverse drug reactions. Br J Clin Pharmacol. 2017;83:1896–911.
Gentry CA, Rodvold KA. How important is therapeutic drug monitoring in the prediction and
avoidance of adverse reactions? Drug Saf. 1995;12:359–63.
Gerlach M, Egberts K, Dang SY, Plener P, Taurines R, Mehler-Wex C, Romanos M. Therapeutic
drug monitoring as a measure of proactive pharmacovigilance in child and adolescent psychi-
atry. Expert Opin Drug Saf. 2016;15:1477–82.
Guerrini R, Perucca E. Genetic testing to prevent adverse reactions to antiepileptic drugs: Primum
non nocere. Neurology. 2018;90:155–6.
Hadi MA, Neoh CF, Zin RM, Elrggal ME, Cheema E. Pharmacovigilance: pharmacists' perspective
on spontaneous adverse drug reaction reporting. Int Pharm Res Pract. 2017;6:91–8.
98 M. Scherf-Clavel

Haen E. Therapeutic drug monitoring in pharmacovigilance and pharmacotherapy safety.

Pharmacopsychiatry. 2011;44:254–8.
Harmark L, van Grootheest AC. Pharmacovigilance: methods, recent developments and future
perspectives. Eur J Clin Pharmacol. 2008;64:743–52.
Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts
K, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R,
Janssen G, Jaquenoud E, Laux G, Messer T, Mossner R, Muller MJ, Paulzen M, Pfuhlmann B,
Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B,
Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G,
Baumann P. Consensus guidelines for therapeutic drug monitoring in neuropsychophar-
macology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Backers
L, Rothe P, Cipriani A, Davis J, Salanti G, Leucht S. Comparative efficacy and tolerability of 32
oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a
systematic review and network meta-analysis. Lancet. 2019;394:939–51.
Inacio P, Cavaco A, Airaksinen M. The value of patient reporting to the pharmacovigilance system:
a systematic review. Br J Clin Pharmacol. 2017;83:227–46.
Jaquenoud Sirot E, van der Velden JW, Rentsch K, Eap CB, Baumann P. Therapeutic drug monitoring
and pharmacogenetic tests as tools in pharmacovigilance. Drug Saf. 2006;29:735–68.
Lader M. Some adverse effects of antipsychotics: prevention and treatment. J Clin Psychiatry.
1999;60(Suppl 12):18–21.
Lai EC, Pratt N, Hsieh CY, Lin SJ, Pottegard A, Roughead EE, Kao Yang YH, Hallas J. Sequence
symmetry analysis in pharmacovigilance and pharmacoepidemiologic studies. Eur J Epidemiol.
2017;32:567–82.
Martin LG, Hanssens Y, Paudyal V. Overview of this issue: pharmacovigilance, what is new? Int J
Clin Pharm. 2018;40:737–9.
Meyboom RH, Egberts AC, Gribnau FW, Hekster YA. Pharmacovigilance in perspective. Drug Saf.
1999;21:429–47.
Moore TJ, Cohen MR, Furberg CD. Serious adverse drug events reported to the food and drug
administration, 1998-2005. Arch Intern Med. 2007;167:1752–9.
Olsson S, Pal SN, Dodoo A. Pharmacovigilance in resource-limited countries. Expert Rev Clin
Pharmacol. 2015;8:449–60.
Osanlou O, Pirmohamed M, Daly AK. Pharmacogenetics of adverse drug reactions. Adv
Pharmacol. 2018;83:155–90.
Perroud N. Suicidal ideation during antidepressant treatment: do genetic predictors exist? CNS
Drugs. 2011;25:459–71.
Pitts PJ, Louet HL, Moride Y, Conti RM. 21st century pharmacovigilance: efforts, roles, and
responsibilities. Lancet Oncol. 2016;17:e486–e92.
Potts J, Genov G, Segec A, Raine J, Straus S, Arlett P. Improving the safety of medicines in the EU:
from signals to action. Clin Pharmacol Ther. 2019;107(3):521–9.
Rajkumar RP, Melvin G. Pharmacovigilance for psychiatrists: an introduction. Indian J Psychiatry.
2014;56:176–81.
Ralph EI. Causality assessment in pharmacovigilance: still a challenge. Drug Saf. 2017;40:365–72.
Schütze G, Schwarz MJ. Therapeutic drug monitoring for individualised risk reduction in
psychopharmacotherapy. TrAC Trends Anal Chem. 2016;84:14–22.
Toledano R, Gil-Nagel A. Adverse effects of antiepileptic drugs. Semin Neurol. 2008;28:317–27.
Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C
Embryo Today. 2015;105:140–56.
Verheijen RB, Yu H, Schellens JHM, Beijnen JH, Steeghs N, Huitema ADR. Practical recommen-
dations for therapeutic drug monitoring of kinase inhibitors in oncology. Clin Pharmacol Ther.
2017;102:765–76.
Pharmacovigilance 99

Villalba-Moreno AM, Alfaro-Lara ER, Perez-Guerrero MC, Nieto-Martin MD, Santos-Ramos B.

Systematic review on the use of anticholinergic scales in poly pathological patients. Arch
Gerontol Geriatr. 2016;62:1–8.
Westerdijk K, Desar IME, Steeghs N, van der Graaf WTA, van Erp NP. Imatinib, sunitinib and
pazopanib: from flat-fixed dosing towards a pharmacokinetically guided personalized dose. Br J
Clin Pharmacol. 2019;86(2):258–73.
WHO-UMC. The use of the WHO-UMC system for standardised case causality assessment. World
Health Organisation – the Uppsala Monitoring Centre. https://www.who.int/medicines/areas/
quality_safety/safety_efficacy/WHOcausality_assessment.pdf Accessed 13 Dec 2019.
WHO. Pharmacovigilance: ensuring the safe use of medicines. Geneva: World Health Organization;
2004. https://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/
Accessed 22 Nov 2019
Pharmacoeconomics

Richard Dodel, Christopher Kruse, Annette Conrads-Frank, and

Uwe Siebert

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Categories of Health Economic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
In Which Cases Is a Health Economic Evaluation Recommended? . . . . . . . . . . . . . . . . . . . . . . . 106
Parameters of Health Economic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Time Horizon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Decision-Analytical Models and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Institutions for Evaluating Cost-Effectiveness in Health Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Health Technology Assessment and Cost-Effectiveness Thresholds . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Pharmacoeconomic Evaluation of Drugs Prescribed for Brain Disorders . . . . . . . . . . . . . . . . . . . . . 114
Supplement: Pharmacoeconomic Evaluations of Brain Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

Abstract
Newly developed drugs and medical devices have made a major contribution to
improving the health of populations. However, the rise in health care expenditure
has been a major concern due to the financial pressure it imposes on public
budgets. In response health authorities seek instruments to contain drug

R. Dodel (*)
Department of Geriatric Medicine, University Duisburg-Essen, Essen, Germany
e-mail: Richard.dodel@uk-essen.de
C. Kruse
Uniklinik Essen, Essen, Germany
e-mail: Christopher.kruse@uk-essen.de
A. Conrads-Frank · U. Siebert
Department of Public Health, Health Services Research and Health Technology Assessment,
UMIT – University for Health Sciences, Medical Informatics and Technology, Hall, Tyrol, Austria
e-mail: Annette.Conrads-Frank@umit.at; Uwe.siebert@umit.at

© Springer Nature Switzerland AG 2022 101

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_381
102 R. Dodel et al.

expenditures while still supporting further health improvements. No group of

chronic diseases burdens the world more than brain disorders. WHO data suggest
that brain disorders cause 1/3 of the burden of all diseases; it represents the largest
contributor to the “all cause morbidity” burden as measured by DALYs.
In recent years, the instruments of economic evaluation research have increas-
ingly been used to assess the efficiency of medical measures. Depending on the
chosen outcome of the study, a distinction is made between cost-minimization,
cost-benefit, cost-effectiveness, and cost-utility studies.
If the available cost and effectiveness data do not have sufficient external
validity because they do not fully reflect the practice of health care provision,
health economic modeling can be carried out using decision-analytical proce-
dures. The aim of decision analysis is to identify the strategy with the maximum
expected value after weighting the medical benefit, the risks, and, if necessary, the
costs of the various alternatives for action. Despite the strong power of the
methodology, it should be kept in mind that the decision analysis only has a
supporting function with regard to the decision-making process.
This chapter provides an introduction to pharmacoeconomics and displays a
list of health economics studies in neuropsychiatric diseases.

Introduction

Over the past decades, newly developed drugs and medical devices have made a
major contribution to improving the health of populations (Grootendorst et al. 2009).
However, in most countries, the rise in health care expenditure has been a major
concern due to the financial pressure it imposes on public budgets: during 1995–
2005 the OECD countries have experienced an annual average health expenditure
growth per capita of 4%, which outpaced the economic growth of 2.2%. According
to a new OECD forecast, health expenditure will outpace GDP growth over the next
15 years in almost every OECD country; health spending per capita will grow at an
average annual rate of 2.7% across the OECD and will reach 10.2% of GDP by 2030,
up from 8.8% in 2018 (OECD 2019).
This health expenditure growth has been attributed to several factors including
the advance of medical science, the ageing of societies, the increasing prevalence of
chronic conditions, health care price inflation, but also due to an increased expen-
diture on medications. The latter caused an annual average growth in per capita of
4,6% (1995–2006) exceeding the annual rise in health expenditure (OECD 2019).
From 2013–2017 spending on pharmaceuticals increased more modestly at 1.6% per
year (OECD 2019), however in 2017, retail pharmaceuticals still accounted for
almost one-fifth of all health care expenditure and represented the third largest
pending component in OECD countries after inpatient and outpatient care (OECD
2019).
In response to this development, health authorities seek instruments to contain
drug expenditures while still supporting further health improvements.
Pharmacoeconomics 103

In recent years, the instruments of economic evaluation research (e.g., cost-

benefit analysis, cost-effectiveness analysis, cost-utility analysis) have increasingly
been used to assess the efficiency of medical measures. With the help of these
approaches, benefits, risks, and costs are recorded and allocated over the relevant
period.
The aim of a complete economic evaluation is not to determine the pure costs of a
procedure, but to transparently investigate the achievable health effects (e.g.,
improvement of quality of life, reduction of blood pressure, etc.) per unit of required
resources (e.g., costs, personnel, etc.) in comparison of one technology to another.
The results (e.g., costs per year of life gained or costs per quality-adjusted year of
life) gained of the different options can be compared and assessed within the
framework of decisions regarding the macro- and/or microeconomic use of
resources. The economic evaluation of medical alternatives is intended to provide
decision-makers (e.g., health insurance companies and physicians) with an orienta-
tion or decision support regarding an economic use of the technology in question.
The use of economic instruments does not contradict the quality of therapy and
medical care, but is an additional source of information in health policy decision-
making.
The evaluation of drugs is called Pharmacoeconomics and is a subsidiary of
health economics which particularly focuses upon costs and benefits of drug therapy
(Walley and Haycox 1997).

Categories of Health Economic Evaluation

Health economic studies are basically divided into two categories: comparative and
noncomparative study types (Fig. 1). The choice of the study type depends on the
research question and the purpose (e.g., is the use of a new drug therapy in question
in comparison with the previous standard therapy or is the aim to decide about the
allocation of financial resources to one or another patient group).
Cost studies are the simplest form of an economic evaluation and may serve
different purposes. It deals either with the costs of a specific measure (e.g., costs of a
cCT, performance of a genetic test) or, in a cost-of-illness study, all costs associated
with the disease are determined. Cost-of-illness studies are primarily used to deter-
mine the economic burden of a disease to society by measuring costs of diagnosing
and treating a disease, as well as costs arising as a result of the disease (e.g.,
productivity losses) (Onukwugha et al. 2016). These studies serve as reference
standards for economic analyses and provide important information on resource
allocation for decision-makers in the health care environment.
So-called complete health economic evaluations are studies that carry out a
comparative assessment between different procedures and put the resulting resource
consumption (e.g., costs) in relation to an outcome (Table 1). The outcome may be
expressed in improvements in the health status (clinical effectiveness):
104 R. Dodel et al.

Health economic evaluation

Comparing Non-comparing

Cost-cost analysis Cost analysis

Cost-of-illness
Cost-benefit analysis analysis

Cost-effectiveness
analysis

Cost-utility analysis

Fig. 1 Categories of health economic evaluation

Table 1 Health economic analyses

Unit of measure for
Method costs Unit of health effect Objective
Cost-minimization € per unit in health None. The results of Determine the
study outcome gained the treatments are alternative that
equivalent. generates the lowest
costs.
Cost-benefit study € per unit in health Monetary. Determine the
outcome gained alternative that has the
greatest net benefit.
Cost-effectiveness € per unit in health Health outcomes in Determine the
study outcome gained natural units (mmHG incremental cost-
blood pressure, life effectiveness ratio.
expectancy extension
in years)
Cost-utility study € per unit in health Patient preference (e. Determine the
outcome gained g., QALYs or other incremental cost-utility
utility values) ratio.

1. In natural units (health effects, life years)

2. In utility adjusted units (e.g., QALY, DALY)

Depending on the chosen outcome of the study, a distinction is made between

cost-minimization studies, cost-benefit studies, cost-effectiveness studies, and cost-
Pharmacoeconomics 105

utility studies. In the context of cost-minimization analyses, it is assumed that the

clinical outcome to be evaluated is identical to the clinical outcome of the medical
intervention to be compared. The evaluation of the measures is based solely on a cost
comparison.
In a cost-benefit analysis, all costs and benefits of the interventions to be
evaluated are assessed in monetary units (allocation of certain monetary amounts
for a human year of life or a human life in total). In Germany for instance, cost-
benefit analyses are discouraged on ethical grounds among others (Schöffski and
von der Schulenburg 2011). The cost-effectiveness analysis offers the possibility to
consider medical effects. The results are in “natural” units (e.g., lowering blood
pressure, prolonging life in years, reducing tumor size, etc.). This measurable
difference between the two drugs is put in relation to the costs. This makes it possible
to compare two different therapeutic options.
In the cost-utility analysis, the assessment of the treatment success can be
made by taking into account life prolongation as well as the patient’s prefer-
ence (“utilities”) with regard to certain health conditions. Cost-per-quality
adjusted life years (QALY) gained (also referred to as cost-per-QALY) is an
approach, in which the costs and effects of programs and at least one alterna-
tive are calculated and presented in a ratio of incremental cost to incremental
effect.
The preference of the respondent can be determined by different approaches, for
example, the “Standard Gamble” procedure, or the “Time (Person) Trade-off”
procedure. These methods measure the utility of different health conditions. For a
detailed description of the different methods, we may refer to the literature (Feeny et
al. 2017). The internationally most frequently used method for including preference
based utility values in the clinical effectiveness is the QALY concept (quality-
adjusted life-years) (Smith et al. 2009). It is based on the assumption that human
life can be represented by the two dimensions of remaining life expectancy and
utility value.
Residual life expectancy ranges from the time of observation to the death of the
individual. The quality of life is anchored by the two values of 1 for complete health
and 0 for death. The two dimensions quality of life and life expectancy are combined
to form a new aggregate (one-dimensional outcome measure). In addition, the
treatment outcome is normalized for all indications, that is, each medical measure
can be evaluated according to the same pattern. This enables comparisons of
interventions within the health care system with a single measure, even across
indications. The results of cost-utility analyses based on the QALY concept can
therefore be arranged and compared with each other in so-called league tables:
monetary value units per QALY are given as costs of treatment alternatives
(Table). Although the QALY concept is the basis of many studies, the QALY
concept is not undisputed (Schöffski and von der Schulenburg 2011). More recently,
disability-adjusted life years (DALYs) have also been evaluated in cost-effectiveness
analyses (Neumann et al. 2016).
106 R. Dodel et al.

Difference in cost

II I
Intervention is Intervention is
medically inferior medically
and more superior and
expensive more expensive
+
Difference in result
– IV
III
Intervention is
Intervention is
medically
medically inferior
superior and less
and less
expensive
expensive

Fig. 2 Diagram of cost-effectivity

In Which Cases Is a Health Economic Evaluation Recommended?

To perform an economic evaluation is not always necessary. No economic

evaluation is required for interventions that are located in quadrants II and IV
shown in Fig. 2. Interventions located in quadrant IV are medically superior and
less costly and can immediately be classified as cost-effective. Interventions in
quadrant II deliver a worse result for a higher price and can therefore be
classified as not cost-effective. On the other hand, medical measures that fall
into the I and III quadrants should always be subjected to a health economic
evaluation. In particular, innovations that fall into quadrant I should prove their
cost-effectiveness ratio. Interventions that are located in quadrant III are often
rejected because of the lower estimated clinical benefit. However, it could be
argued that significantly less expensive technologies that are associated with only
a minimal loss of clinical benefit could be a possible option (e.g., large scale
screening procedures).

Parameters of Health Economic Studies

The results of economic studies are determined by the way the underlying data/
information is collected and evaluated. In the following section, the different types of
costs, the possible perspectives, and the problem of the cost and benefit flows
occurring at different times are briefly addressed.
Pharmacoeconomics 107

Table 2 Cost categories and their services and resources

Direct nonmedical
Direct medical costs costs Indirect costs Intangible costs
Outpatient medical Patient time Incapacity to work Pain
costs
Hospital costs Relatives time Disability to work Physical impairment
Rehabilitation costs Housekeeping Premature death Loss of quality of life
Drugs Travel expenses
Ancillary therapy
(e.g., physiotherapy)
Ancillary therapy
(e.g., physiotherapy)
Medical aids

Costs

Direct medical costs and nonmedical costs consist of costs directly attributable to
the treatment and care of patients (Table 2). Examples of such costs are drug costs or
hospital costs. Indirect costs mainly describe costs due to productivity loss, that is,
the loss of work potential that a society suffers due to the absence from work due to
illness or limited performance at work. Indirect costs can be calculated using the
human capital approach (Ernst 2006). Alternative approaches are, for example, the
friction cost approach (Koopmanschap et al. 1995), which, however, have not yet
been included in all recommendations for the implementation of health economic
analyses. The friction cost approach is based on the assumption that a loss of
productivity is only assumed for the duration of the average vacancy of unfilled
positions (so-called friction period). This is intended to avoid an overestimation of
costs due to the loss of work, as is conceivable in the human capital approach. For a
detailed discussion, please refer to the special literature (Krol et al. 2013; Sach and
Whynes 2003).
Intangible costs are costs due to pain, joy, suffering, disability, or a change in
quality of life that are difficult to measure and barely quantifiable in monetary terms
(Gold et al. 1996). Particularly in the case of chronic diseases, it is important for the
assessment of a service to make the changes in well-being transparent. Intangibles
costs pose a challenge in the survey, as these costs are difficult to measure and
usually cannot be evaluated. In cost-utility analyses, intangible costs are assessed in
terms of quality of life reduction and are included in the denominator of the cost-
utility ratio.

Perspective

Perspective is the viewpoint from which costs and benefits are recorded and evalu-
ated. Health economic analyses can be carried out from different perspectives, for
108 R. Dodel et al.

example, those of society, funding agencies, service providers, and/or patients.

International and national guidelines for health economic evaluation recommend
that health economic evaluation studies always take the comprehensive societal
perspective into account (Neumann et al. 2017a). This means that all costs and
benefits – regardless of who generates them – are included in the health economic
analysis. This is because decisions on the allocation of health care services should in
principle realize a social optimum. The guidelines also recommend disaggregating
the societal perspective transparently into the other perspectives included. The
following perspectives are of fundamental importance:

• Patients
• Service provider (e.g., hospital, general practitioner)
• Service providers (e.g., health insurance companies)
• Society

For example, from the patient’s perspective, costs should include direct non-
medical costs and intangible costs, expenses that are borne by the patient or are
relevant to the patient while the “costs” for hospitalization and medication (excep-
tion: co-payment) are “irrelevant” from the patient’s perspective, since he or she does
not have to pay them. This does not apply if the costs are to be determined from the
perspective of the health insurance companies; here the direct costs due to hospital
stay, rehabilitation clinic, and diagnostics are relevant.

Time Horizon

The time horizon describes the duration of the evaluation period of a study. This can
be measured in days, months, years, but also in cycles. This should be taken into
account in particular if the costs and benefits of different medical measures do not
arise within a short period of time, then direct comparability is limited. In order to
enable a comparison of costs and consequences/benefits at the current point in time,
future costs and benefits are discounted.
Data basis of economic evaluation studies. The data basis on which health
economic evaluations can be carried out can vary and depends on factors such as
time and the available budget for carrying out the analysis. In principle, it is possible
to collect information prospectively or retrospectively within the framework of field
studies (e.g., within the framework of clinical studies) or to draw on previously
published studies.

Decision-Analytical Models and Procedures

If the available cost and effectiveness data do not have sufficient external validity
because they do not fully reflect the practice of health care provision, health
economic modeling can be carried out using decision-analytical procedures
Pharmacoeconomics 109

(Siebert 2003b). Decision analysis is defined as a systematic, explicit, and quan-

titative approach to decision making under uncertainty (Weinstein 2006). The aim
of decision analysis is to identify the strategy with the maximum expected value
after weighting the medical benefit, the risks and, if necessary, the costs of the
various alternatives for action. The decision analysis follows the principle of
benefit maximization. The structure of the sequence of all possible events is
represented in the form of event trees, which contain the probabilities of these
events with their various medical and/or economic consequences. Probabilistic
models and procedures are used to analyze these data, in particular the decision tree
method and Markov models (Neumann et al. 2017b). The type of benefit to be
maximized has to be determined or operationalized prior to the analysis. This can
be a single parameter, such as higher survival probability, better quality of life or
lower costs, or a weighted combination or ratio of different parameters. The
process of decision analysis reveals the structure, elements, and parameters of
the decision problem and thus makes them accessible for discussion. The results of
such a decision analysis can serve as a basis for a decision for a single patient, but
can also be used for decisions on health programs (Siegel et al. 1996). It should be
emphasized that the function of decision analysis is to support the decision-making
process, not to determine it. The final decision for one or another therapeutic option
depends on more complex determinants (social, political, ethical preferences). A
complete health economic decision analysis compares at least two medically
effective strategies for action with each other, taking costs and effects into account.
The incremental approach (difference in costs in relation to the difference in effects
of the compared alternatives) should be chosen (Siebert 2003b). Before a decision
problem can be analyzed quantitatively, a decision model must be established.
With such a model, an attempt is made to depict the relevant health aspects and the
determining costs as well as possible and to simplify the less relevant aspects (Fig.
3). As an example, the calculation of costs is shown in path 2: p*Kompl*(1-pLetal)
*€4000 ¼ 0.2*0.9*€4000 ¼ €720. Similarly, the other paths are calculated
according to costs, life expectancy, etc. Accordingly, the following results are
obtained for the different strategies:

Incremental Incremental Incremental cost-

Strategy Costs in € costs QALY QALY effectiveness ratio
No therapy 0 – 33,100 – –
Screening 10,800 10,800 33,509 0.409 26,429
Therapy 50,000 39,200 31,948 1.561 dominated
cTest, Costs of the test; cTherapy, Cost of therapy; LeHealthy_treated, Life expectancy of a
healthy person with therapy; LeHealthy_untreated, Life expectancy of a healthy person without
therapy; LeDiseased_treated, Life expectancy of a sick person with therapy;
LeDiseased_untreated, Life expectancy of a sick person without therapy; pComplication,
probability of occurrence of complications; pDisease, prevalence of the disease in the risk
population; pLetal, portion of lethal complications; Sens, sensitivity; Spec: specificity;
uDisability, utility; uDisease, relative utility Disease vs. health; uTherapy, relative utility therapy
vs. No therapy
110 R. Dodel et al.

When modeling or analyzing the decision problem, several methods are distin-
guished, including the decision tree method and Markov models. The decision tree
method is used for simple decision situations that usually have a short time horizon
in which all events related to the action strategy occur. In contrast, Markov models or
state-transition models (Siebert et al. 2012) are mainly used for more complex
problems with a longer time horizon. For studies with “queuing problems” (e.g.,
organ transplant list), discrete event simulations can be helpful (Karnon et al. 2012).
For further and more complex model methods, we refer to previous review articles
(Brennan et al. 2006; Kuntz et al. 2017). In the decision tree method, the possible
decisions, events, and outcomes are structured in the form of a tree (Fig. 3). The
decision tree contains the temporal and logical structure of the decision problem and
all relevant alternative strategies, uncertain events, their probability of occurrence
and the expected consequences. The “tree” starts at its trunk on the left side of the
diagram, where the target population of the decision problem is named. It is followed
by a so-called decision node, which represents the choice between different action
alternatives. For each action alternative, there are places in the tree that are marked
by so-called chance nodes. At a chance node, different events can occur or features
can be revealed that are not predictable and thus embody the uncertainty of the
decision problem. Various event paths lead from the trunk to the right side of the
decision tree and end there at the leaves of the tree, result nodes. At a result node, the
consequences of the decision of interest are listed, examples are epidemiological
measures, health conditions, laboratory values, costs.
An event with all subsequent event paths is called a branch of the event tree. For
each alternative strategy, the expected value of the clinical outcome can be calculated
as a weighted average of all possible outcomes by using the probabilities of
occurrence as weights. Decision tree analyses are used, especially in situations
where all relevant events occur within a short time horizon. This pattern represents
the basic scheme of all decision analyses (including nonmedical). Many decision
problems under uncertainty can be structured or broken down into subproblems in
such a way that the question arises as to whether a certain action should be taken,
whether it should be omitted, or whether further information should be obtained first
to reduce the uncertainty.
Markov models, on the other hand, are used if

1. The decision problem contains time-varying parameters such as transition prob-

abilities, utility values, or costs.
2. The time of occurrence of an event plays a role.
3. Relevant events occur several times. Especially for chronic diseases, where rates
of progression, utility, or costs change over time, Markov models play an
essential role. In this procedure, a hypothetical cohort of patients passes through
defined health states (“Markov states”) where time is represented in given cycles.
In these cycles the patient can (1) remain in his current state of health, (2) change
to another state of health, or (3) die. This transition to the different states of health
occurs as a result of certain transition probabilities. From this, target values such
as the cumulative incidence of clinical events, life expectancy, quality corrected
 Pharmacoeconomics

Fig. 3 Hypothetical case study: Decision tree analysis for a screening test (Siebert 2003a). Disease K occurs more frequently in a risk population and, without
treatment, leads to a reduction in life expectancy and quality of life. The disease can be successfully treated and the therapy leads to a significant increase in life
expectancy and quality of life. In healthy people it leads to a reduction. There is a screening test which has a certain error rate and a risk of complications.
Therapy (€50,000) and the screening test (€4,000) lead to increased costs. The following alternatives are to be evaluated: 1. Therapy is started immediately for all
persons in a risk group; 2. Therapy is not started for all persons in the risk group; 3. A screening test is carried out once and the test positive persons are treated. In
doing so, one accepts the risk of complications and lethality and false test results
111
112 R. Dodel et al.

Table 3 Steps in modeling and decision analysis

1. Background and precise 7. Determination of the event probabilities
formulation of the decision-
making problem
2. Choice of perspective 8. Quantitative evaluation of the consequences
3. Definition of the time horizon 9. Explicit formulation of the assumptions
4. Identification of the medical 10. Calculation of the expected values
alternatives
5. Specification of the possible 11. Sensitivity analyses
clinical consequences
6. Presentation of the course of 12. Interpretation of the results
events

life expectancy (QALYs), and total costs over time can then be determined for
each alternative and compared accordingly.

The robustness of the results is then tested by sensitivity analyses, systematically

evaluating the effects of different model assumptions on the decision to be made. A
great value of sensitivity analyses is to identify those uncertain parameters whose
characteristics have an influence on the result, that is, are sensitive for the decision.
The identification of these influential parameters can significantly contribute to the
definition of further research projects and the sensible allocation of research
resources (Table 3).

Limitations

The decision analysis contains dangers if used improperly. Care must be taken to
ensure that complex interrelationships are not oversimplified based on unrealistic
assumptions and lead to a pseudo-scientific presentation of the facts. In particular,
the complex methodology has a negative effect here, since these models are no
longer transparent if the documentation is inadequate (Husereau et al. 2013). For
users, a model can present itself as a black box whose contents cannot be understood.
In summary, it can be said that desk research is the only possibility for structured and
systematic decision-making in situations where conventional study approaches reach
their limits. However, responsible communication of results is important: results
should be based on the current state of knowledge and their validity depends on the
accuracy of the model structure, the underlying assumptions, and the parameters
chosen. Recently, the Consolidated Health Economic Evaluation Reporting Stan-
dards (CHEERS) statement was introduced as an attempt to consolidate and update
previous health economic evaluation guidelines efforts into one current, useful
reporting guidance (Husereau et al. 2013). It provides a framework on which
transparent reporting is possible and should be followed.
Pharmacoeconomics 113

Finally, it should be noted that the decision analysis only has a supporting
function with regard to the decision-making process.

Institutions for Evaluating Cost-Effectiveness in Health Care

The reason for the discussion on the introduction of cost-effectiveness assessment

for the evaluation of medical technologies (e.g., drugs) arises on the one hand from
the constantly increasing expenditure in the health care system and the constant
expansion of medical progress on the other hand. This development is clearly
illustrated by the growing importance of HTA (Health Technology Assessment) as
a method for evaluating medical technologies and the “fourth hurdle” as an instru-
ment for regulation in the pharmaceutical sector, which is often based on a cost-
effectiveness analysis. Australia was the first country to make the reimbursement of
drugs dependent on cost-effectiveness as early as 1993; the following year the
Canadian province of Ontario introduced this (for a brief history of milestones in
cost-effective analysis see (Neumann et al. 2017a)). Since the end of the 1990s,
numerous examples of the incorporation of cost-effectiveness into regulation in the
pharmaceutical sector can be demonstrated in Europe. In the Netherlands, since
2005, only those drugs whose additional benefit and incremental cost-effectiveness
can be proven by the manufacturer within the framework of pharmacoeconomic
studies can be exempted from the formation of reference prices. However, the most
comprehensive consideration of cost-effectiveness as an instrument of regulation in
the sense of a “fourth hurdle” is found in Australia (PBAC; Pharmaceutical Benefit
Scheme). While NICE is already investigating reimbursable drugs (NICE; National
Institute for Health and Clinical Excellence) (Rawlins 2004), health economic
evaluations to prove the cost-effectiveness of drugs that must be provided by the
manufacturer are a necessary prerequisite for their reimbursability in Australia. Since
January 2008, the consideration of cost-effectiveness has also been introduced in
Germany within the framework of regulation in the pharmaceutical sector by the
Institute of Quality and Efficiency in Health Care (IQWIG) (Klingler et al. 2013).
For an overview of the developments in Australia, England, and other interna-
tional health care systems, please refer to the relevant literature (Neumann et al.
2007, 2017a).
Furthermore, a number of health care systems have introduced a reference price
Scheme (RP) for drugs as a reimbursement system (Galizzi et al. 2011). RP policy
includes bundling drugs according to some equivalence criteria and defining a
reference price for each cluster: drugs can be bundled according to chemical
(identical products with same active principle), pharmacological (chemically differ-
ent but pharmacologically related drugs), or therapeutic equivalence (all drugs used
to treat a particular condition). The groups may include or exclude patented drugs.
Under all RP systems, the third-party payer will reimburse no more than the
reference price for each drug in that cluster. For a detailed description, please see
Gregson et al. (2005).
114 R. Dodel et al.

Health Technology Assessment and Cost-Effectiveness

Thresholds

Health technology assessment (HTA) has become a standard policy tool for
informing decision makers who must manage the entry and use of pharmaceuticals,
medical devices, and other technologies (including complex interventions) within
health systems, for example, through reimbursement and pricing.
HTA relies on evaluations of the clinical, epidemiological, and economic data to
make decisions about the allocation of the scarce resources of public healthcare. The
centerpiece of a cost-effectiveness analysis is the incremental cost-effectiveness ratio
(ICER), which measures the differential cost for a unit of extra benefit gained from a
new therapeutic strategy. In almost all situations, new drug options that apply for
public funding present higher costs and effectiveness than the drugs currently in use.
For a new drug to be recommended based on economic assessments, several
authorities have argued that the ICER must be compared to a cost-effectiveness
threshold (CET) value that should represent the highest acceptable cost for an extra
unit of benefit.
In the UK, NICE introduced a cost per QALY threshold of £20.000–30.000 per
QALY. For cost-per QALY amounts below £20.000, NICE will generally recom-
mend coverage; for cost-per QALY amounts over £30.000, NICE will generally not
recommend the intervention to be covered. In between those amounts, NICE will
more carefully consider a coverage decision. The WHO provided similar recom-
mendations if the intervention’s cost-effectiveness ratio is less than the gross domes-
tic product per capita, it is considered very cost-effective; if between one and three
times GDP per capita, it is considered cost-effective. Above three times GDP per
capita, it is considered something to be evaluated with caution. Recently, the WHO
moved away from this characterization of thresholds and has been examining
alternative threshold estimation methods (Brock et al. 2017).
Cost-effectiveness threshold values around different healthcare system have been
summarized in a recent article by Santos et al. and the reader is referred to this
chapter for further information (Santos et al. 2018).

Pharmacoeconomic Evaluation of Drugs Prescribed for Brain

Disorders

No group of chronic diseases burdens the world more than mental illnesses (Report
of the secretary (WHO) 2011). WHO data suggest that brain disorders cause one-
third of the burden of all diseases; according to current epidemiological estimates,
brain dis-orders account for approximately 13% of global disease prevalence,
surpassing both cardiovascular diseases and cancer (Collins et al. 2011). It represents
the largest contributor to the ‘all cause morbidity’ burden as measured by disability-
adjusted life years (DALYs). A burden of illness study from the European brain council
estimated total cost of brain disorders (19 groups of disorders) including 30 European
countries to be €798 billion, with direct health care cost 37%, direct nonmedical cost
Pharmacoeconomics 115

23%, and indirect cost 40%. The average cost per inhabitant was €5.550. The European
average cost per person with a disorder of the brain ranged between €285 for headache
and €30,000 for neuromuscular disorders (Gustavsson et al. 2011).
The spectrum of brain disorders is large, covering hundreds of disorders with a
considerable number of drugs registered. Thus, a detailed description of the various
pharmacoeconomic evaluations would go beyond the aim of this chapter. However,
to provide an overview and to identify probable gaps of currently available
pharmacoeconomic evaluations, we devised a list of each major brain disorder based
on a systematic search in PubMed for the years 2010–2020 using MesH headings. The
selection of the disorders was based on the DSM-V and the ICD-10 for neurological
disorders. Where an adequate review on pharmacoeconomic evaluations was avail-
able, this review was included in representation of earlier published research articles.
In the supplemental table, we compiled the currently available evidence.
In conclusion from the results of this systematic literature search, there are
considerable gaps in the pharmacoeconomic evaluation of the drugs used for brain
disorders. This is in contrast to the immense burden of those disorders.
As Gustavson et al. pointed out in their major work on the burden of disease in
Europe: “Disorders of the brain are one of the major economic challenges for
European healthcare now and for the future” (Gustavsson et al. 2011).

Supplement: Pharmacoeconomic Evaluations of Brain Disorders

A literature search was conducted in line with a previous publication of our group in
the databases “PubMed”(Dams et al. 2011). The following keywords were
employed: “decision analysis,” “decision-analytic,” “decision model,” “health care
model,” “health care evaluation model,” “decision tree,” “Markov model,” “discrete
event simulation,” “cost-effectiveness,” “cost-utility,” “cost-benefit,” “cost-minimiz
(s)ation,” “QALY,” “and the respective disease. The following diseases were
searched: Psychiatric diseases (neurodevelopmental disorders, Schizophrenia spec-
trum and other psychotic disorders, bipolar and related disorders, depressive disor-
ders, anxiety disorders, obsessive-compulsive and related disorders, trauma- and
stressor-related disorders, dissociative disorders, somatic symptom and related dis-
orders, feeding and eating disorders, elimination disorders, sleep-wake disorders,
sexual dysfunctions, gender dysphoria, disruptive, impulse-control, and conduct
disorders substance-related and addictive disorders, neurocognitive disorders/
dementia, personality disorders, paraphilic disorders); Neurologic diseases (head-
ache, tinnitus, vertigo, epilepsy, stroke, meningitis, multiple sclerosis, myasthenia
gravis, restless legs syndrome, Parkinson’s disease, atypical parkinsonian syn-
dromes, ataxias, Wilson’s disease, amyotrophic lateral sclerosis, tremor, poly-
neuropathy, myopathies).
Furthermore, we examined reference lists of studies identified and reviewed
articles from the archives of the authors. The search was restricted to the following
three languages: English, German, Spanish. We only included published full papers
that employed a decision-analytic model or another type of mathematical healthcare
 116

Table 4
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Neurodevelopmental disorders
Hassiotis et al. GBR 2018 Neurodevelopmental – Manual-assisted face- RCT QALY (among “Findings from the
(2018) disorders (intellectual to-face positive others) main study and the
disorder, ID) behavior support (PBS) naturalistic follow-up
training to therapists suggest that staff
and treatment as usual training in PBS as
(TAU) compared with delivered in this study
TAU only in the control is insufficient to
arm achieve significant
clinical gains beyond
TAU in community
ID services. Although
there is an indication
that training in PBS is
potentially cost-
effective, this is not
maintained in the
longer term. There is
increased scope to
develop new
approaches to
challenging behavior
as well as optimizing
the delivery of PBS in
routine clinical
practice”
Zimovetz et al. GBR 2018 Neurodevelopmental Lisdexamfetamine Lisdexamfetamine Decision- Cost- “From the perspective
(2018) disorders (ADHD) dimesylate (LDX), dimesylate (LDX) analytic model effectiveness of the UK NHS, LDX
methylphenidate extended versus methylphenidate is likely to provide a
release (MPH-ER), extended release cost-effective
atomoxetine (ATX) (MPH-ER) and treatment for adults
atomoxetine (ATX) with ADHD. This
R. Dodel et al.
 conclusion may be
drawn with more
certainty in
comparison with ATX
than with MPH-ER”
Zimovetz et al. GBR 2016 Neurodevelopmental Lisdexamfetamine Lisdexamfetamine Decision- Cost- “From the perspective
(2016) disorders (ADHD) dimesylate (LDX), dimesylate (LDX) analytic model effectiveness of the UK NHS, LDX
Pharmacoeconomics

atomoxetine (ATX) versus atomoxetine provides a cost-

(ATX) effective treatment
option for children
and adolescents who
are inadequate
responders to
methylphenidate”
Sohn et al. (2016) USA 2016 Neurodevelopmental Atypical antipsychotics AAPs vs Atomoxetine Decision- expected “In the cost-
disorders (ADHD) (AAPs), Atomoxetine, versus selective α2- analytic model health effectiveness analysis,
selective α2-adrenergic adrenergic agonists outcomes and the AAP strategy was
agonists (clonidine and (clonidine and cost- dominated as it was
guanfacine) guanfacine) effectiveness less effective and
more costly than other
two strategies.
Compared to
clonidine/guanfacine,
AAPs provided lower
QALYs (0.11 QALY
lost) at an additional
cost of $2186 on
average. Compared to
atomoxetine, AAPs
resulted in 0.10
QALYs lost at an
additional cost of
$2186. In this
decision analysis
model, AAPs provide
117

(continued)
 118

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
lower expected health
outcomes than other
ADHD medications
in children and
adolescents who
failed prior stimulant
therapy. Furthermore,
AAPs were not a cost-
effective option”
Lachaine et al. CAN 2016 Neurodevelopmental Guanfacine extended release, GXR + stimulant versus Markov model Cost- “This economic
(2016) disorders (ADHD) amphetamine mixed salts, long-acting stimulant effectiveness evaluation
methylphenidate HCl monotherapy demonstrates that
formulations, and GXR + stimulant is
lisdexamfetamine dimesylate cost-effective
compared to stimulant
alone in the treatment
of children and
adolescents with
ADHD in Canada”
Maia et al. (2016) BRA 2016 Neurodevelopmental Methylphenidate immediate- MPH-IR versus no Markov model Cost- “MPH-IR treatment
Disorders (ADHD) release (MPH-IR) treatment effectiveness of children and
adolescents is cost-
effective for ADHD
patients from the
Brazilian public
health system
perspective. Both
patients and the
healthcare system
might benefit from
such a strategy”
R. Dodel et al.
Tilford et al. USA 2015 Neurodevelopmental Melatonin, cognitive Melatonin versus CBT Prospective Cost- “Predicted treatment
(2015) disorders (Autism) behavioral therapy (CBT) versus Melatonin and cohort study effectiveness effects for melatonin
CBT versus Parent and behavioral
based sleep education interventions were
similar in magnitude
for the child and for
the caregiver.
Accounting for
Pharmacoeconomics

caregiver spillover
effects associated
with treatments for
the child with ASD
increases treatment
benefits and improves
cost-effectiveness
profiles”
Schawo et al. NLD 2015 Neurodevelopmental Methylphenidate immediate- OROS versus IR Markov model Cost- “The results indicate
(2015) disorders (ADHD) release (IR) versus effectiveness that, for children
methylphenidate osmotic- responding
release oral system (OROS) suboptimally to
treatment with IR, the
beneficial effect of
OROS on compliance
may be worth the
additional costs of
medication. The
presented model adds
to the health
economic information
available for
policymakers and to
considerations on a
broader perspective in
cost-effectiveness
analyses”
(continued)
119
Table 4 (continued)
120

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Catala-Lopez ESP 2013 Neurodevelopmental Medications launched in Systematic Cost- “The pharmacological
et al. (2013) disorders (ADHD) Spain for treatment of ADHD review of effectiveness treatment of ADHD
in children and adolescents literature in children and
adolescents, with the
reservations arising
from the
generalization of
results to different
settings, is probably
cost-effective in the
short term. The
existing studies do not
allow the relative
efficiency of different
treatments to be
established, either in
the long-term
treatment or in patient
subgroups with
specific
characteristics or
comorbidities”
Erder et al. USA 2012 Neurodevelopmental Guanfacine extended-release GXR versus ATX Matching- Cost- “To our knowledge,
(2012) disorders (ADHD) (GXR), atomoxetine (ATX) adjusted indirect effectiveness this is the first
comparison application of the
(MAIC) novel comparative
efficacy method of
MAIC to a CEA
model. The MAIC
results indicate that
GXR (0.075–
0.12 mg/kg/day) was
more effective than
R. Dodel et al.
 ATX (1.2 mg/kg/day)
in the trial population.
The CEA results
indicate that GXR is
cost effective
compared with ATX
for the treatment of
ADHD in children
Pharmacoeconomics

and adolescents”
Sikirica et al. USA 2012 Neurodevelopmental Guanfacine extended-release GXR + stimulant versus Markov model Cost- “The impairment
(2012) disorders (ADHD) (GXR) stimulant monotherapy effectiveness associated with
residual ADHD
symptoms after
stimulant therapy is
becoming
increasingly
recognized. This is
the first analysis of the
cost effectiveness of
stimulants combined
with an adjunctive
medication. This
study suggests that
the adjunctive therapy
of GXR with
stimulants is a cost-
effective treatment
based on a
willingness-to-pay
threshold of
$US50,000/QALY.
This may address an
unmet need among
patients with
suboptimal response
(continued)
121
 122

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
to stimulant
monotherapy”
Tilford et al. USA 2012 Neurodevelopmental Sensitivity of two Cost- “The HUI3 was more
(2012) disorders (Autism) generic preference- effectiveness sensitive to clinical
based instruments measures used to
relative to ASD-related characterize children
conditions and with autism compared
symptoms with the Quality of
Well-Being Self-
Administered
(QWB-SA) scale. The
findings provide a
benchmark to
compare scores
obtained by
alternative methods
and instruments.
Researchers should
consider
incorporating the
HUI3 in clinical trials
and other longitudinal
research studies to
build the evidence
base for describing
the cost effectiveness
of services provided
to this important
population”
R. Dodel et al.
Wu et al. (2012) USA 2012 Neurodevelopmental Lisdexamfetamine, Pharmacotherapies for Systematic Cost- “Among children and
disorders (ADHD) guanfacine extended-release ADHD, including review of effectiveness adolescents with
and clonidine extended- stimulants and literature ADHD, there was
release nonstimulants consistent evidence
that
pharmacotherapies
are cost effective
compared with no
Pharmacoeconomics

treatment or
behavioral therapy.
Adequate data are
lacking to draw
conclusions regarding
the relative cost
effectiveness of
different
pharmacological
agents. More
economic evaluations
with standardized
methods, such as
effectiveness
measures and cost
components, are
warranted. To better
inform payers about
the economic value of
existing medications,
future studies should
also consider
identifying subgroups
that may have
heterogeneous
responses to different
treatments, including
(continued)
123
 124

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
analyses of recently
approved treatments
(e.g.,
lisdexamfetamine,
guanfacine extended-
release and clonidine
extended-release) and
expanding the time
horizon to incorporate
long-term outcomes”
Schlander (2010) DEU 2010 Neurodevelopmental Child psychiatric drug Systematic Cost- “In many cases,
disorders (ADHD) treatment review of effectiveness effectiveness data
and in general: child literature came from short-term
psychiatric drug studies, and
treatment extrapolation to a
one-year time horizon
was usually based on
assumptions. Even
those evaluations
attempting to address
longer time horizons
by way of modeling
did not include the
impact of treatment
on long-term sequelae
of the conditions
studied, mainly due to
a paucity of robust
clinical data.
Nevertheless,
currently available
health economic
R. Dodel et al.
 evaluations broadly
suggest an acceptable
to attractive cost
effectiveness of
medication
management of
ADHD, whereas there
is no such evidence
Pharmacoeconomics

for child psychiatric

disorders other than
ADHD”
Denchev et al. USA 2010 Neurodevelopmental Performing a history Markov model Cost- “Relative to current
(2010) disorders (ADHD) and physical effectiveness practice, adding ECG
examination with screening to history
cardiology referral if and physical
abnormal (current examination
standard of care) vs pretreatment
performing a history screening for children
and physical with attention deficit/
examination plus ECG hyperactivity disorder
after negative history has borderline cost-
and physical effectiveness for
examination, with preventing SCD
cardiology referral if (sudden cardiac
either is abnormal death). Relative cost-
versus performing a effectiveness may be
history and physical improved by basing
examination plus ECG, cardiology referral on
with cardiology referral ECG alone. Benefits
only if ECG is abnormal of ECG screening
arise primarily by
restricting children
identified with SCD
risk from competitive
sports”
(continued)
125
 126

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Prasad et al. GBR 2009 Neurodevelopmental Atomoxetine Atomoxetine versus Markov model Cost- “Atomoxetine is cost-
(2009) disorders (ADHD) treatment alternatives effectiveness effective and may
have advantages over
stimulants, including
benefits to HRQL and
no abuse liability and
is the only treatment
in the UK licensed for
continued treatment
into adulthood in
adolescents who have
shown a response
from treatment”
Romeo et al. GBR 2009 Neurodevelopmental Risperidone, haloperidol Risperidone versus RCT Cost- “The treatment of
(2009) disorders (intellectual haloperidol versus effectiveness challenging behavior
disorder) placebo in ID with
antipsychotic drugs is
not a cost-effective
option”
Hong et al. ESP 2009 Neurodevelopmental Atomoxetine, immediate- Methylphenidate versus Markov model Cost- “The economic
(2009) disorders (ADHD) release methylphenidate Atomoxetine effectiveness evaluation showed
hydrochloride (MPH), that atomoxetine is an
extended-release effective alternative
methylphenidate across a range of
hydrochloride (MPH) ADHD populations
and offers value-for
money in the
treatment of ADHD”
R. Dodel et al.
Cottrell GBR 2008 Neurodevelopmental Atomoxetine, immediate- Methylphenidate versus Markov model Cost- “The economic
et al. (2008). disorders (ADHD) release methylphenidate Atomoxetine effectiveness evaluation showed
hydrochloride (MPH), atomoxetine is an
extended-release effective alternative
methylphenidate across a range of
hydrochloride (MPH) ADHD populations
and offers value-for-
money in the
Pharmacoeconomics

treatment of ADHD”
Faber et al. NLD 2008 Neurodevelopmental Long-acting methylphenidate Long-acting Cost- “Methylphenidate-
(2008) disorders (ADHD) osmotic release oral system methylphenidate effectiveness OROS is a cost-
(OROS), immediate-release osmotic release oral effective treatment for
(IR) methylphenidate system (OROS) with youths with ADHD
youths for whom IR for whom treatment
methylphenidate is with IR
suboptimal methylphenidate is
suboptimal. Higher
medication costs of
methylphenidate-
OROS were
compensated for by
savings on resource
use, yielding similar
10-year costs
compared with
treatment with IR
methylphenidate. Our
analysis is sensitive to
both clinical
parameters and
(differences in)
resource utilization
and costs between the
groups modelled,
warranting further
(continued)
127
 128

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
research within
clinical trials and
observational
databases, and into
the full scope of
costs”
King et al. (2006) GBR 2006 Neurodevelopmental Oral methylphenidate Oral methylphenidate Systematic Cost- “Drug therapy seems
disorders (ADHD) hydrochloride (MPH), hydrochloride (MPH) review of effectiveness to be superior to no
dexamfetaminesulphate versus literature drug therapy, no
(DEX) and atomoxetine dexamfetaminesulphate significant differences
(ATX (DEX) and atomoxetine between the various
(ATX) in children and drugs in terms of
adolescents (<18 years efficacy or side effects
of age) were found, mainly
owing to lack of
evidence, and the
additional benefits
from behavioral
therapy
(in combination with
drug therapy) are
uncertain. Given the
lack of evidence for
any differences in
effectiveness between
the drugs, the
economic model
tended to be driven by
drug costs, which
differed considerably.
Future trials
examining MPH,
R. Dodel et al.
 DEX and ATX should
include the
assessment of
tolerability and safety
as a priority”
Donnelly et al. AUS 2004 Neurodevelopmental Dexamphetamine (DEX), Dexamphetamine RCT Cost- “MPH and DEX are
(2004) disorders (ADHD) methylphenidate (MPH) (DEX) versus effectiveness cost-effective
Pharmacoeconomics

methylphenidate interventions for

(MPH) childhood ADHD.
DEX is more cost-
effective than MPH,
although if MPH were
listed at a lower price
on the Pharmaceutical
Benefits Scheme it
would become more
cost-effective.
Increased uptake of
stimulants for ADHD
would require policy
change. However, the
medication of
children and wider
availability of
stimulants may
concern parents and
the community”
Gilmore and GBR 2001 Neurodevelopmental Methylphenidate Methylphenidate versus Systematic Cost- “Short-term treatment
Milne (2001) disorders (ADHD) placebo review of effectiveness of hyperkinetic
literature children with
methylphenidate is
effective and cost-
effective”
(continued)
129
 130

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Schizophrenia spectrum and other psychotic disorders
Debaveye et al. BEL 2019 Schizophrenia Paliperidone Paliperidone for Markov model Benefit- “The overall
(2019) Spectrum and other 1 month (PP1M) versus analysis environmental burden
psychotic disorders 3 months (PP3M) was lower for PP1M
compared to Treatment and PP3M treatment
Interruption (TI) as a than Treatment
control group Interruption because
patients are kept more
stable, which reduces
the environmental
burden due to
hospitals. Moreover,
the Human Health
burden was
outweighed by the
Human Health
benefit”
Zhao CHN 2019 Schizophrenia Olanzapine Olanzapine orally Microsimulation Cost- “As the first-line
et al. (2019). spectrum and other disintegrating tablet model effectiveness treatment for
psychotic disorders (ODT) versus schizophrenia in
olanzapine standard China, olanzapine-
oral tablet (SOT) ODT is cost-effective
compared to
olanzapine-SOT and
olanzapine-SOT is
cost-effective
compared to
aripiprazole-SOT”
R. Dodel et al.
Potaufeu et al. FRA 2019 Schizophrenia Olanzapine pamoate Olanzapine pamoate Mirror model Cost- “By its mirror design,
(2019) spectrum and other versus the hospital cost effectiveness the study was placed
psychotic disorders differential in real conditions of
care of the patient
with schizophrenia. A
total of 61.5% of
patients maintained
treatment with
Pharmacoeconomics

olanzapine pamoate
for a minimum of 1
year. This long-acting
antipsychotics) is
more effective
without significantly
increasing the cost
compared to the
previous therapeutic
strategy (including
oral olanzapine). The
additional cost is
partly due to the
administration
restriction in a
hospital setting in
relation to risk of
Postinjection
Delirium/Sedation
Syndrome (PDSS).
There is currently no
acceptable efficiency
limit. The results of
this cost-effectiveness
analysis cannot be
extrapolated to the
other long-acting
(continued)
131
Table 4 (continued)
132

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
antipsychotics since it
is the only one with
hospital reserve
status. The current
limitations of medico-
economics in
psychiatry derive
from the
heterogeneity of
clinical forms and the
management of
mental pathologies”
Howard et al. GBR 2018 Schizophrenia Low-dose amisulpride Low-dose amisulpride RCT Cost- “Low-dose
(2018) spectrum and other versus placebo effectiveness amisulpride is
psychotic disorders effective and well
tolerated as a
treatment for Very
late-onset (aged >/¼
60 years)
schizophrenia-like
psychosis, with
benefits maintained
by prolonging
treatment. Potential
adverse events
include clinically
significant
extrapyramidal
symptoms and falls”
Wijnen et al. HLD 2018 Schizophrenia Antipsychotic medication Treatment as usual RCT Cost- “In the Dutch context
(2018) spectrum and other versus TAU augmented effectiveness where TAU for
psychotic disorders with cognitive behavior psychosis is guideline
R. Dodel et al.
 therapy for social congruent and well
activation (CBTsa) implemented there
appears no added
value for adjunct
CBTsa. In other
settings where the
treatment for the
schizophrenia
Pharmacoeconomics

spectrum disorders
solely relies on
antipsychotics, add-on
CBTsa may lead to
clinically superior
outcomes, but it
should still be
evaluated if adjunct
CBTsa therapy is a
cost-effective
alternative”
Men et al. (2018) CHN 2018 Schizophrenia Amisulpride, Olanzapine Amisulpride versus Review Cost- “As the first meta-
spectrum and other Olanzapine minimization analysis and cost-
psychotic disorders analysis minimization analysis
comparing the
efficacy, safety, and
cost of amisulpride
and olanzapine within
a Chinese setting, the
study suggests that
amisulpride may be
an effective, well-
tolerated, and cost-
saving antipsychotic
drug alternative in
China”
(continued)
133
 134

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Basu et al. (2018) USA 2018 Schizophrenia Long-acting injectable (LAI) One monthly and once Decision model Treatment “Our results suggest
spectrum and other formulations of paliperidone every 3 months long- effectiveness that using PP1M and
psychotic disorders palmitate, oral antipsychotics acting injectable (LAI) PP3M treatment
(Oas) formulations of strategies for patients
paliperidone palmitate with schizophrenia
versus oral receiving Medicaid
antipsychotics (Oas) could result in
reduced
hospitalizations. This
finding, along with
improvement to
patients’ health,
should be considered
when assessing the
value of these LAIs”
Girardin et al. USA 2019 Schizophrenia Clozapine Clozapine as a third-line Semi-Markovian Cost- “Up to a decision
(2019) spectrum and other antipsychotic model effectiveness threshold of
psychotic disorders medication $3.9 million per
quality-adjusted life-
year (90-fold the US
gross domestic
product per capita),
the base-case results
indicate that
compared with
current ANCM
(absolute neutrophil
R. Dodel et al.
 count monitoring),
genotype-guided
blood sampling prior
to clozapine initiation
appeared cost-
effective for targeted
blood monitoring
only in patients with
Pharmacoeconomics

HLA susceptibility
alleles. Sensitivity
analysis demonstrated
that at a cost of
genotype testing of up
to USD700, HLA
genotype-guided
blood monitoring
remained a cost-
effective strategy
compared with either
current ANCM or
clozapine
substitution”
Nuhoho et al. UAE 2018 Schizophrenia Oral antipsychotics Paliperidone palmitate Decision tree Cost- “PP1M is estimated to
(2018) spectrum and other once monthly (PP1M) model effectiveness save the UAE
psychotic disorders with oral healthcare system
supplementation versus money, while at the
Paliperidone palmitate same time improving
once monthly (PP1M) patient outcomes”
without oral
supplementation
(continued)
135
 136

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Barnes et al. GBR 2017 Schizophrenia Clozapine, Amisulpride Clozapine with RCT Cost- “The risk-benefit of
(2017) spectrum and other amisulpride versus effectiveness amisulpride
psychotic disorders clozapine with placebo augmentation of
clozapine for
schizophrenia that has
shown an insufficient
response to a trial of
clozapine
monotherapy is
worthy of further
investigation in larger
studies. The size and
extent of the side
effect burden
identified for the
amisulpride-
clozapine
combination may
partly reflect the
comprehensive
assessment of side
effects in this study.
The design of future
trials of such a
treatment strategy
should take into
account that a clinical
response may be not
be evident within the
R. Dodel et al.
4- to 6-week follow-
up period usually
considered adequate
in studies of
antipsychotic
treatment of acute
psychotic episodes.
Economic evaluation
Pharmacoeconomics

indicated the need for

larger, longer-term
studies to address
uncertainty about the
extent of savings
because of
amisulpride and
impact on QALYs.
The extent and nature
of the side effect
burden identified for
the amisulpride-
clozapine
combination has
implications for the
nature and frequency
of safety and
tolerability
monitoring of
clozapine
augmentation with a
second antipsychotic
in both clinical and
research settings”
(continued)
137
 138

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Einarson et al. NLD 2017 Schizophrenia Paliperidone, haloperidol PP3M vs once-monthly Decision tree Cost- “PP3M dominated all
(2017b) spectrum and other long-acting therapy paliperidone (PP1M), model effectiveness commonly used
psychotic disorders (HAL-LAT), risperidone haloperidol long-acting drugs. It is cost-
microspheres (RIS-LAT), oral therapy (HAL-LAT), effective for treating
olanzapine (oral-OLZ) risperidone chronic schizophrenia
microspheres in the Netherlands.
(RIS-LAT), and oral Results were robust
olanzapine (oral-OLZ) over a wide range of
sensitivity analyses.
For patients requiring
a depot medication,
such as those with
adherence problems,
PP3M appears to be a
good alternative
antipsychotic
treatment”
Einarson et al. ESP 2017 Schizophrenia Paliperidone PP3M versus PP1M Decision tree Cost- “PP3M dominated
(2017a) spectrum and other model effectiveness PP1M in all analyses
psychotic disorders and was, therefore,
cost-effective for
treating chronic
relapsing
schizophrenia in
Spain. For patients
who require long-
acting therapy, PP3M
appears to be a good
alternative anti-
psychotic treatment”
R. Dodel et al.
Nemeth et al. HUN 2017 Schizophrenia Cariprazine, risperidone Cariprazine versus Markov model QALY gains “Cariprazine, which
(2017) spectrum and other risperidone showed clinically
psychotic disorders meaningful
improvement in the
symptoms, and
personal and social
performance, can also
provide significant
Pharmacoeconomics

QALY gain in the

treatment of patients
with predominant
negative symptoms of
schizophrenia
compared with
risperidone”
Vincent et al. CAN 2017 Schizophrenia Paliperidone palmitate Paliperidone palmitate Mirror model Hospitalization “PP as a first LAI
(2017) spectrum and other (long acting injectable
psychotic disorders antipsychotics)
improved adherence,
decreased hospital
visits and duration
was cost neutral.
Drawbacks are the
retrospective design
and lack of
comparator and safety
data. Strengths are
naturalistic design
and adherence
calculation. A subset
of patients responds
well to LAI, leading
to meaningful
reductions in hospital
services
requirements”
139

(continued)
Table 4 (continued)
140

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Druais et al. FRA 2017 Schizophrenia Aripiprazole LAI (long- Aripiprazole LAI Markov model Cost- “This analysis, to the
(2017) spectrum and other acting injectable; ALAI), (ALAI) versus effectiveness best of our
psychotic disorders olanzapine LAI (OLAI), olanzapine LAI (OLAI) knowledge, is the first
paliperidone LAI (PLAI), versus paliperidone LAI of its kind to assess
risperidone LAI (RLAI), (PLAI) versus the cost-effectiveness
haloperidol decanoate (HD), risperidone LAI (RLAI) of antipsychotics
oral olanzapine versus haloperidol based on French
decanoate (HD) versus observational data.
oral olanzapine PLAI was associated
with the highest
probability of being
the optimal treatment
from the French
health insurance
perspective”
Correll et al. USA 2016 Schizophrenia Long-acting injectable Long-acting injectable Review Cost- “The evidence review
(2016) spectrum and other antipsychotics (LAIs) antipsychotics (LAIs) effectiveness demonstrated that
psychotic disorders versus oral LAIs are superior to
antipsychotic placebo for acute and
maintenance
treatment of
schizophrenia and, in
general, appear to be
similar to one another
in terms of
schizophrenia relapse
prevention. Study
design impacts the
demonstrated efficacy
of LAIs versus oral
antipsychotics, but
recent database and
randomized
R. Dodel et al.
controlled studies
favor the use of LAIs
in early-phase
schizophrenia
patients. LAIs vary
considerably in their
propensity to cause
certain adverse
Pharmacoeconomics

effects, including
weight gain,
metabolic effects,
extrapyramidal
symptoms, and
prolactin elevation,
and these differences
can be used to help
guide LAI selection.
Some studies, but not
all, have
demonstrated
significant reductions
in health care
utilization or overall
costs with LAIs. The
expert panel identified
several barriers to
LAI use in current
practice, including
clinician lack of
knowledge, negative
attitudes about LAIs,
and resource and cost
issues. The
participants also
identified a number of
(continued)
141
 142

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
additional factors that
should be considered
when weighing the
use of LAI therapy,
including medication
adherence, relapse
risk and severity,
cognitive impairment,
ease of use, substance
misuse, access and
cost, stigma, social
support, patient
autonomy, control
over medication
dosing, fear of
needles, and the
potential for patient
harm due to relapses
and associated loss of
functioning. This
evidence review,
discussion, and
summary
recommendations
may help clinicians,
patients, families,
payers, and other
stakeholders to better
characterize the role
of LAIs in the
treatment of
schizophrenia”
R. Dodel et al.
Bipolar and related disorders
Augusto et al. USA 2018 Bipolar and related Aripiprazole, Risperidone Aripiprazole versus Markov model Cost- “AOM 400 may be
(2018) disorders LAI, Paliperidone palmitate, Ris-peri-done LAI effectiveness considered cost
Cariprazine, Asenapine, BSC versus Paliperidone effective in the
palmitate versus maintenance
Cariprazine versus Ase- monotherapy
na-pine versus BSC treatment of BP-I
Pharmacoeconomics

(best supportive care<9 (bipolar I disorder) in

adults”
Simon et al. GBR 2018 Bipolar and related Quetiapine, lamotrigine, folic Quetiapine plus RCT Cost-utility “Lamotrigine
(2018) disorders acid lamotrigine versus analysis, Cost- improved clinical
quetiapine monotherapy effectiveness ratings in bipolar
(and folic acid versus depression compared
placebo in an add-on with placebo. This
factorial design) differential effect was
not detected using the
EQ-5D-3L. The
additional cost of
lamotrigine was
balanced by
significant savings in
some other medical
costs which made its
use cost neutral to the
health service.
Compared to placebo,
folic acid produced
neither clinical nor
significant health
economic benefits.
The study supports
the use of lamotrigine
in combination with
other drugs to treat
bipolar depression”
(continued)
143
 144

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Mavranezouli GBR 2017 Bipolar and related Lithium, antipsychotics (e.g., Depending on reviewed Review Cost-utility, “Pharmacological
and Lokkerbol disorders aripiprazole, asenapine, study cost- interventions are cost
(2017) haloperidol, lurasidone, effectiveness, effective, compared
olanzapine, quetiapine, cost-benefit with no treatment, in
risperidone), antidepressants and cost- the management of
(e.g., fluoxetine, imipramine, consequence BD, both in the acute
paroxetine, venlafaxine) and analyses and maintenance
antiepileptics (such as phases. However, it is
carbamazepine, lamotrigine difficult to draw safe
and valproate, either as conclusions on the
valproic acid or sodium relative cost
valproate) effectiveness between
drugs due to
differences across
studies and
limitations
characterizing many
of them. Future
economic evaluations
need to consider the
whole range of
treatment options
available for the
management of BD
and adopt appropriate
methods for evidence
synthesis and
economic modelling,
R. Dodel et al.
 to explore more
robustly the relative
cost effectiveness of
pharmacological
interventions for
people with BD”
Depressive disorders
Pharmacoeconomics

Sado et al. (2019) JPN 2019 Depressive disorders Mirtazapine, SSRIs, other Mirtazapine versus Markov model Cost- “When considering
antidepressants other antidepressants effectiveness the early stage
efficacy of
mirtazapine, it
appeared to be cost-
effective compared to
selective serotonin
reuptake inhibitors,
especially for severe
depression and in the
early stage treatment
in the Japanese
setting. However, our
study has some
limitations. First,
mirtazapine is
compared with
batched selective
serotonin reuptake
inhibitors rather than
individual ones.
Second, we did not
consider
antidepressant
combination therapy
as treatment options”
(continued)
145
Table 4 (continued)
146

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Rubio-Valera ESP 2019 Depressive disorders Antidepressants Antidepressants versus RCT Cost-utility, “Incremental cost-
et al. (2019) active monitoring Cost- utility ratios favor
effectiveness pharmacological
treatment as a first-
line approach for
patients with mild-
moderate major
depressive disorder.
While our results
should be interpreted
with caution and
further real world
research is needed,
clinical practice
guidelines should
consider
antidepressant
therapy for mild-
moderate major
depressive patients as
an alternative to
active monitoring in
PC”
Yoon et al. USA 2018 Depressive disorders Aripirazole, bupropion Ariprazole versus RCT Cost- “In treatment of
(2018) bupropion versus effectiveness depression with less
ariprazole with switch than optimal
to bupropion response,
augmentation with
either aripiprazole or
bupropion was cost-
effective relative to
switching to
bupropion”
R. Dodel et al.
Kessler et al. GBR 2018 Depressive disorders SSRI, SNRI, oral mirtazapine Oral mirtazapine and RCT Cost- “This study did not
(2018) usual medication versus effectiveness find convincing
placebo and usual evidence of a
medication clinically important
benefit for
mirtazapine in
addition to a SSRI or
a SNRI antidepressant
Pharmacoeconomics

over placebo in
primary care patients
with TRD. There was
no evidence that the
addition of
mirtazapine was a
cost-effective use of
NHS resources. GPs
and patients were
concerned about
adding an additional
antidepressant”
Groessl et al. USA 2018 Depressive disorders Standard of care (SOC) Pharmacogenetic test Markov model Cost- “Pharmacogenetic
(2018) medication management (Idx) versus SOC effectiveness testing among
moderate to severe
MDD patients
improved QALYs and
resulted in cost
savings. Sensitivity
analyses supported
the robust nature of
the current findings of
the dominant IDGx
test to guide
treatment”
(continued)
147
 148

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Christensen and NOR 2018 Depressive disorders Vortioxetine, Duloxetine Vortioxetine versus Cost- “Vortioxetine may be
Munro (2018) duloxetine effectiveness a cost-effective
alternative to
duloxetine, owing to
its superior ability to
improve functional
capacity. The dual-
response STP concept
introduced here
represents a more
comprehensive
analysis of the cost-
effectiveness of
antidepressants”
Lee et al. (2018) CAN 2018 Depressive disorders Agomelatine, bupropion, Depending on reviewed Review Work place “Extant data suggest
desvenlafaxine, duloxetine, study functioning that antidepressant
fluoxetine, levomilnacipran, treatment improves
paroxetine, sertraline, workplace outcomes
venlafaxine, vortioxetine in MDD. The
capability of
antidepressants in
improving measures
of workplace
functioning should be
considered in cost-
benefit analyses to
better inform cost-
modelling studies
pertaining to
antidepressant
therapy”
R. Dodel et al.
Voigt et al. USA 2017 Depressive disorders Antidepressant medication, Repetive Transcranial Markov model Cost- “rTMS was identified
(2017) Repetive Transcranial Magnetic Stimulation effectiveness as the dominant
Magnetic Stimulation (rTMS) (rTMS) Antidepressant therapy compared to
medication antidepressant
medication trials over
the life of the patient
across the lifespan of
adults with MDD,
Pharmacoeconomics

given current costs of

treatment. These
models support the
use of rTMS after a
single failed
antidepressant
medication trial
versus further
attempts at
medication treatment
in adults with MDD”
Young et al. GBR 2017 Depressive disorders Vortioxetine, duloxetine, Vortioxetine versus Decision tree Cost-utility “This model provides
(2017) escitalopram, citalopram, duloxetine versus with Markov an overview for the
sertraline, venlafaxine escitalopram versus component management of
citalopram versus patients receiving
sertraline versus third-line treatment
venlafaxine where limited
evidence currently
exists. Vortioxetine,
with its novel
mechanism of action,
is expected to be a
dominant treatment
option versus relevant
comparators in the
UK”
(continued)
149
 150

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Peterson et al. USA 2017 Depressive disorders Antidepressants Antidepressant Review Cost- “Certain
(2017) treatment versus usual effectiveness pharmacogenomics
care among others tools show promise of
improving short-term
remission rates in
women in their
mid-40s with few
comorbidities. But,
important evidence
limitations preclude
recommending their
widespread use and
indicate a need for
further research”
Rosenblat et al. CAN 2017 Depressive disorders Antidepressant medication Pharmacogemomic Review Cost- “A limited number of
(2017) testing versus unguided effectiveness studies have shown
groups promise for the
clinical utility of
pharmacogenomic
testing; however,
cost-effectiveness of
pharmacogenomics,
as well as
demonstration of
improved health
outcomes, is not yet
supported with
replicated evidence”
R. Dodel et al.
Ophuis et al. NLD 2017 Anxiety Disorders Pregabalin, SSRI, Pharmacological versus Cost- Review “Forty-two studies
(2017) venlafaxine, diazepan, pharmacological and effectiveness reporting cost-
citalopram, escitalopram, pharmacological versus effectiveness of
paroxetin psychological interventions for
anxiety disorders
were identified. iCBT
was cost-effective in
comparison with the
Pharmacoeconomics

control conditions.
Psychological
interventions for
anxiety disorders
might be more cost-
effective than
pharmacological
interventions”
Obsessive-compulsive and related disorders
Fineberg et al. GBR 2018 Obsessive- SSRI CBT versus SSRI RCT Cost- “The mean Quality
(2018) compulsive and versus SSRI+CBT effectiveness Adjusted Life Year
related disorders scores for sertraline
were 0.1823 (95%
confidence interval:
0.0447–0.3199)
greater than for CBT
and 0.1135 (95%
confidence interval:
0.0290-0.2560),
greater than for
(continued)
151
 152

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
combined treatment.
Combined treatment
appeared the most
clinically effective
option, especially
over CBT, but the
advantages over SSRI
monotherapy were
not sustained beyond
16 weeks. SSRI
monotherapy was the
most cost-effective. A
definitive study can
and should be
conducted”
Skapinakis et al. GBR 2016 Obsessive- SSRI Pharmacological versus Review Cost- “In adults,
(2016) compulsive and placebo and effectiveness psychological
related disorders psychological versus interventions,
placebo and clomipramine, SSRIs
pharmacological versus or combinations of
psychological these are all effective,
whereas in children
and adolescents,
psychological
interventions, either
as monotherapy or
combined with
specific SSRIs, were
more likely to be
effective. Future
RCTs should improve
R. Dodel et al.
 their design, in
particular for
psychotherapy or
combined
interventions”
Trauma- and stressor-related disorders
Painter et al. USA 2017 Trauma- and stressor- RET Cost- “Because of the
Pharmacoeconomics

(2017) related disorders effectiveness upfront training costs

and the resource-
intensive nature of
this intervention,
associated expenses
were high. Although
PTSD (posttraumatic
stress disorder)-
specific effectiveness
measures were
significantly
improved, these
changes did not
translate to QALYs in
the main analysis.
However, analyses
focusing on patient
subgroups with
comorbid mental
disorders indicated
greater QALY
improvement for TOP
(Telemedicine
Outreach for PTSD)
at lower cost”
(continued)
153
 154

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Mihalopoulos AUS 2015 Trauma- and stressor- SSRI SSRI versus trauma- Economic Cost- “The three Guideline
et al. (2015) related disorders focused cognitive modelling effectiveness recommended
behavioral therapy interventions
(TF-CBT) and current evaluated in this study
practice in Australia are likely to have a
versus TF-CBT (for positive impact on the
children) economic efficiency
of the treatment of
PTSD (posttraumatic
stress disorder) if
adopted in full. While
there are gaps in the
evidence base, policy-
makers can have
considerable
confidence that the
recommendations
assessed in the current
study are likely to
improve the
efficiency of the
mental health care
sector”
Le et al. (2014) USA 2014 Trauma- and stressor- Sertraline Sertraline versus Randomized Cost- “Giving PTSD
related disorders prolonged exposure preference trial effectiveness (posttraumatic stress
therapy disorder) patients a
choice of treatment
appears to be cost-
R. Dodel et al.
 effective. When
choice is not possible,
prolonged exposure
therapy may provide a
cost-effective option
over
pharmacotherapy
Pharmacoeconomics

with sertraline”
Polak et al. NLD 2012 Trauma- and stressor- Paroxetine Parxetine versus RCT Cost- “This study is unique
(2012) related disorders psychological first line effectiveness for its direct
treatment (TF-CBT) comparison of the
most commonly used
psychological
intervention
(TF-CBT) and
pharmacological
intervention
(paroxetine) on (cost-)
effectiveness on the
short and the long
term. The anticipated
results will provide
relevant evidence
concerning long-term
effects and relapse
rates and will be
beneficial in reducing
societal costs. It may
also provide
information on who
may benefit most from
which type of
intervention. Some
methodological issues
will be discussed”
(continued)
155
 156

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Somatic symptom and related disorders
Wortman et al. NLD 2018 Somatic symptom Pharmacotherapy Review Cost- “This review provides
(2018) and related disorders versus behavioral effectiveness an overview of
therapy among others 39 included studies of
interventions for
patients with MUS
and FSS (medically
unexplained
symptoms (MUS) or
functional somatic
syndromes (FUS))
and the
methodological
quality of these
studies. Considering
the limited
comparability due to
the heterogeneity of
the studies, group
interventions might
be more cost-effective
than individual
interventions”
Le et al. (2018) AUS 2018 Feeding and eating Antidepressant medication Depending on reviewed Review Cost- “Cost-effectiveness
disorders study effectiveness studies in eating
disorder appear to be
increasing in number
over the last 6 years.
Findings were
inconsistent and no
R. Dodel et al.
 firm conclusion can
be drawn with regard
to comparative value-
for-money
conclusions.
However, some
promising
Pharmacoeconomics

interventions were
identified. Further
research with
improved
methodology is
required”
Elimination disorders
Ankjaer-Jensen DNK 1994 Elimination disorders Desmopressin Desmopressin versus Cost- “Treatment with a
and Sejr (1994) Desmopressin and effectiveness buzzer alarm or a
buzzer alarm combined treatment is
therefore from a
health economic point
of view preferable.
The health economic
consequences of the
introduction of new
treatments are
discussed, and it is
recommended that
health economic
analyses are
performed before the
introduction of new
treatments”
(continued)
157
 158

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Sleep wake disorders
Nishimura and JPN 2018 Sleep wake disorders Suvorexant, zolpidem Suvorexant versus Decision tree Cost- “Suvorexant seemed
Nakao (2018) (insomnia) zolpidem model effectiveness to be more cost-
effective than the
alternative zolpidem.
The findings
suggested that
suvorexant might be a
viable alternative to
zolpidem for elderly
patients with
insomnia. A
sensitivity analysis
showed that outcome
varied depending on
the relative risk for
hip fractures
associated with
suvorexant. Further
investigations may be
needed for more
precise results”
Bolin et al. SWE 2017 Sleep wake disorders Sodium oxybate Sodium oxybate versus Markov model Cost-utility “The estimated cost
(2017) (narcolepsy) standard treatment and cost- per additional QALY
effectiveness for the sodium
oxybate treatment
alternative compared
with standard
treatment was
estimated above the
informal Swedish
willingness-to-pay
R. Dodel et al.
 threshold (SEK
500,000). The
estimated cost per
additional QALY
obtained here is likely
to overestimate the
true cost-
Pharmacoeconomics

effectiveness ratio as
potentially beneficial
effects on
productivity of
treatment with
sodium oxybate were
not included (due to
lack of data)”
Tannenbaum CAN 2015 Sleep wake disorders Sedative hypnotics sedative-hypnotics Decision tree Cost- “Failure to consider
et al. (2015) versus CBT versus no model effectiveness drug harms such as
treatment drug-induced falls
and hospitalization
represents a growing
public health concern,
significantly
underestimating the
cost of sedative-
hypnotic therapy and
loss in quality of life
for the elderly. Public
payers should
reconsider
reimbursement of
sedative-hypnotic
drugs as first-line
treatment for
insomnia in older
adults”
(continued)
159
 160

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Perraudin et al. FRA 2013 Sleep wake disorders Screening strategy with Markov model Cost- “CP involvement in
(2013) (sleep apnea) community pharmacist effectiveness OSAS (obstructive
and general practitioner sleep apnea
versus screening with syndrome) screening
general practitioner is a cost-effective
alone versus no strategy. This
screening proposal is consistent
with the trend in
Europe and the
United States to
extend the practices
and responsibilities of
the pharmacist in
primary care”
Snedecor et al. USA 2009 Sleep wake disorders Eszopiclone Eszopiclone versus Double-blind, Cost- “Our model, based on
(2009) (insomnia) placebo Placebo effectiveness efficacy data from a
controlled clinical trial,
clinical trial demonstrated
eszopiclone was cost-
effective for the
treatment of primary
insomnia in adults,
especially when lost
productivity costs
were included”
Morin and USA 2009 Sleep wake disorders Eszopiclone Eszopiclone versus Review Cost- “Eszopiclone has
Willett (2009) (insomnia) other treatments effectiveness been shown to be an
efficacious and cost-
effective option for
the treatment of
transient and chronic
insomnia in adults”
R. Dodel et al.
Lees et al. (2008) GBR 2008 Sleep wake disorders Pramipexole, Ropinirole Pramipexole versus no Markov model Cost- “Pramipexole is cost-
(restless legs) treatment versus effectiveness effective compared to
ropinirole no treatment and
ropinirole for patients
with moderate to very
severe RLS”
Hair et al. (2008) NZL 2008 Sleep wake disorders Eszopiclone Depending on reviewed Review Cost-utility “Well designed,
Pharmacoeconomics

(insomnia) study comparative trials

with other
nonbenzodiazepine
hypnotics are needed
to determine its
relative efficacy and
tolerability. A cost-
utility analysis
suggested that
eszopiclone is cost
effective for the
treatment of primary
insomnia in the
US. Therefore,
eszopiclone is a
useful therapeutic
option in the
management of adult
and elderly patients
with primary or
co-morbid insomnia.
Unlike most other
hypnotics,
eszopiclone is not
limited to short-term
use”
(continued)
161
 162

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Matsuo and JPN 2007 Sleep wake disorders Midazolam, Flunitrazepam Midazolam versus Retrospective Cost- “Intravenous
Morita (2007) (insomnia) Flunitrazepam multicenter study effectiveness midazolam and
flunitrazepam
appeared to be almost
equal about efficacy
and safety for primary
insomnia, but
flunitrazepam is less
expensive and shows
lower risk of tolerance
development. A
future prospective
comparison study is
necessary”
Balkrishnan et al. USA 2007 sleep wake disorders Estazolam, Flurazepam, Authorization Economic model “This model showed
(2007) (insomnia) Quazepam, Temazepam, that requiring prior
Triazolam, Zolpidem, authorization for
Zaleplon, Ramelteaon, newer sleep
Eszopiclone treatments might not
be a cost-saving
strategy for managed-
care organizations”
Dundar et al. GBR 2004 Sleep wake disorders Zaleplon, zolpidem, zopiclon, Z-drugs versus Review Cost- “The short-acting
(2004) (insomnia) benzodiazepines benzodiazepines effectiveness drugs seem equally
effective and safe
with minor
differences that may
lead a prescriber to
favor one over
another in different
R. Dodel et al.
patients. There is no
evidence that one is
more cost-effective
than any other.
Analysis of the
additional costs to the
NHS, depending on
Pharmacoeconomics

the rate of change

from benzodiazepine
prescriptions to
Z-drug prescriptions,
at current levels of
hypnotic prescribing,
range from GBP2
million to GBP17
million per year.
There are clear
research needs in this
area; in particular,
none of the existing
trials adequately
compare these
medications. It is
suggested that further
consideration should
be given to a formal
trial to allow head-to-
head comparison of
some of the key drugs
in a double-blind
RCT lasting at least
2 weeks, and of
sufficient size to draw
reasonable
(continued)
163
 164

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
conclusions. We
would also
recommend that any
such trial should
include a placebo
arm. It should also
collect good-quality
data around sleep
outcomes and in
particular quality of
life and daytime
drowsiness. We do
not believe that any
formal study of risk of
dependency is
feasible at present.
Finally, the
management of long-
term insomnia is
suggested for further
investigation:
considering the
frequency of this
symptom and its
recurring course, the
short-term trial of
medication and lack
of long-term follow-
up undermine
attempts to develop
R. Dodel et al.
 evidence-based
guidelines for the use
of hypnotics in this
condition, or indeed
for its whole
management”
Sexual dysfunctions
Pharmacoeconomics

Martin et al. USA 2013 Sexual dysfunctions Sildenafil citrate Sildenafil versus other Review cost, cost- “The relative value of
(2013) active-treatment options effectiveness, sildenafil
cost of illness, vs. surgically
cost implanted prosthetic
consequence, devices and other
resource use, PDE5 inhibitors, is
productivity, underscored by
work loss, and patients’ WTP
willingness to (willingness to pay),
pay and cost-effectiveness
in ED patients with
comorbidities”
Aspinall et al. USA 2011 Sexual dysfunctions Vardenafil Vardenafil versus no Markov model Cost- “Although four doses
(2011) treatment and vardenafil effectiveness per month of
versus vardenafil in vardenafil was the
varying doses most cost-effective
strategy, the use of six
or eight doses per
month also compares
favorably with other
accepted medical
treatments. The
results were stable
across a range of
inputs and help to
support the current
(continued)
165
Table 4 (continued)
166

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Veterans Affairs
policy on the number
of vardenafil doses
provided per month
for erectile
dysfunction”
Stolk et al. (2000) NLD 2000 Sexual dysfunctions Sildenafil, papaverine- Sildenafil versus Trial Cost-utility, “Treatment with
phentolamine injections papaverine- cost-benefit, sildenafil is cost
phentolamine injections cost- effective. When
effectiveness considering funding
sildenafil, healthcare
systems should take
into account that the
frequency of use
affects cost
effectiveness”
Whittington and 1994 Sexual dysfunctions Oral conjugated estrogens, Overview Cost-utility, “The cost benefit and
Faulds (1994) oral ethinyl estradiol, cost-benefit, cost effectiveness of
transdermal estradiol cost- HRT in the treatment
effectiveness of menopausal
symptoms have not
been fully researched,
although preliminary
results suggest that
conjugated estrogens
and transdermal
estradiol compare
well with alternative
therapies such as
veralipride and
Chinese medicines.
A Swedish study
R. Dodel et al.
using a prevalence-
based approach
estimated that estriol
treatment in all
women with urinary
incontinence aged
greater than or equal
Pharmacoeconomics

to 65 years resulted in
monetary savings
compared with
treating 20% of
women. Cost-utility
data indicated that the
change in quality-
adjusted life years
(QALYs) with HRT
was always positive,
but the degree of
change was
determined by the
baseline assumptions.
Estimated changes in
QALYs with HRT
ranged from 0.006 for
5 years of treatment
with unopposed
estrogen in women
with intact uteri, to
0.5 for 10 years of the
same treatment in
women with severe
menopausal
symptoms following
hysterectomy.
Compliance with
(continued)
167
Table 4 (continued)
168

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
HRT is suboptimal as
5 to 50% of women
withdraw from
therapy, thereby
increasing costs per
year of life saved”
Gender dysphoria
Marfori et al. USA 2018 Gender dysphoria Review “This review
(2018) summarizes the
available literature on
surgical techniques in
addition to reporting
our institutional
outcomes using a
novel 2-port
laparoscopic
approach. Additional
preoperative and
perioperative
considerations are
needed when caring
for this patient
population and are
reviewed”
Disruptive, impulse-control, and conduct disorders
McConaghy and GBR 1988 Disruptive, impulse- Case report “Expectancy of
Blaszczynski control, and conduct improvement did not
(1988) disorders appear to play a major
role in their response,
but it appears
impossible to
disprove that
R. Dodel et al.
 expectancy
determines the
response to this or any
form of
psychotherapy.
Whether or not
imaginal
Pharmacoeconomics

desensitization acted
specifically in the
present study, in view
of its cost-efficacy it
is suggested it is
worthy of trial in
impulse disorders
which have persisted
despite treatment”
Substance-related and addictive disorders
Sluiter et al. NLD 2018 Substance-related Naltrexone, acamprosate Naltrexone (G-allele Markov model Cost- “In conclusion,
(2018) and addictive carriers)/acamprosate or effectiveness pharmacogenetic
disorders (alcohol) naltrexone treatment allocation
(AA Homozygotes) of AUD (Alcohol use
versus standard care disorders) patients to
(random treatment of naltrexone, based on
acamprosate or OPRM1 (μ1 opioid
natrexone) receptor) genotype,
can be a cost-effective
strategy, and could
have potential
individual and
societal benefits.
However, more
evidence on the
impact of genotype-
guided treatment
allocation on relapse
169

(continued)
 170

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
is needed to
substantiate these
conclusions, as there
is contradictory
evidence about the
effectiveness of
OPRM1 genotyping”
Bansback et al. CAN 2018 Substance-related Diacetylmorphine, injectable Diacetylmorphine RCT Cost- “In patients with
(2018) and addictive hydromorphone, methadone versus injectable effectiveness severe opioid use
disorders (opioids) hydromorphone (and disorder enrolled into
indirect versus the SALOME trial,
methadone) injectable
hydromorphone
provided similar
outcomes to
injectable
diacetylmorphine.
Modelling outcomes
during a patient’s life-
time suggested that
injectable
hydromorphone
might provide greater
benefit than
methadone alone and
may be cost-saving,
with drug costs being
offset by costs saved
from reduced
involvement in
criminal activity”
R. Dodel et al.
Krebs et al. CAN/ 2018 Substance-related Opioid agonist treatment Opioid agonist Semi-Markov Cost- “The value of
(2018) USA and addictive (OAT) treatment (OAT) versus model effectiveness publicly funded
disorders (opioids) standard of care treatment of opioid
use disorder in
California is
maximized when
OAT is delivered to
all patients presenting
Pharmacoeconomics

for treatment,
providing greater
health benefits and
cost savings than the
observed standard of
care”
Carter et al. USA 2017 Substance-related Subdermal implantable Subdermal implantable Markov model Cost- “BSI was preferred
(2017) and addictive buprenorphine (BSI), buprenorphine (BSI) effectiveness over SL-BPN from a
disorders (opioids) sublingual buprenorphine versus sublingual health-economic
(SL-BPN) buprenorphine perspective for
(SL-BPN) treatment of OUD in
clinically-stable
adults. These findings
should be interpreted
carefully, due to some
relationships having
been modeled from
inputs derived from
multiple sources, and
would benefit from
comparison with
outcomes from
studies that employ
administrative claims
data or a naturalistic
comparative design”
(continued)
171
 172

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Kenworthy et al. GBR 2017 Substance-related Buprenorphine maintenance Buprenorphine Decision tree Cost- “OST can be
(2017) and addictive treatment (BMT), methadone maintenance treatment model effectiveness considered cost-
disorders (opioids) maintenance treatment (BMT) and methadone effective vs no OST
(MMT) maintenance treatment from the UK
(MMT) versus no NHS/PSS
opioid substitution perspective, with a
therapy (OST) cost per QALY well
below the UK’s
willingness-to-pay
threshold. There were
only small differences
between BMT and
MMT. The
availability of two or
more cost-effective
options is beneficial
to retaining patients in
OST programs. From
a societal perspective,
OST is estimated to
save over £14,032
and £17,174 per year
for BMT and MMT vs
no OST, respectively,
due to savings in
victim costs. Further
work is required to
fully quantify the
clinical and health
R. Dodel et al.
 economic impacts of
different OST
formulations and their
societal impact over
the long-term”
Dunlop et al. AUS 2017 Substance-related Buprenorphine-naloxone Buprenorphine- RCT Cost- “When compared to
(2017) and addictive naloxone versus no effectiveness remaining on a
Pharmacoeconomics

disorders (opioids) clinical intervention waitlist, take-home

self-administered
buprenorphine-
naloxone treatment is
associated with
significant reductions
in heroin use for
people with DSM-IV-
TR heroin
dependence. This
cost-effective
approach may be an
efficient strategy to
enhance treatment
capacity”
Idrisov et al. RUS 2017 Substance-related Methadone Methadone versus State model (not Cost- “This study suggests
(2017) and addictive current therapies further specified) effectiveness that implementing a
disorders (opioids) methadone therapy
program in Russia
would be highly cost-
effective due to its
effectiveness in
averting DALYs
among people who
inject drugs. Russia’s
robust health
workforce and its
constitutionally
173

(continued)
 174

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
assured right to health
provide a formidable
implementation
framework for
updating the Russian
addiction treatment
and rehabilitation
standards to include
international,
evidence-based
addiction treatment
with opioid agonist
medication. This will
reduce the burden of
disease related to
substance use and
associated conditions
such as HIV and
TB. By reconsidering
its position on opioid
agonist therapy,
Russia could create
substantial progress in
the country’s fight
against the burden of,
OUD, HIV and other
drug-related diseases,
as well as the human
tragedies behind
them”
R. Dodel et al.
King et al. (2016) USA 2016 Substance-related Buprenorphine, Methadone Buprenorphine versus Markov model Cost- “The authors
and addictive Methadone effectiveness conclude that MMT is
disorders (opioids) cost-effective
compared with BMT
for the treatment of
patients with opioid
dependence.
However, the
Pharmacoeconomics

treatment of
substance abuse is
complex, and
decision makers
should also consider
individual patient
characteristics when
making coverage
decisions”
Laramee et al. GBR 2016 Substance-related Nalmefene Nalmefene plus Markov model Cost- “Nalmefene
(2016) and addictive psychosocial support effectiveness represents a highly
disorders (alcohol) versus psychosocial cost-effective
support alone treatment option in
this population. The
analysis shows that
integrating nalmefene
within the current UK
clinical treatment
pathway for alcohol
dependence could
reduce the economic
burden on the NHS by
limiting harmful
events and disease
progression”
(continued)
175
 176

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Thursz et al. GBR 2015 Substance-related Prednisolone and Placebo/placebo versus RCT Cost- “We conclude that
(2015) and addictive pentoxifylline (PTX) placebo/prednisolone effectiveness prednisolone reduces
disorders (alcohol) versus PTX/placebo the risk of mortality at
versus 28 days, but this
PTX/prednisolone benefit is not
sustained beyond
28 days. PTX had no
impact on survival.
Future research
should focus on
interventions to
promote abstinence
and on treatments that
suppress the hepatic
inflammation without
increasing
susceptibility to
infection”
Stevenson et al. GBR 2015 Substance-related Nalmefene Depending on trial Review Cost- “The clinical
(2015) and addictive effectiveness evidence provided in
disorders (alcohol) the company’s
submission, which
was based on the
results of three pivotal
trials, confirmed the
efficacy and safety of
treatment with
nalmefene together
with psychosocial
support. However,
there were a number
R. Dodel et al.
 of limitations and
uncertainties in the
evidence base which
warrant caution in the
interpretation of the
data. In particular, the
inference of treatment
Pharmacoeconomics

effects may be
confounded by the
high drop-out rates
and the use of post
hoc subgroup
analyses to define the
licensed population”
Jackson et al. USA 2015 Substance-related Injectable extended-release Injectable extended- Markov model Cost- “XR-NTX is a cost-
(2015) and addictive naltrexone (XR-NTX), release naltrexone effectiveness effective medication
disorders (opioids) methadone (XR-NTX) versus for treating opioid
methadone dependence if state
addiction treatment
payers are willing to
pay at least $72 per
opioid-free day”
Laramee et al. GBR 2014 Substance-related Nalmefene Nalmefene plus Markov model Cost- “Nalmefene can be
(2014) and addictive psychosocial support effectiveness seen as a cost-
disorders (alcohol) versus psychosocial effective treatment for
support alone alcohol dependence,
with substantial
public health
benefits”
(continued)
177
 178

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Reddy et al. IND 2014 Substance-related Baclofen, chlordiazepxide, Baclofen versus RCT Cost- “Both study drugs
(2014) and addictive lorazepam chlordiazepoxide effectiveness provided relief of
disorders (alcohol) withdrawal
symptoms.
Chlordiazepoxide
was more cost-
effective than
baclofen. Baclofen
was relatively less
effective and more
expensive than
chlordiazepoxide”
Schwartz et al. USA 2014 Substance-related Methadone Interim versus standard RCT Cost-benefit “The net benefits of
(2014) and addictive methadone treatment were greater
disorders (opioids) for the IM (interim
methadone) condition
but controlling for the
baseline variables
noted above, the
difference between
conditions in net
monetary benefits was
not significant. For
the combined sample,
there was a pre- to
posttreatment net
benefit of $1470 (95%
CI: -$625; $3584) and
a benefit-cost ratio of
1.5 (95% CI: 0.8, 2.3),
but using our
R. Dodel et al.
 conservative
approach to
calculating benefits,
these values were not
significant”
Ruger et al. USA 2012 Substance-related Buprenorphine, naltrexone Buprenorphine versus RCT Cost- “Buprenorphine
(2012) and addictive naltrexone versus effectiveness appears to be a cost-
Pharmacoeconomics

disorders (opioids) placebo effective alternative to

naltrexone that might
enhance economic
productivity and
reduce drug use over a
longer term”
Nosyk et al. CAN 2012 Substance-related Diacetylmorphine, Diacetylmorphine Semi-Markov Cost- “Using mathematical
(2012) and addictive methadone versus methadone model effectiveness modelling to
disorders (opioids) extrapolate results
from the North
American Opiate
Medication Initiative,
we found that
diacetylmorphine
may be more effective
and less costly than
methadone among
people with chronic
opioid dependence
refractory to
treatment”
Popova et al. CAN 2011 Substance-related Acamprosate Depending on study Review Cost-benefit “To date, only a few
(2011) and addictive studies exist that have
disorders (alcohol) examined the cost-
benefit of
psychotherapy or
pharmacotherapy
treatment of
179

(continued)
Table 4 (continued)
180

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
AD. Most of the
available treatment
options for AD appear
to produce marked
economic benefits”
Saul et al. (2011) USA 2011 Substance-related Nicotine replacement Observational Cost- “Results of this
and addictive therapy with patches study effectiveness evaluation indicate
disorders (tobacco) versus nictotine that while satisfaction
replacement therapy rates increase among
with gum those receiving more
counseling and NRT,
quit rates do not, even
when controlling for
demographic and
tobacco use
characteristics”
Keating and NZL 2010 Substance-related Varenicline Depending on reviewed Review Cost- “Indeed, despite their
Lyseng- and addictive study effectiveness limitations, available
Williamson disorders (tobacco) pharmacoeconomic
(2010) analyses from
numerous countries
support the use of
varenicline for 12 or
24 weeks as a cost-
effective treatment
relative to other
smoking cessation
therapies in smokers
who wish to quit
smoking. For
example, in modelled
cost-effectiveness
R. Dodel et al.
 analyses conducted
from a healthcare
payer perspective,
12 weeks’ treatment
with varenicline
consistently
dominated bupropion
Pharmacoeconomics

sustained release and

nicotine replacement
therapy, and was
dominant over, or
considered cost
effective relative to,
unaided cessation,
brief counseling or
nortriptyline, with
regard to the
incremental costs per
quality-adjusted life-
year or life-year
gained”
Shearer et al. GBR 2010 Substance-related Modafinil Modafinil plus RCT Cost- “Strategies to
(2010) and addictive counseling versus effectiveness improve the uptake of
disorders placebo counselling are
recommended as cost-
effective”
Linden et al. FIN 2010 Substance- Varenicline Varenicline versus Markov model Cost- “Varenicline
(2010) RELATED AND bupropion versus effectiveness dominated over its
ADDICTIVE unaided comparators, i.e., it
DISORDERS was more effective
(Tobacco) and resulted in cost
saving compared with
bupropion and
unaided cessation”
(continued)
181
 182

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Adi et al. (2007) GBR 2007 Substance-related Naltrexone Naltrexone versus Review Cost- “Following
and addictive placebo versus other effectiveness successful withdrawal
disorders (opioids) pharmacological from opioids,
treatments versus naltrexone may be
psychosocial administered on a
interventions versus no chronic basis to block
treatment any future effects of
opioids. Naltrexone
appears to have some
limited benefit in
helping formerly
opioid-dependent
individuals to remain
abstinent, although
the quality of the
evidence is relatively
poor and
heterogeneous. The
limited quality and
extent of the studies
precluded an analysis
of subgroups likely to
benefit from
naltrexone
prescribing. Oral
naltrexone is used
infrequently in
current UK practice,
and this review
suggests that this is
R. Dodel et al.
 appropriate as there is
little evidence to
support its wider
implementation.
There is an important
deficit in information
about the quality of
Pharmacoeconomics

life of people who use

illicit opioids and this
would perhaps be a
worthwhile area of
research in informing
policy questions
about the cost-
effectiveness of
different programs
and interventions”
Jofre-Bonet et al. GBR 2004 Substance-related Methadone, disulfiram Disulfiram plus RCT Cost- “Results from this
(2004) and addictive methadone versus effectiveness cost-effectiveness
disorders (opioids) methadone analysis imply that,
even though
disulfiram increases
slightly the cost of
methadone treatment,
its increase in
effectiveness may be
important enough to
warrant its addition
for treating cocaine
dependence in
methadone-
maintained opiate
addicts”
(continued)
183
 184

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Neurocognitive disorders
da Silva et al. BRA 2019 Neurocognitive Donepezil, Rivastigme Donepezil versus Markov model Cost- “The findings of this
(2019) disorders (dementia) Rivastigme effectiveness, study contradict the
cost-benefit, standard of care for
cost-utility mild and moderate
AD in Brazil, which is
based on
rivastigmine. A
pharmacological
treatment option
based on current
Brazilian clinical
practice guidelines for
AD suggests that
rivastigmine is less
cost-effective (0.39
QALY/BRL
32,685.77) than
donepezil.
Probabilistic analysis
indicates that
donepezil is the most
cost-effective
treatment for mild and
moderate AD”
Ebrahem and CAN 2018 Neurocognitive Cholinesterase inhibitors, Depending on reviewed Review Cost- “The literature
Oremus (2018) disorders (dementia) memantine study effectiveness suggested AD
medications generally
dominated
comparator
treatments (e.g.,
R. Dodel et al.
placebo). Expert
opinion: The authors
noted several
limitations of the
included economic
evaluations. These
limitations suggest
Pharmacoeconomics

the results of the

economic evaluations
should be interpreted
with caution. Many
economic models
were not transparent
with respect to
sources of
probabilities and cost
data, and data
collected in certain
jurisdictions were
applied to other
jurisdictions without
considering the
validity of such
applications.
Measuring health
utilities in cognitively
impaired populations
raises questions about
the validity of quality-
adjusted life years,
but this issue was
unaddressed in the
included studies.
Most included studies
(continued)
185
Table 4 (continued)
186

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
were sponsored by
industry and the
results tended to
overwhelmingly
support the
manufacturer’s
product”
Carrasco et al. ESP 2016 Neurocognitive Dexmedetomidine, Dexmedetomidine RCT Cost- “In the study
(2016) disorders (delirium) haloperidol versus haloperidol effectiveness, conditions,
cost-benefit dexmedetomidine
shows to be useful as
a rescue drug for
treating agitation due
to delirium in
nonintubated patients
in whom haloperidol
has failed, and it
seems to have a better
effectiveness, safety,
and cost-benefit
profile than does
haloperidol”
Djalalov et al. CAN 2012 Neurocognitive Donepezil, Rivastigme Donepezil versus and Markov model Cost- “Using presently
(2012) disorders (amnesia) genetic screening of effectiveness available clinical
apolipoprotein versus evidence, this
standard of care exploratory study
illustrates that genetic
testing combined with
preventive donepezil
treatment for AMCI
(amnestic mild
cognitive impairment)
R. Dodel et al.
 patients may be
economically
attractive. Since our
results were based on
a secondary post hoc
analysis, our study
alone is insufficient to
Pharmacoeconomics

warrant
recommending APOE
genotyping in AMCI
patients. Future
research on the
effectiveness of
preventive donepezil
as a targeted therapy
is recommended”
Personality disorders
Crawford et al. GBR 2018 Personality disorders Lamotrigine Lamotrigine versus RCT Cost- “The addition of
(2018) (borderline) placebo effectiveness lamotrigine to the
usual care of people
with BPD was not
found to be clinically
effective or provide a
cost-effective use of
resources”
Headache
Bellingham and CAN 2010 Headache Duloxetine Duloxetine versus other Review Cost- “Randomized trials
Peng (2010) antidepressants effectiveness have documented
among others significant analgesic
effects for managing
chronic pain
associated with
fibromyalgia and
diabetic peripheral
neuropathic pain.
187

(continued)
 188

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Studies have also
suggested that pain
associated with major
depressive disorder
can be reduced with
this medication.
Modest effects for
headache,
osteoarthritic pain,
and pain secondary to
Parkinson disease
have also been
documented, but data
are obtained from
single-blinded or
open-label trials that
require further
corroboration with
larger randomized
studies. Duloxetine
has not yet been
directly compared
with other
antidepressants or
anti-convulsants for
the treatment of pain
syndromes”
Gracia Naya ESP 2001 Headache Tritapanes (sumatriptan, Sumatriptan versus Cost- “In chronic, recurrent
(2001) naratriptan, zolmitriptan, naratriptan versus effectiveness disorders such as
rizatriptan, almotriptan) zolmitriptan versus migraine, when the
rizatriptan versus cost of treatment
almotriptan using triptans is
R. Dodel et al.
 assessed, one has not
only to evaluate the
cost per unit but also
to introduce other
parameters such as the
efficacy of the drug,
which is one of the
Pharmacoeconomics

most important”
Epilepsy
Choi and Mohit USA 2019 Epilepsy Carbamazepine Screening for Markov model Cost- “Our analysis
(2019) HLA-B*1502 versus no effectiveness confirms the 2007 US
screening Food and Drug
Administration
recommendation to
screen for
HLA-B*1502 allele
before starting
treatment with
carbamazepine in
patients of Asian
ancestry in the United
States”
Geitona et al. GRC 2019 Epilepsy Lacosamide, zonisamide Lacosamide versus Discrete event Cost- “Lacosamide is a
(2019) zonisamide simulation model effectiveness cost-effective option
at a willingness-to-
pay threshold of
€30,000 per QALY,
representing a
valuable
monotherapy
treatment option for
patients with focal
epileptic seizures in
the Greek setting”
(continued)
189
 190

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Mkrtchyan and RUS 2019 Epilepsy Carbamazepine (CBZ), Carbamazepine (CBZ) “CBZ, OXZ and
Kaimovsky oxcarbazepine (OXZ), versus oxcarbazepine LCM can be used as
(2019) lamotrigine (LTG), (OXZ) versus monotherapy in
lacosamide (LCM) lamotrigine (LTG) patients with newly
versus lacosamide diagnosed
(LCM) FE. Monotherapy
with LCM is
associated with
lowest costs for
stopping focal
seizures and the
highest percentage of
seizure-free patients.
CBZ remains the
most economical
AED: the cost-
effectiveness is
minimal compared to
all other AEDs used
in the study. However,
monotherapy with
LCM is advisable if it
is necessary to
minimize side-effects
in patients with newly
diagnosed FE”
Tremblay et al. ESP 2018 Epilepsy Perampanel, other Perampanel versus Markov model Cost- “Our study
(2018) antiepileptic drugs other antiepileptic drugs effectiveness demonstrates that
perampanel is likely
to be a cost-effective
option”
R. Dodel et al.
Elliott et al. CAN 2018 Epilepsy (Dravet Stiripentol, clobazam, Stiripentol versus Markov model Cost- “From the perspective
(2018) Syndrome) valproate clobazam versus effectiveness of the Canadian
valproate public healthcare
payer, stiripentol is
not cost effective at its
current price at a
willingness-to-pay
threshold of
Pharmacoeconomics

$Can50,000. Funding
stiripentol will be
associated with
important opportunity
costs that bear
consideration”
Picot et al. (2016) FRA 2016 Epilepsy Medical group versus Markov model Cost- “Our study suggests
surgery group effectiveness that in addition to
being safe and
effective, respective
surgery of epilepsy is
cost-effective in the
medium term. It
should therefore be
considered earlier in
the development of
epilepsy”
Jacoby et al. GBR 2015 Epilepsy Carbamazepine, Lamotrigine, Carbamazepine versus RCT QoL “The choice of initial
(2015) gabapentin, oxcarbazepine, lamotrigine, treatment had no
topiramate, valproate gabapentin, significant effect on
oxcarbazepine and QoL by 2-year
topiramate, and follow-up. However,
valproate versus overall QoL was
lamotrigine and reduced with
topiramate continued seizures,
adverse events, and
failure of the initial
treatment”
191

(continued)
 192

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Darba et al. ESP 2014 Epilepsy Pregabalin Depending on reviewed Review Cost- “The majority of
(2014) study effectiveness published evidence
supports the
possibility that
pregabalin could be a
cost-effective and/or
cost-saving
alternative for the
treatment of
refractory epilepsy,
GAD, and
neuropathic pain, in
both treatment-naïve
patients and in those
who have
demonstrated
inadequate response
or intolerance to
previous therapy”
Clements et al. USA 2013 Epilepsy Lamotrigine, rufinamide, Lamotrigine versus Trial-based Cost- “Over a 3-month
(2013) topiramate rufinamide versus economic model effectiveness horizon, clobazam
topiramate was more effective
and less expensive
than comparators,
with the assumption
that >0.77% of drop
seizures required
medical care. Below
this threshold,
topiramate was less
costly than clobazam.
With the base-case
R. Dodel et al.
 assumption that 2.3%
of drop seizures were
medically attended,
costs for patients
receiving clobazam
totaled $30,147
versus $34,223–$
Pharmacoeconomics

35,378 for
comparators.
Clobazam was more
efficacious and less
costly than rufinamide
over a 2-year horizon.
The percentage of
medically attended
drop seizures was a
driver of results.
Clobazam treatment
may be cost-saving”
Rattanavipapong THA 2013 Epilepsy Carbamazepine Carbamazepine with Decision tree and Cost- “Universal
et al. (2013) screening versus no Markov model effectiveness HLA-B*15:02
screening screening represents
good value for the
money in terms of
preventing SJS/TEN
(Stevens-Johnson
syndrome; toxic
epidermal necrolysis)
in CBZ-treated
patients with
neuropathic pain at
the Thai ceiling ratio
of 120,000
THB/QALY gained.
However, the
prevalence of
193

(continued)
 194

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
CBZ-induced
SJS/TEN in the Thai
population and the
positive predictive
value (PPV) are major
factors that influence
the cost-effectiveness
of HLA-B*15:02
screening. Therefore,
an active surveillance
system to make a
more accurate
assessment of the
prevalence
CBZ-induced
SJS/TEN in the Thai
population would
enhance the
generalizability of the
results”
Lee et al. (2013) GBR 2013 Epilepsy Buccolam Buccolam versus Decision tree Cost- “This model
diazepam and buccal effectiveness demonstrates the
midazolam possibility of
constructing a
thorough economic
case when trial or
real-world data are
not available. The
results of the model
show Buccolam to be
cost saving compared
with rectal diazepam
R. Dodel et al.
 due to a reduction in
the need for
ambulance callouts
and hospital stays,
and compared with
unlicensed buccal
midazolam, through
Pharmacoeconomics

reduced drug costs

and wastage”
Kristian et al. SWE 2013 Epilepsy Retigabine, lacosamide Retigabine or Decision tree Cost- “The estimated cost
(2013) lacosamide and placebo effectiveness per additional QALY,
for the retigabine vs
no add-on treatment
comparison, is well
within the range of
newly published
estimates of
willingness to pay for
an additional QALY.
Thus, add-on
retigabine treatment
for people with focal-
onset epilepsy with
no/limited response to
standard antiepileptic
treatment appears to
be cost-effective”
Dong et al. SGP 2012 Epilepsy Carbamazepine, phenytoin Treatment with Decision tree Cost- “Because of the
(2012) screening versus no effectiveness different population
screening allele frequencies of
HLA-B*1502 among
different ethnic
groups, genotyping
for HLA-B*1502 and
providing alternate
AEDs to those who
195

(continued)
 196

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
test positive is cost-
effective for
Singaporean Chinese
and Malays, but not
for Singaporean
Indians. Population
frequency of
HLA-B*1502, PPV,
duration of treatment
relative to life
expectancy, and costs
of alternative drugs
are the key drivers
influencing cost-
effectiveness”
Bolin and SWE 2012 Epilepsy Antiepileptic drugs Depending on reviewed Review Cost- “Although failure to
Forsgren (2012) study effectiveness meet good practice
guidelines influences
the reliability of the
presented evidence
adversely, a sufficient
number of the
included studies were
found to comply
enough with the
guidelines in order for
the qualitative content
of the cost-
effectiveness results -
that some of the
newer AEDs are cost
R. Dodel et al.
effective - to be
reliable. In fact, this
conclusion is likely to
be relatively robust,
since the effect of
improved seizure
control on labor
Pharmacoeconomics

market performance
was not included in
the base-case results
in any of the included
studies and improved
seizure control need
only to have a
moderate effect on
sickness absenteeism
in order for the
corresponding
treatment to be cost
effective even when
willingness to pay for
an additional QALY is
low. However, the
cost effectiveness of
newer AEDs has only
been studied for a
small number of
settings, and hence
future studies
incorporating
additional settings are
needed”
(continued)
197
Table 4 (continued)
198

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Stroke
Bowrin et al. FRA 2020 Stroke Rivaroxaban, vitamin K Rivaroxaban versus Markov model Cost- “Although there is no
(2020) antagonists vitamin K antagonists effectiveness official willingness-
to-pay threshold in
France, these results
suggest that
rivaroxaban is likely
to be cost-effective
compared to VKA in
French patients with
AF from a national
insurance
perspective”
de Jong et al. NLD 2019 Stroke Vitamin K antagonists NOAC apixaban versus RCT Cost- “Based on RCTs
(2019) (VKAs)-non-VKA oral other NOACs effectiveness (randomized
anticoagulants (NOACs) (dabigatran, edoxaban, controlled trials) as
and rivaroxaban) and well as RWD (real-
VKA world data), we
conclude that
apixaban is generally
cost-effective or even
cost-saving (less
costly and more
effective) compared
to VKA and other
NOACs in the overall
population of patients
with atrial fibrillation”
Yagudina et al. RUS 2019 Stroke Ethylmethylhydroxypyridine Ethylmethylhydroxy- Cost- “Mexidol has the
(2019) succinate (mexidol), inosine, pyridine succinate effectiveness same efficacy as
nicotinamide, riboflavin, (mexidol), inosine + alternatives. However
succinic acid (cytoflavin) nicotinamide + mexidol is superior to
R. Dodel et al.
 riboflavin + succinic cytoflavin and
acid (cytoflavin), and a actovegin in terms of
deproteinized cost minimization
hemoderivate of the analysis. The savings
blood of calves from one course of
(actovegin) alternatives will cover
costs of treatment of
Pharmacoeconomics

five patients with IS

using mexidol. The
increase in the
proportion of patients
receiving mexidol is
associated with
savings, which allows
us to consider
mexidol therapy of
mild IS as budget-
saving in the Russian
Federation”
Malhotra et al. USA 2019 Stroke Endovascular thrombectomy Markov model Cost- “Our study
(2019) (EVT), intravenous effectiveness demonstrates the
thrombolysis (IVT) impact of relevant
factors on the
effectiveness of EVT
in patients above
80 years of age.
Morbidity and
mortality after both
IVT and EVT
strategies
significantly influence
the outcomes in both
healthy and disabled
patients at baseline.
(continued)
199
Table 4 (continued)
200

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Better identification
of patients not
benefiting from IVT
would optimize the
selective use of EVT
thereby improving its
effectiveness”
Kabore et al. FRA 2019 Stroke Mechanical thrombectomy IV-tPA versus MT-IV- Markov model Cost- “Although there is no
(2019) (MT) plus intravenous tissue- tPA effectiveness universally accepted
type plasminogen activator willingness-to-pay
(IV-tPA) (MT-IV-tPA) threshold in France,
our analysis suggests
that MT combined to
IV-tPA can be
considered a cost-
effective treatment
compared with
IV-tPA alone”
Reeves et al. AUS 2018 Stroke Reperfusion therapy with Multimodal computed Cost-utility “In a healthcare
(2018) alteplase tomography imaging setting where
(MMCT) versus multimodal imaging
reperfusion therapy technologies are
with alteplase available and
reimbursed, their use
in screening patients
presenting with acute
stroke to determine
eligibility for
alteplase treatment is
cost-effective given a
range of willingness-
to-pay thresholds and
R. Dodel et al.
 warrants
consideration as an
alternative to routine
practice”
Pickett et al. USA 2018 Stroke Standard medical therapy Foramen ovale closure RCT Cost- “In comparison to
(2018) versus medical therapy effectiveness medical therapy
alone, PFO closure
Pharmacoeconomics

appears to be cost-
effective and
clinically efficacious”
Ruggeri et al. ITA 2018 Stroke Intravenous tissue MT and intravenous Markov model Cost- “MT plus IV t-PA for
(2018) plasminogen activation tissue plasminogen effectiveness AIS patients with
activation (MT plus IV LVO is cost-effective
t-PA) versus IV t-PA from year 1 through
year 3, and cost-
saving from year
4 onward in the Italian
context, achieving
better results, both in
terms of efficacy and
in terms of resource
consumption”
Reddy et al. USA 2018 Stroke Warfarin, non-vitamin K Left atrial appendage Markov model Cost- “Upfront procedure
(2018) antagonist oral anticoagulants closure (LAAC) effectiveness costs initially make
dabigatran, apixaban, compared with warfarin LAAC higher cost
rivaroxaban and the non-vitamin K than warfarin and the
antagonist oral non-vitamin K
anticoagulants antagonist oral
dabigatran 150 mg, anticoagulants, but
apixaban and within 10 years,
rivaroxaban LAAC delivers more
quality-adjusted life
years and has lower
total costs, making
LAAC the most cost-
201

(continued)
Table 4 (continued)
202

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
effective treatment
strategy for secondary
prevention of stroke
in atrial fibrillation”
Leppert et al. USA 2018 Stroke Percutaneous transcatheter Percutaneous Markov model Cost- “PFO closure for
(2018) closure of patent foramen transcatheter closure of effectiveness cryptogenic strokes in
ovale (PFO closure), patent foramen ovale the right setting is
antiplatelet therapy (PFO closure) plus cost-effective,
antiplatelet therapy producing benefit in
versus antiplatelet QALYs gained and
therapy potential cost savings.
However, patient
selection remains
vitally important as
marginal declines in
treatment
effectiveness can
dramatically affect
cost-effectiveness”
Roffe et al., GBR 2018 Stroke Nocturnal oxygen Low-dose oxygen vs no RCT Cost- “Routine low-dose
2018) oxygen effectiveness oxygen
supplementation in
stroke patients who
are not severely
hypoxic is safe, but
does not improve
outcome after stroke”
Joo et al. (2017) USA 2017 Stroke Intravenous recombinant Intravenous Markov model Cost- “IV rtPA saved costs
tissue plasminogen activator recombinant tissue effectiveness and improved health
plasminogen activator outcomes for patients
vs no treatment aged 18–64 years and
was cost effective for
R. Dodel et al.
 those aged 65 years.
These findings
support the use of IV
rtPA”
Amiri et al. IRN 2018 Stroke Tissue plasminogen activator tPA versus no tPA Markov model Cost- “The balance of
(2018) (tPA) effectiveness hospitalization and
rehabilitation costs
Pharmacoeconomics

and QALYs support

the conclusion that
treatment with
intravenous tPA in the
4.5-h time window is
cost-effective from
the perspectives of the
third party payer and
inclusion of tPA in the
insurance benefit
package being
reasonable”
Heller et al. USA 2017 Stroke Statins Statins versus other Cardiovascular Cost- “At a population
(2017) guidelines disease policy effectiveness level, the ACC/AHA
model guideline for
expanded statin use
for primary
prevention is
projected to treat
more people, to save
more lives, and to cost
less compared with
Adult Treatment
Panel III in both men
and women. Whether
individuals benefit
from long-term statin
use for primary
203

(continued)
 204

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
prevention depends
more on the disutility
associated with pill
burden than their
degree of
cardiovascular risk”
Davies et al. USA 2017 Stroke Ezetimibe, statin Ezetimibe and statin Markov-like Cost- “Compared with
(2017) versus statin model effectiveness statin monotherapy,
ezetimibe with statin
therapy was cost-
effective for
secondary prevention
of CHD and stroke
and for primary
prevention of these
conditions in patients
whose LDL-C levels
are 100 mg/dL and
in patients with
diabetes, taking into
account a 90% cost
reduction for
ezetimibe”
Kunz et al. GER 2016 Stroke Endovascular therapy, Endovascular therapy Markov model Cost- “EVT + SC is cost-
(2016) standard care and standard care effectiveness effective in most
depending on patients subgroups. In patients
NIHSS score with ASPECTS 5 or
with M2 occlusions,
cost-effectiveness
remains uncertain
based on current data”
R. Dodel et al.
Costa et al. PRT 2015 Stroke Non-vitamin K antagonist Apixaban, dabigatran, Markov model Cost- “Apixaban is a cost-
(2015) oral anticoagulants rivaroxaban versus effectiveness effective alternative to
warfarin warfarin and
dabigatran and is
dominant over
rivaroxaban in AF
patients from the
perspective of the
Pharmacoeconomics

Portuguese national
healthcare system.
These conclusions are
based on indirect
comparisons, but
despite this limitation,
the information is
useful for healthcare
decision-makers”
Kamae et al. JPN 2015 Stroke Apixaban, warfarin Apixaban versus Markov model Cost- “Although most
(2015) warfarin effectiveness participants in the
Apixaban for
Reduction in Stroke
and Other
Thromboembolic
Events in Atrial
Fibrillation
(ARISTOTLE) trial
used for the efficacy
data of apixaban in
the model were
non-Japanese
patients, the impact of
the limitations on our
results was
considered small, and
our results were
deemed robust
205

(continued)
 206

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
because of the
additional effect in
Japanese patients
compared with that in
the global population
according to the
subanalysis of
Japanese patients in
the trial. Therefore,
based on an
adaptation of a
published Markov
model, apixaban is a
cost-effective
alternative to warfarin
in Japan for stroke
prevention among
patients with NVAF”
Moretti et al. ITA 2015 Stroke Intravenous thrombolysis Depending on reviewed Review Cost- “Twenty years after
(2015) with recombinant tissue studies effectiveness the NINDS trial,
plasminogen activator (rtPA), among others i.v. rtPA therapy
endovascular treatments within 4.5 h from
(EVT), other thrombolytic stroke onset remains
agents, antiplatelet therapy the mainstay of AIS
therapy, although far
from ideal. Various
alternative strategies
and agents have been
extensively
investigated to
increase the
percentage of patients
R. Dodel et al.
treated, improve
outcome and lower
SICH. Promising
findings are emerging
from the extension of
time window beyond
4.5 h, the
Pharmacoeconomics

sonothrombolysis, the
novel thrombolytic
agents (hopefully
with a greater
commitment by the
industry), the
combination of
intravenous and
endovascular
treatments and the use
of mechanical
recanalization
devices, mainly
stents, for selected
patients in highly
specialized stroke
units. In this context,
the following
recommendations by
STAIR (Stroke
Therapy Academic
Industry Roundtable)
remain appropriate:
(i) reducing
unsubstantiated
contraindications to
treatment (based more
on regulatory
(continued)
207
 208

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
requirements than
clinical data) such as
mild stroke, patient’s
age, the association of
diabetes and prior
stroke, and
(ii) improving
prehospital and
in-hospital
organization in order
to minimize delay of
treatment. There is
great expectation for
increasing the
numbers of treated
patients, and
achieving a better
quality of therapies
(in terms of efficacy,
lower adverse effects
and reduced long-
term disabilities). Not
only are these goals
crucial in order to
meet medical need,
but could also have a
substantial impact on
global costs”
R. Dodel et al.
Leppert et al. USA 2015 Stroke Intravenous tissue-type Intra-arterial treatment Decision- Cost- “Intra-arterial
(2015) plasminogen activator, intra- and intravenous tissue- analytic model effectiveness treatment after
arterial treatment type plasminogen intravenous tissue-
activator versus type plasminogen
intravenous tissue-type activator for patients
plasminogen with anterior
circulation strokes
within the 6-hour
Pharmacoeconomics

window is likely cost-

effective. From a
societal perspective,
increased investment
in access to intra-
arterial treatment for
acute stroke may be
justified”
Gyrd-Hansen GER 2015 Stroke Treatment with shorter delays RCT Cost- “Depending on
et al. (2015) effectiveness willingness-to-pay
thresholds in societal
perspectives, the
STEMO prehospital
stroke concept has the
potential of providing
a reasonable
innovation even in
health-economic
dimensions”
(continued)
209
 210

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Holmes et al. GBR 2015 Stroke Alteplase Alteplase versus Review Cost- “The incremental
(2015) standard medical and effectiveness cost-effectiveness
supportive management ratios (ICER) for all
treatment windows
were well below
accepted willingness
to pay thresholds. The
ERG had no major
concerns regarding
the completeness of
the submission or the
robustness of the
evidence presented.
For all treatment
windows considered,
alteplase was found to
be cost-effective
compared with
standard treatment”
Pan et al. (2014a) CHN 2014 Stroke Intravenous tissue-type Intravenous tissue-type Markov model Cost- “Intravenous tPA
plasminogen activator (tPA plasminogen activator effectiveness treatment within 4.5 h
(tPA) versus non-tPA- is highly cost-
treatment effective for acute
ischemic strokes in
China”
Pan et al. (2014b) CHN 2014 Stroke Clopidogrel, asprin Clopidogrel and aspirin Markov model Cost- “Early 90-day
versus aspirin effectiveness clopidogrel-aspirin
regimen for acute TIA
or minor stroke is
highly cost-effective
in China. Although
clopidogrel is generic,
R. Dodel et al.
 Plavix is brand in
China. If Plavix were
generic, treatment
with clopidogrel-
aspirin would have
been cost saving”
Yang et al. (2014) CHN 2014 Stroke Aspirin, clopidogrel Aspirin and clopidogrel Markov model Cost- “To prevent recurrent
Pharmacoeconomics

versus clopidogrel effectiveness stroke in patients with

versus aspirin intracranial artery
stenosis, especially in
those patients with a
history of TIA or
coronary artery
disease, medical
therapy with
clopidogrel plus
aspirin should be
considered in
preference to aspirin
alone”
Ademi et al. AUS 2015 Stroke Warfarin, Apixaban Apixaban versus Markov model Cost- “Compared to
(2015) Warfarin effectiveness warfarin, apixaban is
likely to represent a
cost-effective means
of preventing stroke-
related morbidity and
mortality in patients
with AF”
(continued)
211
 212

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Rognoni et al. ITA 2014 Stroke Apixaban, dabigatran and Apixaban, dabigatran Markov model Cost- “Our analysis
(2014) rivaroxaban, warfarin and rivaroxaban versus effectiveness suggests that NOAs
warfarin (new oral
anticoagulants) are a
cost-effective
treatment for the
prevention of stroke
in patients with
NVAF (Nonvalvular
atrial fibrillation) in
the Italian healthcare
setting”
Doan et al. GBR 2013 Stroke OnabotulinumtoxinA Usual care plus Simulation Cost- “Based on a model,
(2013) onabotulinumtoxinA model effectiveness UC plus
versus usual care onabotulinumtoxinA
improved disability,
which translated into
greater QALYs but
also increased direct
medical costs
compared with UC
alone; however, the
resulting ICER can be
considered cost-
effective. Moreover,
UC plus
onabotulinumtoxinA
can be cost-saving if
reduction in caregiver
burden was included.
OnabotulinumtoxinA
R. Dodel et al.
 offers value for
money in the
management of
ULPSS in Scotland”
Pan et al. (2012) USA 2012 Stroke Intravenpus thrombolysis, Depending on reviewed Review Cost- “Intravenous
clopidogrel, statin, warfarin, study effectiveness thrombolysis is
dabigatran consistently shown to
Pharmacoeconomics

be the most cost-

effective option for
acute stroke
treatment.
Clopidogrel, statin,
warfarin and
dabigatran are
considered as the
most cost-effective
treatments for
secondary stroke
prevention. However,
lack of long-term
outcome data and
long-term resource
use data adds
tremendous
uncertainty to the
cost-effectiveness
stories of these
treatments. Economic
studies that are
updated with more
recent clinical
findings and studies
that seek to identify
the cost-effective
combinations of
(continued)
213
 214

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
different types of
treatments are
warranted. Also, few
of the published
economic evaluations
considered the
economic impact of
these treatments on
subgroups and
individuals with
different risks”
Meningitis
Tuon et al. (2019) BRA 2019 Meningitis Deoxycholate amphotericin B Deoxycholate Cost- Cost- “Treatment with
(d-AMB), lipid formulations amphotericin B minimization minimization ABLC (amphotericin
(d-AMB) versus lipid model B lipid complex)
amphotericin B would be cost saving
in comparison to
d-AMB treatment, if
early switch of
treatment occurred in
patients presenting
AKI. The change
should be as soon as
possible to avoid
further complication,
like dialysis, which is
associated with a
lower life
expectancy.2”
R. Dodel et al.
Merry and USA 2016 Meningitis Amphotericin B, flucytosine, Amphotericin B Cost- “Flucytosine is
Boulware (2016) fluconazole deoxycholate for effectiveness currently cost-
4 weeks versus effective in the United
amphotericin and States despite a
flucytosine (100 mg/kg/ dramatic increase in
day) for 2 weeks versus price in recent years.
amphotericin and Combination therapy
with amphotericin
Pharmacoeconomics

fluconazole (800 mg/

day) for 2 weeks and flucytosine is the
most attractive
treatment strategy for
cryptococcal
meningitis, though
the rising price may
be creating access
issues that will
exacerbate if the trend
of profiteering
continues”
Kaplan et al. USA 2015 Meningitis Antifungals Screening for serum Review Cost- “Although limited,
(2015) cryptococcal antigen effectiveness the body of evidence
(CrAg) among others regarding CrAg
screening and
treatment suggests
that the intervention
may have an impact
on preventing
cryptococcal
meningitis and death
in persons with AIDS.
Additional research is
needed to quantify the
intervention’s
(continued)
215
Table 4 (continued)
216

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
effectiveness and
identify optimal
treatment dosing and
implementation best
practices”
Rajasingham UGA 2012 Meningitis Fluconazole, flucytosine, Fluconazole (800– Decision- Cost- “Short-course (7-d)
et al. (2012) amphotericin 1200 mg/d) analysis effectiveness amphotericin
monotherapy versus induction therapy
fluconazole + coupled with high-
flucytosine (5FC) dose (1200 mg/d)
versus short-course fluconazole is very
amphotericin ‘cost effective’ per
(7-d) + fluconazole World Health
versus 14-d of Organization criteria
amphotericin alone vs and may be a worthy
amphotericin + investment for policy-
fluconazole versus and makers seeking cost-
amphotericin +5FC effective clinical
outcomes. More
head-to-head clinical
trials are needed on
treatments for this
neglected tropical
disease”
Trotter and GBR 2006 Meningitis Meningococcal serogroup C Alternative vaccination Transmission Cost- “Models that do not
Edmunds (2006) conjugate (MCC) vaccination strategies dynamic model effectiveness include the indirect
effects of vaccination
will underestimate the
impact of MCC
vaccination and may
lead to distorted
decision making”
R. Dodel et al.
Multiple sclerosis
Furneri et al. ITA 2019 Multiple sclerosis Natalizumab, Natalizumab versus Markov model Cost- “Adopting the Italian
(2019) immunomodulators switching among effectiveness social perspective,
(interferons/glatiramer immunomodulators, early escalation to
acetate) followed by subsequent natalizumab is
escalation to dominant versus
natalizumab switching among
Pharmacoeconomics

immunomodulators,
in RRMS patients
who do not respond
adequately to
conventional
immunomodulators”
D’Amico et al. ITA 2019 Multiple sclerosis Synthetic therapies, other Depending on reviewed Review Cost- “The emerging and
(2019) disease-modifying treatments study effectiveness more expensive
DMTs for MS
represent a
considerable
challenge for health-
care systems and
resource
consumption. Future
research should focus
on the long-term
efficacy of DMTs and
the cost of treating
MS in a real-life
setting. Future
biological and
radiological
biomarkers could help
stratify patients at
early stages of MS,
helping physicians
design a personalized
therapeutic approach
217

(continued)
Table 4 (continued)
218

Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
that could have a
positive impact in
economic terms”
Melendez-Torres GBR 2017 Multiple sclerosis Beta-interferon, glatiramer Depending on reviewed Review Cost- “DMTs were
et al. (2017) acetate study effectiveness clinically effective for
RRMS and CIS but
cost-effective only for
CIS. Both RCT
evidence and RSS
data are at high risk of
bias. Research
priorities include
comparative studies
with longer follow-up
and systematic review
and meta-synthesis of
qualitative studies”
Restless legs syndrome
Reinhold et al. GER 2009 Restless legs Ropinirole, Pramipexole Ropinirole versus Review Cost- “The cost-of-illness
(2009) syndrome Pramipexole effectiveness studies were
heterogeneous but
indicated that RLS
was associated with a
substantial economic
burden, resulting in
high direct and
indirect costs to
society. Although
effective and cost-
effective treatments
appear to be available,
further research is
R. Dodel et al.
 warranted, especially
regarding the
economic burden of
RLS and the cost
effectiveness of
available treatment
options”
Pharmacoeconomics

Lees et al. (2008) GBR 2008 Sleep wake disorders Pramipexole, Ropinirole Pramipexole versus no Markov model Cost- “Pramipexole is cost-
(restless legs) treatment versus effectiveness effective compared to
ropinirole no treatment and
ropinirole for patients
with moderate to very
severe RLS”
Parkinson’s disease
Wang and USA 2019 Parkinson’s disease Dopaminergic medications, Depending on reviewed Review Cost-benefit “Overall, the authors
Gunzler (2019) laxatives, blood pressure study analysis; cost- found a scarcity of
raising medications, effectiveness primary PD
antidepressants, antipsychotic analysis; cost- pharmacoeconomic
minimization literature in the
analysis; cost- twenty-first Century.
utility analysis Given the myriad of
PD motor and
nonmotor treatments,
only 24 papers
evaluating motor
treatments and two
papers evaluating
nonmotor treatments
met our search
criteria. More studies
are clearly needed to
better define the
pharmacoeconomics
of PD therapeutics”
(continued)
219
 220

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
Amyotrophic lateral sclerosis
Ringel (2002) USA 2002 Amyotrophic lateral Review Cost- “Many clinical trials
sclerosis effectiveness have one or more
shortcomings that
limit the
generalizability of the
study results.4–5 For
example, the duration
of a trial is often short,
so that the value of an
agent over the long
term is seldom
assessed. High drop-
out rates are also
common in ALS
studies, because of
co-morbid conditions,
unwanted side-effects
or ineffectiveness of
the agent. Patients
selected for trials are
often unrepresentative
of the population of
patients in the real
world, since they have
to meet rigid entry
criteria and travel to
research centers. The
design of trials may
have other biases as
well, such as failure to
have a prospective
R. Dodel et al.
 comparison (placebo)
group, or inadequate
blinding and
randomization. Since
we are facing
demands to limit
healthcare
Pharmacoeconomics

expenditures, we
must understand the
design and limitations
of studies to assess the
cost-effectiveness of
treatment
recommendations”
Tavakoli and GBR 2001 Amyotrophic lateral Riluzole Riluzole versus best Markov model Cost-utility “Using the Markov
Malek (2001) sclerosis supportive care model and the
transitional
probabilities the base
case cost per life year
gained was estimated
at pound sterlings
14,370 and applying
Standard Gamble
utility scores, the base
case cost per QALY
was assessed as
pound sterlings
20,904. The effect of
discounting costs and
benefits altered the
cost effectiveness
analysis to pound
sterlings 17,760 per
life year gained while
a sensitivity analysis
(continued)
221
 222

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
around median or
mean scores for the
utility weight resulted
in a range of pound
sterlings 19,020 to
pound sterlings
25,794 per QALY
gained”
Polyneuropathy
Rajabally and GBR 2019 Polyneuropathy Intravenous immunoglobulin Intravenous Cost-effective “Our results indicate
Afzal (2019) (IVIg), standard dosing immunoglobulin (IVIg) that an individualized
regimes versus standard dosing IVIg treatment
regimes protocol is clinically
noninferior and 10–
25% more cost-
effective than
standard dosing
regimens in CIDP”
Bamrungsawad THA 2016 Polyneuropathy Intravenous immunoglobulin IVIG plus Markov model Cost-effective “At a threshold of
et al. (2016) (IVIG), corticosteroids corticosteroids versus US$4672 per QALY
immunosuppressants gained, IVIG plus
plus corticosteroids in corticosteroids is
steroid-resistant CIDP considered a cost-
patients effective treatment for
steroid-resistant CIDP
patients in Thailand”
R. Dodel et al.
Lazzaro et al. ITA 2014 Polyneuropathy Intravenous immunoglobulin Subcutaneous versus Cost- Cost- “Overall costs per
(2014) (IVIG), subcutaneous intravenous minimization minimization patient amount to
immunoglobulin administration of model €49,534.75 (SCIG;
immunoglobulin subcutaneous
immunoglobulins)
and €50,895.73
(IVIG); saving in
favor of SCIG reaches
Pharmacoeconomics

€1360.98. For both

SCIG and IVIG, the
cost driver was
immunoglobulin
(94.06 vs. 86.06% of
the overall costs,
respectively).
Sensitivity analyses
confirmed the
consistency of the
baseline results. SCIG
may be a cost-saving
therapy for Italian
CIDP patients”
(continued)
223
 224

Table 4 (continued)
Economic
Author Country Year Indication Medication Comparator Study design Evaluation Authors conclusion
McCrone et al. GBR 2003 Polyneuropathy Intravenous immunoglobulin, Intravenous Cost-utility “Using a net-benefit
(2003) prednisolone immunoglobulin versus approach it was
prednisolone shown that the
probability of IVIg
being cost-effective in
comparison with
prednisolone was 0.5
or above (i.e., was
more likely to be cost-
effective than cost-
ineffective) only if
one QALY was
valued at over euro
250,000. The cost-
effectiveness of IVIg
is greatly affected by
the price of IVIg and
the amount
administered. The
impact of later side-
effects of
prednisolone on long-
term costs and quality
of life are likely to
reduce the cost per
QALY of IVIg
treatment”
R. Dodel et al.
Pharmacoeconomics 225

model (including decision trees, Markov models, DES, and sets of mathematical
equations), and that evaluated therapeutic interventions or diagnostic procedures,
following the definition of a “model” as suggested by Weinstein et al. (Weinstein
2006). Additionally, at least two treatment options had to be compared and the
primary aim of the studies had to be a health economic evaluation of these treat-
ments. We excluded studies using models only as an illustration of methodological
aspects or those published as abstracts.
Abbreviations of listed countries follow the code of ISO 3166 alpha-3. Authors
conclusion were taken and adapted from the abstract or the main text of the
respective article and is set in parenthesis.

References
Ademi Z, Pasupathi K, Liew D. Cost-effectiveness of apixaban compared to warfarin in the
management of atrial fibrillation in Australia. Eur J Prev Cardiol. 2015;22:344–53.
Adi Y, Juarez-Garcia A, Wang D, et al. Oral naltrexone as a treatment for relapse prevention in
formerly opioid-dependent drug users: a systematic review and economic evaluation. Health
Technol Assess. 2007;11: iii-iv, 1–85.
Amiri A, Goudarzi R, Amiresmaili M, et al. Cost-effectiveness analysis of tissue plasminogen
activator in acute ischemic stroke in Iran. J Med Econ. 2018;21:282–7.
Ankjaer-Jensen A, Sejr TE. Costs of the treatment of enuresis nocturna. Health economic conse-
quences of alternative methods in the treatment of enuresis nocturna. Ugeskr Laeger.
1994;156:4355–60.
Aspinall SL, Smith KJ, Cunningham FE, et al. Incremental cost-effectiveness of various monthly
doses of vardenafil. Value Health. 2011;14:97–101.
Augusto M, Greene M, Touya M, et al. Cost-effectiveness of long-acting injectable aripiprazole
once-monthly 400 mg in bipolar I disorder in the USA. J Comp Eff Res. 2018;7:637–50.
Balkrishnan R, Joish VN, Bhosle MJ, et al. Prior authorization of newer insomnia medications in
managed care: is it cost saving? J Clin Sleep Med. 2007;3:393–8.
Bamrungsawad N, Upakdee N, Pratoomsoot C, et al. Economic evaluation of intravenous immu-
noglobulin plus corticosteroids for the treatment of steroid-resistant chronic inflammatory
demyelinating polyradiculoneuropathy in Thailand. Clin Drug Investig. 2016;36:557–66.
Bansback N, Guh D, Oviedo-Joekes E, et al. Cost-effectiveness of hydromorphone for severe
opioid use disorder: findings from the SALOME randomized clinical trial. Addiction.
2018;113:1264–73.
Barnes TR, Leeson VC, Paton C, et al. Amisulpride augmentation in clozapine-unresponsive
schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical
effectiveness and cost-effectiveness. Health Technol Assess. 2017;21:1–56.
Basu A, Benson C, Alphs L. Projecting the potential effect of using paliperidone palmitate once-
monthly and once-every-3-months long-acting injections among medicaid beneficiaries with
schizophrenia. J Manag Care Spec Pharm. 2018;24:759–68.
Bellingham GA, Peng PW. Duloxetine: a review of its pharmacology and use in chronic pain
management. Reg Anesth Pain Med. 2010;35:294–303.
Bolin K, Forsgren L. The cost effectiveness of newer epilepsy treatments: a review of the literature
on partial-onset seizures. PharmacoEconomics. 2012;30:903–23.
Bolin K, Berling P, Wasling P, et al. The cost-utility of sodium oxybate as narcolepsy treatment.
Acta Neurol Scand. 2017;136:715–20.
Bowrin K, Briere JB, Fauchier L, et al. Real-world cost-effectiveness of rivaroxaban compared with
vitamin K antagonists in the context of stroke prevention in atrial fibrillation in France. PLoS
One. 2020;15:e0225301.
226 R. Dodel et al.

Brennan A, Chick SE, Davies R. A taxonomy of model structures for economic evaluation of health
technologies. Health Econ. 2006;15:1295–310.
Brock D, Daniel N, Neumann PJ, et al. Ethical and distributive considerations. In: Neumann PJ,
Sanders G, Russell L, et al., editors. Cost-effectivenes in health and medicine. New York:
Oxford University Press; 2017.
Carrasco G, Baeza N, Cabre L, et al. Dexmedetomidine for the treatment of hyperactive delirium
refractory to haloperidol in nonintubated ICU patients: a nonrandomized controlled trial. Crit
Care Med. 2016;44:1295–306.
Carter JA, Dammerman R, Frost M. Cost-effectiveness of subdermal implantable buprenorphine
versus sublingual buprenorphine to treat opioid use disorder. J Med Econ. 2017;20:893–901.
Catala-Lopez F, Ridao M, Sanfelix-Gimeno G, et al. Cost-effectiveness of pharmacological treat-
ment of attention deficit hyperactivity disorder in children and adolescents: qualitative synthesis
of scientific evidence. Rev Psiquiatr Salud Ment. 2013;6:168–77.
Choi H, Mohit B. Cost-effectiveness of screening for HLA-B*1502 prior to initiation of carbamaz-
epine in epilepsy patients of Asian ancestry in the United States. Epilepsia. 2019;60:1472–81.
Christensen MC, Munro V. Cost per successfully treated patient for vortioxetine versus duloxetine
in adults with major depressive disorder: an analysis of the complete symptoms of depression
and functional outcome. Curr Med Res Opin. 2018;34:593–600.
Clements KM, Skornicki M, O’Sullivan AK. Cost-effectiveness analysis of antiepileptic drugs in
the treatment of Lennox-Gastaut syndrome. Epilepsy Behav. 2013;29:184–9.
Collins PY, Patel V, Joestl SS, et al. Grand challenges in global mental health. Nature. 2011;475:27–30.
Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in
schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77:1–24.
Costa J, Fiorentino F, Caldeira D, et al. Cost-effectiveness of non-vitamin K antagonist oral
anticoagulants for atrial fibrillation in Portugal. Rev Port Cardiol. 2015;34:723–37.
Cottrell S, Tilden D, Robinson P, et al. A modeled economic evaluation comparing atomoxetine
with stimulant therapy in the treatment of children with attention-deficit/hyperactivity disorder
in the United Kingdom. Value Health. 2008;11:376–88.
Crawford MJ, Sanatinia R, Barrett B, et al. Lamotrigine for people with borderline personality
disorder: a RCT. Health Technol Assess. 2018;22:1–68.
D’amico E, Chisari CG, Gitto L, et al. Pharmacoeconomics of synthetic therapies for multiple
sclerosis. Expert Opin Pharmacother. 2019;20:1331–40.
Da Silva LR, Vianna CMM, Mosegui GBG, et al. Cost-effectiveness analysis of the treatment of
mild and moderate Alzheimer’s disease in Brazil. Braz J Psychiatry. 2019;41:218–24.
Dams J, Bornschein B, Reese JP, et al. Modelling the cost effectiveness of treatments for
Parkinson's disease: a methodological review. PharmacoEconomics. 2011;29:1025–49.
Darba J, Kaskens L, Perez C, et al. Pharmacoeconomic outcomes for pregabalin: a systematic
review in neuropathic pain, generalized anxiety disorder, and epilepsy from a Spanish perspec-
tive. Adv Ther. 2014;31:1–29.
Davies GM, Vyas A, Baxter CA. Economic evaluation of ezetimibe treatment in combination with
statin therapy in the United States. J Med Econ. 2017;20:723–31.
De Jong LA, Groeneveld J, Stevanovic J, et al. Cost-effectiveness of apixaban compared to other
anticoagulants in patients with atrial fibrillation in the real-world and trial settings. PLoS One.
2019;14:e0222658.
Debaveye S, De Smedt D, Heirman B, et al. Human health benefit and burden of the schizophrenia
health care pathway in Belgium: paliperidone palmitate long-acting injections. BMC Health
Serv Res. 2019;19:393.
Denchev P, Kaltman JR, Schoenbaum M, et al. Modeled economic evaluation of alternative
strategies to reduce sudden cardiac death among children treated for attention deficit/hyperac-
tivity disorder. Circulation. 2010;121:1329–37.
Djalalov S, Yong J, Beca J, et al. Genetic testing in combination with preventive donepezil
treatment for patients with amnestic mild cognitive impairment: an exploratory economic
evaluation of personalized medicine. Mol Diagn Ther. 2012;16:389–99.
Pharmacoeconomics 227

Doan QV, Gillard P, Brashear A, et al. Cost-effectiveness of onabotulinumtoxinA for the treatment
of wrist and hand disability due to upper-limb post-stroke spasticity in Scotland. Eur J Neurol.
2013;20:773–80.
Dong D, Sung C, Finkelstein EA. Cost-effectiveness of HLA-B*1502 genotyping in adult patients
with newly diagnosed epilepsy in Singapore. Neurology. 2012;79:1259–67.
Donnelly M, Haby MM, Carter R, et al. Cost-effectiveness of dexamphetamine and methylpheni-
date for the treatment of childhood attention deficit hyperactivity disorder. Aust N Z J Psychi-
atry. 2004;38:592–601.
Druais S, Doutriaux A, Cognet M, et al. Comparison of medical and economic benefits of
antipsychotics in the treatment of schizophrenia in France. L'Encéphale. 2017;43:311–20.
Dundar Y, Boland A, Strobl J, et al. Newer hypnotic drugs for the short-term management of
insomnia: a systematic review and economic evaluation. Health Technol Assess. 2004;8: iii-x,
1–125.
Dunlop AJ, Brown AL, Oldmeadow C, et al. Effectiveness and cost-effectiveness of unsupervised
buprenorphine-naloxone for the treatment of heroin dependence in a randomized waitlist
controlled trial. Drug Alcohol Depend. 2017;174:181–91.
Ebrahem AS, Oremus M. A pharmacoeconomic evaluation of cholinesterase inhibitors and
memantine for the treatment of Alzheimer’s disease. Expert Opin Pharmacother.
2018;19:1245–59.
Einarson TR, Bereza BG, Garcia Llinares I, et al. Cost-effectiveness of 3-month paliperidone
treatment for chronic schizophrenia in Spain. J Med Econ. 2017a;20:1039–47.
Einarson TR, Bereza BG, Tedouri F, et al. Cost-effectiveness of 3-month paliperidone therapy for
chronic schizophrenia in the Netherlands. J Med Econ. 2017b;20:1187–99.
Elliott J, Mccoy B, Clifford T, et al. Economic evaluation of stiripentol for Dravet syndrome: a cost-
utility analysis. PharmacoEconomics. 2018;36:1253–61.
Erder MH, Xie J, Signorovitch JE, et al. Cost effectiveness of guanfacine extended-release versus
atomoxetine for the treatment of attention-deficit/hyperactivity disorder: application of a
matching-adjusted indirect comparison. Appl Health Econ Health Policy. 2012;10:381–95.
Ernst R. Indirect costs and cost-effectiveness analysis. Value Health. 2006;9:253–61.
Faber A, Van Agthoven M, Kalverdijk LJ, et al. Long-acting methylphenidate-OROS in youths with
attention-deficit hyperactivity disorder suboptimally controlled with immediate-release methyl-
phenidate: a study of cost effectiveness in The Netherlands. CNS Drugs. 2008;22:157–70.
Feeny D, Krah M, Prosser LA, et al. Valuing health outcomes. In: Cost-effectiveness in health and
medicine. New York: Oxford University Press; 2017.
Fineberg NA, Baldwin DS, Drummond LM, et al. Optimal treatment for obsessive compulsive
disorder: a randomized controlled feasibility study of the clinical-effectiveness and cost-effec-
tiveness of cognitive-behavioural therapy, selective serotonin reuptake inhibitors and their
combination in the management of obsessive compulsive disorder. Int Clin Psychopharmacol.
2018;33:334–48.
Furneri G, Santoni L, Ricella C, et al. Cost-effectiveness analysis of escalating to natalizumab or
switching among immunomodulators in relapsing-remitting multiple sclerosis in Italy. BMC
Health Serv Res. 2019;19:436.
Galizzi MM, Ghislandi S, Miraldo M. Effects of reference pricing in pharmaceutical markets: a
review. PharmacoEconomics. 2011;29:17–33.
Geitona M, Stamuli E, Giannakodimos S, et al. Lacosamide as a first-line treatment option in focal
epilepsy: a cost-utility analysis for the Greek healthcare system. J Med Econ. 2019;22:359–64.
Gilmore A, Milne R. Methylphenidate in children with hyperactivity: review and cost-utility
analysis. Pharmacoepidemiol Drug Saf. 2001;10:85–94.
Girardin FR, Poncet A, Perrier A, et al. Cost-effectiveness of HLA-DQB1/HLA-B
pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine.
Pharm J. 2019;19:211–8.
Gold MR, Siegel JE, Lb R, et al. Cost-effectiveness in health and medicine. New York: Oxford
University Press; 1996.
228 R. Dodel et al.

Gracia Naya M. Cost effectiveness of treatment with triptanes in Spain. Rev Neurol. 2001;33:921–4.
Gregson N, Sparrowhawk K, Mauskopf J, et al. Pricing medicines: theory and practice, challenges
and opportunities. Nat Rev Drug Discov. 2005;4:121–30.
Groessl EJ, Tally SR, Hillery N, et al. Cost-effectiveness of a pharmacogenetic test to guide
treatment for major depressive disorder. J Manag Care Spec Pharm. 2018;24:726–34.
Grootendorst P, Pierard E, Shim M. Life-expectancy gains from pharmaceutical drugs: a critical
appraisal of the literature. Expert Rev Pharmacoecon Outcomes Res. 2009;9:353–64.
Gustavsson A, Svensson M, Jacobi F, et al. Cost of disorders of the brain in Europe 2010. Eur
Neuropsychopharmacol. 2011;21:718–79.
Gyrd-Hansen D, Olsen KR, Bollweg K, et al. Cost-effectiveness estimate of prehospital thrombol-
ysis: results of the PHANTOM-S study. Neurology. 2015;84:1090–7.
Hair PI, Mccormack PL, Curran MP. Eszopiclone: a review of its use in the treatment of insomnia.
Drugs. 2008;68:1415–34.
Hassiotis A, Poppe M, Strydom A, et al. Positive behaviour support training for staff for treating
challenging behaviour in people with intellectual disabilities: a cluster RCT. Health Technol
Assess. 2018;22:1–110.
Heller DJ, Coxson PG, Penko J, et al. Evaluating the impact and cost-effectiveness of statin use
guidelines for primary prevention of coronary heart disease and stroke. Circulation.
2017;136:1087–98.
Holmes M, Davis S, Simpson E. Alteplase for the treatment of acute ischaemic stroke: a NICE
single technology appraisal; an evidence review group perspective. PharmacoEconomics.
2015;33:225–33.
Hong J, Dilla T, Arellano J. A modelled economic evaluation comparing atomoxetine with
methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder in
Spain. BMC Psychiatry. 2009;9:15.
Howard R, Cort E, Bradley R, et al. Amisulpride for very late-onset schizophrenia-like psychosis:
the ATLAS three-arm RCT. Health Technol Assess. 2018;22:1–62.
Husereau D, Drummond M, Petrou S, et al. Consolidated health economic evaluation reporting
standards (CHEERS) statement. Int J Technol Assess Health Care. 2013;29:117–22.
Idrisov B, Murphy SM, Morrill T, et al. Implementation of methadone therapy for opioid use
disorder in Russia – a modeled cost-effectiveness analysis. Subst Abuse Treat Prev Policy.
2017;12:4.
Jackson H, Mandell K, Johnson K, et al. Cost-effectiveness of injectable extended-release naltrex-
one compared with methadone maintenance and buprenorphine maintenance treatment for
opioid dependence. Subst Abus. 2015;36:226–31.
Jacoby A, Sudell M, Tudur Smith C, et al. Quality-of-life outcomes of initiating treatment with
standard and newer antiepileptic drugs in adults with new-onset epilepsy: findings from the
SANAD trial. Epilepsia. 2015;56:460–72.
Jofre-Bonet M, Sindelar JL, Petrakis IL, et al. Cost effectiveness of disulfiram: treating cocaine use
in methadone-maintained patients. J Subst Abus Treat. 2004;26:225–32.
Joo H, Wang G, George MG. Age-specific cost effectiveness of using intravenous recombinant tissue
plasminogen activator for treating acute ischemic stroke. Am J Prev Med. 2017;53:S205–12.
Kabore N, Marnat G, Rouanet F, et al. Cost-effectiveness analysis of mechanical thrombectomy
plus tissue-type plasminogen activator compared with tissue-type plasminogen activator alone
for acute ischemic stroke in France. Rev Neurol (Paris). 2019;175:252–60.
Kamae I, Hashimoto Y, Koretsune Y, et al. Cost-effectiveness analysis of apixaban against warfarin
for stroke prevention in patients with nonvalvular atrial fibrillation in Japan. Clin Ther.
2015;37:2837–51.
Kaplan JE, Vallabhaneni S, Smith RM, et al. Cryptococcal antigen screening and early antifungal
treatment to prevent cryptococcal meningitis: a review of the literature. J Acquir Immune Defic
Syndr. 2015;68(Suppl 3):S331–9.
Karnon J, Stahl J, Brennan A, et al. Modeling using discrete event simulation: a report of the
ISPOR-SMDM Modeling Good Research Practices Task Force-4. Med Decis Mak.
2012;32:701–11.
Pharmacoeconomics 229

Keating GM, Lyseng-Williamson KA. Pharmacoeconomic spotlight on varenicline as an aid to

smoking cessation. CNS Drugs. 2010;24:797–800.
Kenworthy J, Yi Y, Wright A, et al. Use of opioid substitution therapies in the treatment of opioid
use disorder: results of a UK cost-effectiveness modelling study. J Med Econ. 2017;20:740–8.
Kessler D, Burns A, Tallon D, et al. Combining mirtazapine with SSRIs or SNRIs for treatment-
resistant depression: the MIR RCT. Health Technol Assess. 2018;22:1–136.
King S, Griffin S, Hodges Z, et al. A systematic review and economic model of the effectiveness
and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of
attention deficit hyperactivity disorder in children and adolescents. Health Technol Assess.
2006;10: iii-iv, xiii-146.
King JB, Sainski-Nguyen AM, Bellows BK. Office-based buprenorphine versus clinic-based
methadone: a cost-effectiveness analysis. J Pain Palliat Care Pharmacother. 2016;30:55–65.
Klingler C, Shah SM, Barron AJ, et al. Regulatory space and the contextual mediation of common
functional pressures: analyzing the factors that led to the German Efficiency Frontier approach.
Health Policy. 2013;109:270–80.
Koopmanschap MA, Rutten FF, Van Ineveld BM, et al. The friction cost method for measuring
indirect costs of disease. J Health Econ. 1995;14:171–89.
Krebs E, Enns B, Evans E, et al. Cost-effectiveness of publicly funded treatment of opioid use
disorder in California. Ann Intern Med. 2018;168:10–9.
Kristian B, Wachtmeister K, Stefan F, et al. Retigabine as add-on treatment of refractory epilepsy – a
cost-utility study in a Swedish setting. Acta Neurol Scand. 2013;127:419–26.
Krol M, Brouwer W, Rutten F. Productivity costs in economic evaluations: past, present, future.
PharmacoEconomics. 2013;31:537–49.
Kuntz K, Russell L, Douglas K, et al. Decision models in cost-effectiveness analysis. In: Neumann
PJ, Sanders G, Russell L, et al., editors. Cost-effectivenes in health and medicine. New York:
Oxford University Press; 2017.
Kunz WG, Hunink MG, Sommer WH, et al. Cost-effectiveness of endovascular stroke therapy: a
patient subgroup analysis from a US healthcare perspective. Stroke. 2016;47:2797–804.
Lachaine J, Sikirica V, Mathurin K. Is adjunctive pharmacotherapy in attention-deficit/hyperactivity
disorder cost-effective in Canada: a cost-effectiveness assessment of guanfacine extended-
release as an adjunctive therapy to a long-acting stimulant for the treatment of ADHD. BMC
Psychiatry. 2016;16:11.
Laramee P, Brodtkorb TH, Rahhali N, et al. The cost-effectiveness and public health benefit of
nalmefene added to psychosocial support for the reduction of alcohol consumption in alcohol-
dependent patients with high/very high drinking risk levels: a Markov model. BMJ Open.
2014;4:e005376.
Laramee P, Bell M, Irving A, et al. The cost-effectiveness of the integration of nalmefene within the
UK healthcare system treatment pathway for alcohol dependence. Alcohol Alcohol.
2016;51:283–90.
Lazzaro C, Lopiano L, Cocito D. Subcutaneous vs intravenous administration of immunoglobulin
in chronic inflammatory demyelinating polyneuropathy: an Italian cost-minimization analysis.
Neurol Sci. 2014;35:1023–34.
Le QA, Doctor JN, Zoellner LA, et al. Cost-effectiveness of prolonged exposure therapy versus
pharmacotherapy and treatment choice in posttraumatic stress disorder (the optimizing PTSD
treatment trial): a doubly randomized preference trial. J Clin Psychiatry. 2014;75:222–30.
Le LK, Hay P, Mihalopoulos C. A systematic review of cost-effectiveness studies of prevention and
treatment for eating disorders. Aust N Z J Psychiatry. 2018;52:328–38.
Lee D, Gladwell D, Batty AJ, et al. The cost effectiveness of licensed oromucosal midazolam
(Buccolam((R))) for the treatment of children experiencing acute epileptic seizures: an approach
when trial evidence is limited. Paediatr Drugs. 2013;15:151–62.
Lee Y, Rosenblat JD, Lee J, et al. Efficacy of antidepressants on measures of workplace functioning
in major depressive disorder: a systematic review. J Affect Disord. 2018;227:406–15.
Lees M, Roberts G, Tabberer M, et al. Cost-effectiveness of licensed treatment options for restless
legs syndrome in the UK and Sweden. Curr Med Res Opin. 2008;24:2919–30.
230 R. Dodel et al.

Leppert MH, Campbell JD, Simpson JR, et al. Cost-effectiveness of intra-arterial treatment as an
adjunct to intravenous tissue-type plasminogen activator for acute ischemic stroke. Stroke.
2015;46:1870–6.
Leppert MH, Poisson SN, Carroll JD, et al. Cost-effectiveness of patent foramen ovale closure
versus medical therapy for secondary stroke prevention. Stroke. 2018;49:1443–50.
Linden K, Jormanainen V, Linna M, et al. Cost effectiveness of varenicline versus bupropion and
unaided cessation for smoking cessation in a cohort of Finnish adult smokers. Curr Med Res
Opin. 2010;26:549–60.
Maia CR, Stella SF, Wagner F, et al. Cost-utility analysis of methylphenidate treatment for children
and adolescents with ADHD in Brazil. Braz J Psychiatry. 2016;38:30–8.
Malhotra A, Wu X, Payabvash S, et al. Comparative effectiveness of endovascular Thrombectomy
in elderly stroke patients. Stroke. 2019;50:963–9.
Marfori CQ, Wu CZ, Katler Q, et al. Hysterectomy for the transgendered male: review of
perioperative considerations and surgical techniques with description of a novel 2-port laparo-
scopic approach. J Minim Invasive Gynecol. 2018;25:1149–56.
Martin AL, Huelin R, Wilson D, et al. A systematic review assessing the economic impact of
sildenafil citrate (Viagra) in the treatment of erectile dysfunction. J Sex Med. 2013;10:1389–
400.
Matsuo N, Morita T. Efficacy, safety, and cost effectiveness of intravenous midazolam and
flunitrazepam for primary insomnia in terminally ill patients with cancer: a retrospective
multicenter audit study. J Palliat Med. 2007;10:1054–62.
Mavranezouli I, Lokkerbol J. A systematic review and critical appraisal of economic evaluations of
pharmacological interventions for people with bipolar disorder. PharmacoEconomics.
2017;35:271–96.
Mcconaghy N, Blaszczynski A. Imaginal desensitization: a cost-effective treatment in two
shop-lifters and a binge-eater resistant to previous therapy. Aust N Z J Psychiatry.
1988;22:78–82.
Mccrone P, Chisholm D, Knapp M, et al. Cost-utility analysis of intravenous immunoglobulin and
prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol.
2003;10:687–94.
Melendez-Torres GJ, Auguste P, Armoiry X, et al. Clinical effectiveness and cost-effectiveness of
beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and
economic evaluation. Health Technol Assess. 2017;21:1–352.
Men P, Yi Z, Li C, et al. Comparative efficacy and safety between amisulpride and olanzapine in
schizophrenia treatment and a cost analysis in China: a systematic review, meta-analysis, and
cost-minimization analysis. BMC Psychiatry. 2018;18:286.
Merry M, Boulware DR. Cryptococcal meningitis treatment strategies affected by the explosive cost
of flucytosine in the United States: a cost-effectiveness analysis. Clin Infect Dis. 2016;62:1564–8.
Mihalopoulos C, Magnus A, Lal A, et al. Is implementation of the 2013 Australian treatment
guidelines for posttraumatic stress disorder cost-effective compared to current practice? A cost-
utility analysis using QALYs and DALYs. Aust N Z J Psychiatry. 2015;49:360–76.
Mkrtchyan VR, Kaimovsky IL. Pharmacoeconomic aspects of monotherapy of focal epilepsy. Zh
Nevrol Psikhiatr Im S S Korsakova. 2019;119:92–8.
Moretti A, Ferrari F, Villa RF. Pharmacological therapy of acute ischaemic stroke: achievements
and problems. Pharmacol Ther. 2015;153:79–89.
Morin AK, Willett K. The role of eszopiclone in the treatment of insomnia. Adv Ther. 2009;26:500–18.
Nemeth B, Molnar A, Akehurst R, et al. Quality-adjusted life year difference in patients with
predominant negative symptoms of schizophrenia treated with cariprazine and risperidone. J
Comp Eff Res. 2017;6:639–48.
Neumann PJ, Thorat T, Zhong Y, et al. A systematic review of cost-effectiveness studies reporting
cost-per-DALY averted. PLoS One. 2016;11:e0168512.
Neumann PJ, Russell LB, Siegel J, et al. Using cost-effectiveness analysis in health and medicine.
Experiences since the original panel. New York: Oxford University Press; 2017a.
Neumann PJ, Sanders G, Russell L, et al. Cost-effectivenes in health and medicine. New York:
Oxford University Press; 2017b.
Pharmacoeconomics 231

Nishimura S, Nakao M. Cost-effectiveness analysis of suvorexant for the treatment of Japanese

elderly patients with chronic insomnia in a virtual cohort. J Med Econ. 2018;21:698–703.
Nosyk B, Guh DP, Bansback NJ, et al. Cost-effectiveness of diacetylmorphine versus methadone
for chronic opioid dependence refractory to treatment. CMAJ. 2012;184:E317–28.
Nuhoho S, Saad A, Saumell G, et al. Economic evaluation of paliperidone palmitate once monthly
for treating chronic schizophrenia patients in the United Arab Emirates. Curr Med Res Opin.
2018;34:601–11.
OECD. Health at a glance 2019: OECD indicators. Paris: OECD Publishing; 2019.
Onukwugha E, Mcrae J, Kravetz A, et al. Cost-of-illness studies: an updated review of current
methods. PharmacoEconomics. 2016;34:43–58.
Ophuis RH, Lokkerbol J, Heemskerk SC, et al. Cost-effectiveness of interventions for treating
anxiety disorders: a systematic review. J Affect Disord. 2017;210:1–13.
Painter JT, Fortney JC, Austen MA, et al. Cost-effectiveness of telemedicine-based collaborative
care for posttraumatic stress disorder. Psychiatr Serv. 2017;68:1157–63.
Pan F, Hernandez L, Ward A. Cost-effectiveness of stroke treatments and secondary preventions.
Expert Opin Pharmacother. 2012;13:1751–60.
Pan Y, Chen Q, Zhao X, et al. Cost-effectiveness of thrombolysis within 4.5 hours of acute ischemic
stroke in China. PLoS One. 2014a;9:e110525.
Pan Y, Wang A, Liu G, et al. Cost-effectiveness of clopidogrel-aspirin versus aspirin alone for acute
transient ischemic attack and minor stroke. J Am Heart Assoc. 2014b;3:e000912.
Perraudin C, Le Vaillant M, Pelletier-Fleury N. Cost-effectiveness of a community pharmacist-led
sleep apnea screening program – a Markov model. PLoS One. 2013;8:e63894.
Peterson K, Dieperink E, Anderson J, et al. Rapid evidence review of the comparative effectiveness,
harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment versus
usual care for major depressive disorder. Psychopharmacology. 2017;234:1649–61.
Pickett CA, Villines TC, Resar JR, et al. Cost effectiveness and clinical efficacy of patent foramen
ovale closure as compared to medical therapy in cryptogenic stroke patients: a detailed cost
analysis and meta-analysis of randomized controlled trials. Int J Cardiol. 2018;273:74–9.
Picot MC, Jaussent A, Neveu D, et al. Cost-effectiveness analysis of epilepsy surgery in a controlled
cohort of adult patients with intractable partial epilepsy: a 5-year follow-up study. Epilepsia.
2016;57:1669–79.
Polak AR, Witteveen AB, Visser RS, et al. Comparison of the effectiveness of trauma-focused
cognitive behavioral therapy and paroxetine treatment in PTSD patients: design of a randomized
controlled trial. BMC Psychiatry. 2012;12:166.
Popova S, Mohapatra S, Patra J, et al. A literature review of cost-benefit analyses for the treatment
of alcohol dependence. Int J Environ Res Public Health. 2011;8:3351–64.
Potaufeu J, Langree B, Drapier D, et al. Cost-effectiveness study of olanzapine pamoate: Mirror-
image analysis after one yearapap. L'Encéphale. 2019;45:232–8.
Prasad S, Arellano J, Steer C, et al. Assessing the value of atomoxetine in treating children and
adolescents with ADHD in the UK. Int J Clin Pract. 2009;63:1031–40.
Rajabally YA, Afzal S. Clinical and economic comparison of an individualised immunoglobulin
protocol vs. standard dosing for chronic inflammatory demyelinating polyneuropathy. J Neurol.
2019;266:461–7.
Rajasingham R, Rolfes MA, Birkenkamp KE, et al. Cryptococcal meningitis treatment strategies in
resource-limited settings: a cost-effectiveness analysis. PLoS Med. 2012;9:e1001316.
Rattanavipapong W, Koopitakkajorn T, Praditsitthikorn N, et al. Economic evaluation of HLA-
B*15:02 screening for carbamazepine-induced severe adverse drug reactions in Thailand.
Epilepsia. 2013;54:1628–38.
Rawlins MD. NICE and the public health. Br J Clin Pharmacol. 2004;58:575–80.
Reddy VK, Girish K, Lakshmi P, et al. Cost-effectiveness analysis of baclofen and chlordiazepoxide
in uncomplicated alcohol-withdrawal syndrome. Indian J Pharm. 2014;46:372–7.
Reddy VY, Akehurst RL, Amorosi SL, et al. Cost-effectiveness of left atrial appendage closure
with the WATCHMAN device compared with warfarin or non-vitamin K antagonist oral
anticoagulants for secondary prevention in nonvalvular atrial fibrillation. Stroke.
2018;49:1464–70.
232 R. Dodel et al.

Reeves P, Edmunds K, Levi C, et al. Cost-effectiveness of targeted thrombolytic therapy for stroke
patients using multi-modal CT compared to usual practice. PLoS One. 2018;13:e0206203.
Reinhold T, Muller-Riemenschneider F, Willich SN, et al. Economic and human costs of restless
legs syndrome. PharmacoEconomics. 2009;27:267–79.
Report of the Secretary (WHO). Global burden of mental disorders and the need for a comprehen-
sive, coordinated response from health and social sectors at the country level WHO. 2011.
https://apps.who.int/iris/handle/10665/78898
Ringel SP. Cost effectiveness: summary. Amyotroph Lateral Scler Other Motor Neuron Disord.
2002;3(Suppl 1):S67–9.
Roffe C, Nevatte T, Bishop J, et al. Routine low-dose continuous or nocturnal oxygen for people
with acute stroke: three-arm Stroke Oxygen Supplementation RCT. Health Technol Assess.
2018;22:1–88.
Rognoni C, Marchetti M, Quaglini S, et al. Apixaban, dabigatran, and rivaroxaban versus warfarin
for stroke prevention in non-valvular atrial fibrillation: a cost-effectiveness analysis. Clin Drug
Investig. 2014;34:9–17.
Romeo R, Knapp M, Tyrer P, et al. The treatment of challenging behaviour in intellectual
disabilities: cost-effectiveness analysis. J Intellect Disabil Res. 2009;53:633–43.
Rosenblat JD, Lee Y, Mcintyre RS. Does pharmacogenomic testing improve clinical outcomes for
major depressive disorder? A systematic review of clinical trials and cost-effectiveness studies. J
Clin Psychiatry. 2017;78:720–9.
Rubio-Valera M, Penarrubia-Maria MT, Iglesias-Gonzalez M, et al. Cost-effectiveness of antide-
pressants versus active monitoring for mild-to-moderate major depressive disorder: a multisite
non-randomized-controlled trial in primary care (INFAP study). Eur J Health Econ.
2019;20:703–13.
Ruger JP, Chawarski M, Mazlan M, et al. Cost-effectiveness of buprenorphine and naltrexone
treatments for heroin dependence in Malaysia. PLoS One. 2012;7:e50673.
Ruggeri M, Basile M, Zini A, et al. Cost-effectiveness analysis of mechanical thrombectomy with
stent retriever in the treatment of acute ischemic stroke in Italy. J Med Econ. 2018;21:902–11.
Sach TH, Whynes DK. Measuring indirect costs: is there a problem? Appl Health Econ Health
Policy. 2003;2:135–9.
Sado M, Wada M, Ninomiya A, et al. Does the rapid response of an antidepressant contribute to
better cost-effectiveness? Comparison between mirtazapine and SSRIs for first-line treatment of
depression in Japan. Psychiatry Clin Neurosci. 2019;73:400–8.
Santos AS, Guerra-Junior AA, Godman B, et al. Cost-effectiveness thresholds: methods for
setting and examples from around the world. Expert Rev Pharmacoecon Outcomes Res.
2018;18:277–88.
Saul JE, Lien R, Schillo B, et al. Outcomes and cost-effectiveness of two nicotine replacement treatment
delivery models for a tobacco quitline. Int J Environ Res Public Health. 2011;8:1547–59.
Schawo S, Van Der Kolk A, Bouwmans C, et al. Probabilistic Markov model estimating cost
effectiveness of methylphenidate osmotic-release oral system versus immediate-release meth-
ylphenidate in children and adolescents: which information is needed? PharmacoEconomics.
2015;33:489–509.
Schlander M. The pharmaceutical economics of child psychiatric drug treatment. Curr Pharm Des.
2010;16:2443–61.
Schöffski O, Von Der Schulenburg JM. Gesundheitsökonomische Evaluationen. Berlin: Springer;
2011.
Schwartz RP, Alexandre PK, Kelly SM, et al. Interim versus standard methadone treatment: a
benefit-cost analysis. J Subst Abus Treat. 2014;46:306–14.
Shearer J, Shanahan M, Darke S, et al. A cost-effectiveness analysis of modafinil therapy for
psychostimulant dependence. Drug Alcohol Rev. 2010;29:235–42.
Siebert U. Transparente Entscheidungen in Public Health mittels systematischer Entscheidung-
sanalyse. In: Schwartz Fw BB, Busse R, Leidl R, Raspe H, Siegrist J, editors. Das public health
Buch. Munich: Urban and Fischer; 2003a.
Pharmacoeconomics 233

Siebert U. When should decision-analytic modeling be used in the economic evaluation of health
care? Eur J Health Econ. 2003b;4:143–50.
Siebert U, Alagoz O, Bayoumi AM, et al. State-transition modeling: a report of the ISPOR-SMDM
Modeling Good Research Practices Task Force-3. Value Health. 2012;15:812–20.
Siegel JE, Weinstein MC, Russell LB, et al. Recommendations for reporting cost-effectiveness
analyses. Panel on cost-effectiveness in health and medicine. JAMA. 1996;276:1339–41.
Sikirica V, Haim Erder M, Xie J, et al. Cost effectiveness of guanfacine extended release as an
adjunctive therapy to a stimulant compared with stimulant monotherapy for the treatment of
attention-deficit hyperactivity disorder in children and adolescents. PharmacoEconomics.
2012;30:e1–15.
Simon J, Geddes JR, Gardiner A, et al. Comparative economic evaluation of quetiapine plus
lamotrigine combination vs quetiapine monotherapy (and folic acid vs placebo) in patients
with bipolar depression (CEQUEL). Bipolar Disord. 2018;20:733–45.
Skapinakis P, Caldwell D, Hollingworth W, et al. A systematic review of the clinical effectiveness
and cost-effectiveness of pharmacological and psychological interventions for the management
of obsessive-compulsive disorder in children/adolescents and adults. Health Technol Assess.
2016;20:1–392.
Sluiter RL, Kievit W, Van Der Wilt GJ, et al. Cost-effectiveness analysis of genotype-guided
treatment allocation in patients with alcohol use disorders using naltrexone or acamprosate,
using a modeling approach. Eur Addict Res. 2018;24:245–54.
Smith MD, Drummond M, Brixner D. Moving the QALY forward: rationale for change. Value
Health. 2009;12(Suppl 1):S1–4.
Snedecor SJ, Botteman MF, Bojke C, et al. Cost-effectiveness of eszopiclone for the treatment of
adults with primary chronic insomnia. Sleep. 2009;32:817–24.
Sohn M, Talbert J, Moga DC, et al. A cost-effectiveness analysis of off-label atypical antipsychotic
treatment in children and adolescents with ADHD who have failed stimulant therapy. Atten
Defic Hyperact Disord. 2016;8:149–58.
Stevenson M, Pandor A, Stevens JW, et al. Nalmefene for reducing alcohol consumption in people
with alcohol dependence: an evidence review group perspective of a NICE single technology
appraisal. PharmacoEconomics. 2015;33:833–47.
Stolk EA, Busschbach JJ, Caffa M, et al. Cost utility analysis of sildenafil compared with
papaverine-phentolamine injections. BMJ. 2000;320:1165–8.
Tannenbaum C, Diaby V, Singh D, et al. Sedative-hypnotic medicines and falls in community-
dwelling older adults: a cost-effectiveness (decision-tree) analysis from a US Medicare perspec-
tive. Drugs Aging. 2015;32:305–14.
Tavakoli M, Malek M. The cost utility analysis of riluzole for the treatment of amyotrophic lateral
sclerosis in the UK. J Neurol Sci. 2001;191:95–102.
Thursz M, Forrest E, Roderick P, et al. The clinical effectiveness and cost-effectiveness of STeroids
Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2  2 factorial randomised controlled
trial. Health Technol Assess. 2015;19:1–104.
Tilford JM, Payakachat N, Kovacs E, et al. Preference-based health-related quality-of-life outcomes
in children with autism spectrum disorders: a comparison of generic instruments. PharmacoE-
conomics. 2012;30:661–79.
Tilford JM, Payakachat N, Kuhlthau KA, et al. Treatment for sleep problems in children with autism
and caregiver spillover effects. J Autism Dev Disord. 2015;45:3613–23.
Tremblay G, Howard D, Tsong W, et al. Cost-effectiveness of perampanel for the treatment of
primary generalized tonic-clonic seizures (PGTCS) in epilepsy: a Spanish perspective. Epilepsy
Behav. 2018;86:108–15.
Trotter CL, Edmunds WJ. Reassessing the cost-effectiveness of meningococcal serogroup C conju-
gate (MCC) vaccines using a transmission dynamic model. Med Decis Mak. 2006;26:38–47.
Tuon FF, Florencio KL, Rocha JL. Burden of acute kidney injury in HIV patients under
deoxycholate amphotericin B therapy for cryptococcal meningitis and cost-minimization anal-
ysis of amphotericin B lipid complex. Med Mycol. 2019;57:265–9.
234 R. Dodel et al.

Vincent PD, Demers MF, Doyon-Kemp V, et al. One year mirror-image study using paliperidone
palmitate for relapse prevention of schizophrenia in four university hospitals in Canada.
Schizophr Res. 2017;185:96–100.
Voigt J, Carpenter L, Leuchter A. Cost effectiveness analysis comparing repetitive transcranial
magnetic stimulation to antidepressant medications after a first treatment failure for major
depressive disorder in newly diagnosed patients – a lifetime analysis. PLoS One. 2017;12:
e0186950.
Walley T, Haycox A. Pharmacoeconomics: basic concepts and terminology. Br J Clin Pharmacol.
1997;43:343–8.
Wang AS, Gunzler SA. Systematic review of the pharmacoeconomics of Parkinson disease
medications. Expert Opin Pharmacother. 2019;20:1659–70.
Weinstein MC. Recent developments in decision-analytic modelling for economic evaluation.
PharmacoEconomics. 2006;24:1043–53.
Whittington R, Faulds D. Hormone replacement therapy: I. A pharmacoeconomic appraisal of its
therapeutic use in menopausal symptoms and urogenital estrogen deficiency. PharmacoE-
conomics. 1994;5:419–45.
Wijnen BFM, Pos K, Velthorst E, et al. Economic evaluation of brief cognitive behavioural therapy
for social activation in recent-onset psychosis. PLoS One. 2018;13:e0206236.
Wortman MSH, Lokkerbol J, Van Der Wouden JC, et al. Cost-effectiveness of interventions for
medically unexplained symptoms: a systematic review. PLoS One. 2018;13:e0205278.
Wu EQ, Hodgkins P, Ben-Hamadi R, et al. Cost effectiveness of pharmacotherapies for attention-
deficit hyperactivity disorder: a systematic literature review. CNS Drugs. 2012;26:581–600.
Yagudina RI, Kulikov AY, Krylov VA, et al. Pharmacoeconomic analysis of the neuroprotective
medicines in the treatment of ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova.
2019;119:60–8.
Yang J, Chen L, Chitkara N, et al. A Markov model to compare the long-term effect of aspirin,
clopidogrel and clopidogrel plus aspirin on prevention of recurrent ischemic stroke due to
intracranial artery stenosis. Neurol India. 2014;62:48–52.
Yoon J, Zisook S, Park A, et al. Comparing cost-effectiveness of aripiprazole augmentation with
other “next-step” depression treatment strategies: a randomized clinical trial. J Clin Psychiatry.
2018;80:18m12294.
Young AH, Evitt L, Brignone M, et al. Cost-utility evaluation of vortioxetine in patients with Major
Depressive Disorder experiencing inadequate response to alternative antidepressants in the
United Kingdom. J Affect Disord. 2017;218:291–8.
Zhao J, Jiang K, Li Q, et al. Cost-effectiveness of olanzapine in the first-line treatment of
schizophrenia in China. J Med Econ. 2019;22:439–46.
Zimovetz EA, Beard SM, Hodgkins P, et al. A cost-utility analysis of lisdexamfetamine versus
atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity
disorder and inadequate response to methylphenidate. CNS Drugs. 2016;30:985–96.
Zimovetz EA, Joseph A, Ayyagari R, et al. A cost-effectiveness analysis of lisdexamfetamine
dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK. Eur
J Health Econ. 2018;19:21–35.
Compliance and Psychoeducation

Stefan Unterecker

Contents
Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Psychoeducation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

Abstract
Noncompliance or nonadherence is a well-known but still underestimated prob-
lem in pharmacological treatment in general and in neuropsychopharmacological
therapy in detail. Approximately 50% of all patients with chronic diseases exhibit
poor compliance regarding drug therapy. Poor adherence is a worldwide problem
of striking magnitude. Increasing the effectiveness of adherence interventions
might have a far greater impact than any improvement in specific medical
treatments. Psychoeducation is effective and has the potential to reduce the rate
of nonadherence significantly.

Compliance

The term “compliance” is used in different disciplines; still its use in medicine
is most widespread with the meaning of obeying an order, rule, or request. More
and more, in medicine instead of “compliance” the term “adherence” is used, which
in contrast to compliance implies aspects of self-management and self-responsibility
of the patient. Even if nonadherence is the most important factor for suboptimal

S. Unterecker (*)
Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University
Hospital of Würzburg, Würzburg, Germany
e-mail: Unterecker_S@ukw.de

© Springer Nature Switzerland AG 2022 235

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_6
236 S. Unterecker

outcomes and yet underestimated and underassessed (Hatch et al. 2017), there is
rather little scientific activity regarding this research topic since several years (De
Las Cuevas and De Leon 2017). Besides reports on a high medical service utilization
and medical costs in schizophrenia and related disorders by nonadherence (Joe and
Lee 2016), there are also unequivocal study results regarding economic aspects of
nonadherence (Pennington and McCrone 2018).
The World Health Organization (WHO 2003) defined adherence as “the extent
to which the patient follows medical instructions,” even if the term “medical” was
discussed to be insufficient in describing the wide range of interventions in the
treatment of chronic diseases. Moreover, it is noteworthy that the term “instructions”
underestimates the aspect of active collaboration of the patient and partnership
between healthcare provider and patient.
Comprehensively, the WHO in 2003 discussed the issue of adherence to long-
term therapies according to different chronic diseases. Poor adherence is a world-
wide problem of striking magnitude with growing in the same way as chronic
diseases increase worldwide. Adherence is an important modifier of effectiveness
in the health system and increasing the effectiveness of adherence interventions
might have a far greater impact than any improvement in specific medical treatments
(WHO 2003). Different influence factors on adherence need to be considered like
social and economic factors, characteristics of the disease, disease therapies, and
patient-related factors. Adherence is a dynamic process that needs to be followed up,
and health professionals need to be trained in adherence. A key factor for success in
improving adherence lies in the family, in the community, and in patients’ organi-
zations, so that a multidisciplinary approach is needed (WHO 2003).
Obviously, nonadherence is highly relevant in clinical medicine and is still an
underestimated problem in public health. Approximately 50% of all patients with
chronic diseases exhibit poor compliance regarding drug therapy (Gold and
McClung 2006). In patients with depressive disorders, several studies have
shown prevalence rates of nonadherence being dependent on the drug class: in
primary care setting 40% discontinued a treatment with tricyclics within 12 weeks
(Peveler et al. 1999). While only 20% of patients to whom tricyclics had been
prescribed filled four or more prescriptions within 6 months, 34% of patients under
newer antidepressants did (Katon et al. 1992). Regarding drug type several meta-
analyses described a small, but mostly significant difference between tricyclic
antidepressants and SSRIs with lower discontinuation rates for the latter (Mont-
gomery and Kasper 1995; Anderson and Tomenson 1995; Hotopf et al. 1997), so
that drug type is interpreted as a highly influential factor on drug adherence. The
co-medication of benzodiazepines for up to 8 weeks reduced the discontinuation
rates of antidepressant drug therapy only marginally (Furukawa et al. 2001).
Moreover, comorbid somatoform symptoms increase the rate of nonadherence
(Keeley et al. 2000), and sensation-seeking personality traits seem to do so
(Ekselius et al. 2000).
In a recent Spanish study on long-term antidepressant treatment, only 21% of
anxiety patients and 28% of depressed patients were compliant with higher rates
in patients under polypharmacy (Serna et al. 2015).
Compliance and Psychoeducation 237

The adherence to antidepressant drug therapy is more likely in patients who are
well-educated regarding the following aspects: daily medication intake, no benefit
by the treatment for the first 2–4 weeks, necessity of continuation even if feeling
better, and no stop of drug intake without consultation of the physician (Lin et al.
1995). The reasons for noncompliance in the treatment with antidepressant drugs
must be discussed in categories of illness, physician, patient, and antidepressant drug
(Demyttenaere 1998).
In a previous literature review on patients with bipolar disorder, a nonadherence
rate between 45% and 50% was found and good adherence was discussed as an
exception (Greene et al. 2018). In the context of adherence, the parameter of
medication possession ratio (MPR) often is used. The definition of MPR as ratio
between days of medication supply and the total period of observation within the
study in bipolar patients revealed that an MPR of at least 80% ranged from 8.3%
to 54.1% with a median of 28% and the mean MPR ranged from 19% to 77% with
a median of 47.1%. In bipolar patients no difference in adherence was found
between second-generation antipsychotics and mood stabilizers (Greene et al.
2018). Defining MPR as ratio between days of medication supply and the period
between first and last day of medication supply comes to higher adherence rates with
MPR of at least 80% in 58–62% and a mean MPR of 68–71% in patients under
different second-generation antipsychotics. Most often younger age and comorbid
substance use disorder in bipolar disorder are associated with poor adherence
(Greene et al. 2018).
In the treatment with antipsychotic drugs in contrast to other psychotropic drug
classes, different options of long-acting injectables are available, regarding both
first- and second-generation antipsychotic drugs. These formulations help to increase
drug adherence and avoid drug discontinuation, not alone by improved symptom
remission (Anderson et al. 2017). This is necessary as in schizophrenia patients after
1 year with oral antipsychotic therapy, the discontinuation rate is 51% – in contrast
to injectable paliperidone palmitate (27%) (Anderson et al. 2017). This difference
of higher adherence rates in patients under long-acting injectables in comparison to
oral atypical antipsychotics has been proved for different antipsychotic drugs like
paliperidone, risperidone, aripiprazole, and olanzapine (Pilon et al. 2017).
Regarding the assessment of adherence with antipsychotic medication in schizo-
phrenia, an overview on objective and subjective methods is available (Haddad et al.
2014; Table 1).
In contrast to the described adherence rates in affective disorder and schizophre-
nia, the 1-year compliance rate of patients under anti-dementia drugs in Germany
with about 60% is higher, and a treatment by specialist physician led to an increase of
the compliance rate (Bohlken et al. 2015).
Furthermore, in patients with epilepsy drug adherence must be considered. The
prevalence of adherence to antiepileptic drugs in epilepsy patients varies from 20%
to 80% (Hargrave and Remler 1996; Buck et al. 1997; Lannon 1997; Getnet et al.
2016) and seems to be lower in children in comparison to adult patients (Michaelis et
al. 2018). The factors of nonadherence in epilepsy treatment are socioeconomic-
related, health system-related, condition-related, treatment-related, and patient-
238 S. Unterecker

Table 1 Methods of assessing medication adherence (Haddad et al. 2014)

Objective adherence measurement Subjective adherence measurement
Medication container with electronic Clinician’s view on adherence (often based on
monitoring, e.g., Medication Event Monitoring therapeutic response and side effects)
System (MEMS)
Pill count Patient or key other report
Biological markers Patient diary of medication intake
Observed intake Questionnaires, e.g., Drug Attitude Inventory
(DAI), Medication Adherence Rating Scale
(MARS)
Medication possession ratio
Medication plasma level
Electronic ingestible event marker

related (WHO 2003). Most important nonadherence factors are misunderstanding

about drug intake (Garnett 2000; Hargrave and Remler 1996; Buck 1997), combined
or complex drug regimens (Hargrave and Remler 1996; Cloyd et al. 1992), forget-
fulness (Garnett 2000), and fear of stigmatization (Buck et al. 1997).
The facilities of influencing adherence become more and more sophisticated with
the possibility of an application of technological tools like smartphone assistance
(Wenze et al. 2016) or even digital medicine system with the component of an
ingestible sensor in medication tablets (Profit et al. 2016; Rohatagi et al. 2016). On
the other hand, also simple interventions like medication monthly blister packaging
instead of dispense-as-usual help to increase the rate of adherence significantly
(Gutierrez et al. 2017).
Generally, predictors of adherence like frequency of dosing, education, drug
type, co-medication and psychiatric co-morbidity, and personality traits need to be
addressed (WHO 2003). No difference in the randomly defined times of pill intake
(once or three times) was found, but patients who chose to take the medication three
times a day reported better adherence. That means that personal control of the patient
was more decisive than frequency of dosing (Myers and Branthwaite 1992).
From a global point of view, the five dimensions of adherence comprise social
and economic factors, healthcare team and system-related factors, condition-related
factors, therapy-related factors, and patient-related factors (WHO 2003).
All in all, in developed countries only 50% are adherent to long-term therapies,
and even less in developing countries (WHO 2003), but it is necessary to study
nonadherence in detail, avoid generalized estimation of adherence rates, and con-
sider the respective method of adherence assessment in studies (Mathes et al. 2012).

Psychoeducation

In general, psychoeducation is an elementary and essential part of therapeutic

interventions in different kinds of psychiatric disorders, and meanwhile several
disorder-specific manuals are available (Bäuml et al. 2016). The consideration of
Compliance and Psychoeducation 239

psychoeducational aspects is a prerequisite for a successful therapy in the treatment

of psychiatric but also neurological and somatic diseases (Bäuml et al. 2016).
Regarding medication adherence the NICE guidelines (2009) need to be
considered. They cover the involvement of the patient in decision-making, the
increase of adherence, the review of the medication during long-term treatments,
and the communication between different healthcare professionals. A check of this
guideline in 2019 confirmed the recommendations in this guideline. Recently,
several successful psychoeducation approaches in different neuropsychiatric dis-
eases have been described, e.g., in patients with bipolar affective disorder (Jawad
et al. 2018; Chen et al. 2019), schizophrenia (Haddad et al. 2014; Phan 2016),
depression (Conradi et al. 2017), anxiety, alexithymia, and fibromyalgia (Melin et al.
2018) as well as epilepsy (Michaelis et al. 2018).
Very recently, the “GET READY relapse prevention program for anxiety
and depression” study protocol has been described, an E-health program with
different modes of psychoeducation, which just has been developed (Krijnen-de
Bruin et al. 2019).
Even if several dimensions of adherence exist, the most effective intervention to
enhance patient’s adherence is patient directed with a cost-to-savings ratio of unto
1:10 by the application of a chronic disease self-management program (Lorig et al.
1999). In patients with recurrent depression in a 2-year follow-up, psychoeducation
is effective in terms of drug adherence and even attachment to the labor market
(Aagaard et al. 2017).
Knowing factors affecting adherence to treatment for depression like poor
health education of the patient, psychiatric co-morbidity, high frequency of dose,
or personality traits helps to improve adherence (WHO 2003). Multiple interventions
have proved to be effective in increasing adherence in patients with depression like
multidisciplinary care (Lin et al. 1999; Katon et al. 1999), training of health pro-
fessionals on adherence (Peveler et al. 1999), or monitoring of patients (Katon et al.
1995). Moreover, the education of the patient on the use of medication (Lin et al.
1995) and patient-tailored prescriptions (Claxton 2000) is helpful. Psychoeducation
should be an integral part of every program of disease management (Gold and
McClung 2006). Psychoeducation is effective not only for adult patients but also
for children patients, parents, and caregivers (Michaelis et al. 2018).
It is important to note that psychoeducation is more than giving the patient an
information leaflet, which for itself has no positive effect on adherence in antide-
pressant drug therapy in contrast to counselling (Peveler et al. 1999). Especially, in
patients with schizophrenic disorder, personalized psychoeducation is necessary to
raise the adherence rate and to address the “unmet need” of treatment adherence
(Pompili et al. 2017). In patients with schizophrenia-spectrum disorders at least
a positive attitude to the medication and illness insight via psychoeducation need to
be announced (Sendt et al. 2015). Generally, it is necessary to consider essential
psychological risk factors of nonadherence like the doctor-patient relationship,
the individual history of nonadherence, the illness acceptance, fear of side effects,
comorbid depression, and cognitive impairment (Arlt et al. 2017). Therefore, suc-
cessful pharmacotherapy must include psychoeducation under consideration of
patient’s health belief model (De Las Cuevas et al. 2016) and the potential of
240 S. Unterecker

“pharmacophobia” which doubles the low adherence rate (De Leon and De Las
Cuevas 2017). Regarding an improvement of adherence, therapeutic drug monitor-
ing has the potential to optimize pharmacotherapy (Hiemke et al. 2018), not only by
controlling adherence via drug concentration measurement but also by including
information about the mode of action of pharmacotherapy in psychoeducation.
Obviously, patient information and education is effective and reduces the rate
of nonadherence, even if 6 months after patient education one third of patients is
not compliant (Gold and McClung 2006). Therefore, more attention is needed to
identify patients who are least likely to be adherent to drug therapy and intensify
psychoeducation individually (Gold and McClung 2006; Berk et al. 2010).
A recent randomized clinical trial showed that psychoeducation including a
treatment initiation and participation program is effective and increases the
adherence rate for three to five times in antidepressant treated patients (Sirey
et al. 2017).
After the identification of barriers of adherence, it is important to consider
facilitators and to include them in psychoeducation because targeted interventions
are necessary (Ho et al. 2017).
Therefore, psychoeducation has the potential of a meaningful impact on public
health.

References
Aagaard J, Foldager L, Makki A, Hansen V, Müller-Nielsen K. The efficacy of psychoeducation
on recurrent depression: a randomized trial with a 2-year follow-up. Nord J Psychiatry. 2017;
71:223–9.
Anderson IM, Tomenson BM. Treatment discontinuation with selective serotonin reuptake inhib-
itors compared with tricyclic antidepressants: a meta-analysis. Br Med J. 1995;310:1433–8.
Anderson JP, Icten Z, Alas V, Benson C, Joshi K. Comparison and predictors of treatment adherence
and remission among patients with schizophrenia treated with paliperidone palmitate or atypical
oral antipsychotics in community behavioral health organizations. BMC Psychiatry. 2017;
17:346.
Arlt AD, Nestoriuc Y, Rief W. Why current drug adherence programs fail: addressing psychological
risk factors of nonadherence. Curr Opin Psychiatry. 2017;30:326–33.
Bäuml J, Behrendt B, Henningsen P, Pitschel-Walz G. Handbuch der Psychoedukation. Stuttgart:
Schattauer; 2016.
Berk L, Hallam KT, Colom F, Vieta E, Hasty M, Macneil C, Berk M. Enhancing medication
adherence in patients with bipolar disorder. Human Psychopharmacology: Clinical and Exper-
imental 2010;25(1):1–16.
Bohlken J, Weber S, Rapp MA, Kostev K. Continuous treatment with antidementia drugs in
Germany 2003–2013: a retrospective database analysis. Int Psychogeriatr. 2015;27:1335–42.
Buck D, Jacoby A, Baker GA, Chadwick DW. Factors influencing compliance with antiepileptic
drug regimes. Seizure. 1997;6:87–93.
Chen R, Zhu X, Capitao LP, Zhang H, Luo J, Wang X, Xi Y, Song X, Feng Y, Cao L, Malhi GS.
Psychoeducation for psychiatric inpatients following remission of a manic episode in bipolar I
disorder: a randomized controlled trial. Bipolar Disord. 2019;21:76–85.
Claxton A, Klerk E. de, Parry M, Robinson JM, Schmidt ME. Patient compliance to a new enteric-
coated weekly formulation of fluoxetine during continuation treatment of major depressive
disorder. The Journal of Clinical Psychiatry 2000;61(12):928–932.
Compliance and Psychoeducation 241

Cloyd JC, Kriel RL, Jones-Saete CM, Ong BY, Jancik JT, Remmel RP. Comparison of sprinkle
versus syrup formulations of valproate for bioavailability, tolerance, and preference. J Pediatr.
1992;120:634–8.
Conradi HJ, Bos EH, Kamphuis JH, de Jonge P. The ten-years course of depression in primary care
and long-term effects of psychoeducation, psychiatric consultation and cognitive behavioral
therapy. J Affect Disord. 2017;217:174–82.
De Las Cuevas C, de Leon J. Reviving research on medication attitudes for improving pharmaco-
therapy: focusing on adherence. Psychother Psychosom. 2017;86:73–9.
De Las Cuevas C, Penate W, Cabrera C. Perceived health control: a promising step forward in our
understanding of treatment adherence in psychiatric care. J Clin Psychiatry. 2016;77:e1233–9.
De Leon J, de Las Cuevas C. The art of pharmacotherapy – reflections on pharmacophobia. J Clin
Psychopharmacol. 2017;37:131–7.
Demyttenaere K. Noncompliance with antidepressants: who’s to blame? Int Clin Psychopharmacol.
1998;13:S19–25.
Ekselius L, Bengtsson F, von Knorring L. Non-compliance with pharmacotherapy of depression is
associated with a sensation seeking personality. Int Clin Psychopharmacol. 2000;15:273–8.
Furukawa TA, Streiner DL, Young LT. Is antidepressant-benzodiazepine combination therapy
clinically more useful? A meta-analytic study. J Affect Disord. 2001;5:173–7.
Garnett WR. Antiepileptic drug treatment: outcomes and adherence. Pharmacotherapy. 2000;20:
S191–9.
Getnet A, Woldeyohannes SM, Bekana L, Mekonen T, Fekadu W, Menberu M, Yimer S, Assaye A,
Belete A, Belete H. Antiepileptic drug nonadherence and its predictors among people with
epilepsy. Behav Neurol. 2016;2016:3189108.
Gold DT, McClung B. Approaches to patient education: emphasizing the long-term value of
compliance and persistence. Am J Med. 2006;119:S32–7.
Greene M, Paladini L, Lemmer T, Piedade A, Touya M, Clark O. Systematic literature review
on patterns of pharmacological treatment and adherence among patients with bipolar disorder
type I in the USA. Neuropsychiatr Dis Treat. 2018;14:1545–59.
Gutierrez PM, Wortzel HS, Forster JE, Leitner RA, Hostetter TA, Brenner LA. Blister packaging
medication increases treatment adherence in psychiatric patients. J Psychiatr Pract. 2017;23:
320–7.
Haddad PM, Brain C, Scott J. Nonadherence with antipsychotic medication in schizophrenia:
challenges and management strategies. Patient Relat Outcome Meas. 2014;5:43–62.
Hargrave R, Remler MP. Noncompliance. J Natl Med Assoc. 1996;88:7, 11
Hatch A, Docherty JP, Carpenter D, Ross R, Weiden PJ. Expert consensus survey on medication
adherence in psychiatric patients and use of a digital medicine system. J Clin Psychiatry. 2017;
78:e803–12.
Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts
K, Gerlach M, Greiner C, Gründer G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R,
Janssen G, Jaquenoud E, Laux G, Messer T, Mössner R, Müller MJ, Paulzen M, Pfuhlmann B,
Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B,
Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G,
Baumann P. Consensus guidelines for therapeutic drug monitoring in neuropsychophar-
macology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Ho SC, Jacob SA, Tangiisuran B. Barriers and facilitators of adherence to antidepressants among
outpatients with major depressive disorder: a qualitative study. PLoS One. 2017;12:e0179290.
Hotopf M, Hardy R, Lewis G. Discontinuation rates of SSRIs and tricyclic antidepressants: a meta-
analysis and investigation of heterogeneity. Br J Psychiatry. 1997;170:120–7.
Jawad I, Watson S, Haddad PM, Talbot PS, McAllister-Williams RH. Medication nonadherence
in bipolar disorder: a narrative review. Ther Adv Psychopharmacol. 2018;8:349–63.
Joe S, Lee JS. Association between non-compliance with psychiatric treatment and non-
psychiatric service utilization and costs in patients with schizophrenia and related disorders.
BMC Psychiatry. 2016;16:444.
Katon W. Collaborative management to achieve treatment guidelines. JAMA 1995;273(13):1026.
242 S. Unterecker

Katon W, von Korff M, Lin E, Bush T, Ormel J. Adequacy and duration of antidepressant treatment
in primary care. Med Care. 1992;30:67–76.
Katon W, Von Korff M, Lin E, Simon G, Walker E, Unützer J, Bush T, Russo J, Ludman E. Stepped
collaborative care for primary care patients with persistent symptoms of depression: a random-
ized trial. Arch Gen Psychiatry. 1999;56:1109–15.
Keeley R, Smith M, Miller J. Somatiform symptoms and treatment nonadherence in depressed
family medicine outpatients. Arch Fam Med. 2000;9:46–54.
Krijnen-de Bruin E, Muntingh AD, Hoogendoorn AW, van Straten A, Batelaan NM,
Maarsingh OR, van Balkom AJ, van Meijel B. The GET READY relapse prevention pro-
gramme for anxiety and depression: a mixed-methods study protocol. BMC Psychiatry.
2019;19:64.
Lannon SL. Using a health promotion model to enhance medication compliance. J Neurosci Nurs.
1997;29:170–8.
Lin EH, Von Korff M, Katon W, Bush T, Simon GE, Walker E, Robinson P. The role of the primary
care physician in patients’ adherence to antidepressant therapy. Med Care. 1995;33:67–74.
Lin EH, Simon GE, Katon WJ, Russo JE, Von Korff M, Bush TM, Ludman EJ, Walker EA. Can
enhanced acute-phase treatment of depression improve long-term outcomes? A report of
randomized trial in primary care. Am J Psychiatry. 1999;156:643–5.
Lorig KR, Sobel DS, Stewart AL, Brown BW, Bandura A, Ritter P, Gonzalez VM, Laurent DD,
Holman HR. Evidence suggesting that a chronic disease self-management program can improve
health status while reducing hospitalization: a randomized trial. Med Care. 1999;37:5–14.
Mathes T, Pieper D, Antoine SL, Eikermann M. 50% adherence of patients suffering chronic
conditions – where ist he evidence? Ger Med Sci. 2012;10:Doc16.
Melin EO, Svensson R, Thulesius HO. Psychoeducation against depression, anxiety, alexithymia
and fibromyalgia: a pilot study in primary care for patients on sick leave. Scand J Prim Health
Care. 2018;36:123–33.
Michaelis R, Tang V, Goldstein LH, Reuber M, LaFrance WC, Lundgren T, Modi AC, Wagner JL.
Psychological treatments for adults and children with epilepsy: evidence-based recom-
mendations by the international league against epilepsy psychology task force. Epilepsia.
2018;59:1282–302.
Montgomery SA, Kasper S. Comparison of compliance between serotonin reuptake inhibitors and
tricyclic antidepressants: a meta-analysis. Int Clin Psychopharmacol. 1995;9:33–40.
Myers ED, Branthwaite A. Out-patient compliance with antidepressant medication. Br J Psychiatry.
1992;160:83–6.
National Institute for Health and Care Excellence. Medicines adherence: involving patients in
decisions about prescribed medicines and supporting adherence. NICE guidelines CG76.
London: Royal College of General Practitioners; 2009.
Pennington M, McCrone P. Does non-adherence increase treatment costs in schizophrenia?
Pharmacoeconomics. 2018;36:941–55.
Peveler R, George C, Kinmonth AL, Campbell M, Thompson C. Effect of antidepressant drug
counselling and information leaflets on adherence to drug treatment in primary care: randomised
controlled trial. BMJ. 1999;319:612–5.
Phan SV. Medication adherence in patients with schizophrenia. Int J Psychiatry Med.
2016;51:211–9.
Pilon D, Tandon N, Lafeuille MH, Kamstra R, Emond B, Lefebvre P, Joshi K. Treatment pattern,
health care resource utilization, and spending in Medicaid beneficiaries initiating second-
generation long-acting injectable agents versus oral atypical antipsychotics. Clin Ther. 2017;
39:1972–85.
Pompili M, Giordano G, Luciano M, Lamis DA, Del Vecchio V, Serafini G, Sampogna G, Erbuto D,
Falkai P, Fiorillo A. Unmet needs in schizophrenia. CNS Neurol Disord Drug Targets.
2017;16:870–84.
Compliance and Psychoeducation 243

Profit D, Rohatagi S, Zhao C, Hatch A, Docherty JP, Peters-Strickland TS. Developing a digital
medicine system in psychiatry: ingestion detection rate and latency period. J Clin Psychiatry.
2016;77:e1095–100.
Rohatagi S, Profit D, Hatch A, Zhao C, Docherty JP, Peters-Strickland TS. Optimization of a digital
medicine system in psychiatry. J Clin Psychiatry. 2016;77:e1101–7.
Sendt KV, Tracy DK, Bhattacharyya S. A systematic review of factors influencing adherence to
antipsychotic medication in schizophrenia-spectrum disorders. Psychiatry Res. 2015;225:
14–30.
Serna MC, Real J, Cruz I, Galvan L, Martin E. Monitoring patients on chronic treatment with
antidepressants between 2003 and 2011: analysis of factors associated with compliance. BMC
Public Health. 2015;15:1184.
Sirey JA, Banerjee S, Marino P, Bruce ML, Halkett A, Turnwald M, Chiang C, Liles B, Artis A,
Blow F, Klaes HC. Adherence to depression treatment in primary care – a randomized clinical
trial. JAMA Psychiatry. 2017;74:1129–35.
Wenze SJ, Armey MF, Weinstock LM, Gaudiano BA, Miller IW. An open trial of a smartphone-
assisted, adjunctive intervention to improve treatment adherence in bipolar disorder. J Psychiatr
Pract. 2016;22:492–504.
World Health Organization. Adherence to long-term therapies: evidence for action. Geneva:
World Health Organization; 2003. http://www.who.int/chp/knowledge/publications/adherence_
report/en/
Psychopathology: Rating Scales for the
Assessment of Mental Status

Rolf-Dieter Stieglitz and Hans-Peter Volz

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Assessment Aims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Characteristics of Instruments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Evaluation Criteria and Selection of Rating Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Selected Areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
Scales for Measuring Sexual Functioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Scales for Measuring Extrapyramidal Motor Side Effects (EPS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Other Domains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Ascertainment of Progression and Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Requirements for the Use of Interviews and Rating Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Examples of Practical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Conclusion and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

Abstract
In the context of psychopharmacotherapy, diagnostic instruments have always
played a prominent role, in order either to assist the classification of a patient or to
measure the degree of severity of psychopathological syndromes at a given stage
as well as during the course of the disorder. In both these cases, but also in
connection with other clinical areas, rating scales and diagnostic interviews are

R.-D. Stieglitz (*)

Emeritus (Klinische Psychologie und Psychiatrie) Klinische Psychologie und Psychotherapie,
Basel, Switzerland
e-mail: rdstieglitz@bluewin.ch
H.-P. Volz
Krankenhaus für Psychiatrie, Psychotherapie und Psychosomatische Medizin Schloss Werneck,
Werneck, Germany
e-mail: hans-peter.volz@kh-schloss-werneck.de

© Springer Nature Switzerland AG 2022 245

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_5
246 R.-D. Stieglitz and H.-P. Volz

the instruments most frequently applied. A rating scale is generally understood to

be an assessment scale. A distinction is made between self- and observer-rating
scales. A self-rating scale is a procedure where the entire assessment process lies
in the hands of the patient. By contrast, with an observer-rating scale the
assessment process is conducted by independent examiners who include their
own (or those of third parties) as well as the patient’s observations in their final
assessment. Rating scales serve above all to record the severity of the psychopa-
thology and side effects. In studies, especially observer-rating scales are the most
important outcome criteria. However, the use of interviews and rating scales
requires a comprehensive training.

Introduction

In the context of psychopharmacotherapy, diagnostic instruments have always

played a prominent role, in order either to assist the classification of a patient or to
measure the degree of severity of psychopathological syndromes at a given stage as
well as during the course of the disorder. In both these cases, but also in connection
with other clinical areas, rating scales and interviews are the instruments most
frequently applied. A rating scale is generally understood to be an assessment
scale. In the following, a distinction is made between self- and observer-rating
scales. A self-rating scale is a procedure where the entire assessment process lies
in the hands of the patient. By contrast, with an observer-rating scale the assessment
process is conducted by independent examiners who include their own (or those of
third parties) as well as the patient’s observations in their final assessment.
In addition, diagnostic interviews are of great importance. In general terms, an
interview can be defined as a target-oriented human interaction between two people
(the interviewer and the interviewee) for the purpose of gathering information on various
aspects of the interviewee’s experience (e.g., feelings) and behavior. In the context of
classification systems, for example, this means the adoption of questioning strategies for
the gathering of information in accordance with the criteria contained in a specific
diagnostic system (symptom criteria; time and progression criteria; inclusion and exclu-
sion criteria). With rating scales, interviews contain an itinerary of questions for the
purpose of, for example, the recording of specific psychopathological symptoms.
The aim of this chapter is to provide an overview of interviews and rating scales
in the field of psychopharmacotherapy which have proved reliable and valid in both
clinical as well as research settings.

Assessment Aims

Diagnostic instruments in psychopharmacotherapy serve a variety of purposes (cf.

Bech 1993; Rush et al. 2010; van Riezen and Segal 1988). Interviews are designed to
avoid important potential sources of error and variation (variation in observation and
Psychopathology: Rating Scales for the Assessment of Mental Status 247

information gathering). From the viewpoint of classificatory diagnosis, a struc-

tured or standardized interview (see below) is expected to reliably assess a patient
in accordance with one of the two current classification systems, ICD-10 or DSM-
IV/ 5.
The main purpose of rating scales is to determine the degree of severity in
specific psychopathological areas at different stages of the disorder. In research,
these scales also assist in the selection of patients for study participation (e.g.,
based on certain cutoff values in the Hamilton Depression Rating Scale, HDRS). In
clinical practice, they often form the basis for decision-making on therapeutic
intervention. In clinical practice as well as in research, the evaluation of the
efficacy of therapeutic intervention is of primary concern. Rating scales find
further application in the assessment of other clinically relevant aspects such as
side effects and quality of life (see below).

Characteristics of Instruments

Interviews and rating scales are differentiated according to a variety of characteris-

tics. Interviews are distinguished by the degree of structure contained in the process
of information gathering. Generally, a contrast is made between structured and
standardized interviews. Structured interviews dictate a systematic structure for the
information gathering process. The examiner is greatly assisted in the diagnostic
process by mandatory pre-formulated questions (introductory and supplemental
questions). As a rule, the evaluation and weighting of the patient’s answers remain
the responsibility of the clinical examiner (clinical judgment), although in some
instances directions for rating are provided to facilitate the decision-making process.
By contrast, in standardized interviews, all levels of the diagnostic process and all
elements of the information gathering process are clearly specified, from the struc-
turing of the examination procedure through to the type and sequencing of questions,
the scoring of answers, and the (mostly computerized) establishment of a diagnosis.
In cases where, for example, a patient experiences problems of understanding, the
interviewer is only allowed to repeat the question either as a whole or in part
or, where available, ask supplemental questions or read out pre-printed directions.
Table 1 contains the most important ICD-10- and/or DSM-IV/ 5-oriented inter-
views for classificatory diagnosis (for specific subgroups of psychiatric disorders,
e.g., personality disorders, see Antony and Barlow 2010).
With rating scales, the distinction between self- and observer-rating scales
referred to above is of special significance. There are a number of further possible
and important differentiations:

• Unidimensional versus multidimensional rating scales

• Global versus additive rating scales
• Short versus long rating scales
• Verbal versus visual analogue rating scales
248 R.-D. Stieglitz and H.-P. Volz

Table 1 Assessment instruments based on ICD-10 and DSM-IV/ 5

Type of
instrument Name System Authors
StrI Structured Clinical Interview for DSM-5© DSM-5 First et al.
disorders (SCID-5) (2016a, b)
StrI Anxiety and related disorders interview DSM-5 Brown and
schedule for DSM-5 (ADIS-5) Barlow (2014)
StrI Schedules for clinical assessment in ICD-10/ Wing et al.
neuropsychiatry (SCAN) DSM-IV (1990)
StrI Mini international neuropsychiatric interview DSM-IV/ Sheehan (1998)
(M.I.N.I.) ICD-10
StaI Composite international diagnostic interview DSM-IV/ Kessler and
(CIDI) ICD-10 Üstün (2004)
StrI structured interview, StaI standardized interview

Unidimensional rating scales, for example, the HDRS, only produce one scale
value representing the sum score of individual items, thus limiting themselves to a
single indicator of degree of severity for a specific syndrome (e.g., depressive
syndrome). Multidimensional rating scales, by contrast, such as the AMDP-System
(Broome et al. 2018), allow for a wide spectrum of different syndromes to be
assessed and are therefore applicable to various groups of disorders. Both types of
procedure involve mostly additive rating scales where the scale value or values are
calculated by simply adding up the individual scores of items assessed. The obtained
value or values are then used as indicator(s) of the constructs examined for. Global
rating scales, as their name suggests, aim to facilitate assessment of particular
phenomena based on a global impression rather than the sum total of individual
symptoms. The most widely used such scale is the Clinical Global Impressions Scale
(CGI; cf. AMDP and CIPS 1990). Its first component, the CGI-Severity (CGI-S)
Scale, contains a scale giving ratings from 1 (normal, not at all ill) to 7 (among the
most severely ill patients), which allows for a global evaluation of the patient’s
overall condition (unrelated to a specific disorder). The second component, the CGI
Improvement (CGI-I) Scale, contains treatment response ratings ranging from 1
(marked improvement since initiation of treatment) to 7 (marked deterioration
since initiation of treatment), which allows for a global assessment of change. The
CGI is one of the most widely applied scales in (psychopharmacological) trial
studies.
A further global assessment scale frequently referred to in the literature is the
Sheehan Disability Scale (SDS, Sheehan 1983), a self-rating scale. In a 10-point
Likert Scale (scored from 0 not at all to 10 extremely), the level of impairment to
functionality during the preceding month is assessed in the following three areas:
work and occupation; social contacts and leisure activities; family life and household
duties.
The distinction between short and long rating scales stems from attempts to
develop shorter and more concise versions of existing, valid, and reliable scales.
For the Symptom Check List – Revised (SCL-90-R), a short version, the Brief
Psychopathology: Rating Scales for the Assessment of Mental Status 249

Symptom Inventory (BSI), has been available for many years. Instead of the original
90-item scale, this abbreviated version is limited to 53 items, which are divided into
the same 9 subscales as in the long version.
In most self- and observer-rating scales, assessment options take the form of
verbal descriptors (generally ranging from not present to mild, moderate, and severe)
or operationalized levels of assessment (as in, e.g., the Montgomery Åsberg Depres-
sion Rating Scale, MADRS). Differentiated from such scales are visual analogue
rating scales. This group of scales follows the general principle of inviting the rater
to mark, on a roughly 100 mm long line ending on either side in polar opposites, the
position corresponding with the extent of agreement or disagreement with either of
the two opposing extremes given. The most commonly used scale in this category is
Aitken’s (1969) VAS to examine for depressive moods. This scale was formerly
predominantly applied in research settings, where repeated assessment was a fre-
quent requirement (e.g., in the treatment of sleep deprivation).

Evaluation Criteria and Selection of Rating Scales

The number of available instruments is now such that maintaining a comprehensive

overview proves difficult (e.g., there are more than 100 rating scales for depressive
disorders alone). Against this background, only those rating scales of sufficiently
proven psychometric quality (cf. Ayearst and Bagby 2010), especially in regard to
reliability and validity, should be used. Both these criteria allow for further differ-
entiation in respect to a range of partial aspects which are significant to varying
degrees for rating scales and interviews. The following points are particularly
noteworthy.
Reliability. For rating scales, above all the criterion of internal consistency is
important (testing for homogeneity of an individual component, mostly calculated
by means of Cronbach’s alpha). For interviews, the criterion of interrater reliability is
of central concern, that is to say, the level of agreement reached among different
interviewers in their respective assessments of the same patient. The same criterion
applies equally to observer-rating scales.
Validity. The criterion of validity allows for discrimination between a number of
different aspects (cf. Ayearst and Bagby 2010). Of particular importance for rating
scales are convergent validity (the correlation with other, construct-related, rating
scales), divergent validity (the correlation with other, construct-unrelated, rating
scales), the ability to differentiate between groups (e.g., between depressive and
schizophrenic patients in certain syndromes), and sensitivity to measure change (i.e.,
the ability to capture changes over time).
With interviews, procedural validity in respect to the degree of correlation with
other approaches/groups of procedures for the recording of a specific phenomenon
(here a diagnosis) is especially relevant.
In addition, in the evaluation and selection of rating scales, there are clearly also
practice-related aspects to consider, as follows:
250 R.-D. Stieglitz and H.-P. Volz

• Economy of time (including economy of cost)

• Guidance in the interpretation of scores and measurements in the form of norma-
tive data or, at the very least, cutoff values.

In clinical practice, the question of economy of time is always of central concern,

as, against the background of a variety of other necessary tasks, the diagnostic
process should take up as little time as possible. In research settings, multimodal
diagnosis has been playing a large role for a number of years (cf. Stieglitz 2003). The
aim of multimodal diagnosis is to respect the complexity of human experience and
behavior in all its multifaceted diversity and for this to be reflected in a carefully
detailed diagnostic assessment procedure. This calls for instruments which assess
symptoms reliably and in a time-efficient manner. In practical terms, correct inter-
pretation of rating scores is of the essence. Normative data (e.g., T-scores, percentile
ranks) are desirable, as they enable accurate assessment of individual patients in
relation to a reference population (e.g., a healthy control group, other patients).
Given the costly and time-consuming process of obtaining normative data, these are
rarely available and, if so, generally only for self-rating scales. On a less nuanced
level are so-called cutoff values. They allow for rough estimates, mostly expressed in
degrees of severity of a particular syndrome (e.g., mild-moderate-severe depressive
syndrome). For a reliable interpretation, reference scores are a minimum require-
ment. These generally take the form of mean scores (and standard deviations) of
scale values across different populations.
Lastly, another point for consideration in the selection of a suitable rating scale is
the fundamental choice between self-rating or observer-rating scales. Both types
have their advantages and disadvantages (cf. Table 2) which need to be weighed up
carefully. In research settings, the use of observer-rating scales dominates where
primary or main outcomes of studies are concerned (particularly also on account of
their greater sensitivity to measure change and better differentiation between degrees
of severity). In clinical practice, self-rating scales are preferred for time reasons. In
addition, self- and observer-rating scales vary in their appropriateness depending on
the group of disorders examined for. In cases of, for example, dementia and

Table 2 Self- and observer-rating scales: advantages and disadvantages

Self-rating scale Observer-rating scale
Advantages Time-efficient Suitable for all levels of severity
Broad area of application Sensitive to measure change
Norms mostly available Good capability to differentiate
between degrees of severity
Disadvantages Judgment errors possible Time-consuming
Not applicable for all disorders Training necessary
Not suitable for severely disturbed Continuous supervision necessary
patients In general no norms available
Less sensitive to measure change
Partly low capability to differentiate
between degrees of severity
Psychopathology: Rating Scales for the Assessment of Mental Status 251

schizophrenic disorders, the use of observer-rating scales prevails; with anxiety

disorders, self-rating scales are more common; with depressive disorders, both scales
are applied equally frequently. In general, it is recommended that both types are
used, as studies have confirmed that one group of procedures cannot substitute for
the other. They are each attributed a complementary function.
The criteria mentioned so far may assist the individual clinical examiner in
the selection of a suitable instrument. However, in view of the large number of
instruments available, this undertaking proves difficult, and the user is referred
to overviews for support. The following are especially recommended:

• AMDP and CIPS (1990)

• Antony and Barlow (2010)
• Rush et al. (2010)

In addition, there are subject-specific recommendations available for particular

groups of disorders (e.g., Keefe 2012 for schizophrenia), and specialists regularly
publish recommendations for suitable instruments and suggestions for the assess-
ment of specific domains. Thus, the results of various consensus conferences on
psychopharmacological studies have been published, for example:

• Angst et al. (1989): Antidepressants

• Angst et al. (1991): Antipsychotics
• Angst et al. (1994): Long-term studies

These publications, however, chiefly discuss general and basic considerations and
recommendations (e.g., evaluation of therapy success; types of scale to be applied).

Selected Areas

Given the large number of rating scales available, only a limited selection can be
addressed here. Initially, the first consideration is whether an instrument is applicable
with different groups of disorders (so-called general rating scales) or whether it is
specifically designed for one particular group only (disorder-specific rating scales).
As expected, most rating scales fall into the latter category.
Table 3 contains an overview of the best known self- and observer-rating scales
which find application in more than one group of disorders. A distinction is made
between rating scales screening for specific syndromes and those screening for more
general aspects of psychiatric impairment (i.e., mood).
On account of their prevalence, the following groups of disorders are of particular
interest and discussed below: schizophrenic disorders, affective disorders, and
anxiety disorders.
Schizophrenic disorders. As a result of the close link between the discovery of
psychotropic drugs and the development of rating scales, instruments screening for
schizophrenic symptoms were among the first to be developed (cf. Stieglitz et al.
252 R.-D. Stieglitz and H.-P. Volz

Table 3 Self- and observer-rating scales: general psychopathology

Domain Instrument (authors) Characteristics
General Symptom Checklist (SCL-90- Self-rating scale
psychopathology R; Derogatis 1994) 90 items, 9 subscale, 3 global scales
Norms
AMDP-System (AMDP; Observer-rating scale
Broome et al. 2018) 140 items, 9 subscales,
Norms
Inpatient Multidimensional Observer-rating scale
Scale (IMPS; Lorr and Klett 90 items, 12 subscales,
1967) Norms
Nurses Observation Scale for Observer-rating scale
Inpatient Evaluation (NOSIE; 30 items, 7 subscales, total score
Honigfeld et al. 1976) Norms
Mood Profile of Mood States (POMS; Self-rating scale
McNair et al. 1971) 35 items, 4 subscales

Table 4 Self- and observer-rating scales: schizophrenia (examples)

Domain Instrument (authors) Characteristics
General Brief Psychiatric Rating Scale Observer-rating scale
psychopathology (BPRS; Overall and Gorham 18 symptom complexes, 4 subscales,
1976; Ventura et al. 1993) 8 phenomenological types
Reference values
Positive and Negative Observer-rating scale
Syndrome Scale (PANSS; Kay Positive scale 7 items, negative scale 7
et al. 1987) items, 16 global scales
Reference values and percentiles
Scale for the Assessment of Observer-rating scale
Positive Symptoms (SAPS), 90 items, 12 subscales, 3 overall scales
Negative Symptoms (SANS; Norms
Andreasen 1981, 1984)
Depression Calgary Depression Rating Observer-rating scale
Scale for Schizophrenia 9 items, total score
(CDSS; Addington et al. 1990) Reference values
Anhedonia Snaith-Hamilton-Pleasure- Self-rating scale
Scale (SHAPS; Snaith et al. 14 items, total score
1995) Cutoff values

2017). In order to measure and evaluate the efficacy of newly discovered substances,
instruments have been continuously developed since the 1960s, a number of which
remain in use today. Table 4 contains a summary of the most important of these
instruments. They serve to assess the primary symptom dimensions in schizophrenic
disorders such as delusions, hallucinations, or thought disorders, which are, in some
instances, grouped according to negative and positive symptom domains. The
instruments listed remain the most important instruments in neuroleptic (antipsy-
chotic) studies.
Psychopathology: Rating Scales for the Assessment of Mental Status 253

Affective disorders. Rating scales in the area of affective disorders are grouped
into scales for measuring depressive symptoms and scales for measuring manic
symptoms. While there are over a hundred instruments available for depressive
symptoms, only a small number exists for manic symptoms. Table 5 again provides
a summary of the most important instruments still in use today. In respect to
depression rating scales, the following points are of particular interest:

• Contents of assessed areas: To some extent, individual instruments vary con-

siderably in the aspects they screen for (cf. Bech 1993, among others). This is mainly
due to the fact that there is as yet no authoritative definition for the depressive
syndrome, the recording of which is achieved through rating scales. While some
instruments tend to focus more on cognitive aspects (e.g., Beck Depression Inven-
tory, BDI), others put greater emphasis on somatic (e.g., HDRS) and affective aspects
(e.g., Paranoid Depression Scale, PD-S; AMDP and CIPS 1990).
• Methodological considerations: The psychometric quality of individual screening
instruments is extremely variable (Möller 2009). While in the case of the HDRS, the
most widely used depression scale in the world, methodological weaknesses have
been demonstrated repeatedly (e.g., no one-dimensionality; cf., e.g., Østergaard et al.
2014)), for others, satisfactory to good levels of reliability and validity have been
confirmed (e.g., MADRS; Bech Rafaelson Melancholia Scale, BRMS).
• Link between dimensional and categorical diagnosis: Based on the example of
depressive disorders, efforts are under way to link categorical and dimensional
views. A categorical diagnosis based on classification systems has the disadvan-
tage that only dichotomous decisions are possible, with differences in degrees of
severity being lost as a result. Against this background, increasingly frequent
attempts are made (especially with depressive disorders) to develop procedures
which indicate the presence of disorders and simultaneously allow for the assess-
ment of their degrees of severity. To this end, the diagnostic criteria of specific
groups of disorders are generally carried over into questionnaire items (e.g.,
Major Depressive Inventory, MDI; Olsen et al. 2003).
• Areas of disorders: Depressive symptoms can present with various groups of
disorders. General scales have been found less, or not at all, suitable for the
ascertainment of depressive symptoms in specific groups. Various methodologi-
cal studies on the HDRS, BRMS, and MADRS have shown that with schizo-
phrenic disorders, for example, these instruments demonstrate a different
dimensional structure to that with depressive patients (cf. Schennach et al.
2012). Increased efforts are therefore under way to develop specific scales for
areas such as postpartum depression, depressions in schizophrenic patients, and
depressions also in geronto-psychiatric patients, where the use of specifically
designed instruments is particularly desirable. The following are of interest:

– Cornell Dysthymia (Rating) Scale (CDRS) by Mason et al. (1993)

– Edinburgh Postnatal Depression Scale (EPDS) by Cox et al. (1987)
– Calgary Depression Rating Scale for Schizophrenia (CDSS) by Addington
et al. (1990)
254 R.-D. Stieglitz and H.-P. Volz

While there is a considerable number of instruments available for depression,

unfortunately this fails to be the case for manic disorders (cf. Table 5).
Anxiety disorders. In accordance with DSM-IV/ 5, anxiety disorders also
should be more broadly assessed to include disorders which contain anxiety com-
ponents (e.g., compulsive disorders). Table 6 provides examples of frequently
applied screening procedures (for a comprehensive overview, cf. Antony and Barlow
2010).
It is beyond the scope of this chapter to discuss all groups of psychiatric disorders
here (cf. Antony and Barlow 2010).
Rating scales are not only useful for the assessment of psychopathological
symptoms but also of other clinically relevant aspects such as quality of life (cf.
van Riezen and Segal 1988; Rush et al. 2010).

Side Effects

In the context of clinical studies, side effects are now largely known as adverse
events (AEs) or adverse reactions (ARs). The term AE refers to any unintended
medical occurrence in patients or participants in clinical studies after administration
of a particular drug, independent of any causal relation to the medication in question.
An AR, on the other hand, denotes any unintended and adverse reaction to a trial

Table 5 Self- and observer-rating scales: affective disorders (examples)

Domain Instrument (authors) Characteristics
Depression Beck Depression Inventory (BDI-II; Beck et al. Self-rating scale
1996) 21 items, total score
Norms and cutoff values
Major Depression Inventory (MDI; Bech et al. Self-rating scale
2001) 10 items, total score
Cutoff values
Hamilton Depression Rating Scale (HDRS; Observer-rating scale
Hamilton 1960) 21 items, total score
Cutoff values
Bech Rafaelsen Melancholie Scale (BRMS; Bech Observer-rating scale
and Rafaelsen 1986) 11 items, total score
Cutoff values
Montgomery Åsberg Depression Rating Scale Observer-rating scale
(MADRS; Montgomery and Åsberg 1979) 10 items, total score
Cutoff values
Mania Bech Rafaelsen Mania Scale (BRMAS; Bech et al. Observer-rating scale
1978) 11 items, total score
Cutoff values
Young Mania Rating Scale (YMRS; Young et al. Observer-rating scale
1978) 11 items, total score
Cutoff values
Psychopathology: Rating Scales for the Assessment of Mental Status 255

Table 6 Self- and observer-rating scales: anxiety disorders (examples)

Domain Instrument (authors) Characteristics
General anxiety Beck Anxiety Inventory (BAI; Beck and Steer Self-rating scale
1993) 21 items, total score
Norms and cutoff
values
Hamilton Anxiety Scale (HAMA; Hamilton Observer-rating scale
1959) 13 symptom
complexes, total score
Reference scores
Agoraphobia/panic Agoraphobic Cognitions Questionnaire (ACQ; Self-rating scale
disorder Chambless et al. 1984) 15 items, total score
Norms and cutoff
values
Body Sensations Questionnaire (BSQ; Self-rating scale
Chambless et al. 1984) 18 items, total score
Norms and cutoff
values
Mobility Inventory for Agoraphobia (MI; Self-rating scale
Chambless et al. 1985) 27 items, total score
Norms and cutoff
values
Social phobia Social Phobia Inventory (SPIN; Conner et al. Self-rating scale
2000) 17 items, total score
Cutoff values
Liebowitz Social Anxiety Scale (LSAS; Observer-rating scale
Liebowitz 1987) 24 items, total score, 2
subscores
Cutoff values
Obsessive- Yale-Brown Obsessive Compulsive Scale Observer-rating scale
compulsive (Y-BOCS; Goodman et al. 1989) 19 items, 2 subscales,
disorder total score
Cutoff values

substance independent of the size of dosage administered (Harnisch et al. 2012), thus
indicating a clear causal relation. ARs therefore closely approximate what would
traditionally have been referred to as side effects.
Accurate assessment of AEs and ARs is decisive in the effective evaluation of
benefit and risk potentials of particular therapeutic measures. Assessment of AEs
tends to be restricted to medical therapies, while the practice of recording AEs or
ARs in the context of psychotherapeutic intervention remains in its infancy (see,
e.g., Linden 2013). A benefit-risk assessment is of particular importance in the
clinical development of pharmaceutical substances, especially during Phase II
and Phase III trials. Usually, this takes the form of group statistical comparisons
with placebos or a reference substance. The assessment of side effects continues
to play a pivotal role during later administration of a substance to individual
patients.
256 R.-D. Stieglitz and H.-P. Volz

It is thus all the more surprising to find that while there exist – at least in the
context of clinical studies – various conventions of assessing the efficacy of medical
substances (e.g., the Hamilton Depression Rating Scale or the Montgomery-Åsberg
Depression Rating Scale), there appears to be almost no consensus on how the
presence of AEs (or ARs) should be systematically ascertained.
Admittedly, it is far simpler to assess and classify AEs as ARs, since the causal
attributions which qualify AEs as ARs are relatively unreliable.

Chiefly, two methods are distinguished in the assessment of AEs:

1) On the one hand, patients are asked in an open question whether any AEs were
noticed. Where this is confirmed, further questions follow as to the nature of
these AEs, so they can be attributed to various organ classes based on a
universally applicable classification system. In some cases, assessment includes
the level of severity of AEs experienced. A system frequently applied to match
AEs to specific organ classes is the MedDRA-System (Medical Dictionary for
Regulatory Activities). MedDRA follows a multiaxial structure, in which a
preferred term (PT) may be matched to one or more System Organ Classes
(SOCs). However, in order to prevent double counting, every PT has a primary
allocation. MedDRA is hierarchically organized. The SOCs represent the
highest of five levels (i.e., the first level with 26 organ classes), with PTs
representing the fourth level. Based on this, tables are established (e.g., in
final reports on clinical trials) which comprise the SOCs (the first level) and,
for example, show individual AEs as PTs (fourth level) (thus, e.g., SOC = ner-
vous system, PT = headache).
This way of recording AEs may lead to instances of “underreporting” and AEs
being recorded to a lesser extent than actually present. Conversely, explicit
questioning as to AEs, or the use of rating scales, may lead to cases of “over-
reporting.” This dilemma remains unresolved.
2) Alternatively, systematic AE screening instruments are used. These, however, are
not available for every spectrum of side effects (exception the scale “Somatic
Symptoms” in the AMDP system; Stieglitz et al. 2017; Broome et al. 2018). The
best and most extensive rating scales are those designed to assess sexual dys-
functions and extrapyramidal motor symptoms (EPS) (after administration of
antipsychotic drugs). Both types of scales are investigated in more detail in the
following.

Scales for Measuring Sexual Functioning

The most commonly used scales in this area are summarized in Table 7.
The Arizona Sexual Experience Scale (ASEX). The ASEX (McGahuey et al.
2000) consists of five questions aiming at sexual interest, arousal, lubrification/
erection, orgasm, and satisfaction (Clayton 2001). The scale can be used in hetero-
or homosexual populations irrespective of the availability of a sexual partner. Global
Psychopathology: Rating Scales for the Assessment of Mental Status 257

Table 7 Comparison of assessment instruments for sexual functioning. (Adapted from Clayton
2001)
ASEX CFSQ-C DISF-SR RSI
No. of questions 5 14 25 29 M/18 F
<10 min Yes Yes No Yes
Validated Moderate Good Good Good
Measures change Yes Yes No Yes
Explicit/intrusive No No Yes Yes
Likert scale Yes Yes Yes Only 5 items
Abbreviations: ASEX arizona sexual experiences scale, CSFQ changes in sexual functioning
questionnaire, DISF-SR derogatis interview for sexual functioning-short report, RSI rush sexual
inventory

scores above 18 or single item scores above 4 indicate sexual dysfunction and may
be used to monitor change in function over time.
The Changes in Sexual Functioning Questionnaire-Clinical version (CSFQ-C).
The CSFQ-C (Clayton et al. 1997) uses 14 questions to measure sexual activity in five
domains: sexual pleasure, sexual desire/frequency, sexual desire/interest, arousal, and
orgasm (Clayton 2001). Since a definition of sexual activity (intercourse, masturbation,
sexual fantasy) is initially given, the patient is not required to report specific sexual
behaviors. Global scores below 48 for men and below 42 for women are indicative of
sexual dysfunction.
The Derogatis Interview for Sexual Functioning – Short Report (DISF-SR).
The DISF-SR (Derogatis 1997) measures quality of sexual functioning with 25
questions in 5 domains: sexual cognition, arousal, sexual behavior and experiences,
orgasm, and sexual drive (Clayton 2001). Questions aiming at frequency of specific
sexual behaviors might be perceived as intrusive by the patient.
The Rush Sexual Inventory (RSI). The RSI (Zajecka et al. 1997) measures
sexual functioning over time with 29 questions addressed to men and 18 questions to
women (Clayton 2001). Questions about the frequency of specific sexual behavior
may be perceived as intrusive. Five items use a visual analogue scale; the other items
require a yes/no answer.

Scales for Measuring Extrapyramidal Motor Side Effects (EPS)

A systematic literature overview (Knol et al. 2010) identified a total of 17 scales for
evaluating EPS. Table 8 contains a summary of the scales most used.
The Drug-Induced Extra Pyramidal Symptoms Scale (DIEPSS). The DIEPSS
(Knol et al. 2010; Inada et al. 1996, 2003) consists of nine items, five for parkin-
sonism and one each for akathisia, dystonia, dyskinesia, and severity. Items are
scored on a five-point scale. The scale showed good inter- and intrarater reliability.
The parkinsonism items show high agreement with the Simpson-Angus Scale
(SAS).
258 R.-D. Stieglitz and H.-P. Volz

Table 8 Comparison of assessment instruments for extrapyramidal symptoms. (EPS; adapted from
Knol et al. 2010)
DIP Manual Duration
Scale Total items Items available Scoring Interpretation [in mins]
DIEPSS 9 5 Yes Clear Clear ?
ESRS
Questionnaire 7 16 Yes Clear Unclear 15
complex
Examination 34
Global 4
impression
SAS 10 10 Yes Clear Clear 10
UKU
Single items 48 3 Yes Clear Unclear 30
complex
Global 2X2 (patient
assessment and physician)
BAR 4 0 Yes Clear Clear 5
complex
Abbreviations: BAR bar akathisia rating scale, DIEPSS drug-induced extra pyramidal symptoms
scale, DIP drug-induced parkinsonism, EPS extrapyramidal symptoms, ESRS extrapyramidal
symptom rating scale, SAS simpson angus scale, UKU udvalg for kliniske undersogelse

The Extrapyramidal Symptom Rating Scale (ESRS). The ESRS (Chouinard

and Margolese 2005) comprises eight items: a questionnaire, examination scales for
parkinsonism, dystonia, and dyskinesia and subscales for global impression of
severity of tardive dyskinesia, parkinsonism, dystonia, and akathisia. The interrater
reliability is good, the agreement between the ESRS and the Abnormal Involuntary
Movement Scale (AIMS) for dyskinesia is high, but, as Knol et al. (2010) report,
validity data for the other subscales including parkinsonism is lacking. The instru-
ment is highly complex, e.g., the rigidity in each limb and tremors in eight different
body areas including the amplitude must be assessed.
The Simpson Angus Scale (SAS). The SAS (Simpson and Angus 1970; Hawley
et al. 2003) is a scale with ten items measuring gait (hypokinesia, one item), rigidity
(6 items), and glabella tap, tremor, and salivation (one item each). The items are
scored on a five-point scale (0–4). The total score is the sum of the separate items
divided by 10; a total score higher than 0.3 indicates parkinsonism. The internal
consistency of the scale is good, as is its interrater reliability. Knol et al. (2010) note
that some items, such as the head drop item, are difficult to score.
The Udvalg for Kliniske Undersogelse (UKU). The UKU (Lingjaerde et al.
1987; Day et al. 1995) consists of 48 items scored on a four-point scale (0–3). It
comprises four categories: psychic (10 items), neurological (8 items including three
parkinsonism items), autonomic (11 items), and other adverse events (19 items). In
addition, both the patient and the physician score the extent to which AEs interfere
with daily living. As Knol et al. (2010) state, the results for interrater reliability are
divergent, and data about intrarater reliability and internal consistency are lacking.
Psychopathology: Rating Scales for the Assessment of Mental Status 259

The correlation between patient- and physician-rated AEs regarding parkinsonism

items is low.
The Barnes Akathisia Rating Scale (BARS). The BARS (Barnes 2003) is a
four-item scale with one objective and two subjective items assessed on a four-point
scale (0–3) and a Global Clinical Assessment of Akathisia scale (scored from 0–5).
Barnes (2003) confirms a high interrater reliability, while data for internal consis-
tency are lacking.

Other Domains

Besides the assessment of various aspects of psychopathology and side effects in the
context of psychopharmacology, assessing other domains, such as quality of life as
an additional outcome, is important. Again, there is now a wide variety of reliable
instruments available in this respect (cf. also Bech 1993). Depending on the nature of
a specific disorder, further domains require evaluation. With schizophrenia, for
example, important areas are cognitive functioning (e.g., Barnett et al. 2010) or
adherence or insight (e.g., Keefe 2012).

Ascertainment of Progression and Changes

Special rating scales to measure degrees of severity are particularly useful also for
the assessment of change. There are several options available, as shown in Table 9.
While therapy response is traditionally defined as a 50% decrease in the score
from baseline of a rating scale, increasingly complex and demanding approaches are
coming into use. Some of these are briefly discussed below, in particular the concept
of clinical significance and ways to operationalize remission and recovery.

Table 9 Proposals for outcome criteria

Criteria Definition Example
% reduction Reduction in relation to baseline or 50% reduction Hamilton
previous assessment depression rating scale (HDRS)
Cutoff value Below or above a defined value 1 or 2 in the clinical global
impressions (CGI; scale
“improvement”)
Diagnosis at Patient no longer meets the criteria for the Criteria for severe depressive
discharge disorder episode in ICD-10
Functional Clinical decision based on functional Discharge, therapy success
criteria criteria
Normalization Return to the previous functional level, or T score < 60 in the symptom
patient falls within the range of a normal checklist (SCL-90 R)
group
Clinical Statistically reliable change and patient MADRS <5 and difference
significance falls within the range of a normal group between pre- and post-test
score  6 points
260 R.-D. Stieglitz and H.-P. Volz

The concept of clinical significance is based on the following two premises:

• A change is regarded as reliable only on condition that it is significantly greater

than a chance occurrence (i.e., a statistically reliable change).
• A change, furthermore, is regarded as relevant only on condition that it is of
clinical relevance, that is, if at therapy-end the patient’s score in a particular rating
scale falls within the range of a normal group (change from a dysfunctional to a
functional level).

Where both these requirements are met, a clinically significant change is deemed
to have occurred (cf. Ogles 2013). Unfortunately, this rather conservative approach
to evaluating therapy success has hitherto found little application in research.
There are numerous suggestions for ways to approach the operationalization of
response or remission, some of which are briefly outlined here:

• Based on the HDRS, O’Donavan (2004) attempts to define response as well as

various parameters of disease progression in depression (cf. Table 10). This is
achieved through a percentile reduction of baseline scores and/or a definition of
cutoff values.
• For social phobias, Ballenger (1999) suggests various criteria for the definition of
remission not only in relation to different psychopathological aspects but also
functional impairment (cf. Table 11).
• In the context of schizophrenic disorders, differentiated response criteria based on
the Positive and Negative Syndrome Scale (PANSS) developed by Andreasen et
al. (2005) (cf. Table 12) are proposed for the first time. Symptoms screened for are
those of delusions, thought disorders, hallucinations, and affect/drive.

Table 10 Definitions of response, remission, and recovery based on the Hamilton Depression
Rating Scale. (HDRS; adapted from O’Donavan 2004)
Definition
Nonresponse 20% reduction
Partial response 21–49% reduction
Response 50% reduction
Residual symptoms Response and total score  8
Remission Response and total score  7
Recovery Remission and return of function

Table 11 Remission criteria for social phobia. (Adapted from Ballenger 1999)
Symptomatology Operationalization
Abolish core symptoms e.g., 70% improvement LSAS
Reduction anxiety e.g., HAMA 7–10
Reduction depression e.g., HAMD 7
Resolve functional impairments SDS  1 (mildly disabled)
LSAS liebowitz social anxiety scale, HAMA hamilton anxiety scale, HAMD hamilton depression
scale, SDS sheehan disability scale
Psychopathology: Rating Scales for the Assessment of Mental Status 261

Table 12 Remission criteria for schizophrenia based on the Positive and Negative Syndrome Scale
PANSS. (Adapted from Andreasen et al. 2005)
PANSS items all 3
P1 Delusions
G9 Unusual thought content
P3 Hallucinatory behavior
P2 Conceptual disorganization
G5 Mannerisms/posturing
N1 Blunted affect
N4 Social withdrawal
N6 Lack of spontaneity

Requirements for the Use of Interviews and Rating Scales

In respect of interviews and rating scales, a number of points demand careful

consideration. They are briefly outlined here as follows:

• Selection of instruments. Where the aim is not simply to rely on past recom-
mendations, a knowledge and understanding of the psychometric quality of
assessment instruments is mandatory in order to be able to evaluate these effec-
tively. Only an evaluation of available evidence as to the reliability and validity of
a chosen instrument allows for a valid decision on the appropriacy of the
instrument in a given case.
• Conducting the examination. Particularly in the context of interviews and
observer-rating scales, formal training and practical experience in the administra-
tion of specific instruments is an essential prerequisite. For this purpose, a number
of carefully designed concepts are available (e.g., Kobak et al. 2004, 2005). In
clinical practice, and to some extent also in research, the need for this indisputably
essential requirement fails to be adequately recognized. Especially in routine
clinical practice, screening procedures are being deployed by medical practi-
tioners who have undergone no formal training in their use and administration.
• Interpretation. The use of rating scales also requires at least a basic knowledge
of standardization methods (e.g., the significance of percentile ranks and T-
scores). As already outlined above, rating scale values alone are meaningless.
Only their evaluation in relation to benchmark values and reliable standards of
comparison allows for meaningful interpretation of scores attained.

Examples of Practical Application

For the purpose of illustrating their specific benefits, there follow some examples of
interviews and rating scales in practical application.

Example 1 Figure 1 demonstrates the use of two rating scales applied at various
points during therapy (here the BDI and the BRMS). At the start of therapy, the
262 R.-D. Stieglitz and H.-P. Volz

Cut-Off-Value
BDI
severe
SEVERITY

moderate

BRMS
mild

no depressive syndrome

1 4 6 8 12 14 16 18 end
Therapy in number of weeks

Fig. 1 Course of therapy: data obtained with the BDI and the BRMS

example shows relatively little agreement between respective scores of self- and
observer-rating scales. This is a widely observed phenomenon, and agreement
between both data sources usually improves only during the course of treatment. It
is further recognizable that at therapy-end, both rating scales provide equally clear
data in relation to therapy success (Möller 2009).

Example 2 Figure 2 illustrates a pre-post comparison of a schizophrenic patient

based on the AMDP-System (Broome et al. 2018; Stieglitz et al. 2017). The eight
syndromes allow for a clear representation of syndromes and their changes during
therapy. While at the start of in-patient treatment the productive symptoms clearly
dominate (e.g., high scores in the respective scales for paranoid-hallucinatory and
hostility syndromes), end-of-therapy scores indicate distinct changes in these areas,
with negative symptoms clearly becoming more pronounced, as is to be expected
(high score value for apathy syndrome).

Example 3 Adli et al. (2002) demonstrated the usefulness of rating scales in

reaching concrete therapy decisions by developing a therapy algorithm for
pharmacotherapy in depressive disorders. They define a therapy algorithm as a
systematic progression of therapy strategies, usually in sequential order in the
form of an operationalized, staged treatment plan. Essential elements of therapy
algorithms are a previously defined therapy aim and the standardized evaluation
of therapy success (mostly by means of rating scales). In the context of their
standardized stepwise drug treatment regimen algorithm of depressive disorders,
the Bech-Rafaelsen Melancholia Scale (BRMS) was used as a decision criterion for
whether to continue or change the course of therapy. Patient response to the chosen
pharmacological treatment in each case (with fortnightly evaluations) was defined as
follows:
Psychopathology: Rating Scales for the Assessment of Mental Status 263

80

70

60

50
T-Score

40
Discharge
30
Admission
20

10

0
ParHal Depres Psyorg Mani Host Veget Apa Obs

Fig. 2 AMDP syndrome profiles: schizophrenic patient at admission and discharge

• Remission: BRMS score value  5

• No response: BRMS symptom reduction 25%
• Partial response: BRMS symptom reduction 26%

Conclusion and Perspectives

In the context of psychopharmacotherapy for psychiatric disorders, both clinicians

and researchers now have a broad spectrum of well-established and psychometri-
cally sound screening instruments at their disposal. With the help of interviews for
classificatory diagnosis, it has become possible to establish reliable diagnoses in
terms of ICD-10 and DSM-IV/ 5. Rating scales serve above all to measure the
degree of severity of syndromes and to record other clinically significant domains
(e.g., side effects, quality of life). In respect of the classification of psychopathology,
studies have shown that the use of a combination of self- and observer-rating scales
represents a sensible approach.
However, despite the considerable advances made in recent years, there remain a
number of weaknesses:

• In clinical practice, and especially in research, instruments of questionable

psychometric quality remain in persistent use (e.g., the HDRS as a gold standard
in research into depression).
• Instruments based on an explicit theoretical foundation are still the exception.
• The point made above regarding the absence of an explicit theoretical foundation
applies equally in the case of procedures developed in conjunction with a specific
therapy.
264 R.-D. Stieglitz and H.-P. Volz

• At the level of test theory, no approaches to measuring change exist which are
included in the construction of scales. Another point of concern is the fact that
classical test theory, which forms the basis for all scale development, offers
no scope for weighting symptoms differently. As a result, symptoms such as
disturbed concentration and suicidal behavior are afforded equal weight in the
sum score of a scale.
• For certain domains, there remains a continued shortage of suitable instruments
(e.g., for the assessment of compliance).
• Another general deficiency in the field of diagnosis is the absence of approaches
to evidence based assessment (EBA; Hunsley and Mash 2007; analogous to
evidence based medicine) as well as the lack of explicit guidelines for diagnosing
psychiatric disorders at syndrome and categorical levels.

References
Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. Schizophr Res.
1990;3:247–51.
Adli M, Berghöfer A, Linden M, Helmchen H, Müller-Oerlinghausen B, Mackert A, Stamm T.
Bauer, M. Effectiveness and feasibility of a standardized stepwise drug treatment regimen
algorithm for inpatients with depressive disorders: Results of a 2-year observational algorithm
study. J Cin Psychiatry; 2002;63:782–790.
Aitken RCB. Measuring of feelings using analogue scales. Proc R Soc Med. 1969;62:989–993.
AMDP, CIPS. Rating scales for psychiatry. Weinheim: Beltz; 1990.
Andreasen NC. Scale for the assessment of negative symptoms (SANS). Iowa City: University of
Iowa; 1981.
Andreasen NC. Scale for the assessment of positive symptoms (SAPS). Iowa City: University of
Iowa; 1984.
Andreasen NC, Carpenter WT, Kane JM, et al. Remission in schizophrenia: proposed criteria and
rational for consens. Am J Psychiatry. 2005;162:441–9.
Angst J, Bech P, Boyer P, Bruinvels J, Engel R, Helmchen H, Hippius H, Lingjaerde O, Racagni G,
Saletu B, Sedvall G, Silverstone JT, Stefanis CN, Stoll K, Woggon B. Consensus conference
on the methodology of clinical trials of antidepressants, Zurich, march 1988: report of the
consensus committee. Pharmacopsychiat. 1989;22:3–7.
Angst J, Bech P, Bobon D, Engel R, Hippius H, Janzen GJ, Lecrubier Y, Lingjaerde O, Möller HJ,
Montgomery SA, Paes de Sousa M, Rossi A, Saletu B, Sedvall G, Stefanis C, Stoll KD, Woggon
B. Report on the third consensus conference on the methodology of clinical trials with
antipsychotic drugs. Pharmacopsychiat. 1991;24:149–52.
Angst J, Bech P, Bruinvels J, Engel RR, Ferner U, Guelfi JD, Lingjaerde O, Müller-Oerlinghausen
B, Paes de Sousa M, Paykel E, Rimon R, Rzewuska M, Saletu B, Spiegel R, Stassen HH, Stoll
KD, Wiesel FA, Woggon B, Zvolsky P. Report on the fifth consensus conference: methodology
of long-term clinical trials in psychiatry. Pharmacopsychiat. 1994;27:101–7.
Antony MM, Barlow DH, editors. Handbook of assessment and treatment planning for
psychological disorders. 2nd ed. New York: Guilford; 2010.
Ayearst LE, Bagby RM. Evaluating the psychometric properties of psychological measures.
In: Antony MM, Barlow DH, editors. Handbook of assessment and treatment planning for
psychological disorders. 2nd ed. New York: Guilford; 2010. p. 23–61.
Ballenger JC. Clinical guidelines for establishing remission in patients with depression and anxiety.
J Clin Psychiatry. 1999;50(suppl 22):29–34.
Barnes TR. The Barnes akathisia rating scale – revisited. J Psychopharmacol. 2003;17:365–70.
Barnett JH, Eobbins TW, Leeson VC, Sahakian BJ, Joyce EM, Blackwell AD. Assessing cognitive
function in clinical trials of schizophrenia. Neurosci Biobehav R. 2010;34:1161–77.
Psychopathology: Rating Scales for the Assessment of Mental Status 265

Bech P. Rating scales for psychopathology, health status and quality of life. Berlin: Springer; 1993.
Bech P, Rafaelsen OJ. The melancholia scale: development, consistency, validity and utility. In:
Sartorius N, Ban TA, editors. Assessment of depression. Berlin: Springer; 1986. p. 259–69.
Bech P, Rafaelsen OJ, Kramp P, Bolwig TG. The mania rating scale: scale construction and inter-
observer agreement. Neuropharmacology. 1978;17:430–1.
Bech P, Rasmussen NA, Olsen LR, Noerholm V, Abildgaard W. The sensitivity and specificity of
the major depression inventory, using the present state examination as the index of diagnostic
validity. J Affect Dis. 2001;66:159–64.
Beck AT, Steer RA. Beck anxiety inventory manual. San Antonio: The Psychological Corporation;
1993.
Beck AT, Steer RA, Brown GK. Beck depression inventory-II (BDI-II). San Antonio: Psychological
Corporation; 1996.
Broome MR, Bottlender R, Rösler M, Stieglitz RD. The AMDP system. Manual for the assessment
and documentation of psychopathology in psychiatry 9th ed. Göttingen: Hogrefe; 2018.
Brown TA, Barlow DH. Anxiety and related disorders interview schedule for DSM-5 (ADIS-5) –
adult version. New York: Oxford University Press; 2014.
Chambless DL, Caputo GC, Bright P, Gallagher R. Assessment of fear in agoraphobics: the body
sensations questionnaire and the agoraphobic cognition questionnaire. J Consult Clin Psychol.
1984;52:1090–7.
Chambless DL, Caputo GC, Jasin FE, Gracley EJ, Williams C. The mobility inventory for
agoraphobia. Behav Res Ther. 1985;23:35–44.
Chouinard G, Margolese HC. Manual for the extrapyramidal symptom rating scale (ESRS).
Schizophr Res. 2005;76:247–65.
Clayton AH. Recognition and assessment of sexual dysfunction associated with depression. J Clin
Psychiatry. 2001;62(Suppl 3):5–9.
Clayton AH, McGarvey EL, Clavet GJ. The changes in sexual functioning questionnaire (CSFQ):
development, reliability, and validity. Psychopharmacol Bull. 1997;33:731–45.
Conner KM, Davidson JRT, Churchill LE, Sherwood A, Foa E, Weisler RH. Psychomatric
properties of the social phobia inventory (SPIN): a new self-rating scale. Br J Psychiatry.
2000;176:379–86.
Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item
Edingurgh postnatal depression scale. Br J Psychiatry. 1987;150:782–6.
Day JC, Wood G, Dewey M, Bentall RP. A self-rating scale for measuring neuroleptic side-effects.
Validation in a group of schizophrenic patients. Br J Psychiatry. 1995;166:650–3.
Derogatis LR. SCL-90-R, administration, scoring & procedures manual-II for the R(evised)
version and other instruments of the psychopathology rating scales series. Towson: Clinical
Psychometric Research; 1994.
Derogatis LR. The Derogatis interview for sexual functioning (DISF/DISF-SR): an introductory
report. J Sex Marital Ther. 1997;23:291–304.
First MB, Williams JBW, Karg RS, Spitzer RL. Structured clinical interview for DSM-5©
disorders – clinical version (SCID-5-CV). Washington, DC: American Psychiatric Associa-
tion; 2016a.
First MB, Williams JBW, Smith Benjamin L, Spitzer RL. Structured clinical interview for DSM-5©
disorders – personality disorders (SCID-5-PD). Washington, DC: American Psychiatric
Association; 2016b.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR,
Charney DS. The Yale-Brown obsessive compulsive scale. I. Development, use, and reliability.
Arch Gen Psychiatr. 1989;46:1006–11.
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50–5.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23(1):56–62.
Harnisch S, Schade-Brittinger S, Rief W. Assessing adverse reactions in clinical trials [Deutsch].
Dtsch Med Wochenschr. 2012;137:1421–5.
Hawley C, Fineberg N, Roberts A, Baldwin D, Sahadevan A, Sharman V. The use of the Simpson
Angus scale for the assessment of movement disorder: a training guide. Int J Psychiatry Clin
Pract. 2003;7:349–2257.
266 R.-D. Stieglitz and H.-P. Volz

Honigfeld G, Gillis RD, Klett JC. NOSIE. Nurses‘ observation scale for inpatient evaluation. In:
Guy W, editor. ECDEU assessment manual for psychopharmacology (rev.ed.). Rockville:
National Institute of Mental Health; 1976. p. 265–73.
Hunsley J, Mash EJ. Evidence-based assessment. Ann Rev Clin Psychol. 2007;3:29–51.
Inada T, Yagi G, Gardos G. Inter-rater reliability and the drug-induced-extrapyramidal symptoms
scale (DIEPSS). Eur Neuropsychopharmacol. 1996;6:62.
Inada T, Beasley CM Jr, Tanaka Y, Walker DJ. Extrapyramidal symptom profiles assessed with the
drug-induced extrapyramidal symptom scale: comparison with western scales in the clinical
double-blind studies of schizophrenic patients treated with either olanzapine or haloperidol. Int
Clin Psychopharmacol. 2003;18:39–48.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANNS) for schizo-
phrenia. Schiz Bull. 1987;13:261–76.
Keefe R. Assessment scales in schizophrenia. London: Springer Health Care; 2012.
Kessler RC, Ustün TB. The World Mental Health (WMH) Survey Initiative Version of the World
Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Int J
Methods Psychiatr Res. 2004;13:93–121.
Knol W, Keijsers CJ, Jansen PA, van Marum RJ. Systematic evaluation of rating scales for drug-
induced parkinsonism and recommendations for future research. J Clin Psychopharmacol.
2010;30:57–63.
Kobak KA, Engelhardt N, Williams JBW, Lipsitz JD. Rater training in multicenter clinicla trials:
issues and recommendations. J Clin Psychopharmacol. 2004;24:113–7.
Kobak KA, Lipsitz JD, Williams JBW, Engelhardt N, Bellew KM. A new approach to rater training
and certification in a multicenter clinical trial. J Clin Psychopharmacol. 2005;25:407–12.
Liebowitz MR. Social phobia. Mod Probl Pharmacopsychiatry. 1987;22:141–73.
Linden M. How to define, find and classify side effects in psychotherapy: from unwanted events to
adverse treatment reactions. Clin Psychol Psychother. 2013;20:286–96.
Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new
comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in
neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1–100.
Lorr M, Klett JC. Inpatient multidimensional psychiatric scale (IMPS). Manual. Palo ALTO:
Consulting Psychologists Press; 1967.
Mason BJ, Kocsis JH, Leon AC, et al. Measurement of severity and treatment response in
dysthymia. Psychiatic Ann. 1993;23:625–31.
McGahuey CA, Gelenberg AJ, Laukes CA, Moreno FA, Delgado PL, McKnight KM, Manber R.
The Arizona sexual experience scale (ASEX): reliability and validity. J Sex Marital Ther.
2000;26:25–40.
McNair DM, Lorr M, Droppleman LF. Manual for the profile of mood sates (POMS). San Diego:
Educational Testing Services; 1971.
Möller HJ. Standard rating scales in psychiatry: methodological basis, their possibilities and
limitations and description of important rating scales. World J Biol Psychiatry. 2009;10:6–26.
Montgomery SA, Åsberg M. A new depression rating scale designed to be sensitive to change.
Br J Psychiatry. 1979;134:382–9.
O’Donavan C. Achieving and sustaining remission in depression and anxiety disorder: introduc-
tion. Can J Psychiatr. 2004;49(suppl. 1):5–9.
Ogles BM. Measuring change in psychotherapy research. In: Lambert MJ, editor. Handbook of
psychotherapy and behavior change. 6th ed. New York: Wiley; 2013. p. 134–66.
Olsen LR, Jensen DV, Noerholm V, Martiny K, Bech P. The internal and external validity of the
major depression inventory in measuring severity of depressive states. Psychol Med.
2003;33:351–6.
Østergaard SD, Bech P, Trivedi MH, Wisniewski SR, Rush AJ, Fava M. Brief, unidimensional
melancholia rating scales are highly sensitive to the effect of citalopram and may be have
biological validity: implications for the research domain criteria (RDoC). J Affect Dis.
2014;163:18–24.
Psychopathology: Rating Scales for the Assessment of Mental Status 267

Overall JE, Gorham DR. 047 BPRS. Brief psychiatric rating scale. In: Guy W, editor. ECDEU
assessment manual for psychopharmacology (rev.ed.). Rockville: National Institute of Mental
Health; 1976. p. 157–69.
Rush AJ, First MB, Blacker D. Handbook of psychiatric measures. 2nd ed. Washington, DC:
American Psychiatric Association; 2010.
Schennach R, Obermeier M, Seemüller F, Jäger M, Schmauss M, Laux G, Pfeiffer H, Naber D,
Schmidt LG, Gaebel W, Klosterkötter J, Heuser I, Maier W, Lemke MR, Rüther E, Klingberg S,
Gastpar M, Riedel M, Möller HJ. Evaluating depressive symptoms in schizophrenia: a
psychometric comparison of the Calgary depression scale for schizophrenia and the Hamilton
depression rating scale. Psychopathology. 2012;45:276–85.
Sheehan DV. The anxiety disease. New York: Charles Scribner & Sons; 1983.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R,
Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development
and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin
Psychiatry. 1998;59(Suppl 20):22–33.
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand
Suppl. 1970;212:11–9.
Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the
assessment of hedonic tone the Snaith-Hamilton pleasure scale. Br J Psychiatry.
1995;167:99–103.
Stieglitz RD. Multimodal assessment (including triangulation). In: Fernandez-Ballesteros R, editor.
Encyclopedia of psychological assessment. London: Sage; 2003. p. 606–10.
Stieglitz RD, Haug A, Fähndrich E, Rösler M, Trabert W. Comprehensive psychopathological
assessment based on the Association for Methodology and Documentation in Psychiatry,
(AMDP) system: development. Methodological foundation, application in clinical routine,
and research. Front Psych. 2017;8:45. https://doi.org/10.33389/fpsyt.2017.00045.
van Riezen H, Segal M. Comparative evaluation of rating scales for clinical psychopharmacology.
Amsterdam: Elsevier; 1988; 1988
Ventura J, Lukoff D, Nuechterlein KH, Liberman RP, Green MF, Shaner A. Brief Psychiatric Rating
Scale (BPRS) expanded version (4.0): scales, anchor points, and administration manual. Int J
Methods Psych Res. 1993;3:227–43.
Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R, Jablenski A, Regier D, Sartorius N.
SCAN. Schedules for clinical assessment in neuropsychiatry. Arch Gen Psychiatry.
1990;47:589–93.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and
sensitivity. Br J Psychiatry. 1978;133:429–35.
Zajecka J, Mitchell S, Fawcett J. Treatment-emergent changes in sexual function with selective
serotonin reuptake inhibitors as measured with the Rush sexual inventory. Psychopharmacol
Bull. 1997;33:755–60.
Xenobiotic Interactions in
Psychopharmacotherapy: Classification and
Handling

Ekkehard Haen

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
Xenobiotic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
Potentially Inadequate Medication (PIM), Potentially Inadequate Prescription (PIP) . . . . . . . . . 272
Classification of Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Pharmacodynamic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Pharmacokinetic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
PD1 Interactions (So-Called “Double Prescriptions”) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
PD2 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
PD3 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
PD4 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
PK1 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
PK2 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
PK3 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
PK3c Interactions: Prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
Number of Potential Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
How to Handle Xenobiotic Interactions? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Data Bases to Check a Medication for Risk of Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Drug Information Services (AID) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
Therapeutic Drug Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
The Clinical Pharmacological TDM Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
KONBEST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
AMBEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

E. Haen (*)
Clinical Pharmacology, Institut AGATE gGmbH Pentling, Pentling, Germany
Department of Psychiatry and Psychotherapy, Department of Pharmacology and Toxicology,
University of Regensburg, Regensburg, Germany
e-mail: ekkehard.haen@klinik.uni-regensburg.de

© Springer Nature Switzerland AG 2022 269

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_10
270 E. Haen

Abstract
Drug-drug-interactions (DDI) are a major topic in programs for continuous
medical education (CME). Lectures on this topic usually attract a great audience.
Many physicians are afraid of being trapped in charges with malpractice. The idea
that a drug-drug interaction is evidence of medical malpractice supports this
notion. Some computer databases accessible via internet feed this anxiety by
presenting a red exclamation mark if a “drug-drug interaction” is detected in a
patient’s medication. Even worse is to categorize this warning like a traffic light.
The medical problem is not the drug-drug interaction (DDI) but the adverse drug
effect (ADE) that arises from a drug-drug interaction in the individual patient!
DDI belong to routine medical practice, and it is often impossible to avoid them.
Moreover, they do not just occur between drugs but between any kind of foreign
substances (xenobiotica), such as food as well as legal (tobacco smoke, caffeine,
alcohol) and illegal drugs. Therefore, the medical challenge is not to just avoid
any interaction. Instead, the physician faces the question how to proceed with
drug treatment in the presence of such interactions. Based on their medical
education, the physician has to judge first of all by themself whether there is a
risk for interactions in the prescription they are planning for an individual patient.
The classification of interactions into just seven categories proposed in this
chapter might hereby help as a sort of checklist. For information that is more
detailed, the physician can then consult one of the databases that address the risk
for ADE, such as PSIAC (www.psiac.de) or MediQ (www.mediq.ch). Pharma-
cokinetic interactions may be easily assessed, monitored, and controlled by
therapeutic drug monitoring (TDM). Besides these tools, it is important to keep
in mind that nobody knows everything; even physicians do not know everything.
So take pride in asking someone who might help. For this purpose, AGATE offers
its drug information service AID (www.amuep-agate.de). Just good for nothing
are computer programs without any kind of medical basis that judge prescriptions
without taking into account a patient’s individual peculiarities. In case these types
of programs produce red exclamation marks or traffic lights to underline their
judgment, they might even work contrapuntal by just eliciting insecurity and
terror.

Introduction

“Drug-Drug Interactions” (DDI) is a very exciting and in many instances and for
many persons alarming topic. Lectures on this topic usually attract a great audience.
Physicians are afraid one of their patients might be harmfully caught by a drug-drug
interaction. The idea that a drug-drug interaction is evidence of medical malpractice
supports this notion. Computer databases accessible via Internet feed this anxiety by
presenting a red exclamation mark if a drug-drug interaction is detected in a patient’s
medication. Even worse is to categorize this warning like a traffic light without
taking into account specific aspects of the individual case: Red ¼ risk of a very
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 271

severe drug-drug interaction, yellow ¼ risk of a moderate drug-drug interaction, and

green ¼ no risk. Lectures on drug-drug interactions thrill their audience by compil-
ing frightening examples of what has already happened. People leave these types of
“sex-and-crime” lectures shaking their heads, because it is impossible to keep in
mind all these examples, and hoping nothing will occur in their own daily routine.
In fact we are talking about “normal” medical routine. Very often a physician
cannot avoid drug-drug interactions: As soon as she or he prescribes more than just
one drug a DDI is inevitable. The number of mathematically (i.e., theoretically)
possible DDI follows the binomial formula shown in Fig. 1 and increases with the
number of prescribed drugs (better “applied” drugs, since people consume numerous
drugs that they obtain by themselves without medical prescriptions!). However, a
drug-drug interaction is not automatically medical malpractice; sometimes it might
even support an effective drug therapy. Moreover, a drug-drug interaction cannot be
“severe” in itself: It is the adverse drug effect (ADE) caused by a drug-drug
interaction that might be “severe.” In addition, whether this ADE is “severe” or
not depends on the individual patient: A weak, premorbid individual might suffer a
lot, and his life might even be endangered; on the other hand a young, strong patient

2018
14 (91)
13
12 i = (n2-n)/2 (66)
number of prescribed drugs

11 (55)
10 (45)
9 (36)
8 (28)
7 (21)
6 (15)
5 (10)
4 ( 6)
3 ( 3)
2 ( 1)
1 (0)
0
0 5 10 15 20 25
proportion of patients [%]

Fig. 1 Number of drugs (psychopharmaca as well as non-psychopharmaca) prescribed to schizo-

phrenic (F2x) patients in AGATE institutions in 2018. Data were collected from n ¼ 319 patients on
the two index days in spring and fall. The numbers in parenthesis give the theoretically (i.e.,
mathematically) possible interaction between the prescribed drugs calculated by the binominal
formula
272 E. Haen

might not be at risk at all by the same DDI. This chapter is intended to explain the
facts, to organize all occurring drug-drug interactions into just seven different
categories, and to compile recommendations on how to handle interactions.

Xenobiotic Interactions

To begin with, it has to be stated that the term “drug-drug interaction” is incorrect.
The body does not care, whether a foreign substance (i.e., a “xenobiotic”) adminis-
tered into the body, is intended

• To cure diseases or to alleviate symptoms (i.e., a “medicine,” e.g., a

psychopharmacon, an antihypertensive drug etc.)
• To deliver energy, fluid and/or components of body structures (i.e., “food,” e.g.,
barbecued meat, broccoli, grapefruit juice etc.)
• To evoke or increase good feelings (“legal or illegal drugs” such as alcohol,
tobacco smoking, caffeine, cannabis etc.)

The body treats all of these substances in the same way; all of them therefore give
rise to interactions. Consequently, the correct term is “interaction among xenobi-
otics” or “xenobiotic interactions.”
One fascinating aspect of psychopharmacology is that patients suffering from a
psychiatric disease also suffer from all diseases the apparently sane population can
suffer as well. So, a psychopharmacologist must not be familiar with just
psychopharmaca but with all other pharmaca, too.

Potentially Inadequate Medication (PIM), Potentially Inadequate

Prescription (PIP)

If the potential risk of a medication outweighs its potential benefit, it is by definition

a “potentially inadequate medication” (PIM) or a “potentially inadequate prescrip-
tion” (PIP) (Nobili et al. 2012). Unfortunately, the prescription of PIM is rather the
rule than the exception in drug therapy in various countries. The prevalence ranges
from 15 to almost 50% of the evaluated medications depending on the studied
healthcare setting (general practice, ambulatories, nursing homes, or hospitals) and
country (van der Hooft et al. 2005; Barry et al. 2006; Maio et al. 2006, 2010; Johnell
et al. 2007; Hosia-Randell et al. 2008; Prudent et al. 2008; Corsonello et al. 2009).
By far the most often prescribed PIM are “PID” (potentially inadequate drugs), risky
drugs that may be easily avoided by safer alternatives. Other PIM are mistakes in use
(see below). The most often prescribed PID in studies were certain psychopharmaca
(antidepressants, antipsychotics, sedative drugs) and cardiovascular drugs (Thiem
2012; Thiem et al. 2011). For years now, there are lists of drugs compiled by
international experts who dissuade from prescribing (e.g., The 2019 American
Geriatrics Society Beers Criteria ® Update Expert Panel 2019). The PRISCUS list,
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 273

for example, contains 83 such active substances available on the German drug
market with a particular risk for people >65 years of age (Holt et al. 2010). These
lists can be easily integrated in computer software to warn a prescribing physician;
however, neither the lists nor the respective software addresses the individual case.
The following classification of PIM has been suggested in 2018 (Haen et al.
2018a), prescriptions bearing a risk for xenobiotic interactions are potentially inad-
equate medications of type 7 (PIM7):

• PIM1: Drugs that should be prescribed only under supervision because of

known health risks (PID 1).
• PIM2: Drugs that may be prescribed if necessary in an individual case in spite of
known health risks (PID 2).
• PIM3: Drugs that should be avoided in any case because the potential risks
endanger the patients (PID 3).

Other medication errors are classified as PIM even if the drugs itself have a
positive risk-benefit evaluation when properly used:

• PIM4: Inappropriate duration of use: Drugs are prescribed not long enough to
become effective or longer than necessary (e.g., antidepressants for one week or
less, benzodiazepines for weeks).
• PIM5: inappropriate application (e.g., certain penicillins per os) or inappropriate
route of administration (e.g., sustained-release capsules for patients with prob-
lems in swallowing).
• PIM6: Underdosing/overdosing: The drug should be applied in a dosage or
frequency to bring the concentration in the individual patient over the lower limit
but not over the upper limit of the therapeutic reference range (TRR) (Hiemke
et al. 2017).
• PIM7: Xenobiotic interaction. Prescriptions bearing a risk for xenobiotic inter-
actions. To this type of PIM also belong “double prescriptions,” that is, the
prescription of two pharmacologically identical drugs (pharmacodynamics inter-
action type PD1, see below).
• PIM8: Contraindication: A drug with an otherwise positive risk-benefit evalu-
ation is inappropriate in certain conditions (e.g., pregnancy, young or old age,
certain comorbidities).
• PIM9: Cascades of polypharmacy: A drug is not recognized as cause of an ADE
and a new drug is prescribed against the new complain again with other health
risks.

Classification of Interactions

Xenobiotic interactions are one out of these nine classes of potentially inappropriate
medications (PIM7). The huge number of theoretically (i.e., mathematically) possi-
ble interactions and the often frightening stories of what might happen can be cut
274 E. Haen

down to just seven classes of interactions according to their pharmacological

mechanism (Fig. 2) (Haen 2014).
First, we have to distinguish between pharmacodynamic (PD, interaction at the
level of pharmacological effects) and pharmacokinetic (PK, interaction during
passage of the substances though the body) interactions. Then, there are four classes
of pharmacodynamic (PD1 to PD4) and three classes of pharmacokinetic (PK1 to
PK3) interactions, some of them subdivided by “a” (increase in clinical effective-
ness) and “b” (decrease in clinical effectiveness). A special subclass has to be added
for prodrugs (PK3c) subdivided by “+” (increase in clinical effectiveness) and “”
(decrease in clinical effectiveness).

a
pharmacodynamic pharmacokinetic

Similar drugs Interaction at

absorption

Interaction Interaction at
at the receptor distribution

Similar effects
Interaction at
elimination
Interaction
of different effects and metabolism
(prodrugs)

b
pharmacodynamic pharmacokinetic

a
PD1 PK1
b
a
PD2 PK2
b
a
PD3
b a
PK3
b
PD4 +
Prodrugs c
-

Fig. 2 Classification of xenobiotic interactions according to their pharmacological mechanism

here further elaborated based on an earlier suggestion (Haen 2014). (a) Description, (b) Classifica-
tion. a and +: increase in clinical effectiveness, b and : decrease in clinical effectiveness
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 275

Pharmacodynamic Interactions

• PD1: Pharmacodynamically identical, but chemically different active substances

have the same desired as well as adverse effects, which add to each other (additive
effects, double prescription). They are marketed for completely different
indications.
• PD2: Pharmacodynamically active substances use the same pharmacological
mechanism as agonists or antagonists. Desired (DDE) as well as adverse drug
effects (ADE) may be additively increased or potentiated (PD2a) or decreased
(PD2b).
• PD3: Pharmacodynamically active substances exert their effects via different
pharmacological mechanism on the same body function. Desired (DDE) as well
as adverse drug effects (ADE) may be additively increased or potentiated (PD3a)
or decreased (PD3b).
• PD4: Pharmacodynamically active substances have different effects. The sub-
stances do not interact by themselves but on the level of their effects. An adverse
drug effect (ADE) might be increased or this mechanism give rise to new ADE.

Pharmacokinetic Interactions

• PK1: Interaction during absorption. Desired (DDE) as well as adverse drug

effects (ADE) may be increased (PK1a) or decreased (PK1b).
• PK2: Interaction in distribution.
• PK3: Interaction during metabolism and excretion. Desired (DDE) as well as
adverse drug effects (ADE) may be increased (PK3a) or decreased (PK3b).
– PK3c: The substance applied is a so called “prodrug”: The active substance is
formed as metabolite in the body. Desired (DDE) as well as adverse drug
effects (ADE) may be increased by enzyme induction (PK3c+) or decreased by
enzyme inhibition (PK3c).

PD1 Interactions (So-Called “Double Prescriptions”)

The interaction of pharmacodynamically identical active substances appears very

easily to identify and to avoid. However, it is a huge problem in clinically routine,
because

• The active substances bear different names (INN, international non-proprietary

names).
• The respective commercial products are licensed for different clinical indications.
• The medications are prescribed by different physicians or medical specialists who
treat the same patient but do not pay enough attention to their interdisciplinary
communication. The body, however, does not care for the medical license or the
reason why a xenobiotic enters.
276 E. Haen

A psychopharmacologically relevant example is the prescription of several ben-

zodiazepines outlined in an earlier publication (Haen 2014, 2018a): Lorazepam was
prescribed because of anxiety disorder, lormetazepam because of sleeping disorders,
and oxazepam because of muscle tension. In spite of the fact that each medical
discipline seems to have their own favorite benzodiazepine (e.g., psychiatry loraz-
epam, neurology clonazepam, etc.) there are no clinically relevant pharmacody-
namic differences (i.e., DDE and ADE) between benzodiazepines. The patient in the
case was admitted for “lorazepam detoxication” not for benzodiazepine
detoxication.
Another example of PD1 interactions is the prescription of various methylxan-
thines (Fig. 3): Many people use caffeine as a legal drug to fight sedation, fatigue,
and sleepiness. It is both a component of caffeinated drinks (like coffee, tea,
chocolate, and power drinks like, e.g., “Red Bull”) and it can be prescribed medi-
cally as central stimulant or as a component of analgesics. Theophylline is used as a
bronchodilator today preferably in chronic bronchitis, but still sometimes in asthma,
too. Pentoxifylline, finally, is prescribed against inhibition of circulation in periph-
eral arteries (peripheral artery disease). In spite of intense efforts to separate desired
effects of methylxanthines from their adverse effects in the 80-ties of the last century,
these studies did not lead to any clinically relevant developments (Haen and
Emslander 1989). All known methylxanthines cause more or less the same adverse
drug effects that become additive if prescribed in comedication: gastrointestinal
pain, diarrhea, tachycardia, tremor, headache, sleepiness, and epileptic seizures.
The problem in clinical routine is that literally nobody has any idea of the caffeine
concentration in an individual patient that arises due to the daily alimentary use of
caffeinated beverages. We had a chance to measure caffeine in six individuals that
participated in a small bioequivalence study set up to compare theophylline prepa-
rations (Fig. 4). The caffeine concentrations show a marked circadian pattern:
Caffeine concentrations are particular high during morning and early afternoon

Fig. 3 Example of “similar

drugs,” type PD1 interaction.
The indication is given
licensed in most states for
pharmaceuticals containing caffeine central stimulant
the particular drug

theophylline bronchodilatator

pentoxifylline disturbed circulation

Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 277

15

12
caffeine concentration (µg / ml)

0
8 12 16 20 24 4 8
time of day (clock hours)

Fig. 4 Caffeine concentration in plasma of six healthy subjects. Blood was drawn every 4 h for
24 h. (Reproduced with permission from Haen E, Frankewitsch T, Decker W, Fichtl B, Emslander
HP (1991): Plasmakonzentrationen von Methylxanthinen unter Therapie mit Theophyllin bei
chronisch-obstruktiven Atemwegserkrankungen. Atemw.-Lungenkrkh. 17, 421–423, permission
granted by Jörg Feistle, Dustri-Verlag Dr. Karl Feistle GmbH & Co. KG, 19.10.2020)

hours after people usually had their caffeinated beverages for breakfast and at lunch
time. It is not surprising that the interindividual variation is huge, there are subjects
with very high caffeine concentrations and others with almost no caffeine in their
blood. However, because of its pharmacological effects, it is important for clinical
routine to pay attention to the caffeine concentration in each individual caffeine
consumer.
A third example of PD1 interactions is the prescription of sulphonamides against
microbial infections in combination with antidiabetics. The potential of
sulphonamides to decrease blood sugar was discovered by alerted physicians in
the early fifties who noticed hypoglycemia in patients they treated for bacterial
infections. This led to the development of sulphonyl urea derivatives as oral antidi-
abetics. Today the prescription of sulphonamides is rather rare because better
effective and tolerable drugs are available. Sulphonamides, however, are still com-
ponents of drugs like cotrimoxazol (an antifolic combination of trimethoprim and
sulfamethoxazole prescribed against urinary infections) and Fansidar ® (an antifolic
combination of pyrimethamin and sulfadoxine prescribed against malaria
infections).
278 E. Haen

PD2 Interactions

PD2 interactions are the classic type of drug-drug interactions: At the level of
pharmacological receptors agonists stimulate the receptors, antagonists block them
which results in loss of effectiveness of the physiological ligand or an agonist. These
receptors are not just part of a theoretical pharmacological concept; they are real
existing biochemical structures, usually proteins. Physiologically, the receptors are
part of the information system of the body (Fig. 5) that constitutes of the nerve

K+
Gs Gq
Gi

K+ Na+

Fig. 5 The information system of the human body. Information is transmitted throughout the body
via the nervous system (depicted as bulb like nerve endings in different colors ¼ different neuro-
transmitters), the endocrine system (depicted as blood vessel, upper left corner), and the immune
system (depicted as different immune cells, lymphocyte, granulocyte, macrophage). The differently
colored dots in between these structures symbolize the various first information messengers, that is,
neurotransmitters, hormones, and cytokines, transmitting their information strictly on the scene
(neurotransmitters in the synaptic cleft) or over a more or less close or longer distance (hormones
and cytokines). The curved line at the bottom symbolizes a postsynaptic membrane or another cell
membrane bearing various receptor types. Upon interaction of a first information messenger with
one of these receptor types a second information messenger molecule is formed inside the cell or an
ion channel is opened/closed that conveys the information upon the biochemical reactions inside the
cell altering the cell function. The figure is meant as a “confusion diagram” to create an idea of the
huge and complex information of the human body. The dot in the blood vessel symbolizes a
psychopharmacon arriving in this physiological information system of the human body. It interacts
with the existing receptor systems thereby modifying cell functions. At present knowledge, it seems
to be a characteristic of psychopharmaca to interact not selectively with just one receptor system but
at the same time with several of these receptor systems more or less effectively. Because of this
unselectivity pharmacologists call psychopharmaca “dirty drugs”
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 279

system, the hormonal system, and the immune system (Haen 2018b). Each of these
systems uses messenger molecules (“first messenger”) to convey their message to a
cell, a tissue, or an organ. Upon interaction of the first messenger with one of these
receptors, the message of the molecule is transmitted into the cell.
The risk is particularly high in psychopharmacology that PD2 interactions occur:
In contrast to most of the drugs used in internal medicine psychopharmaca are not
very selective in their affinity to pharmacological “receptors”: Psychopharmaca are
pharmacologically “dirty drugs.” Both large groups of psychopharmaca, antipsy-
chotics (receptor profile see Fig. 1.4.5 in Haen 2018b), and antidepressants (Fig. 6)
interact with more than just one receptor system, and the receptor is usually blocked.
Antidepressants can block the same receptors as antipsychotics thereby additively
increasing the effect usually transmitted by this receptor (interaction of type PD2a).
An example is the anticholinergic effect that is additively increased in a combination
of the antipsychotic quetiapine and the tricyclic antidepressant amitriptyline. The
resulting clinical effect might be urinary retention, obstipation up to an ileus, or an
anticholinergic delirium. Such a situation might be even more aggravated if
biperiden is used to treat extrapyramidal symptoms (EPMS) in the patient or a
urologist has issued a prescription of a spasmolytic drug like oxybutynin or
tolterodine against urinary incontinence.
Particularly difficult to handle is a psychosis in a patient suffering from
Parkinson’s disease. Dopaminergic drugs like levodopa, an agonist at dopamine

inhibition antagonism
SR NR DR 5-HT2A H1 M1 α1 α 2

TCA + + + + + + + +
α2-antagonists - - - + + - - +
SSRI + - - - - - - -
SNRI - + - - - - - -
SSNRI + + - - - - - -
SNDRI - + + - - - - -

Fig. 6 Receptor profile of antidepressants. The table gives the information on which class of
antidepressants (TCA: Tricyclic antidepressants; SSRI: Selective serotonin reuptake inhibitor;
SNRI: Selective norepinephrine reuptake inhibitor; SSNRI: Selectivly combined serotonin and
norepinephrine reuptake inhibitor; SNDRI: Selectivly combined norepinephrine and dopamine
reuptake inhibitor) inhibits a certain neurotransmitter reuptake mechanism from the synaptic cleft
(SR: Serotonin reuptake; NR: Norepinephrine reuptake; DR: Dopamine reuptake). Some, mostly older
antidepressants antagonize receptor systems, too, which might contribute to the desired drug effects; it
definitely contributes to the adverse drug effects (5-HT2A: Serotonin receptor type 2A; H1: Histamine
receptor type 1; M1: muscarine receptor type 1; α1: alpha-adrenergic receptor type 1; α2: alpha-
adrenergic receptor type 2). Many of the older antidepressants (TCA) unselectively inhibit neurotrans-
mitter reuptake mechanisms that were not studied at the time of their development. Newer antidepres-
sants were designed on the drawing board guided by a certain idea of interaction with
neurotransmitter reuptake mechanisms or receptor systems
280 E. Haen

D2 receptors, improve symptoms of Parkinsons’s disease; an increase in the dopa-

minergic tone, however, usually deteriorates psychotic symptoms. On the other
hand, most antipsychotics prescribed to suppress psychotic symptoms will counter-
act the effectiveness of the antiparkinson medication (interaction of type PD2b).
Antipsychotics with anticholinergic side effects such as clozapine, olanzapine, or
quetiapine may ameliorate such a situation.
Another PD2b interaction arises between coumarin anticoagulants (like
phenprocoumon, warfarin among others) and food containing vitamin K
(phytomenadione). Anticoagulants are to prevent thrombosis and embolism, and
various cabbage species, sprouts, vegetable oil, and liver and liver products contain
larger quantities of vitamin (Fig. 7a). A group of 12 proteins (the clotting factors) are
synthesized in the liver. The biosynthesis of four of them (factors II, VII, IX, and X)
depends on the availability of vitamin K. The mentioned anticoagulants are vitamin
K antagonists blocking the biosynthesis of the four clotting factors thereby reducing
clotting of blood. Since the formed clotting factors have to be used up it takes 2–
3 days before the anticoagulation effect becomes clinically relevant. People eating
food stuff rich in vitamin K are difficult to anticoagulate on a stable dose of
coumarins depending on the content of vitamin K (Fig. 7a) and the amount eaten
(Fig. 7b).

PD3 Interactions

Some drugs exert similar effects via different pharmacological mechanisms. Such an
example is the antihypertensive effect of drugs. Five different pharmacological
mechanisms are at present accepted for first-line treatment of hypertension (The
Task Force for the management of arterial hypertension of the European Society of
Cardiology (ESC) and the European Society of Hypertension (ESH) 2018):

• Blockade of ß-adrenoceptors (ß-blockers)

• Excretion of sodium and water (saluretics, diuretics)
• Blockade of calcium ion channels (Ca-channel blockers)
• Inhibition of the angiotensin-converting enzyme – 1 (ACE-1 inhibitors)
• Blockade of angiotensin-II type 1A – receptors (AT-II1A receptor blockers)

Type PD3 interactions emerge when patients have an antihypertensive prescrip-

tion without taking into account the additive effects. Elderly patients in particular
have an antihypertensive medication, often a combination of several pharmacolog-
ical mechanisms to take advantage of the desired effects with minimal risk for
adverse effects. The patients are not just at risk because of hypotension. They
might collapse because of orthostatic failure, and falls are one of the most frequent
dangers elderly people face. In psychopharmacology this problem aggravates
 a

b
am ount of f ood vitamin K content of 100 g food [µg]
containing 1 µ g vitam in K [g]

0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
850

live
r (c
hi

0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
live cken )
liver r(
(ch live beef )
liver icken ) r (p
live ork )
liver (beef ) r
( m ea (calf )
t
liver pork ) m ea (beef)
mea (calf ) t (p
t ork)
mea (beef) whi
t (po te c
rk) ab
whit
e ca sau bage
sau bageb Bru
red erkrau
c t
erk sse abbag
Bru red cab raut ls s
sse prou e
cau
ls spbage liflo ts
cau routs wer
liflow b
er Chi roccoli kale
b nes
e ca (raw)
Chi roccol kale bba
nes i (ra
e ca w ge

food
bba )
ge

food
spin
s w he a
at g ch
whe pinach
at g soy erm
soy erm a flo
a flo wer lettuce
(full

taken from (Roche Pharma AG Grenzach-Wyhlen, Germany 2013)

wer lettuce -fat
(full
-fa be )
be t) port ans
ulac
port ans
ulac a
oil ( a oil (
s
sun oil ( unflow
oil ( flow oil ( corn er)
oil ( c e pum g
pum orn ge r) pkin erm )
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling

pkin rm) see

see
d) d)

wate chive wat chive

rcre ercr
ss ess

Fig. 7 Vitamin K content of food. (a) Vitamin K content of 100 g various foodstuffs, cross lined

taken from (Souci et al. 2016). (b) Amount of various foodstuffs that contain 1 μg vitamin K, data
bar: Daily need (60–80 μg vitamin K1) according to the German Society of Nutrition (DGE), data
281
282 E. Haen

because, as mentioned above, many psychopharmaca block α1-adrenoceptors

thereby suspending constriction of blood vessels in response to a shift in posture
(see Fig. 1.4.5 in Haen (2018b) for antipsychotics as well as Fig. 6 for antidepres-
sants). If a psychiatric patient is on psychopharmaca, when an antihypertensive
medication becomes necessary, the antihypertensive has to be started with low
dosage under blood pressure measurements including “Schellong’s test” to test for
blood pressure response to switch in posture (comparison of laying and standing
blood pressure). The dosage may be slowly increased up to a probably surprisingly
low dosage needed. On the other hand, if a hypertensive patient needs
psychopharmaca, the drug has to be started with low dosage and then increased
under blood pressure measurements, while the dosage of the antihypertensive
medication has to be adapted as necessary. In both cases the psychopharmacon has
to be properly dosed as needed in the respective clinical situation, the antihyperten-
sive dosage is the one to be adapted. There are many examples for such a type PD3
interaction in the ADE database of the AGATE, for example, no. LL-07-057: A 57-
years-old woman fell under 350 mg quetiapine (antipsychotic with affinity to α1-
adrenoceptors) and 5 mg enalapril (ACE-1 blocker); the AGATE expert panel
evaluated the cause-effect relationship between collapse and this type of PD3a
interaction as “likely” (Haen 2010; Haen and Laux 2011).

PD4 Interactions

Some drugs give rise to interactions because their effects interact though being
completely different. An example is the long-known interaction between cardiac
glycosides (such as digoxin and digitoxin) and saluretic drugs (such as hydrochlo-
rothiazide or chlortalidone among others) or laxatives (such as bisacodyl or sorbitol
among others). Cardiac glycosides block the ATP-dependent sodium/potassium
pump that plays an important role for repolarization of the membrane potential in
the electrical conduction system of the heart (Fig. 8). Important ADEs of cardiac
glycosides include all kinds of cardiac arrhythmia (mechanism 1). Saluretic drugs
and laxatives lead to a loss of potassium thereby lowering the extracellular potassium
concentration (mechanism 2). A low extracellular potassium concentration, how-
ever, increases the risk for cardiac arrhythmia, thereby increasing toxicity of cardiac
glycosides (interaction of both mechanisms, Fig. 9). Because cardiac glucosides
have been replaced nowadays in most of their indications by ACE-1 inhibitors or AT-
II1A receptor antagonists, the clinical relevance of this particular type of PD4
interaction example is almost negligible today. However, low potassium concentra-
tions increase the risk of all kinds of cardiac arrhythmias. Prolongation of the QT-
interval in the ECG has become a clinically very important cardiac arrhythmia,
because a long QT-Interval bears the risk of a sudden onset of tachycardia, a so-
called torsade-de-pointes tachycardia (TdP) (Haen 2020). TdP tachycardia may be
self-limiting within a few seconds or it leads to nausea, palpitation, syncope,
ischemia triggered grand-mal seizure, or even sudden cardiac death. Among others,
there are almost no psychopharmaca not bearing the risk for QT prolongation
(Wenzel-Seifert et al. 2011). The list of QT prolonging drugs becomes longer and
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 283

[K+] 2 K+
[Ca2+] P
[Na+] U
DM
P
3 Na+

exchange site

2Na+ Ca2+

Fig. 8 Mode of action of cardiac glycosides. The action potential on a cell membrane is driven by
influx and efflux of ions. A fast sodium influx drives the steep increase, a slow potassium efflux the
repolarization. The original intra-/extracellular ion gradient (intracellular: low sodium/high potas-
sium concentration, extracellular: high sodium/low potassium concentration) is restored by an
energy (ADP) consuming ion pump. It transports three sodium ions/ATP molecule outwards of
the cell, by bringing two potassium ions/ATP molecules back inside. Cardiac glycosides block this
ion pump thereby lowering the intracellular potassium concentration

longer, a continuously updated list of these drugs is available via Internet (Woosley
et al. 2020). Therefore, type PD4 interactions are nowadays clinically more relevant
than ever.

PK1 Interactions

Pharmacokinetic interactions (PK interactions) follow the active substance through

the body. PK1 type interactions occur on the level of absorption, after oral intake
from the gastrointestinal tract (GIT). The most easily understandable example is the
interaction between bivalent cations (e.g., Mg++, Ca++, Fe++) and other active sub-
stances, for which maintaining high enough concentrations in the body is essential
for their effectiveness (e.g., anti-infective agents, such as doxycycline). Bivalent
cations form complexes with many drugs and prevent them from being taken up into
the body. It is not necessary that such cations are active agents such as antacids, they
can be a food component, too, for example, in milk. Bivalent cations lead to PK1b
type interactions, that is, they lower the bioavailability thereby decreasing drug
concentrations in the body and lowering their clinical effectiveness. Milk may
increase concentrations of active agents, too, preferentially of lipophilic drugs,
because milk is an excellent emulgator that facilitates the absorption of lipophilic
agents. Besides this direct influence on the bioavailability of drugs the GIT passage
284 E. Haen

saluretics
laxatives cardiac glycosides

extracellular cardiac arrhythmia

hypokalemia

PD4 QTc

Fig. 9 Scheme of type PD4 interactions (interaction of drug mode of actions). Type 4 interactions
were originally described for saluretics or laxatives and cardiac glycosides. Important ADEs of
cardiac glycosides include all kinds of cardiac arrhythmia (mechanism 1). Saluretic drugs and
laxatives lead to a loss of potassium thereby lowering the extracellular potassium concentration
(mechanism 2). A low extracellular potassium concentration, however, increases the risk for cardiac
arrhythmia thereby increasing toxicity of cardiac glycosides (interaction of both mechanisms).
Because cardiac glucosides have been replaced nowadays in most of their indications by ACE-1
inhibitors or AT-II1A receptor antagonists the clinical relevance of this particular type PD4 interac-
tion example is almost negligible today. However, low potassium concentrations increase the risk of
all kinds of cardiac arrhythmias. Prolongation of the QT-interval in the ECG has become a clinically
very important cardiac arrhythmia, because a long QT-Interval bears the risk of a sudden onset of
tachycardia, a so-called torsade-de-pointes tachycardia (TdP). Almost all psychopharmaca bear the
risk for QT prolongation. For this reason PD4 type interaction are still clinically highly important

time influences the absorbed amount of drugs which might be accelerated or slowed
down by other drugs (e.g., laxatives and opioids, respectively). A clinically relevant
example for the effect of food in psychopharmacology is the antipsychotic
ziprasidone: If ziprasidone is orally administered into an empty stomach (e.g.,
after an overnight fast of 8 h), the resulting drug peak plasma concentration is
50% lower compared to be taken together with food (Fig. 10) (Hamelin et al. 1998).
Besides these few general considerations, it is very difficult to foresee the effect
food may have on the uptake of a particular active agent into the body. It has to be
evaluated for each active agent separately. Wunderer (1998) gives an excellent
overview, and Welling published an English review on the topic (Welling 1996).
Oral administration of the agents concerned 2 h apart may alleviate or even prevent
PK1 type interactions (Fig. 10).

PK2 Interactions

The typical and up to now almost exclusively displayed example of a PK2 type
interaction is the displacement of a drug from its plasma protein binding (PPB).
Among others, proteins in body fluids (most of all albumin and alpha1-acid-
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 285

120

n = 8 healthy male subjects

20 mg/d ziprasidone orally
maximal concentration Cm ax [ng/m l]

100

80

60

40

20

0
after an overnight fast of 8h directly after standard breakfast 2h after standard breakfast

Fig. 10 Influence of a meal on ziprasidone concentrations. In a randomized cross-over design on

three consecutive weekends, eight healthy male subjects received a single dose of 20 mg
ziprasidone (capsule) after an overnight fast of 8 hours (left bar), directly after a standard breakfast
(two eggs, bacon, ham, toast with butter and jelly, and 8 fluid ounces of whole milk, middle bar),
and 2 hours after the same breakfast (right bar). Peak plasma ziprasidone concentration (Cmax) is
some 50% higher when ziprasidone is taken immediately after breakfast than after an overnight fast
into an empty stomach. (Data taken from (Hamelin et al. 1998))

glycoprotein [¼ orosomucoid] in blood) and tissue bind drugs thereby increasing

their volume of distribution. Only unbound molecules, the so-called free or active
fraction, can cross biological membranes from blood to reach their site of action, but
also to enter hepatocytes and tubulocytes, in which they are metabolized or from
which they are filtrated into renal tubules and then excreted.
Xenobiotics can displace active agents from their protein binding sites in blood.
This can be easily studied in vitro: You need a two-chamber jar separated by a
semipermeable membrane. In one chamber you put human plasma and a solution
with the active agent into the other. During dialysis unbound molecules may cross
the semipermeable membrane and bind to proteins solubilized in plasma. After
reaching a steady state (usually within 24 h) the concentration in the solution
chamber has been equilibrated with the free fraction of the concentration in the
plasma chamber, the concentration in the plasma chamber is the total concentration,
that is, bound + unbound fraction. If you now add a second drug into the solution
chamber, the free fraction of the first active agent will reach a new equilibrium with
an increased free concentration in case of displacement from plasma proteins by the
second drug. Such displacement studies yield very impressive results with active
agents that are highly bound to plasma proteins: The antidepressant amitriptyline, for
example, is bound to plasma proteins by 95% (Bayer Vital GmbH Leberkusen/
286 E. Haen

Germany 2018) with 5% of the total concentration as active fraction. If another drug
(e.g., valproic acid) displaces amitriptyline by reducing the bound fraction, for
example, to 90% of the total concentration, the free or active fraction is increased
to 10% of the total concentration, that is, the active concentration is doubled!
This example sounds very dramatic – and, it is still very dramatically presented
nowadays! Nevertheless, the problem for drug therapy is much more complicated
and lies in a different area: Human bodies are no in vitro reaction jars! Figure 11
displays an example with real data that demonstrates the order of magnitude of what

free (= active) concentration

bound concentration
1000
Diazepam concentration [ng/ml]

800

600

400

200

0
diazepam monotherapy diazepam + valproic acid diazepam + valproic acid
in vitro human body

Fig. 11 Schematic illustration of plasma protein binding (PPB) as PK2 type interaction. 98% of the
total diazepam concentration is normally bound to plasma albumin (Roche Pharma AG Grenzach-
Wyhlen, Germany 2013), that is, in a total diazepam concentration of 1000 ng/ml 980 ng/ml are
bound to plasma proteins, 20 ng/ml (¼2% of the total diazepam concentration) are free (active
fraction, left bar). If a drug like valproic acid displace diazepam from these proteins thereby
increasing the free diazepam concentration up to 25 ng/ml, the bound fraction is just lowered by
0.5% to 97.5% of total concentration, but the active fraction of the drug is increased by 25% of the
original free concentration (Desitin Arzneimittel GmbH Hamburg, Germany 2016) (situation in an
in-vitro reaction jar, middle panel). In a human body with undisturbed function of the excretion
organs, most drugs are eliminated with first order elimination kinetics, that is, the molecules of the
increased free concentration are ready to enter hepatocytes and tubulocytes, in which they are
metabolized or from which they are filtrated into renal tubules, that is, they will be eliminated until
the steady state concentration with 20 ng/ml free concentration is re-established. The difference is
now that 20 ng/ml free concentration represent 2.5% of total concentration, which means that the
total diazepam concentration is lowered to 800 ng/ml (situation in a human body, right panel). If
drug therapy is adapted to the individual need of a patient by therapeutic drug monitoring (TDM),
which nowadays usually determines the total concentration of a drug, this lowered total drug
concentration must not be raised by increasing the prescribed dosage.
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 287

is going on. As mentioned before, only free molecules enter hepatocytes and
tubulocytes, in which they are metabolized or from which they are filtrated into
renal tubules. In an otherwise healthy body with undisturbed elimination organs,
such a free concentration will increase just for a short period, if at all, because most
drugs follow first order elimination kinetics, that is, the amount of drug eliminated is
proportional to its free concentration (Fichtl 2001). Therefore, the increased free
concentration is immediately eliminated down to the normal free concentration.
Therefore, the patient will not experience an increased, potentially adverse drug
effect. However, if the patient’s drug therapy is individualized by therapeutic drug
monitoring (TDM), it has to be kept in mind that TDM does not usually distinguish
between free and bound fraction, and the therapeutic reference ranges refer to the
total drug concentration. In case of displacement from plasma protein binding total
drug concentration decreases with the normal free drug concentration being now the
higher free fraction, that is, the drug now has another lower therapeutic reference
range in this patient, his dosage must not be increased.
This effect is the more important the higher the bound fraction of a drug to plasma
proteins. Up to now no clinical evidence is available as to its relevance in daily
routine. Oie and Levy reported in 1979 an animal experiment with rats (Oie and
Levy 1979): Endogenous bilirubin is bound 99.9% to albumin. Sulfonamides
displace bilirubin from its protein binding, and Oie and Levy used sulfisoxazole in
their experiments. Upon rapid injection of sulfisoxazole free bilirubin concentration
rapidly increased accompanied by a drop of total bilirubin concentration within
15 min. Free bilirubin concentration sharply decreased again within the next
15 min, the increase lasted for 60 min in total. Free bilirubin concentration did not
increase, if sulfisoxazole was slowly infused; nevertheless, total bilirubin concen-
tration still decreased slowly. If sulfisoxazol concentration slowly increases during
infusion the bilirubin is so slowly displaced from its protein binding sites that there is
enough time to redispose in the body into other compartments.

PK3 Interactions

PK3 type interactions include all kinds of interactions involving metabolic and or
elimination mechanisms. Xenobiotic interactions in the kidneys were within the
focus of interest in former decades, namely the 1970s and 1980s. Nevertheless, they
are still clinically very relevant! Examples (e.g. case report 1) are interactions of
lithium ions (prescribed for bipolar affective disorders) and all kinds of active agents
stimulating the excretion of sodium such as diuretics, laxatives, and inhibitors of the
renin-angiotensin-aldosterone-system (RAAS, such as angiotensin-converting-
enzyme inhibitors (ACE inhibitors) and angiotensin-II1A receptor antagonists).
Everything that leads to a decrease in sodium concentration is eventually coupled
to an increased lithium retention by the kidneys leading to an increase in clinical
effectiveness of lithium (PK3a interaction). The onset of this effect might take up to
six weeks (Ortlieb et al. 2012).
288 E. Haen

Case Report 1
A 58-years-old man was diagnosed 20 years ago with bipolar disease. For the
last 19 years the same community specialist for psychiatry and psychotherapy
is attending him. The patient has further health problems including lumbar
osteochondrosis, spinal disc herniation, arterial hypertension, and
nephrolithiasis. With regard to drug-drug interaction the diagnosis “arterial
hypertension” need special attention, because those patients usually have
antihypertensive prescriptions. However, the psychiatrist just filed amitripty-
line, desipramine, nitrazepame, and lithium carbonate, that is, the drugs she
had prescribed.
In the beginning of December, the psychiatrist noted that the psychopatholog-
ical situation of her patient had deteriorated. So she decided to increase the lithium
dose from 2 tablets/day up to 3 tablets/day, an increase by 50%. Before the patient
started his new dosage the physician draw blood for lithium quantification:
0.88 mval/l. The next entry into the patient’s file dates from next February:
Apparently, the psychopathological situation had not improved. The psychiatrist
decided to stop the double medication of amitriptyline and desipramine and
switched the patient to just one antidepressant (mirtazapine). Two weeks later
she saw the patient again: The switch to mirtazapine had not changed the
psychopathological situation. The patient reported diarrhea and a strange, metallic
taste since beginning of February. His general practitioner had prescribed “tablets”
(no further details) against diarrhea. The next file entry dates to April 28, when the
patient was admitted to a hospital emergency room because of increasing drows-
iness and movement problems. The patient was diagnosed with increasing som-
nolence and pneumonia and transferred to the intensive care unit (ICU).
Laboratory test revealed a white blood cell count (WBC) of 17.100 Zellen/μl,
C-reactive protein (CRP) of 39.1 mg/l, and lithium concentration of 3.24 mval/l.
In the intensive care unit, the complete medication was recorded: In addition to
the abovementioned psychopharmaca, the patient was on enalapril (an ACE
inhibitor, ACE ¼ angiotensin-converting enzyme), candesartan (an angiotensin-
II-receptor1A inhibitor) + hydrochlorothiazide (a thiazid diuretic), piretanide (a
loop diuretic), and nitrendipine (a calcium channel blocker). This means the
patient was on at least four drugs that are known to increase lithium concentration
by type PK3a interactions.
We do not know when this polymedication started. Judged from the
patient’s complaints it must have been by end of January or beginning of
February. For the case, it was only important that the psychiatrist basically
treated the patient according to the rules. She drew blood, before she increased
the lithium dose. Because of the linear correlation between dose and concen-
tration, she was allowed to expect a lithium concentration around 1.32 mval/l
after dose increase. She just had to confirm this calculation. However, it was
Christmas time, so the psychiatrist was on holiday. When she had returned, the

(continued)
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 289

patient was not available. In February, both psychiatrist and patient had
forgotten. Later the psychiatrist and the general practitioner argued who was
responsible for controlling the lithium concentration.
Conclusion: Communicate with colleagues that are involved in the care of
your patients. Note all medications of your patient in your files not just the
medication of your speciality. Lithium concentration might increase in com-
bination with a multitude of drugs. Keep in mind that lithium concentration
might increase for up to 2 months after a change in medication.

A diminished kidney function may have the same effect, whether resulting from
aging or induced by other drugs, such as cephalosporines (case report 2, Geisslinger
et al. 2020).

Case Report 2
A woman, 58 years of age, was diagnosed some 30 years ago with bipolar
disease. The same community specialist for psychiatry and psychotherapy
took care of her for 24 years, before he turned his ambulatory over to a
younger colleague. He had set the woman on lithium 10 years after the
diagnosis, which she had well tolerated now for 20 years. Shortly before
Christmas, when the problems started, the woman was on trimipramine,
hydroxyzine, and lithium carbonate. For the last 3 months, the younger
physician had tried to wean the patient from a long-standing medication of
zopiclone (that she had started because of severe sleeping problems) over
chloral hydrate to the combination of trimipramine and hydroxyzine. On
December 22, she was admitted to the emergency room of a local hospital
because of respiratory insufficiency, bronchial infection, and an unclear speech
difficult to understand. Lithium concentration in blood was 2.44 mval/l. The
patient was transferred to the intensive care unit (ICU) for 3 days, lithium was
stopped until January 4, and lithium concentration fell over 0.8 mval/l on
December 25 down to 0.0 mval/l on January 4. On December 27, the patient
had to be referred back to the ICU, where she was intubated and artificially
ventilated because of CO2 narcosis until January 4.
Explaining to the patient what had happened the hospital physicians asked
the woman, why she took all these sedating medications: “Did you want to kill
yourself?” The hospital report lists as admittance diagnosis “lithium intoxica-
tion due to drug-drug interaction.” Of course, the patient had not intended to
kill herself! Her husband wrote to the young community specialist for psychi-
atry and psychotherapy asking him with respect to the hospital report why he
had issued this prescription of sedating agents in combination with lithium. In
his reply, the community psychiatrist argues: “The drugs I had prescribed,

(continued)
290 E. Haen

Chloraldurat ®, zopiclone, and trimipramine (Cefixim ®) had not been pre-

scribed by me, do not lead to intoxication symptoms in combination with
lithium.” The patient’s husband, who had compiled all prescriptions for his
wife, angrily sought the assistance of a lawyer.
This is (almost) correct: PSIAC (Eckermann G, Haen E, Hiemke C (eds):
PSIAC – Polymedication under control. Springer Verlag GmbH Heidel-berg/
Deutschland, accessible via https://www.psiac.de, accessed 28.01.2021) and
the summary of product characteristics (SPC) concerned do not indicate any
risk for lithium intoxication, and there is no evident pharmacological mecha-
nism that could explain an intoxication by lithium in combination with chloral
hydrate, zopiclone, and trimipramine. The medical riddle originated from a
spelling mistake in the community psychiatrist’s reply: He closed the paren-
thesis behind “Cefixim ®” instead of including “had not been prescribed by
me.” A second physician, a general practitioner, also took care of the patient
for many years. From his files, it became evident that the woman had heavily
smoked for decades. She suffered from chronic bronchitis and had been hit by
an acute exacerbation on December 15. On December 17, the general practi-
tioner prescribed cefixime, an oral antimicrobial agent from the class of
cephalosporins. Textbooks of Pharmacology mention under cephalosporin
therapy an occasional and reversible increase in creatinine and urea indicating
an attenuating effect on kidney function (e.g., Ortlieb et al. 2012). This
information together with the close timely relationship with the start of
cefixime application points to the cephalosporin as perpetrator of the lithium
intoxication.

PK3 type interactions in the liver are mainly due to metabolic interactions. The
body always tries to avoid the effect of a xenobiotic. One successful strategy among
others is to fasten inactivation and/or elimination: Enzymes metabolizing a xenobi-
otic increase in amount and activity. Such a process involves genetic alterations
(gene amplification, induced transcription), and it takes a couple of days to become
effective. Once metabolism is more effective, the enzymes may catalyze other
substrates than the originator as well, a mechanism that is called “enzyme induc-
tion.” Enzyme induction causes a diminished clinical effect (PK3b interaction).
“Enzyme inhibition” originates from the same phylogenetic mechanisms (Fig. 12)
besides that the originator’s affinity to the active center of the enlarged enzyme is
higher than the victim’s affinity. The victim agent is not able to displace the
originator (also called “perpetrator”) from the active center of the enzyme, so that
the latter metabolism is slowed down and clinical effectiveness increases (PK3a
interaction). In contrast to enzyme induction, enzyme inhibition becomes evident
parallel to the increase of the xenobiotic concentration in the body. Enzyme inhibi-
tion is concentration dependent: It depends on both the concentration of the origi-
nator and the victim agent. Often enzyme inhibitors are compiled in lists, for
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 291

enzyme induction
xenobiotic induces transcription of the genetic code
enzyme meabolises faster
other xenobiotics as well

enzyme inhibition
xenobiotic with high affinity to the active center
blocks enzyme activity even in induced enzymes
for other xenobiotics with lower affinity

Fig. 12 Schematic presentation of type PK3 interactions at the level of metabolism. Enzyme
induction: Xenobiotics induce their inactivation by metabolism, that is, transcription of the genetic
code for metabolizing enzymes is stimulated. This process takes a couple of days. The induced
enzyme is then ready to metabolize other xenobiotics with affinity to its active center, too. Enzyme
inhibition: Xenobiotics block as high affinity substrates the active center of their metabolizing
enzymes. The metabolism of other substrates with lower affinity to the active center of the enzyme
is blocked as well, depending on their affinities and concentrations. This process accompanies the
increase in substrate concentration, that is, it just takes minutes up to hours. Xenobiotics might also
block enzymes that have been induced before. Both processes are reversible over a similar time as
their activation

example, in summaries of product characteristics (SPC) of drugs (e.g., Teva B.V.

Haarlem/The Netherlands 2020) or in guidelines (e.g., Hiemke et al. 2017). Those
lists are easy to understand, but they are basically wrong or at least incomplete:
Enzyme inhibition depends on the affinity of both interacting drugs to the active
center of the enzyme, which means that an active agent might be an inhibitor with
one drug, but not with another drug. These lists just pay tribute to the fact that it is
simply impossible to investigate enzyme inhibition of each drug with all other drugs
during development of a new drug. Therefore, these lists just compile very potent
enzyme inhibitors that are clinically most relevant. The actual situation in the
individual patient becomes evident by therapeutic drug monitoring when drug
concentrations are determined and properly commented by clinical pharmacologists.

Case Report 3
We received a blood specimen for determination of citalopram concentration
drawn from a 30-years-old man at 07h30. The patient was on 30 mg

(continued)
292 E. Haen

citalopram. Citalopram concentration was determined at 35 ng/ml, therapeutic

reference range (TRR) 30–130 ng/ml, dose-related reference range (DRR) for
30 mg 31–45 ng/ml, elimination half-life t1/2 36 h (KONBEST case no.
48165). Since the concentration was just above the lower TRR limit, the
physician intended to increase the dose and calculated the estimated concen-
tration for 60 mg citalopram as 70 ng/ml. Three weeks later, we received the
control blood specimen. Citalopram concentration was determined as 133 ng/
ml, and DRR for 60 mg 61–91 ng/ml (KONBEST case no. 48412). Citalopram
concentration was surprisingly high, and DRR was exceeded by more than
40%. The reason was that the patient’s medication was altered in two posi-
tions: Citalopram dose was doubled and the patient was put on mirtazapin, a
second antidepressant. Mirtazapin inhibited the metabolism in this patient.

These processes are best investigated in the oxidative xenobiotic metabolism

(phase I metabolism, reduction/oxidation reactions). There is increasing evidence
that the basic mechanisms underlying the adaptation processes also apply to phase II
(transferases) and phase III metabolism (transportation proteins) (Klein and Haen
2018). The chemical structure of enzymes of the oxidative xenobiotic metabolism
contains a cytochrome ring in its active center. The enzymes may be quantified
photometrically at a wavelength of 450 nm, and they are therefore called cyto-
chrome-P450-isoenzymes (CYP). Each isoenzyme has a more or less elaborated
substrate selectivity. Some 50–60 CYP isoenzymes are known in the living world,
fauna as well as flora. Twelve of them play a major role in xenobiotic metabolism in
men. These isoenzymes differ to some extent in their amino acid (AA) sequence
(Fig. 13). Figure 14 depicts the main 12 CYP isoenzymes of the oxidative xenobiotic
metabolism in men indicating as an example the substrate selectivity for citalopram
and escitalopram.

PK3c Interactions: Prodrugs

If prodrugs are applied in a medication, the active agents are only formed in the
metabolism, whereas the mother substances might be more or less inactive. The
adaptation processes presented above now apply to the formation of the active agents
but with opposite consequences: Enzyme induction leads to an increase in clinical
effectiveness (PK3c+ interaction), and enzyme inhibition to a decrease in clinical
effectiveness (PK3c interaction). Among others, clinically relevant examples are
clopidogrel, an anticoagulant that inhibits the aggregation of thrombocytes, and
tamoxifen, a selective estrogen-receptor modulator used in breast cancer patients
to stop estrogen-sensitive breast cell growth.
Clopidogrel is metabolized by CYP1A2, CYP2B6, CYP2C9, CYP2C19, and
CYP3A4 (Kazui et al. 2010). The active metabolite is a thiolderivative of the
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 293

CYP

14 gene families AA-sequence homology > 40 %

20 out of 26 subfamilies
known in men
isoforms
33 bekannt AA-sequence homology > 55 %
12 relevant for drug metabolism

Fig. 13 The cytochrome-P450-isoenzymes of men. Depending on the AA sequence homology we

distinguish gene families (labeled by a number), subfamilies (labeled by a letter), and isoforms
(again labeled by a number). Twelve of these isoenzymes are involved in most metabolic reactions
with xenobiotics

(es)citalopram 1
1 A 2

A 6
B 6
CYP 8
2 C 9
18
19
D 6
E 1
4
3 A
5

Fig. 14 Metabolic pathway of citalopram and escitalopram. Please read the figure like a book from
left to right: (Es)citalopram is metabolized by CYP2C19 and CYP2D6

inactive mother substance. Therefore, CYP1A2, CYP2B6, CYP2C9, CYP2C19, and

CYP3A4 inducers/inhibitors may potentially alter the clinical effectiveness of a
clopidogrel medication (Lau et al. 2004).
294 E. Haen

Tamoxifen is metabolized by CYP2C9, CYP2D6, and CYP3A4. The mother

substance tamoxifen has, but only little affinity to both estrogen receptors, whereas
its metabolites 4-hydroxytamoxifen (4-OHT, afimoxifene) and N-desmethyl-4-
hydroxytamoxifen (endoxifen) have a 30–100 times greater affinity (Ahmad et al.
2010). Therefore, CYP2C9, CYP2D6, and CYP3A4 inducers/inhibitors may poten-
tially alter the clinical effectiveness of a tamoxifen medication (Newman et al. 2008).

Number of Potential Interactions

The number of theoretically, that is, mathematically possible drug-drug interaction

follows the binomial formula.


i ¼ n2  n =2

with i ¼ theoretically number of drug-drug interactions and n ¼ number of admin-

istered drugs.
An example is given in Fig. 1 depicting the number of drugs (psychopharmaca
and non-psychopharmaca) prescribed to patients treated under the diagnosis of
schizophrenia (F2x) in the AGATE (Arbeitsgemeinschaft zur Unterstützung einer
sowohl rationalen wie rationellen Arzneimitteltherapie bei [psychiatrischen]
Erkrankungen; English: Working group to support both a rational and economic
drug therapy in [psychiatric] diseases, Haen and Laux 2011) institutions in 2016:

• 14% of the patients were under monotherapy (number of mathematically possible

interactions: 0).
• 19% of the patients had a prescription of two drugs (number of mathematically
possible interactions: 1).
• 23% of the patients had a prescription of three drugs (number of mathematically
possible interactions: 3).
• 14% of the patients had a prescription of four drugs (number of mathematically
possible interactions: 6).
• 7% of the patients had a prescription of seven drugs (number of mathematically
possible interactions: 21).

It is important to emphasize that this theoretical risk estimation does not mean,
that each of these mathematically possible interactions will also give rise to a
clinically relevant adverse drug effect (ADE). What will eventually happen in the
patient does not have anything to do with this type of theoretical risk calcuation. On
the contrary, the clinical risk evaluation reveals in some instances that one of these
mathematically possible interactions causes several different complaints of the
patient instead of just one ADE. For example, one often applied combination of
two drugs in the pharmacotherapy of psychoses, the combination of benzodiazepine
antipsychotics (e.g., clozapine) with a benzodiazepine (e.g., diazepam), may lead to
four different clinical situations: (1) Fatigue and sedation until unconsciousness and
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 295

coma, (2) depression of breathing until arrest, (3) hypotension, and 4. malignant
neuroleptic syndrome (MNS) (Haen 2019).

How to Handle Xenobiotic Interactions?

Nobody can avoid drug-drug interactions in prescriptions of more than one drug.
The interaction problem for the treating physician does not consist of avoiding an
interaction; he or she has to find a way to deal with the interaction. For this purpose,
physicians may

• Check databases
• Consult drug information services
• Quantify xenobiotic concentrations (therapeutic drug monitoring, TDM)

Data Bases to Check a Medication for Risk of Interaction

Many Internet sources list (iso)enzymes together with their substrates and informa-
tion of inducers and inhibitors. However, the bedside physician needs the informa-
tion the other way round: The bedside physician, the general practitioner, the
community specialist, and the pharmacist have a list of prescriptions to a patient.
Göpfert and Haen therefore started in 2006 to compile the available information in
alphabetical order of the INN (elimination pathway table). Unfortunately, the infor-
mation available via Internet is very scarcely validated by references of the interna-
tional literature. The 2017 version is available in print (Haen and Göpfert 2018). The
table is continuously updated in KONBEST and AMBEW (see below) PSIAC and,
by now independently, in KONBEST and AMBEW (see below) PSIAC. The PSIAC
table is more and more backed with international references that remarkably
decrease the number of entries. PSIAC is meant to check for medication risks. The
entries are therefore carefully double-checked to avoid overalerting. The KONBEST
and AMBEW platform is compiled for interpretation of a measured drug concentra-
tion; the elimination pathway table therefore contains all the available internet
information.
Databases accessible via internet offer an interaction check of a medication
(Quick et al. 2018). Several electronic data banks list all kind of pharmacological
and pharmaceutical data of drugs. Some of them are available by registration or as
part of electronic communication systems in outpatient practices, hospitals, and
pharmacies:

• ABDATA (Avoxa – Mediengruppe Deutscher Apotheker GmbH n.d.-a) for

pharmacies and ABDAMED (Avoxa – Mediengruppe Deutscher Apotheker
GmbH n.d.-b) for medical practitioners
• Ifap-Index, drug data integrated in various software products used by hospitals
(ifap Service-Institut für Ärzte und Apotheker GmbH 2020)
296 E. Haen

• Gelbe Liste Pharmindex (Medizinische Medien Informations GmbH)

• AMIS data bank of the German Institute for Medical Documentation and Infor-
mation (DIMDI) (Deutsches Institut für Medizinische Dokumentation und Infor-
mation (DIMDI) 2020)
• IBM Micromedex (IBM Watson Health Cambridge 2020)

Others are available free of charge:

• drugs.com (Accessible via. https://www.drugs.com/. Accessed 26 Jan 2020)

• Apotheken Umschau (Wort and Bild Verlag Konradshöhe GmbH and Co 2020)

Few data banks are especially designed and compiled to yield information on
drug-drug interactions or, in a broader sense, xenobiotic interactions:

• PSIAC (Eckermann et al. 2020)

• MediQ (mediQ – Qualitätszentrum für Medikamentensicherheit 2020)

Both data banks do not intend to replace a pharmacological textbook. Therefore,

they do not contain plenty of pharmacological data. Upon entering at least two or more
(unlimited number) of INN (international non-proprietary names) and/or trademarks
both data banks return ADE that might occur because of an interaction. The data are
based on the official warning published in the summary of product characteristics
(SPC), on review publications and/or case reports in scientific journals, and/or on
pharmacological expertise. PSIAC is somewhat simpler to handle, easier to survey and
gives the elimination pathway table of the medication entered (see above). MediQ
contains much scientific information on mechanisms of interactions together with
references. MediQ classifies the risk of an interaction by a traffic light system; PSIAC
evaluates the risk in eight categories that is not meant as ranking:

• Cave, combination with risk of serious ADE

• Combination with increased risk of ADE
• Critical combination for patients at risk
• Interaction expected, at present, however, no evidence based data available for
clinical relevance
• Combination without known risk of interaction
• Uncritical combination
• Combination without any clinical sense
• Recommended combination

The PSIAC categorization emphasizes that it is not the interaction, which is

“serious,” “tolerable,” or “slight,” but the ADE that might occur because of the
interaction; and the “seriousness” itself depends on the risk of the individual patient,
that is, the risk is not equal for each patient.
Besides the clinical effect that might be evoked by an interaction, PSIAC returns
the respective pharmacological mechanism, evaluates the risk, and suggests what to
do if the interaction cannot be avoided.
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 297

Drug Information Services (AID)

People, healthcare professionals, and patients may contact drug information services
to get information on questions regarding medications. AGATE (the working group
to support both a rational and economic drug therapy in [psychiatric] diseases,
German: Arbeitsgemeinschaft zur Unterstützung einer sowohl rationalen wie
rationellen Arzneimitteltherapie bei [psychiatrischen] Erkrankungen) is a nonprofit
assembly of healthcare professionals devoted to support a rational and economical
drug therapy (Haen and Laux 2011). It offers unbiased information on drugs
independent from any lobby interest in the healthcare system. Everybody may ask
any question and is encouraged to do so. Its budget comes from membership fees,
tutorials, scholarships, and donations free of healthcare lobby interests.

Therapeutic Drug Monitoring

Therapeutic drug monitoring learly identifies all pharmacokinetic interactions. In

contrast to a conviction that dates back to a witchcraft trial against Dr. Paracelsus
(1493–1541) in Nuremberg/Germany in the beginning of the sixteenth century, it is
not the dose that correlates with the clinical effect of an active agent, but its
concentration that emerges from a certain dose in the body (Haen 2018c). Indepen-
dent of the drug or xenobiotic concerned, given the same dose to various individuals,
this concentration may vary by a factor of 10–20! This has been repeatedly demon-
strated over decades for such different drugs like gentamicine (an aminoglycoside
antibiotic Heimann et al. 1983), the antipsychotic quetiapine (Haen et al. 2008), and
the direct oral anticoagulant (DOAC) rivaroxaban (Boehr and Haen 2017). Besides
(non)compliance, aging, diseases of excreting organs, and genetic polymorphisms in
the xenobiotic metabolism, pharmacokinetic interactions are the main causes of this
large interindividual variability. Correlating the quantified concentration to the
applied dose the extent of such an interaction becomes obvious (dose-related
reference range, DRR (Haen et al. 2008)). Since the concentration directly correlates
with the applied dose, the concentration that is expected in a “normal” patient (i.e.,
the individual out of the patient population of the phase-II clinical trial that deter-
mined the total clearance (Haen et al. 2008)) may be calculated as

cav ¼ De =24h  F=Clt ð1Þ

cav ¼ 24 h-mean concentration of the active agent [ng/ml],

De ¼ daily maintenance dose [ng], F ¼ bioavailability, Clt ¼ total clearance [ml/h],
(De is eventually to be corrected for the molecular weight of the applied salt down to
the respective base).

The dose-related reference range (DRR) is obtained by putting the total clearance
as mean + 1 standard deviation (SD) and mean – 1 SD into Eq. (1).
The thus defined DRR contains statistically 68.27 % of drug concentrations built
up in compliant “normal patients” under the constant dose De after the
298 E. Haen

pharmacokinetic steady state has been reached. It is independent of the dosing

interval, specific dosage forms or whether De is split or not with partial doses spread
equally or unequally over the day. A problem arises because the concentration cav
calculated by Eq. (1) is the 24 h-mean of the concentration, whereas it is
recommended in TDM to draw blood for quantification of drugs at the time of
trough values, that is, in the morning before the first dose of the day is administered
(Hiemke et al. 2017). Therefore it was suggested (Hiemke et al. 2017) to use an
equation published by Gex-Fabry for the postabsorptive phase after application of a
drug (i.e. the equation correctly describes the concentration-time-curve after intra-
venous bolus injection, Fichtl 2001, Gex-Fabry et al. 2003) instead. It may be used
as an approximation or extravasal application of a drug and is presented here in
corrected form to take the absorptive phase into account:

ct ¼ ðDe =τÞ∙ðF=Clt Þ∙½ðke∙τÞ=ð1  ekexτ Þ∙ðekexðtTmaxÞ Þ (2)

ct ¼ concentration of the active agent at time t after application of last dose

ct ¼ cmin if blood is drawn at time of trough concentration Tmin
Tmax ¼ time to peak plasma concentration (absorptive phase)
De ¼ daily maintenance dose [ng], F ¼ bioavailability, τ ¼ application interval,
Clt ¼ total clearance [ml/h]
ke ¼ elimination rate constant ¼ ln2/t1/2
(De is eventually to be corrected for the molecular weight of the applied salt down to
the respective base).

DRR calculated with Eq. (1) is usually not too much different from the results
of Eq. (2). Differences are larger the shorter the elimination half-live of the
xenobiotic. The TDM consensus guideline suggested an elimination half-live
above 24 h as a limit (Hiemke et al. 2017) to use Eqs. (1) and (2) for shorter
elimination half-lives. However, the difference between the two equations
depends linearly from the length of the elimination half-life; therefore, it is better
to use Eq. (2) whenever applicable. Note: Eq. (2) is only mathematically valid if
the daily dose is either applied once daily or at equal time intervals within
24 hours in equal partial doses.
In clinical routine, however, physicians prescribe drugs at every possible admin-
istration schedule. In our experience, it is reasonable to use Eq. (2) for once daily
application or twice daily every 12 h. In all other cases, particularly with dosing
emphasis in the second half of the day, we use Eq. (1). The discussion goes on. If the
“correct” (whatever that is?) concentration is to be predicted, an iterative summation
is to be used with an extra term for each partial dose at its particular application time
(Endres and Haen 2020).
Unfortunately, DRC factors in Table 5 of the TDM consensus guideline (Hiemke
et al. 2017) are struck by two calculation errors: (1) The absorptive phase, i.e. Tmax,
is not taken into account. (2) The factors have not been calculated in two steps (total
clearance mean + and – one standard deviation) but after calculating the arithmetic
mean, the result has been then adapted with the coefficient of variation to the low and
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 299

high factors. The respective Table 1.7.3 in Klein and Haen (2018) has ameliorated
these errors (Haen et al. 2018b).

The Clinical Pharmacological TDM Report

Usually just the concentration value determined in a laboratory is reported back to

the physician, who ordered TDM, together with the therapeutic reference range
(TRR). It is left up to the physician to evaluate this value at the TRR, a process
that yields pharmacodynamic information on the chance of the prescription to
become effective and its risk to evoke adverse drug reactions. However, a drug
concentration contains much information. The pharmacokinetic situation of the
individual patient can be addressed by relating the drug concentration to the dose-
related reference range (DRR). It is used to discriminate an individual patient from
the population of “normal” patients and thus yields information on (non)compliance,
xenobiotic interactions, age effects, diseases of the excreting organs, and xenobiotic
interactions. The complete information is summed up in the clinical pharmacological
TDM-report (Haen 2018d). It has been developed since 2004 (Haen 2005, 2011,
2012) and contains (Fig. 15):

• The analytical laboratory value of the drug concentration

• The dose-related reference range (DRR) for the dose prescribed to the patient
• The therapeutic reference range (TRR) for the drug in its licensed indication
• The 9-field-board of TDM, a graphical display simply demonstrating the relation
of the determined concentration to both reference ranges (DRR and TRR)
• The elimination pathway table of the patient’s complete medication, food, and
legal drug consumption assorted in alphabetical order of the INN (international
non-proprietary name)
• A graphical display of earlier quantifications
• The clinical pharmacological TDM evaluation including therapeutic recommen-
dation and the answer to questions raised in the TDM request form

KONBEST

It is impossible for bedside physicians to keep in mind all the pharmacological data
and patient relevant information necessary to evaluate properly and comprehen-
sively a drug concentration. There are softwares to support the composition of a
clinical pharmacological TDM report: Köstlbacher (software programmer) and Haen
(algorithms, databases) created between 2008 and 2010 KONBEST, an Internet-
based platform that supports compiling clinical pharmacological TDM reports
(Köstlbacher and Haen 2008; Köstlbacher 2012). KONBEST contains pharmaco-
logical databases. Upon entering therapeutically relevant, anonymous patient data,
KONBEST sorts along pharmacological algorithms the pharmacological to the
individual patient data. The result is presented to a clinical pharmacological expert
300 E. Haen

Fig. 15 Clinical pharmacological report set up by KONBEST. The example shows KONBEST
case no. 48412. The report gives all clinically relevant information contained in a drug blood
concentration (Haen 2018d, 2012). Furthermore, the clinical pharmacological expert answers
questions formulated on the TDM request form.

who checks the information, evaluates it, and adds the therapeutic recommendation.
The finalized and issued TDM reports are stored in the KONBEST reports database;
by May 2020 this database contains some 65,000 clinical pharmacological TDM
reports. KONBEST is property of AGATE (www.amuep-agate.de).

AMBEW

AMBEW is the second generation of KONBEST. The experience collected with

KONBEST was used to extend the clinical pharmacological TDM reports to the
clinical pharmacological evaluation of (poly)medications. AMBEW allows adapta-
tion of pharmacokinetic modeling of expected individual drug concentrations to the
ongoing state of scientific discussion. Besides interpreting the pharmacokinetic
information of drug concentrations AMBEW evaluates the pharmacodynamic infor-
mation of medications. This involves pharmacodynamic interactions, in-line and off-
line prescriptions, documentation and estimations of ADE, as well as adaptation
processes. AMBEW supports clinical pharmacological experts issuing therapeutic
recommendation. Supported by Dr. Robert Pfleger-Stiftung Bamberg/Germany
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 301

AMBEW was created by Herdt & Klon (software programmers) and Haen (algo-
rithms, databases). It is available since March 13, 2017. AMBEW is property of
AGATE (www.amuep-agate.de).

Cross-References

▶ Adverse Drug Reactions, Intoxications and Interactions of Neuropsychotropic

Medications
▶ Pharmacokinetic and Pharmacodynamic Principles

References
Ahmad A, Shahabuddin S, Sheikh S, Kale P, Krishnappa M, Rane RC, Ahmad I. Endoxifen, a new
cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bio-
availability in healthy human subjects. Clin Pharmacol Ther. 2010;88(6):814–7.
ABDATA for pharmacies Avoxa – Mediengruppe Deutscher Apotheker GmbH, Eschborn. n.d.-a.
Accessible via https://abdata.de/datenangebot/abda-datenbank. Accessed 26 Jan 2020.
ABDAMED for medical practitioners Avoxa – Mediengruppe Deutscher Apotheker GmbH,
Eschborn. n.d.-b. Accessible via https://abdata.de/datenangebot/abdamed. Accessed 26 Jan
2020.
Barry PJ, O’Keefe N, O’Connor KA, O’Mahony D. Inappropriate prescribing in the elderly: a
comparison of the Beers criteria and the improved prescribing in the elderly tool (IPET) in
acutely ill elderly hospitalized patients. J Clin Pharm Ther. 2006;31(6):617–26.
Bayer Vital GmbH Leberkusen/Germany. Fachinformation (Summary of Product Characteristics)
Saroten ® retard Tabs 75 mg. (2018). issued Nov 2018.
Boehr S, Haen E. Development of an UHPLC-UV-method for quantification of direct oral antico-
agulants: apixaban, rivaroxaban, dabigatran, and its prodrug dabigatran etexilate in human
serum. Ther Drug Monit. 2017;39(1):66–76.
Corsonello A, Pranno L, Garasto S, Fabietti P, Bustacchini S, Lattanzio F. Potentially inappropriate
medication in elderly hospitalized patients. Drugs Aging. 2009;26(Suppl 1):31–9.
Desitin Arzneimittel GmbH Hamburg, Germany. Fachinformation (Summary of Product Informa-
tion) Orfiril ® magensaftresistentes (gastro-fluid resistant) Dragee 155, 300 und 600 mg. 2016,
issued Nov 2016.
Deutsches Institut für Medizinische Dokumentation und Information (DIMDI), Köln. 2020. Acces-
sible via https://www.dimdi.de/dynamic/de/arzneimittel. Accessed 26 Jan 2020.
Eckermann G, Haen E, Hiemke C, editors. PSIAC – polymedication under control. Heidelberg:
Springer; 2020. Accessible via https://www.psiac.de. Accessed 27 Jan 2020.
Endres K, Haen E. The dose-related reference range – a new approach with improved predictive
quality. Pharmacopsychiatry. 2020;53(3):140–1.
Fichtl B. Arzneistoffkonzentration im Organismus in Abhängigkeit von der Zeit: Pharmakokinetik
im engeren Sinn. In: Forth W, Henschler D, Rummel W, Förstermann U, Starke K, editors.
Allgemeine und Spezielle Pharmakologie und Toxikologie. 8th ed. München/Jena: Urban &
Fischer Verlag; 2001. p. 72–4.
Geisslinger G, Menzel S, Gudermann T, Hinz B, Ruth P, editors. Mutschler Arzneimittelwirkungen.
11th ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH; 2020. p. 1002.
Gex-Fabry M, Balant-Gorgia AE, Balant LP. Therapeutic drug monitoring of olanzapine: the
combined effect of age, gender, smoking, and comedication. Ther Drug Monit. 2003;25:46–53.
Haen E. Bedeutung der klinisch-pharmakologischen Befundung von Wirkstoffkonzentrations-
messungen zur Therapieleitung. Psychopharmakotherapie. 2005;12:138–43.
302 E. Haen

Haen E. Der Klinikverbund AGATE: Ein Pharmakokompetenzzentrum flächendeckend in und für

Bayern. Bayer Aztebl. 2010;65(12):702–3.
Haen E. Therapeutic drug monitoring in pharmacovigilance and pharmacotherapy safety.
Pharmacopsychiatry. 2011;44:254–8.
Haen E. Der TDM-Befund. Psychopharmakotherapie. 2012;19:129–34.
Haen E. Arzneimittelinteraktionen – Interaktionen zwischen körperfremden Substanzen.
Nervenarzt. 2014;85:417–26.
Haen E. Interaktionen von Xenobiotika. In: Klein HG, Haen E, editors. Pharmakogenetik und
Therapeutisches Drug Monitoring. Berlin/Boston: Walter de Gruyter GmbH; 2018a. p. 32–44.
ISBN 978-3-11-035286-3; e-ISBN (PDF) 978-3-11-035290-0, e-ISBN (EPUB) 978-3-11-
038780-3.
Haen E. Pharmakodynamik. In: Klein HG, Haen E, editors. Pharmakogenetik und Therapeutisches
Drug Monitoring. Berlin/Boston: Walter de Gruyter GmbH; 2018b. p. 20–31. ISBN 978-3-11-
035286-3; e-ISBN (PDF) 978-3-11-035290-0, e-ISBN (EPUB) 978-3-11-038780-3.
Haen E. Concentratio, non dosis facit venenum. In: Klein HG, Haen E, editors. Pharmakogenetik
und Therapeutisches Drug Monitoring. Berlin/Boston: Walter de Gruyter GmbH; 2018c. p.
159–61. ISBN 978-3-11-035286-3, e-ISBN (PDF) 978-3-11-035290-0, e-ISBN (EPUB) 978-3-
11-038780-3.
Haen E. Der klinisch-pharmakologische Befund zu Wirkstoffkonzentrationen (TDM-Befund). In:
Klein HG, Haen E, editors. Pharmakogenetik und Therapeutisches Drug Monitoring. Berlin/
Boston: Walter de Gruyter GmbH; 2018d. p. 131–46. ISBN 978-3-11-035286-3, e-ISBN (PDF)
978-3-11-035290-0, e-ISBN (EPUB) 978-3-11-038780-3.
Haen E. Olanzapine and diazepam. In: Eckermann G, Haen E, Hiemke C, editors. PSIAC –
polymedication under control. Internet based data base of drug-drug-interactions. Berlin/Hei-
delberg: Springer; 2019. https://www.psiac.de/interaction/query/A197+A240. Accessed 11 Dec
2019.
Haen E. Channelopathy: individualised pharmacotherapy in aquired long QT syndrome. Päd Praxis.
2020;93:269–75.
Haen E, Emslander HP. Chronisch obstruktive Atemwegserkrankungen: Die Optimierung der
Therapie mit Methylxanthinen. Dtsch Ärzteblatt. 1989;86:1625–30.
Haen E, Göpfert C. Tabelle der Stoffwechselwege. In: Klein HG, Haen E, editors. Pharmakogenetik
und Therapeutisches Drug Monitoring. Berlin/Boston: Walter de Gruyter GmbH; 2018. p. 60–
108. ISBN 978-3-11-035286-3; e-ISBN (PDF) 978-3-11-035290-0, e-ISBN (EPUB) 978-3-11-
038780-3.
Haen E, Laux G. Arzneimitteltherapiesicherheit/Pharmakovigilanz in der klinischen Psychophar-
makotherapie – Das Kliniknetzwerk AGATE. Psychopharmakotherapie. 2011;18:238–43.
Haen E, Greiner C, Bader W, Wittmann M. Wirkstoffkonzentrationsbestimmungen zur
Therapieleitung - Ergänzung therapeutischer Referenzbereiche durch dosisbezogene
Referenzbereiche. Nervenarzt. 2008;79(5):558–66.
Haen E, Schwarz M, Pascucci G. Identifizierung von Arzneimittelinteraktionen. In: Klein HG,
Haen E, editors. Pharmakogenetik und Therapeutisches Drug Monitoring. Berlin/Boston: Wal-
ter de Gruyter GmbH; 2018a. p. 44–9. ISBN 978-3-11-035286-3, e-ISBN (PDF) 978-3-11-
035290-0, e-ISBN (EPUB) 978-3-11-038780-3.
Haen E, Fay B, Hiemke C. Tabellarische Zusammenstellung der dosisbezogenen und der
therapeutischen Referenzbereiche einiger klinisch wichtiger Wirkstoffe. In: Klein HG, Haen
E, editors. Pharmakogenetik und Therapeutisches Drug Monitoring. Berlin/Boston: Walter de
Gruyter GmbH; 2018b. p. 137–46. ISBN 978-3-11-035286-3, e-ISBN (PDF) 978-3-11-035290-
0, e-ISBN (EPUB) 978-3-11-038780-3.
Hamelin BA, Allard S, Laplante L, Miceli J, Wilner KD, Tremblay J, Lebel M. The effect of timing
of a standard meal on the pharmacokinetics and pharmacodynamics of the novel atypical
antipsychotic agent ziprasidone. Pharmacotherapy. 1998;18(1):9–15.
Heimann G, Schug S, Bergt U. Pharmacokinetics of combined antibiotic therapy in the newborn
infant. Monatsschr Kinderheilkd. 1983;13:58–62.
Xenobiotic Interactions in Psychopharmacotherapy: Classification and Handling 303

Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts

K, Gerlach M, Greiner C, Gründer G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R,
Janssen G, Jaquenoud E, Laux G, Messer T, Mössner R, Müller MJ, Paulzen M, Pfuhlmann B,
Riederer P, Saria A, Schoppek B, Schoretsantis G, Schwarz M, Silva Gracia M, Stegmann B,
Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker M, Waschgler R, Zernig G, Zurek G,
Baumann P. Consensus guidelines for therapeutic drug monitoring in neuropsychophar-
macology: update 2018. Pharmacopsychiatry. 2017;51(01/02):9–62. https://doi.org/10.1055/s-
0043-116492. Published online 2017.
Holt S, Schmiedl S, Thürmann P. Potentially inappropriate medication in the elderly – PRISCUS
list. Dtsch Arztebl Int. 2010;107:543–51.
Hosia-Randell HM, Muurinen SM, Pitkala KH. Exposure to potentially inappropriate drugs and
drug-drug interactions in elderly nursing home residents in Helsinki, Finland: a cross-sectional
study. Drugs Aging. 2008;25(8):683–92.
IBM Watson Health Cambridge, MA 02142/USA. 2020. Accessible via https://www.
micromedexsolutions.com/micromedex2/librarian/deeplinkaccess?institution¼COMMHOS%
5eCOMMHOS%5e33486. Accessed 26 Jan 2020.
ifap Service-Institut für Ärzte und Apotheker GmbH, Martinsried/Germany. 2020. Accessible via
https://www.ifap.de/arzneimitteldaten. Accessed 26 Jan 2020.
Johnell K, Fastbom J, Rosen M, Leimanis A. Inappropriate drug use in the elderly: a nation-wide
register-based study. Ann Pharmacother. 2007;41(7):1243–8.
Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A.
Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in
the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos.
2010;38(1):92–9.
Klein HG, Haen E. Pharmakogenetik und Therapeutisches Drug Monitoring. Berlin/Boston: Walter
de Gruyter GmbH; 2018. p. 20–31. ISBN 978-3-11-035286-3; e-ISBN (PDF) 978-3-11-
035290-0, e-ISBN (EPUB) 978-3-11-038780-3.
Köstlbacher A. Eine Informationssystem-Infrastruktur für das Therapeutische Drug Monitoring.
Planung, Umsetzung und Integration der Wechselwirkungsdatenbank PsiacOnline, des
semantischen Wikis OpenDrugWiki.org und des Laborinformationssystems KONBEST.
Dissertation Universität Regensburg 2012. Herausgegeben vom Hochschulverband für
Informationswissenschaft (HI) e.V. Konstanz (Hrsg.): Schriften zur
Informationswissenschaft Band 61. Boi-zenburg: Verlag Werner Hülsbusch; 2012. ISBN
978-3-86488-019-3.
Köstlbacher A, Haen E. Konbest – a web-based laboratory information management system (LIMS)
for TDM-laboratories. Pharmacopsychiatry. 2008;41:212.
Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE, Tait AR, Bates ER.
Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of
clopidogrel resistance. Circulation. 2004;109(2):166–71.
Maio V, Yuen EJ, Novielli K, Smith KD, Louis DZ. Potentially inappropriate medication pre-
scribing for elderly outpatients in Emilia Romagna, Italy: a population-based cohort study.
Drugs Aging. 2006;23(11):915–24.
Maio V, Del Canale S, Abouzaid S. Using explicit criteria to evaluate the quality of prescribing in
elderly Italian outpatients: a cohort study. J Clin Pharm Ther. 2010;35(2):219–29.
mediQ – Qualitätszentrum für Medikamentensicherheit, Psychiatrische Dienste Aargau AG, Brugg.
Accessible via https://www.mediq.ch. Accessed 27 Jan 2020
Medizinische Medien Informations GmbH, Neu-Isenburg/Germany. Accessible via https://www.
gelbe-liste.de. Accessed 26 Jan 2020.
Newman WG, Hadfield KD, Latif A, Roberts SA, Shenton A, McHague C, Lalloo F, Howell S,
Evans DG. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients.
Clin Cancer Res. 2008;14(18):5913–8.
Nobili A, Pasina L, Mangiagalli A, Marchetti A, Frau S, Zimol R. Farmaci e anziani metodi per
gestire l’inappropriatezza prescrittiva. Dialogo sui farmaci. 2012;3:112–20.
304 E. Haen

Oie S, Levy G. Effect of sulfisoxazole on pharmacokinetics of free and plasma protein-bound

bilirubin in experimental unconjugated hyperbilirubinemia. J Pharm Sci. 1979;68(1):6–9.
Ortlieb J, Baier M, Röder-Aigner J, Müller-Oerlinghausen B, Haen E. Welches Diuretikum bei
Lithium-Therapie? Psychopharmakotherapie. 2012;19:275–7.
Prudent M, Drame M, Jolly D, Trenque T, Parjoie R, Mahmoudi R, Lang PO, Somme D, Boyer F,
La-niece I, Gauvain JB, Blanchard F, Novella JL. Potentially inappropriate use of psychotropic
medications in hospitalized elderly patients in France: cross-sectional analysis of the prospec-
tive, multicentre SAFEs cohort. Drugs Aging. 2008;25(11):933–46.
Quick M, Schwarz M, Haen E. Datenbanken zur Identifizierung von Arzneimittelinteraktionen. In:
Klein HG, Haen E, editors. Pharmakogenetik und Therapeutisches Drug Monitoring. Berlin/
Boston: Walter de Gruyter GmbH; 2018. p. 49–60. ISBN 978-3-11-035286-3.
Roche Pharma AG Grenzach-Wyhlen, Germany. Fachinformation (Summary of Product Informa-
tion) Valium ® Tabletten 5 und 10 mg. 2013. issued July 2013.
Souci SW, Fachmann W, Kraut H. Die Zusammensetzung der Lebensmittel, Nährwert-Tabellen. 8th
ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2016.
Teva B.V. Haarlem/The Netherlands. Summary of product characteristics for clopidogrel
ratiopharm 75 mg film-coated tablets. 2020, issued February 2020.
The 2019 American Geriatrics Society Beers Criteria ® Update Expert Panel. American Geriatrics
Society 2019 Updated AGS Beers Criteria ® for Potentially Inappropriate Medication Use in
Older Adults. J Am Geriatr Soc. 2019;67(4):674–94. https://doi.org/10.1111/jgs.15767.
The Task Force for the management of arterial hypertension of the European Society of Cardiology
(ESC) and the European Society of Hypertension (ESH). 2018 ESC/ESH Guidelines for the
management of arterial hypertension. Eur Heart J. 2018;39:3021–104. https://doi.org/10.1093/
eurheartj/ehy339.
Thiem U. Potentiell inadäquate Medikamente, Qualität der Arzneimitteltherapie bei Älteren. Inter-
nist (Berl). 2012;53(9):1125–30.
Thiem U, Hinrichs T, Muller CA, Holt-Noreiks S, Nagl A, Bucchi C, Trampisch U, Moschny A,
Platen P, Penner E, Junius-Walker U, Hummers-Pradier E, Theile G, Schmiedl S, Thurmann PA,
Scholz S, Greiner W, Klaassen-Mielke R, Pientka L, Trampisch HJ. Voraussetzungen für ein
neues Versorgungsmodell für ältere Menschen mit Multimorbidität. Ergebnisse und Schlussfol-
gerungen aus 3-jähriger Forschung im PRISCUS-Verbund [Prerequisites for a new health care
model for elderly people with multiple morbidities: results and conclusions from 3 years of
research in the PRISCUS consortium]. Z Gerontol Geriatr. 2011;44(Suppl 2):101–12.
van der Hooft C, Jong G, Dieleman J, Verhamme K, Van der Cammen T, Stricker B, Sturkenboom
M. Inappropiate drug prescribing in older adults: the updated 2002 Beers criteria -a population-
based cohort study. Br J Clin Pharmacol. 2005;60(2):137–44.
Welling PG. Effects of food on drug absorption. Annu Rev Nutr. 1996;16(1):383–415.
Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of
torsade de pointes. Dtsch Arztebl Int. 2011;108:687–93. https://doi.org/10.3238/arztebl.2011.
0687.
Woosley RL, Heise CW, Gallo T, Tate J, Woosley D, Romero KA. QTdrugs List. 2020. www.
crediblemeds.org. Accessed 25 Apr 2020. AZCERT (Arizona Center for Education and
Research on Therapeutics), Inc., 1822 Innovation Park Drive, Oro Valley, AZ 85755, USA.
Wort & Bild Verlag Konradshöhe GmbH & Co. KG Baierbrunn bei München/Germany: Alles
Wichtige über Medikamente. 2020. Accessible via https://www.apotheken-umschau.de/
Medikamente. Accessed 26 Jan 2020.
Wunderer H. Wechselwirkungen mit der Nahrung. Eschborn: Govi Verlag Pharmazeutischer Verlag
GmbH; 1998. ISBN 978-3-7741-0702-1.
Randomized Controlled Trials and the
Efficacy of Psychotropic Medications

Boadie Waid Dunlop and Carolina Medeiros Da Frota Ribeiro

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
A Brief History of the Randomized Controlled Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
The Role of Governmental Oversight of Medical Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Key Characteristics of Modern Clinical Trial Designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Protection of Human Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Trial Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Participant Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Confirmation of Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Control Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
Study Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Statistical Considerations of RCTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Effect Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
P-value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
Confidence Interval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
Intention-to-Treat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Missing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Internal Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
External Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Challenges to Detecting Efficacy of Drugs in RCTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Placebo Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Nonadherence to Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
Treatment Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

B. W. Dunlop (*) · C. Medeiros Da Frota Ribeiro

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta,
GA, USA
e-mail: bdunlop@emory.edu; carolina.medeiros.da.frota.ribeiro@emory.edu; cmedei2@emory.edu

© Springer Nature Switzerland AG 2022 305

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_4
306 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

RCT Considerations for Specific Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

Major Depressive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Schizophrenia and Schizoaffective Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
Generalized Anxiety Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
Panic Disorder and Agoraphobia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Social Anxiety Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
Post-traumatic Stress Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
Attention-Deficit Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
Substance Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Safety and Tolerability Assessment in RCTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Criticism of Psychiatric Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
“Me-too” Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

Abstract
Randomized controlled trials (RCTs) are the most important component of the
evidence base justifying the use of psychiatric medications in clinical practice.
Establishing efficacy of an investigational new drug through RCTs requires
careful consideration of factors related to trial design, patient enrollment, study
conduct, and data analysis. Each disorder has unique characteristics that require
tailoring of RCT designs in terms of duration, assessment, and treatment setting.
Placebo effects and patient nonadherence to study medication present significant
challenges to identifying truly efficacious drugs. Although RCTs have been
criticized for being vulnerable to various forms of bias, they remain the best
means for identifying treatments to relieve mental suffering. Mental health
practitioners can benefit from a deeper understanding of clinical research pro-
cedures and the standards used for evaluating a medication’s efficacy, safety, and
tolerability. This understanding can inform clinicians’ judgment regarding the
generalizability of RCT results to their clinical practice.

Introduction

The development and clinical application of effective psychotropic medications

since World War II is one of the great advances in the history of medicine. People
previously powerless against their mental illnesses have been able to achieve
mental stability and live outside the walls of the asylums through the power of
psychopharmacotherapy. Of course, for too many the treatments have proven
inadequate, or to cause side effects that diminish physical health and quality of
life, so the need for discovery of more effective and safer treatments persists. This
chapter reviews how psychopharmaceuticals are evaluated for psychiatric
disorders.
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 307

A Brief History of the Randomized Controlled Trial

Prior to the development of controlled clinical trials, medical treatments were

applied based on a mixture of observation, philosophical and religious beliefs,
common sense, and tradition (1). Although these classical approaches yielded a
few pharmaceuticals that are still used today (e.g., aspirin from willow bark), the
public health is best served by objective, controlled evaluations of a treatment’s
efficacy and safety. Today, the standard for evaluating new treatments for psychiatric
disorders is the double-blind, placebo-controlled, randomized controlled trial (RCT).
The concept of a controlled comparison of treatments was most famously intro-
duced in 1747 by James Lind, a ship’s surgeon from Scotland, who assigned 12 sailors
with scurvy to 1 of 6 treatment arms. Each arm involved administration of a different
type of dietary acid to reduce the putrefaction of the body, which Lind believed to be
scurvy’s etiology. Only citrus supplementation proved efficacious, later determined to
act by repleting sailors’ low vitamin C levels, the true cause of scurvy. Lind’s trial
provides two enduring lessons for RCTs today: (1) large treatment effects can be
observed when an intervention directly addresses the underlying pathophysiology of a
disease (though unfortunately this rarely applies to psychiatry’s complex disorders);
and (2) an efficacious drug’s theorized mechanism of action should not be considered
proof that the drug is directly remedying a disease’s underlying pathophysiologic
process. In the current psychiatric pharmacopeia, examples include the medications
that modulate monoamine signaling and are efficacious, despite the paucity of evi-
dence indicating that disruptions in monoamine activity underlie the development of
these disorders (Coppen 1967; Schildkraut and Kety 1967; Hindmarch 2002).
Pill placebos were the next crucial development for RCTs. American physician
Austin Flint, studying rheumatic fever, was the first to introduce placebos as a
comparator treatment in 1863, as a means of moving beyond simple observation
of untreated disease when evaluating the efficacy of active treatments. The first use
of placebo in a psychiatric clinical trial occurred in 1938 when Drs. Leonard Dub
and Louis Lurie evaluated the efficacy of benzedrine for depression in a placebo-
controlled crossover trial (Shorter 2011). Notably, this trial was also double-blind,
with both the patients and the investigators unaware of which treatment the patient
was receiving. Randomization of patients to parallel treatment arms was introduced
in Britain in the late 1940s in studies of active treatments for tuberculosis. Finally,
the first true double-blind, placebo-controlled RCTs in psychiatry were conducted in
the early 1950s by investigators in Denmark, North America, and the United
Kingdom, studying lithium, hypnotics, mephenesin, nucleotides, and reserpine for
various psychiatric conditions (Shorter 2011).

The Role of Governmental Oversight of Medical Products

Complementing the enhancements in clinical trial methodology has been the expan-
sion of the role of government in managing the public release of pharmaceuticals,
though this has been primarily a reactive process. Before governments began to take
308 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

an active role, the American Medical Association formed the Council on Pharmacy
and Chemistry in 1905 as a reaction to the growth of “patent” medicines. These
formulations promised a variety of health benefits, typically without any supporting
studies. The Council would, for a fee, award the AMA’s Seal of Acceptance to the
drug if it passed their ingredient quality testing, and the Council members adjudged
the product to produce symptomatic relief. This initial step to bring some semblance
of order to the free-for-all in marketing drugs to the public was followed in 1906 by
the passage of the Pure Food and Drugs Act by the United States. The statute made it
illegal for manufacturers to print “false and misleading” statements and required
listing potentially dangerous ingredients on the product label, but overall the statute
provided minimal public health protections because government interventions could
only occur after drugs had been marketed.
The subsequent United States’ Food, Drug, and Cosmetic Act of 1938 was the
most important single step toward effective government oversight of pharmaceu-
tical development. Spurred by a tragedy in which over 100 people died from an
antibiotic that was suspended in toxic diethylene glycol, this was the first
legislation to require drug manufacturers to submit both efficacy and safety
data, as part of a New Drug Application (NDA), to the newly formed Food and
Drug Administration (FDA) prior to marketing their products. The act thus
endowed the FDA with the power to prevent dangerous drugs from reaching
the market rather than removing them once harms had emerged. Notably, the
1938 law did not require testing on animals prior to human use and did not
empower the FDA to require clinical trials demonstrating efficacy of the product.
National regulatory bodies’ ability to regulate pharmaceutical development was
substantially increased again in 1962 following the infamous tragedy of thalid-
omide, an anti-nausea medication that was given during pregnancy and resulted
in thousands of infants to be born with severe limb malformations. The FDA
formalized regulations following the 1962 Kefauver-Harris Amendments in the
United States to require drug manufacturers to submit an Investigational New
Drug (IND) application in order to be permitted to conduct studies in humans for
a drug under development and established the clinical trial phases of drug
development. For the first time, drug manufacturers now were required to dem-
onstrate that their products were efficacious for the condition being studied. In
the subsequent decades, the FDA continued to refine its role in overseeing drug
development and today actively works with drug manufacturers in designing
their clinical trials to ensure the efficacy and safety aspects are addressed to its
satisfaction (Junod 2008).
In Europe, government regulation of drugs proceeded more slowly. Each Euro-
pean nation originally had its own set of regulations for approving drugs for public
use, making the marketing and distribution of medications across the continent
highly problematic and expensive. Following the founding of the European Union
in 1993, the European Medicines Agency (EMA) was formed in 1995 with the goal
of harmonizing drug approval processes and reducing costs for drug companies. The
Clinical Trials Directive (EU Directive 2001/20/EC) established the framework for
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 309

clinical trials in Europe, but implementation varied across the member states.
Consequently, Clinical Trials Regulation (Regulation (EU) 536/2014) was adopted,
which aimed to further harmonize clinical trials rules across the EU and is expected
to go into force in 2019. Although the terminology of the oversight process differs
between the EMA and FDA (e.g., “Clinical Trial Application” versus the IND of the
FDA), the overall components and procedures are very similar. Perhaps the most
important difference is that in the United States, the only route to marketing approval
is through the FDA, but in Europe drugs can be approved through one of four routes,
including a centralized process that applies to all member states (though no psychi-
atric drugs can be approved via this route), as well as decentralized or nation-level
processes (van Norman 2016). Other important national drug regulatory agencies
include the Australian Therapeutic Goods Administration, founded in 1989, and the
Pharmaceuticals and Medical Devices Agency of Japan, founded in 2004. The
national regulatory agencies differ regarding the degree to which they consider
evidence from clinical trials conducted outside their regions of oversight when
making decisions about marketing approval in their countries. Consequently, many
psychotropic drugs are available in ex-US nations that have either not undergone
FDA review or failed approval, including widely prescribed antidepressants
(agomelatine, moclobemide, milnacipran, reboxetine) and antipsychotics
(amisulpride, zotepine, zuclopenthixol).

Key Characteristics of Modern Clinical Trial Designs

The methodology and goals of trials to evaluate investigational drugs vary

depending on their phase of development (Table 1). This chapter emphasizes the
“pivotal” RCTs conducted to obtain marketing approval by a governmental regula-
tory agency. Successful conduct and evaluation of RCTs of investigational medica-
tions depends on several key components.

Protection of Human Subjects

At the forefront of all clinical research is the need to ensure the rights of each study
participant are protected. The 1964 World Medical Association Declaration of
Helsinki and its subsequent amendments lay out the ethical principles governing
research with human subjects (World Medical Association 2013). The process of
obtaining the informed consent of a participant prior to performing any research
procedures is a crucial component of the respect for persons and is a foundational
component in the conduct of clinical trials. Adherence to the principles of ethical
research is the responsibility of the investigators, with oversight for safeguarding the
rights and welfare of research participants provided by Ethics Committees or
Institutional Review Boards. Participants in clinical trials are always free to with-
draw from studies at any time and for any reason.
310 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Table 1 Phases of drug development for psychotropic agents

Number of
human
Phase Method Goals subjects
Preclinical Laboratory and animal Target engagement, metabolism, 0
testing toxicities, dosing guidance for
humans
I Healthy human adults given Pharmacokinetics, dosing range, Dozens
single or repeated doses safety
IIa Small placebo-controlled Initial testing for efficacy, selection Dozens to
studies in adults with the of dose(s) for phase III, additional hundreds
disease safety evaluations
IIIb Large placebo-controlled Pivotal trials for marketing Several
studies in adults with disease approval hundreds to
>1000
IV Various types of large studies Post-marketing evaluation of Hundreds
conducted after marketing safety, comparative effectiveness, to
approval efficacy in sub-populations thousands
a
May be divided into phase IIa, pilot trials focused on primarily on safety, and phase IIb, focused on
efficacy and optimal dose identification. Some phase IIb trials may be included with phase III trials
as pivotal trials for consideration for marketing approval
b
May be divided into phase IIIa, trials conducted to be included in the NDA application to the FDA
or other regulatory body, and phase IIIb, trials conducted after the application to provide additional
information about efficacy and safety
Spilker (1984), Food and Drug Administration (2018a)

Trial Design

The primary aim of pivotal RCTs is to evaluate a drug’s efficacy for a disease.
Determinations of efficacy require a comparison between the investigational (some-
times called “active”) treatment and another intervention, typically placebo in
psychiatric RCTs. Perhaps the ideal RCT design is a crossover study. These trials
possess the great advantage of having each participant serve as their own control,
thereby eliminating most potential confounding factors. In a crossover design, a
subject is randomly assigned to first receive either the active treatment or the
comparator for a specified period of time and then subsequently given the other
treatment for an equivalent period. Often a “washout” period of 1–2 weeks is used
between the treatment periods to allow for the effects of the first treatment to resolve.
Despite their appeal, crossover designs have found limited application in psychiatry
because treatments change people; that is, the first treatment can result in carry-over
effects that may last far longer than the washout period (e.g., once a person’s
depression remits, it may not return for years), so participants are not in the same
state when they start the second treatment as they were when they started the first.
Chronic insomnia is the psychiatric disorder perhaps best suited for study in cross-
over designs.
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 311

The randomized, parallel-group trial has become the most widely used and
accepted trial design to evaluate the efficacy of psychiatric drugs. In this design,
“parallel group” means each subject is assigned to receive only one treatment so that
the two arms run “in parallel”; the patients never cross between treatments (Atkins
2009). The comparison made to determine efficacy is based on the mean (average)
outcomes of the subjects in the treatment arms. Dosing may be either fixed (patient
remains on the same dose throughout the trial) or flexible (prescriber may adjust the
patient’s dose based on tolerability and response). Fixed-dose studies are used in
phase II trials to determine the dose-response relationships and plan doses for phase
III trials, which may use fixed or flexible dosing regimens. Flexible dosing is
associated with reduced frequency of dropout in trials of antipsychotics (Rabinowitz
et al. 2008) but not antidepressants (Khan et al. 2003).
A more complicated design is the factorial trial, which evaluates the effect of two
or more treatments simultaneously using combinations of the treatments. This design
has more statistical power than a standard parallel-group design, but if the two
treatments have interaction effects, the interpretation of the results can be difficult.
In psychiatric trials, these designs are typically used for drugs that already have
marketing approval, such as combining an antidepressant and an agent to reduce the
use of substances in patients with comorbid mood and substance use disorders.
The trial design most commonly used to evaluate a medication’s efficacy in
preventing recurrence of an episode of a disorder is a double-bind placebo-controlled
discontinuation trial. These trials typically use an open-label stabilization treatment
phase for 1–6 months, depending on the disorder, in which all patients receive the
active medication. Those who respond to the medication are then randomized in a
double-blind manner to continue on the medication or switch to placebo using a
short taper, with outcomes assessed over follow-up periods of 6 months to 2 years
(Glue et al. 2010; Lindström et al. 2017; Leucht et al. 2012; Batelaan et al. 2017).
Outcomes in these trials in mood disorders are usually recurrence of a full episode or
an increase in symptom rating scale score above a certain threshold; outcomes for
other disorders may additionally include time to hospitalization or need for change in
treatment.
Recently, clinical trials designed to identify long-term protective effects of med-
ications have been applied to psychiatric illnesses. Such “disease modification” trials
evaluate whether a treatment slows the progression of clinical symptoms in associ-
ation with a significant effect on a validated biomarker for the illness (European
Medicines Agency 2018). When a treatment is believed to directly or indirectly
restore or prevent the loss of functioning of neurons, it may be considered
“neuroprotective” and contribute to disease modification. Among neuropsychiatric
disorders, Alzheimer’s disease and Parkinson’s disease, where the pathobiology is
best established, have received the most study, but no drugs have proven to be
disease modifying to date. Many approaches to demonstrating disease modification
have been applied, including washin, washout, delayed start, and time-to-event
clinical trial designs, though it has been difficult to clearly distinguish a treatment’s
312 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

effects on reducing symptom expression versus its effects on the progression of the
illness (McGhee et al. 2016). Currently, schizophrenia and bipolar disorder are the
psychiatric disorders for which disease modification and neuroprotection studies are
of greatest interest, utilizing neuroinflammation and gray and white matter brain
volumes as potential biomarkers (Robertson et al. 2019).

Duration

The length of an RCT depends on the question to be answered, the naturalistic course
of the illness studied, and the pharmacokinetics and mechanism of action of the
investigational drug. RCTs assessing acute efficacy may be as short as 4–6 weeks,
whereas trials evaluating relapse prevention may last a year or more. For illnesses
such as obsessive-compulsive disorder (OCD) or post-traumatic stress disorder
(PTSD), where substantial gains may not emerge until 2–3 months of treatment,
shorter trials risk falsely concluding that a drug is ineffective (Soomro et al. 2008;
Stein et al. 2006). Alternatively, trials may be excessively long for conditions that
can improve naturalistically on shorter time frames, such as the mood episodes of
bipolar disorder (Thase et al. 2008).

Participant Selection

Selecting participants in an RCT requires application of eligibility requirements,

operationalized as inclusion and exclusion criteria. The former specifies the charac-
teristics individuals must have for participation; the latter refers to characteristics that
will eliminate potential participants, typically factors that could act to diminish the
effect of the intervention, increase the risks to the subject, or are associated with
higher rates of placebo response.

Confirmation of Diagnosis

For most psychiatric RCTs, the presence of the targeted disorder in an individual is
assessed through a combination of a psychiatrist’s evaluation and administration of a
structured or semi-structured clinical interview. These assessments also serve to
ensure that excluded disorders are absent. The most commonly used diagnostic
instruments in RCTs are the Structured Clinical Interview for DSM (SCID), avail-
able in versions reflecting the DSM-IV criteria and the DSM-V criteria (First et al.
2015); the Mini Neuropsychiatric Interview (MINI), with multiple versions
reflecting corrections and revised DSM criteria (Sheehan et al. 1998); and the
World Health Organization’s Composite International Diagnostic Interview v2.1
(Robins et al. 1988), which assesses disorders defined by ICD and DSM criteria.
The World Health Organization’s World Mental Health Composite International
Diagnostic Interview (WMH-CIDI) was developed to replace the WHO CIDI,
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 313

incorporating risk factors, treatment histories, and other queries in addition to the
diagnostic criteria assessments (Kessler and Ustün 2004).

Control Group

The control group in pivotal RCTs in psychiatry is nearly always placebo. Pill
placebos should have similar appearance, odor, and taste to maximize blinding. If
the investigational drug proves superior to placebo, the RCT is considered a “pos-
itive trial”; if not, it is a “negative trial.” Some RCTs employ three arms, with the
third arm being an “active control,” i.e., a medication that is already marketed for the
condition. Having an active control arm allows for assessment of the “assay sensi-
tivity” of the enrolled sample. Specifically, if the investigational treatment and the
active control treatment do not prove superior to placebo, then the RCT is considered
a “failed trial.” With this result, the investigational medication cannot be concluded
to lack efficacy, but rather that the RCT itself, either through its design or the subjects
enrolled, was inadequate for detecting the hypothesized effects. Despite the advan-
tages of having an active control, the additional arm greatly increases the number of
required subjects, thereby reducing feasibility of achieving the necessary enrollment,
and may also increase placebo response rates through increases in patient expecta-
tion for improvement (Sinyor et al. 2010; Woods et al. 2005). Notably, these RCTs
are usually not designed to test whether the investigational drug is superior to the
active comparator, and head-to-head comparisons between the two drugs are rarely
reported.

Randomization

Randomizing patients to treatment arms balances potential confounders in order to

isolate the specific effect of the drug on trial outcomes. Importantly, randomization
balances variables that are known to affect outcomes as well as variables that could
affect outcomes that are not known to the investigators. Randomization’s balancing
of potential confounders is most likely to be successful with large samples because
imbalance can still arise by chance in small samples. Randomization of a subject in
RCTs is performed after all screening procedures have been completed and eligibil-
ity confirmed, typically at the baseline visit.
Upon completion of the trial, characteristics of the patients in each treatment
arm are summarized (customarily Table 1 in the publication of an RCT), which
allows for assessment of the success of the randomization. If the arms appear well-
balanced with respect to potential confounders, there is greater confidence that the
observed results derive from the drug’s effect. If randomization failed (i.e., one or
more potential confounders were unequally distributed between the treatment
arms), statistical analyses can be used to adjust for the imbalance, though this
approach is less preferable than using stratified randomization to avoid
confounding.
314 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Stratification

If the effect of a medication is expected to differ based on a specific characteristic of

the subjects, patients may be stratified into separate groups based on that character-
istic. Examples of factors used for stratification include gender (male vs female) or
disease severity (mild/moderate vs severe). In effect, instead of randomizing all
patients off a single list, with stratification separate randomization lists are created
for the levels of the characteristic (e.g., a list for men and a list for women).
Stratification prevents the possibility of a randomization failure based on the char-
acteristic (e.g., a greater proportion of men in one treatment arm than the other),
which could confound the results. With very large sample sizes, it is possible to
stratify based on multiple characteristics.

Blinding

Blinding (also known as “masking”) refers to efforts to prevent patients, their family
members, physician-investigators, or outcome assessors from knowing which treat-
ment the patient has been assigned to in an RCT. Blinding of participants is
important to minimize expectancy of improvement, which is a major driver of
placebo response. Similarly, blinding of investigators and assessors is important to
prevent biases arising from ratings assessments or early withdrawal of patients due to
potential allegiance to the investigational treatment (Mora et al. 2011). “Single-
blind” usually means that the patient is unaware, but that the physician knows the
treatment; in trials where patient blinding is not possible (e.g., psychotherapy versus
medication trials), the term is used to indicate that the outcome assessor was blind.
“Double-blind” refers to both the patient and the physicians/assessors being unaware
of treatment assignment; sometimes this is referred to as “triple-blind” to emphasize
that the outcome assessor (if different from the investigator) is unaware.
“Allocation concealment” refers to blinding of investigators to the randomization
sequence. Lack of concealment could lead an investigator to defer a certain patient’s
randomization visit for various reasons (e.g., wanting to ensure they received the
active treatment), thereby undermining the goal of randomization. Maintaining the
blind after the study treatment is initiated is also very important and challenging.
During treatment, it may be possible for patients and investigators to “see through
the blind,” often due to the emergence of side effects within an individual. This
concern is particularly great for medications with side effects that are well-known
and common, such as sedation with quetiapine (Calabrese et al. 2005). Although
rarely used, “active placebos” (i.e., medications that can mimic the investigational
drug’s side effect) have been proposed, such as using low-dose diphenhydramine as
a placebo for investigational drugs with the side effect of sedation. However, there is
a potential ethical concern about giving clinical trial participants a product with
known adverse effects without expected therapeutic benefit. Despite their potential
utility, active placebos have received scant use in modern trials (Perlis et al. 2010).
An exception is RCTs of depression or PTSD that evaluate sub-anesthetic doses of
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 315

ketamine (which produces rapid and obvious mental effects), for which midazolam
has been used as an active placebo (Fava et al. 2018).

Outcomes

RCT outcomes should be clinically relevant, practical, sensitive to the intervention,

and amenable to statistical analysis. Three types of outcomes in psychiatric RCTs are
used: continuous (e.g., symptom rating scale scores), categorical (e.g., remission vs
non-remission), and event-time (e.g., time to relapse). The primary outcome to be
analyzed to determine efficacy must be asserted in the study protocol prior to starting
enrollment, in order to prevent selective reporting of more favorable outcome
measures after the trial results are known.
Quantification of illness severity is a major challenge across all psychiatric
clinical trials. Unlike common medical disorders such as diabetes or hypertension,
there is as yet no way to assess the illness through an objective laboratory analysis.
Investigators must rely upon rating scales (clinician-administered or patient self-
report) that are scored based on the patient’s subjective experiences. This limitation
produces a substantial amount of measurement error that can reduce the precision of
the assessment of treatment effects.
With a few exceptions, the symptom rating scales used to assess primary out-
comes in RCTs of the major psychiatric disorders are nearly all 40 years old.
Continued use of older scales has the advantage of allowing for consistent compar-
ison of treatment effects across time but suffers the disadvantage of assessing
symptoms that are not aligned with the current diagnostic criteria for the illnesses.
Additionally, for the most part, the major scales do not differentially weight symp-
tom items, though certain core symptoms, such as anhedonia or suicidal ideation in
MDD, may have greater clinical importance than non-core or non-criterion symp-
toms such as appetite change or anxiety.
Clinical Global Impression Scales. The most common measure used across trials
is the Clinical Global Impression Scale, which can be scored as a severity measure
(CGI-S) or change from baseline (CGI-C, also known as the CGI-I, for improve-
ment) (Guy 1976). The CGI scores are based on the investigator’s overall (i.e.,
“global”) assessment, incorporating both symptomatic and functional status. The
CGI-S is scored from 1 to 7, with “1” reflecting “normal, not at all ill,” and “7”
reflecting “among the most extremely ill patients.” A CGI-S score of 4 (“moderately
ill”) or higher is commonly used as an inclusion criterion for clinical trials. Scores on
the CGI-C also range from 1 to 7, with “1” representing “very much improved,” “4”
representing “no change,” and “7” representing “very much worse.” CGI scores may
be analyzed as a continuous outcome or as a categorical outcome, counting the
number of participants who fall into each score level. Response on the CGI-C is
classified as a score of “1” (very much improved”) or “2” (much improved). The
appeal of the CGI scores is their intuitiveness – the scoring levels can be more easily
understood by clinicians than effect sizes or changes on symptom rating scale scores.
Additionally, the CGI measures can be used across disorders. Weaknesses of the CGI
316 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

include their dependence on the rater’s range of experience with patients and the
unanchored, coarse nature of the scoring levels. Inter-rater reliability training or
assessment for the CGI scales is rarely conducted prior to beginning the RCTs. For
these reasons, CGI outcomes are usually used as secondary measures of treatment
efficacy. Efforts to bring greater standardization to CGI scoring across disorders
have recently been published (Dunlop et al. 2017).

Study Monitoring

Before, during and after the completion of a clinical trial, sites conducting the study
undergo external monitoring to ensure the study protocol is being followed correctly
and that the documentation of clinical data, study medication accountability, and
regulatory procedures are all appropriate. Government authorities have the power to
audit research sites and are particularly vigilant for concerns around a site’s data
quality and protection of research subjects.

Statistical Considerations of RCTs

Ultimately, whether a medication is determined to be efficacious for a medical

condition is a statistical question. Interpretation of RCT results involves assessment
of the magnitude, direction, statistical significance, and clinical relevance of differ-
ences between treatment groups.

Effect Size

The magnitude of the difference between treatments is often referred to as effect size.
Many different measures can be considered effect sizes, the simplest being the
difference in rating scale scores between treatment arms. For many disorders,
different scales may be used across trials, making direct comparisons difficult. For
this reason, a difference between treatment arm scores may be converted to a
standardized mean difference (SMD), also known as Cohen’s d. This measure of
effect size is calculated by dividing the mean difference between the treatments by
the pooled standard deviation. A d = 1 indicates that two compared groups differ by
one standard deviation. By convention, an SMD (d) of 0.2 is considered to be a small
effect, 0.5 a medium effect, and 0.8 a large effect, though Cohen cautioned that these
thresholds may not apply in all contexts (Cohen 1988). Another SMD measure,
Hedges’ g, is calculated similarly to Cohen’s d but uses pooled weighted standard
deviations (as opposed to unweighted) and is considered a better measure when
sample sizes are small (Hedges 1981). When the outcome of an RCT is not a
continuous measure (e.g., score change) but rather a categorical outcome (e.g.,
response, remission, relapse), then relative risk may be used as the effect size. In
this usage, “risk” does not imply a bad outcome, but simply a ratio: the proportion of
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 317

active drug-treated patients with the categorical outcome divided by the proportion
of comparator-treated patients with the categorical outcome. Across all psychiatric
disorders, the relative risk for active medications compared to placebo in preventing
relapse/recurrence is larger than for achieving response or remission with acute
treatment.
Perhaps the most clinically applicable measure of effect size is the number needed
to treat (NNT), which gives an absolute measure: the number of patients that would
need to receive the active drug to achieve one more positive outcome than if the same
number had received the comparator. Number needed to harm (NNH) is the oppo-
site: the number of patients treated who would need to receive the active drug to
experience one additional harm (typically a specific side effect) above the number
occurring in the control condition. The specific harms evaluated by this metric may
range from discomforting side effects to severe adverse reactions or death. Effect
sizes derived from placebo-controlled RCTs for selected medications for psychiatric
treatments are presented in Table 2.

P-value

Much emphasis is placed on the p-value (i.e., the probability that the study results
would have occurred if the null hypothesis was true, i.e. that there is no difference in
efficacy between the treatments). The results are declared to be “statistically signif-
icant” if the p-value is below a certain threshold, traditionally p < 0.05 (meaning that
there was <1/20 chance that the results could have arisen if the drug is truly no better
than placebo). Small-magnitude differences between treatments, which may have
little clinical relevance, can reach “statistical significance” if the sample size is large
enough, or the standard deviations of the means are very narrow. Conversely, a large
difference between groups may appear to have high clinical relevance, but if derived
from a small sample, the possibility that the results arose simply by chance is greater,
and statistical significance not achieved. When multiple outcomes are assessed, a
downward adjustment needs to be applied to the threshold p-value because with each
additional statistical comparison the probability of a chance finding increases.

Confidence Interval

Although trials produce a specific outcome measurement (e.g. symptom scale

difference or relative risk of response), this measurement is only a point estimate
of the true value. Confidence intervals provide a range of values both higher and
lower than the point estimate, within which the true value exists with a given level of
confidence (Altman et al. 1983). In keeping with the conventional use of the 0.05
threshold for a significant p-value, confidence intervals are typically calculated using
a confidence level of 95%. Narrow confidence intervals suggest the point estimate is
relatively precise; conversely, wide confidence intervals mean the measure of effect
should be treated with caution, regardless of its statistical significance.
318 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Table 2 Effect sizes of selected medications based on placebo-controlled RCTs

SMD
Disorder State Drug class (95% CI) NNT (95% CI) Reference
Major Acute SSRI 0.31 8.7 (7.0–11.5) Gibertini
depressive (0.25–0.36) et al. (2012),
disorder SNRI 0.34 10.2 (8.0–14.0) Undurraga
(0.27–0.41) and
TCA 6.2 (5.2–7.5) Baldessarini
(2012)
Maintenance All ADM 4.4 (3.8–5.2) Sim et al.
12 months (2015)
Maintenance All ADM 3.8 (3.3–4.6)
>12 months
Bipolar Acute Manic 2nd-Gen AP 0.40 6.3 (5.3–7.7) Yildiz et al.
disorder (0.32–0.47) (2011)
Haloperidol 0.54 5.0 (3.6–8.3)
(0.35–0.73)
Lithium 0.39 6.3 (4.4–11.1)
(0.22–0.55)
Valproate 0.28 5.9 (3.9–12.5)
(0.09–0.47)
Acute Quetiapine 0.37 5.9 (4.7–7.8) Selle et al.
Depressed (0.28–0.46) (2014)
Lurasidone 0.32 4.6 (3.3–7.8)
(0.13–0.51)
Olanz + Fluox 0.45 1.8 (2.7–7.2)
(0.21–0.70)
Maintenance Antipsychotics 4.3 (3.3–6.1) Vázquez
Lithium 4.9 (3.1–11.0) et al. (2015)
Anti-convulsants 13 (6.0–56)
Schizophrenia Positive Antipsychotics 0.45 Leucht et al.
symptoms (0.40–0.50) (2017)
Negative Antipsychotics 0.35
symptoms (0.31–0.40)
Maintenance 3 (2–3) Leucht et al.
(2012)
Generalized Acute SSRI 0.33 Gomez et al.
anxiety (0.26–0.39) (2018)
disorder SNRI 0.36
(0.29–0.42)
Benzodiazepines 0.50
(0.41–0.58)
Panic disorder Acute SSRI 8 (6–12) Bighelli et al.
SNRI 6 (4–23) (2018)
TCA 6 (5–11)
(continued)
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 319

Table 2 (continued)
SMD
Disorder State Drug class (95% CI) NNT (95% CI) Reference
Social anxiety Acute SSRI 0.44 Curtiss et al.
disorder (0.37–0.51) (2017)
Venlafaxine 0.45
(0.35–0.55)
MAOI 0.36
(0.21–0.51)
Post- Acute SSRI 0.23 Hoskins
traumatic (0.12–0.33) et al. (2015)
stress disorder Venlafaxine 0.20
(0.05–0.35)
Obsessive- Acute SSRI 3.2 Soomro et al.
compulsive (3.8–2.6) (2008)
disorder YBOCS
points
Adult ADHD Acute Amphetamine 0.79 Cortese et al.
(0.58–0.99) (2018)
Methylphenidate 0.49
(0.34–0.65)
Atomoxetine 0.45
(0.58–0.32)
2nd Gen AP second-generation antipsychotic, ADHD attention deficit hyperactivity disorder, ADM
antidepressant medications, MAOI monoamine oxidase inhibitor, Olanx + Fluox olanzapine-fluox-
etine combination, NNT number needed to treat to achieve one more response or prevent one more
relapse, SMD standardized mean difference, SNRI serotonin-norepinephrine reuptake inhibitor,
SSRI selective serotonin reuptake inhibitor, TCA tricyclic antidepressant, YBOCS Yale-Brown
Obsessive Compulsive Scale

Intention-to-Treat

Intent-to-treat (ITT) is not a statistical technique, but rather a principle of analysis.

With ITT, all patients are analyzed based on the treatment they were randomized to,
regardless of whether, or for how long, they adhered to the treatment. ITT analyses
address the questions of the benefit and safety of a treatment among all people who
entered the study; thus, ITT analyses may underestimate the benefits of treatment
among those who are fully adherent and complete the trial. Often the primary
analysis of an RCT is based on a “modified ITT,” which analyzes only those
randomized patients who returned to complete at least one efficacy assessment
after the baseline visit.

Missing Data

Missing data are a significant challenge in analyzing RCTs. Study participants who miss
scheduled trial visits, or who dropout prior to completion are sources of missing data.
320 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

There is no single agreed upon approach to handling missing data in statistical analyses,
other than to emphasize trial designs and procedures should minimize the factors that
contribute to missing data. For purposes of analysis, missing data can be broadly
subdivided into data that are “missing at random” versus “missing not at random”
(Little and Rubin 2002). The former applies to data that are missing due to reasons
unrelated to their actual values. The later applies when the cause for the data to be
missing is related to the actual values of the missing data. The distinction is important
because the results may be biased by the causes for the missing data, thereby impacting
analytic approaches.
The last observation carried forward (LOCF) principle is a means of imputing
final outcomes for missing data, based on the last measure for the outcome obtained
during the trial. For patients who complete the trial, no imputation is necessary; their
last measure is the protocol-specified outcome. However, for patients who drop out,
the last measure obtained is used as their outcome. Although regulatory agencies
historically preferred LOCF analyses of RCTs, considering them to be more con-
servative than analyses of complete cases (Harmer and Simpson 2009), there are
many statistical concerns about using LOCF. In particular, it uses the unrealistic
assumption that participants who drop out would continue responding at exactly the
same level at the end of the trial as they did at the time of dropout, which may
unpredictably bias results either toward or away from the null hypothesis.
Mixed model repeated measure (MMRM) approaches to data analysis are a
superior means of handling missing data in RCTs, now accepted by regulatory
agencies. With MMRM, likelihood-based methods using data collected prior to
dropout are used to predict the outcomes that would have been likely to occur
after dropout. The term “mixed models” is used because these analyses generally
incorporate both fixed effects (variables not thought to vary between participants,
such as treatment arm) and random effects (variables that differ between participants,
such as baseline severity). MMRM approaches make more efficient use of the data
and are robust when data are missing at random. They remain susceptible to bias
when data are missing not at random, in which case sensitivity analyses are required
to evaluate the robustness of the results under various assumptions about the data
structure (Mallinckrodt et al. 2008). Simulation and evaluation of NDA datasets
comparing MMRM versus LOCF approaches have found that they generally pro-
duce similar results in terms of estimating effect sizes, but that LOCF analysis of
variance approaches tend to underestimate standard errors and increase the risk of
Type I error (Siddiqui et al. 2009).

Internal Validity

Internal validity of RCTs refers to the whether the observed (measured) difference
between treatment arms reflects a true difference in the efficacy of the medications,
and not some other factor distorting the measured difference. Internal validity
emerges from the quality of the design and conduct of the clinical trial. Low internal
validity can arise from either a systemic bias or from uncontrolled confounding
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 321

variables (Sackett 1979). Randomization effectively controls for confounding vari-

ables, particularly in large samples, but it does not address bias. Bias is present when
a process systematically distorts the results or conclusions of a study away from the
truth. Depending on the source of bias in trial, Type I or Type II errors may result.
Bias can arise during the design of a study, during participant enrollment, during the
conduct of study procedures, or during the analysis of the study data. Bias may also
occur in the differential dissemination of positive or negative study results, such as
publication or presentations.

External Validity

The external validity (often referred to as generalizability) of RCT results refers to

how applicable the results of a trial are to the broader population of patients
suffering from the condition studied, either in terms of efficacy or safety of the
treatment. The major threat to generalizability from Phase II and III RCTs stems
from the inclusion and exclusion criteria used to select patients (Wisniewski et al.
2009). To maximize the ability of an RCT to detect beneficial effects of an
investigational drug, potential confounding variables that may act to diminish
differences between drug and placebo are identified as exclusionary criteria. The
most significant inclusion and exclusion criteria that reduce generalizability
include: (1) requirement for a specific threshold of severity, which excludes mildly
ill patients; (2) maximum durations on the current episode of illness, which
excludes more chronically ill patients; (3) exclusion of many comorbid disorders,
particularly active substance abuse; and (4) prohibition of concomitant psychiatric
medications. Additional exclusions are made for safety reasons, particularly for
children, the elderly, and patients with significant medical disease burden, who
would be more vulnerable if a medication-induced serious adverse event occurred.
An additional, less established threat to generalizability is that most psychiatric
RCTs use community advertising as a source of recruitment, which may be the
primary source of patients for some trials. Community-recruited participants, who
may not be actively seeking treatment, may vary in clinically relevant ways from
participants in active care referred by their clinician, with uncertain effects on
generalizability (Winhusen et al. 2011). Finally, when RCTs have a duration of
only a few weeks or months, the generalizability of the results to patients requiring
long-term treatment remains unknown.

Challenges to Detecting Efficacy of Drugs in RCTs

Placebo Response

The greatest challenge in assessing the efficacy of drugs for psychiatric disorders is
the degree of placebo response. Placebo response rates in RCTs for depression,
anxiety, and schizophrenia have been increasing over the past three decades, in
322 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

synchrony with decreasing effect sizes of active medications (Walsh et al. 2002;
Dunlop et al. 2012; Rutherford et al. 2014, 2015). Response to placebo in an RCT
derives from three factors that can drive improvement: (1) natural waning of
symptoms over time as part of an episodic illness, (2) regression to the mean
(which is particularly relevant when high severity scores are required for study
entry) (Khan et al. 2007); and (3) the placebo effect, i.e., positive psychological
effects and an expectation for improvement patients experience simply by receiving
care. Important elements of the placebo effect include instillation of hope,
psychoeducation resulting from repeated assessments of symptoms and an explan-
atory model for understanding their illness, and high frequency (often weekly) of
contact with concerned research staff. (Frank 1973). In antidepressant RCTs,
response rates decrease and dropouts increase with increasing probability of receiv-
ing placebo, which may stem from expectancy effects (Salanti et al. 2018). Nocebo
responses can also occur, when expectations of harm result in adverse events or
symptomatic worsening with inert treatment.
An insidious contributor to apparent placebo response is selective score
inflation (Landin et al. 2000). Because RCT investigators receive payment for
enrolling eligible subjects, there can be an incentive for over-rating (i.e., inflat-
ing) symptoms at the screening or baseline visits to achieve the necessary
symptom severity threshold required for the patient to qualify. After randomiza-
tion, this pressure to over-rate resolves and more accurate ratings may be
conducted at subsequent visits, leading to a rapid drop in the severity score. A
visual demonstration of these effects in is displayed in Fig. 1a. This factor, along
with the other drivers of placebo response, can result in the frequently observed
graph of symptom change over time in RCTs for major depression, where the
largest reductions in symptoms are observed in the first 2 weeks after starting
treatment (Fig. 1b), which is not consistent with trajectories of improvement
observed in clinical practice.
Several approaches have been developed to minimize the effect of placebo
response in RCTs. A single-blind placebo-lead in phase, in which a 1–2-week
treatment with placebo is given prior to the randomization visit, may be used to
exclude patients who show 25% improvement with the placebo. To address
selective score inflation, centralized raters have been increasingly incorporated into
psychiatric RCTs. With centralized rating, after a patient has been identified by an
investigator at a trial site as appropriate for the study, an independent off-site clinical
assessor conducts a second evaluation via telephone or internet to confirm the
diagnosis and ensure the patient meets the symptom severity criteria. Centralized
ratings may also be used for evaluating symptom scale assessments of efficacy
through the trial, which may suffer from poor inter-rater reliability at trial sites and
be vulnerable to bias arising from unblinding occurring at the site (Kobak et al.
2010).
The ethics of continuing to test investigational drugs against placebo in mental
health disorders despite the existence of effective treatments has been criticized, on
the basis that use of placebo amounts to an unethical withholding of treatment
(Michels and Rothman 2003). However, there are strong arguments for continuing
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 323

Fig. 1 Expectation, change, and the potential effect of selective score inflation on placebo-
controlled RCT results. (a) Theoretical figure representing patient expectations and symptom
ratings during the early phases of an RCT. Speech bubbles contain thoughts patients may have as
they enter an RCT. The solid curve represents patient’s “true” symptom level scores over time, with
a sharp decline between the screening and baseline visits reflecting increases in hope and expec-
tation. It is possible that this improvement is sufficiently great that the patient’s true severity score
may drop below the minimum score required to be eligible to be randomized at the baseline visit.
The dotted lines between screening and week 1 reflect the site rater’s actual scores. At the baseline
visit, selective score inflation occurs if site raters inflate their ratings to ensure that the patient
remains eligible to continue in the study. The difference between the “true” score and the inflated
score is the selective score inflation amount. At week 1, no minimum score is required for the
patient to remain in the study, so the incentive to over-rate the score is removed and the “true” score
is reported, resulting in an apparent steep drop in score from baseline to week 1. Other factors
related to placebo effects may also contribute to this rapid decline. After starting treatment, an
efficacious investigational drug (solid line) will show increasing separation from placebo (dashed
line) over time, but the statistical significance of this difference may be reduced due to the steep
324 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

to require investigational psychiatric drugs to be tested against placebo in short-term

trials on both ethical and public health grounds (Brendel and Miller 2008; Dunlop
and Banja 2009).

Nonadherence to Treatment

Medication nonadherence is another threat to the internal validity of clinical trials

(Shiovitz et al. 2016). Trial participants who often miss doses of study medication
due to side effects or disorganization are effectively under-dosed and thus may
reduce the ability of the drug to induce change (Kane et al. 2013). Over the past
decade, nonadherence by so-called professional patients (i.e., subjects entering a trial
purely for the financial compensation of participating) has emerged as a major threat
to RCTs. Remarkably high levels of medication nonadherence have been detected by
using pharmacokinetic assessments of drug exposure, which provide a better esti-
mate of pill adherence than traditional pill counts used to document adherence
(McCann et al. 2015).

Treatment Resistance

Patients with histories of poor response to multiple treatments are unlikely to

respond to the active treatment in an RCT and are often excluded from trial
participation. The term “treatment resistant” has struggled to achieve consensus
definitions, with variability in usage both within and across disorders. Failure to
respond to one, two, or more adequate trials of medications has been used to define
treatment resistant as a categorical state (Trevino et al. 2014; Howes et al. 2017). As
an alternative, means for measuring treatment resistance as a continuous variable
have been developed for MDD (Fekadu et al. 2018) and PTSD (Dunlop et al. 2014).
Alternatively, RCTs may specifically evaluate a drug for its efficacy in treatment
resistant patients. Notably, aripiprazole, brexpiprazole, quetiapine extended-release,
and a combination pill of fluoxetine-olanzapine all have FDA approval for treat-
ment-resistant MDD, defined as failure to respond to at least two prior antidepressant
medication trials in the current episode. Clozapine is the only drug with a marketing
approval for treatment-resistant schizophrenia.

Fig. 1 (continued) declines in recorded scores that occur in both treatment arms at the week 1 visit.
(b) Outcome data from a placebo-controlled RCT of desvenlafaxine and placebo (Dunlop et al.
2011). It is notable that 65% of the 10-point change in the placebo arm occurred in the first 2 weeks,
with the other 35% gradually accruing over the next 10 weeks. A similar pattern is observed in the
desvenlafaxine arm, which is not consistent with the slower rates of improvement usually observed
in clinical practice. Although the degree of selective score inflation in this trial could not be
assessed, it is a possible contributor to this improvement curve, a pattern also found in many
other RCTs of mood and anxiety disorders
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 325

RCT Considerations for Specific Psychiatric Disorders

Major Depressive Disorder

Major depressive disorder (MDD) is a leading cause of disability around the globe,
with lifetime prevalence estimates ranging from 10% to 18% (Kessler and Bromet
2013). Roughly 80% of patients with MDD experience recurrent episodes (Burcusa
and Iacono 2007), so both acute treatment and relapse prevention are important
treatment targets. MDD is the most common psychiatric disorder studied in RCTs;
placebo effects present a major challenge, with even proven antidepressants failing
to beat placebo in about half of trials (Khin et al. 2011). Psychotherapy and
pharmacotherapy have been shown to be roughly equally efficacious for mild-to-
moderate depression (Weitz et al. 2015), though the presence of psychotic symptoms
(APA 2010) or suicidal ideation (Dunlop et al. 2018; Boschloo et al. 2019) warrants
treatment with medication.
The earliest RCTs with tricyclic antidepressants were usually 4 weeks in
duration and showed large effect sizes over placebo (Undurraga and Baldessarini
2012). With the development of the first selective serotonin reuptake inhibitor
(SSRI), fluoxetine, a belief developed that these agents took 4 weeks or more to
work and the length of the double-blind phase of RCTs trials for modern antide-
pressants is now typically 6–8 weeks. However, the slow time to onset of effect of
fluoxetine likely derives from its long elimination half-life (and that of its primary
metabolite, norfluoxetine), which prolongs the time required to reach effective
plasma and cerebral spinal fluid concentrations of the drug (Altamura et al. 1994;
Henry et al. 2005). Other SSRIs or serotonin-norepinephrine reuptake inhibitors
(SNRIs) have half-lives of a day or less, leading to steady-state levels within the first
week of treatment (Anderson 2001). Meta-analyses have demonstrated that these
shorter half-life agents achieve separation from placebo by the first or second week
of treatment (Hieronymus et al. 2016), though for some patients the specific antide-
pressant effect may not emerge until week 8 (Henssler et al. 2018).
The primary outcome in MDD trials is change from baseline on a clinician-rated
continuous measure of depression severity. The most commonly used scales are the
clinician-rated Hamilton Rating Scale for Depression (HAM-D) (Hamilton 1967) or
the Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery and
Asberg 1979). Although both scales are quite old, newer scales developed to align
with the DSM diagnostic criteria for MDD have not proven to have better psycho-
metrics than these older scales. Self-report measures, such as the Beck Depression
Inventory (BDI) (Beck et al. 1961) or the Quick Inventory of Depressive Symptom-
atology Self-Report (Rush et al. 2003), are often used as secondary assessments of
antidepressant efficacy.
Several versions of the HAM-D exist, ranging from 17 to 31 items. The 17-item
version is the original and most commonly used version, with item scores ranging
from 0 to 4 or 0 to 2 depending on the item, and a total score range of 0–54. Factor
analyses of the HAM-D have identified 2–6 factors, indicating it is not a unidimen-
sional measure of depression (Bagby et al. 2004). Briefer six-item versions of the
326 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

HAM-D (Bech et al. 1981; Maier and Philipp 1985) may be more sensitive to
detecting differences between active and placebo treatments, particularly for drugs
with minimal anticholinergic or antihistaminergic effects (Boessen et al. 2013). The
MADRS is composed of 10 items, each scored 0–6 with scores ranging from 0 to 60.
Severity eligibility thresholds for MDD RCTs typically use a score of 18 22 on
the HAM-D or 25 30 on the MADRS, with the higher scores representing a
moderate-to-severe level of depression severity.
“Response” and “remission” are secondary categorical outcomes that reveal the
proportion of patients who benefit within each treatment arm. Response in MDD is
defined as a 50% reduction in score from baseline. The outcome of remission is
important because it implies a near-complete absence of ongoing symptoms, which
is associated with better psychosocial functioning and lower relapse risk (Judd et al.
1998). The MacArthur criteria define the most widely employed remission thresh-
old: 7 on the 17-item HAM-D (Frank et al. 1991). Concerns have been raised that
this threshold is too high and should be lowered to achieve greater specificity for
positive long-term outcomes (Dunlop and Rapaport 2016; Zimmerman et al. 2012a).
For the MADRS, the remission threshold is less well-agreed upon; total scores 10
appear to correlate best with the HAM-D score of 7, though the scales’ differing
items will result in a lack of agreement on remission for some patients (Zimmerman
et al. 2004). Response rates in short-term trials are 50–60% with antidepressants and
30–40% with placebo (Walsh et al. 2002); remission rates are typically 25–35% vs
15–20% (Depression Guideline Panel 1993), respectively.
The sustained benefits of maintenance antidepressant treatment, particularly in
patients with recurrent depression, have been consistently demonstrated in double-
blind discontinuation studies (Borges et al. 2014). The absolute reduction in recur-
rence risk among individuals maintained on the active antidepressant compared to
those switched to placebo is roughly 20% over 1–2 years of follow-up (Borges et al.
2014; Glue et al. 2010). Although some have raised concern that the higher rates of
depressive relapse with placebo in these trials are artificially elevated due to antide-
pressant withdrawal/discontinuation effects (Fava et al. 2018), this explanation
would require that a substantial proportion of observed recurrences occur during
the first month following the switch to placebo. However, recurrence rates remain
relatively constant over the duration of the follow-up phase, indicating that antide-
pressant withdrawal symptoms do not explain these medications’ protective effects
during long-term treatment (Borges et al. 2014).

Bipolar Disorder

Bipolar disorder is a chronic and debilitating illness characterized by periods of mania

(Bipolar type I) or episodes of major depression and hypomania (Bipolar type II).
Although major depressive episodes are not required for a diagnosis of Bipolar type I,
they occur in approximately 95% of patients with this form of bipolar disorder;
treatment of patients with recurrent unipolar mania without major depressive
episodes has rarely been the focus of controlled treatment trials (Angst and
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 327

Grobler 2015). Bipolar disorder is diagnosed categorically, but there is strong evidence
for conceptualizing its symptomatology on a spectrum, with lifetime prevalence of
bipolar disorder being roughly 1% in adults, and another 1.5% have subsyndromal
symptoms (Merikangas et al. 2011). Due to its episodic nature, most bipolar disorder
trials target specific phases of the illness, specifically treatment of an acute mixed or
manic episode, an acute depressive episode, or maintenance treatment to prevent
recurrence of mood episodes. Regulatory approval of medications is given specifically
for each of these components.
Depressive episodes cause the majority of disability, and time spent ill in patients
with bipolar disorder (Judd et al. 2005). The importance of maintenance treatment is
evident from the 20% to 30% average annual risk for recurrence of a mood episode
(Vázquez et al. 2015). The mainstay of treatment is pharmacotherapy, though
individual and carer-focused therapies can enhance medication adherence and
reduce mood episode recurrences (Chatterton et al. 2017).
Nearly all trials for the treatment of acute mania have used a duration of 3 weeks,
typically enrolling patients in hospital, who may transition to outpatient care before
the end of the trial. The majority have used the Young Mania Rating Scale (YMRS)
as the primary outcome measure. The YMRS consists of 11 items, with 7 items
scored from 0 to 4 and 4 scored from 0 to 8, for a total range from 0 to 60 (Young
et al. 1978). Less commonly used are the Bech-Rafaelsen Mania Rating Scale (11
items rated 0–4, range 0–4) (Bech et al. 1979) and the Mania Rating Scale (11 items,
range 0–52) derived from the Schedule for Affective Disorders and Schizophrenia
(Spitzer and Endicott 1987).
A score of 20 on the YMRS is a common threshold used to select patients for
modern mania trials. Response is defined as a 50% reduction in total score from
baseline. Remission from mania is less well-defined, with many studies using a
YMRS <12 to indicate remission, though the International Society for Bipolar
Disorders has recommended a threshold of <8 or <5 be used, based on the
association of these thresholds with high-functioning status (Tohen et al. 2009).
The mood stabilizers lithium, valproic acid, carbamazepine and several atypical
antipsychotics have marketing approval for the treatment of acute manic episodes.
Clinical trials for acute major depressive episodes of bipolar patients have a
duration of 6–8 weeks and employ the HAM-D or MADRS as the primary outcome
measure, using the same thresholds for eligibility, response, and remission as in
MDD trials. In addition, excessive mood elevation or switch to mania is assessed
with a Mania Rating Scale. Only quetiapine, lurasidone, cariprazine, and the com-
bination of olanzapine-fluoxetine have marketing approval from the US FDA for the
treatment of acute depressive episodes in bipolar disorder. The efficacy of antide-
pressant medications for bipolar depressive episodes has been subject to substantial
debate (Sidor and MacQueen 2011; Gitlin 2018). Perhaps the most consistent finding
is that antidepressants given to patients who are not on a stable dose of a mood
stabilizer increase the risk of manic or mixed episode induction. This risk is
particularly prominent among patients with rapid cycling or depression with mixed
features (Gitlin 2018; Yatham et al. 2018); these patients are typically excluded from
RCTs of medications for bipolar depressive episodes.
328 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

RCTs evaluating medications’ efficacy in preventing the recurrence of mood

episodes have used durations of 6 months to 2 years and have largely been limited
to patients with Bipolar type I. These trials usually have an open-label stabilization
phase in which patients who demonstrate stable mood for 2–3 months enter the
randomized double-blind placebo-controlled discontinuation phase and are followed
for mood recurrence. Lithium, lamotrigine, and several antipsychotics have market-
ing approval from the US FDA for the prevention of mood episodes in bipolar
disorder, and carbamazepine carries this indication in some European nations.

Schizophrenia and Schizoaffective Disorder

Schizophrenia and schizoaffective disorder are psychotic disorders differentiated

primarily by the frequency mood episodes that occur in addition to the psychotic
symptoms. The disorders have a peak age of onset in third decade of life and result in
lifelong disability for most patients (McGrath et al. 2008). Lifetime prevalence of
schizophrenia is approximately 0.5%; for schizoaffective disorder data are less
established, with a prevalence estimate of 0.3% (Perälä et al. 2007). Medication is
the mainstay of treatment, though psychotherapy can help improve functioning,
quality of life, and positive symptoms among patients receiving antipsychotics
(Bighelli et al. 2018). Clinical trials for these disorders can assess efficacy of
medication on short-term (<3 months), medium-term (3–12 months), and long-
term (>12 months) time frames. RCTs may also selectively enroll patients early in
their illness, chronically ill subjects, or a mixture of these (Buchanan et al. 2010). As
in bipolar mania trials, RCTs in schizophrenia often enroll inpatients, following them
as outpatients after discharge. Attrition is a particular concern in schizophrenia
studies; dropout rates average of 37% in modern acute treatment RCTs (Leucht et
al. 2017).
Antipsychotics approved during the 1960s and 1970s are often referred to as
“first-generation antipsychotics” and are characterized by a shared mechanism of
dopamine type 2 (D2) receptor antagonism. In contrast, from the 1980s onward,
“second-generation antipsychotics,” the first of which was clozapine, have been
marketed. These agents have a more balanced affinity for serotonin type 2 (5HT2)
and D2 receptors and a lower risk of extrapyramidal motor side effects. The positive
psychotic symptoms of hallucinations, delusions, and disorganized speech and
behavior historically have been the primary focus of schizophrenia RCTs, with
many trials also enrolling patients with schizoaffective disorder. The past two
decades have seen an increased interest in improving negative symptoms (affective
flattening, alogia, avolition, asociality, and anhedonia) and cognitive dysfunction,
both of which are important drivers of long-term functional impairments in patients
with schizophrenia (Meyer et al. 2014; Ventura et al. 2009). Despite hope that
second-generation antipsychotics would prove more effective for the overall syn-
drome of schizophrenia, large trials have found that except for clozapine, they are
roughly equally effective as first-generation drugs for positive symptoms, with
limited benefit for negative symptoms (Hasan et al. 2012).
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 329

The two most commonly employed rating scales in schizophrenia RCTs are the
Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome
Scale (PANSS). The original BPRS, published in 1962, has 16 items, but a revised
version with 18 items (which added the symptoms of “excitement” and “disorienta-
tion”) has become the standard for RCTs (Overall and Gorham 1962). An expanded
version of the BPRS with 24 items has also been used. The BPRS was not
specifically designed for psychosis studies but received widespread use in schizo-
phrenia due to the absence of alternative scales and its brief length. Each item is
scored from 0 to 7, with total scores ranging from 0 to 126 on the 18-item version.
An 18-item BPRS score 45 is often used as a minimum severity entry criterion for
modern schizophrenia RCTs (Canadian Agency for Drugs and Technologies in
Health 2011).
The PANSS, published in 1987, was specifically developed to be sensitive to drug
treatments in schizophrenia and consists of 30 items scored 1–7. Three subscales,
including general psychopathology (score range 16–112), positive symptoms
(PANSS-P, range 7–49), and negative symptoms (PANSS-N, range 7–49) can be
derived from the scale (Kay et al. 1987). Threshold scores to include patients in most
RCTs are usually set between 60 and 80. A limitation of the PANSS is the time
taken to administer it; a six-item version of the PANSS has been developed but
awaits validation (∅stergaard et al. 2016). Less commonly used are the Scale for the
Assessment of Positive Symptoms (Andreasen and Olsen 1982) and the Scale for the
Assessment of Negative Symptoms (Andreasen 1982).
Unlike mood disorders, response in schizophrenia RCTs lacks a consistent
definition. Investigators have used reductions on the BPRS or PANSS as low as
20% and as high as 50% to define responders, while others have used CGI-I score of
2 (“much improved”) or a combination of CGI-I and rating scale scores (Samara
et al. 2019). Schizophrenia remission criteria are not widely used but have been
proposed to require low levels of eight key symptoms for at least 6 months
(Andreasen et al. 2005).
The psychosis rating scales do not capture the cognitive impairments of schizo-
phrenia. In order to develop a pathway for the US FDA to approve treatments for the
cognitive impairments of schizophrenia, the Measurement and Treatment Research
to Improve Cognition in Schizophrenia (MATRICS) initiative was developed by the
NIMH (Nuechterlein et al. 2004). The resulting MATRICS Consensus Cognitive
Battery (MCCB) consists of ten tests assessing seven cognitive domains that may be
responsive to treatment: verbal learning and memory, visual learning and memory,
working memory, attention and vigilance, processing speed, reasoning and problem-
solving, and social cognition (Nuechterlein et al. 2008). Currently approved anti-
psychotics have not proven to have robust effects on MCCB measures.
Long-acting injectable (LAI) versions of antipsychotics offer important advan-
tages over oral forms, including more consistent blood concentrations and improved
treatment adherence (Fagiolini et al. 2017; Kane et al. 2013; Alphs et al. 2014).
Demonstrating advantages of LAI over oral therapy in traditional RCTs has been
very challenging, with meta-analyses finding no significant benefit over oral therapy,
in large part because the requirements of participating in an RCT (frequent visits and
330 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

monitoring, which increase treatment adherence) run directly counter the major
advantage LAIs offer in routine clinical settings (Kishimoto et al. 2014). Marketing
approval for LAIs may be achieved through RCTs demonstrating noninferiority or
superiority of the LAI formulation compared to oral therapy for symptoms (Euro-
pean Medicines Agency 2012) or real-world outcomes (Alphs et al. 2016).
Evidence derived from RCTs of LAIs has been supplemented with naturalistic
studies, such as mirror-image studies and cohort studies. In mirror-image studies,
patients undergo a retrospective evaluation of their illness course during oral therapy
and then are prospectively assessed after initiating LAI treatment, so that each
patient serves as their own control. These designs are susceptible to recall, selection,
and expectation biases, as well as regression to the mean effects. In cohort studies of
LAIs, patients nonrandomly assigned to LAI or oral therapy are evaluated, prospec-
tively or retrospectively, for differences in outcomes. Confounding arising from the
lack of randomization, as well as attrition or recall bias, can impact cohort studies.
Meta-analyses have found large effect sizes for LAIs in reducing hospitalization for
both mirror-image and cohort designs (Kishimoto et al. 2013, 2018). To address the
discrepancy between RCT and naturalistic trials, effectiveness trials, using few
exclusion criteria and which minimally alter the usual setting for treatment delivery,
have shown efficacy for LAIs (Naber et al. 2015; Schreiner et al. 2015), and likely
represent the best approach for assessing LAI moving forward (Kane et al. 2013).

Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is typically a chronic disorder of waxing and

waning intensity characterized by excessive and uncontrollable worry about multiple
topics occurring along with psychological and somatic symptoms more days than
not for at least 6 months. Lifetime prevalence is roughly 6% in Western nations, with
peak prevalence during mid-life (Alonso et al. 2007). Psychological treatments have
demonstrated efficacy for GAD, and several medication classes have marketing
approval for the condition.
RCTs of medications for GAD are usually 8–12 weeks in duration, though shorter
trials evaluating benzodiazepines have been used. The Hamilton Anxiety Rating
Scale (HAM-A, HARS, or HRSA) (Hamilton 1959) is used almost exclusively as the
primary rating scale outcome in pharmacotherapy trials. The HAM-A consists of 14
items rated 0–4, with total scores ranging from 0 to 56. Sub-scores for psychic and
somatic anxiety (seven items each) can also be calculated (Rickels et al. 1993). Total
scores 18 indicate moderate to severe anxiety and are used as the severity threshold
for eligibility in most trials.
The issue of comorbidity is particularly salient for GAD RCTs. Over 90% of
patients with GAD meet lifetime criteria for at least one other psychiatric disorder,
with MDD, dysthymia, alcohol use disorder, and social phobia being most common
(Wittchen et al. 1994). The generalizability of GAD RCTs is significantly threatened
by comorbidity exclusion criteria; roughly 70% of primary care GAD patients would
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 331

be excluded from GAD trials, with presence of a current major depressive episode
the most important exclusion criterion (Hoertel et al. 2012).
The classes of medications with marketing indications for GAD include benzo-
diazepines, SSRIs, SNRIs, pregabalin, and hydroxyzine. Benzodiazepines were
developed before GAD was defined by the DSM; their labeled indication for the
management of anxiety disorders may be construed to include GAD. Efficacy of
SSRIs and SNRIs in GAD RCTs may be underestimated because several somatic
symptoms of anxiety assessed on the HAM-A (gastrointestinal, genitourinary, and
autonomic symptoms) may also arise as side effects of these medications, leading to
elevations in HAM-A scores by blinded raters. Although benzodiazepines have the
largest effect sizes for GAD, clinical practice guidelines recommend SSRIs or SNRIs
as first-line agents due to benzodiazepines’ higher risk of abuse, lack of efficacy for
comorbid depression, and potential for cognitive impairments (Gomez et al. 2018).

Panic Disorder and Agoraphobia

Panic attacks consist of the rapid-onset periods of fear or anxiety associated with
multiple physiological symptoms. When these attacks occur unexpectedly (i.e.,
without an obvious triggering event or situation), are recurrent, and are followed
by persistent worry of having additional attacks or avoidance of situations associated
with the attacks, panic disorder can be diagnosed. Panic disorder affects roughly 5%
of Western adults in their lifetime, with lower rates observed in other global regions
(Lewis-Fernández et al. 2010) and is often comorbid with mood disorders or other
anxiety disorders (Kessler et al. 2005). Psychological therapies, specifically CBT-
based treatments, and pharmacotherapy demonstrate roughly equal efficacy in the
treatment of panic disorder with or without agoraphobia (Imai et al. 2016).
RCTs for panic disorder typically range from 8 to 12 weeks. In comparison to other
psychiatric disorders, there has been little consistency in the measures used to assess
efficacy in panic disorder (Weise et al. 1996). Many RCTs have used primary outcome
measures that were not specific for panic attacks, such as the HAM-A or the Clinical
Anxiety Scale, a six-item scale derived from the HAM-A (Snaith et al. 1982). There
are several panic-specific questionnaires available, all of which contain one or more
questions about the frequency of panic attacks and associated somatic or avoidance
symptoms. A count of full panic attacks in the prior week, or number of patients being
free of panic attacks at trial endpoint, are the simplest outcome measures and have
been used as a primary or secondary outcome measure in most trials. Due to the
heterogeneity in outcome measures, meta-analyses have used CGI-C scores (Imai
et al. 2016; Bighelli et al. 2018). The Panic Disorder Severity Scale (PDSS), (7 items
rated 0–4, range 0–28) is available in clinician-rated and self-report versions and has
undergone the most complete psychometric evaluation of panic-specific measures,
making it the best option for use in future studies (Shear et al. 2007). An endpoint
score  5 on the PDSS has been proposed as a remission threshold, with a  40%
reduction from baseline representing response (22). Interest in the pharmacologic
332 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

treatment of panic disorder has diminished greatly since the number of RCTs peaked in
the late 1990s, with no placebo-controlled trials conducted in the past decade.
Agoraphobia, which by DSM-IV criteria could only be diagnosed in patients with
panic disorder, was revised to be a free-standing illness in DSM-V. Agoraphobia
symptoms improve with treatment among patients with panic disorder, but there
have been no pharmacotherapy RCTs of patients with agoraphobia who do not have
panic disorder (Perna et al. 2011).

Social Anxiety Disorder

Social anxiety disorder is among the most common psychiatric disorders, affecting
up to 12% of adults. Fear of public speaking is the most common manifestation of
this illness, and many patients forgo pharmacotherapy and choose employment
where presentations are not required or simply use an anxiolytic on an as-needed
basis. In more generalized forms of social anxiety disorder, patients may have
difficulty speaking up in small groups, to authority figures, or engaging in behaviors
such as eating or writing while being observed. The adverse life consequences for
these individuals are much greater, with lower likelihood of marriage, promotion,
and increased risk for major depression (Wong et al. 2011). CBT can effectively treat
social anxiety disorder and is roughly equally as effective as pharmacotherapy. For
patients with more generalized forms of social anxiety, several medications have
proven effective, including SSRIs and venlafaxine, which have marketing indica-
tions, phenelzine, moclobemide, benzodiazepines, and anti-convulsants (Williams
et al. 2017).
Response to pharmacotherapy in social anxiety disorder is slow, with most
placebo-controlled RCTs lasting 10–12 weeks. The Liebowitz Social Anxiety
Scale (LSAS), which is available in well-correlated self-rated and clinician-rated
forms (Fresco et al. 2001), has emerged as the preferred primary symptom measure.
The LSAS lists 24 social scenarios, each of which is scored twice: once for fear of
the scenario and once for avoidance of it. Fear and avoidance are both scored from
0 to 3, resulting in total scores ranging from 0 to 144. The LSAS score can also be
divided into sub-scores assessing performance situations and social interaction
situations. A threshold of LSAS 50 or 60 is usually used as the severity inclusion
score for RCTs.
A score of <30 has been used to define remission on the LSAS, as this threshold
has been found to distinguish between people who meet criteria for social anxiety
disorder versus those who do not (von Glischinski et al. 2018). However, social
anxiety disorder, perhaps more than any other psychiatric disorder, is impacted by
cultural norms. Indeed, LSAS mean scores among those clinically diagnosed with
social anxiety vary substantially across cultures (von Glischinski et al. 2018),
suggesting that remission scores may warrant individualizing by culture. Response
definitions in RCTs have usually used a 50% reduction from baseline, but this
amount of change does not align with CGI-I scores (Bandelow et al. 2006). Although
an optimal percent improvement for defining response in social anxiety disorder
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 333

trials has not been determined, some work suggests a 30% reduction from baseline
may be most appropriate (Bandelow et al. 2006; von Glischinski et al. 2018).

Post-traumatic Stress Disorder

PTSD is a persisting state of re-experiencing, avoidance, and hyperarousal that

develops in the wake of a traumatic event, defined as a threat to the life or physical
integrity of a person or one they witness occurring to a loved one or others in close
physical proximity to them. Lifetime prevalence estimates for PTSD around the
globe range from 3% to 9%, with current incidence ranging from 1% to 3.5%
(Katzman et al. 2014; Stein et al. 2014). Most clinical treatment guidelines recom-
mend patients with PTSD be treated first with a trauma-focused psychotherapy
before applying pharmacotherapy treatments, though dropout from these demanding
psychotherapies is high (Yehuda et al. 2015).
Of the common psychiatric disorders, PTSD is the most complex to diagnose
based on the number and distribution of symptoms. DSM-IV involved 17 symptoms
across 3 clusters (re-experiencing, avoidance/numbing, hyperarousal), whereas the
DSM-V assesses 20 symptoms across 4 clusters (intrusion, avoidance, negative
alterations in cognitions and mood, alterations of arousal and reactivity). The ICD-
10 criteria used 13 symptoms and were relatively close to the DSM-IV criteria, but
the proposed ICD-11 criteria will use only 6 symptoms (dissociative flashbacks,
nightmares, hypervigilance, exaggerated startle response, avoidance of external
reminders, and avoidance of thoughts and feelings associated with the trauma). If
adopted as proposed, the ICD-11 criteria are expected to exclude one-third to one-
half of patients who meet ICD-10 criteria, yielding a smaller and more severely ill
population (Barbano et al. 2018). Generalizability of clinical trial results, and
comparability with prior RCTs, will therefore be impacted based on the diagnostic
criteria used to select participants.
The gold standard for assessing PTSD symptom severity is the Clinician-Admin-
istered PTSD Scale (CAPS, Blake et al. 1995). The nomenclature for this scale has
changed over time, which has led to some confusion in the literature. The original
release of the CAPS for the DSM-IV included two versions. The CAPS-1 assessed
symptoms over a 1-month period, which could be used for current or lifetime
diagnosis of PTSD. The CAPS-2 assessed symptoms over the prior week, a better
interval to assess change in short-term clinical trials. The names for the CAPS-1 and
CAPS-2 were subsequently changed to CAPS-DX (for diagnosis) and CAPS-SX
(for symptoms), respectively. Ultimately, the two versions were combined to be used
for either purpose and called simply CAPS (also known as CAPS-IV, to emphasize
the DSM-IV criteria). All these versions of the CAPS consist of 30 items, of which
17 items are the DSM-IV diagnostic criteria from the 3 symptom clusters and are
used to calculate the total score. Each of these 17 items are scored twice from 0 to 4,
once for the intensity of the symptoms and once for their frequency. Thus, the total
score ranges from 0 to 136 (17  8), and a score 50 or 60 was most often used as
the severity eligibility threshold for RCTs. To match the DSM-5 PTSD criteria,
334 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

the CAPS-5 was released, incorporating the new symptoms and revising the scoring
of the symptom items (Weathers et al. 2018). On the CAPS-5, each of the 20 items is
only scored once from 0 to 4, incorporating severity and frequency together,
resulting in a range of 0–80. Current studies using the CAPS-5 use scores of
28–32 as the inclusion threshold.
Other scales commonly used in PTSD RCTs are the PTSD Checklist for DSM-5
(PCL-5), a self-report of 20 items rated 0–4 that reflect the DSM-5 symptom criteria,
and the Impact of Events Scale-Revised (IES-R), a self-report scale assessing 22
symptoms from 0 to 4 over the past week. The CAPS-IV and PCL-5 have shown
good correlation with the CAPS-5, indicating compatibility across trials using these
instruments (Weathers et al. 2018). On the CAPS-IV, response in RCTs has been
most commonly defined as a reduction in total CAPS scores of 30%, with
remission defined as an endpoint score <20 (Stein et al. 2006). Improvement
thresholds for the CAPS-5 have not yet been established. Many other measures for
assessing PTSD symptoms have been developed but have not received widespread
use (American Psychological Association 2017).
The variety of symptoms subsumed within the PTSD diagnostic criteria results in
heterogeneous samples in RCTs, particularly in the levels of re-experiencing or
hyperarousal symptoms across patients. The broad variability in symptomatology
can produce highly variable outcomes of pharmacotherapy trials. The SSRIs and
venlafaxine broadly improve the syndrome but appear less effective for
re-experiencing symptoms than for the other clusters (Stein et al. 2006). Prazosin
is helpful for insomnia and nightmares, and atypical antipsychotics such as risper-
idone and quetiapine have also proven to be particularly efficacious for re-experienc-
ing symptoms either as monotherapy or when added to an SSRI (Dunlop and
Davidson 2019).
The importance of patient selection for PTSD RCT outcomes is evident from the
remarkable differences in efficacy of agents tested in civilians with PTSD versus US
military veterans with PTSD. SSRIs, prazosin, and risperidone all have demon-
strated efficacy in multiple PTSD RCTs enrolling civilians, but all three have failed
in large trials administered through the US Veterans Affairs (VA) health system.
Reasons for these discrepancies remain uncertain but may result from the greater
chronicity or severity of PTSD in military samples, secondary gain concerns, or
aspects of the VA trial designs, including broad inclusion criteria, including signif-
icant medical comorbidity, and allowing multiple concomitant psychotropic medi-
cations during the trial. These trial design features all act to reduce the probability of
identifying differences in efficacy between an active intervention and placebo. Trials
conducted in the VA may be more appropriately considered effectiveness trials in a
chronic and severely ill population, rather than classic RCTs assessing efficacy.

Obsessive-Compulsive Disorder

OCD involves the experience of obsessive thoughts or compulsive behaviors that are
distressing or impairing or occupy the patient for more than 1 h per day. OCD affects
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 335

roughly 2% of adults, commonly comorbid with tic disorders (Hirschtritt et al.

2017). Effective treatments for OCD include cognitive-behavioral therapies (partic-
ularly exposure and response prevention) or medications that inhibit serotonin
reuptake, specifically the SSRIs or the TCA clomipramine, which has high selectiv-
ity for inhibiting the serotonin transporter (Hirschtritt et al. 2017; Soomro et al.
2008). Several antipsychotics have proven effective as augmentation agents for
OCD and may be particularly effective among patients with a comorbid tic disorder
(Bloch et al. 2006).
Response to pharmacotherapy is typically slower for OCD compared to other
psychiatric disorders, and RCTs are often 12 weeks in duration. The Yale-Brown
Obsessive-Compulsive Scale (Y-BOCS) is used almost exclusively the primary
outcome measure in modern trials (Goodman et al. 1989); older studies often used
the National Institute of Mental Health Obsessive Compulsive Scale (Insel et al.
1983). The Y-BOCS begins with a checklist assessing for the presence of 64 types of
obsessions or compulsions. The severity of these symptoms is then assessed with 10
items (5 for obsessions and 5 for compulsions) rated by a clinician from 0 to 4. For
most studies, a total score 16 is used as the severity criterion to determine
eligibility. The range of improvement from baseline in YBOCS total scores used
to define response is 25–35%. Placebo-controlled discontinuation studies have found
high rates of relapse after tapering off effective SSRI or clomipramine treatment,
indicating that treatment should be sustained for 1–2 years, and may need to be
lifelong in many cases (Fineberg et al. 2007, 2012).

Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is characterized by the childhood

onset of symptoms of inattention, hyperactivity, or impulsivity, which affects
roughly 5% of children and adolescents, of whom approximately 15% continue to
meet full criteria in adulthood (Faraone et al. 2006). Pharmacological agents are the
mainstay of treatment, with psychological therapies such as contingency manage-
ment and CBT used as adjunctive interventions (Catalá-López et al. 2017).
The great majority of ADHD intervention trials have been conducted in children,
though adult ADHD has gained interest over the last decade. RCT durations vary
widely from 2 to 24 weeks, with 8 to 12 weeks being the most common (Cortese
et al. 2018). A variety of severity measures have been used (Cortese et al. 2018), with
the most commonly primary outcome measure in modern trials being the ADHD
Rating Scale for DSM-IV (ADHD-RS-IV), a parent- or teacher-rated scale consisting
of 18 items reflecting the 18 symptom criteria in the DSM-IV (DuPaul et al. 1998).
DSM-5 led to some changes in the wording of the symptom items for diagnosis, which
are reflected in the most current version, the ADHD-RS-5. The items are scored 0–4,
with severity thresholds required for trial eligibility typically 26 or 28. The
Conners Rating Scale (Conners 1973), a parent-reported assessment, was widely
used in older trials, though several limitations have been identified, and it has been
largely displaced by the ADHD-RS in modern trials (Gianarris et al. 2001).
336 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Thresholds for response and remission are not well-established for ADHD. Reductions
of 25–30% from baseline on rating scales have been proposed to define response,
which aligns with a one-level change on the CGI-C scale (Steele et al. 2006; Goodman
et al. 2010). RCTs for adult ADHD are similar in design to those for children and
adolescents, most often using the ADHD-RS or Conners Adult ADHD Rating Scale as
symptom outcome measures (Cunill et al. 2016).

Eating Disorders

Anorexia nervosa, bulimia nervosa, and binge eating are not common, with preva-
lence in Western nations of 0.5%, 2%, and 4%, respectively (with lower rates in other
regions), but they carry high rates of morbidity and mortality (Hoek 2016;
Westmoreland et al. 2016). Psychotherapeutic treatments are the primary modality
of treatment for eating disorders, though medications may be used adjunctively. No
medications carry a marketing indication for anorexia nervosa; fluoxetine is the only
drug with an FDA indication for bulimia nervosa, and lisdexamfetamine is the only
drug with an indication for binge eating disorder.
One 11-week phase II and two 12-week phase III trials have demonstrated the
efficacy of lisdexamfetamine for binge eating disorder. The trials used as the primary
outcome the change in days per week of eating binges, with a secondary outcome
being the proportion of patients with complete cessation of binge eating for 4 weeks
(McElroy et al. 2015, 2016). A single 6-month, double-blind discontinuation trial
with this drug, which defined relapse as 2 binge eating days per week for 2
consecutive weeks and a 2-point CGI-S score increase, found significantly fewer
patients continuing on the medication relapsed (4%), compared to those assigned to
placebo (32%) (Hudson et al. 2017). Although lisdexamfetamine significantly
reduced body mass index in the acute treatment trial of binge eating disorder
(McElroy et al. 2015), the effects on BMI in the long-term study were not reported.
As a continuous outcome measure, a 10-item version of the Y-BOCS modified for
binge eating (Y-BOCS-BE) has demonstrated sensitivity to treatment effects (Deal
et al. 2015).
Most pharmacotherapy RCTs for bulimia are 6–52 weeks in duration. SSRIs
(particularly fluoxetine) and TCAs are the most studied medications, though MAOIs
have also been tested (Svaldi et al. 2019). Remission in bulimia has been defined as
either the abstinence of bulimia-related symptoms for 2 weeks, or as no longer
meeting diagnostic criteria for bulimia nervosa (including the cognitive elements)
(Slade et al. 2018). Reduction of binge eating episodes and compensatory behaviors
are additional outcomes assessed. Meta-analyses have found pharmacotherapy to be
substantially less effective than psychotherapy, though the combination together
improve outcomes (Slade et al. 2018; Svaldi et al. 2019).
Pharmacotherapy RCTs for anorexia nervosa are conducted as add-on treatments
to a psychosocial treatment program. Trials have ranged from 7 to 52 weeks in
duration, with most having very small sample sizes and only two analyzing >100
patients. Weight gain is the primary outcome for most studies, though hormonal
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 337

interventions have looked at several biological indices, particularly bone mineral

density. Effect sizes with antidepressants and antipsychotics are small and did not
achieve statistical significance in a meta-analysis (de Vos et al. 2014).

Substance Use Disorders

Throughout the world, substance use disorders (SUD) are widespread and are
leading causes of disability, though the specific patterns of drugs abuse vary by
nation (Peacock et al. 2018). Medication-assisted treatment (MAT), in which med-
ications are prescribed within a psychosocial treatment approach, is considered the
optimal form of treatment for SUD, and pharmacotherapy RCTs for SUD are
conducted within this paradigm. Unlike other psychiatric disorders, SUD outcomes
can be objectively assessed through laboratory testing using biochemical verification
to supplement self-reported measures. Unfortunately, overall success rates in treating
SUD remain unsatisfactory. A novel approach under development is to use vaccines
for SUD, most of which act by inducing production of drug-specific polyclonal
antibodies, thereby retaining the abused drug in the systemic circulation, preventing
or slowing its penetration into the central nervous system (Heekin et al. 2017).
Because substance use disorders are often characterized by binge use or frequent
relapses, the primary outcome in substance abuse RCTs is typically sustained
abstinence, which may be defined as 6 months or longer without use. Other out-
comes commonly assessed include (1) number or percent of days/weeks abstinent
from the substance; (2) proportion of the sample abstinent for a minimum period
(e.g., 3 weeks); (3) proportion of sample abstinent at end-of-treatment; (4) changes
on a scale assessing drug addiction (e.g., the drug scale of the Addiction Severity
Index-5) (McLellan et al. 1992); and (5) biochemical assessments, such as the
number or percent of negative drug screens during treatment. The most rigorous
assessments of abstinence use a combination of self-reported use and biochemical
verification measures. Biochemical verification has particular value when studying
populations who may feel pressure to under-report their use, such as pregnant
women or post-surgical patients when queried about recent smoking (SRNT Sub-
committee on Biochemical Verification 2002).
Nicotine, alcohol, and opiate use disorders each have medications with marketing
approval for their treatment. After alcohol and tobacco, cannabis is the most widely
used substance of abuse, and the efforts to legalize cannabis products proceeding in
many nations are likely to increase its usage and associated harms (Ammerman et al.
2015). RCTs for medications to address withdrawal symptoms or maintenance
treatment for cannabis (Sherman and McRae-Clark 2016), cocaine (Shorter and
Kosten 2011), or amphetamines (Lee et al. 2018) have thus far failed to identify
medications that safely and effectively enhance treatment outcomes.

Nicotine
Although the prevalence of nicotine use disorder has been declining for several
decades, it remains the leading cause of premature death and preventable disease
338 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

around the world. Smoking rates vary widely across nations, ranging from 10% to
>50%, with 12% of all deaths among people over 30 years old attributable to
tobacco (Drope et al. 2018). Roughly one-third of adults with mental illness
smoke cigarettes, compared to 15% without mental illness, and they smoke more
intensively (Drope et al. 2018). A variety of psychotherapeutic interventions have
proven helpful, though their efficacy is enhanced when combined with pharmaco-
therapy (Stead and Lancaster 2012). Pharmacological interventions for nicotine use
disorders can be considered aid-to-cessation trials, which test a treatment in smokers
currently willing to cease use, using long-term abstinence rate as the primary
outcome measure. Medications with marketing approval as aids to smoking cessa-
tion include varenicline (a nicotinic acetylcholine receptor partial agonist),
bupropion (a noradrenergic and dopaminergic antidepressant), and nicotine replace-
ment therapy (NRT, delivered via patch, tablets, inhalers or sprays, or gum).
The self-assessment Fagerstrom Test for Nicotine Dependence (Heatherton et al.
1991) is the most widely used assessment for diagnosis of nicotine use disorder,
consisting of six items that total from 0 to 10. Scores of 1–2 reflect low dependence;
scores of 8–10 reflect very high dependence. Duration of RCTs for nicotine use
disorder is usually 12 weeks, and often have participants set a target quit date.
Because patients commonly fail to fully quit on the specified date, the Society for
Research on Nicotine and Tobacco suggests a 2-week grace period beyond the quit
date (Hughes et al. 2003), during which any smoking does not count toward
abstinence failure. Thus, the targeted quit date needs to be clearly defined.
A wide variety of outcome measures have been used in pharmacotherapy RCTs
for nicotine use disorder. The optimal outcome is abstinence, which has been
characterized in three constructs:

(1) Continuous abstinence refers to sustained abstinence from the quit date through
the end of the follow-up period.
(2) Prolonged abstinence is another measure of sustained abstinence but begins
from the end of the grace period following the quit date through the end of
follow-up
(3) Point-prevalence abstinence is abstinence in a specific time window (usually
7 days) prior to the follow-up assessment (Hughes et al. 2003).

A measure of sustained abstinence (6 or more months) is the most preferred

outcome because it is more stable and better predicts lifelong abstinence; of the two
forms, prolonged abstinence is preferred over continuous abstinence because only a
minority of smokers are able to completely quit without experiencing a lapse or
relapse (Cheung et al. 2017). Shorter trials using only a few months of follow-up are
better considered as proof-of-concept trials rather than definitive trials proving an
intervention’s efficacy (Hughes et al. 2003). Point-prevalence abstinence as an
outcome has the benefit of being less susceptible to memory bias and can identify
people who take longer to achieving smoking cessation after intervention.
Patients not currently wishing to achieve abstinence may nevertheless desire to
reduce their level of cigarette consumption. NRT is the most common intervention
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 339

for these trials, using the number of cigarettes per day (CPD) or the proportion of
participants reducing CPD by 50% as the primary outcome measure. Whether such
reductions actually reduce the health harms from smoking has not been adequately
resolved (Lindson-Hawley et al. 2016).
Biochemical verification, using cotinine or exhaled carbon monoxide, may be
used to confirm self-reported abstinence. Cotinine is a major metabolite of nicotine
and can be detected in blood, urine, and saliva. Plasma and salivary cotinine levels
are closely correlated, and the half-life of cotinine in plasma is 15–20 h (compared to
1–2 h for nicotine), allowing for detection of nicotine exposure 3–7 days after last
use. Urinary cotinine concentrations are fourfold to sixfold greater than in plasma,
making urine cotinine the most sensitive biomarker of exposure. However, most
RCTs that employ cotinine measures use salivary assessments due to the ease of
collection. A limitation of cotinine is that abstinent patients on NRT will continue to
test positive for it (Jatlow et al. 2008). Exhaled carbon monoxide (CO) may also be
used for verification, with the advantage of being valid for NRT trials. Although
exhaled CO is only able to detect very recent nicotine use (i.e., up to 9 h prior to
testing), the ease of administration with a breathalyzer, which provides real-time
results, offers high utility. The Russell standard for smoking cessation recommends
the use of self-reported prolonged abstinence with biochemical validation using
exhaled CO (West et al. 2005).

Alcohol
The diagnosis of alcohol use disorder (AUD) requires that a patient meets at least 2
of 11 DSM-V criteria and can be classified as mild, moderate, or severe depending
on the number of symptoms endorsed. The global 1-year prevalence of AUD is
nearly 5%, affecting more than 100 million people (GBD 2016 Alcohol and Drug
Use Collaborators 2018). AUD has devastating health impacts (Kranzler and Soyka
2018) and drives 5.1% of global disability-adjusted life years (World Health Orga-
nization 2018). Combination of psychotherapy (often provided through 12-step
groups, such as Alcoholics Anonymous or outpatient therapists) combined with
comprehensive medical care and pharmacological approaches are considered opti-
mal care (43).
The duration of most pharmacotherapy trials for AUD is between 12 and
17 weeks, though several have treatment periods up to 1 year. Studies typically
evaluate medications added on to a psychosocial intervention, enrolling patients
immediately after detoxification who have a minimum of 3 days of sobriety. The
primary outcome is usually the proportion of patients remaining abstinent from
alcohol (Jonas et al. 2014). Although abstinence is the most desirable result and
associated with the best long-term health, many patients wish to reduce drinking
without becoming completely abstinent. Based on data from the COMBINE trial
(Anton et al. 2006), the US FDA also accepts the surrogate outcome of “no heavy
drinking days,” with a heavy drinking day defined for men as >4 standard drinks and
for women as >3 standard drinks (FDA 2015; Falk et al. 2010).
Three medications have US FDA marking approval for alcohol use disorder,
disulfiram, acamprosate, and naltrexone, which is available in oral and long-acting
340 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

injectable formulations. Despite their efficacy, <10% of patients who could benefit
from these medications receive them in the United States (Mark et al. 2009).
Disulfiram was approved in 1949 by the US FDA, though meta-analyses of RCTs
have found no benefit over control treatments placebo (Skinner et al. 2014). Because
the mechanism of disulfiram depends on the psychological fear of experiencing a
disulfiram-ethanol reaction, and the risk is similarly present in placebo arm, identi-
fying a specific effect of disulfiram is challenging (Suh et al. 2006).
Nalmefene, an antagonist at μ- and δ-opioid receptors and partial agonist at
κ-opioid receptors, is approved for treatment of alcohol use disorder in Europe for
a highly specific subset of drinkers. When used as needed when feeling tempted to
drink, nalmefene reduced total alcohol consumption and number of heavy drinking
days per month compared to placebo (Jonas et al. 2014). Several concerns exist
about the data used to justify approval of nalmefene, including post hoc outcome
definitions and a retrospectively defined subset of patients analyzed (Fitzgerald et al.
2016).

Opiates
Opioid use disorder (OUD) is considered to be at an epidemic level in the United
States (Scholl et al. 2018) and is the fastest growing substance use disorder globally
(GBD 2016 Alcohol and Drug Use Collaborators 2018). Unlike other substance use
disorders, behavioral treatments without medication assistance show low success
and are rarely used. Pharmacotherapy for opioid dependence is divided between the
acute treatment phase, designed to minimize opioid withdrawal symptoms, and the
maintenance treatment phase, where the primary goals are to prevent relapse and
minimize harms resulting from use. A key consideration in opiate use disorder RCTs
is determining the population to enroll based on the form of opiate abused. Com-
pared to heroin users, prescription opioid users have better treatment outcomes on
average, likely resulting in large part from better a variety of positive predictive
factors (Potter et al. 2013; Weiss and Rao 2017).
Four drugs carry FDA indications for use in the treatment of OUD: methadone, a
long-acting mu-receptor agonist approved for both detoxification and maintenance
treatment; buprenorphine, a mu-opioid receptor partial agonist, which is also
marketed as a sublingual film combination product of buprenorphine and naloxone
(a mu-receptor antagonist) approved for maintenance treatment; naltrexone, an
opioid receptor antagonist approved for maintenance when delivered in a long-
acting injectable form; and lofexidine, a structural analog of clonidine that agonizes
central α2 receptors, approved for the mitigation of opiate withdrawal symptoms.
Although lofexidine was approved for the treatment of opiate withdrawal in the
United Kingdom in 1992, it did not receive approval in the United States until 2018.
Additionally, an extended-release version of buprenorphine delivered as a weekly or
monthly injection has received tentative approval from the FDA (FDA 2018b).
Acute treatment is designed to minimize opioid withdrawal symptoms. Patients
entering acute treatment may complete detoxification or undergo transition to long-
acting opioid treatment with methadone or buprenorphine as part of agonist main-
tenance. RCTs vary in their design depending on whether the intent is for patients to
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 341

enter long-term agonist treatment after detoxification. Detoxification alone without

maintenance treatment is associated with very high rates of relapse (Sigmon et al.
2012). Many scales have been developed to assess opioid withdrawal symptoms, the
most widely used of which is the Clinical Opiate Withdrawal Scale, a clinician-
administered scale of 11 items rated 0–4 or 0–5 (range 0–48) (Wesson and Ling
2003). However, these scales are only used to guide withdrawal treatment; the
primary outcome for acute treatment OUD RCTs is the proportion of patients
completing treatment, also incorporating the proportion with negative urine drug
screens.
Transitioning patients from other opiates to agonist maintenance with methadone
or buprenorphine-containing products begins with induction followed by stabiliza-
tion to find the optimal dose for the individual for use during the maintenance phase.
Due to their ability to induce abrupt opiate withdrawal, buprenorphine-containing
products are only administered after the first signs of opioid withdrawal appear; this
precaution is not necessary for methadone induction (Weiss and Rao 2017). In
outpatient settings, 4-week tapers using buprenorphine have proven superior to
1- or 2-week tapers (Sigmon et al. 2013). Following detoxification, patients may
alternatively undergo induction to naltrexone for use in maintenance treatment,
though the pill form is associated with poor compliance and only the injectable
form is approved by the US FDA for maintenance treatment of OUD.
Although sustained abstinence is ideal, few patients achieve this outcome. Con-
sequently, the FDA also considers change in drug use pattern as an outcome measure
in opioid use disorder RCTs. Given the pressures of the opioid use epidemic, the
FDA has announced it is now open to other surrogate measures of efficacy for OUD,
including adverse outcomes (e.g., mortality or hepatitis C seroconversion), DSM-5-
defined remission status, and patient-reported outcomes, such as intensity of craving
(Food and Drug Administration 2018b).

Safety and Tolerability Assessment in RCTs

Safety and tolerability are important considerations in investigational drug trials but
historically have received less attention than efficacy assessments. Risk is unavoid-
able in evaluating new medications, and the potential benefit to the individual should
be commensurate with the known risks. The risk-benefit ratio may change through
the trial as data accumulates. Particularly in phase I, when a drug is being adminis-
tered to humans for the first time, risks not seen from animal studies may emerge. In
later phases, when the drug is given to hundreds of people with the psychiatric illness
being studied, rarer medical risks may emerge. Monitoring for emergent risks in an
RCT may be conducted by the study sponsor or by an independent Data Safety
Monitoring Committee, which reviews the safety data at intervals while the trial is
ongoing. New safety concerns, such as liver or cardiac toxicity, that emerge during
the trial may sufficiently increase the risk to result in trial termination. In addition,
the potential “futility” of the intervention may be evaluated by a statistical analysis of
the data at an interim assessment, which may determine that even with continued
342 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

enrollment of subjects, the intervention could not statistically prove to be efficacious.

Although rare in psychiatric studies, a trial may also be terminated early due to
evidence of overwhelming benefit of the intervention.
Safety in phase II and III RCTs is assessed with physical exams, electrocardio-
grams, and laboratory testing. In addition to general chemistry and hematology
monitoring, liver function is closely monitored, and additional laboratory tests
(e.g., prolactin) may be monitored depending on potential concerns detected from
preclinical studies or related compounds.
An adverse event is any untoward change in physical or mental health occurring
after a patient consents to participate in a study, including a subjective side effect, an
objective physical change, or a clinically significant change in a laboratory test or
electrocardiogram. Subjectively experienced side effects during RCTs are most often
assessed by nondirective, open-ended general inquiries by the investigator regarding
any physical or mental health problems the patient has experienced since the
previous assessment. Attributing any such changes to the investigational product
always carries uncertainty, and usually a probability rating is assigned to each side
effect, ranging from “not related” to “definitely related.” Nondirective inquiries may
significantly underestimate side effect frequency (Rabkin et al. 1992). More specific
questionnaires have been developed but are not consistently implemented in RCTs
due to concerns about time burden, the desire to avoid suggestion effects in eliciting
side effects, and the potential to elicit clinically trivial side effects (Rabkin et al.
1992). Two of the more widely used side effect assessments in psychiatric trials are
the 77-item Systematic Assessment for Treatment Emergent Effects, Specific Inquiry
(SAFTEE-SI) (Levine and Schooler 1986), and the Udvalg for Kliniske
Undersøgelser Side Effect Rating Scale (UKU-SERS), a 48-item assessment devel-
oped by the Scandinavian College of Neuropsychopharmacology (Lingjaerde et al.
1987). Both scales are also available in self-report versions. A briefer self-report
scale, the Patient-Rated Inventory of Side Effects (PRISE), has recently seen
increasing use (Rush et al. 2004).
Structured assessment of side effects has received the most focus in antipsy-
chotic drug development due to the importance of extrapyramidal symptoms (EPS)
and tardive dyskinesia. In modern trials, EPS symptoms are most often assessed
using three scales: akathisia with the 4-item Barnes Akathisia Scale (Barnes 1989);
drug-induced parkinsonism with the 10-item Simpson Angus Scale (Simpson and
Angus 1970); and dyskinesias with the Abnormal Involuntary Movement Scale
(Guy 1976). The finding that antidepressants (Stone et al. 2009) and possibly anti-
epileptic medications (Ferrer et al. 2014) can increase the risk of suicidal ideation
among patients, particularly children and young adults, led to the incorporation of
specific measures of suicidal ideation and behavior into clinical trials. The Colum-
bia-Suicide Severity Rating Scale (C-SSRS) is perhaps the most commonly used
instrument, though several others exist (Posner et al. 2011; Erford et al. 2018). Side
effects arising from discontinuation of antidepressants and benzodiazepines can be
assessed with the Physician Withdrawal Checklist (Rickels et al. 1990, 2008) or the
Discontinuation Emergent Signs and Symptoms assessment (Rosenbaum et al.
1998).
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 343

When a drug receives marketing approval, the number of patients who have been
exposed to the compound in phase I–III trials is usually only on the order of several
hundred. Thus, rare side effects or other complications of treatment may not have
been detected, leading to the need for post-marketing pharmacovigilance for risks
emerging in the broader population. For example, the US FDA may require the
sponsor to conduct additional studies or surveillance after giving approval to market
a drug. In addition, systems such as the FDA Adverse Event Reporting System
(comprised of safety reports from manufacturers and MedWatch reports clinicians
and patients), the FDA’s Sentinel system (monitoring electronic health records and
administrative claims data), and the World Health Organization’s Program for
International Drug Monitoring all provide means for detecting emerging risks once
a drug is widely prescribed. Pharmacovigilance for liver toxicity has led to warnings
or market removal for several psychiatric medications, including amineptine,
nefazodone, and pemoline (Spina and Trifirò 2016). In addition, the FDA Center
for Drug Evaluation and Research conducts a scheduled safety analysis after 10,000
patients have been prescribed the drug or 18 months after approval, whichever is
later.

Criticism of Psychiatric Clinical Trials

Despite the success of RCTs in identifying efficacious medications that are widely
adopted by clinicians, several criticisms have been levied against the widespread use
of psychopharmacological drugs and the RCT evidence base supporting their use,
particularly for antidepressants (Moncrieff 2008). These concerns can be broadly
divided into aspects of internal validity, external validity, and safety.
Concerns about internal validity stem from potential for bias in the design,
conduct, or analysis of RCTs. Potential sources of bias in modern phase II or III
clinical trials are listed in Table 3. To mitigate many of the potential biases of RCTs,
the Consolidated Standards of Reporting Trials (CONSORT) have been developed
(http://www.consort-statement.org/), to support the full reporting of trial elements
that could lead to bias or confounding.
Additional concerns have been raised regarding the internal validity of relapse
prevention studies. Because patients who do not benefit from the study medication
during the open-label phase are dropped from the study, these “enrichment” designs
have been critiqued for selection bias, in that only patients who benefit from the
medication are studied (Ghaemi and Selker 2017). Attrition bias (dropout) during the
maintenance phase can be a more significant factor that has unpredictable conse-
quences for effect sizes, in that patients who dropout prior to a relapse are usually
censored in the statistical analysis (i.e., contribute no further data beyond the time of
dropout); the effects of medication may be inflated if these subjects are dropping out
for reasons related to the medication (Nunan et al. 2018).
Generalizability of psychiatric RCT results is a widespread concern (Wisniewski
et al. 2009; Licht 2002; Gilbody et al. 2002). External validity is threatened by the
aforementioned inclusion and exclusion criteria, which greatly narrow the subset of
344 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Table 3 Sources of bias threatening the internal validity of randomized controlled trials
Type of bias Description Example
Design bias Writing the study protocol in a Using an active comparator at high
way that will artificially enhance doses so that tolerability appears
the efficacy or tolerability of the better for the investigational drug
investigational drug versus the
comparator
Selection bias Enrollment of patients specifically Offering trial participation only to
more likely to show benefit of the patients with good responses in the
investigational drug versus the past to a treatment similar to the
comparator one under study
Measurement The scoring of clinical measures is The clinician assessing side effects
(ascertainment) bias influenced by the investigator/ is the same one rating efficacy,
assessor which increases the likelihood of
unblinding
Analytic bias Statistical analysis of the study Analyzing as the primary outcome
data in a way that differs from the efficacy detected on a self-report
originally specified plan, including measure of symptoms instead of
changes in the primary outcome the pre-specified primary
reported, exclusion of certain clinician-rated scale
subjects from analysis, and sub-
group analyses without indicating
the testing to be exploratory
Competing interest Investigators or sponsors with a Decisions made during the trial,
bias financial interest in the results of such as dose increases in a flexible
the trial, usually acting via one of dose trial, may be influenced by
the other sources of bias investigators with a financial
interest in the trial’s outcome
Lewis and Warlow (2004), Gul (2016)

patients with a disorder who are studied. For example, two widely reported meta-
analyses concluded that antidepressants are not meaningfully better than placebo for
non-severe forms of major depression (Kirsch et al. 2008; Fournier et al. 2010).
However, individual patient-level meta-analyses have found that SSRIs and SNRIs
are roughly equally effective across the range of severity of MDD (Gibbons et al.
2012; Furukawa et al. 2018). Furthermore, the effect size of antidepressants is even
larger in placebo-controlled RCTs for dysthymia (a form of milder, chronic depres-
sion) than for MDD (Levkovitz et al. 2011). Effectiveness studies (also known as
large simple trials) are used to assess the broader clinical utility of drugs established
by RCTs to have therapeutic efficacy.
Another criticism is the emphasis on symptom change outcome measures in
RCTs, which may inappropriately focus the goals of treatment away from those
that patients most care about: improvements in quality of life and functional status
(Zimmerman et al. 2012b). Symptom improvement and functional gains are corre-
lated, though symptom improvement typically precedes gains in functioning and
quality of life (McKnight and Kashdan 2009; Sheehan et al. 2017). The categorical
outcome of “response” in depression trials has also been criticized as a statistically
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 345

misused measure to create an illusion of drug efficacy (Kirsch and Moncrieff 2007).
Notably, the categorical outcome of remission has not been similarly criticized,
perhaps given its clear association with better functioning and duration of wellness
(Möller 2008).
Another form of bias is the selective publication of trial results, which can convey
false impression of a drug’s efficacy and distort meta-analyses (Kirkham et al. 2010;
Dal-Ré et al. 2017). These forms of bias include failing or delaying publication of
negative trials or reporting a trial as positive using a secondary outcome measure
when the primary outcome did not find efficacy; these problems have been identified
in mood, anxiety, and psychotic disorder clinical trials (Turner et al. 2008; Roest et
al. 2015; Lancee et al. 2017). The effect of publication bias on overall estimates of
drug efficacy appears to be small (roughly 15% relative increase in effect size), at
least for antidepressants used for anxiety disorders (Roest et al. 2015). Pharmaceu-
tical industry sponsorship and investigator conflicts of interest in RCTs in particular
have been identified as a source of publication bias (Lundh et al. 2012). Concerns
about publication and analytic bias produced pressures for more transparency about
clinical trials. In the United States, the 1997 FDA Modernization Act required the
NIH to create a registry of clinical trials; the subsequent 2007 FDA Amendments Act
greatly expanded the types of trials to be included and required submission of results
after trial completion (Avorn et al. 2018). From this legislation was born
clinicaltrials.gov, the first and largest registry of RCTs. The European Union
launched the EU Clinical Trials Register (clinicaltrialsregister.eu) in 2011. Many
other registries now exist around the globe, allowing patients to easily search for
studies looking for participants and to access summarized results of prior research.
Among the safety concerns is the underreporting of side effects as discussed
previously, particularly if the side effect is similar to a symptom that occurs as part of
the disorder (e.g., fatigue is a symptom of depression, but can also be a side effect of
antidepressant medications) (Hughes et al. 2014). There is also a relative paucity of
safety evaluations of chronic medication use, which is how many psychotropic
agents are prescribed in clinical practice. Specific concerns have been raised about
chronic use of antidepressants worsening the long-term course of major depression
(Fava 1994; El-Mallakh et al. 2011) and of antipsychotics deleteriously affecting
brain volume (Ho et al. 2011). Unfortunately, observed long-term adverse outcomes
with psychotropic agents may be confounded by the natural progression of the
disease process, which may be associated with chronic use of the prescribed
medications; adequate data to resolve this issue does not exist (Targum 2014; Goff
et al. 2017). An additional concern is that many drugs studied in adults are used also
in children and adolescents, though little safety data is available for these age groups.

“Me-too” Drugs

Another line of criticism of pharmaceutical RCTs is the development and testing of

new compounds considered similar in action or efficacy to existing marketed drugs.
These medications are known as “me-too” drugs and are argued to drive up drug
346 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

costs without adding value to patient care (Angell 2005). Some critics assert that new
drugs should not be approved unless they demonstrate superiority over an active
comparator already on the market. Common examples of me-too drugs cited in
psychiatry include SSRIs and atypical antipsychotics. While there is no question that
the pharmaceutical industry has engaged in shameful and egregious promotional
practices (Qureshi et al. 2011), whether drugs labeled as “me-too” products are
problematic is less clear (Huskamp 2006).
The challenge of designating a new psychiatric drug as a “me-too” agent is that
the pathophysiology of psychiatric disorders is complex and poorly understood.
Drugs that do not show overall better efficacy may nevertheless prove highly
valuable for certain patients, due to biological characteristics that are relevant to a
specific drug response but not yet known to science. For example, if bupropion
(a marketed antidepressant) was in fact being tested as an investigational medication
today, it would fail to pass the superior efficacy test because it does not produce
greater mean change or remission rates than SSRIs in patients with depression
(Cipriani et al. 2018). However, the medication is highly valuable in clinical settings,
as some patients can respond better to it than SSRIs or find it more tolerable or better
treats a comorbid disorder, though they may be a smaller proportion of the overall
depressed population.
It is also unclear what level of pharmacological difference justifies a drug to be
considered novel versus a copy of an existing drug. For example, vilazodone is
classified as an SSRI but also acts as a 5HT1a receptor partial agonist. This
secondary action does not produce a superior antidepressant effect but appears to
cause less sexual dysfunction than the older SSRIs (Cipriani et al. 2018; Clayton et
al. 2017). Whether such a difference should exclude it from a “me-too” designation
is an open question. Furthermore, drugs with similar pharmacodynamic mechanisms
of action may differ greatly in their pharmacokinetic properties, including metabo-
lism pathways, half-lives, and susceptibility to extrusion from the CNS via p-gly-
coprotein, which may all may be affected by an individual’s specific genotypes. For
example, fluoxetine and paroxetine were two of the first SSRIs. Both are very strong
inhibitors of cytochrome P450 2D6, and sertraline is a moderate inhibitor of this
enzyme. Without the development of citalopram, which has minimal inhibitory
effects on CYP2D6, patients who were on other drugs with a narrow therapeutic
index that are metabolized through CYP2D6 (e.g., tricyclic antidepressants) or a
prodrug that needs CYP2D6 activity to create an active metabolite (e.g. tamoxifen)
would face difficult clinical options. Finally, patients who do not respond to one
SSRI often respond to a second one, suggesting that classifying “me-too” drugs
simply on their presumed mechanism of action is simplistic and carries a significant
risk of excluding potentially useful medications from reaching clinical practice.

Summary

Determining the efficacy of pharmacotherapies for psychiatric disorders is a com-

plex process with many opportunities for error. Replication of results in multiple
trials is crucial for establishing confidence in a treatment, and appropriate controls
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 347

must be used to minimize bias and confounding that could lead to false conclusions.
Phase II and III RCTs designed to assess efficacy necessarily use inclusion and
exclusion criteria that may reduce generalizability of the results; large simple trials of
effectiveness in broader populations are needed to determine how efficacious med-
ications are best used in clinical settings. Despite the limitations of psychiatric RCTs,
they remain the best means for identifying treatments that truly work to improve
mental health.

References
Alonso J, Lepine JP, Committee for the European Study of Mental Disorders. Overview of key data
from the European Study of the Epidemiology of Mental Disorders (ESEMeD). J Clin Psychi-
atry. 2007;68(suppl 2):3–9.
Alphs L, Schooler N, Lauriello J. How study designs influence comparative effectiveness out-
comes: the case of oral versus long-acting injectable antipsychotic treatments for schizophrenia.
Schizophr Res Treat. 2014;156(2–3):228–32.
Alphs L, Mao L, Lynn Starr H, Benson C. A pragmatic analysis comparing once-monthly
paliperidone palmitate versus daily oral antipsychotic treatment in patients with schizophrenia.
Schizophr Res. 2016;170(2–3):259–64.
Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. Clin
Pharmacokinet. 1994;26(3):201–14.
Altman DG, Gore SM, Gardner MJ, Pocock SJ. Statistical guidelines for contributors to medical
journals. Br Med J. 1983;286:1489–93.
American Psychiatric Association. Practice guideline for the treatment of patients with major
depressive disorder. 3rd ed. Washington, DC: American Psychiatric Association; 2010.
American Psychological Association. PTSD Assessment Instruments. 2017. https://www.apa.org/
ptsd-guideline/assessment/index.aspx. Accessed 19 Dec 2018.
Ammerman S, Ryan S, Adelman WP, Committee on Substance Abuse, the Committee on Adoles-
cence. The impact of marijuana policies on youth: clinical, research, and legal update. Pediat-
rics. 2015;135(3):e769–85.
Anderson IM. Meta-analytical studies on new antidepressants. Br Med Bull. 2001;57:161–78.
Andreasen NC. Negative symptoms in schizophrenia: definition and reliability. Arch Gen Psychi-
atry. 1982;39:784–8.
Andreasen NC, Olsen S. Negative v positive schizophrenia: definition and validation. Arch Gen
Psychiatry. 1982;39:789–94.
Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in
schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162
(3):441–9.
Angell M. The truth about the drug companies: how they deceive us and what to do about it. New
York: Random House; 2005.
Angst J, Grobler C. Unipolar mania: a necessary diagnostic concept. Eur Arch Psychiatry Clin
Neurosci. 2015;265(4):273–80.
Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, et al. Combined
pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE
study: a randomized controlled trial. JAMA. 2006;295(17):2003–17.
Atkins DC. Clinical trials methodology: randomization, intent-to-treat, and random-effects regres-
sion. Depress Anxiety. 2009;26:697–700.
Avorn J, Kesselheim A, Sarpatwari A. The FDA Amendments Act of 2007 – assessing its effects a
decade later. N Engl J Med. 2018;379(12):1097–9.
Bagby RM, Ryder AG, Schuller DR, Marshall MB. The Hamilton Depression Rating Scale: has the
gold standard become a lead weight? Am J Psychiatry. 2004;161(12):2163–77.
348 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Bandelow B, Baldwin DS, Dolberg OT, Andersen HF, Stein DJ. What is the threshold for
symptomatic response and remission for major depressive disorder, panic disorder, social
anxiety disorder, and generalized anxiety disorder? J Clin Psychiatry. 2006;67(9):1428–34.
Barbano AC, van der Mei WF, Bryant RA, Delahanty DL, deRoon-Cassini TA, Matsuoka YJ, et al.
Clinical implications of the proposed ICD-11 PTSD diagnostic criteria. Psychol Med.
2018;14:1–8.
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672–6.
Batelaan NM, Bosman RC, Muntingh A, Scholten WD, Huijbregts KM, van Balkom AJLM. Risk
of relapse after antidepressant discontinuation in anxiety disorders, obsessive-compulsive
disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse
prevention trials. BMJ. 2017;358:j3927.
Bech P, Bolwig TG, Kramp P, Rafaelsen OJ. The Bech-Rafaelsen Mania Scale and the Hamilton
Depression Scale. Acta Psychiatr Scand. 1979;59:420–30.
Bech P, Allerup P, Gram LF, Reisby N, Rosenberg R, Jacobsen O, et al. The Hamilton depression
scale. Evaluation of objectivity using logistic models. Acta Psychiatr Scand. 1981;63:290–9.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression.
Arch Gen Psychiatry. 1961;4:561–71.
Bighelli I, Salanti G, Huhn M, Schneider-Thoma J, Krause M, Reitneir C, et al. Psychological
interventions to reduce positive symptoms in schizophrenia: systematic review and network
meta-analysis. World Psychiatry. 2018;17(3):316–29.
Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, et al. The develop-
ment of a clinician-administered PTSD scale. J Trauma Stress. 1995;8:75–90.
Bloch MH, Landeros-Weisenberger A, Kelmendi B, Coric V, Bracken MB, Leckman JF.
A systematic review: antipsychotic augmentation with treatment refractory obsessive-compul-
sive disorder. Mol Psychiatry. 2006;11(7):622–32.
Boessen R, Groenwold RH, Knol MJ, Grobbee DE, Roes KC. Comparing HAMD(17) and HAMD
subscales on their ability to differentiate active treatment from placebo in randomized controlled
trials. J Affect Disord. 2013;145(3):363–9.
Borges S, Chen YF, Laughren TP, Temple R, Patel HD, David PA, et al. Review of maintenance
trials for major depressive disorder: a 25-year perspective from the US Food and Drug
Administration. J Clin Psychiatry. 2014;75(3):205–14.
Boschloo L, Bekhuis E, Borsboom D, Weitz ES, Reijnders M, DeRubeis RJ, et al. The symptom-
specific efficacy of cognitive behavioral therapy versus antidepressant medication in the treat-
ment of depression: results from an individual patient data meta-analysis. World Psychiatry.
2019;18(2):183–91.
Brendel DH, Miller FG. A plea for pragmatism in clinical research ethics. Am J Bioeth. 2008;8
(4):24–31.
Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, et al. Schizophrenia
patient outcomes research team (PORT). The 2009 schizophrenia PORT psychopharmacolog-
ical treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71–93.
Burcusa SL, Iacono WG. Risk for recurrence in depression. Clin Psychol Rev. 2007;27:959–85.
Calabrese JR, Keck PE, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, et al. A randomized,
double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression.
Am J Psychiatry. 2005;162:1351–60.
Canadian Agency for Drugs and Technologies in Health. Appendix 9, Inclusion and exclusion
criteria reported in included RCTs. In: A Systematic Review of Combination and High-Dose
Atypical Antipsychotic Therapy in Patients with Schizophrenia. Canadian Agency for Drugs
and Technologies in Health. 2011. https://www.ncbi.nlm.nih.gov/books/NBK169687/.
Accessed 21 Jan 2019.
Catalá-López F, Hutton B, Núñez-Beltrán A, Page MJ, Ridao M, Macías Saint-Gerons D, et al. The
pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder
in children and adolescents: a systematic review with network meta-analyses of randomised
trials. PLoS One. 2017;12(7):e0180355.
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 349

Chatterton ML, Stockings E, Berk M, Barendregt JJ, Carter R, Mihalopoulos C. Psychosocial

therapies for the adjunctive treatment of bipolar disorder in adults: network meta-analysis. Br J
Psychiatry. 2017;210(5):333–41.
Cheung KL, de Ruijter D, Hiligsmann M, Elfeddali I, Hoving C, Evers SMAA, et al. Exploring
consensus on how to measure smoking cessation. A Delphi study. BMC Public Health. 2017;17
(1):890.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative
efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major
depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391
(10128):1357–66.
Clayton AH, Durgam S, Li D, Chen C, Chen L, Mathews M, et al. Effects of vilazodone on sexual
functioning in healthy adults: results from a randomized, double-blind, placebo-controlled, and
active-controlled study. Int Clin Psychopharmacol. 2017;32(1):27–35.
Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Lawrence
Earlbaum Associates; 1988.
Conners CK. Rating scales for use in drug studies with children. Psychopharmacol Bull.
1973;9:24–84.
Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967;113:1237–64.
Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, et al. Comparative
efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children,
adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry.
2018;5(9):727–38.
Cunill R, Castells X, Tobias A, Capellà D. Efficacy, safety and variability in pharmacotherapy for
adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over
9000 patients. Psychopharmacology. 2016;233(2):187–97.
Curtiss J, Andrews L, Davis M, Smits J, Hofmann SG. A meta-analysis of pharmacotherapy for
social anxiety disorder: an examination of efficacy, moderators, and mediators. Expert Opin
Pharmacother. 2017;18(3):243–51.
Dal-Ré R, Bobes J, Cuijpers P. Why prudence is needed when interpreting articles reporting clinical
trial results in mental health. Trials. 2017;18(1):143.
de Vos J, Houtzager L, Katsaragaki G, van de Berg E, Cuijpers P, Dekker J. Meta analysis on
the efficacy of pharmacotherapy versus placebo on anorexia nervosa. J Eat Disord. 2014;2
(1):27.
Deal LS, Wirth RJ, Gasior M, Herman BK, McElroy SL. Validation of the Yale-Brown Obsessive
Compulsive Scale modified for binge eating. Int J Eat Disord. 2015;48(7):994–1004.
Depression Guideline Panel. Clinical practice guideline 5: depression in primary care, vol 2:
treatment of major depression. Rockville: US Department of Health and Human Services; 1993.
Drope J, Schluger N, Cahn Z, Drope J, Hamill S, Islami F, et al. The tobacco atlas. American Cancer
Society and Vital Strategies. 2018. https://tobaccoatlas.org. Accessed 18 Jan 2019.
Dunlop BW, Banja J. A renewed defense of placebo-controlled trials of new treatments for major
depression and anxiety disorders. J Med Ethics. 2009;35:384–9.
Dunlop BW, Davidson JRT. Pharmacotherapy for posttraumatic stress disorder. In: by Simon N,
Hollander E, Rothbaum BO, Stein DJ, editors. The American Psychiatric Association textbook
of anxiety, trauma and OCD-related disorders. Washington, DC: American Psychiatric Associ-
ation; 2019; in press.
Dunlop BW, Rapaport MH. When should a patient be declared recovered from a major depressive
episode? J Clin Psychiatry. 2016;77(8):e1026–8.
Dunlop BW, Reddy S, Yang L, Lubaczewski S, Focht K, Guico-Pabia CJ. Symptomatic and
functional improvement in employed depressed patients: a double-blind clinical trial of
desvenlafaxine versus placebo. J Clin Psychopharmacol. 2011;31(5):569–76.
Dunlop BW, Thase ME, Wun C, Fayyad R, Guico-Pabia C, Musgnung J, et al. A meta-analysis of
factors impacting detection of antidepressant efficacy in clinical trials: the importance of
academic sites. Neuropsychopharmacology. 2012;37:2830–6.
350 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Dunlop BW, Kaye JL, Youngner C, Rothbaum B. Assessing treatment-resistant posttraumatic stress
disorder: the Emory Treatment Resistance Interview for PTSD (E-TRIP). Behav Sci (Basel).
2014;4(4):511–27.
Dunlop BW, Gray J, Rapaport MH. Transdiagnostic clinical global impression scoring for routine
clinical settings. Behav Sci (Basel). 2017;7(4):40.
Dunlop BW, Polychroniou P, Rakofsky JJ, Nemeroff CB, Craighead WE, Mayberg HS. Suicidal
ideation and other persisting symptoms after CBT or antidepressant medication treatment for
major depressive disorder. Psychol Med. 2018; epub ahead of print.
DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD rating scale-IV: checklists, norms, and
clinical interpretation. New York: Guilford Press; 1998.
El-Mallakh RS, Gao Y, Jeannie RR. Tardive dysphoria: the role of long term antidepressant use in-
inducing chronic depression. Med Hypotheses. 2011;76(6):769–73.
Erford BT, Jackson J, Bardhoshi G, Duncan K, Atalay Z. Selecting suicide ideation assessment
instruments: a meta-analytic review. Meas Eval Couns Dev. 2018;51:42–59.
European Medicines Agency. Guideline on clinical investigation of medicinal products, including
depot preparations in the treatment of schizophrenia. In: Committee for Medicinal Products for
Human Use; 2012.
European Medicines Agency. Guideline on the clinical investigation of medicines for the treatment
of Alzheimer’s disease. In: Committee for Medicinal Products for Human Use; 2018.
Fagiolini A, Rocca P, De Giorgi S, Spina E, Amodeo G, Amore M. Clinical trial methodology to
assess the efficacy/effectiveness of long-acting antipsychotics: randomized controlled trials vs
naturalistic studies. Psychiatry Res. 2017;247:257–64.
Falk D, Wang XQ, Liu L, Fertig J, Mattson M, Ryan M, et al. Percentage of subjects with no heavy
drinking days: evaluation as an efficacy endpoint for alcohol clinical trials. Alcohol Clin Exp
Res. 2010;34:2022–34.
Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity
disorder: a meta-analysis of follow-up studies. Psychol Med. 2006;36(2):159–65.
Fava GA. Do antidepressant and antianxiety drugs increase chronicity in affective disorders?
Psychother Psychosom. 1994;61(3–4):125–31.
Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, et al. Double-blind, placebo-
controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-
resistant depression (TRD). Mol Psychiatry. 2018; epub ahead of print.
Fekadu A, Donocik JG, Cleare AJ. Standardisation framework for the Maudsley staging method for
treatment resistance in depression. BMC Psychiatry. 2018;18(1):100.
Ferrer P, Ballarín E, Sabaté M, Vidal X, Rottenkolber M, Amelio J, et al. Antiepileptic drugs and
suicide: a systematic review of adverse effects. Neuroepidemiology. 2014;42(2):107–20.
Fineberg NA, Pampaloni I, Pallanti S, Ipser J, Stein DJ. Sustained response versus relapse: the
pharmacotherapeutic goal for obsessive-compulsive disorder. Int Clin Psychopharmacol.
2007;22(6):313–22.
Fineberg NA, Brown A, Reghunandanan S, Pampaloni I. Evidence-based pharmacotherapy of
obsessive-compulsive disorder. Int J Neuropsychopharmacol. 2012;15(8):1173–91.
First MB, Williams JBW, Karg RS, Spitzer RL. Structured clinical interview for DSM-5 – research
version. Washington, DC: American Psychiatric Association; 2015.
Fitzgerald N, Angus K, Elders A, de Andrade M, Raistrick D, Heather N, et al. Weak evidence on
nalmefene creates dilemmas for clinicians and poses questions for regulators and researchers.
Addiction. 2016;111(8):1477–87.
Food and Drug Administration. Guidance for industry: alcoholism: developing drugs for treatment.
Silver Spring: Department of Health and Human Services; 2015.
Food and Drug Administration. Step 3: clinical research. 2018a. https://www.fda.gov/patients/drug-
development-process/step-3-clinical-research. Accessed 11 Sept 2019.
Food and Drug Administration. Guidance for industry: opioid use disorder: endpoints for demon-
strating effectiveness of drugs for medication-assisted treatment. Silver Spring, Maryland:
Department of Health and Human Services; 2018b.
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 351

Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al. Antide-
pressant drug effects and depression severity: a patient-level meta-analysis. JAMA.
2010;303:47–53.
Frank JD. Persuasion & healing. Baltimore: Johns Hopkins University Press; 1973.
Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, et al. Conceptualization and
rationale for consensus definitions of terms in major depressive disorder. Remission, recovery,
relapse, and recurrence. Arch Gen Psychiatry. 1991;48(9):851–5.
Fresco DM, Coles ME, Heimberg RG, Liebowitz MR, Hami S, Stein MB, et al. The Liebowitz
Social Anxiety Scale: a comparison of the psychometric properties of self-report and clinician-
administered formats. Psychol Med. 2001;31(6):1025–35.
Furukawa TA, Maruo K, Noma H, Tanaka S, Imai H, Shinohara K, et al. Initial severity of major
depression and efficacy of new generation antidepressants: individual participant data meta-
analysis. Acta Psychiatr Scand. 2018;137(6):450–8.
GBD 2016 Alcohol and Drug Use Collaborators. The global burden of disease attributable to
alcohol and drug use in 195 countries and territories, 1990–2016: a systematic analysis for the
global burden of disease study 2016. Lancet Psychiatry. 2018;5(12):987–1012.
Ghaemi SN, Selker HP. Maintenance efficacy designs in psychiatry: randomized discontinuation
trials – enriched but not better. J Clin Transl Sci. 2017;1(3):198–204.
Gianarris WJ, Golden CJ, Greene L. The Conners’ Parent Rating Scales: a critical review of the
literature. Clin Psychol Rev. 2001;21(7):1061–93.
Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. Benefits from antidepressants: synthesis of 6-
week patient-level outcomes from double-blind placebo-controlled randomized trials of fluox-
etine and venlafaxine. Arch Gen Psychiatry. 2012;69(6):572–9.
Gibertini M, Nations KR, Whitaker JA. Obtained effect size as a function of sample size in
approved antidepressants: a real-world illustration in support of better trial design. Int Clin
Psychopharmacol. 2012;27(2):100–6.
Gilbody S, Wahlbeck K, Adams C. Randomized controlled trials in schizophrenia: a critical
perspective on the literature. Acta Psychiatr Scand. 2002;105(4):243–51.
Gitlin MJ. Antidepressants in bipolar depression: an enduring controversy. Int J Bipolar Disord.
2018;6(1):25.
Glue P, Donovan MR, Kolluri S, Emir B. Meta-analysis of relapse prevention antidepressant trials
in depressive disorders. Aust N Z J Psychiatry. 2010;44:697–705.
Goff DC, Falkai P, Fleischhacker WW, Girgis RR, Kahn RM, Uchida H, et al. The long-term effects
of antipsychotic medication on clinical course in schizophrenia. Am J Psychiatry. 2017;174
(9):840–9.
Gomez AF, Barthel AL, Hofmann SG. Comparing the efficacy of benzodiazepines and serotonergic
anti-depressants for adults with generalized anxiety disorder: a meta-analytic review. Expert
Opin Pharmacother. 2018;19(8):883–94.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-
Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry.
1989;46(11):1006–11.
Goodman D, Faraone SV, Adler LA, Dirks B, Hamdani M, Weisler R. Interpreting ADHD rating
scale scores: linking ADHD rating scale scores and CGI levels in two randomized controlled
trials of lisdexamfetamine dimesylate in ADHD. Primary Psychiatry. 2010;17(3):44–52.
Gul M. Bias in a randomized controlled trial and how these can be minimized. J Psychiatry.
2016;19:2.
Guy W. Clinical global impressions. ECDEU assessment manual for psychopharmacology. Rock-
ville: US Department of Health, Education, and Welfare; 1976. p. 217–22.
Hamer RM, Simpson PM. Last observation carried forward versus mixed models in the analysis of
psychiatric clinical trials. Am J Psychiatry. 2009;166(6):639–41.
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50–5.
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol.
1967;6:278–96.
352 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. World Federation of
Societies of Biological Psychiatry (WFSBP) task force on treatment guidelines for schizo-
phrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for
biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizo-
phrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13
(5):318–78.
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom test for nicotine
dependence: a revision of the Fagerstrom tolerance questionnaire. Br J Addict.
1991;86:1119–27.
Heekin RD, Shorter D, Kosten TR. Current status and future prospects for the development of
substance abuse vaccines. Expert Rev. Vaccines. 2017;16(11):1067–77.
Hedges L. Distribution theory for Glass’s estimator of effect size and related estimators. J Educ Stat.
1981;6(2):107–28.
Henry ME, Schmidt ME, Hennen J, Villafuerte RA, Butman ML, Tran P, et al. A comparison of
brain and serum pharmacokinetics of R-fluoxetine and racemic fluoxetine: a 19-F MRS study.
Neuropsychopharmacology. 2005;30(8):1576–83.
Henssler J, Kurschus M, Franklin J, Bschor T, Baethge C. Trajectories of acute antidepressant
efficacy: how long to wait for response? A systematic review and meta-analysis of long-term,
placebo-controlled acute treatment trials. J Clin Psychiatry. 2018;79(3):pii:17r11470.
Hieronymus F, Nilsson S, Eriksson E. A mega-analysis of fixed-dose trials reveals dose-depen-
dency and a rapid onset of action for the antidepressant effect of three selective serotonin
reuptake inhibitors. Transl Psychiatry. 2016;6(6):e834.
Hindmarch I. Beyond the monoamine hypothesis: mechanisms, molecules and methods. Eur
Psychiatry. 2002;17(3):294–9.
Hirschtritt ME, Bloch MH, Mathews CA. Obsessive-compulsive disorder: advances in diagnosis
and treatment. JAMA. 2017;317(13):1358–67.
Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and
brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry.
2011;68(2):128–37.
Hoek HW. Review of the worldwide epidemiology of eating disorders. Curr Opin Psychiatry.
2016;29(6):336–9.
Hoertel N, Le Strat Y, Blanco C, Lavaud P, Dubertret C. Generalizability of clinical trial results for
generalized anxiety disorder to community samples. Depress Anxiety. 2012;29(7):614–20.
Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA, et al. Pharmacotherapy for post-
traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry. 2015;206
(2):93–100.
Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, et al.
Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP)
working group consensus guidelines on diagnosis and terminology. Am J Psychiatry.
2017;174(3):216–29.
Hudson JI, McElroy SL, Ferreira-Cornwell MC, Radewonuk J, Gasior M. Efficacy of lisdexam-
fetamine in adults with moderate to severe binge-eating disorder: a randomized clinical trial.
JAMA Psychiat. 2017;74(9):903–10.
Hughes JR, Keely JP, Niaura RS, Ossip-Klein DJ, Richmond RL, Swan GE. Measures of abstinence
in clinical trials: issues and recommendations. Nicotine Tob Res. 2003;5(1):13–25.
Hughes S, Cohen D, Jaggi R. Differences in reporting serious adverse events in industry sponsored
clinical trial registries and journal articles on antidepressant and antipsychotic drugs: a cross
sectional study. BMJ Open. 2014;4:e005535.
Huskamp HA. Prices, profits, and innovation: examining criticisms of new psychotropic drugs'
value. Health Aff (Millwood). 2006;25(3):635–46.
Imai H, Tajika A, Chen P, Pompoli A, Furukawa TA. Psychological therapies versus pharmaco-
logical interventions for panic disorder with or without agoraphobia in adults. Cochrane
Database Syst Rev. 2016;10:CD011170.
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 353

Insel TR, Murphy DL, Cohen RM, Alterman I, Kilts C, Linnoila M. Obsessive compulsive disorder.
A double-blind trial of clomipramine and clorgyline. Arch Gen Psychiatry. 1983;40:605–12.
Jatlow P, Toll BA, Leary V, Krishnan-Sarin S, O'Malley SS. Comparison of expired carbon
monoxide and plasma cotinine as markers of cigarette abstinence. Drug Alcohol Depend.
2008;98(3):203–9.
Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy for
adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis.
JAMA. 2014;311(18):1889–900.
Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, et al. A prospective 12-year study
of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders.
Arch Gen Psychiatry. 1998;55(8):694–700.
Judd LL, Akiskal HS, Schettler PJ, Endicott J, Leon AC, Solomon DA, et al. Psychosocial disability
in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch
Gen Psychiatry. 2005;62(12):1322–30.
Junod SW. FDA and clinical drug trials: a short history. In: Davies M, Kerimani F, editors. A quick
guide to clinical trials. Washington, DC: Bioplan, Inc; 2008. p. 25–55.
Kane JM, Kishimoto T, Correll CU. Non-adherence to medication in patients with psychotic
disorders: epidemiology, contributing factors and management strategies. World Psychiatry.
2013;12(3):216–26.
Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, et al. Canadian clinical
practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compul-
sive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizo-
phrenia. Schizophr Bull. 1987;13(2):261–76.
Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health.
2013;34:119–38.
Kessler RC, Ustün TB. The World Mental Health (WMH) survey initiative version of the World
Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Int J
Methods Psychiatr Res. 2004;13(2):93–121.
Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comor-
bidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch
Gen Psychiatry. 2005;62(6):617–27.
Khan A, Khan SR, Walens G, Kolts R, Giller EL. Frequency of positive studies among fixed and
flexible dose antidepressant clinical trials: an analysis of the food and drug administration
summary basis of approval reports. Neuropsychopharmacology. 2003;28(3):552–7.
Khan A, Schwartz K, Kolts RL, Ridgway D, Lineberry C. Relationship between depression severity
entry criteria and antidepressant clinical trial outcomes. Biol Psychiatry. 2007;62(1):65–71.
Khin NA, Chen YF, Yang Y, Yang P, Laughren TP. Exploratory analyses of efficacy data from major
depressive disorder trials submitted to the US Food and Drug Administration in support of new
drug applications. J Clin Psychiatry. 2011;72(4):464–72.
Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome
reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ. 2010;340:
c365.
Kirsch I, Moncrieff J. Clinical trials and the response rate illusion. Contemp Clin Trials.
2007;28:348–51.
Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-
analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45.
Kishimoto T, Nitta M, Borenstein M, Kane JM, Correll CU. Long-acting injectable versus oral
antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies.
J Clin Psychiatry. 2013;74(10):957–65.
Kishimoto T, Robenzadeh A, Leucht C, Leucht S, Watanabe K, Mimura M, et al. Long-acting
injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of
randomized trials. Schizophr Bull. 2014;40(1):192–213.
354 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Kishimoto T, Hagi K, Nitta M, Leucht S, Olfson M, Kane JM, et al. Effectiveness of long-acting
injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective
and retrospective cohort studies. Schizophr Bull. 2018;44(3):603–19.
Kobak KA, Leuchter A, DeBrota D, Engelhardt N, Williams JB, Cook IA, et al. Site versus
centralized raters in a clinical depression trial: impact on patient selection and placebo response.
J Clin Psychopharmacol. 2010;30(2):193–7.
Kranzler HR, Soyka M. Diagnosis and pharmacotherapy of alcohol use disorder: a review. JAMA.
2018;320(8):815–24.
Lancee M, Lemmens CMC, Kahn RS, Vinkers CH, Luykx JJ. Outcome reporting bias in random-
ized-controlled trials investigating antipsychotic drugs. Transl Psychiatry. 2017;7(9):e1232.
Landin R, DeBrota DJ, DeVries TA, Potter WZ, Demitrack MA. The impact of restrictive entry
criterion during the placebo lead-in period. Biometrics. 2000;56(1):271–8.
Lee NK, Jenner L, Harney A, Cameron J. Pharmacotherapy for amphetamine dependence: a
systematic review. Drug Alcohol Depend. 2018;191:309–37.
Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, et al. Antipsychotic drugs versus
placebo for relapse prevention in schizophrenia: a systematic review and metaanalysis. Lancet.
2012;379:2063–71.
Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, et al. Sixty years of placebo-
controlled antipsychotic drug trials in acute schizophrenia: systematic review, bayesian meta-
analysis, and meta-regression of efficacy predictors. Am J Psychiatry. 2017;174(10):927–42.
Levine J, Schooler NR. SAFTEE: a technique for the systematic assessment of side effects in
clinical trials. Psychopharmacol Bull. 1986;22(2):343–81.
Levkovitz Y, Tedeschini E, Papakostas GI. Efficacy of antidepressants for dysthymia: a meta-
analysis of placebo-controlled randomized trials. J Clin Psychiatry. 2011;72:509–14.
Lewis SC, Warlow CP. How to spot bias and other potential problems in randomised controlled
trials. J Neurol Neurosurg Psychiatry. 2004;75(2):181–7.
Lewis-Fernández R, Hinton DE, Laria AJ, Patterson EH, Hofmann SG, Craske MG, et al. Culture
and the anxiety disorders: recommendations for DSM-V. Depress Anxiety. 2010;27(2):212–29.
Licht RW. Limits of the applicability and generalizability of drug trials in mania. Bipolar Disord.
2002;4(Suppl 1):66–8.
Lindson-Hawley N, Hartmann-Boyce J, Fanshawe TR, Begh R, Farley A, Lancaster T. Interven-
tions to reduce harm from continued tobacco use. Cochrane Database Syst Rev. 2016;10:
CD005231.
Lindström L, Lindström E, Nilsson M, Höistad M. Maintenance therapy with second generation
antipsychotics for bipolar disorder – a systematic review and meta-analysis. J Affect Disord.
2017;213:138–50.
Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new
comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in
neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1–100.
Little RJA, Rubin DB. Statistical analysis with missing data. Hoboken: Wiley; 2002.
Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research
outcome. Cochrane Database Syst Rev. 2012;12:MR000033.
Maier W, Philipp M. Improving the assessment of severity of depressive states: a reduction of the
Hamilton Depression Scale. Pharmacopsychiatry. 1985;18:114–5.
Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso JP. Recommendations for the primary
analysis of continuous endpoints in longitudinal clinical trials. Drug Inf J. 2008;42:303–19.
Mark TL, Kassed CA, Vandivort-Warren R, Levit KR, Kranzler HR. Alcohol and opioid depen-
dence medications: prescription trends, overall and by physician specialty. Drug Alcohol
Depend. 2009;99(1–3):345–9.
McCann DJ, Petry NM, Bresell A, Isacsson E, Wilson E, Alexander RC. Medication nonadherence,
“professional subjects,” and apparent placebo responders: overlapping challenges for medica-
tions development. J Clin Psychopharmacol. 2015;35(5):566–73.
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 355

McElroy SL, Hudson J, Ferreira-Cornwell MC, Radewonuk J, Whitaker T, Gasior M. Lisdexam-

fetamine dimesylate for adults with moderate to severe binge eating disorder: Results of two
pivotal phase 3 randomized controlled trials. Neuropsychopharmacology. 2016;41(5):1251–60.
McElroy SL, Hudson JI, Mitchell JE, Wilfley D, Ferreira-Cornwell MC, Gao J, et al. Efficacy and
safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating
disorder: a randomized clinical trial. JAMA Psychiat. 2015;72(3):235–46.
McGhee DJ, Ritchie CW, Zajicek JP, Counsell CE. A review of clinical trial designs used to detect a
disease-modifying effect of drug therapy in Alzheimer’s disease and Parkinson’s disease. BMC
Neurol. 2016;16:92.
McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, preva-
lence, and mortality. Epidemiol Rev. 2008;30:67–76.
McKnight PE, Kashdan TB. The importance of functional impairment to mental health outcomes: a
case for reassessing our goals in depression treatment research. Clin Psychol Rev. 2009;29
(3):243–59.
McLellan A, Kushner H, Metzger D, Peter R, Smith I, Grissom G, et al. The fifth edition of the
addiction severity index: historical critique and normative data. J Subst Abus Treat.
1992;9:199–213.
Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of
bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry.
2011;68(3):241–51.
Meyer EC, Carrion RE, Cornblatt BA, Addington J, Cadenhead KS, Cannon TD, et al. The
relationship of neurocognition and negative symptoms to social and role functioning over
time in individuals at clinical high risk in the first phase of the North American prodrome
longitudinal study. Schizophr Bull. 2014;40(6):1452–61.
Michels KB, Rothman KJ. Update on unethical use of placebos in randomized trials. Bioethics.
2003;17(2):188–204.
Möller HJ. Outcomes in major depressive disorder: the evolving concept of remission and its
implications for treatment. World J Biol Psychiatry. 2008;9(2):102–14.
Moncrieff J. The myth of the chemical cure. New York: Palgrave Macmillan; 2008.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J
Psychiatry. 1979;134:382–9.
Mora MS, Nestoriuc Y, Rief W. Lessons learned from placebo groups in antidepressant trials. Philos
Trans R Soc Lond Ser B Biol Sci. 2011;366(1572):1879–88.
Naber D, Hansen K, Forray C, et al. Qualify: a randomized head-to-head study of aripiprazole once-
monthly and paliperidone palmitate in the treatment of schizophrenia. Schizophr Res. 2015;168
(1–2):498–504.
Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of
separable cognitive factors in schizophrenia. Schizophr Res. 2004;72(1):29–39.
Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. The MATRICS
consensus cognitive battery, part 1: test selection, reliability, and validity. Am J Psychiatry.
2008;165:203–13.
Nunan D, Aronson J, Bankhead C. Catalogue of bias: attrition bias. BMJ Evid Based Med. 2018;23
(1):21–2.
∅stergaard SD, Lemming OM, Mors O, Correll CU, Bech P. PANSS-6: a brief rating scale for the
measurement of severity in schizophrenia. Acta Psychiatr Scand. 2016;133:436–44.
Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799–812.
Peacock A, Leung J, Larney S, Colledge S, Hickman M, Rehm J, et al. Global statistics on alcohol,
tobacco and illicit drug use: 2017 status report. Addiction. 2018;113(10):1905–26.
Perälä J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsä E, Pirkola S, et al. Lifetime prevalence of
psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry. 2007;64(1):19–28.
Perlis RH, Ostacher M, Fava M, Nierenberg AA, Sachs GS, Rosenbaum JF. Assuring that double-
blind is blind. Am J Psychiatry. 2010;167(3):250–2.
356 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Perna G, Daccò S, Menotti R, Caldirola D. Antianxiety medications for the treatment of complex
agoraphobia: pharmacological interventions for a behavioral condition. Neuropsychiatr Dis
Treat. 2011;7:621–37.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three
multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–77.
Potter JS, Marino EN, Hillhouse MP, Nielsen S, Wiest K, Canamar CP, et al. Buprenorphine/
naloxone and methadone maintenance treatment outcomes for opioid analgesic, heroin, and
combined users: findings from starting treatment with agonist replacement therapies (START).
J Stud Alcohol Drugs. 2013;74(4):605–13.
Qureshi ZP, Sartor O, Xirasagar S, Liu Y, Bennett CL. Pharmaceutical fraud and abuse in the United
States, 1996–2010. Arch Intern Med. 2011;171(16):1503–6.
Rabinowitz J, Levine SZ, Barkai O, Davidov O. Dropout rates in randomized clinical trials of
antipsychotics: a meta-analysis comparing first- and second-generation drugs and an examina-
tion of the role of trial design features. Schizophr Bull. 2008;35(4):775–88.
Rabkin JG, Markowitz JS, Ocepek-Welikson K, Wager SS. General versus systematic inquiry about
emergent clinical events with SAFTEE: implications for clinical research. J Clin
Psychopharmacol. 1992;12(1):3–10.
Rickels K, Schweizer E, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. I.
Effects of abrupt discontinuation. Arch Gen Psychiatry. 1990;47:899–907.
Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized
anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam.
Arch Gen Psychiatry. 1993;50(11):884–95.
Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20).
J Clin Psychopharmacol. 2008;28(4):447–51.
Robertson OD, Coronado NG, Sethi R, Berk M, Dodd S. Putative neuroprotective pharmacother-
apies to target the staged progression of mental illness. Early Interv Psychiatry. 2019;13
(5):1032–49.
Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J, et al. The Composite International
Diagnostic Interview: an epidemiologic instrument suitable for use in conjunction with different
diagnostic systems and in different cultures. Arch Gen Psychiatry. 1988;45:1069–77.
Roest AM, de Jonge P, Williams CD, de Vries YA, Schoevers RA, Turner EH. Reporting bias in
clinical trials investigating the efficacy of second-generation antidepressants in the treatment of
anxiety disorders: a report of 2 meta-analyses. JAMA Psychiat. 2015;72:500–10.
Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor
discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44:77–87.
Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. The 16-item Quick
Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report
(QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychi-
atry. 2003;54:573–83.
Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, et al. Sequenced
treatment alternatives to relieve depression (STARD): rationale and design. Control Clin Trials.
2004;25:119–42.
Rutherford BR, Pott E, Tandler JM, Wall MM, Roose SP, Lieberman JA. Placebo response in
antipsychotic clinical trials: a meta-analysis. JAMA Psychiat. 2014;71(12):1409–21.
Rutherford BR, Bailey VS, Schneier FR, Pott E, Brown PJ, Roose SP. Influence of study design on
treatment response in anxiety disorder clinical trials. Depress Anxiety. 2015;32(12):944–57.
Sackett DL. Bias in analytic research. J Chronic Dis. 1979;32:51–63.
Salanti G, Chaimani A, Furukawa TA, Higgins JPT, Ogawa Y, Cipriani A, et al. Impact of placebo
arms on outcomes in antidepressant trials: systematic review and meta-regression analysis. Int J
Epidemiol. 2018;47(5):1454–64.
Samara MT, Nikolakopoulou A, Salanti G, Leucht S. How many patients with schizophrenia do not
respond to antipsychotic drugs in the short term? An analysis based on individual patient data
from randomized controlled trials. Schizophr Bull. 2019;45(3):639–46.
Schildkraut JJ, Kety SS. Biogenic amines and emotion. Science. 1967;156(3771):21–30.
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 357

Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and opioid-involved overdose deaths –
United States, 2013–2017. WR Morb Mortal Wkly Rep. 2018;67(5152):1419–27.
Schreiner A, Aadamsoo K, Altamura AC, Franco M, Gorwood P, Neznanov NG, et al. Paliperidone
palmitate versus oral antipsychotics in recently diagnosed schizophrenia. Schizophr Res.
2015;169(1–3):393–9.
Selle V, Schalkwijk S, Vázquez GH, Baldessarini RJ. Treatments for acute bipolar depression:
meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and anti-
psychotics. Pharmacopsychiatry. 2014;47(2):43–52.
Shear MK, Barlow D, Brown T, et al. Panic Disorder Severity Scale (PDSS). In: Rush AJ, First MB,
Blacker D, editors. Handbook of psychiatric measures. 2nd ed. Washington, DC: American
Psychiatric Association; 2007. p. 542–3.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-Interna-
tional Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured
diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59
(20):22–33.
Sheehan DV, Nakagome K, Asami Y, Pappadopulos EA, Boucher M. Restoring function in major
depressive disorder: a systematic review. J Affect Disord. 2017;215:299–313.
Sherman BJ, McRae-Clark AL. Treatment of cannabis use disorder: current science and future
outlook. Pharmacotherapy. 2016;36(5):511–35.
Shiovitz TM, Bain EE, McCann DJ, Skolnick P, Laughren T, Hanina A, et al. Mitigating the effects
of nonadherence in clinical trials. J Clin Pharmacol. 2016;56(9):1151–64.
Shorter E. A brief history of placebos and clinical trials in psychiatry. Can J Psychiatr. 2011;56
(4):193–7.
Shorter D, Kosten TR. Novel pharmacotherapeutic treatments for cocaine addiction. BMC Med.
2011;9:119.
Siddiqui HM, Hung J, O’Neill R. MMRM vs. LOCF: a comprehensive comparison based on
simulation study and 25 NDA datasets. J Biopharm Stat. 2009;19:227–46.
Sidor MM, MacQueen GM. Antidepressants for acute treatment of bipolar depression: a systematic
review and meta-analysis. J Clin Psychiatry. 2011;72:156–67.
Sigmon SC, Bisaga A, Nunes EV, O'Connor PG, Kosten T, Woody G. Opioid detoxification and
naltrexone induction strategies: recommendations for clinical practice. Am J Drug Alcohol
Abuse. 2012;38(3):187–99.
Sigmon SC, Dunn KE, Saulsgiver K, Patrick ME, Badger GJ, Heil SH, et al. A randomized, double-
blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. JAMA
Psychiat. 2013;70(12):1347–54.
Sim K, Lau WK, Sim J, Sum MY, Baldessarini RJ. Prevention of relapse and recurrence in adults
with major depressive disorder: systematic review and meta-analyses of controlled trials. Int J
Neuropsychopharmacol. 2015;19(2):pii:pyv076.
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiat Scand.
1970;212(Suppl):11–9.
Sinyor M, Levitt AJ, Cheung AH, Schaffer A, Kiss A, Dowlati Y, et al. Does inclusion of a
placebo arm influence response to active antidepressant treatment in randomized con-
trolled trials? Results from pooled and meta-analyses. J Clin Psychiatry. 2010;71
(3):270–9.
Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol
dependence: a meta-analysis. PLoS One. 2014;9(2):e87366.
Slade E, Keeney E, Mavranezouli I, Dias S, Fou L, Stockton S, et al. Treatments for bulimia
nervosa: a network meta-analysis. Psychol Med. 2018;48(16):2629–36.
Snaith RP, Baugh SJ, Clayden AD, Husain A, Sipple MA. The Clinical Anxiety Scale: an
instrument derived from the Hamilton Anxiety Scale. Br J Psychiatry. 1982;141:518–23.
Soomro GM, Altman DG, Rajagopal S, Oakley BM. Selective serotonin re-uptake inhibitors
(SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst
Rev. 2008;1:CD001765.
Spilker B. Guide to clinical trials. Philadelphia: Lippincott Williams & Wilkins; 1984.
Spina E, Trifirò G. Pharmacovigilance in psychiatry. Cham: Adis; 2016.
358 B. W. Dunlop and C. Medeiros Da Frota Ribeiro

Spitzer RL, Endicott J. Schedule for affective disorders and schizophrenia – change version. 3rd ed.
New York: Biometrics Research; 1987.
SRNT Subcommittee on Biochemical Verification. Biochemical verification of tobacco use and
cessation. Nicotine Tob Res. 2002;4(2):149–59.
Stead LF, Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking
cessation. Cochrane Database Syst Rev. 2012;10:CD008286. Update in: Cochrane Database
Syst Rev. 2016;3:CD008286.
Steele M, Jensen PS, Quinn DMP. Remission versus response as the goal of therapy in ADHD: a
new standard for the field? Clin Ther. 2006;28(11):1892–908.
Stein DJ, Ipser JC, Seedat S, Sager C, Amos T. Pharmacotherapy for post-traumatic stress disorder
(PTSD). Cochrane Database Syst Rev. 2006;1:CD002795.
Stein DJ, McLaughlin KA, Koenen KC, Atwoli L, Friedman MJ, Hill ED, et al. DSM-5 and ICD-11
definitions of posttraumatic stress disorder: investigating “narrow” and “broad” approaches.
Depress Anxiety. 2014;31:494–505.
Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, et al. Risk of suicidality in
clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and
Drug Administration. BMJ. 2009;339:b2880.
Suh JJ, Pettinati HM, Kampman KM, O'Brien CP. The status of disulfiram: a half of a century later.
J Clin Psychopharmacol. 2006;26:290–302.
Svaldi J, Schmitz F, Baur J, Hartmann AS, Legenbauer T, Thaler C, et al. Efficacy of psychother-
apies and pharmacotherapies for bulimia nervosa. Psychol Med. 2019;49(6):898–910.
Targum SD. Identification and treatment of antidepressant tachyphylaxis. Innov Clin Neurosci.
2014;11(3–4):24–8.
Thase ME, Jonas A, Khan A, Bowden CL, Wu X, McQuade RD, et al. Aripiprazole monotherapy in
nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin
Psychopharmacol. 2008;28(1):13–20.
Tohen M, Frank E, Bowden CL, Colom F, Ghaemi SN, Yatham LN, et al. The International Society
for Bipolar Disorders (ISBD) task force report on the nomenclature of course and outcome in
bipolar disorders. Bipolar Disord. 2009;11(5):453–73.
Trevino K, McClintock SM, McDonald Fischer N, Vora A, Husain MM. Defining treatment-
resistant depression: a comprehensive review of the literature. Ann Clin Psychiatry. 2014;26
(3):222–32.
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antide-
pressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:252–60.
Undurraga J, Baldessarini RJ. Randomized, placebo-controlled trials of antidepressants for acute
major depression: thirty-year meta-analytic review. Neuropsychopharmacology. 2012;37
(4):851–64.
Van Norman GA. Drugs and devices: comparison of European and U.S. approval processes. JACC
Basic Transl Sci. 2016;1(5):399–412.
Vázquez GH, Holtzman JN, Lolich M, Ketter TA, Baldessarini RJ. Recurrence rates in bipolar
disorder: systematic comparison of long-term prospective, naturalistic studies versus random-
ized controlled trials. Eur Neuropsychopharmacol. 2015;25(10):1501–12.
Ventura J, Hellemann GS, Thames AD, Koellner V, Nuechterlein KH. Symptoms as mediators of
the relationship between neurocognition and functional outcome in schizophrenia: a meta-
analysis. Schizophr Res. 2009;113:189–99.
von Glischinski M, Willutzki U, Stangier U, Hiller W, Hoyer J, Leibing E, et al. Liebowitz Social
Anxiety Scale (LSAS): optimal cut points for remission and response in a German sample. Clin
Psychol Psychother. 2018;25(3):465–73.
Walsh TB, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression.
JAMA. 2002;287(14):1840–7.
Weathers FW, Bovin MJ, Lee DJ, Sloan DM, Schnurr PP, Kaloupek DG, et al. The Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5): development and initial psychometric evalu-
ation in military veterans. Psychol Assess. 2018;30(3):383–95.
Randomized Controlled Trials and the Efficacy of Psychotropic Medications 359

Weise RE, Shear MK, Maser JD. On the need for standardization in panic disorder treatment
research: survey of the literature, 1980–1992. Anxiety. 1996;2:257–64.
Weiss RD, Rao V. The prescription opioid addiction treatment study: what have we learned. Drug
Alcohol Depend. 2017;173(Suppl 1):S48–54.
Weitz E, Hollon SD, Twisk J, van Straten A, David D, DeRubeis RJ, et al. Does baseline depression
severity moderate outcomes between CBT and pharmacotherapy? An individual participant data
meta-analysis. JAMA Psychiat. 2015;72:1102–9.
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs.
2003;35(2):253–9.
West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials: proposal for a
common standard. Addiction. 2005;100(3):299–303.
Westmoreland P, Krantz MJ, Mehler PS. Medical complications of anorexia nervosa and bulimia.
Am J Med. 2016;129(1):30–7.
Williams T, Hattingh CJ, Kariuki CM, Tromp SA, van Balkom AJ, Ipser JC, et al. Pharmacotherapy
for social anxiety disorder (SAnD). Cochrane Database Syst Rev. 2017;10:CD001206.
Winhusen T, Winstanley EL, Somoza E, Brigham G. The potential impact of recruitment method on
sample characteristics and treatment outcomes in a psychosocial trial for women with co-
occurring substance use disorder and PTSD. Drug Alcohol Depend. 2011;120(1–3):225–8.
Wisniewski SR, Rush AJ, Nierenberg AA, Gaynes BN, Warden D, Luther JF, et al. Can phase III
trial results of antidepressant medications be generalized to clinical practice? A STARD report.
Am J Psychiatry. 2009;166(5):599–607.
Wittchen HU, Zhao S, Kessler RC, Eaton WW. DSM-III-R generalized anxiety disorder in the
National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(5):355–64.
Wong N, Sarver DE, Beidel DC. Quality of life impairments among adults with social phobia: the
impact of subtype. J Anxiety Disord. 2011;26(1):50–7.
Woods SW, Gueorguieva RV, Baker CB, Makuch RW. Control group bias in randomized atypical
antipsychotic medication trials for schizophrenia. Arch Gen Psychiatry. 2005;62(9):961–70.
World Health Organization. Global status report on alcohol and health 2018. Geneva: World Health
Organization; 2018.
World Medical Association. Declaration of Helsinki: ethical principles for medical research involv-
ing human subjects. JAMA. 2013;310(20):2191–4.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al. Canadian Network for
Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders
(ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord.
2018;20(2):97–170.
Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, et al. Post-
traumatic stress disorder. Nat Rev Dis Primers. 2015;1:15057.
Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of
randomized, controlled trials. Neuropsychopharmacology. 2011;36(2):375–89.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and
sensitivity. Br J Psychiatry. 1978;133:429–35.
Zimmerman M, Posternak MA, Chelminski I. Derivation of a definition of remission on the
Montgomery-Asberg depression rating scale corresponding to the definition of remission on
the Hamilton rating scale for depression. J Psychiatr Res. 2004;38(6):577–82.
Zimmerman M, Martinez J, Attiullah N, Friedman M, Toba C, Boerescu DA, et al. Further evidence
that the cutoff to define remission on the 17-item Hamilton Depression Rating Scale should be
lowered. Depress Anxiety. 2012a;29(2):159–65.
Zimmerman M, Martinez JA, Attiullah N, Friedman M, Toba C, Boerescu DA, et al. Why do some
depressed outpatients who are in remission according to the Hamilton Depression Rating Scale
not consider themselves to be in remission? J Clin Psychiatry. 2012b;73(6):790–5.
Adverse Drug Reactions, Intoxications
and Interactions of Neuropsychotropic
Medications

Gerald Zernig, Sabine Bischinger, and Christoph Hiemke

Contents
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
Adverse Drug Reactions and Intoxications: Definition, Prevalence, Severity . . . . . . . . . . . . . . . . . 367
Information on ADRs on the Internet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
ADRs Due to the Pharmacologic Target Profile of the Prescribed Medication . . . . . . . . . . . . 397
ADRs Due to Enantioselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
Enantiomer Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
ADRs Due to Chemical Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
ADRs Due to Treatment Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Clinically Most Impressive Toxidromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
ADRs Due to Pharmacologic Target(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Clozapine ADRs and Clozapine Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Medications Not Covered in the Present Chapter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
Optimization of Pharmacotherapy in Clinical Practice: An Example . . . . . . . . . . . . . . . . . . . . . . . . . . 409
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

G. Zernig (*)
Department of Psychiatry 1, Medical University of Innsbruck, Innsbruck, Tirol, Austria
e-mail: gerald.zernig@i-med.ac.at
S. Bischinger
Hospital Pharmacy, University Hospital of Innsbruck, Innsbruck, Austria
e-mail: sabine.bischinger@tirol-kliniken.at
C. Hiemke
Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany
e-mail: hiemke@uni-mainz.de

© Springer Nature Switzerland AG 2022 361

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_8
362 G. Zernig et al.

Abstract
Any medication has desirable effects (e.g., alleviation of depressive symptoms)
and may produce undesirable, unintended effects (e.g., headache or vomiting)
which are called ‘adverse reactions’ or ‘adverse drug reactions’ (ADRs). ADRs
can be ‘severe’ / ‘serious’ and have to be differentiated from ‘side effects’ and
‘adverse events.’ Definitions for these terms are given in this chapter. Many
ADRs can be explained by the pharmacologic target(s) of the prescribed medi-
cation. This chapter gives a comprehensive review of these molecular target-
based ADRs. To emphasize, some ADRs cannot be explained yet in sufficient
detail by the pharmacologic target profile of the prescribed drug. Fortunately, we
live in a great era with respect to wealth of and ease of access to information
(i.e., the Internet). As no single individual can hold all the ADR information
currently available and as it is not advisable to rely on a single database only, this
chapter also contains a comprehensive description of available databases
on ADRs, pharmacogenetic profiles of drug metabolism, drug interactions –
including pharmacogenetic ones – and toxicologic information on medications.

Abbreviations

To ease access of the text through the search function of various software, no
hyphens are given in the text. To increase simplicity, no subscripts are given either.
Therefore, the compound “MK-801” is given simply as “MK801,” or the “5-HT1A
receptor” is given simply as “5HT1A receptor.”

5HT 5-Hydroxytryptamine ¼ serotonin

5HT1A Serotonin receptor, subtype 1A ¼ 5HT1A receptor ¼ 5HT1A
receptor
5HTT Serotonin transporter
AADC Aromatic L-amino acid decarboxylase
AChE Acetylcholine esterase ¼ acetylchlinesterase
ADR Adverse drug reaction
ALDH Aldehyde dehydrogenase
AMPA Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
BPS British Pharmacological Society
BZD Benzodiazepine(s)
cAMP Cyclic adenosine monophosphate
CNS Central nervous system, i.e., brain and spinal cord
D2 Dopamine receptor, subtype 2 ¼ D2 receptor ¼ D2 receptor
D2L, D2S D2 receptor, long/short splice variant
DAT Dopamine transporter
DDS Dopamine dysregulation syndrome
Adverse Drug Reactions, Intoxications and Interactions of. . . 363

DKA Diabetic ketoacidosis

DXE Desired effect of a medication
FDA Food and Drug Administration (United States of America)
GABA Gamma-aminobutyric acid
GABAA Gamma-aminobutyric acid receptor, subtype A
GBL Gamma-butyrolactone, a prodrug for GHB
GHB Gamma-hydroxybutyrate
Gi/o/q/s/11, etc. G protein, guanine nucleotide binding protein, different alpha
subunits
GSK3 Glycogen synthase kinase, subtype 3
H1 Histamine receptor, subtype 1
hERG Human ether-a-go-go-related gene (see Kv11.1)
HHS Hyperglycemic hyperosmolar syndrome
IKr Rapidly activating delayed rectifier (potassium) current through
Kv11.1
IP3 Inositol 1,4,5-triphosphate
IUPAC International Union of Pure and Applied Chemistry
IUPHAR International Union of Basic and Clinical Pharmacology
Kd Dissociation constant, the free concentration of a ligand at which
50% of the receptors are occupied
Ki Inhibitory dissociation constant, the Kd as determined in compe-
tition binding experiments
KOMM Knockout mouse model, an experimental approach to prevent the
expression of a pharmacologic target
Kv11.1 Alpha subunit of a potassium channel mediating IKr
M1 Acetylcholine receptor, muscarinic type (mAChR), M1
subsubtype
mAChrR Acetylcholine receptor, muscarinic type
MAOA Monoamine oxidase A ¼ MAO, subtype A
MAOB Monoamine oxidase B ¼ MAO, subtype B
MAOI Monoamine oxidase inhibitor
MK801 (+)-MK-801 ¼ dizocilpine
nAChrR Acetylcholine receptor, nicotinic type
NAM Negative allosteric modulator
NARI Noradrenaline reuptake inhibitor
NaSSA Noradrenergic and specific serotonergic antidepressant
NAT Noradrenaline transporter, same as NET
NET Norepinephrine transporter, same as NAT
NMDA N-methyl-D-aspartate
PAM Positive allosteric modulator
PCP Phencyclidine
PI Phosphatidylinositol
PKA Protein kinase A, cAMP-dependent protein kinase
364 G. Zernig et al.

pKi Ki (see above) expressed as negative logarithm of mol/l, i.e., pKi

9 ¼ 109 mol/l ¼ 1 nmol/l
PLA2 Phospholipase A2, cleaving the second fatty acid from the
glycerol
PLC Phospholipase C
QTc QT interval, corrected for heart rate
RCT Randomized clinical trial
RIMA Reversible inhibitor of MAOA
RLS Restless legs syndrome
SERT Serotonin transporter
SERTI Serotonin transporter inhibitor, see also SSRI
SGA Second-generation antipsychotic
SNRI Serotonin norepinephrine reuptake inhibitor
SPC Summary of product characteristics
SSRI Selective serotonin reuptake inhibitor
TCA Tricyclic antidepressant
UK United Kingdom
VMAT2 Vesicular monoamine transporter, subtype 2
VSCC Calcium channel, voltage sensitive
VSSC Sodium channel, voltage sensitive

Introduction

Different terms and definitions (see below) exist for a phenomenon that we will in
the following refer to as an ‘adverse drug reaction’ (ADR). ADRs are of keen interest
for the prescribing physician, not only the ADRs caused by the medication itself, but
also ADRs to drug interaction and ADRs due to the pharmcogenetic disposition of
the patient.
We live in a great era with respect to the wealth of information and the ease of
access to it. This also means that no single individual (whom we are aware of) can
hold all the information available on ADRs. To emphasize, some ADRs cannot be
explained yet in sufficient detail by the pharmacologic target profile (receptor
binding profile) of the prescribed drug. Consequently, a major focus of the present
review is a short description of Internet databases available to the single prescribing
physician or patient (Table 1). For an overview of the clinically most impressive
toxidromes, see Table 2 below. A comprehensive overview of ADRs that can be
explained on the basis of the pharmacologic target(s) of the medication is given in
Table 3.
As stated above, the wealth of information is overwhelming. In order to help the
individual user orient her/himself, some databases have tried to consolidate ADRs in
a limited number of categories. For example, diagnosia (enterprise.diagnosia.com)
Adverse Drug Reactions, Intoxications and Interactions of. . . 365

Table 1 Internet databases on adverse drug reactions (ADRs), drug drug interactions, and
pharmacogenetic profiles
SPC or website
(in alphabetical order)
yearly costs for single user Advantages Disadvantages
SPC (many SPCs are Legally binding document Inconsistencies between
available free of charge on different SPCs (i.e., between
the Internet) originator brand and generics
or between different generics)
Difficult to find relevant
information for a distinct
combination
Lack of explicit information on
the escitalopram + quetiapine
combination
Apotheken-Umschau German language only
(https://www.apotheken-
umschau.de/Medikamente/
Wechselwirkungscheck)
Austria Codex (shop. Collection of SPCs only
apoverlag.at/austria-codex, No drug interaction software
160 EUR)
Diagnosia Beneficial interaction between
escitalopram and quetiapine
(i.e., augmentation of
antidepressant effect) not
mentioned
drugs.com (free of charge) Information for both patients References NOT unequivocally
and health-care professionals linked to claim of ADR
given in tailored form Beneficial interaction between
References given escitalopram or SSRIs in
When searching for general and quetiapine
“amlodipine candesartan (i.e., augmentation of
ezetimibe,” the website alerts antidepressant effect) not
to a drug interaction (liver mentioned
damage, myopathy) given for a Drug interaction given for
combination of simvastatin and pharmacologic class (e.g.,
(1) amlodipine (CYP3A4 benzodiazepines and opioids)
inhibition) or (2) ezetimibe but NOT for specific
(cause unknown) compounds
Lexicomp ¼ online. No interaction between
lexi.com (free trial upon escitalopram and quetiapine
request, 669 USD) given
Interaction between
hydrocodone and oxazepam
given IF oxazepam BUT NOT
IF hydrocodone is search item
References NOT unequivocally
linked to claim of ADR or drug
interaction
(continued)
366 G. Zernig et al.

Table 1 (continued)
SPC or website
(in alphabetical order)
yearly costs for single user Advantages Disadvantages
mediq.ch (250 CHF/EUR, References (with PubMed link; German language only
free trial access, 15 days) no references for interaction References NOT unequivocally
between hydrocodon and linked to claim of ADR
oxazepam) Link to complete SPC
Partial SPC directly shown unwieldy
Pharmacogenetics table Beneficial interaction between
Pharmacodynamic table (but escitalopram and quetiapine
not for escitalopram) (i.e., augmentation of
Pharmacodynamic drug antidepressant effect) not
interactions mentioned
Orienting therapeutic range and
laboratory alert level
(conflicting values for
aripiprazole, Kirschbaum
2008)
Recommended dosage
Pharmacologic targets
New interactions alert, monthly
update
micromedexsolutions.com Recommended dosage Beneficial interaction between
(8900 EUR, access to free Drug–pregnancy interaction escitalopram and quetiapine
trial unwieldy) Drug–drug of abuse test (i.e., augmentation of
interaction antidepressant effect) not
Phytopharmaceuticals mentioned
Pediatric patients
Elderly patients
Toxicology
Physicochemical
incompatibility
Global coverage of availability/
trade name
psiac.de (120 EUR, free References (with PubMed link) German language only
trial access, 7 + 7 days) references NOT unequivocally Focused on psychiatric and
linked to claim of ADR neurologic medications
Pharmacogenetics table References NOT unequivocally
including drug interactions linked to claim of ADR
exceeding search profile Interaction between
Pharmacodynamic drug hydrocodone and oxazepam
interactions not mentioned
Main emphasis on drug
interactions
ADRs grouped in only three
domains: delirium/
anticholinergic, QTc
prolongation/TdP, 5HT effects
Links to only some SPCs
(continued)
Adverse Drug Reactions, Intoxications and Interactions of. . . 367

Table 1 (continued)
SPC or website
(in alphabetical order)
yearly costs for single user Advantages Disadvantages
Wikipedia (free of charge) ADRs, drug interactions and Depth of information varies
pharmacogenetics often given considerably between drugs
ADRs, drug interactions, and
pharmacogenetics listed but
mostly not detailed
References given sparingly

gives seven ADR categories: (1) anticholinergic, (2) sodium level changes, (3) QTc
prolongation, (4) orthostasis, (5) seizures, (6) serotoneric, and (7) bleeding/potas-
sium level changes, obstipation, renal toxicity, and sedation; whereas psiac (www.
psiac.de) gives three ADR categories: (1) delirogenic/anticholinergic, (2) torsade de
pointes (TdP)/QTC prolongation, and (3) serotonergic.
Ideally, wide accessibility to ADR information can greatly improve a patient’s
knowledge about the prescribed medication and, hence, hopefully increase her/his
treatment adherence. It may, however, also lead to less desirable phenomena that
warrant a prescribing physician’s close attention to ADRs, for example, legal
liability issues. To illustrate, one of the authors (GZ) served as an expert court
witness in a claim of damages by a patient who was mistakenly handed escitalopram
by the pharmacist instead of the prescribed esomeprazole. The patient sued the
pharmacy and claimed to have most of the ADRs known in the summary of product
characteristics of escitalopram. Prolonged and costly litigation ensued.
To access to the information of this chapter easily, we strongly encourage the
reader to make ample use of the search function of her/his reading software. We have
therefore taken pains to give as many synonyms for the most important terms and
concepts as feasible.

Adverse Drug Reactions and Intoxications: Definition, Prevalence,

Severity

A medication has desirable/desired effects (DXEs, e.g., alleviation of depressive

symptoms) and may have undesirable/undesired ones (e.g., headache or vomiting).
A pharmaceutical, according to the European Commission, produces an “undesir-
able effect” if it engenders an “adverse reaction” (ec.europa.eu/health/files/eudralex/
vol-2/c/smpc_guideline_rev2_en.pdf, accessed 5 Nov 2019). The World Health
Organization (WHO) defines an “adverse reaction” or “adverse drug reaction” as
follows (https://www.who.int › coordination › English_Glossary, accessed 5 Nov
2019):
368 G. Zernig et al.

Table 2 Differential diagnosis of the toxidromes presenting with agitation, delirium, or coma. This
table is a modification of the excellent Table 3 of Scotton et al. (2019)
Other clinical
Toxidrome Caused by Timecourse Vital signs features
Malignant Inhalational Very sudden Severe Rigor mortis –
hyperthermia anesthetics or onset (minutes to hyperthermia like rigidity,
succinylcholine hours), resolves up to 46  C, hyporeflexia,
(a depolarizing within 24–48 h tachycardia, hypoactive bowel
muscle relaxant) with treatment hypertension, sounds, rising
in genetically tachypnea end-tidal CO2,
susceptible mottled skin with
individuals flushing,
cyanosis, normal
pupils;
rhabdomyolysis,
high blood
potassium
Serotonin Serotonergic Sudden onset Hyperthermia Neuromuscular
syndrome drugs, i.e., 5HT <24 h, most >41.1  C, hyperactivity:
receptor resolve within tachycardia, tremor, clonus,
agonists or 5HT 24 h with hypertension, myoclonus,
transporter treatment (25% tachypnea hyperreflexia;
inhibitors develop diaphoresis;
symptoms hyperactive
>24 h) bowel sounds
Anticholinergic Acetylcholine Sudden onset Mil Normal muscle
syndrome receptor <24 h, resolves hyperthermia tone and reflexes,
blockers (e.g., within hours to usually mumbling,
M1 blockers) days with <38.8  C, slurred speech,
treatment tachycardia, picking behavior,
mild dry flushed skin
hypertension, and mucous
tachypnea membranes,
hypoactive bowel
sounds, urinary
retention,
hyperkinesis
(myoclonus,
choreoathetosis),
seizures (rare)
Neuroleptic Dopamine D2 Slower onset Hyperthermia Neuromuscular
malignant receptor (days to weeks), >41.1  C, hypoactivity
syndrome blockers or resolves within tachycardia, (lead pipe
“dopamine 10 days with hypertension, rigidity),
withdrawal” treatment tachypnea bradykinesia,
(Scotton et al. hypoactive bowel
2019), i.e., sounds
abrupt cessation
of levodopa or
DA agonists
(Brunton et al.
2017)
Table 3 Desired effects (DXEs) and adverse drug reactions (ADRs) explained by pharmacologic target. Whenever a consensus for DXEs and/or ADRs
was found, all respective references are given at the same place in the text. When a source gave additional DXEs and/or ADRs, this is stated separately in the
text. If DXEs and/or ADRs were obtained from a Summary of Product Characteristics, preferably from the originator, this is declared as SPC information (eg
Lyrica ® SPC). In some cases, different sources vary consideriably in their description of a certain toxidrome. These different descriptions are given in order to
empower the reader with greater flexibiliy.
Adverse Drug Reactions, Intoxications and Interactions of. . .
369
370 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 371
372 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 373
374 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 375
376 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 377
378 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 379
380 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 381
382 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 383
384 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 385
386 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 387
388 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 389
390 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 391
392 G. Zernig et al.
Adverse Drug Reactions, Intoxications and Interactions of. . . 393
394 G. Zernig et al.

An adverse drug reaction is a response to a medicinal product which is noxious and

unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis
or therapy of disease or for the restoration, correction or modification of physiological
function. (WHO 1972)

Interestingly, the precise reference for “(WHO 1972)” is not given in the WHO
glossary cited above. An ADR is called “unerwuenschte Arzneimittelwirkung”
(UAW) in German and “effet indésirable médicamenteux” (EIM) in French. To
complicate matters, the term “side effect” (“Nebenwirkung,” “effet secondaire”) is
still often used when describing an ADR. In fact, a “side effect” may very well be a
desirable effect under certain circumstances (e.g., the delay of ejaculation by selec-
tive serotonin reuptake inhibitors (SSRIs) when treating premature ejaculation or the
sedative/hypnotic or muscle relaxant effect of “old,” i.e., centrally acting, antihista-
minic drugs like diphenhydramine). A “side effect” can thus be defined as an
unintended effect occurring at a recommended dosage and is most likely related to
the pharmacologic properties of the prescribed medication during on-label use
(“intended use,” “bestimmungsgemaesser Gebrauch,” “avec autorisation de mise
sur le marché, avec AMM, selon l’AMM”).
A medication may also be used “off-label,” that is, outside the approved indica-
tion/s (“Off-label-Gebrauch,” “hors AMM,” “sans AMM”). In the neuropsychiatric
field, off-label use is notorious in the treatment of children or adolescents (Hiemke
et al. 2018), arguably due to the scarcity of (costly) clinical trials in these patient
populations. Often, governing bodies allow off-label use but require the prescribing
physician to scientifically justify her/his off-label use and exercise extra caution and
monitoring.
The WHO (https://www.who.int › coordination › English_Glossary, pdf auto-
matically downloaded 5 Nov 2019 and 13 Dec 2019) differentiates an ADR from
an “adverse event” which occurs during treatment with a drug but is not suspected
to be causally related to the medicine. An adverse event (AE) is, especially in the
context of clinical trials, is sometimes called a “treatment emergent adverse event”
(TEAE).
The WHO further defines a “serious adverse reaction” as an ADR requiring
inpatient hospitalization or prolongation of existing hospitalization or an ADR that is
life-threating or fatal or results in persistent or significant disability or incapacity, or
is a congenital anomaly/birth defect caused by a medication. The WHO also defines
an “unexpected adverse reaction” as an adverse reaction “the nature, severity or
outcome of which is not consistent with the summary of product characteristics.”
ADRs can also be differentiated according to their causality as “certain,” “probable,”
“possible,” “unlikely,” or “conditional/unclassified” (Edwards and Biriell 1994).
All summaries of product characteristics (SPCs or SmPCs, Fachinformationen,
résumés des caractéristiques du produit) list ADRs and group and rank them
according to their prevalence (in Europe, this information can be found in section
4.8 of the SPC). The SPC is a legally binding document that must be available for
every approved medicine and has undergone scrutiny by regulatory governmental
bodies. The SPC should be based on controlled clinical trials during development
Adverse Drug Reactions, Intoxications and Interactions of. . . 395

and is updated according to clinical observation after the medication’s release

(pharmacovigilance, post-marketing surveillance, see below). However, a 2007
analysis of available SPCs revealed a number of shortcomings, most notably a
lack of transparency (Ulrich et al. 2007). Many databases (see below) and textbooks
give the ADR information as listed in the SPC. Especially when choosing poly-
pharmacy, it is highly inconvenient to use SPCs for a proper evaluation of safety and
tolerability risks for every day practice.
ADR prevalence is ranked according to the convention of the Council for
International Organizations of Medical Sciences (CIOMS, cioms.ch; see also
ec.europa.eu/health/files/eudralex/vol-2/c/smpc_guideline_rev2_en.pdf, accessed
5 Nov 2019 and 13 Dec 2019):

Very common (sehr haeufig, très fréquemment) in at least 10%, i.e., at least 10 cases
per 100 patients
Common (haeufig, fréquemment): in less than 10%, i.e., 1/10 but at least 1%, i.e.,
1/100
Uncommon (gelegentlich, peu fréquemment): in less than 1%, i.e., 1/100 but at least
0.1%, i.e., 1/1000
Rare (selten, rarement): in less than 0.1%, i.e., 1/1000 but more than 0.01%, i.e.,
1/10,000
Very rare (sehr selten, très rarement): in less than 0.01%, i.e., 1/10,000 patients
[Frequency] not known ([Haeufigkeit] unbekannt, frequence indeterminée): Fre-
quency cannot be estimated from the available data

With respect to the severity of an ADR or the differentiation between a desirable

drug effect and an intoxication with the same medication, the reader is reminded of
the famous quotation of Parcelsus (Philippus Aureolus Theophrastus Bombastus von
Hohenheim): “Sola dosis facit venenum” (“Only the dose makes the poison”; “Seule
la dose fait le poison”; “Alle Dinge sind Gift, und nichts ist ohne Gift; allein die
Dosis machts, dass ein Ding kein Gift sei.”) (Paracelsus 1538, quoted in de.
wikipedia.org, accessed 30 Dec 2019). Many psychopharmacologic agents, most
notably benzodiazepines and mu opioid receptor agonists, act as central nervous
depressants, producing anxiolytic/hypnotic/sedative effects at lower dosages/con-
centrations, while causing coma and death at higher to very high dosages/concen-
trations, all along the same pharmacologic continuum, that is, the “concentration
effect curve,” more commonly known as the “dose response curve” (the chapter on
pharmacokinetic and pharmacodynamic principles in the present ebook or, e.g.,
Zernig et al. 2007, 2009; Eggart et al. 2011; Stahl 2013; Hiemke 2019). In some
cases, a medication affects different pharmacologic targets at different concentra-
tions. Consequently, a psychotropic medication’s dosage/concentration increases
from an “ineffective range” to an “orienting therapeutic range,” also called a
“therapeutic reference range” or a “therapeutic window” (Hiemke et al. 2018) to
an “alert level” (Hiemke et al. 2018) to a “toxic” range and, finally, in some cases, to
a “comatose-lethal range” (Repetto and Repetto 1997; Regenthal et al. 1999; Schulz
and Schmoldt 2003; Schulz et al. 2012).
396 G. Zernig et al.

Information on ADRs on the Internet

As stated above, ADRs and the frequency of their occurrence during on-label use
have to be listed in the SPC of the prescribed medication (specifically, in section
4.8 of the European SPC or section 6 of the FDA-approved medication guide in
the USA). SPCs are widely available on the Internet. Although SPCs are, to our
knowledge, meant for the use of health-care professionals only, SPCs for many
medications can be downloaded from the World Wide Web by patients as well. As
a further example of SPC availability for patients on the Internet, the website
www.drugs.com gives information for both the “consumer” and the “health-care
professional.” Patient-tailored information is added to the medication package as
a paper handout in form of a “medication package insert” or “label”
(wikipedia.org) or “medication guide” (FDA term) or “consumer information”
(drugs.com). German or French terms are: “Patienteninformation,”
“Packungsbeilage,” “Beipackzettel,” “notice patient,” and “notice d’emballage.”
In addition, databases that focus on drug interactions and/or pharmacogenetic
disposition (see below) give information on ADRs, sometimes precisely as listed
and frequency-ranked in the SPC. Information on ADRs is therefore easily
available for any approved medicine. In clinical practice, however, SPCs are
rarely used by general practitioners, especially under routine conditions and in
case of polypharmacy (Gahr et al. 2020).
Thus, for the prescribing physician whose pharmacologic knowledge has become
a little rusty (see Table 3 below for a comprehensive refresher), Internet databases
offer a convenient way to get abundant information on ADRs, especially because, as
stated above, some ADRs cannot be explained yet in sufficient detail by the
pharmacologic target profile of the prescribed drug, such as clozapine-induced
agranulocytosis, which is considered an immunologic and/or toxic ADR (see
below). A downside of the plethora of information available on ADRs and drug–
drug interactions is “alert fatigue,” leading clinicians to override the alerts. An
analysis of 213,253 alerts issued between 2009 and 2012 to physicians at a
tertiary-care teaching facility of Harvard Medical School (Nanji et al. 2018) found
that in 73%, the alert was overriden by the prescribing physician. When the over-
riding physician declared that the patient would be monitored as recommended, did
actually monitor the patient, and documented this monitoring, the override was
considered “appropriate.” Such an appropriate alert override, however, occurred in
only 61% of the overrides (Nanji et al. 2018).
Despite incurring the risk of alert fatigue, our analysis of the available Internet
databases (Table 1 below) indicates that it is not advisable to rely on a single
database only. Even within the same databank, drug interactions may be given
when searching for one medication of a pair but not when searching for the other.
Table 1 gives an overview of the databases tested by us from October to December
2019 by searching for information on ADRs, drug interactions, and pharmacogenetic
disposition for the following drug combinations: (1) escitalopram + quetiapine,
(2) hydromorphone + oxazepam, and (3) amlodipine + candesartan + ezetimibe. These
are the reasons for our choice of drug combinations: (1) The escitalopram + quetiapine
Adverse Drug Reactions, Intoxications and Interactions of. . . 397

combination was chosen as it is, on the one side, risky because of an at least additive
prolongation of the corrected QT interval (QTc), a very common ADR of psychophar-
macologic agents, but most likely also conveys the beneficial drug interaction of an
increase in the antidepressant effect of the SSRI escitalopram by quetiapine (see, e.g.,
McIntyre et al. 2007; Quante et al. 2013; Wen et al. 2014). (2) The
hydromorphone + oxazepam combination was chosen because it is very common (at least
at the university hospital in Innsbruck; SB, personal communication) and the (at least)
additive sedation may cause serious problems for the patient and, consequently, the
prescribing physician. (3) The amlodipine + candesartan + ezetimibe combination was
chosen to test if non-psychopharmacologic medications are also covered in the tested
database and because the consensus of the authors was that this combination is essentially
free of adverse drug interactions, allowing us to probe for overreporting of ADRs and
adverse drug interactions by the database. The preference for a certain type of presenta-
tion of information (i.e., the layout) is highly subjective; we have therefore refrained from
giving any information on that aspect.

ADRs Due to the Pharmacologic Target Profile of the Prescribed

Medication

Most ADRs can be logically explained on the basis of the pharmacologic target
profile of the medication just like the desired effects (DXEs) of this medication.
For the understanding of an ADR, it is therefore very worthwhile to consider the
pharmacologic profile of the medication causing the ADR. By “pharmacologic
target profile” or “receptor (binding) profile,” we mean the sum total of the target
structures (e.g., dopamine receptors vs. dopamine transporters) which have recep-
tor(s) for the medication. Very broadly speaking, the overwhelming majority of
psychopharmacologic mediations bind to neurotransmitter receptors (e.g., dopa-
mine D2 receptors and 5HT2A receptors in the case of most antipsychotics) or
monoamine transporters (e.g., the serotonin [5HT] transporter in the case of
selective serotonin reuptake inhibitors, SSRIs) (Stahl 2013). Only three enzymes
are known as targets for neuropsychiatric medications, that is, acetylcholine
esterase (AChE), monoamine oxidase (MOA), and glycogen synthase kinase
(GSK) (Stahl 2013). Conventional antipsychotic activity is conferred by dopamine
D2 receptor inhibition (blockade; more on that below). Also very broadly speak-
ing, antidepressants seem to elevate the concentrations of monoamine neurotrans-
mitters in the synaptic cleft, mostly by blocking transporters that move the
neurotransmitter back into the neuron.
With respect to the pharmacologic target profile, it also has to be considered with
which respective affinities the medication binds to the receptors of different target
structures. In that context, remember that a transporter, such as the dopamine
transporter (DAT), also has a receptor (binding site) for medications, for example,
the antidepressant bupropion. This receptor on the DAT transporter is not to be
confused with the dopamine receptor, for example, the D2 receptor that mediates the
antipsychotic effect of antipsychotics/neuroleptics.
398 G. Zernig et al.

As an example for medications that interact with different pharmacologic

targets with different affinities, the antidepressant duloxetine, as its name indicates,
targets two receptor systems at therapeutic concentrations, that is, the serotonin
transporter (SERT or 5HTT) and the noradrenaline transporter (NAT or NET).
Duloxetine’s binding affinity, however, is slightly different for both targets. As an
explanatory insert, the binding affinity of any medication to a receptor can be
quantified as the concentration at which 50% of the receptors are occupied and is
called the dissociation constant, Kd, if determined in saturation binding assays
(rarely performed), or called Ki, when determined in binding inhibition/competi-
tion assays (frequently performed). Duloxetine inhibits the SERT with a Ki of
4.6 nmol/l and the NAT at a 3.5-fold higher concentration, that is, with a Ki of
16 nmol (Bymaster et al. 2001). This difference is more pronounced, that is,
sevenfold, for the antidepressant venlafaxine, the Ki value being 77 nmol/l for
the SERT and 538 nmol for the NAT. This more pronounced difference in SERT-
versus NAT affinity may be the reason why the recommended dosage, according to
the respective SPCs, is 60–120 mg/day for duloxetine, that is, a twofold range,
whereas it is 75–375 mg/day for venlafaxine, that is, a fivefold range. Their
orienting therapeutic range (OTR, “therapeutic reference range”), however,
seems the same, that is, 30–120 ng/ml for duloxetine and 100–400 ng/ml for
venlafaxin and its active metabolite, O-desmethylvenlafaxine, both OTRs span-
ning a fourfold range (Hiemke et al. 2018). When comparing affinities for the
SERT only, the 17-fold difference in inhibitory affinity (i.e., 77 nmol/l
vs. 4.6 nmol/l) found in vitro corresponds to only a threefold difference in the
lower end of the OTR (i.e., 30 ng/ml vs. 100 ng/ml). These numerical inconsis-
tencies may be due to the fact that the in vitro experiments were obviously
performed and published 8 years apart, that is, 1993 for duloxetine (Wong et al.
1993) versus 2001 for venlafaxine (Bymaster et al. 2001), albeit by the same
laboratory. Overall, however, the higher affinity of duloxetine in comparison to
venlafaxine for either the SERT or the NAT than venlafaxine is reflected both in a
lower recommended dosage and a lower orienting therapeutic concentration in the
blood for duloxetine versus venlafaxine. Some medications are pharmacologically
“pure,” that is, interact with only one pharmacologic target at therapeutic concen-
tration, such as the selective serotonin reuptake inhibitor (SSRI) escitalopram (see,
e.g., Table 15.2 of Brunton et al. 2017; Table 3 of this chapter; or Stahl 2013). In
addition to the term “SSRI,” other descriptors such as “NARI,” “SNRI,” or
“NaSSA” have been coined to differentiate antidepressants on the market; these
abbreviations have been explained above.
It should also be considered if the medication acts as an inverse agonist, neutral
antagonist, partial agonist/antagonist or full agonist at each of this target structures
(for a detailed explanation of these terms, see, e.g., the pharmacodynamics chapter
by Zernig and Hiemke in the present handbook or Stahl (2013). To help the reader
to differentiate better, the pharmacologically correct terms “agonist/antagonist”
(the opposite pharmacologic effect being just differentiated by the three letters
Adverse Drug Reactions, Intoxications and Interactions of. . . 399

“nta”) have been replaced by the more jargon-like terms “agonist/blocker.”

Accordingly, terms like “dopamine D2 receptor antagonist” have been shortened
to “D2 blocker.”
To illustrate how both desired effects and ADR can be explained by the same
pharmacologic target: Conventional antipsychotics (e.g., haloperidol) are essentially
only dopamine D2 blockers which renders them effective for the treatment of the
positive symptoms of schizophrenia (delusions, hallucinations, hostility, etc. (Kay
et al. 1987)). At the same time, the same D2 blockade confers a higher ADR risk of
conventional antipsychotics (compared to atypical antipsychotics) with respect to
(1) undesired locomotor effects such as acute extrapyramidal symptoms, EPS, and
tardive dyskinesia, and (2) hyperprolactinemia resulting in breast secretions, amen-
orrhea, and other symptoms such as sexual dysfunction (Stahl 2013). Conventional
antipsychotics, that is, simple D2 blockers, are also less effective in treating the
negative symptoms of schizophrenia (Stahl 2013), that is, defects in a variety of
beneficial brain functions, such as blunted affect, emotional and social withdrawal,
and difficulty in abstract thinking (Kay et al. 1987).
Atypical antipsychotics (second-generation antipsychotics) are not only D2
blockers, but high-affinity 5HTA2 blockers as well. The prime example is clozapine,
which has a 20-fold higher affinity for 5HT2A receptors than D2 receptors (Schotte
et al. 1996). However, an atypical antipsychotic may also be antidepressant and
mitigate EPS due to it partial agonist action at 5HT1A receptors and D2 receptors
(Stahl 2013), with aripiprazole being the prime example of a partial D2 agonist
(more precisely, a partial agonist D2- and D3 receptors (Stahl 2013)). According to
aripiprazole’s SPC, it acts as a partial agonist at D2- and 5HT1A receptors, as a
blocker at 5HT2A receptors, and has lower affinity for the D4-, 5HT2C-, 5HT7-,
alpha1-, and H1 receptors. Unfortunately, the SPC does not state if aripiprazole acts
as an agonist, partial agonist, or blocker at these pharmacologic targets; it is likely
that it acts as a blocker at all these receptors (Stahl 2013). Thus, depending on the
concentration of aripiprazole obtained in blood and, hence, brain, and depending of
the level of activation of various dopaminergic neuronetworks (systems) in the
patient, a different spectrum of desired effects and ADRs may result.
Considerable ADRs can be caused by an imbalance in the cholinergic system(s)
of the periphery and/or within the brain. These cholinergic ADRs can be mediated by
direct blockade of muscarinic M1 or nicotinic acetylcholine receptors but also by
blocking D2 receptors located on the dendrites of cholinergic interneurons, with the
D2 blockade disinhibiting acetylcholine release in these neurons, causing, for
example, EPS and cognitive dysfunction (Stahl 2013).
Some of the ADRs can be explained by unwanted interaction with neurotrans-
mitter/neuroanatomical systems that are quite removed from the desired pharmaco-
logic targets of the medication, for example, cardiovascular ADRs or cognitive
ADRs including delirium by acetylcholine receptor blockade. Table 3 gives a
broad overview of the desired effects and ADRs that can be explained by the
pharmacologic target profile of the medication.
400 G. Zernig et al.

ADRs Due to Enantioselectivity

A short refresher on enantioselectivity, enantiomers, racemate, chirality, stereochem-

istry, diastereomers, and other terms is helpful to understand the different desired
effects and ADRs of some medications, for example, citalopram (a racemate) versus
the pure enantiomer escitalopram, (racemic) ketamine versus the pure enantiomer
esketamin, or (racemic) methadone versus the pure enantiomer levomethadone.
Like the hands (the term “chirality” derives from Greek “χειρ,” “[cheir]” or
“[kheir]” for “hand”), these racemic medications contain a 50:50 mixture (racemate)
of two molecules that have the same number of side chains (like the fingers of our
hands) but exist in two nonsuperimposable forms or “mirror images” (like our hands:
just try to superimpose your hands palm over palm). These two mirror image
molecules are called enantiomers. The enantiomer that produces the effects we
want is called the eutomer (the “good” enantiomer), and the other is called the
distomer (the “bad” one).
For example, the eutomer escitalopram (“es” for the “S” in (S)-Citalopram, see
below) binds to two allosterically coupled receptors (a primary binding site and a
secondary site) at the serotonin transporter and acts as an antidepressant, whereas the
distomer (R)-citalopram (“arcitalopram”), by binding to this secondary (allosteric)
site, not only inhibits the binding of escitalopram to the secondary site, but also
decreases the time that escitalopram remains bound to the primary site (i.e., makes
escitalopram dissociate from the primary binding site faster), thereby decreasing
escitalopram’s inhibitory effect on the SERT and, hence, decreasing escitalopram’s
antidepressant effect (Sanchez 2006). Consequently, the recommended anti-
depressive dosage is 20–40 mg/day for citalopram, that is, the racemate (SPC for
Seropram ®), and 10–20 mg/day for escitalopram (SPC for Cipralex ®, both SPCs
accessed 17 Mar 2020).
In the case of (racemic) methadone, levomethadone binds to the mu opioid
receptor with about 30-fold higher affinity than dextromethadone in rat brain
(Horng et al. 1976) and, consequently, was found to be roughly 50-fold more
potent analgesic in humans (Horng et al. 1976 and other evidence quoted in
Gorman et al. (1997)). Racemic methadone was found to bind to the cloned
human mu opioid receptor with a Ki (inhibitory dissociation constant) in the
nanomal range, that is, 6 nmol/l (Raynor et al. 1995). Levomethadone’s Ki in
postmortem human brains was 3 nmol/l (Lotsch et al. 2006), strongly indicating
that at clinically used dosages of (racemic) methadone, essentially only the
eutomer levomethadone binds to and interacts with the human mu opioid receptor.
Unfortunately, we could not find an original article that directly compared the
binding affinities of levo- and dextromethadone for human mu opioid receptors. In
contrast to the mu opioid receptor, both levomethadone and dextromethadone bind
with about equal and about 1000-fold lower, that is, micromolar, affinity to the
dizocilpine binding site (“dizocilpine site” or “PCP site”) of the NMDA receptor in
rat brain (Gorman et al. 1997), the respective Ki values (in μmol/l) being 8.3 for
Adverse Drug Reactions, Intoxications and Interactions of. . . 401

racemic methadone, 3.4 for levomethadone, and 7.4 for dextromethadone. Of

relevance for interspecies scaling, racemic methadone was found (Raynor et al.
1995) to bind to the cloned human mu opioid receptor with an approximately 3.4-
fold higher affinity (i.e., with a Ki of 5.6 nmol/l) than to the rat brain mu opioid
receptor (19 nmol/l). Therefore, the PCP site binding affinities as determined in rat
brain could reasonably be expected in human brain to be 1 μmol/l for
levomethanone and 2 μmol/l for dextromethadone. Consequently, the desired
effects (analgesia, substitution of opioid dependent patients) of racemic methadone
at clinically used dosages are mediated by levomethadone (marketed as
L-Polamidon ®), whereas the interaction of both enantiomers to the dizocilpine/
PCP site of the NMDA receptor may contribute to ADRs. Thus, on pharmacologic
principle, one should prescribe the pure eutomer levomethadone rather than race-
mic methadone, because levomethadone is twofold less likely to produce ADRs
due a PCP site interaction (or interactions due to low affinity interactions with yet
unidentified unwanted pharmacologic targets).
In the case of racemic ketamine, the eutomer esketamine binds to the dizocilpine
(binding) site (PCP (binding) site) of the NMDA receptor with a three- to fourfold
higher affinity than arketamine (Vollenweider et al. 1997). The SPC for Ketanest ®
(esketamine) also gives an approximately fourfold higher anesthetic and analgesic
potency of esketamine than arketamine (sold as Ketalar ® previously in Austria and
still in Switzerland) and alerts prescribing physicians that esketamine is about
twofold more effective than racemic ketamine at the same dose. In contrast to the
PCP site of the NMDA receptor, only arketamine binds to the sigma receptor, most
likely the reason for the higher incidence of schizophrenia-like ADRs (i.e., psychotic
symptoms) of the racemate (Vollenweider et al. 1997). Consequently, racemic
ketamine (sold as Ketalar ® previously in Austria or still in Switzerland) has mostly
been replaced with the pure enantiomer esketamine (Ketanest ®, www.pfizer.de,
accessed 16 Mar 2020). Interestingly, the manufacturer of Ketanest ® (www.
pfizer.de), in the German language version of the SPC for Ketanest ®, links
ketamine’s abuse liability to ARDs such as reexperience of previous emotional states
(a symptom we would term a “flashback”), hallucinations, dysphoria, disorientation,
and insomnia. The manufacturer of the intranasal esketamine spray Spravato® lists
anxiety; dysphoria; disorientation; insomnia; flashback; hallucinations; feelings of
floating, detachment, and to be “spaced out”; and abuse liability as ADRs but does
not explicitly link the psychotropic effects to ketamine’s abuse liability. In the
experience of one of us (GZ), it is very plausible that any psychotropic medication
that changes an individual’s perception and emotional state to a certain degree has
abuse liability, even if – as in the case of ketamine or PCP – the internal drug stimuli
(i.e., drug-induced emotions and perceptions) are considered “negative” by most of
us (as opposed to, say, the euphoric effects that many drugs of abuse engender).
Finally, ketamine may also cause cystitis (including a hemorrhagic one) and hepa-
totoxicity. To our knowledge, there is no consensus as to which pharmacologic
targets are responsible for these ADRs.
402 G. Zernig et al.

Enantiomer Nomenclature

With respect to the nomenclature of enantiomers, several categorizing systems still

coexist (the most easily understandable summary can be found under “absolute
configuration” in Wikipedia, accessed 16 Mar 2020): If one takes the carbon atom
that is the chiral center of a molecule and arranges the side chains according to
decreasing atomic number, a clockwise arrangement (right form Latin “rectus”) is
designated with the prefix “(R)-,” whereas a counterclockwise arrangement (the
Latin “sinister,” left) gets the designator “(S)-.”
A “(+)-”enantiomer rotates the plane of polarized light traveling toward the
viewer to the right (dextrorotary from the Latin “dexter”), whereas a levoratory
enantiomer (from Latin “laevus”) is designated with the prefix “()-.” The (+)- and
()-enantiomers have also been termed “d-” (lower case d) and “l-” (lower case l).
Because “d-, l-” is easily confused with “D-, L-” (upper case letters), the use of “d-,
l-” is discouraged by the International Union of Pure and Applied Chemistry
(IUPAC) (Moss 1996).
Finally, there is also the “D-” (upper case D) versus “L-” (upper case L)
differentiation: A D-enantiomer of any molecule rotates polarized light in the same
direction, that is, to the right, as (+)-glyceraldehyde, that is, the dextrorotatory
enantiomer of glyceraldehyde, whereas an L-enantiomer rotates it in the same
direction as ()-glyceraldehyde, that is, to the left.
Of note, the different categorization systems need no match: Esketamine (“es”
being the onomatopoetic equivalent of “(S)-”) is (S)-ketamine ¼ (+)-ketamine
(sometimes written as “(S)-(+)-ketamine” or S-(+)-ketamine), escitalopram ¼ (S)-
citalopram ¼ (+)-citalopram, and levomethadone (L-methadone, L-Polamidon ®) is
R-methadone ¼ ()-methadone.
In contrast to structural isomers (enantiomers, chirality, see above), stereoisomers
are different spatial arrangements of the same molecule with the same molecular
formula and sequence of bonded atoms. An example for this is the antipsychotic
flupentixol (sometimes spelled “flupenthixol”), which is marketed as (E, Z)-
flupentixol. The IUPAC prefers the unambiguous E, Z-notation to the cis, trans-
notation (Moss 1996).

ADRs Due to Chemical Structure

Whereas explaining the clinical effect(s) and the ADRs by the pharmacologic
target of the drug of interest currently seems to be the most effective strategy,
explaining ADRs according to chemical structure, for example, butyrophenones
versus benzamides, has, in our opinion, always been unpopular among prescrib-
ing physicians, not least because navigating the chemical names requires
an expertise that is far removed from the clinical routine. More importantly,
chemically very diverse drugs can produce very similar desired effects and
ADRs, for example, haloperidol, a butyrophenone, and risperidone, a
benzisoxazole (and its active metabolite 9-hydroxyrisperidone ¼ paliperidone).
Adverse Drug Reactions, Intoxications and Interactions of. . . 403

On the other hand, chemically similar drugs can produce very different effects,
like amitriptyline, a tricyclic antidepressant, versus flupentixol, a tricyclic anti-
psychotic from the thioxanthene group. For a very helpful overview of different
chemical/pharmacological categorization systems, see the German article by
Laux (2010).

ADRs Due to Treatment Groups

Grouping the drug according to the psychiatric disease category the drug can be
used to treat, for example, antidepressant versus antipsychotic, has retained more
differentiating power, although borders have become blurred (see above). Many
groups in the field use the following categories: antidepressant, antipsychotic
(conventional/first generation vs. atypical/second generation), anti-convulsant
and mood stabilizing, anxiolytic/tranquilizer/used for the treatment of sleep disor-
ders (hypnotic), anti-dementia (nootropic), drugs used for the treatment of
substance-related disorders (including anticraving), drugs used for the treatment
of the attention deficit hyperactivity syndrome (psychostimulant) (see, e.g., Laux
2010; Hiemke et al. 2018).
For the sake of completeness, it should be mentioned that there is an “Anatomical
Therapeutic Chemical” (ATC) classification system adopted by the WHO (https://www.
whocc.no/atc_ddd_index/, accessed 7 Nov 2019), which differentiates “psycholeptics”
(ATC code N05), that is, drugs that produce a calming effect, encompassing antipsy-
chotics (neuroleptics), anxiolytics, and hyponotics/sedatives from “psychoanalep-
tics,”that is, psychostimulants (N06), that is, antidepressants, psychostimulants/agents
used for attention deficit hyperactivity disorder/nootropics; psycholeptics and
psychoanaleptics in combination, and anti-dementia drugs and from “other nervous
system drugs” (N07), with, among others, drugs used in addictive disorders.

Clinically Most Impressive Toxidromes

Table 2 gives a quick overview of the clinically most impressive psychotropic

medication-induced toxidromes associated with agitation, delirium, or coma: sero-
tonin syndrome, anticholinergic syndrome, malignant neuroleptic syndrome, and
malignant hyperthermia. For the pharmacologic targets underlying these toxidromes,
the reader is referred to Table 3.

ADRs Due to Pharmacologic Target(s)

Table 3 gives an overview of the desirable and adverse drug reactions (ADRs) of
most psychopharmacologic compounds and lists their pharmacologic targets. To
enhance understanding of physiologic brain functions, the targets are listed alpha-
betically according to the neurotransmitter that activates them (e.g., the NMDA
404 G. Zernig et al.

receptor can be found under “glutamate receptor”). One receptor for the neurotrans-
mitter glutamate, that is, the NMDA receptor, and one receptor for the neurotrans-
mitter gamma-aminobutyric the GABAA receptor, are (at least in our view) so
formidably complex pharmacologic targets that we have supplemented the text of
Table 3 with two figures, Fig. 1 for the GABAA receptor, and Fig. 2 for the NMDA
receptor, below.
With respect to the desired effects and ADRs of dopamine receptor agonists,
Table 3 lists dose of the levodopamine, that is, the precursor of the physiologic
agonist dopamine itself. A refresher: oral dopamine does not cross the blood–brain
barrier but its precursor levodopa does, and as levodopa is readily converted to
dopamine peripherally by aromatic L-amino acid decarboxylase (AADC), oral
levodopa is combined with an AAC inhibitor, typically either benserazid (e.g., in
Madopar ®) or carbidopa (e.g., in Sinemet ®). Please bear in mind that the desired
effects and ADRs of oral levodopa and, hence, dopamine in the brain have been

Fig. 1 Schematic cross sections of the GABAA receptor and the associated chloride channel.
Shown are two cross sections, that is, (1) various binding sites within the transmembrane domain
(i.e., the chloride pore) on the left and (2) the binding sites on the extracellular domain. Reproduced
with the publisher’s permission from Olsen (2018). For more details on the ethanol binding site, see
Wallner et al. (2014). Abbreviations: Barbs, barbiturates; BZ, benzodiazepines; EtOH, ethanol
(alcohol); Eto, etomidate; Pro, propofol, Pyr, pyrazoloquinolines; volatiles, volatile anesthetics.
Examples for benzodiazepines (BZ, BZD) are: alprazolam, bromazepam, brotizolam, chlordiaz-
epoxide, clobazam, clonazepam, diazepam, desmethyldiazepam, flunitrazepam, flurazepam, loraz-
epam, lormetazepam, medazepam, midazolam, nitrazepam, nordazepam, oxazepam, temazepam,
triazolam. Another pharmacologic group that binds to the BZD site is the alpha1-over-alpha3
preferring (Soderhielm et al. 2018) so-called Z drugs (“Z-drugs”) like zolpidem, zopiclone,
eszopiclone, or zaleplon. Examples for barbiturates are: methohexital (methohexital), phenobarbital
(phenobarbitone), primidone (desoxyphenobarbital), and thiopental (thiopentone)
Adverse Drug Reactions, Intoxications and Interactions of. . . 405

Fig. 2 Schematic cross sections of the NMDA receptor and psychotropic drugs modulating its
function. Abbreviations: 5,7-DCKA, 5,7-dichloro-kynurenic acid, a glycine site blocker; AP5, see
D-AP5; Ca2+, calcium ions; D-AP5, dextrorotatory, that is, R-D()-2-amino-5-phosphonovalerate
or phosphonopentanoate; Mg2+, magnesium ions; N, asparagine N-site for channel blockers; Na+,
sodium ions; NMDA, N-methyl-D-aspartate; NR1, NR2A, NR2B, subunits of the NMDA receptor;
Zn2+, zinc ions. (Reproduced with the publisher’s permission from Parsons et al. (2007))

described in patients with Parkinson’s disease, and therefore may not reflect what
dopamine’s physiologic effects. However, as a first approximation they are worth of
our interest.

Clozapine ADRs and Clozapine Toxicity

Clozapine is, in the eyes of many prescribing psychiatrists, the most effective
antipsychotic medication and, for some, still the only “true” atypical (second
generation) antipsychotic, with a 20-fold higher affinity for 5HT2A receptors than
D2 receptors (Schotte et al. 1996, see above). Unfortunately, clozapine’s use is
jeopardized by a considerable risk of severe ADRs, most notably neutropenia.
Accordingly, from 28 Feb 2019 on, the FDA requires prescribing health-care pro-
fessionals as well as pharmacies dispensing clozapine, to be certified in a Clozapine
Risk Evaluation and Mitigation Strategy (REMS) Program (https://www.fda.gov/
drugs/postmarket-drug-safety-information-patients-and-providers/information-
clozapine, accessed 17 Mar 2020). The SPC for Clozaril ® in the USA (version Feb
406 G. Zernig et al.

2017) lists the following ADRs in its boxed warning (“black box warning”): severe
neutropenia, orthostatic hypotension, bradycardia and syncope, seizure, myocarditis
and cardiomyophathy, increased mortality in elderly patients with dementia-related
psychosis. The SPC for Clozaril ® in the UK (UK, version 6 June 2019) states the
following: “As a consequence of a recent European regulatory initiative, the Clozaril
Summary of Product Characteristics (SmPC) has been harmonised across Europe.
The SmPC states that blood monitoring should be carried out in accordance with
national-specific official recommendations. . . .” The SPC for Clozaril ® in the UK
then proceeds to summarize, in a boxed warning (which is identical to the German
version in Austrian SPCs of clozapine products:

Clozaril can cause agranulocytosis. Its use should be limited to patients:

• with schizophrenia who are non-responsive to or intolerant of antipsychotic

medication, or with psychosis in Parkinson’s disease when other treatment
strategies have failed (see section 4.1),
• who have initially normal leukocyte findings (white blood cell count  3500/
mm3 (3.5  109/l), and ANC  2000/mm3 (2.0  109/l)), and,
• in whom regular white blood cell (WBC) counts and absolute neutrophil
counts (ANC) can be performed as follows: weekly during the first 18 weeks
of treatment, and at least every 4 weeks thereafter throughout treatment.
Monitoring must continue throughout treatment and for 4 weeks after
complete discontinuation of Clozaril (see section 4.4).

Prescribing physicians must comply fully with the required safety mea-
sures. At each consultation, a patient receiving Clozaril must be reminded to
contact the treating physician immediately if any kind of infection begins to
develop. Particular attention must be paid to flu-like complaints such as fever
or sore throat and to other evidence of infection, which may be indicative of
neutropenia (see section 4.4).
Clozaril must be dispensed under strict medical supervision in accordance
with official recommendations (see section 4.4).
Myocarditis
Clozapine is associated with an increased risk of myocarditis which has, in
rare cases, been fatal. The increased risk of myocarditis is greatest in the first
2 months of treatment. Fatal cases of cardiomyopathy have also been reported
rarely (see section 4.4).
Myocarditis or cardiomyopathy should be suspected in patients who expe-
rience persistent tachycardia at rest, especially in the first 2 months of
treatment, and/or palpitations, arrhythmias, chest pain and other signs and
symptoms of heart failure (e.g., unexplained fatigue, dyspnoea, tachypnoea)
or symptoms that mimic myocardial infarction (see section 4.4).

(continued)
Adverse Drug Reactions, Intoxications and Interactions of. . . 407

If myocarditis or cardiomyopathy are suspected, Clozaril treatment should

be promptly stopped and the patient immediately referred to a cardiologist
(see section 4.4).
Patients who develop clozapine-induced myocarditis or cardiomyopathy
should not be re-exposed to clozapine (see sections 4.3 and 4.4).

From the perspective of therapeutic drug monitoring (TDM, see, e.g., Zernig et al.
2009; Hiemke et al. 2011, 2018) it must be noted that the definition of “non-
responsiveness” to antipsychotic medication or “treatment resistance” in the cloza-
pine SPCs is defined only “as a lack of satisfactory clinical improvement despite the
use of adequate doses of at least two different antipsychotic agents, including an
atypical antipsychotic agent, prescribed for adequate duration” does not include a
requirement to quantify the blood concentration of the respective antipsychotic. It is
well known in field that the treatment adherence (compliance) of psychiatric patients
suffering from schizophrenia, depression, or bipolar disorder is notoriously low, with
nonadherence ranging from 10% to 69% (Hiemke et al. 2018), with average
discontinuation rates of 44% for antipsychotics (range, 18–70%), and with patients
taking, on average, only 65% of their prescribed antipsychotic dosage (range,
40–90%) (Zernig et al. 2009). We would argue that before switching a patient to
clozapine, proper TDM of the two previously prescribed antipsychotics be
performed to clarify if these two pre-clozapine antipsychotics have indeed reached
blood concentrations in the orienting therapeutic range for a long enough time span
so that clinical improvement and acceptable tolerability can be expected.
The pathophysiology of clozapine-induced neutropenia (incidences around 3%
for milder cases and 1% fullblown agranulocytosis) has not been clarified in detail
yet and has been attributed to an immune response (Brunton et al. 2017; Regen et al.
2017) and a direct toxic effect on the myeloid cell line (Pick and Nystrom 2014).
In addition to neutropenia/agranulocytosis, the SPC for Clozaril ® in the UK
(version 6 June 2019) lists the following ADRs: eosinophilia, thrombocytopenia,
orthostatic hypotension, myocardial infarction, QT interval prolongation, cerebro-
vascular adverse events, thromboembolism, seizures, anticholinergic effects, fever,
falls, metabolic changes such as hyperglycemia, dyslipidemia, weight gain; rebound,
that is, withdrawal effects, hepatic impairment with preexisting liver disorders, and
increased mortality in elderly people with dementia. The SPC lists drowsiness/
sedation, dizziness, tachycardia, constipation, and hypersalivation as the most com-
mon ADRs of clozapine. The pharmacologic targets for these effects can be found in
Table 3 of the present chapter.

Medications Not Covered in the Present Chapter

Giving a comprehensive overview of the ADRs of all neuropsychotropic med-

ications currently on the market in a book chapter is an impossible task. In the
408 G. Zernig et al.

next section “Further Reading” we will suggest references that have successfully
provided such information. For the sake of transparency, we will list the medi-
cations that we did not cover, based on the comprehensive list in our TDM
update (Hiemke et al. 2018) which gives the pharmacokinetic data for the
medications listed below, their orienting therapeutic ranges, and their metabolic
pathways, including the respective isoforms of cytochrome p450 (CYP)
involved.
A number of medications can be used either as a mood stabilizer or an anti-
convulsant. We tried to cover those compounds but, with a few exceptions, not
medications that are considered to be antiepileptics only (Hiemke et al. 2018).
Therefore, we did not cover brivaracetam, ethosuximide, eslicarbazepine, felbamate,
lacosamide, levetiracetam (mechanism of action not fully understood (Brunton et al.
2017)), methsuximide, perampanel, phenytoin, retigabine, rufinamide, sulthiame,
tiagabine, topiramate, vigabatrin, and zonisamide.
We also did not cover the following antiparkinson drugs (Hiemke et al. 2018):
amantadine, bornaprine, cabergoline, carbidopa, entacapone, rotigotine, and
tolcapone. The following anxiolytics and drugs for the treatment of sleep disorders
(Hiemke et al. 2018) were not covered either: modafinil (unknown mechanism of
action and some abuse liability according to the SPCs, and a schedule IV controlled
drug in the USA (Brunton et al. 2017)), opipramol, prothipendyl, and promethazine.
Finally, we did not cover the tricyclic antidepressant tianeptine the mechanism of
action of which is not clear (Stablon ® SPC) or clomethiazole (Distraneurin ®,
Heminevrin ®), a medication not covered in Stahl (2013) and Brunton et al. (2017),
previously popular in some countries for the treatment of alcohol withdrawal but
jeopardized by considerable ADRs including tolerance, withdrawal, and abuse
liability (SPCs).

Further Reading

For further information on the pharmacologic basis of the desired effects and ADRs
of neuropsychotropic medications, the reader is referred to the informative and
popular book by Stahl which is pleasant to read (Stahl 2013). “Goodman and
Gilman’s: The Pharmacological Basis of Therapeutics)” is a pharmacologic classic
which is currently in its 13th edition and also contains a useful table on pharmaco-
kinetic parameters of selected pharmaceuticals (Brunton et al. 2017). Another
source, in German, is Degner et al. (2004). Over the last decades, SPCs have become
more comprehensive with respect to giving clinical proof of efficacy in randomized
controlled trials (RCTs) and with respect to the pharmacodynamics (i.e., the phar-
macologic target(s)) of some medications. In comparison to pharmacologic text-
books and scholarly articles (including the present chapter), SPCs also have the
advantage of being legally binding documents with respect to the information given
therein.
For an excellent, extremely informative, and authoritative overview of pharmaco-
logic targets, receptor classification, function, selective agonists and blockers etc., the
Adverse Drug Reactions, Intoxications and Interactions of. . . 409

reader can consult the joint website of the International Union of Basic and Clinical
Pharmacology (IUPHAR), and the British Pharmacological Society, www.guidetophar
macology.org. Wikipedia (*wikipedia.org) in its different language version is an
informative source, too, and unsurpassed with respect to speed of access and scope.
Finally, a word of caution: Wikipedia’s information sometimes needs to be cross-
checked – first and most quickly, by cross-checking the different language versions
of the same article. The anonymity of its contributors is problematic with respect to
effective source checking. Sometimes, information from Stahl (2013) and Goodman
and Gilman’s (Brunton et al. 2017) is discrepant. To enable the reader to form an
independent judgment, we have taken care to present both views in the present
chapter and have tried to resolve apparent discrepancies. A shortcoming of both
sources is that claims are only rarely supported by citations. For example, Stahl
claims that guanfacine is 15–60 times more selective for the alpha2A receptor than
for alpha2B- and alpha2C receptors (Stahl 2013) without giving a reference for this
claim. The IUPHAR/BPS website www.guidetopharmacology (accessed 21 Mar
2020) gives guanfacine’s pKi values as 7.1–7.3 for alpha2A, 5.8–6.5 for alpha2B,
and 5.4–6.2 for alpha2C. This translates to a 4–32-fold selectivity for alpha2A/2B
and an 8–79-fold difference for alpha2A/2C.

Pharmacovigilance

According to the World Health Organization (WHO), “pharmacovigilance” is defined

as the science and activities relating to the detection, assessment, understanding, and
prevention of adverse effects or any other drug-related problem (https://cioms.ch/
pharmacovigilance/, accessed 4 Nov 2019). A less comprehensive term would be
“postmarketing surveillance.” Pharmacovigilance is fortunately carried out by a num-
ber of institutions. In many legislations, reporting of ADRs by the prescribing
physician is mandatory. All pharmaceutical companies known to us have a mandatory
ADR reporting procedure. To adequately list all these pharmacovigilance efforts is
way beyond the scope of the present chapter. The reader is referred to the local
regulating authorities. An example for a well-established and active pharmacov-
igilance programs in German-speaking countries are the Institut fuer Arzneimittelsi-
cherheit in der Psychiatrie e.V. (www.amsp.de; Degner et al. 2004; Grohmann et al.
2004; Letmaier et al. 2018) and the Arbeitsgemeinschaft Arzneimitteltherapie bei
psychiatrischen Erkrankungen e.V. (AGATE, https://www.amuep-agate.de/).

Optimization of Pharmacotherapy in Clinical Practice: An

Example

To give an example how clinical pharmacy can be implemented successfully in a

routine hospital setting in a time-efficient manner: A pharmacist from the university
hospital pharmacy in Innsbruck has been meeting regularly once a week for the last
2 years with two psychiatrists responsible for a total of 12 beds in two inpatient
410 G. Zernig et al.

wards in order to optimize pharmacotherapy with an emphasis on avoiding ADRs,

particularly ADRs due to drug interactions (safety of pharmacotherapy, Arzneimit-
teltherapiesicherheit). In preparation for this meeting, all prescribed medications of
selected cases (on average, ten patients per week) are recorded and analyzed by the
pharmacist according to Medication Appropriateness Indices (MAI) criteria (Hanlon
et al. 1996). Results and possible or necessary pharmacotherapeutic interventions are
discussed in the weekly meeting.

Cross-References

▶ Pharmacokinetic and Pharmacodynamic Principles

Conflicts of Interest Christoph Hiemke is one of the editors of the commercially available
database www.psiac.de. Sabine Bischinger and Gerald Zernig declare no conflicts of interest.

References
Anonymous. Wikipedia article 2020. Available from: en.wikipedia.org
Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology.
1999;38(8):1083–152.
Bear MF, Connors BW, Paradiso MA. Neuroscience. 4th ed. Philadelphia: Wolters Kluwer; 2016.
Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors – IUPHAR review 13. Br
J Pharmacol. 2015;172(1):1–23.
Bortolotti F, De Paoli G, Gottardo R, Trattene M, Tagliaro F. Determination of gamma-
hydroxybutyric acid in biological fluids by using capillary electrophoresis with indirect detec-
tion. J Chromatogr B Anal Technol Biomed Life Sci. 2004;800(1–2):239–44.
Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman and Gilman’s the pharmacological basis of
therapeutics. 13th ed. New York: McGraw-Hill; 2017.
Busardo FP, Gottardi M, Tini A, Minutillo A, Sirignano A, Marinelli E, et al. Replacing GHB with
GBL in recreational settings: a new trend in chemsex. Curr Drug Metab. 2018;19(13):1080–5.
Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, et al.
Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine trans-
porters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.
Neuropsychopharmacology. 2001;25(6):871–80.
Carruthers SG. Adverse effects of alpha 1-adrenergic blocking drugs. Drug Saf. 1994;11(1):12–20.
Chae YJ, Jeon JH, Lee HJ, Kim IB, Choi JS, Sung KW, et al. Escitalopram block of hERG
potassium channels. Naunyn Schmiedeberg’s Arch Pharmacol. 2014;387(1):23–32.
Chevillard L, Megarbane B, Baud FJ, Risede P, Decleves X, Mager D, et al. Mechanisms of
respiratory insufficiency induced by methadone overdose in rats. Addict Biol. 2010;15(1):62–80.
Chiara DC, Hamouda AK, Ziebell MR, Mejia LA, Garcia G 3rd, Cohen JB. [(3)H]chlorpromazine
photolabeling of the torpedo nicotinic acetylcholine receptor identifies two state-dependent
binding sites in the ion channel. Biochemistry. 2009;48(42):10066–77.
Degner D, Grohmann R, Kropp S, Ruther E, Bender S, Engel RR, et al. Severe adverse drug
reactions of antidepressants: results of the German multicenter drug surveillance program
AMSP. Pharmacopsychiatry. 2004;37(Suppl 1):S39–45.
Adverse Drug Reactions, Intoxications and Interactions of. . . 411

Degner D, Grohmann R, Ruether E. Unerwuenschte Wirkungen/Nebenwirkungen. In: Riederer P,

Laux G, editors. Grundlagen der Neuro-Psychopharmakologie Ein Therapiehandbuch.
Wien/New York: Springer; 2010.
Dolder PC, Schmid Y, Steuer AE, Kraemer T, Rentsch KM, Hammann F, et al. Pharmacokinetics
and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clin Pharmacokinet.
2017;56(10):1219–30.
Dvir Y, Smallwood P. Serotonin syndrome: a complex but easily avoidable condition. Gen Hosp
Psychiatry. 2008;30(3):284–7.
Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf. 1994;10(2):93–102.
Eggart V, Hiemke C, Zernig G. “There is no dose–response relationship in psychopharma-
cotherapy” vs “pharmacotherapy in psychiatry is based on ligand–receptor interaction”: a
unifying hypothesis and the need for plasma concentration based clinical trials. Psychopharma-
cology. 2011;217(2):297–300.
Euwema MS, Swanson TJ. Deadly single dose agents. Treasure Island: StatPearls; 2019.
Gahr M, Freudenmann RW, Connemann BJ, Schoenfeldt-Lecuona C, Muche R, Hiemke C, et al.
Nutzung von Fachinformationen bei Hausärzten und Apothekern im Zusammenhang der Aut-
idem-Regelung: Ergebnisse einer explorativen Querschnittsbefragung. Z Evid Fortbild Qual
Gesundhwes. 2020;150-152:45–53.
Goettingen U. Toxidrome 2020. Available from: https://www.giz-nord.de/cms/index.php/
informationen-zur-therapie-von-vergiftungen-/477-toxidrome.html
Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the
non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal
cord. Neurosci Lett. 1997;223(1):5–8.
Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences
having substantial and sustained personal meaning and spiritual significance. Psychopharma-
cology. 2006;187(3):268–83.
Grohmann R, Engel RR, Ruther E, Hippius H. The AMSP drug safety program: methods and global
results. Pharmacopsychiatry. 2004;37(Suppl 1):S4–11.
Hanlon JT, Weinberger M, Samsa GP, Schmader KE, Uttech KM, Lewis IK, et al. A randomized,
controlled trial of a clinical pharmacist intervention to improve inappropriate prescribing in
elderly outpatients with polypharmacy. Am J Med. 1996;100(4):428–37.
Hiemke C. Concentration-effect relationships of psychoactive drugs and the problem to calculate
therapeutic reference ranges. Ther Drug Monit. 2019;41(2):174–9.
Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, et al. AGNP consensus
guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry.
2011;44(6):195–235.
Hiemke C, Bergemann N, Broich K, Clement HW, Conca A, Deckert J, et al. AGNP consensus
guidelines for therapeutic drug monitoring in psychiatry and neurology: update 2017.
Pharmacopsychiatry. 2018;51:9–62.
Horng JS, Smits SE, Wong DT. The binding of the optical isomers of methadone, alpha-methadol,
alpha-acetylmethadol and their N-demethylated derivatives to the opiate receptors of rat brain.
Res Commun Chem Pathol Pharmacol. 1976;14(4):621–9.
IUPHAR/BPS. www.guidetopharmacology.org (2020).
janssen.com. Esketamine approved by United States FDA as adjunctive for treatment-resistant
depression. 2020. Available from: https://www.janssen.com/janssen-announces-us-fda-
approval-spravato-esketamine-ciii-nasal-spray-adults-treatment-resistant
Jones CK, Byun N, Bubser M. Muscarinic and nicotinic acetylcholine receptor agonists and
allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology. 2012;37
(1):16–42.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizo-
phrenia. Schizophr Bull. 1987;13(2):261–76.
412 G. Zernig et al.

Kraehenmann R, Pokorny D, Vollenweider L, Preller KH, Pokorny T, Seifritz E, et al. Dreamlike

effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation.
Psychopharmacology. 2017;234(13):2031–46.
Kirschbaum KM, Müller MJ, Malevani J, et al. Serum levels of aripiprazole and
dehydroaripiprazole, clinical response and side effects. World J Biol Psychiatry. 2008;9
(3):212–218.
Laux G. Nomenklatur, Einteilung von Psychopharmaka. In: Riederer P, Laux G, editors.
Grundlagen der Neuropsychopharmakologie. Wien/New York: Springer; 2010. p. 353–66.
Letmaier M, Grohmann R, Kren C, Toto S, Bleich S, Engel R, et al. Venous thromboembolism
during treatment with antipsychotics: results of a drug surveillance programme. World J Biol
Psychiatry. 2018;19(3):175–86.
Lotsch J, Skarke C, Wieting J, Oertel BG, Schmidt H, Brockmoller J, et al. Modulation of the
central nervous effects of levomethadone by genetic polymorphisms potentially affecting its
metabolism, distribution, and drug action. Clin Pharmacol Ther. 2006;79(1):72–89.
Mahoney JJ III, Kalechstein AD, De La Garza R II, Newton TF. Presence and persistence of
psychotic symptoms in cocaine- versus methamphetamine-dependent participants. Am J Addict.
2008;17(2):83–98.
McIntyre A, Gendron A, McIntyre A. Quetiapine adjunct to selective serotonin reuptake inhibitors
or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive
symptoms: a randomized, placebo-controlled pilot study. Depress Anxiety. 2007;24(7):487–94.
Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT. Dopamine uptake through the
norepinephrine transporter in brain regions with low levels of the dopamine transporter:
evidence from knock-out mouse lines. J Neurosci. 2002;22(2):389–95.
Moss GP. Basic terminology of stereochemistry (IUPAC recommendations 1996). Pure Appl Chem.
1996;68(12):2993–222.
Nanji KC, Seger DL, Slight SP, Amato MG, Beeler PE, Her QL, et al. Medication-related clinical
decision support alert overrides in inpatients. J Am Med Inform Assoc. 2018;25(5):476–81.
Nomikos GG, Damsma G, Wenkstern D, Fibiger HC. In vivo characterization of locally applied
dopamine uptake inhibitors by striatal microdialysis. Synapse. 1990;6:106–12.
Olsen RW. GABAA receptor: positive and negative allosteric modulators. Neuropharmacology.
2018;136(Pt A):10–22.
Paracelsus. Die dritte Defension wegen des Schreibens der neuen Rezepte Septem Defensiones.
Darmstadt. 1538. www.zeno.org
Parsons CG, Stoffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves
memory by restoration of homeostasis in the glutamatergic system – too little activation is
bad, too much is even worse. Neuropharmacology. 2007;53(6):699–723.
Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et al. Activation of mGlu2/3
receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med.
2007;13(9):1102–7.
Pick AM, Nystrom KK. Nonchemotherapy drug-induced neutropenia and agranulocytosis: could
medications be the culprit? J Pharm Pract. 2014;27(5):447–52.
Quante A, Regen F, Schindler F, Volkmer K, Severus E, Urbanek C, et al. Quetiapine as
combination treatment with citalopram in unipolar depression with prominent somatic symp-
toms: a randomised, double-blind, placebo-controlled pilot study. Psychiatr Danub. 2013;25
(3):214–20.
Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid
components independently contribute to the mechanism of action of tramadol, an “atypical”
opioid analgesic. J Pharmacol Exp Ther. 1992;260(1):275–85.
Raynor K, Kong H, Mestek A, Bye LS, Tian M, Liu J, et al. Characterization of the cloned human
mu opioid receptor. J Pharmacol Exp Ther. 1995;272(1):423–8.
Regen F, Herzog I, Hahn E, Ruehl C, Le Bret N, Dettling M, et al. Clozapine-induced agranulo-
cytosis: evidence for an immune-mediated mechanism from a patient-specific in-vitro approach.
Toxicol Appl Pharmacol. 2017;316:10–6.
Adverse Drug Reactions, Intoxications and Interactions of. . . 413

Regenthal R, Krueger M, Koeppel C, Preiss R. Drug levels: therapeutic and toxic serum/plasma
concentrations of common drugs. J Clin Monit. 1999;15:529–44.
Repetto MR, Repetto M. Habitual, toxic, and lethal concentrations of 103 drugs of abuse in humans.
J Toxicol Clin Toxicol. 1997;35(1):1–9.
Salous AK, Ren H, Lamb KA, Hu XQ, Lipsky RH, Peoples RW. Differential actions of ethanol and
trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A)
subunit. Br J Pharmacol. 2009;158(5):1395–404.
Sanchez C. The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the
effect of S-citalopram. Basic Clin Pharmacol Toxicol. 2006;99(2):91–5.
Savelyeva MV, Baldenkov GN, Kaverina NV. Receptor binding potencies of chlorpromazine,
trifluoperazine, fluphenazine and their 10-N-substituted analogues. Biomed Biochim Acta.
1988;47(12):1085–7.
Schotte A, Janssen PFM, Gommeren W, Luyten WHML, van Gompel P, Lesage AS, et al.
Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor
binding. Psychopharmacology. 1996;124:57–73.
Schulz M, Schmoldt A. Therapeutic and toxic blood concentrations of more than 800 drugs and
other xenobiotics. Pharmazie. 2003;58(7):447–74.
Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. Therapeutic and toxic blood concen-
trations of nearly 1,000 drugs and other xenobiotics. Crit Care. 2012;16(4):R136.
Scotton WJ, Hill LJ, Williams AC, Barnes NM. Serotonin syndrome: pathophysiology, clinical
features, management, and potential future directions. Int J Tryptophan Res.
2019;12:1178646919873925.
Soderhielm PC, Balle T, Bak-Nyhus S, Zhang M, Hansen KM, Ahring PK, et al. Probing the
molecular basis for affinity/potency- and efficacy-based subtype-selectivity exhibited by
benzodiazepine-site modulators at GABAA receptors. Biochem Pharmacol. 2018;158:339–58.
Stahl SM. Mirror, mirror on the wall, which enantiomer is fairest of them all? J Clin Psychiatry.
2002;63(8):656–7.
Stahl SM. Stahl’s essential psychopharmacology: neuroscientific basis and practical application. 4th
ed. Cambridge: Cambridge University Press; 2013.
Ulrich S, Hiemke C, Laux G, MuellerOerlinghausen B, HavemannReinecke U, Riederer P, et al.
Value and actuality of the prescription information for therapeutic drug monitoring of
psychopharmaceuticals: a comparison with the medico-scientific evidence. Pharmacop-
sychiatry. 2007;40:121–7.
Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J. Differential psychopathology and patterns
of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using
positron emission tomography (PET). Eur Neuropsychopharmacol. 1997;7(1):25–38.
Wallner M, Hanchar HJ, Olsen RW. Alcohol selectivity of beta3-containing GABAA receptors:
evidence for a unique extracellular alcohol/imidazobenzodiazepine Ro15-4513 binding site at
the alpha+beta- subunit interface in alphabeta3delta GABAA receptors. Neurochem Res.
2014;39(6):1118–26.
Wen XJ, Wang LM, Liu ZL, Huang A, Liu YY, Hu JY. Meta-analysis on the efficacy and tolerability
of the augmentation of antidepressants with atypical antipsychotics in patients with major
depressive disorder. Braz J Med Biol Res. 2014;47(7):605–16.
Witchel HJ, Pabbathi VK, Hofmann G, Paul AA, Hancox JC. Inhibitory actions of the selective
serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents.
FEBS Lett. 2002;512(1–3):59–66.
Wong DT, Bymaster FP, Mayle DA, Reid LR, Krushinski JH, Robertson DW. LY248686, a new
inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology. 1993;8(1):23–33.
Zernig G, Issaevitch T, Woods JH. Calculation of agonist efficacy, apparent affinity and receptor
population changes after administration of insurmountable antagonists: comparison of different
analytical approaches. J Pharmacol Toxicol Methods. 1996;35:223–37.
Zernig G, Giacomuzzi S, Riemer Y, Wakonigg G, Sturm K, Saria A. Intravenous drug injection
habits: drug users’ self-reports vs researchers’ perception. Pharmacology. 2003;976:49–56.
414 G. Zernig et al.

Zernig G, Ahmed SH, Cardinal RN, Morgan D, Acquas E, Foltin RW, et al. Explaining the
escalation of drug use in substance dependence: models and appropriate animal laboratory
tests. Pharmacology. 2007;80(2–3):65–119.
Zernig G, Hiemke C, Havemann-Reinecke U, Laux G, Riederer P, Rabl W, et al. Empfehlungen fuer
die gutachterliche Bewertung von Medikamentenspiegeln in der Psychiatrie im gerichtsan-
haengigen Schadensfall. Psychopharmakotherapie. 2009;16(2):57–65.
Zvosec DL, Smith SW, McCutcheon JR, Spillane J, Hall BJ, Peacock EA. Adverse events,
including death, associated with the use of 1,4-butanediol. N Engl J Med. 2001;344(2):87–94.
TCM Substances in
Neuropsychopharmacotherapy: Basic
Aspects with a Focus on Depression

Makoto Naoi, Wakako Maruyama, and Peter Riederer

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
Diet Decreases Incidence of Depression and Improves Symptoms: Meta-analyses and
Clinical Intervention with Healthy Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Antidepressant Function of Herbal Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Antidepressant Phytochemicals: Structure, Activity, and Molecular Mechanism . . . . . . . . . . . . . 424
Structure and Basic Properties of Phytochemicals for Antidepressant Activity . . . . . . . . . . . . 424
Diet and Phytochemicals Enhance 5-HT Level to Exert Antidepressant Activity . . . . . . . . . 432
Phytochemicals Inhibit Type A Monoamine Oxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Phytochemicals Bind to NTF Receptors, Activate Signal Transduction, Induce NTF
Expression, and Function as NTF-Mimics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Anti-Inflammatory Functions of Phytochemicals in Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
Phytochemicals Modulate the HPA Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Phytochemicals Show Anxiolytic Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Novel Antidepressants Synthesized Based on Phytochemical Scaffold . . . . . . . . . . . . . . . . . . . . . . . 440
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
Financial and Competitive Interests Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

M. Naoi (*) · W. Maruyama

Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin
University, Nisshin, Aichi, Japan
e-mail: mnaoi@dpc.agu.ac.jp; maruyama@dpc.agu.ac.jp
P. Riederer
Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital
Wuerzburg, Wuerzburg, Germany
University of Southern Denmark Odense, Odense, Denmark
e-mail: peter.riederer@uni-wuerzburg.de; peter.riederer@mail.uni-wuerzburg.de

© Springer Nature Switzerland AG 2022 415

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_394
416 M. Naoi et al.

Abstract
Depression is one of the most common complexes of heterogeneous psychiatric
disorders. Etiopathogenic factors of depression are deregulation of serotonin,
noradrenaline and dopamine systems, increased activity of type A monoamine
oxidase, deficit of brain-derived neurotrophic factor, and impaired neurogenesis
in the hippocampus and neuroinflammation. Current antidepressant medicines,
such as tricyclic antidepressants, selective serotonin, or noradrenaline reuptake
inhibitors and monoamine oxidase inhibitors, are effective, but about one-third of
the patients are resistant to the therapy. Traditional Chinese medicine, herb, and
plant-derived phytochemicals are proposed as alterative therapeutic agents in
depression. This review presents molecular mechanisms underlying antidepres-
sant effects of diet habits, traditional herbs, St John’s wort, saffron, passion
flower, lavender, valerian, kava, and Ginkgo biloba, and their phytochemical
constituents. Phytochemicals have been proved to modify multiple pathogenic
factors of depression and ameliorate the symptoms in preclinical models. The
epidemiological and clinical intervention studies have presented some beneficial
effects of herb and phytochemicals. However, the intensive rapid metabolism and
poor bioavailability in the brain prevent the clinical application of phytochemi-
cals. Synthesis of more effective and stable compounds based on phytochemical
scaffold and establishment of effective delivery systems are discussed in order to
develop novel therapeutic strategy for depressive disorders by use of
phytochemicals.

Abbreviations
7,8-DHF 7,8-Dihydroxyflavone
BD Bipolar depression
CUMS Chronic un-predictable mild stress
EO Essential oil
ER Estrogen receptor
FST Forced swimming test
GR Glucocorticoid receptor
HDRS Hamilton Depression Rating Scale
HPA Hypothalamic-pituitary-adrenal
IDO Indoleamine 2,3-dioxygenase
MADRS Montgomery–Asberg Depression Rate Scale
MAO-A and –B Type A and B monoamine oxidase
MDD Major depressive disorder
NLRP3 Nucleotide-binding domain, leucine-rich repeat, pyrin
domain containing protein 3
RCT Randomized controlled trial
RPCT Randomized, placebo control trial
TCM Traditional Chinese medicine
THM Traditional herb medicine
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 417

TPH Tryptophan hydroxylase

TRPC Transient receptor potential channel
TRYCAT Tryptophan catabolite
TST Tail suspension test

Introduction

Depression is the most prevalent mental illness and several forms are distinguished:
major depressive disorder (MDD), bipolar depression (BD), seasonal affective
disorder, psychotic, postpartum, premenstrual dysphoric, and situational depression.
MDD itself is a heterogeneous disease characterized by depressive mood, inability to
experience pleasure, cognitive impairment, and autonomic disturbance. The etiology
of depression remains elusive because of lack of identification of disease-responsible
genes and large inter-individual variability. Multiple genetic, social, psychological,
and neurochemical factors are involved in the etiopathogenesis of depression.
Population-based study estimated the hereditability of depression at 42% in
women and 29% in men (Kendler et al. 2006). The impact of negative environmental
factors, such as life stress, traumatic experiences, social and psychological stress,
and neuroinflammation are implicated in depression, particularly in late life, which,
however, might be effected by genetically regulated vulnerability of neuronal circuit
to stress. These results suggest the interaction between genetic and environmental
factors might be the therapeutic target of depression, and epidemiological studies
present that lifestyle factors, such as dietary pattern, sleep, and exercise affect
development of depression (Lopresti et al. 2013). The Mediterranean dietary pattern
reduced risk of developing depression by over 30% (Sanchez-Villegas et al. 2013).
These results indicate that multidisciplinary approach with dietary factors might be
an alternative therapy strategy for depression.
Finding of antidepressant activity of iproniazid (N0 -isopropyl-iso-
nicotinohydazide) and its inhibition of type A monoamine oxidase (MAO-A), a
major enzyme catabolizing serotonin (5-hydroxytryptamine, 5-HT), noradrenaline
(NA) and dopamine (DA), and deregulated serotonergic signal pathways in the
postmortem brain led to the “monoamine hypothesis” and “MAO hypothesis” for
depression pathogenesis (Birkmayer and Riederer 1975). Tricyclic antidepressants
(TCAs), selective serotonin and noradrenaline reuptake inhibitors (SSRIs, SNRIs),
and reversible MAO-A inhibitors (moclobemide, befloxatone) have been developed
based on these hypotheses. Neuropathological analyses and structural MRI studies
have shown the cortical alterations, decrease of the total volume and gray matter of
the hippocampus and functional and structural disruption of neuronal circuit related
in emotional processing in MDD patients (He et al. 2017). Brain-derived
neurotrophic factor (BDNF) decreases in the hippocampus and serum of patients
with MDD, which impairs neurogenesisin the hippocampus and causes atrophy with
neuronal loss of the paraventricular nucleus. The atrophy progresses depending on
disease duration, reduced 5-HT level, increased stress, and neuroinflammation.
418 M. Naoi et al.

Antidepressants reverse BDNF deficit, promote construction of new neuronal cir-

cuit, and improve the behavioral and cognitive abnormality (Duman et al. 1997). In
addition, impaired endocrine systems, changes in γ-aminobutyric acid (GABA) and
glutamate transmission, and immune system are involved in depression.
The current antidepressants could successfully treat 60–70% of all the treated
patients, but the other patients remained insensitive to the treatment. Complementary
and alternative medicine, such as traditional Chinese medicine(TCM), has been
proposed as therapies for treatment-resistant patients. TCM includes herbal therapy
and nonpharmacological therapy, such as acupuncture, tunic (massage), and gigang
(physical and breathing exercise). TCM is derived from philosophical and holistic
concept without clear distinction between the mind and body, and based on empirical
testing instead of scientific evidence in Western medicine. According TCM theory of
five elements (metal, wood, water, fire and earth), depression is considered as the
result of “Qi (気) stagnation” in five viscera, liver, spleen, heart, kidney, and lung.
However, these viscera do not correspond to anatomical concepts used in present
medicine (Scheid 2013). Depression is considered as emotional changes caused by
Qi deregulation of liver, then spleen and heart. Qi-based definition of depression
does not correspond with current definition of depression presented in Diagnostic
and Statistical Manual of Mental disorders (DSM) or International Classification of
Diseases (ICD). An increasing number of studies have presented antidepressant
function of traditional herb medicine (THM), which has developed in China,
Japan, Korea, and Malaysia. For treatment of depression, THMs are used as the
combination of herbs, Hypericum perforatum (St. John’s wort), Scrophularia
ningpoensis, and Plantago asiatica, prepared by specific THM formulas. More
than 100 medical plants have been reported to have antidepressant activity (Martins
and Brijesh 2018). St. John’s wort preparations are the most prescribed antidepres-
sant (44.6% of all the prescriptions) in Germany (Jeschke et al. 2012). Phytochem-
icals are the bioactive constituents of herbs and plant food, and especially flavonoids,
curcumin, and resveratrol have been reported to reduce the incidence of depression,
improve the clinical symptoms, and prevent the recurrence (German-Ponciano et al.
2018). Efficacy of THMs has been shown in many clinical studies, but the thera-
peutic results has been evaluated based on holistic philosophy and syndrome
differentiation, and scientific evidence has been not sufficient to conclude the
beneficial effects (Wang et al. 2019).
This chapter reviews substantiated results on the role of diet and herbs in
prevention and treatment of depression and the molecular mechanism underling
antidepressant function by phytochemical ingredients. Phytochemicals have diverse
activities and modify multiple pathogenic factors of depression: deregulated mono-
amine neurotransmitter systems, MAO-A hyperactivity, BDNF deficit and impaired
neurogenesis in the hippocampus, neuroinflammation, deregulated immune and
neuroendocrine systems, and the impaired hypothalamic-pituitary-adrenal (HPA)
axis. Preclinical studies have presented effectiveness of phytochemicals as antide-
pressants, but clinical trials have not presented consistent results. The designs and
methods of clinical trials should be improved, and more stable and bioavailable
compounds permeable of the blood–brain barrier (BBB) should be developed by
synthesis based on phytochemical scaffold.
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 419

Diet Decreases Incidence of Depression and Improves Symptoms:

Meta-analyses and Clinical Intervention with Healthy Diet

Effects of dietary patterns and nutrients on the incidence of depression have been
presented in clinical studies (Lassale et al. 2019). The degree of adherence to the
healthy diet, in particular Mediterranean diet, was reversely correlated with the rate
of incidence. Inverse dose–response relationship was found for intake of fruit,
vegetables, legumes, nuts, ω-3 unsaturated fatty acid–rich foods, fish and whole
grains, and for avoiding processed foods containing high amounts of refined carbo-
hydrate or sugar. Cohort analyses of diet quality scores [Mediterranean Diet Score,
Pro-vegetarian Dietary Pattern and Alternative Healthy Eating Index-2010] pre-
sented the effects on incidence of depression in the Seguimiento Universidat de
Navarra (SUN) project (Sanchez-Villegas et al. 2015). The SUN cohort study
subjected healthy 15,093 participants for 8.5 years, and depression risk decreased
significantly in subjects with modulate versus lower adherence. Recently an “Anti-
depressant Food Score” was proposed as a scale of antidepressant potency in food,
based on the content of antidepressant nutrients (“Antidepressant Nutrient Density”)
(LaChance and Ramsey 2018). Twelve beneficial nutraceuticals were reported for
the prevention and treatment of depression: vitamins (folic acid, A, B6, B12, C, and
thiamine), minerals (magnesium, potassium, selenium, iron, and zinc), and ω-3 fatty
acids. The highest scored plant foods were leafy greens, lettuces, peppers, and
cruciferous vegetables.
However, a phase II/III, 8-week, double-blind trial of nutraceutical combination
[S-adenosylmethionine, folic acid, ω-3 fatty acids, 5-hydroxytryptophan (5-HTP),
and zinc] did not improve symptoms assessed with Montgomery–Asberg Depres-
sion Rate Scale (MADRS) score in MDD patients (Sarris et al. 2019). A randomized
controlled trial (RCT) of dietary improvement intervention was reported for patients
with MDD (Jacka et al. 2017). The SMILES (Supporting the Modification of
lifestyle In Lowered Emotional State) study was a 12-week, parallel-group, single-
blind trial of an adjunctive dietary intervention in the treatment of moderate-to-
severe depression. The dietary support group demonstrated significantly greater
improvement of MADRS score. About a half of intervention studies of adjunctive
diet reported the positive effects in treatment of moderate-to-severe depression, but
statistical difference was not significant in most studies. The results of clinical
studies are still inconsistent, because of the absence of adequate size and design of
the trials and rational quality control of diet.

Antidepressant Function of Herbal Medication

Therapeutic targets of antidepressant diets, herbs, and phytochemicals are schemat-

ically presented in Fig. 1.
Herbs have a long history of application for treatment of depression and other
psychiatric diseases. Extracts of St Johan’s wort, Crocus sativus (saffron), Passiflora
incarnata L. (passion flower), Lavandula angustifolia (lavender), Melissa officinalis
L. (lemon balm), Valeriana officinalis L. (valerian root), Piper methysticum G Foster
420 M. Naoi et al.

Fig. 1 Diet, herb, and

Etiopathogenic factors:
phytochemicals modify the
etiopathogenic factors of
Monoamine deficits (5-HT, NA, DA)
depression to prevent and treat
MAO-A hyperactivity
depressive disorders
BDNF deficit
Impaired neurogenesis in the hippocampus
Oxidative stress
Neuroinflammation
HPA axis imbalances

Diet, herb and phytochemicals:

5-HT, NA and DA: Synthesis, reuptake

inhibition, binding to receptors
MAO inhibition
BDNF induction
Neurogenesis promotion
Antioxidant
Anti-inflammation
Neuroendocrine modulation

Depression

(kava), and Parax ginseng (ginseng) confer therapeutic benefits in the treatment of
depressive and anxiety disorders. A meta-analysis of clinical trials of herbs has
presented the evidence-based efficacy of herbs: St John’s wort and saffron for
unipolar depression, and kava for generalized anxiety disorder (Sarris et al. 2011).
St John’s wort is used to treat emotional distress in TCM for more than 2000 years
in China and since the late fifteenth century in European countries, and the only
herbal alternative to synthetic antidepressants in therapy of mild-to-moderate depres-
sion. It is available as tablet, tea, oil, and tincture. A large meta-analysis showed that
the efficacy and safety of St John’s wort were comparable to SSRIs in mild and
moderate depressive disorders (Ng et al. 2017). Hypericum perforatum extract, such
as WS ® 5570, LI160, PM23, and ZE117, are applied in treatment of depression, and
WS ® 5570 was effective as paroxetine in mild-to-moderate MDD. The major
ingredients are napthhodianthrones (hypericin, psudohypericin), phloroglucinol
derivatives (hyperforin, adehyperforin), flavonoids, proanthrocyanidins, and
chlorogenic acid. Hyperforin, rutin, and hypericinmainly contribute to antidepres-
sant efficacy. The extract inhibits monoamine reuptake and enhances the synaptic
availability in the hippocampus and hypothalamus, upregulates 5-HT1A and 5-HT2A
receptors, and also has affinity to DA, β-adrenergic, GABA, and δ-opioid receptors.
Hyperforin activates nonselective cation transient receptor potential channel (TRPC)
6, inhibits reuptake of 5-HT and NA, modulates dendritic spine morphology in
pyramidal neurons of hippocampus, and shows BDNF-mimic activity (Zirak et al.
2019). Hyperforin also inhibits tumor cell proliferation, angiogenesis and inflam-
mation, and disaggregates amyloid deposits in Alzheimer’s disease.
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 421

Saffron (Crocus sativus L.) has been used as a medical antidepressant herb in
Arabic and Islamic traditional medicine (Shafiee et al. 2018). Meta-analysis of nine
RCTs presented the effectiveness in treatment of mild-to-moderate depression also in
mothers with postpartum depression (Toth et al. 2019). It improved clinical symp-
toms assessed with Hamilton Depression Rating Scale (HDRS) effectively as fluox-
etine in short-term therapy. A randomized, placebo control trial (RPCT) of
standardized extract from saffron affron® showed improvement of depressive symp-
toms and anxiety in youth assessed in the Revised Child Anxiety and Depression
Scale (RCADS). Major bioactive constituents of saffron are crocetin (a carotenoid
dicarboxylic acid precursor of crocin), crocin (family of six mono- or di-glycosyl
polyene ester), picrocrocin (monoterpene glycoside precursor of safranal), lipophilic
safranal (2,3-dihydro-2,2,6-trimethlbenzaldehyde), and flavonoids (quercetin and
kaempferol). Crocin and safranal are the major ingredients to contribute the antide-
pressant effects of saffron, and crocin significantly improved depression scores in
patients with MDD as an adjunct to SSRI. Saffron can modulate the HPA axis and
induce BDNF and has anti-inflammatory and antioxidant and antidepressant
effects. Saffron extract and crocin inhibit MAO-A and monoamine reuptake and
bind to N-methyl-D-aspartate (NMDA) receptor as an antagonist and to GABA-α
receptor as an agonist, and crocin to 5-HT2C receptor as an antagonist (Leone et al.
2018). Safranal and crocin prevented increase in plasma corticosterone levels and
depressive-like symptoms in rats exposed to chronic restraint stress. Saffron has
anti-inflammatory, anticancer, antioxidant, and neuroprotective properties and is
traditionally used as anti-convulsant, memory enhancer, analgesic, and sedative in
schizophrenia and anxiety disorder.
Passion flower (Passiflora incarnata L.) is a widely used mild sedative and
anxiolytic agent in most European counties. Beneficial effects have been reported
for treatment of insomnia, generalized anxiety disorder, nervous restlessness, atten-
tion-deficit hyperactivity disorder (ADHD), and menopausal symptoms (Miroddi
et al. 2013). It contains flavonoids (apigenin, chrysin, and kaempferol), C-glycosyl
flavones (vitexin, isovitexin, orientin, and isoprientin), MAO-inhibiting indole alka-
loids (harman, harmin, and harmalin), and also a certain amount of GABA, inhibits
GABA uptake and antagonizes GABAB receptors (Appel et al. 2011). Passion
flower flavonoids require metabolic activation by intestinal microflora into
hydroxyphenylacetic acids for anxiolytic effects in preclinical studies.
Clinical trials of aromatherapy show the promising therapeutic effects in depres-
sion. Essential oils (EOs) extracted from lavender (Lavandula angustifolia), lemon
balm (Melissa officinalis L.), and rosemary (Rosmarinus officinalis L.) and their
constituents are applied for treatment of anxiety, stress, and depression (de Sousa
et al. 2017). Lavender tea and the EO are approved by the European Medicines
Agency as anxiolytic and stress-relieving agents, and used for treatment of stress,
anxiety, postpartum depression, agitated behavior in dementia, premenstrual symp-
toms, neurasthenia, and post-traumatic stress disorder or somatization disorder.
Silexan (WS ® 1265) is an oil product of lavender flower approved as a drug in
Germany for the treatment of restlessness related to anxious mood, and in RPCTs it
was effective in generalized anxiety disorder assessed according to DSM-5 criteria
422 M. Naoi et al.

and with the Hamilton Anxiety Rating Scale score (Kasper et al. 2014). Lavender
EO ameliorated depression-like behavior in rats treated with corticosterone and
increased neurogenesis in the hippocampus and subventricular zone. Lavender EO
contains lynalyl acetate (30–50%), linalool (20–35%), garanyl acetate (5%), and
β-caryophyliene (5%) as the most important compounds. Lavender EO antagonized
NMDA receptors and inhibited 5-HT transporter, which mainly contributed to
antidepressant activity, in addition to inhibition of MAO-A and voltage-gated
calcium channel, calcium influx, and binding to 5-TH1A receptor (Lopez et al.
2017). Anxiolytic effect of lavender EO was mediated by serotonergic transmission,
not GABAergic. Linalool-rich EOs from Aniba rosaeodrora (pau-rosa, rosewood),
Aniba paviflara (macacaporanga), and Aellanthus suaveolens (catinga-de-mulata)
have shown antidepressant effects in rodent model of depression.
Lemon balm (Melissa officinalis L.) is a medical plant used in European tradi-
tional medicine and contains flavonoids [quercetin, rhamnocitrin (3,40 ,5-trihydroxy-
7-methoxyflavone), luteolin], phenolic acids (rosmarinic, caffeic, and protocatechuic
acid), triterpenes (ursolic and oleanolic acid), sesquiterpenes, and EOs. In clinical
trials it improved mood, cognition, and memory. In a RCT the extract improved the
insomnia severity score, the Beck Depression Inventory, and Beck Anxiety Inven-
tory, in insomnia, anxiety, and depression (Ranjbar et al. 2018). Cyracos ® Melissa
officinalis L. leaf extract reduced sleep disturbance and anxiety manifestations in
stressed volunteers with mild-to-moderate anxiety disorders. Inhibition of DA and
GABA transmission and activity of MAO-A and acetylcholinesterase, and increase
in serotonergic activity via 5-HT1A receptors contributed antidepressant and anxio-
lytic activity (Shakeri et al. 2016). The EO has anti-agitation effects via GABAergic
transmission.
Rosemary (Rosmarinus officinalis L.) tea, infusions, alcohol extract, and the EO
are used for treatment of depression, nervous agitation, physical and mental
fatigue, and inflammatory diseases. A RCT of oral rosemary (500 mg twice daily
for 1 month) in university students reduced scores of anxiety and depression
(assessed by Hospital Anxiety and Depression Scale) and memory performance
(Prospective and Retrospective Memory Quetionaire) (Nematolahi et al. 2018).
The active components include terpenoids (carnosol, rosmanol, carnosic,
oleanolic, and ursolic acid), flavonoids [diosmin (a glycosyloxylflavone), luteolin,
apigenin, quercetin], and phenolic acids (caffeic, rosmarinic acids). The rosemary
polyphenols (luteolin, carnosic acid, and rosmarinic acid) enhanced 5-HT, DA,
NA, and acetylcholine and expression of genes involving in monoamine synthesis,
modulated GABAA receptors and showed antidepressant activity in a mouse
depression model (Sasaki et al. 2013). The EO, carnosol, and betulinic acid [3β-
hydoxyl-lup-20(29)-en-28-oic acid] had also antidepressant effects in a rodent
model of depression.
Valerian (Valeriana officinalis L.) extract reduces stress and anxiety, improves
sleep, relieves premenstrual syndrome, and has anti-convulsant effect and sedation.
In generalized anxiety disorder valerian extract reduced the total the Hamilton
Anxiety Rating Scale score and the psychiatric factors in a RCT (Andreatini et al.
2002). In patients with psychophysiological insomnia, valerian demonstrated
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 423

positive effects on sleep structure and perception, and valerian extract LI 156 was as
efficacious as oxazepan in treatment of nonorganic insomnia. Extract of valerian root
showed some anti-obsessive and anti-compulsive effects in patients with obsessive–
compulsive disorder. The constituents include alkaloids, flavonoids, and a
sequiterpene valerenic acid. Valeriana wallichii extract increased NA and DA levels
in the forebrain and had antidepressant effects in a mouse model of depression.
Valerenic acid interacted with β2/3 subunits of GABAA receptor as a potent allosteric
modulator and exhibited anxiolytic effects (Khom et al. 2010).
Kava (Piper methysticum G. Forster) has the largest evidences base from in vitro,
in vivo, and clinical studies for use in anxiety disorders, stress, fear, and menstrual
disorder. The major constituents are lipophilic kavalactonees, including kavain
[(R)-6,6,-dihydro-4-methoxy-6-styryl-2H-pyran-2-one] and dihydrokavain [4-meth-
oxy-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one], which have the strongest anxi-
olytic activity. The anxiolytic effects are due to positive allosteric modulation of
GABAA receptors, inhibition of excitatory neurotransmitter release and neuronal
reuptake of NA and DA by blockade of voltage-gated sodium and calcium ion
channels (Sarris et al. 2013). In generalized anxiety disorder, kava extract LI 150 was
effective as opipramol and buspirone (Boerner et al. 2003), and WS ® 1490 improved
anxiety, tension, and restlessness states in RCTs. Treatment with kava tablets
containing 50 mg kavalactones for 3 weeks (5 tablets/day) significantly reduced
Beck Anxiety Inventory and MADR scores (Sarris et al. 2009). The phase III
monotherapy with extract of kava cultivar demonstrated positive effects in subjects
with generalized anxiety disorder (Savage et al. 2015).
Ginkgo biloba extract EGb761 is prepared from dried leaves of Ginkgo tree and
approved in Germany for the treatment of dementia syndromes of neurodegenerative
or vascular origin, cardiovascular impairment, and neurosensory disorders via
neuroprotective, antioxidant, and free radical-scavenging potency. The extract con-
tains ginkgo-flavone glycosides and diterpene trilactones (ginkgolide A, B, C, and
bilobalides). Ginkgolides play a major role in neuroprotection and also antidepres-
sant actions. Ginkgo biloba extract was used as adjunct in elderly depressive patients
treated with citalopram and could relieve anxiety and improve daily living and mood
in elderly patients (Dai et al. 2018). EGb 761 had antioxidant function, enhanced
BDNF expression, and exhibited antidepressant-like effect in mice exposed against
forced swimming test (FST). Bilobalide increased expression of glucocorticoid
receptor (GR) in the mouse hippocampus, and modulate the HPA axis and
ginkgolide B and bilobalide were noncompetitive inhibitors of GABA, glycine,
and 5-HT3 receptors, and exerted anxiolytic and antidepressant effects (Wu et al.
2016a). Ginkgolide B activated NT-3/TrkA (neurotrophin- 3/tropomycin-related
kinase A) and Ras/MAPK (mitogen-activated protein kinase) pathways, induced
BDNF expression and protected hippocampal neurons, and exerted antidepressant
effects.
Ginseng Panax ginseng Meyer is one of the most popular THMs and the major
ingredients ginsenodises have been confirmed to exert antidepressant, anxiolytic,
and anti-fatigue activities in depressive disorders. The details of the pharmacological
properties are present in another chapter of this book (Naoi et al. 2020).
424 M. Naoi et al.

Antidepressant Phytochemicals: Structure, Activity, and

Molecular Mechanism

Psychoactive phytochemicals such as flavonoids, non-flavonoids, alkaloids, ter-

penes, terpenoids, saponins, sapogenins, β-carboline, and isoquinoline alkaloids
have been isolated from medical plants, and their antidepressant potency has been
intensively investigated to find novel better tolerable antidepressants with minimal
side effects (Khan et al. 2018). Phytochemicals increase 5-HT, NA, and DA, inhibit
MAO-A, induce BDNF, promote neurogenesis in the hippocampus, ameliorate
stress, and prevent neuronal loss in the brain. Molecular mechanisms underlying
antidepressant functions of phytochemicals have been clarified mainly in animal
models of depression prepared by FST, tail suspension test (TST), chronic un-
predicable mild stress (CUMS), and chronic restraint stress.

Structure and Basic Properties of Phytochemicals for Antidepressant

Activity

Phytochemicals are recognized as natural antidepressants and polyphenols are the

major bioactive species, contain one or more aromatic rings with hydroxyl groups as
substituents. Postmortem studies have found indication of oxidative stress in the
prefrontal cortex of MDD patients, suggesting that oxidative stress and inflammation
are especially involved in pathophysiology of treatment-resistant depression (Sowa-
Kucma et al. 2018). Polyphenols have antioxidant, anti-inflammatory, and
neuroprotective activities by direct regulation of mitochondrial apoptosis system,
NTF-mimic activity, and modulation of cellular signal pathways (Naoi et al. 2017,
2019). The category, chemical structure, and the major antidepressant functions of
phytochemicals are summarized in Tables 1 and 2.
Flavonoids are the largest group of polyphenols and more than 6000 flavonoids
are found ubiquitously in plants, including fruits, vegetables, cereals, and tea.
Flavonoids are further divided into subgroups: flavonols (found in broccoli, onion,
kale, citrus, apples, cherries, berries, ginkgo, hibiscus, and St John’s wort), flavanols
(green tea, red wine, chocolate, and Uncaria rhychophylai), flavanones (citrus fruits
and tomatoes), flavones (apple skin, parsley, celery, chamomile, passionflower, and
ginkgo), Isoflavones (soybeans, legumes, and pomegranate), and anthocyanidins
(red wine, cherries, grapes, and berry fruits). They share the common chemical
structure: two benzene rings joined by three-carbon chain and a carbon skeleton of
diphenyl propanes (Table 1). High dietary intake of flavonoids reduced incidence of
depression in midlife and older women (Chang et al. 2016). In animal models,
flavonoids have antidepressant and anxiolytic activities, in addition to antioxidant,
anti-inflammatory, neuroprotective, anticancer, and antiepileptic functions. Flavones
(epigen and luteolin), flavonols (kaempferol, quercetin), isoflavones (genistein), and
anthocyanins inhibit MAO-A, modulate monoamine neurotransmission, and exert
antidepressant effects. Isoquercetin and quercetin interact with GABA receptors and
activate neuronal signal pathways to have antidepressant function. Apigenin, fisetin,
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 425

Table 1 Flavonoids: their category, chemical structure, and antidepressant mechanism

3’
2’ 4’
8 1 B
7 O 2
1’ 5’
A C 6’
6 3
5 4

Category Chemical structure Mechanisms

Flavonols

Fisetin 3’,4’,7-trihydroxy- 5-HT MAO-A anti-inflammation

iNOS, COX-2, IL-6, TNF-α BDNF/TrkB/NF-κB
Binding to TrkB receptor
Galangin 5,7-dihydroxy- Antioxidant, anti-inflammation
Icariin kaempferol glycoside MAO-A BDNF anti-inflammation
HPA axis modulation
Isoquercetin 3’,4’,5,7-tetrahydroxy- MAO-A
Kaempferol 5,7,4’-triahydroxy- 5-HT, NA MAO-A
Morin 2’,4’,5,7-pentahydroxy- Oxidative enzymes NF-κB activation
Quercetin 3’,4’,5,7-tetradroxy- MAO-A 5-HT, NA, DA
Binding to GABA, 5-HT1A, 5-HT2A receptors
Anti-inflammation, antioxidant
Rutin quercetin 3-rutinoside MAO-A 5-HT, NA, DA
Flavanols

Epicatechin (EC) (-)-3’4’,5,7-tetrahydroxy- MAO-A BDNF

Epigallocatechin (EGC) 3,3’,4’,5’,5,7-hexahydoxy-
Epigallocatechin gallate EGC-3-gallate Modulation of HPA axis, BDNF
(EGCG) TRPC signal activation, NOS synthesis
TrkA receptor binding, signal activation
(continued)
426 M. Naoi et al.

Table 1 (continued)

Flavanones

Astilbin 3,5,7,3’,4’-pentahydroxy-3-O-rhamnoside 5-HT, NA, BDNF, TRPC

Hesperetin 3’,5,7-trihydoxy-4-methoxy- ER E binding, BDBF, GDNF
Hesperidin 6-(D-L-rhamnosyl-E-D- glucosyl)-hesperetin BDNF, NGF cytokines, MAO-A
5-HT1A, N-opioid receptor binding
Naringenin 4’,5,7-trihydrxy- 5-HT, NA, BDNF MAO-A
Flavones

Acacetein 5,7-dihydrox-4’-methoxy- MAO-A 5-HAT, 5-HT1A binding

Apigenin 4’,5,7-trihydroxy- 5-HT, NA, DA, BDNF MAO-A
Anti-inflammation, iNOS, COX-2, NLRP3, IF-1E
GABA receptor binding
Amentoflavone 3’,8’’-biapigenun Binding to 5-HT1A, 5-HT1D, 5-HT2C, D1-, D2-
adrenergic, D1, D,2, D,3, GABA, J-opiate, BDZ
Baicalein 5,6,7-trihydroxy- BDNF, ERK phosphorylation
Neurogenesis, FOXG1, FGF2. P-AKT
Baicalin Bacalein-7-O-glucuronide TOR receptor 4, anti-inflammation
Inhibition of HMGB1/TLR4/NF-NB
Chrysin 5,7-dihydroxy- MAO-A, IDO activity, TNF-D, IL-1E -6
5-HT, BDNF, NGF
3’,4’-Dihydroxyflavone COX-2, NF-NB anti-inflammation
7,8-Dihydroxyflavone TrkB activation, BDNF, PSD95, synaptophysin
Hispidulin 4,5,7-trihydroxy-6-methoxy- Modulation of GABAA
6-Hydroxyflavone Binding to GABA receptors
Liquiritigenin 4’,7-dihydroxy- BDNF/TrkB pathway
Luteolin 3’,4’,5,7-tetrahydroxy- MAO-A, Oxidative enzymes, NF-NB
Binding to GABAA receptors
Nobiletin 5,6,7,8,3’.4’-hexamethoxy- 5-HT, NA, DA, BDNF, TrkB, synapsin I
5-HT1A, D1-, D2-NA, D1, D2 receptor binding
Vitexin apigenin 8-C-glucoside Binding to 5-HT1A, D2-NA, D1, D2, D3
Wogonin 5,7-dihydroxy-8-methoxy- MAO-A
(continued)
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 427

Table 1 (continued)

Isoflavones
HO O

Daidzein 4’,7-dihydoxy- MAO-A, MAO-B, 5-HT reuptake

Estrogen-like activity
Genistein 4’,5,7-trihyroxy- MAO-A, MAO-B, monoamine reuptake
Binding to 5-HT1A receptors
TRPC5, BDNF, 5-HT, NA transporters
Estrogen-like activity
Puerarin 8-E-glucosyl-4’,7-dihydroxy- HPA hyperactivity, CRH, ACTH
Anthocyanidins

Cyanidin, 3,5,7,3’,4’-pentahydroxyfavylium MAO-A, MAO-B

Proanthrocyanidin polyhydroxyflavan-3-ol Antioxidant, anti-inflammation activity
MAO-A

CRH, corticotropin-releasing hormone; HMGB1/TLR4/NF-κB high mobility group box 1 protein/

Toll-like receptor 4/nuclear factor κB; iNOS, inducible nitric oxide synthase; NLRP3, nucleotide-
binding domain, leucine-rich repeat, pyrin domain containing protein 3; TRPC, transient receptor
potential channel

kaempferol, luteolin, and quercetin have most relevant antidepressant activity.

Hydroxyl group(s) at positions C2, C4, and position C4 of the A ring are associated
with the antidepressant function, and flavone C glycosides have better antidepressant
activities (Guan and Liu 2016). Antioxidant function depends on the number of
hydroxyl groups in the aromatic A and B rings and the presence of 2,3-unsaturation
and a 4-carbonyl in the C ring. Flavonoids donate a hydrogen molecule, form a
phenoxyl radical, and scavenge single oxygen, superoxide, hydroxyl, and peroxyl
radicals by release of another hydrogen. The diol group forms a complex with ferric
iron, copper, and other transition metal ions and prevents reactive oxygen species
(ROS) production. Isoflavones have estrogen-like activity. Estrogen increases gene
expression of tryptophan hydroxylase (TPH), the key enzyme in 5-HT synthesis and
5-HT receptor 2A (5-HTR2A), whereas it downregulates that of 5-HT transporter
(SLC6A4) and MAO-A (German-Ponciano et al. 2018). Genistein aphytoestrogen
alleviated menopause-related depression in postmenopausal women (Atteritano et al.
2014).
Non-flavonoid phytochemicals also have antidepressant potency as summarized
in Table 2. Curcumin is the yellow pigment present in Curcuma longa and composed
428 M. Naoi et al.

Table 2 Non-flavonoid phytochemicals: their category, chemical structure, and antidepressant

mechanisms

Category Chemical structure Mechanisms

Diarylheptanoids
Curcumin

5-HT, BDNF, pCREB, neurogenesis MAO-A

Binding to 5-HT1A, 5-HT2
HPA axis modulation, anti-inflammation,
Stilbenes
Resveratrol trans-3,5,4’-trihydroxy-stilbene

BDNF, GDNF, 5-HT, NA MAO-A Binding to ER β receptors

NF-κB/AP-1 pathway, inflammatory cytokines
Modulation of HPA axis, Wnt/β-catenin
Picearannol 3-hydroxy-resveratrol IL-6, MCP1
5-Methoxy-3-stilbenol IL-6, MCP1
2,3,5,4’-Tetrahydrostilbene-O-β-D-glucoside BDNF, hippocampal neurogenesis,
Antioxidant, anti-inflammation
Terpenes
Hyperforin Hypericin, psudohypercin; R = CH3, CH2OH
O

O OH
HO R

HO CH3
O O

Hyperforin 5-HT, NA binding to 5-HT1A, B, 5-HT, NA reuptake, MAO-A

Hippocampal BDNF, TRPC6, mitochondria activity

(continued)
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 429

Table 2 (continued)

Hypericin 5-HT turnover Inhibition of D3, D4 β-adrenergic receptors

Diterpene lactones
Ginkgolide A, or B (R= H, or OH) Bilobalide
O
O
HO
R O HO
H tBu O
tBu
O O O
O OH
O H O
OH O O
H
O

Ginkgolide A, B, bilobalide Antagonists of GABA receptors

Ginkgolide B Antagonist of 5-HT3 receptors
Bilobalide Hippocampal GR HPA axis modulation

Lavender essential oils

Linalyl acetate linalool Garanyl acetate
H

O
O
H
O
O
O

Lavender essential oil, linalyl acetate, linanol Binding to glutamate NMDA receptor
5-HT transporter
Lavender essential oil 5-HT1A receptor voltage-gated Ca2+ channels
Hippocampal neurogenesis, neuroprotection
Linalool 3,7-dimethyl-1,6- octadien-3-ol Binding to 5-TH1A, D1 receptors

Sequiterpene
Valerenic acid

BDNF Binding to GABAA receptors

Coumarins

Angelicin 7H-fuco[2.3-H]chromen-2-one MAO-A

(continued)
430 M. Naoi et al.

Table 2 (continued)

Bergapten 5-metoxy psoralen MAO-A

Esuprone 7-hydroxy-3,4-dimethyl-coumarin enthanesulfonate MAO-A
Osthenol 7-hydroxy-8-phenyl- MAO-A
Psoralen 7H-fuco[3,2-g]chromen-7-one CRF
Psoralidin 3,9-dihydroxy-2-phenyl- 5-HT serum ACTH, CRF, corticosterone
Scopoletin 7-hydroxy-6-methoxy- Binding to 5-HT1A, α1-, α2-NA, D1, D2
Isoquinoline alkaloids
Berberine Chelerythrin Piperine

Berberine 5-HT, NA, BDNF anti-apoptosis

Anti-inflammation, HPA axis modulation
Chelerythrine MAO-A
Piperine 5-HT synthesis MAO-A 5-HT1A, 5-HT2A binding
Carotinoids
Astaxanthin
O
OH

HO
O

Inflammatory cytokines, IDO, NF-κB antioxidant, anti-inflammation

Benzopyrane
Ellagic acid

5-HT1A/1B, 5-HT2A/2B binding, BDNF NMDA-NO pathway

Phenolic acid
Benzoic acid Cinnamic acid

(continued)
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 431

Table 2 (continued)

Benzoic acid derivatives

Gallic acid 3,4,5-trihydydroxy-benzoic acid MAO-A
Binding to 5-HT1A, α1-, α2-NA, D1, D2
Syringic acid 4-hydroxt-3,5-dimethoxy- Activation of 5-HT transporter, antioxidant

Cinnamic acid derivatives

Caffeic acid 3,4-dihydroxy-cinnamic acid Binding to 5-HT1A, 5-HT2A BDNF
p-Coumaric acid 4-hydroxy- BDNF COX-2, TNF-α
Ferulic acid 4-hydroxy-3-methoxy- MAO-A, IDO 5-HT, NA
Binding to 5-HT1A, 5-HT2A
Rosmarinic acid caffeic-3,4-dihydroxphenyllacticester Neurogenesis, BDNF, GluR-2
Sinaptic acid 3,5-dimethoxy-4-hydroxy- Binding to GABAA receptor
GR, glucocorticoid receptor; IDO, indoleamine 2,3-dihydroxygenase, MCP-1, monocyte
chemotactic peptide-1

of an aliphatic unsaturated heptene linker with two aromatic rings attached at the
both ends. In animal depression models, curcumin inhibited MAO activity, increased
5-HT, NA, and DA and 5-HT1A expression, activated MAPK/ERK (extracellular
signal-related kinase) and NF-κB pathways, and induced BDNF and neurogenesis in
the hippocampus (Kaufmann et al. 2016). It has antioxidant, anti-inflammatory, anti-
cancer, anti-viral, and neuroprotective activities. The hydroxyl and methoxyl groups
can scavenge ROS and reactive nitrogen species (RNS), and prevent lipid peroxi-
dation in vivo and in vitro. Clinical intervention studies with curcumin (500 mg
twice a day) for 8 weeks ameliorated depressive and anxiety symptoms in patients
with MDD and especially with atypical depression (Lopresti et al. 2014). Curcumin
monotherapy (1000 mg/day) presented antidepressant activity measured with
HDRS-17 effectively as fluoxetine monotherapy in a RCT (Sanmukhani et al.
2014). Curcumin supplementation in MDD patients enhanced the efficacy of current
antidepressants by increase of plasma BDNF and decrease of inflammatory cyto-
kines, interleukin(IL)-1,β and tumor necrosis factor-α (TNF-α) (Yu et al. 2015).
Resveratrol is found in red grapes (Vitis vinifera L.), berries, and peanuts and a
compound conferring anti-aging, neuroprotective, anti-cancer, and calorie-restric-
tion mimic functions. It is composed of two phenol rings connected through a
styrene double bond. The trans-3,5,40 -trihydroxystilbene is more bioactive than
the cis-form, and it can directly scavenge hydroxyl radicals with its hydroxyl groups,
and 40 -hydroxyl group is the most reactive. Resveratrol exerts antidepressant effects
in animal models by increasing 5-HT and NA, inhibiting MAO-A expression and
activity, inducing BDNF expression in the hippocampus, suppressing phosphoryla-
tion of Akt/mTOR (mammalian target of rapamycin) pathway, and modulating the
HPA axis (de Oliveira et al. 2018). Tetrahydroxystilbene-2-O-D-glucoside isolated
from Polygonum multiforum induced BDNF and neurogenesis in the hippocampus
and presented antidepressant, antioxidant, and anti-inflammation functions in mouse
432 M. Naoi et al.

models of depression. However, clinical trial of resveratrol in depression has been

scarcely reported except in menopausal women (Davinelli et al. 2017).
Coumarin class of benzopyranes is of natural and synthetic origin and their
derivatives possess antidepressant properties (Patil et al. 2013). Scopoletin isolated
from Polygala sabutosa was reported to have potent in vivo antidepressant activity
through the interaction with 5-HT2A, D1 and D2dopaminergic, and α1- and α2-
adrenergic receptors (Capra et al. 2010). Fucocoumarins (psoraladin) isolated from
Psoralea corylifolia seeds exerted antidepressant effects in FST-subjected mice.
Among coumarins isolated from Angelica archangelica, bergapten(4-
methoxypsoralen) had the maximum affinity to MAO-A and bergapten and angelicin
(isopsoralen) showed high permeability to the BBB and antidepressant activities in
mouse model of depression (Kaur et al. 2020).
Phenolic acids are isolated from grain ban, whole grain, orange, tomato, carrot
and borage, and classified into benzoic and cinnamic acid derivatives. It has elec-
tron-donating 3-methoxy and 4-hydroxy groups on the benzene ring, and the
carboxylic acid with an adjacent unsaturated carbon–carbon double bond binds to
lipid bilayer and prevents lipid peroxidation. Caffeic, ferulic, gallic, syringic, and
rosmarinic acid have antidepressant functions, by activation of serotonergic, cate-
cholaminergic, and cholinergic systems, increase of BDNF and synaptic proteins in
the hippocampus and prefrontal cortex, stimulation of cell proliferation in the dentate
gyrus, and inhibition of neuroinflammation in rodent chronic depression models (Ito
et al. 2008; Jin et al. 2013). Phenolic acids have also antioxidant, neuroprotective,
anti-cancer, antimicrobial and anti-inflammation functions.

Diet and Phytochemicals Enhance 5-HT Level to Exert

Antidepressant Activity

Association of serotonergic system with depression is schematically presented in

Fig. 2. 5-HT is synthesized from L-tryptophan into 5-hydroxy-L-tryptophan by TPH
and then into 5-HT by aromatic amino acid decarboxylase (AADC). Brain-specific
TPH2 is expressed in serotonergic neurons of the dorsal raphe nuclei and single
nucleotide polymorphisms (SNPs) of TPH2 were reported in depression. In the brain
TPH is not saturated with the substrate and 5-HT synthesis depends on the level of
available L-tryptophan. Reduction of L-tryptophan in the plasma and cerebrospinal
fluid (CSF) was correlated to depressive symptoms and effective antidepressant
treatment recovered L-tryptophan levels (Luykx et al. 2013). After acute L-trypto-
phan depletion in humans, L-tryptophan levels decreased by 80–90% in the plasma
and CSF, respectively, but consistent changes in mood were not caused in individ-
uals without a personal or family history. In recovered depressed patients, L-trypto-
phan depletion caused a transient, but striking return of depressive symptoms,
suggesting the vulnerability of depressed patients to fluctuation of 5-HT levels. In
addition, 5-HT transporter gene 5-HTTLPR in SLC6A4 and 5-HT receptor gene
HTR2A have been shown to predict depression, and the polymorphisms are associ-
ated with suicide behaviors in depression.
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 433

Phytochemicals IL-6, IL-1b, IFN-a,b, TNF-a

IDO Astaxanthin, ferulic acid

Dietary restriction L-Tryptophan KNY pathway (TRYCATs)

Flavonoids, curcumin
TPH Phenolic acids
5-HT receptors
5-Hydroxy- NA, DA receptors
Flavonoids
tryptophan Flavonoids,
AADC resveratrol

Vitamin B6 5-HT
TRPC 5-HT transporter MAO-A
Polyphenols 5-HT Hyperforin, silymarin

NE, DA NE, DA
5-HT, NE, DA, Transporter
Resveratrol,
GABA
BDNF genistein Polyphenols
BDNF BDNF

Serotonergic neurons Catecholaminergic neurons

Depression
Fig. 2 Monoaminergic systems in depression and the effects of phytochemicals. 5-HT is synthe-
sized from L-tryptophan by TPH and AADC in serotonergic neurons, whereas DA and NA in
catecholaminergic neurons. Monoamines are released into the synaptic cleft, function as neuro-
transmitters, and are taken up catecholaminergic neurons and metabolized by MAO-A. 5-HT and
BDNF regulate brain architecture and synaptic connection. Phytochemicals modify 5-HT, NA, and
DA systems and exert antidepressant functions. In depression, inflammation-promoting cytokines
activate IDO, which metabolizes L-tryptophan into kynurenine pathway and reduce 5-HT synthesis.
White and black arrows indicate the promoting or inhibitory functions of phytochemicals

Food, plasma L-tryptophan levels, and carbohydrate consumption regulate 5-HT

synthesis in the brain. AADC decarboxylates 5-hydroxy-L-tryptophan into 5-HT and
glutamate into GABA by use of a coenzyme pyridoxal phosphate derived from
vitamin B6 in diet. Several foods, such as cheese, meat, fruits, and vegetables,
contain high levels of L-tryptophan and B6, and effect 5-HT transmission in depres-
sion. Supplementation of blue berry juice containing L-tryptophan and L-tyrosine,
precursor amino acids of 5-HT, DA, and NA, prevented induction of depressive
mood in postpartum women (Dowlati et al. 2017).
Quercetin, hesperidin, and rutin increase 5-HT, NA, and DA levels and also
modulate the monoamine receptors (Fig. 2). Flavonoids (galangin, EGCG, genistein,
naringenin, astilbin, and hyperforin) elevate the activity of nonselective cation
TRPC, induce sodium and calcium entry, inhibit uptake of monoamines into neu-
rons, and increase 5-HT, NA DA, GABA, and glutamate levels in the hippocampus
(Naylor et al. 2016). Resveratrol, ()-trans-ε-vinferin (a resveratrol dimer), and
genistein inhibited uptake of 5-HT and NA into synaptosomes and also MAO
434 M. Naoi et al.

activity (Yanez et al. 2006). Piperine, a major alkaloid of Piper nigrum L. (black
pepper), increased 5-HT synthesis in the hippocampus and frontal cortex, inhibited
MAO and activated 5-HT1A and 5-HT1B receptors, and presented antidepressant
effects in mouse models of depression (Mao et al. 2011).
L-Tryptophan is metabolized also by indoleamine 2,3-dioxygenase (IDO) into
kynurenine and further kynurenic acid and quinolinic acid, a strong agonist of
NMDA receptor. These tryptophan catabolites (TRYCATs) can induce anxiety and
depression in animal models. Pro-inflammatory INF-α, β, -γ, IL-6, TNF-α and
oxidative stress upregulate IDO expression and deplete plasma L-tryptophan. The
negative relationship was reported between the levels of kynurenic acid and C-reac-
tive protein in the blood and the volumes of hippocampal cornu ammonis and
subiculum in patients with MDD, suggesting the association of IDO with the
pathogenesis (Doolin et al. 2018). Trans-Astaxanthin, a red carotenoid pigment
rich in algae and ferulic acid, inhibited IDO in the hippocampus, frontal cortex,
striatum, and hypothalamus, suppressed L-tryptophan-kynurenine pathway, and
increased 5-HT synthesis in a mouse model of depression (Koshiguchi et al. 2017).
Flavonoids, phenolic acids, and curcumin bind to 5-HT1A and 5-HT2A receptors,
activate intracellular signal pathways, and function as antidepressants in animal models.
Chronic curcumin administration increased 5-HT levels, activated cAMP-cAMP response
element binding protein (CREB) pathway, and increased expression of 5-HT1A receptor
and BDNF in the hippocampal CA1, cortex and hypothalamus (Li et al. 2009). Vitexin,
nobiletin, amentoflavone and gallic acid increased monoamines in synaptic cleft and
interacted with 5-HT1A, noradrenergic α2, and D1, D2, and D3 receptors.
During specific development periods, 5-HT affects maturation of the brain archi-
tecture associated with emotional behavior in postnatal life (Suri et al. 2015). In the
adult hippocampus, 5-HT signals from the dorsal and median raphe modulate
neuroplasticity and neurogenesis, and prevent the cortical atrophy and behavioral
and cognitive abnormalities in depression (Kraus et al. 2017). Antidepressants, elec-
troconvulsive shock, exercise, and enriched environment promote proliferation and
survival of newborn neurons in the hippocampus. Postmortem studies of brains from
patients with MDD confirmed that antidepressant treatment increased the total dentate
cell number and dentate gyrus size (Boldrini et al. 2013). 5-HT stimulates 5-HT2A
receptor, increases cAMP production, activates CREB, and induces transcription of
BDNF. Vice versa BDNF promotes the survival and differentiation of 5-HT neurons in
the dentate gyrus. CREB1 polymorphisms were associated with decreased volume and
activity of the hippocampus in BD and MDD. These results indicate that 5-HT
functions not only as a neurotransmitter, but also as a modifier of cell signal transduc-
tion to regulate hippocampal neurogenesis and incidence of depression.

Phytochemicals Inhibit Type A Monoamine Oxidase

In the brain MAO-A is expressed in the presynaptic terminals of catecholaminergic

neurons, whereas MAO-B occurs in serotonergic and histaminergic neurons, astro-
cytes and ventricular cells (Riederer et al. 1986). MAO-A is involved in neuropsy-
chiatric disorders and behavioral traits, like aggression, panic disorders, antisocial
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 435

behaviors, MDD, BD, and ADHD. MAO-A level in the brain is determined before
the birth, and MAO-A and 5-HT regulate development of neuronal architecture.
MAO-B appears only in the postnatal stage and increases with age, and induces
oxidative stress, suggesting its association with the pathogenesis of age-dependent
neurodegeneration. In the brain of MDD patients, MAO-A binding measured using
[11C]harmine PET significantly increased in the prefrontal and anterior cingulate
cortex according to greater disease severity (Chiuccariello et al. 2014). In the
postmortem prefrontal cortex of untreated MDD patients, expression of R1, a
transcriptional repressor of MAO-A protein, significantly decreased and MAO-A
protein increased (Johnson et al. 2011). Chronic stress enhanced glucocorticoid and
activated a transcription factor Krüpple-like factor 11 (KLF11), upregulated Mao-A
expression, and caused hippocampal atrophy (Harris et al. 2015). In the postmortem
prefrontal cortex of patients with MDD, protein expression of KLF11 and MAO-A
significantly increased by 36% and 44% from control, respectively. In the carriers
with longer variant of an upstream variable-number-tandem-repeat (uVNTR) pro-
moter region with high transcription function, enhanced expression of MAO-A was
implicated in depression, insomnia, and suicide attempt (Ziegler and Domschke
2018).
Phytochemicals, especially flavonoids (acacetin, apigenin, chrysin, luteolin, quer-
cetin, and wogonin) are MAO-A inhibitors, which increase available 5-HT, NA, and
DA, suppress ROS/RNS production, and improve depressive behaviors. The inhi-
bition is reversible and in a competitive way to substrates, and does not cause
hypertension crisis called “cheese effect,” a serious side effect of irreversible
MAO-A inhibitors (Carradori et al. 2016). Catechol (ortho-dihydroxy group) struc-
ture of the flavonoid B ring is required for MAO inhibition, whereas a hydroxyl
group at position 3 in the C ring decreases the inhibitory potential. Hydroxyl groups
at position 5 in the A ring and at position 3 of the C ring are required to access to the
substrate binding site, as shown by comparison of genistein (40 ,5,7-tri-
hydroxyisoflavone) with daidzein (40 ,7-dihydroxyisoflavone), and kaempferol
(3,5,7,40 -tetrahydroxyflavonol) with luteolin (5,7,30 ,40 -tetrahydroflavone). The
order of inhibitory potency of flavonoids against MAO is flavone, flavonol >
flavone glycoside > flavanonol (Guan and Liu 2016). Eugenol (4-allyl-2-
methoxyphenol, a major active component of Rhizoma acori graminei), purpurin
(1,2,4-trihydroxanthroquinone), hispidol (6,40 -dihydroxyaurone), chelerythrine (an
isoquinoline alkaloid), and osthenol (a hydroxycoumarin isolated from the roots of
Angelica pubescens) are potent MAO-A inhibitors. On the other hand, non-flavo-
noid polyphenols, curcumin, tetrahyrocurcumin, ellagic acid, trans-resveratrol, and
Ginkgo biloba extract (EGb 761) inhibit MAO-B in preference to MAO-A and show
neuroprotective activities in animal models of neurodegenerative diseases.

Phytochemicals Bind to NTF Receptors, Activate Signal Transduction,

Induce NTF Expression, and Function as NTF-Mimics

BDNF is involved in the viability of neuronal systems regulating emotion, cognition,

memory, sleep, and appetite, and the deficit downregulates dendritic branching and
436 M. Naoi et al.

neurogenesis and is associated with depression. Expression of BDNF and its

receptor TrkB decreased in the hippocampus and frontal cortex of depressive sub-
jects and suicide victims (Dwivedi et al. 2003). Stress and glucocorticoid reduce
BDNF expression by suppressing specific BDNF transcripts containing exons II and
IV, whereas antidepressants, 5-HT, NA, NMDA antagonists, corticosterone, electro-
convulsive shock, and transcranial stimulation increase BDNF expression. The
functional polymorphism of BDNF gene Val66Met is found in approximately 25%
of the population, carriers of BDNF Val66Met show decreased synthesis and release
of mature BDNF and smaller hippocampal volume than Val66Val carriers and
healthy control. BDNF expression is epigenetically regulated and BDNF gene
expression in peripheral blood mononuclear cells was negatively correlated with
DNA methylation at BDNF exon 1 promoter and proposed as a biomarker of MDD
(Fuchikami et al. 2011).
In serum or plasma of patients with MDD, levels of glial cell line–derived
growth factor (GDNF), a dopaminergic neuron-specific NTF, significantly
decreased in accord to the age and clinical severity (Sun et al. 2019). Vascular
endothelial growth factor (VEGF) levels decreased in the CSF of patient with
treatment-resistant MDD and VEGF signaling in the prefrontal cortex was found to
mediate rapid antidepressant effects of ketamine and electroconvulsive therapy
(Deyama et al. 2019).
In RCTs, herb and phytochemicals, in particular flavanols and flavanones,
increased brain and serum BDNF levels in correlation with improvement of depres-
sive symptoms and cognition decline by activation of ERK1/2/CREBS signal
pathway (Polyakova et al. 2015). In women with premenstrual syndrome, curcumin
treatment increased serum BDNF and improved mean score of the symptoms in a
RPCT (Fanaei et al. 2016). Flavonoids, curcumin, phenolic acids, and resveratrol
increased BDNF in the hippocampus of rodent depression models and ameliorated
depression-like behaviors (Moosavi et al. 2016). Flavonoids (apigenin, chrysin,
EGCG, naringen, and rutin) and sesamin (a lignan isolated from Cinnamomum
camphora) increased GDNF levels in astrocytes, and presented neuroprotective,
antidepressant, and anti-inflammatory effects.
BDNF and NT-4/5 bind to TrkB expressed exclusively in the hippocampus and
activate phosphatidylinostol-3-kinase (PI3K)/AKT, MAPK/ERK pathways and
phospholipase Cγ, and promote neuronal differentiation and neurogenesis
(Fig. 3). 7,8-Dihydroxyflavone (7,8-DHF), its O-methyl derivatives, 7,8,30 -tri-
hydroxyflavone, fisetin, huperzine (a lycopodium alkaloid from Huperzia serrata),
and curcumin directly bind to TrkB receptor and displayed antidepressant-like
function in rodent models (Wang et al. 2017). A hydrogen bond acceptor on
position 40 of the flavone B ring, ortho-dihydroxy group on the A ring, and oxygen
atom at the C ring are essentially required for the TrkB agonistic effect (Liu et al.
2010). 7,8-DHF, baicalin and hesperetin increased postsynaptic density protein-
9512.
(PSD-95), a major maturation regulator of excitatory synapses, promoted synap-
tic integrity and exerted antidepressant activities. Hesperetin, EGCG, and gambogic
amide (the major ingredient in resin exuded from Garcinia hanburyi) bound to TrkA
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 437

Rosmarinic acid,
EGCG, EC, 7,8-DHF, 7,8,3’-THF, Curcumin, hesperidin,
6-Hydroxyflavone,
Hesperetin Fisetin, curcumin Quercetin, resveratrol
6-Methoylflavonee

TrkA TrkB GABA NMDA, k-opioid,

receptor receptor receptor estrogen receptor

EGCG, genistein,
Curcumin, resveratrol,
EGCG, quercetin
Berberine, PI3K PKC Baicalein
Amentiflavone
MAPK cascades
Naringen, apigenin, curcumin, hesperidin,
ferulic acid, rosmarinic acid
Naringen, hesperetin,
Genistein, kaempferol,
Berberine, curcumin, AKT/PKB Rutin, liquiritin, icaritin
ERK1/2
Ferulic acid, resveratrol,
Salvianolic acid

Quercetin, apigenin, kaempferol,

CREB
EGCG, curcumin, resveratrol
Berberine, ginsenoside Rg1, Rg3

BDNF, NGF, GDNF

Fig. 3 Schematic presentation of NTF-mimic functions of phytochemicals. Phytochemicals bind
to TrkA, TrkB, GABA, NMDA, κ-opioid, and other receptors, activate downstream signaling
pathway, enhance expression of genes related to mood, and present antidepressant functions. In
nuclei, CREB is activated and BDNF transcription is induced, and enhanced BDNF promotes
neurogenesis and synaptic plasticity to present antidepressant-like activity

specific for NGF, activated MAPK/ERK1/2/, PKA/ or PKC/CREB pathways, and

exhibited antidepressant effects (Jang et al. 2007).
Flavonoids directly activate intracellular signal pathways to display antidepres-
sant function (Mansuri et al. 2014). Hesperetin, ferulic acid, apigenin, resveratrol,
curcumin, astilbin (isolated from wine grape), rutin, liquiritigenin, and its β-glyco-
side (liquiritin) and icaritin (a hydrolytic product of icariin in Epimedium genus)
activated MAPK/ERK and PI3K/AKT pathways, increased CREB phosphorylation
and BDNF expression in the hippocampus and amygdala and exhibited antidepres-
sant effects in rodent depression models (Lv et al. 2014). Luteolin, curcumin, and
coumarin derivatives upregulated miroRNA-132 expression and promoted neurite
growth, neuronal morphology, and excitability (Milenkovic et al. 2013). Hesperetin
and resveratrol bound to estrogen receptor (ER)α and β and enhance expression of
BDNF and GDNF in astrocytes (Saleh et al. 2013).
Fast-acting antidepressants, Ro 25–6981 and CP-101 606, are non-competitive
antagonists of glutaminergic NMDA receptor and downregulate glutamate neuro-
transmission, activate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid
(AMPA) receptor and mTOR signal pathways, enhance BDNF levels transitionally,
438 M. Naoi et al.

and promote structural and functional plasticity of neurons and synapses in the
prefrontal cortex and hippocampus (Ignacio et al. 2016). BDNF, VEGF, and insu-
lin-like growth factor (IGF) activate mTOR pathway and increase protein synthesis
via eukaryotic initiation factor 4E (eIF4E)-binding protein (eIF4BP) and ribosomal
protein S6 kinases (S6Ks) protein. In the brains of MDD patients, mTOR signaling
pathway was impaired and phosphorylated eIF4BP and S6Ks and mTOR/p70S6K/
eIF4B function decreased (Jernigan et al. 2011). Yueju (a TCM consisting of five
herbs) and radix polygalate isolated from the root of Polygala tenuifolia have been
used to treat depression, anxiety, and irritability in China, exerted ketamine-like
rapid antidepressant activity through reversing the reduction of phosphorylated
mTOR, phospho-p70S6K, and immediately increased BDNF expression in the
hippocampus, as shown in rodent depression models (Tang et al. 2015). In a RCT
for patients with MDD, Yueju plus fluoxetine treatment exerted fast-onset antide-
pressant function with significantly decreased HDRS-24 score from day 3 to 7 in
correlation with increase in serum BDNF level (Wu et al. 2015). Among constituent
herbs of Yueju, Gardenia jasminoides J. Ellis exerted rapid antidepressant potency,
to which the ingredients, crocins, gardenosides, and iridoid glycosides (cornin)
contributed (Wu et al. 2016b).

Anti-Inflammatory Functions of Phytochemicals in Depression

Association of oxidative stress and inflammatory responses with the pathophysiol-

ogy of MDD has been suggested by increased levels of ROS/RNS, oxidative DNA
damage (8-hydroxy-20 -deoxyguanosine), lipid peroxidation (F2-isoprostanes), and
ROS-producing enzymes (xanthine oxidase) in patients with MDD and BD, espe-
cially in treatment resistance of depressive patients (Leonard 2018). In the CSF of
patients with MDD, higher levels of pro-inflammatory cytokines were detected in
significant correlation with the clinical severity. In the lymphocytes of depressed
patients, mRNA levels of TNF-α and IL receptors (TNFR1, TNFR2, IL-1R1)
increased.
Flavonoids (quercetin, fisetin, icariin, and proanthocyanidin) and berberine exert
antioxidant and anti-inflammatory activity. Flavonoids can induce antioxidant enzymes,
superoxide dismutase (SOD), catalase and glutathione peroxidase, and also suppress the
expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).
Flavonoids (luteolin, galangin, morin, and 30 40 -dihydroxyflavone) and curcumin
inhibited phospholipase A2, COX and lipoxygenases, and suppressed NF-κB activation
and inflammatory responses (Lim et al. 2019). Apigenin and baicalin upregulated
peroxisome proliferator-activated receptor gamma (PPARγ) expression, downregulated
nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3
(NLRP3) inflammasome expression and IL-1β production, and exhibited antidepressant
effects in CUMS-treated rats. Baicalin inhibited inflammation through downregulation
of high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/NF-κB
pathway and had efficient antidepressant effects in mouse model of depression prepared
by CUMS. Curcumin reduced peripheral levels of IL-6 and -8, and TNF-α in RCTs
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 439

(Derosa et al. 2016). Icariin, ferulic acid, and trans-astaxanthin downregulated expres-
sion of inflammatory cytokines in the hippocampus, increased BDNF, normalized GR
function, HPA hyperactivity, and glucocorticoid sensitivity, and exert antidepressant
activity in a rat model of depression (Liu et al. 2015). Resveratrol inhibited NF-κB and
activator protein-1 (AP-1) and suppressed cytokine expression. Stilbenoids
(picearannol, 5-methoxy-3-stilbenol) inhibited PI3K/AKT pathway and downregulated
production of IL-6 and monocyte chemotactic peptide-1 (MCP1) (Eräsolo et al. 2018).
Fisetin and chiisanoside from the leaves of Acanthopanax sessiliflorus inhibited iNOS
and COX-2, decreased IL-6 and TNF-α levels in serum, activated BDNF/TrkB/NF-κB
pathway in the hippocampus and prefrontal cortex, and showed antidepressant activity
in mouse models of depression.

Phytochemicals Modulate the HPA Axis

Stress, early-life experiences, adverse life events, and physical abuse cause long-
lasting epigenetic alteration of DNA and histone, and are powerful risk factors
influencing the vulnerability to develop depression in adulthood. Under stressful
conditions, corticotropin-releasing hormoneis released from neurons in the para-
ventricular nucleus, and stimulates the synthesis and release of adenocorticotropic
hormone (ACTH) and glucocorticoids. Prolonged severe stress sustains glucocorti-
coid elevation, damages hippocampal neurons, inhibits neurogenesis, and influences
the activity of several cortical and subcortical structures involving in endocrine,
motor, effective, and cognitive functions. Abnormal excessive activation of the HPA
and alterations of the negative feedback were observed in approximately half of the
individuals with depression, and antidepressant treatment could restore the dysfunc-
tion (Surget et al. 2011). In postpartum depression, functional changes in the HPA
axis were correlated with metabolite levels in the anterior cingulate gyrus (de
Rezende et al. 2018). Alterations in the hippocampal GRs and the HPA axis activity
have close relationship with cytokines and inflammatory signal pathways, such as
MAPK-NF-κB pathway.
Puerarin,resveratrol and flavonoids extracted from Xiaobuxin-tang (a TCH
decoction) modulated the HPA axis hyperactivity, decreased corticotropin-releasing
hormone, corticosterone, and ACTH, and inhibited hippocampal GR expression in
depression rodent models (Yang et al. 2017). Apigenin, baicalin, and salvianolic acid
B extracted from Salvia miltiorrhiza inhibited the activation of NLRP3
inflammasome in the prefrontal cortex and IL-1β production, reversed HPA hyper-
activity and showed antidepressant effects in rats exposed to CUMS (Li et al. 2016).

Phytochemicals Show Anxiolytic Functions

Anxiety disorders share many symptoms with depression and anxiety is associated
with depression either as risk markers or causal risk factors, and anxiety occurs in
46% and 52% of patients with MDD and BD. Piper methysticum, Melissa officinalis,
440 M. Naoi et al.

Centella asiatica (gotu cola/kola, pennywort), Ginkgo biloba, Passiflora incarnata,

and Matricaria recutita (chamomilla) (chamomile) ameliorate anxiety by GABA-
mediated mechanisms (Savage et al. 2018). Their bioactive constituents, terpenoids/
sesquiterpenoids, saponins (kavalactones, bilobalide, valernic acid, and rosmarinic
acid), flavonoids [apigenin, apistein (apigenin-7-O-glucoside), baicalein, baicalin
(baicalein-7-O-glucuronide), EGCG, ellagic acid, hispidulin, kaempferol, luteolin,
naringen, wogonin], chlorogenic acid (3-caffeolquinic acid, a phenolic acid), sinapic
acid (a phenylpropanoid), and p-coumaric acid possess anxiolytic effects in animal
models by modulation of GABAA receptors either positively or negatively
(Hanrahan et al. 2011; Fedotova et al. 2017). Flavonoids, such as luteolin have
been shown to positively modulate selective subtypes of GABAA receptors, bind to
benzodiazepine (BDZ) site competitively, indirectly open chloride channels, hyper-
polarize cell membrane, increase the threshold for activity, and exert anxiolytic effect
(Johnston 2015). Chrysin is a partial agonist at the central BDZ site, but apigenin
competitively binds to BDZ site of GABAA receptors. Presence of electronegative
groups at position 6 in the A ring and 30 position of the B ring on flavone backbone
increases the affinity to the BDZ binding site. 6-Hydroxyflavone displays significant
preference for α2- and α5-containing GABA receptor subtypes and showed anxio-
lytic activity (Ren et al. 2010). Hesperidin showed antidepressant-like effect through
interaction with the κ-opioid receptor in mice exposed to FST.

Novel Antidepressants Synthesized Based on Phytochemical

Scaffold

Phytochemicals are extensively metabolized in humans during absorption and xeno-

biotic metabolism and their availability in the brain is quite low. More stable
derivatives with higher therapeutic availability should be developed for prevention
and therapy of depression. Lipophilic polyphenols, including flavonoids (apigen,
catechin, genistein, hesperetin, kaempferol, naringen, and quercetin), curcumin,
resveratrol, and terpenes can be transported into the brain across the BBB and
have high neurobiological activity. Novel antidepressants may be synthesized by
conjugation of the scaffold of BBB-permeable phytochemicals with active ligands
capable of inhibiting MAO-A, enhancing BDNF synthesis, and increasing affinity to
receptors of NTFs, GABA, AMPA, and others.
7,8-DHF derivatives such as 40 -dimethylamino-7,8-DHF, 7,8,20 - and 7,8,30 -tri-
hydroxy-flavone were synthesized as potent TrkB agonists, and 40 -dimethylamino-
7,8-DHF promoted neurogenesis and demonstrated marked antidepressant effects in
mice (Yu et al. 2012). Introduction of a substituted prenyl group in flavonoids
increased the lipophilicity and the BBB permeability, and enhanced the antidepres-
sant activity. 40 -Bromo- and 20 40 -dichloro-7-phenyloxyl-2,3-DHF showed the most
potent antidepressant activity and increased 5-HT and NA in the hippocampus,
hypothalamus, and cortex in mouse models of depression (Zhen et al. 2016).
Flavonoid analogues have been synthesized as ligands of BDZ binding sites for
development of anxiolytics. Six substitutes in the A ring of flavone, 6-bromoflavone,
6-bromo-30 -nitroflavone, and 6,30 -dinitro-flavone have high affinity to GABAA
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 441

receptors. 20 -Hydroxyflavone was an antagonist of GABAA receptor and

6,20 -dihydroxyflavone a negative modulator (Wang et al. 2007). 6-Methy-
lflavone, 20 -methoxy-, 30 -methoxy-, 30 -hydroxy-, and 3-hydroxy-20 -methoxy-
6-methyflavone were allosteric modulators of the α2β2/3γ2L and α4β2/3δ
GABAA receptor subunits and exhibited anxiolytic activity without sedative
and myorelaxant effects (Karim et al. 2012). Many compounds have been syn-
thesized based on coumarin scaffold and 3-phenylcoumarin derivatives showed
antidepressant activities. The mono- and di-methoxy substitutes attached to
3-phenyl ring and alky group attached to position 8 exhibited more potent
antidepressant activity than the tri-methoxy-substituted derivatives (Sashidhara
et al. 2015). Alkylesters of caffeic acid and hydrocinnamic acid, especially decyl
and dodecyl esters, activated ERK1/2 and Akt signal pathways and induced
BDNF (Hosseini et al. 2018). These lipophilic esters can cross the BBB and
possessed neuroprotective potency, but at present the antidepressant function has
not been reported.
A large number of MAO-A inhibitors with antidepressant and neuroprotective
properties have been derived from flavonoid scaffold, such as quercetin (Dhiman
et al. 2019). The structure–activity relationship of flavonoids indicated three impor-
tant sites in the flavonoid structure: C7 position in ring A, C3 position in ring C, and
C30 and C40 position in B ring. Mono-substitution of C30 and C40 position increases
the selectivity to MAO-A, whereas di-substitution promotes that to MAO-B.
Unsaturation at C2-C3 chromone B ring is essential for MAO inhibition, and the
presence of hydroxy group at C3 position decrease the inhibition. Ferulic acid
contains one-half of curcumin, an ary-α,β-unsaturated carbonyl portion attached
with amines, and a series of the amides were found to inhibit MAO-B in competitive
and reversible way. The increase in chain length at the amino terminal turned the MAO-B
selectivity to nonselective, and cy-C6H11 derivative was the most potent MAO-A
inhibitor (Badavath et al. 2016). Curcumin-based 2-methoxy-4-(5-phenyl-4,5-dihydro-
1H-pyrazol-3-yl) phenol (pyrazoline) derivatives were reported to be selective and
reversible MAO-A inhibitors, and the para chloride-substituted 2-methoxy-4-(5-phe-
nyl-4,5-dihydro-1H-pyrazol-3-yl) phenol was most potent (Nath et al. 2018). A curcumin
analogue J147, N-(2,4-dimethlphenyl)-2,2,2-trifluoro-N0 -[(3)-methoxyphenyl]- methyli-
dene]acetohydrazide, enhanced the bioavailability, increased expression of 5-HT1A recep-
tor and BDNF, activated cAMP-PKA-CREB-BDNF pathway, and reduced depression-
like behaviors in mice exposed to FST and TST (Lian et al. 2018). MAO-B inhibitors
derived from flavones, thioflavones, flavanones, and curcumin have been developed for
neuroprotection through suppression of ROS generation (Chimenti et al. 2010).

Discussion

In long history of TCM, medical herbs and the formulas, Chaihu-Shugan-San, Ban-
xia-hou-pu-tang, Gan-mai-da-zao-tang, and Xia-yao-san have been used for the
treatment for depression (Zhang and Cheng 2019). Diverse functions of TCM herbs
and the formulas exert therapeutic effects additively or synergistically, as evaluated
based on the philosophical holism and TCM symptom criteria. However, the clinical
442 M. Naoi et al.

trials designed by evidence-based modern medicine have not proved reproducible

therapeutic effects of individual herb ingredients in depression. One of the critical
reasons of the discrepant clinical results is the inadequate assay system of antide-
pressant efficacy. Plasma levels of BDNF, pro-inflammatory cytokines, and the
TRYCATs have been proposed as specified biomarkers of depressive state and
also efficacy of the treatment. However, more direct and sophisticating assay
methods should be developed to quantify the clinical effects of antidepressants on
multiple pathogenic pathways. The second reason is the poor bioavailability of
phytochemicals in the brain. In order to increase bioavailability and pharmacological
formulation, several delivery systems for phytochemicals have been reported: nano-
particles, liposomes, complexes with phospholipids and amphiphilic polymers, and
conjugation with amino acids and glycosides (Pandareesh et al. 2015). Nano deliv-
ery systems for encapsulation of bioactive polyphenols were proposed for novel
therapeutic strategy for neurodegenerative diseases (Squillaro et al. 2018). Conju-
gation of curcumin with phosphatidylcholine preparation (phytosome) called
“Meriva” has been reported to present anti-inflammatory effects in aging subjects
(Franceschi et al. 2016). These studies are now mainly focused on the therapy of
neurodegenerative disorders and brain tumors, and the benefit of these delivery
systems should be investigated also in treatment of depression.
The interaction of genetic and environmental factors in MDD is another impor-
tant issue (Lockwood et al. 2015). Phytochemicals are associated with the epigenetic
regulation of genes coding TPH, 5-HT transporter (SLC6A4), 5-HT receptor
(5-HT1A) and MAO-A, GR (R3C1), BDNF, and TrkB. Curcumin, genistein,
EGCG, and resveratrol have been reported to inhibit DNA methyltransferase, and
curcumin and sulforaphane inhibit histone acetyl-transferase, histone deacetylase,
and silent information regulator 1 (SIRT1), a NAD+-dependent deacetylase (Remely
et al. 2015). Resveratrol, a well-known SIRT1 activator, and other phytochemicals
should be further investigated to establish the epigenetic regulation by phytochem-
icals in the pathogenesis and therapy in depressive disorders.

Financial and Competitive Interests Disclosure

The authors’ research of food-derived bioactive compounds is supported by the

Grants-in-Aids for Scientific Research, No. 18Kk07430 (W.M.). The authors have
no other relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from that disclosed.

Cross-References

▶ Antidepressants: Molecular Aspects of SSRIs

▶ Antidepressants: Pharmacology and Biochemistry
▶ Hypericum and Depression
▶ TCM Substances in Neuropsychopharmacotherapy
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 443

References
Andreatini R, Sartoni VA, Seabra ML, Leite JR. Effect of valepotriates (valerian extract) in
generalized anxiety disorder: a randomized placebo-controlled pilot study. Phytother Res.
2002;16(7):650–4.
Appel K, Rose T, Fiebich B, Kammier T, Hoffmann C, Weiss G. Modulation of the γ-aminobutyric
acid (GABA) system by Passiflora incarnata L. Phytother Res. 2011;25(6):838–43.
Atteritano M, Mazzaferro S, Bitti A, et al. Genistein effects on quality of life and depression
symptoms in osteopenic postmenopausal women: a 2-year randomized, double-blind, controlled
study. Osteoporos Int. 2014;25(3):1123–9.
Badavath VN, Baysal I, Ucar G, Sinha BN, Jayaprakash V. Monoamine oxidase inhibitory activity
of ferulic acid amides: curcumin based design and synthesis. Arch Pharm Life Sci. 2016;349
(1):9–19.
Birkmayer W, Riederer P. Biochemical post-mortem findings in depressed patients. J Neural
Transm. 1975;37(2):95–109.
Boerner RJ, Sommer H, Berger W, Kuhn U, Schmidt U, Mannel M. Kava-kava extract LI 150 is as
effective as opioramol and buspirone in generalised, double-blind multi-centre clinical trial in
129 out-patients. Phytomedicine. 2003;10(Suppl 4):38–49.
Boldrini M, Santiago A, Hen R, Dwork AJ, Rosoklija GB, Tamir H, Arango V, Mann JJ.
Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and
untreated major depression. Neuropsychopharmacology. 2013;38(6):1068–77.
Capra JC, Cunha MP, Machado DG, Zomkowski AD, Mendes BG, Santos AR, Pizzolatti MG,
Rodrigues AL. Antidepressant-like effect of scopoletin, a coumarin isolated from Polygala
sablola (Polygalacase) in mice: evidence for the involvement of monoaminergic system. Eur J
Pharmacol. 2010;643(2–3):232–8.
Carradori S, Gidaro MC, Petzer A, Costa G, Gulglielmi P, Chimenti P, Alcaro S, Petzer JP.
Inhibition of human monoamine oxidase: biological and molecular modeling studies on selected
natural flavonoids. J Agric Food Chem. 2016;64(47):9004–11.
Chang SC, Cassidy A, Willett WC, Rimm EB, O’Reilley EJ, Okereke OI. Dietary flavonoids intake
and risk of incident depression in midlife and older women. Am J Clin Nutr. 2016;104
(3):704–14.
Chimenti F, Fioravanti R, Bolasco A, et al. A new series of flavones, thioflavones, and flavanones as
selective monoamine oxidase-B inhibitors. Bioorg Med Chem. 2010;18(3):1273–9.
Chiuccariello L, Houle S, Miler L, et al. Elevated monoamine oxidase A binding during major
depression episodes is associated with greater severity and reverse neurovegetative symptoms.
Neuropsychopharmacology. 2014;39(4):973–80.
Dai CX, Hu CC, Shang YS, Xie J. Role of Ginkgo biloba extract as an adjunctive treatment of
elderly patients with depression and on the expression of serum S100B. Medicine (Baltimore).
2018;97(39):e12421.
Davinelli S, Scapagnini G, Marzatico F, Nobile V, Ferrara N, Corbi G. Influence of equal and
resveratrol supplementation on health-related quality of life in menopausal women: a random-
ized, placebo-controlled study. Maturitas. 2017;96:77–83.
de Oliveira MR, Chenet AL, Duarte AR, Scaini G, Quevedo J. Molecular mechanisms
underlying the anti-depressant effects of resveratrol: a review. Mol Neurobiol.
2018;55(6):4543–39.
de Rezende MG, Rosa CE, Garcia-Leal C, et al. Correlation between changes in the hypothalamus-
pituitary-adrenal axis and neurochemistry of the anterior cingulate gyrus in postpartum depres-
sion. J Affect Disord. 2018;239:274–81.
de Sousa DP, Silva RHN, da Silva EF, Gavioli EC. Essential oils and their constituents: an
alternative source for novel antidepressants. Molecules. 2017;22(8):E1290.
Derosa G, Maffioli P, Simental-Mendia LE, Bo S, Sahebkar A. Effect of curcumin on circulating
interleulin-6 concentrations: a systematic review and meta-analysis of randomized controlled
trials. Pharmacol Res. 2016;111:394–404.
Deyama S, Bang E, Wohleb ES, et al. Role of neuronal VEGF signaling in the prefrontal cortex in
the rapid antidepressant effects of ketamine. Am J Psychiatry. 2019;176(5):388–400.
444 M. Naoi et al.

Dhiman P, Malik N, Sobarzo-Sanchez E, Uriarte E, Kharkar A. Quercetin and related chromenone

derivatives as monoamine oxidase inhibitors: targeting neurological and mental disorders.
Molecules. 2019;24:418.
Doolin K, Allers KA, Pleiner S, Liesener A, Farrell C, Tozzi L, O’Hanlon E, Roddy D, Frodi T,
Harkin A, O’Keane V. Altered tryptophan catabolite concentrations in major depressive disorder
and associated changes in hippocampal volumes. Psychoneuroendocrinology. 2018;95:8–17.
Dowlati Y, Ravindran AV, Segal ZV, Stewart DE, Steiner M, Meyer JH. Selective dietary supple-
mentation in early postpartum is associated with resilience against depressed mood. Proc Natl
Acad Sci USA. 2017;114(13):3509–14.
Duman RS, Heninger GR, Nestler EJ. Amolecular and cellular theory of depression. Arch Gen
Psychiatry. 1997;54(7):597–606.
Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga A, Pandey GN. Altered gene expres-
sion of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of
suicide subjects. Arch Gen Psychiatry. 2003;60(8):804–16.
Eräsolo H, Hämäläinen M, Leppänen T, Mäki-Opas I, Laavola M, Haaviko R, Yli-Kauhaluoma J,
Moilanen E. Natural stilbenoids have anti-inflammatory properties in vivo and down-regulate
the production of inflammatory mediators NO, IL6, and MCP1 possibly in a PI3K/Akt-depen-
dent manner. J Nat Prod. 2018;81(15):1131–42.
Fanaei H, Khayat S, Kasaeian A, Javadimehr M. Effect of curcumin on serum brain-derived
neurotrophic factor levels in women with premenstrual syndrome: a randomized, double-blind
placebo-controlled trial. Neuropeptides. 2016;56:25–31.
Fedotova J, Kubatka P, Büsselberg D, et al. Therapeutic strategies for anxiety and anxiety-like
disorders using plant-derived natural compounds and plant extracts. Biomed Pharmacother.
2017;95:437–46.
Franceschi F, Feregalli B, Togni S, Cornelli U, Giacomelli L, Eggenhoffner R, Belcaro G. A novel
phospholipid delivery system of curcumin (MARIVA ®) preserves muscular mass in healthy
aging subjects. Eur Rev Med Pharmacol Sci. 2016;20(4):762–6.
Fuchikami M, Morinobu S, Segawa M, Okamoto Y, Yamawaki S, Ozaki N, Inoue T, Kusumi I,
Koyama T, Tsuchiyama K, Terao T. DNA methylation profiles of the brain-derived neurotrophic
factor (BDNF) genes as a potent diagnostic biomarker in major depression. PLoS One. 2011;6
(8):e23881.
German-Ponciano L, Rosas-Sanchez GU, Rivadeneyra-Dominguez E, Rodriguez-Landa JF.
Advances in the preclinical study of some flavonoids as potential antidepressant agents.
Scientifica. 2018;2018:2963565.
Guan LP, Liu BY. Antidepressant-like effects and mechanisms of flavonoids and related analogues.
Eur J Med Chem. 2016;121:47–57.
Hanrahan JR, Chebib M, Johnston GAR. Flavonoid modulation of GABAA receptors. Br J
Pharmacol. 2011;163(2):234–45.
Harris S, Johnson S, Duncan JW, et al. Evidence revealing deregulation of the KLF11-MAO A
pathway in association with chronic stress and depressive disorders. Neuropsychophar-
macology. 2015;40(6):1371–82.
He H, Sui J, Du Y, Yu Q, Lin D, Yang J, Drevets WC, Savitz JB, Victor TA, Calhoun VD. Co-
altered functional networks and brain structure in unmedicated patients with bipolar and major
depressive disorders. Brain Struct Funct. 2017;229(9):4051–64.
Hosseini R, Moosavi F, Silva T, et al. Modulation of ERK1/2 and Akt pathways involved in the
neurotrophic action of caffeic acid alkyl esters. Molecules. 2018;12:3340.
Ignacio ZM, Reus CZ, Arent CO, Abelaira HM, Pitcher MR, Quevedo J. New perspectives on the
involvement of mTOR in depression as well as in the action of antidepressant drugs. Br J Clin
Pharmacol. 2016;82(5):1280–90.
Ito N, Yabe T, Gamo Y, Nagai T, Oikawa T, Yamada H, Hanawa T. Rosmaric acid from Perillae
herba produces an antidepressant-like effect in mice through cell proliferation in the hippocam-
pus. Biol Pharm Bull. 2008;31(7):1376–80.
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 445

Jacka FN, O’Neil A, Opie R, et al. A randomised controlled trial of dietary improvement for adults
with major depression (the ‘SMILES’ trial). BMC Med. 2017;15:23.
Jang SW, Okada M, Sayeed I, Xiao G, Stein D, Jin P, Ye K. Gambogic amide, a selective agonist for
TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death. Proc
Natl Acad Sci USA. 2007;104(41):16329–34.
Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CK, Karolewicz B. The
mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder.
Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35(7):1774–9.
Jeschke E, Ostermann T, Vollmar HC, Tabali M, Matthes H. Depression, comorbidities, and
prescriptions of antidepressants in a German network of GPs and specialists with sub-
specialisation in anthroposophic medicine: a longitudinal observational study. Evid Based
Complement Alternat Med. 2012;2012:508623.
Jin X, Liu P, Yang F, Zhang Y, Miao D. Rosmarinic acid ameliorates depression-like behaviors in a
rat model of CUS and up-regulates BDNF levels in the hippocampus and hippocampal-derived
astrocytes. Neurochem Res. 2013;38(9):1828–37.
Johnson S, Stockmeier CA, Meyer JH, et al. The reduction of R1, a novel repressor protein for
monoamine oxidase A, in major depressive disorder. Neuropsychopharmacology. 2011;36
(10):2139–48.
Johnston GAR. Flavonoid nutraceuticals and ionotropic receptors for the inhibitory neurotransmit-
ter GABA. Neurochem Int. 2015;89:120–5.
Karim N, Curmi J, Gavande N, Johnston BAR, Hanrahen JR, Tierney ML, Chbib M. 20 -Methoxy-6-
methylflavone: a novel anxiolytic and sedative with subtype selective activating and modulating
actions at GABAA receptors. Br J Pharmacol. 2012;165(4):880–96.
Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Schläfke S, Dienel A. Lavender oil
preparation Silexan is effective in generalized anxiety disorder – a randomized, double-blind
comparison to placebo and paroxetine. Int J Neuropsychopharmacol. 2014;17(6):859–69.
Kaufmann FN, Gazal M, Bastos CR, Kaster MP, Ghisleni G. Curcumin in depressive disorders: an
overview of potential mechanisms, preclinical and clinical findings. Eur J Pharmacol.
2016;784:192–8.
Kaur A, Garg S, Shielh BA, Singh N, Singh P, Bhatti R. In Silico studies and in vivo MAOA
inhibitory activity of coumarins isolated from Angelica archangelica extract: approach towards
antidepressant activity. ACS Omega. 2020;5:15069–76.
Kendler KS, Gatz M, Gardner CO, Redersen M. A Swedish national twin study of lifetime major
depression. Am J Psychiatry. 2006;163(1):109–14.
Khan H, Pervitz S, Sureda A, Nabavi S, Tajada S. Current standing of plant derived flavonoids as an
antidepressant. Food Chem Toxicol. 2018;119:176–88.
Khom S, Stommer B, Ramaharter J, et al. Valerenic acid derivatives as novel subunit-selective GABAA
receptor ligands –in vitro and in vivo characterization. Br J Pharmacol. 2010;16(1):65–78.
Koshiguchi M, Komazaki H, Hirai S, Egashira Y. Ferulic acid suppresses expression of trypto-
phan metabolic ken enzyme indoleamine 2,3-dioxygenase via NF-κB and p38MAPK in
lipopolysaccharide-stimulated microglial cells. Biomed Biotechnol Biochem. 2017;81
(5):966–71.
Kraus C, Castren E, Kasper S, Lanzenberger R. Serotonin and neuroplasticity – links between
molecular, functional and structural pathophysiology in depression. Neurosci Biobehav Rev.
2017;77:317–26.
LaChance LR, Ramsey D. Antidepressant foods: an evidence-based nutrients profiling system for
depression. World J Psychiatry. 2018;8(3):97–104.
Lassale C, Batty GD, Baghdadli A, Jacka F, Sanchez-Villegas A, Kivimäki M, Akbaraly T. Healthy
dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of
observational studies. Mol Psychiatry. 2019;24(7):965–86.
Leonard BE. Inflammation and depression: a causal or coincidental link to the pathophysiology?
Acta Neuropsychiatr. 2018;30(1):1–16.
446 M. Naoi et al.

Leone S, Recinella L, Chiavaroli A, Oriando G, Ferrante C, Leporini L, Brunetti L, Menghini L.

Phytotherapeutic use of the Crocus sativus L. (Saffron) and its potential applications: a brief
overview. Phytother Res. 2018;32(12):2364–75.
Li YC, Wang FM, Pan Y, Qiang LQ, Chenf G, Zhang WY, Kong LD. Anti-depressant-like effects of
curcumin on serotonergic receptor-coupled AC-cAMP pathway in chronic unpredictable mild
stress of rats. Prog Neuro-Psychopharmacol Biol Psychiatry. 2009;33(3):433–49.
Li R, Wang X, Qin T, Qu R, Ma S. Apigenin ameliorates chronic stress-induced depressive behavior
by inhibiting interleukin-1β production and NLRP3 inflammasome activation in the rat brain.
Behav Brain Res. 2016;296:318–25.
Lian L, Xu Y, Zhang J, Yu Y, Zhu N, Guan X, Huang H, Chen R, Chen J, Shi G, Pan J.
Antidepressant-like effects of a novel curcumin derivative J147: involvement of 5-HT1A
receptor. Neuropharmacology. 2018;135:506–13.
Lim H, Heo MY, Kim HP. Flavonoids: broad spectrum agents on chronic inflammation. Biomed
Ther (Seoul). 2019;27(3):241–53.
Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun L, France S, Xiao G, Jia Y, Luo HR,
Ye K. A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent
antidepressant effect. J Med Chem. 2010;53(23):8274–86.
Liu B, Xu C, Wu X, Liu F, Du Y, Sun J, Tao J, Dong J. Icariin exerts an antidepressant effect in an
unpredictable chronic mild stress model of depression in rats and is associated with the
regulation of hippocampal neuroinflammation. Neuroscience. 2015;294:193–205.
Lockwood LE, Su S, Youssef NA. The role of epigenetics in depression: a platform for gene-
environment interactions. Psychiatry Res. 2015;228(3):235–42.
Lopez V, Nielsen B, Solas M, Ramirez MJ, Jäger AK. Exploring pharmacological mechanisms of
Lavender (Lavandula angustifolia) essential oil on central nervous system. Front Pharmacol.
2017;8:280.
Lopresti AL, Hood SD, Drummond PD. A review of lifestyle factors that contribute to important
pathways associated with major depression: diet, sleep and exercise. J Affect Disord. 2013;148
(1):12–27.
Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major
depression: a randomised, double-blind, placebo controlled study. J Affect Disord.
2014;167:368–75.
Luykx JJ, Bakker SC, van Geloven N, et al. Seasonal variation of serotonin turnover in human
cerebrospinal fluid, depressive symptoms and the role of the 5-HTTLPP. Transl Psychiatry.
2013;3:e311.
Lv QQ, Wu WJ, Guo XL, Liu RL, Yang YP, Zhou DS, Zhang JX, Liu JY. Antidepressant activity of
astilbin: involvement of monoaminergic neurotransmitters and BDNF signal pathway. Biol
Pharm Bull. 2014;37(6):987–95.
Mansuri ML, Parihar P, Solanki I, Parithar MS. Flavonoids in modulation of cell survival signaling
pathway. Genes Nutr. 2014;9(3):400.
Mao QQ, Xian YF, Ip SP, Che CT. Involvement of serotonergic system in the antidepres-
sant-like effect of piperine. Prog Neuro-Psychopharmacol Biol Psychiatry.
2011;35(4):1144–7.
Martins J, Brijesh S. Phytochemistry and pharmacology of anti-depressant medical plants: a review.
Biomed Pharmacother. 2018;104:343–65.
Milenkovic D, Jude B, Morand C. miRNA as molecular target of polyphenols underlying their
biological effects. Free Rad Biol Med. 2013;64:40–51.
Miroddi M, Calapai G, Navarra M, Minciulo PL, Gangemi S. Passiflora incarnata L.: Ethnophar-
macology, clinical application, safety and evaluation of clinical trials. J Ethnopharmacol.
2013;150(3):791–804.
Moosavi F, Hosseini R, Saso L, Firuzi O. Modulation of neurotrophic signaling pathways by
polyphenols. Drug Des Devel Ther. 2016;10:23–42.
Naoi M, Inaba-Hasegawa K, Shamoto-Nagai M, Maruyama W. Neurotrophic function of phyto-
chemicals for neuroprotection in aging and neurodegenerative disorders: modulation of intra-
cellular signaling and gene expression. J Neural Transm. 2017;24(12):1515–27.
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 447

Naoi M, Wu Y, Shamoto-Nagai M, Maruyama W. Mitochondria in neuroprotection by phytochem-

icals: bioactive polyphenols modulate mitochondrial apoptosis system, function and structure.
Int J Mol Sci. 2019;20:2451.
Naoi M, Maruyama W, Riederer P. Ginseng and ginsenosides in depression. In: Riederer P, Laux G,
Le W, Nagatsu T, editors. Neuropsychopharmacology. Wien: Springer; 2020.
Nath C, Badavath VN, Thakur A, Ulcar G, Acevedo O, Siddique MUM, Jayaprakash V. Curcumin-
based pyrazoline analogues as selective inhibitors of human monoamine oxidase A.
Medchemcomm. 2018;9(7):1164–71.
Naylor J, Minard A, Gaunt HJ, et al. Natural and synthetic flavonoid modulation of TRPC5
channels. Br J Pharmacol. 2016;173(3):562–74.
Nematolahi P, Mehrabani M, Karami-Mohajeri S, Dabaghzadeh F. Effects of Rosmarinus officinalis
L. on memory performance, anxiety, depression, and sleep quality in university students: a
randomized clinical trial. Complement Ther Clin Pract. 2018;30:24–8.
Ng QX, Venkatanarayanan N, Ho CYX. Clinical use of Hypericum perforatum (St. John’s wort) in
depression: a meta-analysis. J Affect Disord. 2017;210:211–21.
Pandareesh MD, Mythri RB, Srinivas Bharath MM. Bioavailability of dietary polyphenols: factors
contributing to their clinical application in CNS diseases. Neurochem Int. 2015;89:198–208.
Patil PO, Bari SB, Firke SD, Deshmukh PK, Donda ST. Patil DA.A comprehensive review on
synthesis and designing aspects of coumarin derivatives as monoamine oxidase inhibitors for
depression and Alzheimer’s disease. Bioorg Med Chem. 2013;21(9):2434–50.
Polyakova M, Stuke K, Schuemberg K, Mueller K, Shoenknecht P, Schroeter ML. BDNF as a
biomarker for successful treatment of mood disorders: a systematic & quantitative meta-
analysis. J Affect Disord. 2015;174:432–40.
Ranjbar M, Firoozabadi A, Salehi A, Ghorbanifar Z, Zarshenas MM, Sadeghniiat-Haghighi K,
Rezaeizadeh H. Effects of herbal combination (Melissa officinalis L. and Nepeta menthoides
Boiss. & Buhse) on insomnia severity, anxiety and depression in insomniacs: randomized
placebo controlled trial. Integr Med Res. 2018;7(4):328–32.
Remely M, Lovrecic L, de la Garza AL, Migliore L, Peterlin B, Milagro FI, Martinez AJ,
Haslberger AG. Therapeutic perspectives of epigenetically active nutrients. Br J Pharmacol.
2015;172(11):2756–68.
Ren L, Wang F, Xu Z, Chan WM, Zhao C, Xue H. GABAA receptor subtype selectively underlying
anxiolytic effect of 6-hydroxyflavone. Biochem Pharmacol. 2010;79(9):1337–44.
Riederer P, Konradi C, Schay V, Kienzl E, Birkmayer G, Daniekczyk W, Sofic E, Youdim MBH.
Localization of MAO-A and MAO-B in human brain: a step in understanding the therapeutic
action of L-deprenyl. Adv Neurol. 1986;45:111–8.
Saleh MC, Connel BJ, Saleh TM. Resveratrol induced neuroprotection in mediated via both
estrogen receptors, ERα and ERβ. Neurosci Lett. 2013;548:217–21.
Sanchez-Villegas A, Martinez-Gonzalez MA, Estruch R, et al. Mediterranean dietary pattern and
depression: the PREDIMED randomized trial. BMC Med. 2013;11:208.
Sanchez-Villegas A, Henriquez-Sanchez P, Canela MR, Lahortiga F, Molero P, Toledo E, Maritinz-
Gonzalez M. A longitudinal analysis of diet quality scores and the risk of incident depression in
the SUN project. BMC Med. 2015;13:197.
Sanmukhani J, Satodia V, Trivedi J, Patel T, Tiwari D, Panchal B, Goel A, Tripathi CB. Efficacy and
safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res.
2014;28(4):579–85.
Sarris J, Kavanagh DJ, Byrne G, Bone KM, Adams J, Deed G. The Kava Anxiety Depression
Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous
extract of Piper methysticum. Psychopharmacology. 2009;205(3):399–407.
Sarris H, Panossian A, Schweitzer I, Stough C, Scholey A. Herbal medicine for depression, anxiety
and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsycho-
pharmacol. 2011;21(12):841–60.
Sarris J, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C,
Schweitzer I. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized,
placebo-controlled study. J Clin Psychopharmacol. 2013;33(5):643–8.
448 M. Naoi et al.

Sarris J, Byrne GJ, Stough C, et al. Nutraceuticals for major depressive disorder- more is not
merrier: an 8-week double-blind, randomised, controlled trial. J Affect Disord. 2019;245:
1007–15.
Sasaki K, El Omri E, Kondo S, Han J, Isoda H. Rosmarinus officinalis polyphenols produce anti-
depressant like effect through monoaminergic and cholinergic functions modulation. Behav
Brain Res. 2013;238:86–94.
Sashidhara KV, Modukuri RK, Singh S, Rao KB, Teja GA, Gupta S, Shukla S. Design and synthesis
of new series of coumarin-aminopyran derivatives possessing potential anti-depressant-like
activity. Bioorg Med Chem Lett. 2015;25(2):337–41.
Savage KM, Stough CK, Byrne GJ, et al. Kava for the treatment of generalized anxiety disorder (K-
GAD): study protocol for a randomised controlled trial. Trials. 2015;16:493.
Savage K, Firth J, Stough C, Sarris J. GABA-modulating phytomedicines for anxiety: a systematic
review of preclinical and clinical evidences. Phytother Res. 2018;32(1):3–18.
Scheid V. Depression, constraint and the liver: (Dis)assembling the treatment of emotion-related
disorders in Chinese medicine. Cult Med Psychiatry. 2013;37(1):30–58.
Shafiee M, Arekhi A, Omaranzadeh A, Sahebkar A. Saffron in the treatment of depression, anxiety
and other mental disorders: current evidence and potential mechanisms of action. J Affect
Disord. 2018;227:330–7.
Shakeri A, Sahebkar A, Javadi B. Melissa officinalis L. – a review of its traditional uses,
phytochemistry and pharmacology. J Ethnopharmacol. 2016;188:204–28.
Sowa-Kucma M, Styczen K, Siwek M, Misztak P, Nowak RJ, Dudek D, Rybakowski J, Nowak G,
Maes M. Lipid peroxidation and immune biomarkers are associated with major depression and
its phenotypes, including treatment-resistant depression and melancholia. Neurotox Res.
2018;33(2):448–60.
Squillaro T, Cimini A, Peluso G, Giordano A, Melone MAB. Nano-delivery systems for encapsu-
lation of dietary polyphenols: an experimental approach for neurodegenerative diseases and
brain tumors. Biochem Pharmacol. 2018;154:303–17.
Sun J, Kong L, Wu F, Wei Y, Zhu Y, Yin Z, Deng X, Jiang X, Tang Y, Wang F. Decreased plasma
glial cell line-derived neurotrophic factor level in major depressive disorder is associated with
age and clinical severity. J Affect Disord. 2019;245:602–7.
Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, Palme R, Griebel G, Ibarguen-
Vargas Y, Hen R, Belzung C. Antidepressants recruit new neurons to improve stress response
regulation. Mol Psychiatry. 2011;16(12):1177–88.
Suri D, Teixeira CM, Cagliostro MKC, Mahadevia D, Ansorge MS. Monoamine-sensitive devel-
opmental periods impacting adult emotional and cognitive behaviors. Neuropsychophar-
macology. 2015;40:88–112.
Tang J, Xue W, Xia B, et al. Involvement of normalized NMDA receptor and mTOR-related
signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice.
Sci Rep. 2015;5:13573.
Toth B, Hegyi P, Lantos T, et al. The efficacy of saffron in the treatment of mild to moderate
depression: a meta-analysis. Planta Med. 2019;85(1):24–31.
Wang F, Xu Z, Yuen CT, Chow CY, Lui YL, Tsang SY, Xue H. 6,20 -Dihydroxyflavone, a subtype-
selective partial inverse agonist of GABAA receptor benzodiazepine site. Neuropharmacology.
2007;53(4):574–82.
Wang Y, Wang B, Lu J, Shi H, Gong S, Wang Y, Hamdy RC, Chua BHL, Yang L, Xu X. Fisetin
provides antidepressant effects by activating the tropomycin receptor kinase B signal pathway in
mice. J Neurochem. 2017;143(5):561–8.
Wang Y, Shi Y, Xu Z, Fu H, Zeng H, Zheng G. Efficacy and safety of Chinese herbal medicine for
depression: a systematic review and meta-analysis of randomized controlled trials. J Psychiatr
Res. 2019;117:74–91.
Wu R, Zhu D, Xia Y, et al. A role of Yueju in fast-onset antidepressant action on major depressive
disorder and serum BDNF expression: a randomly double-blind, fluoxetine-adjunct, placebo-
controlled, plot clinical study. Neuropsychiatr Dis Treat. 2015;11:2013–21.
TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus. . . 449

Wu R, Shui L, Wang S, Song Z, Tai F. Bilobalide alleviates depression-like behavior and cognitive
deficit induced by chronic unpredictable mild stress in mice. Behav Pharmacol. 2016a;27
(7):596–605.
Wu R, Tao W, Zhang H, et al. Instant and persistent antidepressant response of Gardenia yellow
pigment is associated with acute protein synthesis and delayed upregulation of BDNF expres-
sion in the hippocampus. ACS Chem Neurosci. 2016b;7(8):1068–76.
Yanez M, Fraiz N, Cano E, Orallo F. Inhibitory effects of cis- and trans-resveratrol on noradrenaline
and 5-hydroxytryptamne uptake and on monoamine oxidase activity. Biochem Biophys Res
Commun. 2006;344(2):688–95.
Yang XH, Song SQ, Xu Y. Resveratrol ameliorates chronic unpredictable mild stress-induced
depression-like behavior: involvement of the HPA axis, inflammatory markers, BDNF, and
Wnt/β-catenin pathway in rats. Neuropsychiatr Dis Treat. 2017;13:2727–36.
Yu Q, Chang Q, Liu X, Gang S, Ye K, Lin X. 7,8,30 -Trihydroxyflavone, a potent small molecule
TrkB receptor agonist, protects spiral ganglion neurons from degeneration both in vitro and in
vivo. Biochem Biophys Res Commun. 2012;422(3):387–92.
Yu JJ, Pei LB, Zhang Y, Wen ZY, Yang JL. Chronic supplementation of curcumin enhances the
efficacy of antidepressants in major depressive disorder: a randomized, double-blind, placebo-
controlled pilot study. J Clin Psychopharmacol. 2015;35(4):406–10.
Zhang YW, Cheng YC. Challenge and prospect of traditional Chinese medicine in depression
treatment. Front Neurosci. 2019;13:190.
Zhen HH, Quan YC, Peng Z, Han Y, Zheng ZJ, Guan LP. Design, synthesis and potential
antidepressant-like activity of 7-prenyloxyl-2,3-dihydroxyflavone derivatives. Chem Biol
Drug Des. 2016;87(6):858–66.
Ziegler C, Domschke K. Epigenetic signature of MAOA and MAOB genes in mental disorders.
J Neural Transm. 2018;125(11):1581–8.
Zirak N, Shafiee M, Soltani G, Mirzaei M, Sahebkar A. Hypericum perforatum in the treatment of
psychiatric and neurodegenerative disorders: current evidence and potential mechanisms of
action. J Cell Physiol. 2019;234(6):8496–508.
TCM Substances in
Neuropsychopharmacotherapy

Yong Wang and Jie Li

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
Medicinals of TCM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Ginkgo biloba L. (银杏) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Radix et Rhizoma Ginseng/Ginseng (人参) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Stigma Croci (藏红花) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
Gardeniae Fructus (栀子) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
Rhizoma Curcumae Longae (姜黄) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Radix et Rhizoma Glycyrrhizae (甘草) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
Radix Rehmanniae Raw (生地黄) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Radix Rehmanniae Praeparata (熟地黄) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Bulbus Lilii (百合) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Hypericum perforatum/St.-John’s Wort (贯叶连翘/圣约翰草) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
Formulae of TCM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Yueju Pill (越鞠丸) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
Xiao Buxin Tang Decoction (小补心汤) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
Bulbus Lilii and Radix Rehmanniae Tang Decoction (百合地黄汤) . . . . . . . . . . . . . . . . . . . . . . 477
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480

Abstract
With the unique and comprehensive understanding of human’s body and vari-
ous pathological conditions, Traditional Chinese Medicine (TCM) has undoubt-
edly become a field of increasing interests from doctors, researchers, and even
patients these years. A number of specialties benefited from the combination of

Y. Wang
Tianjin Mental Health Institute, Tianjin Anding Hospital, Tianjin, China
e-mail: ashleywy@126.com
J. Li (*)
Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China
e-mail: jieli@tmu.edu.cn

© Springer Nature Switzerland AG 2022 451

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_393
452 Y. Wang and J. Li

TCM and themselves, for example, cardiology, oncology, orthopedics, etc.

Psychiatry is no exception. The complexity and chronicity of psychiatric dis-
orders requires flexible medication throughout the course of disease, yet the
patient’s conditions, for instance, age, social status, overall health condition,
severity of disease, comorbidity, tolerance to drugs, etc., keep changing, which
makes it difficult to maintain a good compliance. Hence, a new method capable
of taking care of all the aforementioned aspects, especially from a patient-
oriented perspective, is in need. An increasing number of clinical evidence
has found that certain herbs of TCM could be the same effective as antidepres-
sant for patients with depression. Other herbs/medicinals of TCM could allevi-
ate the adverse drug reactions induced by antipsychotic/antidepressive agents.
The flexible rule employed in TCM formula makes it possible to keep a
complicated yet beneficial balance of many sides, including severity of disease,
comorbidity, tolerance, etc. TCM, to some extent, meets the requirements for a
new method in need. In this chapter, typical herbs, medicinals, formulae of
TCM with acknowledged property to treat certain psychiatric disorders, along
with most recent evidence, will be introduced.

Introduction

For years, precision medicine has prevailed not only in clinical medicine, but also
researches from fields related to medicine. Increasing resources have been attracted
to the search for the precise explanations, mechanisms, and treatments for abnormal
conditions, diseases, pathogens, etc. Neither psychiatry nor psychology was excep-
tion. Accumulating breakthroughs and findings have been gathered along the way,
most of which were also proved beneficial for patients. Yet the more breakthroughs
we make, the more intensely we realize that “one drug” or “one formula” seems
reasonable to equalize “one disease,” but not anymore once we switched “one
disease” with “one patient.” Human’s body is a complex system. In physiology,
we learned there are eight systems in a human’s body, yet, we cannot comprehend a
patient’s condition in merely eight aspects accordingly, considering the complexity
and wholism of the human’s body. This could partially explain why Traditional
Chinese Medicine (TCM) caught so much attention these days, aside from its being
equally effective for various diseases and well-acknowledged fewer adverse effects.
According to the theory of TCM, diseases are generally related to disorders of
Zang-fu (脏腑) functions and imbalance between Yin and Yang in human body.
Different pathogenic factors affecting the human body can cause excess or defi-
ciency of Yin or Yang, and the dysfunction of Zang-fu as well as Meridians and
Collaterals (经络). The basic principle of treating diseases with traditional Chinese
materia medica is to enhance the body resistance, expel pathogenic factors, and
restore the normal functions of Zang-fu organs, so that the excess or deficiency of
Yin or Yang can be corrected (Chen et al. 2017).
The symptoms related to psychiatric disorders, such as dysthymia or elation, had
been recognized and documented in different articles and books, which could also be
considered as the imbalance between Yin and Yang and the dysfunction of Zang-fu.
TCM Substances in Neuropsychopharmacotherapy 453

Hence, treatments for these symptoms, or diseases, are focused on the restoration of
the normal balance of Yin-Yang and function of Zang-fu. There are generally two
different ways to adjust Yin and Yang:

Removing the excess: The so-called excess refers to the surplus syndrome of either
Yin or Yang, which can be treated essentially with “removal.” “Treating heat with
cold” (热者寒之), or “treating cold with hot” (寒者热之) as one of the basic
principle of the treatment has been widely accepted in the clinical prescription of
TCM (Chen et al. 2017).
Supplementing the deficiency: This strategy is used to treat different kinds of
deficiency syndromes. It is usually carried out by using medicines that tonify
the Qi, blood, Yin or Yang. In many chronic diseases, deficiency of Yin or Yang
often involves or exists in more than one organ of the body, which is usually
treated with different tonic herbs (Chen et al. 2017).

There are thousands of herbs and medicinals of TCM; the most commonly used
ones are more than 500 nowadays. For practical considerations, this chapter includes
characteristic herbs, medicinals, and formulae of TCM that has been acknowledged
to be effective for psychiatric disorders, and also with abundant evidences form
different studies in recent years.

Medicinals of TCM

Ginkgo biloba L. (银杏)

Ginkgo biloba L., family of Ginkgoaceae, has a bitter, sweet, and astringent flavor.
According to TCM, it is capable of activating blood circulation and resolving stasis,
freeing the collateral vessels and relieving pain, astringing the lung and calming
panting, resolving turbidity (Chen et al. 2017).
Recommended dosage: Decoction, 9–12 g. It is not suggested for patient with
excessive syndrome. It is contraindicated to eat fish when taking Ginkgo Folium.
Cautions and interactions
Case reports have illustrated that Ginkgo biloba may potentiate bleeding when
combined with warfarin or aspirin, increase blood pressure when combined with
thiazide diuretics, and has even led to a coma when combined with trazodone, a
serotonin antagonist and reuptake inhibitor used for depression (Chen et al. 2011).
Researches in recent years:
Previous studies proved that ginkgo biloba extract (GBE) could affect nucleotide
metabolism and protein biosynthesis to enhance cell proliferation, as well as the
metabolism of glutamate and aspartate, which plays an important role in the antide-
pressant effects (Bai et al. 2017; Hu et al. 2018; Liang et al. 2016). The mechanism
of GBE in relieving depressive behaviors was also demonstrated to be related with
reducing inflammatory response which is involved in the development of depression
(Liang et al. 2016). To date, studies available have illustrated that extract from
Ginkgo biloba leaves could reverse depression-associated gut dysbiosis and
454 Y. Wang and J. Li

increased the richness of lactobacillus species which had been proven to be a path to
relieve depression (Chen et al. 2019). Meantime, it was suggested that GBE pro-
duced an antioxidant effect against oxidative stress, which may be partly responsible
for its well-observed neuroprotective effects as well (Rojas et al. 2011).
GBE has been used in treating various diseases, including angina pectoris (Sun et
al. 2015), glaucoma (Kang and Lin 2018), brain injury (Tulsulkar et al. 2016),
depression (Dai et al. 2018), and dementia (Napryeyenko et al. 2009; Scripnikov
et al. 2007). Its antiapoptotic, antioxidative, anti-inflammatory properties have been
widely acknowledged (Diamond and Bailey 2013).
These years, Ginkgo biloba has mostly been applied as augmentative treatment for
dementia, stroke, and cardiovascular diseases, most of which are usually seen among
geriatric population. Increasing concerns about the comorbid depression have caught
more attention from the public. Considering the specific and unusual condition of this
population, treatment of choice should be very cautious. As such, natural herbs are
more preferred than conventional medications. It has been suggested that a dose of
240 mg/d of Ginkgo biloba extract was able to stabilize or slow decline in cognition,
function, behavior at 22–26 weeks in cognitive impairment and dementia, especially
for those with neuropsychiatric symptoms (Tan et al. 2015). Researchers also found
that the GBE was a good augmentation of venlafaxine in treating Post stroke depres-
sion (PSD). Meanwhile, the addition of GBE could significantly reduce the dose of
venlafaxine, which was very important for elderly patients (Liang et al. 2019). Also,
GBE did benefit antidepressant-like behaviors and improved cardiac functions in mice
with heart failure (Zhang et al. 2019).

Radix et Rhizoma Ginseng/Ginseng (人参)

Ginseng (Panax ginseng Meyer) is a well-known traditional medicinal herb which

has been used as a vital energy reinforcing agent with a long history in Chinese
medicine. It is mainly cultivated in northeast China, Korea, Japan, and eastern
Russia. According to the theory of traditional Chinese medicine, it is best for people
who are physically weak, preferably taken in winter (Jin et al. 2019).
Radix et Rhizoma Ginseng is the root and rhizome of Panax ginseng C. A. Mey.
In the family Araliaceae. The fresh ones that are dried after being washed clean are
called sun-dried ginseng (sheng shai shen). Those which are dried after being steam-
processed are called red ginseng (hong shen). The fibrous root fallen in processing is
called ginseng fibril (shen xu). It is usually sliced or ground into powder for
application. It has a unique fragrance and is mildly bitter and sweet in taste. In
TCM, ginseng can supplement original qi powerfully, restore pulse to rescue from
desertion, supplement the spleen and boost the lung, promote fluid production and
nourish blood, calm the mind, and benefit intelligence (Teng et al. 2019).
Clinical applications according to TCM:

1. Original qi desertion: Radix et Rhizoma Ginseng is an important medicinal to

rescue desertion. It can be used in large dosage to treat extreme deficiency of
TCM Substances in Neuropsychopharmacotherapy 455

original qi tending to desert, manifested as shortness of breath, fatigue, and faint

pulse verging on expiry.
2. Qi deficiency of the heart, spleen, lung, and kidney: Radix et Rhizoma can be
used to supplement qi of the heart, spleen, lung, and kidney, so it is an important
medicinal to treat qi deficiency of various Zang organs, especially to supplement
qi of the spleen and lung.
3. Qi deficiency, fluid over-consumption and thirst in febrile disease, and xiao ke
(消渴).
4. Severe palpitations, insomnia, and profuse dreaming: Radix et Rhizoma can
supplement heart qi and treat palpitations, severe palpitations, chest oppression,
shortness of breath, and deficient pulse. Additionally, Radix et Rhizoma can
supplement qi and assist yang, so it is used to treat impotence.

Recommended dosage: Decoction, 3–9 g. To rescue desertion, 15–30 g. It should

be decocted singly with moderate fire and taken orally in divided doses mixed with
decoction. Or it can be ground into powder for swallow. 2 g each time, twice a day.
Contraindications and toxicity:
According to the theory of TCM, patients with excessive syndrome (Shi syn-
drome) should not take ginseng. And healthy persons are not suggested to take
ginseng as food supplement often. Due to the different location of where the herb is
cultivated and various methods of processing, it remains inconclusive to determine
the dose for toxicity. Ginseng is not appropriate to be used with Veratrum nigrum (li
lu) and trogopteroum feces (wu ling zhi).
Furthermore, ginseng reduced the blood levels of warfarin and alcohol as well as
induced mania if taken concomitantly with phenelzine, a nonselective and irrevers-
ible monoamine oxidase inhibitor used as an antidepressant and anxiolytic agent
(Chen et al. 2011).
Researches in recent years:
Several studies have demonstrated that ginseng could produce various phar-
macological activities, including antidepressive, antitumor, antiasthma,
neuroprotective, and memory-improving effects (Attele et al. 1999; Jiang et al.
2018; Oh et al. 2015; Lim et al. 2015).
Studies found that ginseng contains many active ingredients, including
ginsenosides, ginseng polypeptides, ginseng polysaccharides (Jin et al. 2019). So
far, more than 180 species of ginsenosides have been identified (Shin et al. 2015;
Mancuso and Santangelo 2017). Although all ginsenosides have different chemical
structures, they share similar four-ring hydrophobic structures are familiar to them
(Kim et al. 2013). Among them, ginsenosides have impacts on the nervous system,
cardiovascular system, immuglycons, ginsenone system, etc. (Zheng et al. 2018). On
the basis of different chemical structures of their asides can be classified into three
types: protopanaxadiols (PPDs), protopanaxatriols (PPTs), and oleanolic acids. PPD-
type includes ginsenosides Rb1, Rb2, Rc, and Rd; PPT-type includes ginsenosides
Rg1, Rg2, Rf, and Re. Besides, Ro is the main oleanolic acid-type ginsenoside.
Ginseng polysaccharides, as another key bioactive component, also have many
biological activities, such as immune regulation, anticancer, antidepression, and
456 Y. Wang and J. Li

antioxidation. It is a kind of polymer dextran, composed of ginseng neutral sugars and

ginseng acid pectin. Between them, the depression studies of ginseng polysaccharides
mainly focus on the acid sugars-pectin part of ginseng.
Ginsenoside Rb1, active component of the ginseng root, is reported to upregulate
the 5-HT, 5-HIAA, NA, and DA levels in the brain of CUMS rats and also exhibits a
synergistic effect when combined with caffeine and fluoxetine (Wang et al. 2017a).
Ginsenoside Rb1 and its metabolite compound K could act as antidepressants by
regulating 5-HT2A receptors, which was demonstrated by blockade action of
ritanserin pretreatment (Yamada et al. 2011). Gintonin, another active constituent
of the Panax ginseng extract, could improve depression-related symptoms in mice
with alcohol withdrawal through elevating the level of plasma 5-HT which was
released from intestinal enterochromaffin cells (Kim et al. 2017).
Among animal model (rats) with PTSD, daily Korean Red Ginseng (KRG)
administration significantly improved depression-like behaviors in forced swimming
test, increased the number of lines crossed and time spent in the central zone in open
field test, and decreased freezing behavior in contextual and cued fear conditioning.
KRG treatment attenuated SPS (single prolonged stress)-induced decreases in sero-
tonin (5-HT) tissue concentrations in the hippocampus and medial prefrontal cortex
(Lee et al. 2020). Also, researches demonstrate that White Ginseng (WG) has an
antidepressant effect through enhancing 5-HT concentrations. These effects are
likely to be mediated by ingredients of WG such as ginsenosides Rb1 and Rg2.
Rb1 has been reported to be able to enhance serotonergic system by increasing 5-HT
synthesis, decreasing 5-HT degradation, and stimulating 5-HT2A receptor in the
brain (Wang et al. 2017a; Yamada et al. 2011; Hao et al. 2011). Activity of inhibitory
5-HT3A receptor is suppressed by treatment with Rg2 （Castrén & Rantamäki 2010;
Choi et al. 2003） Release of dopamine and norepinephrine is also increased by
administration of Rb1 in the mouse brain (Wang et al. 2017a).
Previous studies demonstrated that chronic stress could lead to BDNF down-
regulation and BDNF plays a key role in depression recovery by promoting neuronal
plasticity (Murakami et al. 2005; Castrén and Rantamäki 2010). BDNF infusion into
the brain could produce an antidepressant effect (Shirayama et al. 2002). Antide-
pressant treatment could enhance the expression of BDNF mRNA and produced
protective effects against the stress-induced brain BDNF decrease (Molteni et al.
2006; Réus et al. 2013). It has been reported that ginseng extract G115 could
improve BDNF expression in the hippocampus and prefrontal cortex of ethanol-
induced depression mice, even superior to amitriptyline, indicating that the antide-
pressant effects may contribute to BDNF-related signaling pathway (Boonlert et al.
2017). Ginsenoside Rb1 also ameliorated chronic stress induced depression-like
behaviors by increase of brain-derived neurotrophic factor (BDNF) expression in
the amygdala of rats (Liu et al. 2016a) and alleviated neuroinflammation-induced
depression-like behavior in rodents by blunting the upregulation in circulating
interleukin (IL)-6 levels (Zheng et al. 2014).
The mechanism through which ginseng prevents diseases found related to regu-
lation of the endocrine and immune systems. Ginseng regulates the hypothalamic
pituitary adrenal (HPA) axis (Lee and Rhee 2017). Ginsenoside Rh1 and Rg3 as
TCM Substances in Neuropsychopharmacotherapy 457

estrogen receptor (ERs) ligands and Rh2 and K as glucocorticoid receptor (GRs)
ligands may affect the function of HPA axis mediated by ERs or GRs (Lee and Ji
2014). Furthermore, Rb1 and Rg3 could attenuate neuronal toxicity, which is related
to glucocorticoid activity (Kim et al. 2010).
Ginseng prevents various diseases by ameliorating tissue injury and immune cell
death, while modulating immune cells to limit inflammatory responses. The HPA
axis is the major pathway regulating the immune response to stress (Lee and Rhee
2017). In the event of severe stress-induced dysfunction of the HPA axis, endocrine
homeostasis is disturbed, which can predispose the patient to a number of diseases.
Patients with depression and anxiety often exhibit increased production of HPA
hormones, including CRH and AVP, as compared to healthy individuals (Scott and
Dinan 1998). Researchers found that chronic pretreatment with ginsenoside-Rg1
prior to stress exposure could suppress inflammatory pathway activity through
alleviating the over-expression of proinflammatory cytokines and the activation of
microglia and astrocytes (Fan et al. 2018).
Amyloid-β peptides (Aβ), regarded as a main pathogenic factor of Alzheimer’s
disease, is playing an emerging role in stress response as well as in depression. An
increasing number of reports have shown that many other kinds of ginsenosides,
such as Re, Rg1, and Rf, had the capability to down-regulate the Aβdeposition and
the tau protein phosphorylation. These results suggest that these ginsenosides might
have antidepressant effects through regulating Aβ (Cao et al. 2016; Du et al. 2018;
Shim et al. 2017).
Different methods of processing the ginseng were demonstrated to affect the
absorption. The rate and extent of absorption of Rg1, Re, Rb1, and Rd (all
ginsenosides) appeared to be affected by the different methods used in processing
the ginseng samples. The areas under the plasma drug concentration-time curves
(AUCs) of Rg1, Re, Rb1, and Rd were significantly higher than those of the pure
ginsenosides (unprocessed). In addition, the AUCs of Rg1, Re, Rb1, and Rd were
different for WG (white ginseng), FG (frozen ginseng), and RG (red ginseng). The
amounts of Rg1, Re, Rd, and Rb1 were significantly (p < 0.05) higher in the
tissues than those of the pure ginsenosides (Chen et al. 2018). Also it showed that
the blood-brain barrier was poorly permeable to the ginsenosides as the concen-
trations of Rg1, Re, Rb1, and Rd in the brain tissues was much lower than those in
the plasma. These results are in agreement with those obtained in a previous study
(Han et al. 1986).
Another study also demonstrated that white ginseng has an antidepressant effi-
cacy in an animal model of menopausal depression (Jang et al. 2019). Ginsenoside
Rb1 and its metabolite compound K ameliorated depression-like behaviors during a
menopausal depressive-like state in female mice through the 5-hydroxytryptamine
2A-receptor (Yamada et al. 2011).
Even with the abundant evidence collected from various models, it is over-
optimistic to conclude that ginseng can be beneficial for depressive patients, espe-
cially without enough support from carefully and strictly conducted randomized
clinical trials or high-quality meta-analyses. Clinical studies with a large sample size,
longer duration, and follow-up should be considered in the future.
458 Y. Wang and J. Li

Stigma Croci (藏红花)

Stigma Croci is the dried flower chapiter of Crocus sativus L., pertaining to
Iridaceae, and has a unique slightly irritating smell and is slightly bitter in taste. It
is sweet in flavor and slightly cold in nature. It has the same functions with Flos
Carthami (hong hua), such as invigorating blood, dispelling stasis, and promoting
menstruation. However, its medical efficacy is much stronger. It can also cool the
blood and resolve toxins, for which it is especially used for purpura caused by heat
entering the ying and blood levels of warm diseases, and dark macula due to heat
stagnancy and blood stasis (Teng et al. 2019). Crocus sativus L.(Saffron) is an herb
used for “blood stasis syndrome” according to the theory of TCM; it also happens to
be the world’s most expensive spice. Apart from its traditional value as a food
additive, recent studies indicate its potential as an anticancer agent and memory
enhancer (Abe and Saito 2000; Abdullaev Jafarova et al. 2002).
Recommended dosage: Decoction, 1–3 g.
Precautions: It should be used with caution for pregnant women.
Researches in recent years:
Saffron exhibits antidepressant activity in mild and moderate depression (Shafiee
et al. 2018) and the meta-analysis of nine RCTs presented the effectiveness of saffron
in treatment of mild and moderate depression, with noninferior to SSRI antidepres-
sants (fluoxetine, citalopram) (Tóth et al. 2019). It improved clinical symptoms
assessed with Hamilton Depression Rating Scale (HDRS) almost same effective as
fluoxetine in short-term therapy (Kashani et al. 2017). Even for patients with MDD,
saffron supplementation still ameliorated symptoms of depression (Hausenblas et al.
2013). A standardized extract from saffron affron® showed improvement in depres-
sive symptoms and anxiety assessed with the Revised Child Anxiety and Depression
Scale (RCADS) in youth treated for 8 weeks (Lopresti et al. 2018). Antidepressant
activity of saffron was also demonstrated in mothers with postpartum depression
(Tabeshpour et al. 2017).
Saffron extract and crocin have exhibited antidepressant function through inhi-
bition of monoamine reuptake and binding to N-methyl-D-aspartate (NMDA) recep-
tor as an antagonist and to GABA-α receptor (Georgiadou et al. 2012). Safranal and
crocin prevented increase in plasma corticosterone levels and depressive-like symp-
toms in rats exposed to chronic restraint stress (CRS) (Ghadrdoost et al. 2011;
Ghalandari-Shamami et al. 2019). Saffron has also showed its antioxidant, anti-
inflammatory, anxiolytic, neuroprotective, anticancer, and memory improving func-
tion (Lopresti and Drummond 2014).
Crocin, one of the main glycosylated carotenoids of saffron, has been found to
have numerous pharmacological activities and reported to be associated with
neuroprotective effects. A study showed that crocin-I exerts significant antidepres-
sant effects in a model of chronic corticosterone (CORT)-induced depression. The
antidepressant activity of crocin-I was probably achieved through the suppression of
neuroinflammation (IL-1β) and oxidative stress in the mouse hippocampus. Addi-
tionally, the oral administration of crocin-I at a dose of 40 mg/kg reduced the CORT-
induced accumulation of nicotinamide in the liver of the mice to improve the
TCM Substances in Neuropsychopharmacotherapy 459

synthesis of NAD+, thereby stimulating the activity of SIRT3 deacetylase to elevate

the activity of antioxidants such as superoxide dismutase-2 and glutathione reduc-
tase. Moreover, crocin-I reduced the levels of oxidative damage markers (reactive
oxygen species and malonaldehyde) to rescue impaired mitochondrial function
caused by CORT treatment, which was represented by electron transport chain and
oxidative phosphorylation normality, and thus rescue ATP production to the level of
that in wild-type mice (Xiao et al. 2019).

Gardeniae Fructus (栀子)

Gardeniae Fructus is the ripe fruit of Gardenia jasminoides Ellis, pertaining to

Rubiaceae, and is mainly produced in Hunan, Jiangxi, and Hubei Provinces. It is
collected from September to November when its fruit ripens with reddish yellow
color. After carpopodium and impurities are removed, it is mildly steamed or scalded
in boiling water and then dried. It has a slight flavor and tastes slightly sour and
bitter. It is used raw, stir-baked to brown, or stir-baked until charred. According to
the theory of TCM, Gardeniae Fructus could drain fire, relieve vexation, clear heat
and drain damp, cool the blood and resolve toxins, and relieve swelling and pain
when used externally.
Clinical applications:

1. Vexation in febrile diseases: Gardeniae Fructus is the most powerful medicinal to

treat irritation and uneasiness in febrile disease, for instance, exuberant fire toxin
of febrile disease and fever in sanjiao, with symptoms of high fever, vexation and
agitation, loss of consciousness, and delirium.
2. Damp-heat jaundice: It treats jaundice, fever, scanty, and reddish urine due to
accumulation of damp-heat in the liver and gallbladder.
3. Strangury with difficult and painful urination: It can be used in cases of heat
strangury with astringent pain or blood strangury.
4. Bleeding due to blood heat: For hematemesis and epistaxis due to blood heat, it is
can be applied.
5. Swollen red eyes with pain, sores, and ulcers due to fire toxin: It treats swollen
and red eyes with pain due to up-attacking fire of the liver and gallbladder.
6. Sprain and contusion: Gardeniae Fructus powder mixed with yellow wine into
paste can relieve swelling and pain to treat sprain and contusion by external
application (Teng et al. 2019).

In pharmacological studies, Gardeniae Fructus also possesses antipathogenic,

anti-inflammation, sedative, cholagogic, and hepatoprotective effects (Chen et al.
2017).
Recommended dosage: Decoction, 6–10 g. For external application, a moderate
amount of powdered raw Gardeniae Fructus should be considered.
Precautions: Cautions should be taken, especially for those with loose stool due to
spleen insufficiency. Gardenoside, an ingredient of Gardeniae Fructus, was found
460 Y. Wang and J. Li

potentially hepatotoxic; hence, monitoring the liver function while applying

Gardeniae Fructus is advised (Chen et al. 2017).
Researches in recent years:
A report illustrated that crude extract of Gardeniae Fructus had biological and
pharmacological activities. In phytochemical studies of Gardeniae Fructus, com-
pounds, such as genipin, rutin, chlorogenic acid, along with ursolic acid, were
detected in extracts (He et al. 2006). Genipin is an aglycone derived from an iridoid
glycoside called geniposide from Gardeniae Fructus, also a natural cross-linker for
proteins, collagen, gelatin, and chitosan cross-linking. It’s been applied for pharma-
ceutical purposes, such as choleretic action for liver diseases, and the relief of
symptoms of type 2 diabetes. Ursolic acid, as a pentacyclic triterpene acid, mostly
used in cosmetics (Shishodia et al. 2003), is also capable of inhibiting various types
of cancer cells by inhibiting the STAT3 activation pathway (Pathak et al. 2007).
Iridoid glycosides (mainly geniposide) and crocetin derivatives (crocins) are
considered as two major active constituents in this herb (Hu et al. 2019).
Studies demonstrated that geniposide and its aglycone genipin have significant
biological activities in inflammatory process. One study showed that genipin possessed
anti-inflammatory activity, which was demonstrated through the results from carra-
geenan-induced rat paw edema and air pouch formation, also the NO content in the
exudates (Koo et al. 2006). Another study found that geniposide showed anti-inflam-
matory activity in lipopolysaccharide (LPS) stimulated primary mouse macrophages
(Fu et al. 2012). Meanwhile, anti-inflammatory and immunoregulatory properties of
geniposide were observed in other studies (Dai et al. 2014). Moreover, another inves-
tigation also found that geniposide exerted anti-inflammatory activity through regulating
TLR4 expression, which, in turn, affected the nuclear factor kappa B (NF-κB) and
mitogen-activated protein kinase (MAPK) signaling pathways (Song et al. 2014).
Crocins, representative carotenoid compounds, have proved their potential in
medicine. Investigations have elucidated that crocetin derivatives (crocins) exhibited
anti-inflammatory property. A previous study found that crocin could reduce inflam-
mation-driven tissue impairment by decreasing the serum pro-inflammatory cyto-
kines, TNF-αand IL-6, and increasing anti-inflammatory cytokine, IL-10 (Yang and
Dong 2017). Another research proved that crocin had a protective effect against
allergic asthma, which was also associated with down-regulating inflammatory
cytokine expression (Yosri et al. 2017).
In previous studies, oil extract of Gardeniae Fructus (OFG) was found effective in
relieving the behavioral despair in normal mice (Tao et al. 2014). Compared with the
control group, the treatment of OFG could significantly reduce the immobility
duration in the forced swimming test (FST) and tail suspension test (TST). With
the pretreatment of selective protein kinase A (PKA) inhibitor H-89, the up-regula-
tion of cAMP response element-binding protein (CREB) expression caused by OFG
was suppressed, suggesting the antidepressant effect of OFG was dependent on the
PKA/CREB/BDNF pathway (Ruan et al. 2019).
cAMP response element-binding protein (CREB), a regulatory factor in nuclei,
acts as an important role in multiple intracellular signaling pathways in the neural
system (Hashimoto et al. 2004; Malberg and Blendy 2005). CREB signaling in the
TCM Substances in Neuropsychopharmacotherapy 461

hippocampus has been involved in the impairment of psychotic as well as cognitive

behaviors. It has been suggested that PKA is required for the activation of CREB.
Studies showed that stress-dependent differences in CREB signaling could lead to
changes of learning and memory-related behaviors (Freitas et al. 2013; Aguiar Jr
et al. 2011; Wang et al. 2008; Patil et al. 2010; Sung et al. 2008).
BDNF, one of the major downstream target genes of CREB, being recruited by
CREB phosphorylation, is considered as one of the most prevalent neurotropic
factors involved in several cerebral dysfunctions (de Sousa et al. 2015). The ethanol
extract of Gardeniae Fructus exhibited rapid antidepressant effect through up-regu-
lating BDNF expression (Zhang et al. 2015a). The Gardenia yellow pigment (GYP),
which is enriched in Gardeniae Fructus, was also exerted antidepressant effect
through promoting CREB and BDNF (Wu et al. 2016).
Unfortunately, the gap between antidepressant effects of Gardeniae Fructus
exhibited in different models and depressive patients still remains. Till recently,
clinical studies are more likely to adopt different formulae having Gardeniae Fructus
as a component, instead of Gardeniae Fructus itself, to ameliorate depressive symp-
toms among patients with other diseases, for example, diabetes, rather than depres-
sion alone. Researches focusing on the specific antidepressant mechanism of
Gardeniae Fructus and its potential effects among depressive patients should be
considered with high priority in the future.

Rhizoma Curcumae Longae (姜黄)

Rhizoma Curcumae Longae is the rhizoma of Curcuma linga L., pertaining to

Zingiberaceae. It is mainly produced in Sichuan, Fujian, and Guangdong provinces
in China. It is collected in winter when the plant has withered. Then, it is washed
clean, boiled or steamed thoroughly, and dried in the sun. After the fibrous roots are
removed, it is cut into shreds. It has unique fragrance and is bitter and acrid in taste.
It is used in the raw form. In TCM, it is believed to invigorate blood and move qi;
unblock the channels and arrest pain.
Clinical applications:

1. Pain in the chest and hypochondriac region caused by qi stagnation and blood
stasis, and abdominal pain caused by menstrual block.
2. Painful bi syndrome (cold bi) due to wind and dampness; it is especially effec-
tively to circulate qi in the limbs and relieve painful bi due to wind and dampness.

In addition, it can be applied externally after ground into powder together with
Radix et Rhizoma Rhei (da huang), Radix Angelicae Dahuricae (bai zhi), and Raidx
Trichosanthis (tian hua fen). It can also treat yang syndromes manifested as furuncle
with redness, swelling, feverish sensation and pain caused by abscess, ulcer, and
sores at early stage.
It contains curcumin and volatile oil and has anticoagulative and antimyocardial
ischemia actions. Besides, it can lower blood pressure, reduce blood lipid, suppress
462 Y. Wang and J. Li

bacteria, resist inflammation, protect the liver, and promote gallbladder function.
Moreover, it can prevent early pregnancy and excite the uterus.
Recommended dosage: Decoction, 3–10 g. An appropriate amount is used
externally. It is contraindicated for pregnant women (Teng et al. 2019).
Researches in recent years:
Curcuma longa, also known as turmeric, is a perennial herb, belonging to
Zingiberaceae family with a total of 133 different species worldwide (Bhat et al.
2019). Curcuma longa is commonly used as spice, food preservative, and coloring
material (Kalaycıoğlu et al. 2017), also as a cosmetic agent, dying agent, and
medicinal herb to treat ailments like skin infections, liver and gastrointestinal
disorders, etc. (Yallapu et al. 2012). Curcuma has high concentrations of poly-
phenols and flavonoids (Hossen et al. 2017). Its biosynthesis begins with phenyl-
alanine, a common precursor in the biosynthesis of flavonoids (Kita et al. 2008;
Sandhu et al. 2011). Flavonoids are crucial for the development of effective
therapeutic agents to treat neurodegenerative diseases; along with their antioxi-
dant properties, these compounds exhibited neuroprotective properties through
interactions with different cellular signaling pathways which is followed by
transcriptions, along with translations that mediate cellular functions (Solanki
et al. 2015). Curcumin, the main polyphenol from the Curcuma longa (turmeric
curry), has exhibited a variety of beneficial effects: anti-inflammatory, antitumor,
immunomodulatory, and neuroprotective properties (Venigalla et al. 2015;
Daverey and Agrawal 2016, 2018). Up till recently, the antidepressant effects of
curcumin have been acknowledged, not only owing to its effectiveness in pre-
venting genesis of depression-like behaviors in different animal models (Andrade
2014; Lopresti et al. 2014; Zhang et al. 2014a), but also available clinical trials
supporting the antidepressant effects of curcumin administration in depressed
patients (Ng et al. 2017a).
It has been evidenced that chronic mild stress (CMS) procedure increased serum
interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels, along with
reduction of natural killer cell (NK cell) activity in splenocytes. CMS-treated rats
exhibited higher corticotropin-releasing factor in serum and medulla oblongata, also
an elevated cortisol levels in serum. A reduction in sucrose intake was observed in
the meantime (Xia et al. 2006).
Inflammatory cytokines are considered as significant pro-apoptotic factors which
are involved in the progression of neurological disorders (Tsai 2017). Researches
have demonstrated that activation of pro-inflammatory factors, including interleu-
kin-1β(IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α(TNF-α), might play
an important role in neuronal damage seen among patients with major depressive
disorder (MDD) (Maes et al. 2012; Rawdin et al. 2013).
The IL-1-type cytokines have been acknowledged as major mediators of neuro-
inflammation and increasing evidence suggested that IL-1βis a key contributor to the
neuronal deterioration in depression (Maes et al. 2012; Kaufmann et al. 2017).
Increased IL-1β was detected in the brain in response to chronic stress (Pan et al.
2014) and inhibiting IL-1β could reverse stress-induced social avoidance in rats
(Ramirez et al. 2015).
TCM Substances in Neuropsychopharmacotherapy 463

Increased serum IL-6 has been observed in depressed patients, which could be
reversed after being treated with antidepressant agents, like fluoxetine (Maes et al.
1995). It has also been reported that the reduction of natural killer (NK) cell activity
could reversed by antidepressant, along with clinical improvement (Jozuka et al.
2003; Frank et al. 1999). Elevated corticotropin-releasing factor (CRF) in cerebro-
spinal fluid and different regulation of adrenocorticotropin hormone (ACTH), along
with abnormal cortisol secretion, have been detected in depressive patients (Plotsky
et al. 1998). Effective antidepressant treatment with fluoxetine could normalize these
hormones (Stout et al. 2002).
Sleep deprivation for 72 h caused weight loss, anxiety like behavior, impaired
locomotor activity. Oxidative damage and weakened antioxidative defense system
were found in sleep deprivation models (Gopalakrishnan et al. 2004; Ramanathan
et al. 2002; Kalonia and Kumar 2007; Kumar and Kalonia 2007). It has been
reported sleep deprivation increased lipid peroxidation, and nitrite level, depleted
reduced glutathione, as well as catalase activity, indicating an oxidative damage in
sleep-deprived animals.
Alzheimer’s disease (AD) is a neural degenerative disorder, which usually leads
to damages to memory, thinking, and behavior (Cole and Frautschy 2006). The main
characteristic pathological changes of AD include aggregations of amyloid-β(Aβ)
and tau proteins (da Costa et al. 2019).
Aβ accumulation leads to the formation of senile plaques, activation of oxidative
damage or even apoptosis to neurons, neuroinflammation, and cognitive deficits
(Zhang et al. 2015b; Huang et al. 2012; Zheng 2005).
Curcuma longa possesses neuroprotective effects against ischemic damage (Jiang
et al. 2007; Dohare et al. 2008; Rathore et al. 2008), Alzheimer’s disease (Frautschy
2001; Yang et al. 2004; Garcia-Alloza et al. 2007), Parkinson’s disease (Mansouri et al.
2012; Jiang et al. 2013), and parathion-induced damage (Canales-Aguirre et al. 2012).
Curcuma longa extracts also exhibited powerful antioxidant, anti-inflammatory,
lipid-reducing, chemo-preventive, immunomodulatory, and sedative properties
(Miquel et al. 2002; Joe et al. 2004).
The ethanolic extracts of Curcuma longa reversed the CMS-induced reduction in
sucrose intake, elevations in serum IL-6, TNF-α, and cortisol levels, along with
reducing corticotropin-releasing factor (CRF) in serum and medulla oblongata, the
decrease in splenic NK cell activity as well (Xia et al. 2006).
Curcuma longa extract contains curcumin, a polyphenolic nonflavonon compound,
which is considered as a pharmacologically active substance (Ganguli et al. 2000).
It can cross the blood-brain barrier and enter brain tissue, regardless of its poor
bioavailability, which was mainly distributed in the hippocampus (Tsai et al. 2011).
Curcumin possesses a strong antidepressant activity in depressive animal models
(Andrade 2014; Hurley et al. 2013; He et al. 2016; Lee and Lee 2018). It acts through
inhibiting the expression of MAO-A and MAO-B enzymes which leads to increase
of norepinephrine, serotonin, and dopamine (Kulkarni and Dhir 2010). It was
reported that curcumin’s antidepressant activity was induced by ERK regulated
increase in the expression of brain-derived neurotrophic factor (BDNF) in the
amygdale (Zhang et al. 2012). Meanwhile, curcumin was also witnessed to promote
464 Y. Wang and J. Li

neurogenesis in hippocampus and improve BDNF in mouse model of chronic stress

(Xu et al. 2006).
Curcumin treatment dramatically attenuated the apoptotic related morphological
and biochemical changes induced by over-expression of IL-1β (P < 0.01). Curcumin
ameliorated IL-1β-induced neuronal apoptosis via suppressing the P38 pathway
within the ventromedial prefrontal cortex (vmPFC) of CUMS exposed rats (Fan
et al. 2019).
In sleep deprivation models, curcumin pretreatment exhibited antianxiety like
behavior, improvement in locomotor activity, along with weight gain and amelio-
rated oxidative damage (lowered lipid peroxidation, restored depleted glutathione,
and catalase activity), which suggested its protective effect against sleep deprivation-
induced behavioral, as well as biochemical changes (Kumar and Singh 2008).
Under normal aging or increased oxidative stress circumstances, memory func-
tion declines due to decrease of BDNF (Wu et al. 2004; Erickson et al. 2010), while
enhancing BDNF could alleviate learning and memory impairments (Caccamo
et al. 2010; Takei et al. 2011). Studies have shown Curcuma longa extract largely
ameliorated memory deficits in D-gal-induced senescence mice (Kumar et al.
2011), and prevented decreases in acetylcholinesterase in aged rats(Conboy et al.
2009; Pyrzanowska et al. 2010), mice with Alzheimer’s disease (Pan et al. 2008)
and those under chronic unpredictable stresses (Rinwa and Kumar 2012). The
protective effect of curcumin on memory deficit was reported as mediated by
prevention of oxidative stress.
The unpreferential side effects induced by haloperidol include increases in extra-
pyramidal movements, which was postulated to be caused by glutamate
excitotoxicity and dopamine turnover in the basal ganglia. These could lead to
increasing generation of free radicals, oxidative stress, also neurotoxicity (Bishnoi
et al. 2011). Pretreatment with curcumin could inhibit almost all these side effects
dose-dependently (Lopresti 2017).
A single-dose of 5 g curcumin/kg body weight (bw) in rats was reported to be
nontoxic (Wahlström and Blennow 1978). In chromosomal aberration assay,
curcumin (100 and 200 mg/kg) was found to decrease the incidence of aberrant
cells (Shukla et al. 2002). A two-generation toxicity study, both male and female
rats being fed with curcumin (1,500, 3,000–10,000 ppm), demonstrated no
adverse or toxic sign among male or female specific toxicity either in parental or
offspring.

Radix et Rhizoma Glycyrrhizae (甘草)

It is the root and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat., or
Glycyrrhiza glabra L., pertaining to Leguminosae. It is mainly produced in Inner
Mongolia Autonomous Region, Gansu, and Heilongjiang provinces in China. It is
collected in spring and autumn. After the fibrils are removed, it is dried in the sun and
sliced into thick pieces. It has mild fragrance and tastes sweet and unique. It is used
raw or honey-fried. According to the theory of TCM, it is able to supplement the
TCM Substances in Neuropsychopharmacotherapy 465

spleen and boost qi, clear heat and resolve toxins, dispel phlegm and relieve cough,
relax spasms and relieve pain, and harmonize all medicinals.
Clinical applications:

1. Spleen qi deficiency: Radix et Rhizoma Glycyrrhizae (gan cao) should be used as

a supplementary medicinal because of its moderate efficacy.
2. Heart qi deficiency: It can be applied to treat palpitations and severe palpitations
due to heat qi insufficiency.
3. Cough and panting with profuse sputum: Radix et Rhizoma Glycyrrhizae (gan
cao) can be used as a supplementary medicinal for cough and panting of cold,
heat, deficiency, or excess patterns, with or without sputum.
4. Spasms and pain of stomach, abdomen, and four limbs: Radix et Rhizoma
Glycyrrhizae (gan cao) is effective to relax spasms and relieve pain.
5. Sores, abscesses, swellings and toxins, sore and swelling throat: It is effective to
treat sores due to heat toxin and swelling throat.
6. Resolving toxins and drastic properties of medicinals: Applied with various
medicinals in many formulae, Radix et Rhizoma Glycyrrhizae (gan cao) can
alleviate drastic properties of medicinals, resolve toxins and side effects, or
regulate properties of medicinals.
7. Radix et Rhizoma Glycyrrhizae (gan cao) is also frequently used in compound
formulae to make medicinals act synergistically. It is sweet in flavor and also used
to protect the spleen and stomach in the middle jiao. In addition, it has a certain
effect of relieving drug toxicity or food poisoning.

Recommended dosage: Decoction, 2–10 g. It should be used raw for clearing heat
and resolving toxins, and it should be dry-fried with liquid adjuvant for
supplementing the center and relaxing spasms.
Precautions: Radix et Rhizoma Glycyrrhizae (gan cao) is not proper to be used
together with sargassum pallidum (turn.) c.ag./ Sargassum fusiforme (Harv.) Setch.
(hai zao), Radix Euphorbiae Pekinensis (jing da ji), Flos Genkwa (yuan hua), and
Radix Kansui (gan sui). It has the side effects of assisting dampness accumulation
and stagnation, so it is not proper for distension, fullness, and edema due to
dampness exuberance. Long-term application in large dose may induce water and
sodium retention and lead to edema (Teng et al. 2019).
Oral administration for a long term may cause hypertension, edema, lowered
blood potassium, headache, dizzy, and palpitation. When orally administered over
500 mg per day for1 month, glycyrrhizin may produce pseudohyperaldosteronism,
the symptoms will be improved or disappeared after withdrawal or treatment with
spironolactone (Chen et al. 2017).
Researches in recent years:
The pharmacopoeia of the People’s Republic of China contains G. uralensis,
G. glabra, and G. inflata as medicinal materials. Their roots and rhizomes are the
medicinal parts, which mainly contain triterpenoids and flavonoids. To date, more
than 400 compounds have been isolated from licorice (Bao et al. 2019), including
flavonoids, triterpenoid saponins, coumarins, lignans, and polysaccharides
466 Y. Wang and J. Li

(Hosseinzadeh and Nassiri-Asl 2015; Yang et al. 2015; Pastorino et al. 2018). It is
reported that licorice showed significant efficacy in relieving coughing and asthma
(Kuang et al. 2018), along with hepatoprotective (Abdel-Kader et al. 2018), anti-
inflammatory (Wang et al. 2017b), antivirus (Fukuchi et al. 2016), antiulcer (Liu
et al. 2018), and antidiabetes (Bai et al. 2018) properties.
Stresses can cause hyperactivity of the HPA axis, increased level of corticoste-
rone, and also have a negative effect on the neurogenesis, especially neurons from
the hippocampus, which are closely related to the onset of depression (Garcia 2002;
Sapolsky 2000).
Flavonoids are secondary metabolites of the plant. It is demonstrated that the total
flavonoids extract from the cultivated Glycyrrhiza uralensis Fisch. could produce
antidepressive effect on chronic unpredictable stress of depression model rats, along
with its neurogenesis protective effect under large dosage (Fan et al. 2012). Licorice
flavonoids extract is evidenced to have an inhibitory effect on Caspase-3 (a key
enzyme having promoting effect in the apoptosis process), to increase Bcl-xl
(a protein having protective effect on the neuronal apoptosis through inhibiting the
activity of adaptor needed for the activation of Caspase-3) (Cheng et al. 2014), and
the number of the new born BrdU positive progenitor cells at the subgranular zone
(SGZ) of dentate gyrus (DG) region in hippocampus, through which licorice flavo-
noids displayed antidepressive effect (Fan et al. 2012).
Researches found that the effective antidepressive components from Glycyrrhiza
also include liquirtin and isoliquirtin (Zhao et al. 2008). Liquirtin is an important
monomer active component among Glycyrrhiza flavonoids, also reversed the
decrease of sucrose consumption among CUMS depressive rats (Su et al. 2011;
Zhao et al. 2006a). Liquirtin and isoliquirtin exhibited antidepression effect, through
increasing the concentration of neurotransmitter 5-HT, norepinephrine in the hippo-
campus, hypothalamus and cortex, inhibiting the metabolism of 5-HT, upregulating
the level of BDNF, enhancing the activity of SOD, removing the free radicals,
preventing lipid peroxidation, reducing the production of MDA (malondialdehyde),
and alleviating the oxidative damage of the brain caused by chronic stress (Ma 2009;
Zhao et al. 2006b, c, 2008).
Processing with honey could increase the content of liquirtin and isoliquirtin
(Zhao et al. 2008). The higher the temperature was, the higher level of liquirtin,
isoliquiritigenin, isoliquirtin. The increase of liquirtin made Glycyrrhiza more suit-
able for treating depression (Zhang et al. 2009).
Glycyrrhizic acid, a rich content triterpenoid saponin, is one of the most important
pharmacologically active components in it. Glycyrrhizic acid have significant effects
similar to adrenal cortical hormone and can be used in clinical for anti-inflammatory,
antiaging, decompression, enhancing body immunity, improving physiological func-
tion, and restraining cancer cells growth, showing really curative effect (Wang et al.
2013). Combining with glycyrrhizic acid, as an anti-inflammatory method, could
provide a more efficient treatment for depression and accompanying cognitive
impairment. For depressive patients with C-reactive protein (CRP) higher than
3 mg/L, glycyrrhizic acid could enhance the therapeutic effects of traditional anti-
depressant agents greatly (Cao 2019).
TCM Substances in Neuropsychopharmacotherapy 467

Glycyrrhizae (gan cao) also exhibits other pharmacological effects, including

inducing adrenal cortex hormone like effects, regulating immune function, relieving
spasm, being hepatoprotective, antibacteria, antivirus, anti-inflammation, antiallergy,
and antiulcer. These effects relate to the traditional efficacies in supplementing the
spleen and boosting Qi, clearing heat and resolving toxin, relaxing tension, and
relieving pain. The effects on relieving cough and eliminating phlegm and detoxifi-
cation may be related to the efficacies in dispelling phlegm, suppressing cough and
harmonizing properties of various herbs.
With its various pharmacological effects, especially harmonizing different properties
of various herbs, Glycyrrhizae has been one of the most frequently used herbs in
different formulae since centuries ago. Yet, it remains rarely witnessed that the appli-
cation of Glycyrrhizae alone for any diseases, including psychiatric disorders or merely
related symptoms. To the best of our knowledge, there has not been any carefully
conducted clinical trials concerning the mono-therapy of Glycyrrhizae for psychiatric
disorders, which leaves us a direction for further studies to narrow the gap between the
theories and the pharmacological effects of Glycyrrhizae for psychiatric patients.

Radix Rehmanniae Raw (生地黄)

It is the root tuber of Rehmannia glutinosa Libosch, pertaining to Scrophulariaceae,

and is mainly produced in Henan Province. It is collected in autumn. After the root-
head, fibrous root, earth, and sands are removed, it is baked to 80% dryness with
mild fire and cut into slices. It has a slight flavor and tastes slightly sweet. Its raw
form is used. In TCM, it is believed that Radix Rehmanniae Raw can clear heat and
cool the blood, nourish yin, and promote fluid production (Teng et al. 2019).
Clinical applications according to TCM:

1. Syndrome of heat entering ying-blood: manifested as a crimson tongue, excessive

thirst, macules and papules, haematemesis, and epistaxis: Radix Rehmanniae
Raw is one of the most powerful medicinals to clear heat, cool the blood, and
stanch bleeding.
2. Syndrome of yin deficiency with internal heat: manifested as steaming bone fever
and tidal fever.
3. Syndrome of fluid consumption with thirst due to internal heat and constipation
due to intestinal dryness.

Recommended dosage: Decoction, 10–15 g. The dosage is doubled when the

fresh form is used. Also the fresh can be pounded into juice for administration.

Radix Rehmanniae Praeparata (熟地黄)

Radix Rehmanniae Praeparata is produced by processing Radix Rehmanniae Raw.

Radix Rehmanniae Raw is steamed and basked repeatedly with adjuvant materials
468 Y. Wang and J. Li

including wine, Fructus Amomi (sha ren), Pericarpium Citri Reticulatae (chen pi)
until both the internal and external become black, oily, and moistening and the
texture becomes soft, sticky, and greasy. Thus Radix Rehmanniae Praeparata is
obtained. It has a mild smell and tastes sweet. It is sliced or dry-fried until charred
for application. Unlike the unprepared Radox Rehmanniae, the prepared, according
to the theory of TCM, it is believed to supplement blood and enrich yin, boost
essence and replenish marrow (Teng et al. 2019).
Clinical applications according to TCM:

1. Syndrome of blood deficiency: Radix Rehmanniae Praeparata is an important

medicinal for supplementing blood. It is used for blood deficiency syndrome
manifested as sallow yellow complexion, vertigo, palpitation, insomnia, men-
strual irregularities.
2. Syndrome of yin deficiency of the liver and kidney, syndrome of insufficiency of
essence and blood: Radix Rehmanniae Praeparata is rich in flavor and greasy,
slimy in property. It can enrich yin and supplement blood, supplement essence
and boost marrow, and drastically supplement liver and kidney.

Recommended dosage: Decoction, 9–15 g.

Precautions: Cautions however must be excised that the isolated chemicals and the
extracts from the herbs are not identical to the original herbs or formulas. Using Sk-
hep1 human hepatoma cells (Choi et al. 2011) found that 50–250 μg/ml of ethanol
extracts of Rehmanniae Radix preparata or water extracts of Radix Rehmanniae dose-
dependently induced cellular lipid accumulation using Nile red staining. However, the
toxicity evidence of this herb itself is weaker because of lack of the data from in vivo
experiments and clinical observations. So far, the traditional properties and indications
of TCM herbs and formulae are the only validated source of interpreting and extrap-
olating assessments of the toxicities (Leung 2006; Ma et al. 2016).
Researches in recent years:
The most commonly applied model for depression is chronic unpredictable mild
stress (CUMS). The liver antioxidant indexes of mice were found altered, 24 h after
the CUMS protocol, which include increased malondialdehyde (MDA), an end
product of lipid peroxidation and a good indicator of oxidative injury, a significant
reduce of glutathione (GSH), as well as impaired antioxidant enzyme activities. The
activity of SOD was decreased significantly in CUMS, and a downward tendency
was witnessed in glutathione peroxidase (GSH-Px) and catalase (CAT). Gastric
ulcers appear to be an inevitable consequence of a stressful life (Rao et al. 2008).
Almost all CUMS mice suffered from gastric ulceration. These alterations could all
be improved by the steamed roots of Rehmannia glutinota Libosch. (SRG) in a dose-
dependent manner. The increased MDA in the livers of the mice by CUMS exposure
could be dose-dependently reduced by SRG administration. The activities of SOD
and CAT have been significantly increased by SRG. In addition, the primary
intercellular antioxidant GSH, acting either directly or via GSH-Px to scavenge
reactive oxygen species (Voehringer 1999), has been increased to the normal level
by SRG administration.
TCM Substances in Neuropsychopharmacotherapy 469

Radix rehmanniae extract (RRE) also showed antidepressant and anxiolytic

effects in ovariectomized mice through behavior tests. RRE restored the levels of
serotonin (5-HT), dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid
(DOPAC), glutamate (Glu), gamma-Aminobutyric acid (GABA), and their related
biomarkers in different brain regions. RRE also reversed ovariectomy-induced
(OVX-induced) decrease in the expression of neurotrophins in uterus and brain
regions. Moreover, RRE restored and even enhanced estrogen receptor β (ERβ)
expression in uterus and brain (Zhou et al. 2019).
The exposure of OVX mice to the CUMS procedure for 2 weeks caused the anxiety-
and depression-like behaviors, displaying diminished sucrose intake in the sucrose
preference test (SPT), increased immobility time in the forced swimming test (FST)
and tail suspension test (TST), shorter duration in and fewer entries into the central
zone of the open field test (OFT) and into the open arms of the elevated plus maze
(EPM). Treatment with RRE increased sucrose consumption in the SPT and reduced
the immobility time in the TST. RRE treatment also increased the duration in and
number of entries into the central zone in the OPT and into the open arms in the EPM,
indicating it has antidepressant- and anxiolytic-like effects (Nakagawasai et al. 2009).
There have been more than 140 compounds isolated and characterized from
Radix Rehmanniae, including monoterpenoids, phenethyl alcohol glycosides, tri-
terpenes, flavonoid glycosides, phenolic acid glycosides, lignans, and Rehmannia
glutinosa polysaccharides, etc. (Fu and Du 2015; Li and Meng 2015; Liu 2013).
Iridoid glycosides are considered to be one of abundant monoterpenoids and respon-
sible for the pharmacological actions of Rehmanniae Radix. The monoterpenoids
include catalpol, rehmannioside A, rehmannioside B, rehmannioside C, rehmaglutin
A, rehmaglutin B, rehmaglutin D, rehmaglutin C, ajugol, rehmannioside D, and
geniposide, gentistic acid, versulin, oleanolic acid, etc.
Results revealed that the ingredients of Rehmanniae Radix were widely distrib-
uted after administration. Furthermore, catalpol, ajugol, and acetoside were easily
detected in the plasma and accepted as main active ingredients of Rehmanniae
Radix. Catalpol has been reported to exhibit protective effects on diabetes (Bao et
al. 2016; Zhou et al. 2015a), neurovascular diseases (Huang et al. 2016), osteopo-
rosis (Lai et al. 2015), breast cancer (Liu et al. 2015), ovarian cancer (Gao et al.
2014), atherosclerosis (Liu and Zhang 2015), and lung injury (Fu et al. 2014) in
animals. It has also been demonstrated that catapol was able to improve bone health
in OVX mice and to attenuate OVX induced-bone loss by decreasing Th1/Th2 ratio
via increasing the mRNA and protein expressions of T-bet and decreasing the
mRNA and protein expressions of GATA-3 (Lai et al. 2015).
Rehmannia glutinosa polysaccharides are also one of the main active constituents
of Rehmanniae Radix and composed of monosaccharides such as rhamnose, glu-
cose, galactose, mannose, xylose, and arabinose (Wang et al. 2015b). So far, it has
been demonstrated that Rehmannia glutinosa polysaccharides exhibited beneficial
activities in improving glucolipid metabolism (Wu et al. 2011; Zhou et al. 2015) and
immunity (Huang et al. 2013, 2014).
Furthermore, rehmannioside C, rehmaionoside A, and oleanolic acid (Pollier and
Goossens 2012) have been demonstrated to possess hepatoprotection activities.
470 Y. Wang and J. Li

Ajugol, gentistic acid (Liu 2013), and oleanolic acid (Anouar el et al. 2015) have the
ability of antioxidation. Versulin (Zhang et al. 2015b) and oleanolic acid (Zhang
et al. 2014b) have the capacity of inhibiting tumor growth. Oleanolic acid (Mengoni
et al. 2002) has been demonstrated to exhibit weak anti-HIV activity.
Aside from different pharmacological effects Rehmannia glutinosa polysaccha-
rides of various constituents from Radix rehmanniae, it is still seen as a herb with
tonic effects these days. It has been acknowledged that Radix rehmanniae bears with
effect of nourishing yin and is usually applied in formulae that nourishes yin to treat
patient with symptoms of yin deficiency, which partially explains the lack of clinical
trials using Radix rehmanniae for patients with psychiatric disorders, since these
disorders are usually seen as excessive syndrome or Yu syndrome (obstruction
syndrome), rather than deficient ones. Hopefully, researchers or clinicians will
consider the administration of Radix rehmanniae as a potential method for patients
with psychiatric disorders.

Bulbus Lilii (百合)

Bulbus Lilii is mainly produced in Anhui, Zhejiang, and Jiangsu provinces in China.
It is collected in autumn and washed clean. After its scale leaves are peeled off. It is
slightly scaled in boiling water and then dried. It has mild smell and tastes mildly
bitter. It is used raw or honey-fried. In TCM, it is able to enrich yin and moisten the
lung; clear heart heat and calm the mind (Teng et al. 2019).
Clinical applications in TCM

1. Syndrome of lung yin deficiency: It is used for yin deficiency and lung dryness
with heat manifested as dry cough with less sputum, hemoptysis, dry throat, and
hoarse voice.
2. Syndrome of heart yin deficiency: (1) To treat heart yin deficiency manifested as
vexation and agitation, insomnia, and profuse dreaming. (2) To treat lily disease
due to deficiency of heart yin and lung yin and malnutrition of the heart spirit,
which is manifested as blurred mind, uncontrolled emotions, bitter taste in the
mouth, dark urine, faint, and rapid pulse. Additionally, it is able to enrich stomach
yin and clear stomach heat, so it is used to treat stomachache due to stomach yin
deficiency with heat.

Recommended dosage: Decoction, 6–12 g. Honey-frying can strengthen the

efficacy of moistening the lung (Teng et al. 2019).
Recent researches:
Phytochemical researches have shown that Bulbus Lilii contains, phenols-glyc-
erides, alkaloids, flavones, amino acids, phospholipids, alkanes and other composi-
tions, and mainly of steroidal saponins and polysaccharides (Liu et al. 2017).
Researchers have demonstrated that saponins from Lilium lancifolium Thunb could
improve the disturbance of monoamine neurotransmitters in the brain of depressive rat
model, which is mainly through the three following mechanisms: 1. increasing the
TCM Substances in Neuropsychopharmacotherapy 471

DA, 5-HT in the brain of depressive rat model, and improving the dysfunction of
monoamine neurotransmitters; 2. decreasing the cortisol, adrenocorticotrophic hor-
mone in blood, reducing the expression of corticotrophin-releasing factor mRNA
(CRFmRNA) in hypothalamus; and 3. enhancing the expression of glucocorticoid
receptor mRNA (GRmRNA) and mineralcorticoid receptor mRNA (MRmRNA) in
hippocampus; attenuating the hyperactivity of the hypothalamic-pituitary-adrenal axis
(Guo et al. 2009; Guo and Li 2009).
It has also been (Huang et al. 2011) detected the changes of substance P (SP),
vasoactive intestinal peptide (VIP), and gastrins (Gas) in blood, stomach, and intestine
of depressive rats. The application of total saponins of Bulbus Lilii could increase
plasma VIP, serum, and colon tissue Gas and SP, as it alleviated the depressive
symptoms in the meantime, indicating that the total saponins of Bulbus Lilii could
improve depressive symptoms through regulation of the brain-gut peptides.
Like Radix rehmanniae, Bulbus Lilii is commonly applied in formulae nourishes
yin. In some parts of China, people even use it as a food supplement. But still,
nothing conclusive, concerning the comprehensive pharmacological effects of
Bulbus Lilii and its definite pharmacological effects among patients, has been
extracted from clinical trials or meta-analyses yet. The detailed responses from
patients with psychiatric disorders to Bulbus Lilii will require more evidence from
clinical trials with large sample size, longer duration, and follow-ups.

Hypericum perforatum/St.-John’s Wort (贯叶连翘/圣约翰草)

St. John’s wort (Hypericum perforatum L.) is named mainly due to the fact that it
flowers at the time of the summer solstice on or around St. John’s day on 24 June.
Having been administered as a remedy by a Roman military doctor as early as the
first century AD (Pöldinger 2000), St. John’s wort is stated to possess sedative and
astringent properties and has been used traditionally for the treatment of excitability,
neuralgia, sciatica, menopausal neurosis, anxiety, depression, and as a nerve tonic,
and in preparations for the treatment of wounds. More recently, in a number of
clinical double-blind trials against placebo and other antidepressants, the whole
extract of St.-John’s wort, for example, as in Jarsin coated tablets, has proved to
be effective for mild and moderate depression. Meta-analyses of reported clinical
trials of herbs in depression, anxiety, and insomnia has presented the evidence-based
efficacy of herbs: St John’s wort and saffron for unipolar depression (Sarris et al.
2011; Apaydin et al. 2016). A large meta-analysis showed that the efficacy and
safety of St John’s wort were comparable to SSRIs in mild and moderate depressive
disorder (Ng et al. 2017b) as well. Hypericum perforatum extract, including WS ®
5700, LI160, PM23, and ZE117, has been applied in clinical trials for treatment of
depression (Zirak et al. 2019). WS 5570 has been demonstrated to be effective as
paroxetine in mild to moderate MDD (Seifritz et al. 2016).
Recent researches:
The major constituents are napthodianthrones (hypericin, pseudohypericin),
phloroglucinol derivatives (hypericin, adehyperforin), flavonoids, biflaonoids,
472 Y. Wang and J. Li

proanthrocyanidins, and chlorogenic acid. A dose-response relationship between the

antidepressant efficacy of Hypericum extract and hyperforin content was confirmed
(Laakmann et al. 1998). Hyperforin activated nonselective cation transient receptor
potential channel (TRPC)6, inhibited reuptake of 5-HT and NA, modulated dendritic
spine morphology in pyramidal neurons of hippocampus, and showed BDNF-mimic
activity (Leuner et al. 2007). Hyperforin has also multiple bioactivities, inhibition of
tumor cell proliferation, angiogenesis, and inflammation and also disaggregation of
amyloid deposits in AD. Recently, the Phytochemical Absorption Prediction (PCAP)
model was applied to predict the pharmacokinetics of phytochemicals. It is
recommended that Hypericum perforatum administration occurs 2 h before meals
to provide optimal secondary health benefits associated with inhibition of postpran-
dial stress (Wise et al. 2019).
Clinical applications:
Various studies showed the efficacy and tolerability of WS ® 5570 for the treat-
ment of acute mild to moderate depression. Beneficial effects could also be
witnessed in patients with moderate and severe depression. A clinical trial had
proved that, compared with paroxetine, WS ® 5570 ensured the patients not only a
reduction in depression severity, but also a greater response and better remission
(Seifritz et al. 2016).
Side effects:
A European drug-monitoring study involving 3250 patients reported an overall
adverse events incidence of only 2.4% for the clinical use of a commercial St John
wort’s extract in the treatment of depression (Woelk et al. 1994). Undesirable effects
most commonly reported were gastrointestinal irritations (0.6%), allergic reactions
(0.5%), fatigue (0.4%), and restlessness (0.3%). A meta-analysis based on traditional
St John’s wort preparations revealed that when adverse reactions occur, they are
generally mild, transient, and similar to placebo (Linde et al. 1996).
In a review of St John’s wort preparations and adverse drug reaction (ADR), the
author noted that this incidence was some ten times less compared to synthetic
antidepressants (Schulz 2002). The most common adverse events (1 per 300,000
treated cases) among the spontaneous reports in a German ADR recording system
between October 1991 and December 1999 involved reactions of the skin exposed to
light (27 incidents) that was followed by increased bleeding time with coumarin-type
oral anticoagulants (16 reports), 8 incidents of breakthrough bleeding with oral
contraceptives, and 7 reported decreases in cyclosporine concentrations in organ
transplant recipients. Further investigations in volunteers determined that photo-
sensitisation occurred only when doses of 2–4 g/day of a commercial St John’s wort
preparation (equivalent to approximately 5–10 mg of the hypericin that causes this
phenomenon) were taken. Analysis of available epidemiological data showed that
though photosensitization had the highest incidence of ADR reports, severe photo-
toxic reactions comparable to cases documented for grazing animals have never been
reported in humans. The 27 phototoxicity reports relative to the incidence of sun
exposure damage in the population do not warrant regulatory intervention. The seven
reports of decreased cyclosporine concentrations represent a much higher incidence
of ADR in the relatively small transplant patient population (Schulz 2002). It was
TCM Substances in Neuropsychopharmacotherapy 473

discussed at that time that cyclosporine concentrations could indicate dosage adjust-
ment with therapeutic drug monitoring; in that case the interaction would be con-
sidered clinically significant.
A plethora of clinical interaction studies and case reports were published in causal
association St John’s wort’s extracts with high-hyperforin content (Chrubasik-
Hausmann et al. 2019; Soleymani et al. 2017; ESCOP 2018). As concluded by the
EMA/HMPC, hyperforin is mainly responsible for pharmacokinetic interactions
with other drug substances, which are metabolised by certain CYP450 isoenzymes
and transported by ABCB1 (P-Glycoprotein, P-gp). Hence, with regard to pharma-
cokinetic interactions, St John’s wort’s products have to consider the daily hyper-
forin dose, which led to the different low-hyperforin preparations (
1 mg/d) and
high-hyperforin ones (>1 mg/d) (ESCOP 2018). In a recently finalized risk assess-
ment of the EMA, it was stated that adequate studies with extracts with low-
hyperforin content are available which could justify exemptions with regard to
contraindications.
Pharmacokinetic interactions with St John’s wort’s preparations correlate directly
with the daily dose of hyperforin (Mueller et al. 2006). The induction of PXR-related
metabolic enzymes and transporters cannot be excluded at daily dosages >1 mg
hyperforin. To avoid pharmacokinetic interactions and to contribute to St John’s
Wort’s product safety, low-hyperforin SJW extracts should be recommended for the
therapeutic use. At daily dosages of maximum 1 mg hyperforin, no clinically
relevant pharmacokinetic interactions are to be expected (ESCOP 2018; EMA/
HMPC 2018; Zahner et al. 2019).
Precautions: Cautions should be taken when applied for pregnant and breast-
feeding women.
St. John’s wort (Hypericum perforatum) contains hypericin and hyperforin as
well as flavonoids, such as quercetin. It has been recommended by midwives for
postpartum depression (Allaire et al. 2000; Dennehy et al. 2010). Both hypericin and
hyperforin are poorly excreted into breast milk; no other components have been
measured in milk. One study found a slightly increased frequency of colic, drows-
iness, and lethargy among breastfed infants whose mothers were taking St. John’s
wort, but none of the effects were severe or required treatment. Most reports were
related to breastfeeding older infants, rather than during the first 2 months postpar-
tum or preterm infants when they are more susceptible to adverse reactions.
Conflicting information still exists on whether St. John’s wort can reduce prolactin
levels or the maternal milk supply. Since there is little publications concerning St.
John’s wort application during breastfeeding, an alternate drug may be preferred,
especially while nursing a newborn or preterm infant (Clauson et al. 2008).

Formulae of TCM

A formula of TCM is usually a combination of several herbs or medicinals. The

combination of Chinese medicinals is selectively combining two or more medic-
inals for appropriate clinical application, which is usually based on the specific
474 Y. Wang and J. Li

needs for different syndromes and diseases and is guided by certain combination
principles of TCM.
The reasons that Chinese medicinals are usually combined are listed as follows:
The efficacy of one medicinal is too limited to treat complex conditions and is not
powerful enough to deal with severe conditions; some medicinals are toxic, so it is
not safe to use singly;
Individual medicinal may have different efficacies, which may do harm to human
body if it is not necessary for the condition.
Hence, the combination of Chinese medicinals, based on the need of conditions and
requirement of medicinals and guided by certain combination rules, can enhance the
medicinal power to promote clinical efficacy. On the other hand, it can relieve or
eliminate the toxicity of medicinals to restrict the harmful effects induced by herbs, but
unnecessary for the conditions and to make medicinals safer (Chen et al. 2017). Some
experts consider the different herbs or medicinals from a formula of TCM as pieces of
a chess; with the right coordination and strategy, these pieces could overwhelm the
counterpart (the diseases). Yet in clinical practice, the strategies applied are far more
complicated than that in the metaphor, considering the fact that different origins,
processing methods, or different dosage of even one herb/medicinal could change
the entire therapeutic effect of a formula, not to mention different perspectives about
the original dosage and production area of genuine medicinals held by experts
nowadays, since many formulae have been documented for thousands of years. As
such, it remains a challenge to elaborate the underlying mechanism of a formula of
TCM, even with the help from the most advanced and sophisticated equipment.
The following formulae were carefully selected, with the acknowledgment of
bearing a therapeutic effect for psychiatric disorders. We hope the following content
may shed light on understanding the formation and the application of formulae of
TCM in psychiatry.

Yueju Pill (越鞠丸)

This formula resolves many types of stagnation or clumping caused by long-term

constraint. It thereby allows the qi to escape the bonds of its restraint, hence the
name.
Source: Teaching of [Zhu] Dan-xi (Dan xi xin fa)
Ingredients:
Rhizoma Atractylodis (cang zhu)
Radix Ligustici Chuanxiong (chuan xiong)
Rhizoma Cyperi Rotundi (xiang fu)
Fructus Gardeniae Jasminoidis (shan zhi zi)
Massa Fermentata (shen qu)
Preparation:
Grind equal amounts of the ingredients into a fine powder and form into pills with
water. Take 6–9 g with warm water. May also be prepared as a decoction with 6–12 g
of each ingredient.
TCM Substances in Neuropsychopharmacotherapy 475

Actions: Promotes the movement of qi and resolves stagnation.

Indications:
The “Six Yu Syndrome,” which manifested as distension in the chest and
abdomen, belching, acid regurgitation, vomiting, indigestion. Distention in the
chest and abdomen, along with indigestion, is the key symptom of “Six Yu Syn-
drome.” Usually, a triggering reason for these symptoms is expected to found.
Pharmacodynamics:
More recently, a relative high dose of Yueju demonstrated rapid antidepressant
efficacy in both preclinical and clinical studies (Wu et al. 2015; Xue et al. 2013).
Results from an experimental investigation using animals-uncovered ketamine-like
rapid antidepressant effects of Yueju: acute administration of Yueju rapidly attenu-
ated depression-like symptoms in learned helplessness paradigm (Taylor et al. 2006)
and novelty-suppressed feeding test (Zhang et al. 2015c), tasks which normally
require chronic treatment of SSRI to exhibit antidepressant efficacy (Wang et al.
2015a). Evidence indicated that the antidepressant effect of Yueju as well as keta-
mine could sustain for 24 h after a single administration of Yueju in ICR mouse
strain (Xue et al. 2013).
Mechanisms:
It has been well documented that chronic SSRI treatment activates transcription
factors, including CREB (cAMP response element binding protein), leading to an
increase in the expression of neurotrophic factors, including BDNF, and their
receptors (Nibuya et al. 1996; Czéh and Simon 2005).
Studies showed that, without changes in CREB activation or BDNF mRNA
expression, BDNF protein in the hippocampus is up-regulated quickly after keta-
mine or Yueju treatment in both KunMing (KM) and ICR mice. This non-
transcriptional BDNF up-regulation was thus responsible for the antidepressant
response immediately post Yueju or ketamine administration. And the antidepressant
effects of Yueju or ketamine last for 1 or 5 days in ICR and KM mice, respectively.
One day after Yueju and ketamine treatment, there was increased expression of total
and phosphorylated CREB protein in KM but not ICR mice. This is followed by up-
regulation of BDNF mRNA expression, likely via CREB signaling for Yueju and
mTOR signaling for ketamine (Xue et al. 2016).
CREB signaling, activated by one of the classic upstream activator protein kinase
A (PKA), regulates expression of genes that promote synaptic and neural plasticity,
including proteins for spine formation (Xue et al. 2016; Finkbeiner et al. 1997). Both
human and experimental studies supported the link of PKA-CREB signaling to
depression and its treatment (Liu et al. 2016b). Activation of PKA-CREB signaling
is capable to upregulate BDNF expression.
Additionally, an increasing number of studies suggest N-methyl- D-aspartate
(NMDA) receptors (NMDAR) are prefoundly associated with depression (Ates-
Alagoz and Adejare 2013; Kiss et al. 2012). NMDARs are glutamate ionotropic
receptors that play an important role in synaptic transmission and plasticity. Some
NMDAR antagonists were identified to rapidly induce antidepressant effect by
instant upregulation of expression of BDNF and spine formation (Motin and
Yasnetsov 2015; Kaniakova et al. 2012). Both ketamine and Yueju rapidly reversed
476 Y. Wang and J. Li

the depression-like responses in the chronic mild stress exposed mice and remained
effective at 5 and 6 days postdrug administration, respectively (Tang et al. 2015).
Studies available have demonstrated that the routine dose of Yueju has significant
antidepressant efficacy and effectively attenuated behavioral deficits in chronic
learned helpless animals. Restoration of neural plasticity via CREB signaling is
crucially involved in the antidepressant effect of Yueju, whereas the inhibition of
NMDA signaling is required and part of the mechanism of antidepressant efficacy of
Yueju (Zou et al. 2017).

Xiao Buxin Tang Decoction (小补心汤)

Source: Auxiliary
Verse On Drugs And Methods For Zangfu Organs (Fu xing jue wu zang yong yao
fa yao)
Ingredients:
Haematitum (dai zhe shi)
Flos Inulae (xuan fu hua)
Folium Phyllostachydis Henonis (zhu ye)
Semen Sojae Preparatum (dan dou chi)
Preparation: Heat the Haematitum till it turns red, then spray it with vinegar.
Grind the Haematitum after heating and spaying for 3 times. 18 g of Haematitum,
Flos Inulae, Folium Phyllostachydis Henonis, respectively, along with 9 g of Semen
Sojae Preparatum are decocted together.
Indications: palpitation due to blood and qi deficiency, irritation, sweating,
periodic low mood, and irregular pulse.
Mechanisms:
Xiaonbuxin-Tang is a decoction with nearly 1000-year history. These years, up to
22 compounds have been isolated from the total flavonoids (XBXT-2) isolated from
the extract of Xiaobuxin-Tang(XBXT) including 21 flavone compounds: japonicins A
and B, onpordin, 30 -O-methylorobol, glycitein, nepetin, patuletin, genistein, luteolin,
daidzein, quercetin, apigenin, isoquercitrin, genistin, nepitrin, quercimeritrin, daidzin,
patulitrin, quercetagitrin, 3-glucosyl isorhamnetin, isoorientin, and an organic acid
protocatechuic acid. Additionally, the rough HPLC fingerprint of the extract demon-
strated that the major constituents of XBXT-2 were flavones, flavonols, isoflavones,
and their glycosides. HPLC analysis also revealed that the flavones and flavonols were
primary derived from Flos Inulae, as well as the isoflavones were derived from Semen
Sojae Preparatum, and the rest of flavones came from Folium Phyllostachydis Henonis
(An et al. 2008a).
Studies indicated that acute treatment with XBXT-2 produced serotonergic, but
not noradrenergic activation. In addition, chronic XBXT-2 (25, 50 mg/kg, p.o.,
28 days) treatments significantly reversed the depressive-like behaviors in chron-
ically mildly stressed (CMS) rats, including the reduced sucrose preference,
deficient locomotor activity, and prolonged latency to novelty-suppressed feeding
(An et al. 2008b).
TCM Substances in Neuropsychopharmacotherapy 477

In animal models, researchers found that the stress hormones including cortico-
sterone and ACTH levels in rats were significantly increased by chronic stress
exposure, as well as the decreased hippocampal glucocorticoid receptors (GRs)
expression, which together manifested the hyperactivity and impaired feedback
inhibition of HPA axis in chronically stressed rats. Chronic administration of
XBXT-2 (25, 50 mg kg1, p.o., 28 days, the effective doses for behavioral
responses) significantly decreased serum corticosterone level and its upstream stress
hormone adrenocorticotropic hormone (ACTH) level in chronically stressed rats.
Furthermore, western blotting result demonstrated XBXT-2 treatment ameliorated
stress-induced decrease of GRs expression in hippocampus, an important target
involved in the hyperactivity of HPA axis (An et al. 2011).
The pretreatment with lipopolysaccharide (LPS) significantly increased the
immobility time in TST and FST in mice, as well as the brain levels of IL-1β and
TNF-α. XBXT-2 (25, 50, and 100 mg/kg, p.o.) administration decreased the duration
of immobility in TST and FST and normalized the cytokines levels. Findings also
demonstrated that XBXT-2 at dose of 100 mg/kg was more efficacious than that of
200 mg/kg, which was also in line with our behavioral results which showed that
XBXT-2 exhibited an inverse U-shaped dose-response curve in acute and subchronic
models (An et al. 2015).
The increase of neurogenesis, as well as expression of BDNF and pCREB in
hippocampus, may be one of the molecular and cellular mechanisms underlying the
antidepressant action of XBXT-2. Also, immunohistochemistry results showed that
concomitant administration of XBXT-2 (25, 50 mg/kg, p.o., 28 days, the effective doses
for behavioral responses) significantly increased hippocampal neurogenesis in chroni-
cally stressed rats. Furthermore, XBXT-2 treatment reserved stress-induced decrease of
hippocampal BDNF and pCREB (Ser133) expression, two important factors which
were closely related to hippocampal neurogenesis. The increase in hippocampal BDNF
and pCREB expression induced by XBXT-2 treatment might be the early potent
stimulation for the increase of hippocampal neurogenesis (An et al. 2008a).
Xiao Buxin Tang Decoction was designed to treat palpitation, irritation, sweating,
irregular pulse, and accompanied periodic low mood, most of which are symptoms
related to heart diseases. It is not surprising that studies and clinical trials concerning
Xiao Buxin Tang Decoction have been focused on symptoms, like palpitation,
arrhythmia, and the underlying mechanisms. Nevertheless, it is not uncommon to
see patients with all the aforementioned symptoms and a normal EKG, which may
indicate a possible diagnosis of somatoform disorder. It is suggested that future
clinical research should put more emphasis on the application of Xiao Buxin Tang
Decoction on patients with psychiatric disorders.

Bulbus Lilii and Radix Rehmanniae Tang Decoction (百合地黄汤)

Source: Synopsis of Golden Chamber (jin kui yao lue)

Ingredients:
Bulbus Lilii (bai he)
478 Y. Wang and J. Li

Radix Rehmanniae Raw (sheng di huang)

Preparation: Keep Bulbus Lilii (7 lily bulbs) soaked with water overnight, dispose
of the supernatant and foam; decoct Bulbus Lilii with fresh spring water (about
400 ml) till half the water remains; dispose of the residues of lily bulbs and add
squeezed juice of Radix Rehmanniae Raw (200 ml); keep decocted until 300 ml
decoction remains.
Indications: Lily disease-syndrome of yin deficiency of heart and lung, with
internal heat.
Decoction of Bulbus Lilii and Radix Rehmanniae (Baihe Dihuang Tang) has
long been used as tonics for nourishing heart and lung, clearing heat, and cooling
blood in the treatment of mental instability, absent mindedness, dysphoria, and
depression (Liu 2014; Zhou et al. 2018; Chen et al. 2012). It was designed for the
“lily disease,” which was initially documented in Synopsis of the Golden Chamber.
The characteristic manifestations of “lily disease” include fluctuated appetite,
frequent silence, restlessness, confused cold and heat body sensation, bitterness
in the mouth and dark urine, red tongue body and less tongue coating, weak and
thready pulse, some of which could also be seen as somatic symptoms among
patients with psychiatric disorders.
Pharmacodynamics:
Both Bulbus Lilii and Radix Rehmanniae have been demonstrated effective for
depression. Hence, undoubtedly, decoction of Bulbus Lilii and Radix Rehmanniae has
been expected to be capable of alleviating depressive symptoms as well. The admin-
istration of decoction of Bulbus Lilii and Radix Rehmanniae significantly reduced the
immobility time in both the forced swim test (FST) and the tail suspension test (TST)
among depressive mice, without increasing the number of crossings and rearings in the
open field test, suggesting the reduction of immobility time elicited by the decoction in
FST and TST was not related to a psychostimulant effect, but rather an antidepressant-
like effect of the decoction (Chi et al. 2019).
Mechanisms:
The application of fresh powder of Bulbus Lilii and Radix Rehmanniae could
increase the weight and the consumption of sugar water and improve the behavioral
score, increase erythrocytes SOD activity and decrease MDA level of plasma,
increase the content of 5-HT, NE and DA of brain homogenate, and improve the
pathological changes of thymus and spleen of chronic stress induced depression
animal models (Miao et al. 2019).
Application for persons in psychological suboptimal health state:
The decoction of Bulbus Lilii and Radix Rehmanniae is also found effective to
improve the mental status of people in the psychological suboptimal health state. The
concept of suboptimal health was first proposed in 1980s. The suboptimal health
status (SHS) was described as an physical state between health and disease (Yan
et al. 2009). The psychological sub-optimal health state (PSHS) is one of the sub-
types which is closely related to depression, anxiety, fear, memory loss, lack of
concentration, and other psychological symptoms. PSHS is an intermediate state
between mental health and mental illness (Jiang 2010). Populations of PSHS have
TCM Substances in Neuropsychopharmacotherapy 479

been sharply increasing, mainly resulting from factors, such as excessive stress of
work and life styles, social failure stress (Dunstan et al. 2013).
Researchers has proved that the SCL-90 scores of PSHS persons could be
significantly decreased after decoction of Bulbus Lilii and Radix Rehmanniae
administrated for 4 weeks, indicating that the decoction was of a significant thera-
peutic effect on the improvement of PSHS (Meng et al. 2018).
It has been noticed that constituents of different herbs and medicinals in a
formula change because of the intermolecular chemical reactions that form novel
molecules or nanostructures, which are mainly governed by electrostatic and
hydrophobic interactions during the decoction procedure (Li et al. 2019). Bulbus
Lilii and Radix Rehmanniae Tang Decoction, therefore, are not appropriate to be
comprehended or applied as merely combination of Bulbus Lilii and Radix
Rehmanniae. Clinical trials with well-designed methodology, large sample size,
and enough follow-ups are required to determine the effectiveness of Bulbus Lilii
and Radix Rehmanniae Tang Decoction for psychiatric disorders.

Conclusion

This chapter makes a brief introduction and description of a few herbs, medicinals, and
formulae of TCM and their applications in psychiatry. This chapter not only includes the
conventional understanding of herbs and formulae, but also provides information of the
latest researches accordingly. It has been the complexity and diversity of herbs, medic-
inals, and formulae that make it remains a huge challenge to depict the underlying
mechanism of herbs and formulae of TCM in psychiatry, some of which stays myste-
rious, let alone other well-known, and less-studied methods of TCM that have been
applied to alleviates symptoms of psychiatric disorders. For instance, acupuncture,
moxibustion, and cupping have been suggested to ease the somatic symptoms of
depression, hysteria, etc. Additional large scale randomized controlled clinical trials
and sophisticated pharmacology studies are still need to be performed at present.
Opportunities permitting, we do hope that more knowledge concerning theories and
clinical methods of TCM could be shared, understood, and accepted in shortly coming
future.

Cross-References

▶ Ginseng and Ginsenosides in Depression

▶ Hypericum and Depression
▶ TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus
on Depression
▶ Tranquilizer/Anxiolytics: Lavender Oil
480 Y. Wang and J. Li

References
Abdel-Kader MS, Abulhamd AT, Hamad AM, et al. Evaluation of the hepatoprotective effect of
combination between Hinokiflavone and Glycyrrhizin against CCl4 induced toxicity in rats.
Saudi Pharm J. 2018;26:496–503.
Abdullaev Jafarova F, Caballero-Ortega H, Riveron-Negrete L, et al. In vitro evaluation of the
chemopreventive potential of saffron. Rev Investig Clin. 2002;54:430–6.
Abe K, Saito H. Effects of saffron extract and its constituent crocin on learning behaviour and long-
term potentiation. Phytother Res. 2000;14:149–52.
Aguiar AS Jr, Castro AA, Moreira EL, et al. Short bouts of mild-intensity physical exercise improve
spatial learning and memory in aging rats: involvement of hippocampal plasticity via AKT,
CREB and BDNF signaling. Mech Ageing Dev. 2011;132(11–12):560–7. https://doi.org/10.
1016/j.mad.2011.09.005.
Allaire AD, Moos MK, Wells SR. Complementary and alternative medicine in pregnancy: a survey
of North Carolina certified nurse-midwives. Obstet Gynecol. 2000;95:19–23.
An L, Zhang YZ, Yu NJ, et al. The total flavonoids extracted from Xiaobuxin-Tang up-regulate the
decreased hippocampal neurogenesis and neurotrophic molecules expression in chronically
stressed rats. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008a;32(6):1484–90. https://doi.
org/10.1016/j.pnpbp.2008.05.005.
An L, Zhang YZ, Yu NJ, et al. Role for serotonin in the antidepressant-like effect of a flavonoid
extract of Xiaobuxin-Tang. Pharmacol Biochem Behav. 2008b;89(4):572–80. https://doi.org/10.
1016/j.pbb.2008.02.014.
An L, Zhang YZ, Liu XM, et al. Total flavonoids extracted from Xiaobuxin-Tang on the hyperac-
tivity of hypothalamic-pituitary-adrenal axis in chronically stressed rats. Evid Based Comple-
ment Alternat Med. 2011:367619. https://doi.org/10.1093/ecam/nep218.
An L, Li J, Yu ST, et al. Effects of the total flavonoid extract of Xiaobuxin-Tang on depression-like
behavior induced by lipopolysaccharide and proinflammatory cytokine levels in mice. J
Ethnopharmacol. 2015;163:83–7. https://doi.org/10.1016/j.jep.2015.01.022.
Andrade C. A critical examination of studies on curcumin for depression. J Clin Psychiatry. 2014;75
(10):e1110–2. https://doi.org/10.4088/JCP.14f09489.
Anouar el H, Zakaria NS, Alsalme A, Shah SA. α-Glucosidase activity of oleanolic acid and its
oxidative metabolites: DFT and Docking studies. Mini-Rev Med Chem. 2015;15(14):1148–58.
https://doi.org/10.2174/1389557515666150724154044.
Apaydin EA, Maher AR, Shanman R, et al. A systematic review of St. John’s wort for major
depressive disorder. Syst Rev. 2016;5(1):148. Published 2016 Sep 2. https://doi.org/10.1186/
s13643-016-0325-2.
Ates-Alagoz Z, Adejare A. NMDA receptor antagonists for treatment of depression. Pharmaceuti-
cals (Basel). 2013;6(4):480–499. Published 2013 Apr 3. https://doi.org/10.3390/ph6040480
Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions.
Biochem Pharmacol. 1999;58(11):1685–93. https://doi.org/10.1016/s0006-2952(99)00212-9.
Bai S, Zhang X, Chen Z, et al. Insight into the metabolic mechanism of Diterpene Ginkgolides on
antidepressant effects for attenuating behavioural deficits compared with venlafaxine. Sci Rep.
2017;7(1):9591. https://doi.org/10.1038/s41598-017-10391-1.
Bai M, Yao GD, Ren Q, et al. Triterpenoid saponins and flavonoids from licorice residues with anti-
inflammatory activity. Ind Crop Prod. 2018;125:50–8.
Bao Q, Shen X, Qian L, Gong C, Nie M, Dong Y. Anti-diabetic activities of catalpol in db/db
mice. Korean J Physiol Pharmacol. 2016;20(2):153–60. https://doi.org/10.4196/kjpp.2016.
20.2.153.
Bao F, Bai HY, Wu ZR, Yang ZG. Phenolic compounds from cultivated Glycyrrhiza uralensis and
their PD-1/PD-L1 inhibitory activities [Published online ahead of print, 2019 Mar 25]. Nat Prod
Res. 2019;1–8. https://doi.org/10.1080/14786419.2019.1586698
Bhat A, Mahalakshmi AM, Ray B, et al. Benefits of curcumin in brain disorders. Biofactors. 2019;
https://doi.org/10.1002/biof.1533.
TCM Substances in Neuropsychopharmacotherapy 481

Bishnoi M, Chopra K, Rongzhu L, et al. Protective effect of curcumin and its combination with
piperine (bioavailability enhancer) against haloperidol-associated neurotoxicity: cellular and
neurochemical evidence. Neurotox Res. 2011;20(3):215–25. https://doi.org/10.1007/s12640-
010-9229-4.
Boonlert W, Benya-Aphikul H, Umka Welbat J, Rodsiri R. Ginseng extract G115 attenuates
ethanol-induced depression in mice by increasing brain BDNF levels. Nutrients. 2017;9
(9):931. Published 2017 Aug 24. https://doi.org/10.3390/nu9090931
Caccamo A, Maldonado MA, Bokov AF, et al. CBP gene transfer increases BDNF levels and
ameliorates learning and memory deficits in a mouse model of Alzheimer’s disease. Proc Natl
Acad Sci U S A. 2010;107(52):22687–92. https://doi.org/10.1073/pnas.1012851108.
Canales-Aguirre AA, Gomez-Pinedo UA, Luquin S, et al. Curcumin protects against the oxidative
damage induced by the pesticide parathion in the hippocampus of the rat brain. Nutr Neurosci.
2012;15(2):62–9. https://doi.org/10.1179/1476830511y.0000000034.
Cao ZY. The clinical effect of glycyrrhizic acid based on the inflammatory mechanism of depres-
sion. Shanghai: Naval Medical University; 2019.
Cao G, Su P, Zhang S, et al. Ginsenoside Re reduces Aβ production by activating PPARγ to inhibit
BACE1 in N2a/APP695 cells. Eur J Pharmacol. 2016;793:101–8.
Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug
action: reactivation of developmental plasticity. Dev Neurobiol. 2010;70(5):289–97. https://doi.
org/10.1002/dneu.20758.
Chen XW, Serag ES, Sneed KB, et al. Clinical herbal interactions with conventional drugs: from
molecules to maladies. Curr Med Chem. 2011;18(31):4836–50. https://doi.org/10.2174/
092986711797535317.
Chen ML, Gao J, He XR, Chen Q. Involvement of the cerebral monoamine neurotransmitters
system in antidepressant-like effects of a chinese herbal decoction, baihe dihuang tang, in mice
model. Evid Based Complement Alternat Med. 2012;2012:419257. https://doi.org/10.1155/
2012/419257.
Chen CX, Wang XB, Nie H, et al. Pharmacology of Chinese Meteria Medica. Beijing: China Press
of Traditional Chinese Medicine; 2017.
Chen J, Li M, Chen L, et al. Effects of processing method on the pharmacokinetics and tissue
distribution of orally administered ginseng. J Ginseng Res. 2018;42(1):27–34. https://doi.org/
10.1016/j.jgr.2016.12.008.
Chen P, Hei M, Kong L, et al. One water-soluble polysaccharide from Ginkgo biloba leaves with
antidepressant activities via modulation of the gut microbiome. Food Funct. 2019;10(12):8161–
71. https://doi.org/10.1039/c9fo01178a.
Cheng RF, Hua B, Jing J, Xue MQ, Zhao WH, Fan ZZ, et al. Modulation of the apoptotic protein
expression in hippocampus is associated with the antidepressant effects of licorice
flavonoids from Glycyrrhiza uralensis in rats. Pharmacol Clin Chinese Materia Medica.
2014;30(2):69–72.
Chi X, Wang S, Baloch Z, et al. Research progress on classical traditional Chinese medicine formula
Lily Bulb and Rehmannia Decoction in the treatment of depression. Biomed Pharmacother.
2019;112:108616. https://doi.org/10.1016/j.biopha.2019.108616.
Choi S, Lee JH, Oh S, Rhim H, Lee SM, Nah SY. Effects of ginsenoside Rg2 on the 5-HT3A
receptor-mediated ion current in Xenopus oocytes. Mol Cell. 2003;15(1):108–13.
Choi YJ, Yoon Y, Choi HS, et al. Effects of medicinal herb extracts and their components on
steatogenic hepatotoxicity in Sk-hep1 cells. Toxicol Res. 2011;27(4):211–6. https://doi.org/10.
5487/TR.2011.27.4.211.
Chrubasik-Hausmann S, Vlachojannis J, McLachlan AJ. Understanding drug interactions with St
John’s wort (Hypericum perforatum L.): impact of hyperforin content. J Pharm Pharmacol.
2019;71(1):129–38. https://doi.org/10.1111/jphp.12858.
Clauson KA, Santamarina ML, Rutledge JC. Clinically relevant safety issues associated with St.
John’s wort product labels. BMC Complement Altern Med. 2008;8:42. Published 2008 Jul 17.
https://doi.org/10.1186/1472-6882-8-42
482 Y. Wang and J. Li

Cole GM, Frautschy SA. Docosahexaenoic acid protects from amyloid and dendritic pathology in
an Alzheimer’s disease mouse model. Nutr Health. 2006;18(3):249–59. https://doi.org/10.1177/
026010600601800307.
Conboy L, Foley AG, O’Boyle NM, et al. Curcumin-induced degradation of PKC delta is
associated with enhanced dentate NCAM PSA expression and spatial learning in adult and
aged Wistar rats. Biochem Pharmacol. 2009;77(7):1254–65. https://doi.org/10.1016/j.bcp.
2008.12.011.
Czéh B, Simon M. Neuroplaszticitás és depresszió [Neuroplasticity and depression]. Psychiatr
Hung. 2005;20(1):4–17.
da Costa IM, Freire MAM, de Paiva Cavalcanti JRL, et al. Supplementation with Curcuma longa
reverses neurotoxic and behavioral damage in models of Alzheimer’s disease: a systematic
review. Curr Neuropharmacol. 2019;17(5):406–21. https://doi.org/10.2174/
0929867325666180117112610.
Dai MM, Wu H, Li H, et al. Effects and mechanisms of Geniposide on rats with adjuvant arthritis.
Int Immunopharmacol. 2014;20(1):46–53. https://doi.org/10.1016/j.intimp.2014.02.021.
Dai CX, Hu CC, Shang YS, et al. Role of Ginkgo biloba extract as an adjunctive treatment of elderly
patients with depression and on the expression of serum S100B. Medicine. 2018;97(39):e12421.
https://doi.org/10.1097/MD.0000000000012421.
Daverey A, Agrawal SK. Curcumin alleviates oxidative stress and mitochondrial dysfunction in
astrocytes. Neuroscience. 2016;333:92–103. https://doi.org/10.1016/j.neuroscience.2016.07.012.
Daverey A, Agrawal SK. Pre and post treatment with curcumin and resveratrol protects astrocytes after
oxidative stress. Brain Res. 2018;1692:45–55. https://doi.org/10.1016/j.brainres.2018.05.001.
de Sousa CN, Meneses LN, Vasconcelos GS, et al. Reversal of corticosterone-induced BDNF
alterations by the natural antioxidant alpha-lipoic acid alone and combined with desvenlafaxine:
emphasis on the neurotrophic hypothesis of depression. Psychiatry Res. 2015;230(2):211–9.
https://doi.org/10.1016/j.psychres.2015.08.042.
Dennehy C, Tsourounis C, Bui L, King TL. The use of herbs by California midwives. J Obstet Gynecol
Neonatal Nurs. 2010;39(6):684–93. https://doi.org/10.1111/j.1552-6909.2010.01193.x.
Diamond BJ, Bailey MR. Ginkgo biloba: indications, mechanisms, and safety. Psychiatr Clin North
Am. 2013;36(1):73–83. https://doi.org/10.1016/j.psc.2012.12.006.
Dohare P, Garg P, Sharma U, et al. Neuroprotective efficacy and therapeutic window of curcuma oil:
in rat embolic stroke model. BMC Complement Altern Med. 2008;8:55. https://doi.org/10.1186/
1472-6882-8-55. PMID: 18826584; PMCID: PMC2573880
Du Y, Fu M, Wang YT, Dong Z. Neuroprotective effects of ginsenoside Rf on amyloid-β-induced
neurotoxicity in vitro and in vivo. J Alzheimers Dis. 2018;64(1):309–22. https://doi.org/10.
3233/JAD-180251.
Dunstan RH, Sparkes DL, Roberts TK, Crompton MJ, Gottfries J, Dascombe BJ. Development of a
complex amino acid supplement, Fatigue Reviva™, for oral ingestion: initial evaluations of
product concept and impact on symptoms of sub-health in a group of males. Nutr J.
2013;12:115. Published 2013 Aug 8. https://doi.org/10.1186/1475-2891-12-115
EMA/HMPC. Assessment report on Hypericum perforatum L., herba Draft EMA/HMPC/244315/
2016. 2018. Available from: https://www.ema.europa.eu/en/documents/herbal-report/draft-assess
ment-report-hypericum-perforatum-l-herba-revision-1_en.pdf
Erickson KI, Prakash RS, Voss MW, et al. Brain-derived neurotrophic factor is associated with age-
related decline in hippocampal volume. J Neurosci. 2010;30(15):5368–75. https://doi.org/10.
1523/JNEUROSCI.6251-09.2010.
ESCOP. Hyperici herba – St. John’s Wort. European Scientific Cooperative on Phytotherapy
(ESCOP). 2018;2018:1–87. Available from: https://escop.com/downloads/hypericum-2018/
Fan ZZ, Zhao WH, Guo J, et al. Antidepressant activities of flavonoids from Glycyrrhiza uralensis
and its neurogenesis protective effect in rats. Acta Pharm Sin. 2012;47(12):1612–7.
Fan C, Song Q, Wang P, Li Y, Yang M, Yu SY. Neuroprotective effects of ginsenoside-Rg1 against
depression-like behaviors via suppressing glial activation, synaptic deficits, and neuronal
apoptosis in rats. Front Immunol. 2018;9:2889. https://doi.org/10.3389/fimmu.2018.02889.
TCM Substances in Neuropsychopharmacotherapy 483

Fan C, Song Q, Wang P, et al. Neuroprotective effects of Curcumin on IL-1β-induced neuronal

apoptosis and depression-like behaviors caused by chronic stress in rats. Front Cell Neurosci.
2019;12:516. Published 2019 Jan 7. https://doi.org/10.3389/fncel.2018.00516
Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME. CREB: a major
mediator of neuronal neurotrophin responses. Neuron. 1997;19(5):1031–47. https://doi.org/10.
1016/s0896-6273(00)80395-5.
Frank MG, Hendricks SE, Johnson DR, Wieseler JL, Burke WJ. Antidepressants augment natural
killer cell activity: in vivo and in vitro. Neuropsychobiology. 1999;39(1):18–24. https://doi.org/
10.1159/000026555.
Frautschy S. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits
and neuropathology. Neurobiol Aging. 2001;22(6):993–1005. https://doi.org/10.1016/s0197-
4580(01)00300-1.
Freitas AE, Machado DG, Budni J, et al. Fluoxetine modulates hippocampal cell signaling
pathways implicated in neuroplasticity in olfactory bulbectomized mice. Behav Brain Res.
2013;237:176–84. https://doi.org/10.1016/j.bbr.2012.09.035.
Fu G, Du X. Research advance on chemical constituents and pharmacological activities of
Rehmannia glutinosa. China Med Pharm. 2015;5(15):21–3.
Fu Y, Liu B, Liu J, Liu Z, Liang D, Li F, Li D, Cao Y, Zhang X, Zhang N, Yang Z. Geniposide, from
Gardenia jasminoides Ellis, inhibits the inflammatory response in the primary mouse macro-
phages and mouse models. Int Immunopharmacol. 2012;14(4):792–8. https://doi.org/10.1016/j.
intimp.2012.07.006. Epub 2012 Aug 9. PMID: 22878137.
Fu K, Piao T, Wang M, et al. Protective effect of catalpol on lipopolysaccharide-induced acute lung injury
in mice. Int Immunopharmacol. 2014;23(2):400–6. https://doi.org/10.1016/j.intimp.2014.07.011.
Fukuchi K, Okudaira N, Adachi K, et al. Antiviral and antitumor activity of licorice root extracts. In
Vivo. 2016;30(6):777–85. https://doi.org/10.21873/invivo.10994.
Ganguli M, Chandra V, Kamboh MI, et al. Apolipoprotein E polymorphism and Alzheimer disease.
Arch Neurol. 2000;57(6):824. https://doi.org/10.1001/archneur.57.6.824.
Gao N, Tian JX, Shang YH, Zhao DY, Wu T. Catalpol suppresses proliferation and facilitates
apoptosis of OVCAR-3 ovarian cancer cells through upregulating microRNA-200 and down-
regulating MMP-2 expression. Int J Mol Sci. 2014;15(11):19394–19405. Published 2014 Oct
24. https://doi.org/10.3390/ijms151119394
Garcia R. Stress, metaplasticity, and antidepressants. Curr Mol Med. 2002;2(7):629–38. https://doi.
org/10.2174/1566524023362023.
Garcia-Alloza M, Borrelli LA, Rozkalne A, et al. Curcumin labels amyloid pathologyin vivo,
disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model.
J Neurochem. 2007;102(4):1095–104. https://doi.org/10.1111/j.1471-4159.2007.04613.x.
Georgiadou G, Tarantilis PA, Pitsikas N. Effects of the active constituents of Crocus Sativus L.,
crocins, in an animal model of obsessive-compulsive disorder. Neurosci Lett. 2012;528
(1):27–30. https://doi.org/10.1016/j.neulet.2012.08.081.
Ghadrdoost B, Vafaei AA, Rashidy-Pour A, et al. Protective effects of saffron extract and its active
constituent crocin against oxidative stress and spatial learning and memory deficits induced by
chronic stress in rats. Eur J Pharmacol. 2011;667(1–3):222–9. https://doi.org/10.1016/j.ejphar.
2011.05.012.
Ghalandari-Shamami M, Nourizade S, Yousefi B, Vafaei AA, Pakdel R, Rashidy-Pour A. Beneficial
effects of physical activity and crocin against adolescent stress induced anxiety or depressive-like
symptoms and dendritic morphology remodeling in prefrontal cortex in adult male rats. Neurochem
Res. 2019;44(4):917–29. https://doi.org/10.1007/s11064-019-02727-2.
Gopalakrishnan A, Ji LL, Cirelli C. Sleep deprivation and cellular responses to oxidative stress.
Sleep. 2004;27(1):27–35. https://doi.org/10.1093/sleep/27.1.27.
Guo QP, Li WM. Studies on quality standard and antidepression effect of Lilium Brownii.
Guangzhou: Guangzhou University of Chinese Medicine; 2009.
Guo QP, Gao Y, Li WM. Effect of extract from Lilium Lancifolium Thunb. on cerebral mono-amine
neurotransmitters of depressive rats. Chin Tradit Patent Med. 2009;31(11):1669–72.
484 Y. Wang and J. Li

Han BH, Park MH, Kim DH, Hong SK. Studies on metabolic fates of ginsenosides. Korean
Biochem J. 1986;19:213–8.
Hao K, Gong P, Sun SQ, et al. Beneficial estrogen-like effects of ginsenoside Rb1, an active
component of Panax ginseng, on neural 5-HT disposition and behavioral tasks in ovariectomized
mice. Eur J Pharmacol. 2011;659(1):15–25. https://doi.org/10.1016/j.ejphar.2011.03.005.
Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood
disorders. Brain Res Brain Res Rev. 2004;45(2):104–14. https://doi.org/10.1016/j.brainresrev.
2004.02.003.
Hausenblas HA, Saha D, Dubyak PJ, Anton SD. Saffron (Crocus sativus L.) and major depressive
disorder: a meta-analysis of randomized clinical trials. J Integr Med. 2013;11(6):377–83. https://
doi.org/10.3736/jintegrmed2013056.
He ML, Cheng XW, Chen JK, et al. Simultaneous determination of five major biological active
ingredients in different parts of Gardenia jasminoides fruits by HPLC with diode-array detec-
tion. Chromatographia. 2006;64:713–7.
He X, Zhu Y, Wang M, et al. Antidepressant effects of curcumin and HU-211 coencapsulated solid
lipid nanoparticles against corticosterone-induced cellular and animal models of major depression.
Int J Nanomed. 2016;11:4975–4990. Published 2016 Oct 3. https://doi.org/10.2147/IJN.S109088
Hosseinzadeh H, Nassiri-Asl M. Pharmacological effects of Glycyrrhiza spp. and its bioactive constit-
uents: update and review. Phytother Res. 2015;29(12):1868–86. https://doi.org/10.1002/ptr.5487.
Hossen MS, Tanvir EM, Prince MB, et al. Protective mechanism of turmeric (Curcuma longa) on
carbofuran-induced hematological and hepatic toxicities in a rat model. Pharm Biol. 2017;55
(1):1937–45. https://doi.org/10.1080/13880209.2017.1345951.
Hu Q, Shen P, Bai S, et al. Metabolite-related antidepressant action of diterpene ginkgolides in the
prefrontal cortex. Neuropsychiatr Dis Treat. 2018;14:999–1011. https://doi.org/10.2147/NDT.
S161351.
Hu Y, Liu X, Xia Q, et al. Comparative anti-arthritic investigation of iridoid glycosides and crocetin
derivatives from Gardenia jasminoides Ellis in Freund’s complete adjuvant-induced arthritis in
rats. Phytomedicine. 2019;53:223–33. https://doi.org/10.1016/j.phymed.2018.07.005.
Huang JJ, Li WM, Gao Y. Studies on quality standard and antidepression effect of the effective parts
of Bulbus Lilii. Guangzhou: Guangzhou University of Chinese Med; 2011.
Huang HC, Xu K, Jiang ZF. Curcumin-mediated neuroprotection against amyloid-β-induced
mitochondrial dysfunction involves the inhibition of GSK-3β. J Alzheimers Dis. 2012;32
(4):981–96. https://doi.org/10.3233/JAD-2012-120688.
Huang Y, Jiang C, Hu Y, et al. Immunoenhancement effect of rehmannia glutinosa polysaccharide
on lymphocyte proliferation and dendritic cell. Carbohydr Polym. 2013;96(2):516–21. https://
doi.org/10.1016/j.carbpol.2013.04.018.
Huang Y, Wu C, Liu Z, et al. Optimization on preparation conditions of Rehmannia glutinosa
polysaccharide liposome and its immunological activity. Carbohydr Polym. 2014;104:118–26.
https://doi.org/10.1016/j.carbpol.2014.01.022.
Huang JZ, Wu J, Xiang S, et al. Catalpol preserves neural function and attenuates the pathology of
Alzheimer’s disease in mice. Mol Med Rep. 2016;13(1):491–6. https://doi.org/10.3892/mmr.
2015.4496.
Hurley LL, Akinfiresoye L, Nwulia E, et al. Antidepressant-like effects of curcumin in WKY rat
model of depression is associated with an increase in hippocampal BDNF. Behav Brain Res.
2013;239:27–30. https://doi.org/10.1016/j.bbr.2012.10.049.
Jang D, Lee HJ, Lee K, et al. White ginseng ameliorates depressive behavior and increases hippo-
campal 5-HT level in the stressed ovariectomized rats. Biomed Res Int. 2019;2019:5705232.
Published 2019 Feb 11. https://doi.org/10.1155/2019/5705232
Jiang LD. Discussion on concepts of the health, subhealth, before sickness and prevention. China J
Tradit Chin Med Pharm. 2010;25(2):167–70.
Jiang J, Wang W, Sun YJ, et al. Neuroprotective effect of curcumin on focal cerebral ischemic rats
by preventing blood–brain barrier damage. Eur J Pharmacol. 2007;561(1–3):54–62. https://doi.
org/10.1016/j.ejphar.2006.12.028.
TCM Substances in Neuropsychopharmacotherapy 485

Jiang TF, Zhang YJ, Zhou HY, et al. Curcumin ameliorates the neurodegenerative pathology in
A53T α-synuclein cell model of Parkinson’s disease through the downregulation of mTOR/
p70S6K signaling and the recovery of macroautophagy. J NeuroImmune Pharmacol. 2013;8
(1):356–69. https://doi.org/10.1007/s11481-012-9431-7.
Jiang N, Zhang BY, Dong LM, et al. Antidepressant effects of dammarane sapogenins in chronic
unpredictable mild stress-induced depressive mice. Phytother Res. 2018;32(6):1023–9. https://
doi.org/10.1002/ptr.6040.
Jin Y, Cui R, Zhao L, Fan J, Li B. Mechanisms of Panax ginseng action as an antidepressant. Cell
Prolif. 2019;52(6):e12696. https://doi.org/10.1111/cpr.12696.
Joe B, Vijaykumar M, Lokesh BR. Biological properties of curcumin-cellular and molecular
mechanisms of action. Crit Rev Food Sci Nutr. 2004;44(2):97–111. https://doi.org/10.1080/
10408690490424702.
Jozuka H, Jozuka E, Takeuchi S, Nishikaze O. Comparison of immunological and endocrinological
markers associated with major depression. J Int Med Res. 2003;31(1):36–41. https://doi.org/10.
1177/147323000303100106.
Kalaycıoğlu Z, Gazioğlu I, Erim FB. Comparison of antioxidant, anticholinesterase, and anti-
diabetic activities of three curcuminoids isolated from Curcuma longa L. Nat Prod Res.
2017;31(24):2914–7. https://doi.org/10.1080/14786419.2017.1299727.
Kalonia H, Kumar A. Protective effect of melatonin on certain behavioral and biochemical
alterations induced by sleep-deprivation in mice. Indian J Pharm. 2007;39(1):48–51.
Kang JM, Lin S. Ginkgo biloba and its potential role in glaucoma. Curr Opin Ophthalmol. 2018;29
(2):116–20. https://doi.org/10.1097/ICU.0000000000000459.
Kaniakova M, Krausova B, Vyklicky V, et al. Key amino acid residues within the third membrane
domains of NR1 and NR2 subunits contribute to the regulation of the surface delivery of N-
methyl-D-aspartate receptors. J Biol Chem. 2012;287(31):26423–34. https://doi.org/10.1074/
jbc.M112.339085.
Kashani L, Eslatmanesh S, Saedi N, et al. Comparison of saffron versus fluoxetine in treatment of
mild to moderate postpartum depression: a double-blind, randomized clinical trial. Pharmacop-
sychiatry. 2017;50(2):64–8. https://doi.org/10.1055/s-0042-115306.
Kaufmann FN, Costa AP, Ghisleni G, et al. NLRP3 inflammasome-driven pathways in depression:
clinical and preclinical findings. Brain Behav Immun. 2017;64:367–83. https://doi.org/10.1016/
j.bbi.2017.03.002.
Kim SO, You JM, Yun SJ, Son MS, Nam KN, Hong JW, Kim SY, Choi SY, Lee EH. Ginsenoside
rb1 and rg3 attenuate glucocorticoid-induced neurotoxicity. Cell Mol Neurobiol. 2010;30
(6):857–62. https://doi.org/10.1007/s10571-010-9513-0. Epub 2010 Mar 25. PMID:
20336484.
Kim JS, Kim Y, Han SH, et al. Development and validation of an LC-MS/MS method for
determination of compound K in human plasma and clinical application. J Ginseng Res.
2013;37(1):135–41. https://doi.org/10.5142/jgr.2013.37.135.
Kim HJ, Park SD, Lee RM, et al. Gintonin attenuates depressive-like behaviors associated with
alcohol withdrawal in mice. J Affect Disord. 2017;215:23–9. https://doi.org/10.1016/j.jad.2017.
03.026.
Kiss JP, Szasz BK, Fodor L, et al. GluN2B-containing NMDA receptors as possible targets for the
neuroprotective and antidepressant effects of fluoxetine. Neurochem Int. 2012;60(2):170–6.
https://doi.org/10.1016/j.neuint.2011.12.005.
Kita T, Imai S, Sawada H, et al. The biosynthetic pathway of curcuminoid in turmeric (Curcuma
longa) as revealed by13C-labeled precursors. Biosci Biotechnol Biochem. 2008;72(7):1789–98.
https://doi.org/10.1271/bbb.80075.
Koo HJ, Lim KH, Jung HJ, Park EH. Anti-inflammatory evaluation of gardenia extract,
geniposide and genipin. J Ethnopharmacol. 2006;103(3):496–500. https://doi.org/10.1016/j.
jep.2005.08.011.
Kuang Y, Li B, Fan J, Qiao X, Ye M. Antitussive and expectorant activities of licorice and its major
compounds. Bioorg Med Chem. 2018;26(1):278–84. https://doi.org/10.1016/j.bmc.2017.11.046.
486 Y. Wang and J. Li

Kulkarni SK, Dhir A. An overview of curcumin in neurological disorders. Indian J Pharm Sci.
2010;72(2):149–54. https://doi.org/10.4103/0250-474X.65012.
Kumar A, Kalonia H. Protective effect of Withania somnifera Dunal on the behavioral and
biochemical alterations in sleep-disturbed mice (Grid over water suspended method). Indian J
Exp Biol. 2007;45(6):524–8.
Kumar A, Singh A. Possible nitric oxide modulation in protective effect of (Curcuma longa,
Zingiberaceae) against sleep deprivation-induced behavioral alterations and oxidative damage
in mice. Phytomedicine. 2008;15(8):577–86. https://doi.org/10.1016/j.phymed.2008.02.003.
Kumar A, Prakash A, Dogra S. Protective effect of curcumin (Curcuma longa) against D-galactose-
induced senescence in mice. J Asian Nat Prod Res. 2011;13(1):42–55. https://doi.org/10.1080/
10286020.2010.544253.
Laakmann G, Dienel A, Kieser M. Clinical significance of hyperforin for the efficacy of Hypericum
extracts on depressive disorders of different severities. Phytomedicine. 1998;5(6):435–42.
https://doi.org/10.1016/S0944-7113(98)80039-1.
Lai N, Zhang J, Ma X, et al. Regulatory effect of catalpol on Th1/Th2 cells in mice with bone loss
induced by estrogen deficiency. Am J Reprod Immunol. 2015;74(6):487–98. https://doi.org/10.
1111/aji.12423.
Lee KJ, Ji GE. The effect of fermented red ginseng on depression is mediated by lipids. Nutr
Neurosci. 2014;17(1):7–15. https://doi.org/10.1179/1476830513Y.0000000059.
Lee B, Lee H. Systemic administration of curcumin affect anxiety-related behaviors in a rat model of
posttraumatic stress disorder via activation of serotonergic systems. Evid Based Complement
Alternat Med. 2018;2018:9041309. Published 2018 Jun 19. https://doi.org/10.1155/2018/9041309
Lee S, Rhee DK. Effects of ginseng on stress-related depression, anxiety, and the hypothalamic-
pituitary-adrenal axis. J Ginseng Res. 2017;41(4):589–94. https://doi.org/10.1016/j.jgr.2017.01.010.
Lee B, Sur B, Lee H, Oh S. Korean Red Ginseng prevents posttraumatic stress disorder-triggered
depression-like behaviors in rats via activation of the serotonergic system. J Ginseng Res.
2020;44(4):644–54. https://doi.org/10.1016/j.jgr.2019.09.005.
Leuner K, Kazanski V, Müller M, et al. Hyperforin – a key constituent of St. John’s wort specifically
activates TRPC6 channels. FASEB J. 2007;21(14):4101–11. https://doi.org/10.1096/fj.07-8110com.
Leung AY. Traditional toxicity documentation of Chinese Materia Medica – an overview. Toxicol
Pathol. 2006;34(4):319–26. https://doi.org/10.1080/01926230600773958.
Li HW, Meng XL. Research progress on chemical constituents and pharmacological activities of
Rehmannia glutinosa. Drug Eval Res. 2015;38(2):218–28.
Li T, Wang P, Guo W, et al. Natural berberine-based Chinese herb medicine assembled nano-
structures with modified antibacterial application. ACS Nano. 2019;13(6):6770–81. https://doi.
org/10.1021/acsnano.9b01346.
Liang Z, Bai S, Shen P, et al. GC-MS-based metabolomic study on the antidepressant-like effects of
diterpene ginkgolides in mouse Hippocampus. Behav Brain Res. 2016;314:116–24. https://doi.
org/10.1016/j.bbr.2016.08.001.
Liang ZH, Jia YB, Wang ML, et al. Efficacy of ginkgo biloba extract as augmentation of
venlafaxine in treating post-stroke depression. Neuropsychiatr Dis Treat. 2019;15:2551–2557.
Published 2019 Sep 3. https://doi.org/10.2147/NDT.S215191
Lim CY, Moon JM, Kim BY, et al. Comparative study of Korean White Ginseng and Korean Red
Ginseng on efficacies of OVA-induced asthma model in mice. J Ginseng Res. 2015;39(1):38–
45. https://doi.org/10.1016/j.jgr.2014.07.004.
Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St John’s wort for
depression – an overview and meta-analysis of randomised clinical trials. BMJ. 1996;313
(7052):253–8. https://doi.org/10.1136/bmj.313.7052.253.
Liu YF. Studies on the active substances and function of Rehmannia Radix. Beijing: Chinese
Academy of Medical Science Peking Union Medical Colloge; 2013.
Liu T. Clinical application of LBRD. Nei Mongol. J Tradit Chin Med. 2014;33(22):94–6.
Liu JY, Zhang DJ. Amelioration by catalpol of atherosclerotic lesions in hypercholesterolemic
rabbits. Planta Med. 2015;81(3):175–84. https://doi.org/10.1055/s-0034-1396240.
TCM Substances in Neuropsychopharmacotherapy 487

Liu C, Wu F, Liu Y, Meng C. Catalpol suppresses proliferation and facilitates apoptosis of MCF-7
breast cancer cells through upregulating microRNA-146a and downregulating matrix meta-
lloproteinase-16 expression. Mol Med Rep. 2015;12(5):7609–14. https://doi.org/10.3892/mmr.
2015.4361.
Liu Z, Qi Y, Cheng Z, Zhu X, Fan C, Yu SY. The effects of ginsenoside Rg1 on chronic stress induced
depression-like behaviors, BDNF expression and the phosphorylation of PKA and CREB in rats.
Neuroscience. 2016a;322:358–69. https://doi.org/10.1016/j.neuroscience.2016.02.050.
Liu X, Guo H, Sayed MD, et al. cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-
like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats. Neuropsychiatr Dis Treat.
2016b;12:219–227. Published 2016 Jan 21. https://doi.org/10.2147/NDT.S90960
Liu P, Lin ZJ, Zhang B. Research progress on chemical constituents and pharmacological effect of
Lilii Bulbus. Chin J Exp Tradit Med Formulae. 2017;23(23):201–11.
Liu D, Huo X, Gao L, Zhang J, Ni H, Cao L. NF-κB and Nrf2 pathways contribute to the protective
effect of Licochalcone A on dextran sulphate sodium-induced ulcerative colitis in mice. Biomed
Pharmacother. 2018;102:922–9. https://doi.org/10.1016/j.biopha.2018.03.130.
Lopresti AL. Curcumin for neuropsychiatric disorders: a review of in vitro, animal and human
studies. J Psychopharmacol. 2017;31(3):287–302. https://doi.org/10.1177/0269881116686883.
Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of
clinical studies and examination of underlying antidepressant mechanisms of action. Hum
Psychopharmacol. 2014;29(6):517–27. https://doi.org/10.1002/hup.2434.
Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major
depression: a randomised, double-blind, placebo controlled study. J Affect Disord.
2014;167:368–75. https://doi.org/10.1016/j.jad.2014.06.001.
Lopresti AL, Drummond PD, Inarejos-García AM, Prodanov M. affron®, a standardised extract
from saffron (Crocus sativus L.) for the treatment of youth anxiety and depressive symptoms: a
randomised, double-blind, placebo-controlled study. J Affect Disord. 2018;232:349–57. https://
doi.org/10.1016/j.jad.2018.02.070.
Ma YT. Synthesis and Antitumor Activity of novel Isoliquiritigenin Analogues. Harbin, Heilong-
jiang Province, China. Northeast Forestry University. 2009.
Ma R, Zhu R, Wang L, et al. Diabetic osteoporosis: a review of its traditional Chinese medicinal
use and clinical and preclinical research. Evid Based Complement Alternat Med.
2016;2016:3218313. https://doi.org/10.1155/2016/3218313.
Maes M, Bosmans E, Meltzer HY. Immunoendocrine aspects of major depression. Relationships
between plasma interleukin-6 and soluble interleukin-2 receptor, prolactin and cortisol. Eur
Arch Psychiatry Clin Neurosci. 1995;245(3):172–8. https://doi.org/10.1007/BF02193091.
Maes M, Song C, Yirmiya R. Targeting IL-1 in depression. Expert Opin Ther Targets. 2012;16
(11):1097–112. https://doi.org/10.1517/14728222.2012.718331.
Malberg JE, Blendy JA. Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci.
2005;26(12):631–8. https://doi.org/10.1016/j.tips.2005.10.005.
Mancuso C, Santangelo R. Panax ginseng and Panax quinquefolius: from pharmacology to toxicol-
ogy. Food Chem Toxicol. 2017;107(Pt A):362–72. https://doi.org/10.1016/j.fct.2017.07.019.
Mansouri Z, Sabetkasaei M, Moradi F, et al. Curcumin has neuroprotection effect on homocysteine
rat model of Parkinson. J Mol Neurosci. 2012;47(2):234–42. https://doi.org/10.1007/s12031-
012-9727-3.
Meng Y, Jia Y, Wu YW, Xiang H, Qin XM, Tian JS. Research progress on Baihe Dihuang decoction
in nervous-mental system. Chin Tradit Herb Drug. 2018;49(1):251–5.
Mengoni F, Lichtner M, Battinelli L, et al. In vitro anti-HIV activity of oleanolic acid on infected
human mononuclear cells. Planta Med. 2002;68(2):111–4. https://doi.org/10.1055/s-2002-20256.
Miao M, Peng M, Chen H, Liu B. Effects of Baihe Dihuang powder on chronic stress depression rat
models. Saudi J Biol Sci. 2019;26(3):582–8. https://doi.org/10.1016/j.sjbs.2018.12.002.
Miquel J, Bernd A, Sempere JM, Díaz-Alperi J, Ramírez A. The curcuma antioxidants: pharmaco-
logical effects and prospects for future clinical use. A review. Arch Gerontol Geriatr. 2002;34
(1):37–46. https://doi.org/10.1016/s0167-4943(01)00194-7.
488 Y. Wang and J. Li

Molteni R, Calabrese F, Bedogni F, et al. Chronic treatment with fluoxetine up-regulates cellular
BDNF mRNA expression in rat dopaminergic regions. Int J Neuropsychopharmacol. 2006;9
(3):307–17. https://doi.org/10.1017/S1461145705005766.
Motin VG, Yasnetsov VV. Effect of NMDA, a specific agonist to NMDA receptor complex, on rat
hippocampus. Bull Exp Biol Med. 2015;159(6):704–7. https://doi.org/10.1007/s10517-015-3053-z.
Mueller SC, Majcher-Peszynska J, Uehleke B, et al. The extent of induction of CYP3A by St.
John’s wort varies among products and is linked to hyperforin dose. Eur J Clin Pharmacol.
2006;62(1):29–36. https://doi.org/10.1007/s00228-005-0061-3.
Murakami S, Imbe H, Morikawa Y, Kubo C, Senba E. Chronic stress, as well as acute stress,
reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res.
2005;53(2):129–39. https://doi.org/10.1016/j.neures.2005.06.008.
Nakagawasai O, Oba A, Sato A, et al. Subchronic stress-induced depressive behavior in ovariec-
tomized mice. Life Sci. 2009;84(15–16):512–6. https://doi.org/10.1016/j.lfs.2009.01.009.
Napryeyenko O, Sonnik G, Tartakovsky I, et al. Efficacy and tolerability of Ginkgo biloba extract
EGb 761 by type of dementia: analyses of a randomised controlled trial. J Neurol Sci. 2009;283
(1–2):224–9. https://doi.org/10.1016/j.jns.2009.02.353.
Ng QX, Koh SSH, Chan HW, Ho CYX. Clinical use of curcumin in depression: a meta-analysis. J
Am Med Dir Assoc. 2017a;18(6):503–8. https://doi.org/10.1016/j.jamda.2016.12.071.
Ng QX, Venkatanarayanan N, Ho CY. Clinical use of Hypericum perforatum (St John’s wort) in
depression: a meta-analysis. J Affect Disord. 2017b;210:211–21. https://doi.org/10.1016/j.jad.
2016.12.048.
Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression
of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci. 1996;16
(7):2365–72. https://doi.org/10.1523/JNEUROSCI.16-07-02365.1996.
Oh J, Jeon SB, Lee Y, et al. Fermented red ginseng extract inhibits cancer cell proliferation and
viability. J Med Food. 2015;18(4):421–8. https://doi.org/10.1089/jmf.2014.3248.
Pan R, Qiu S, Lu DX, Dong J. Curcumin improves learning and memory ability and its
neuroprotective mechanism in mice. Chin Med J. 2008;121(9):832–9.
Pan Y, Chen XY, Zhang QY, et al. Microglial NLRP3 inflammasome activation mediates IL-1β-
related inflammation in prefrontal cortex of depressive rats. Brain Behav Immun. 2014;41:90–
100. https://doi.org/10.1016/j.bbi.2014.04.007.
Pastorino G, Cornara L, Soares S, Rodrigues F, Oliveira MBPP. Liquorice (Glycyrrhiza glabra): a
phytochemical and pharmacological review. Phytother Res. 2018;32(12):2323–39. https://doi.
org/10.1002/ptr.6178.
Pathak AK, Bhutani M, Nair AS, et al. Ursolic acid inhibits STAT3 activation pathway leading to
suppression of proliferation and chemosensitization of human multiple myeloma cells
[published correction appears in Mol Cancer Res. 2018 Sep;16(9):1442]. Mol Cancer Res.
2007; 5(9):943–955. https://doi.org/10.1158/1541-7786.MCR-06-0348.
Patil SS, Schlick F, Höger H, et al. Involvement of individual hippocampal signaling protein levels
in spatial memory formation is strain-dependent [published correction appears in Amino Acids.
2010 Jul;39(2):617–618]. Amino Acids. 2010;39(1):75–87. https://doi.org/10.1007/s00726-
009-0379-8.
Plotsky PM, Owens MJ, Nemeroff CB. Psychoneuroendocrinology of depression. Hypothalamic-
pituitary-adrenal axis. Psychiatr Clin North Am. 1998;21(2):293–307. https://doi.org/10.1016/
s0193-953x(05)70006-x.
Pöldinger W. Zur Geschichte des Johanniskrauts [History of St. Johns wort]. Praxis (Bern 1994).
2000;89(50):2102–9.
Pollier J, Goossens A. Oleanolic acid. Phytochemistry. 2012;77:10–5. https://doi.org/10.1016/j.
phytochem.2011.12.022.
Pyrzanowska J, Piechal A, Blecharz-Klin K, et al. The influence of the long-term administration of
Curcuma longa extract on learning and spatial memory as well as the concentration of brain
neurotransmitters and level of plasma corticosterone in aged rats. Pharmacol Biochem Behav.
2010;95(3):351–8. https://doi.org/10.1016/j.pbb.2010.02.013.
TCM Substances in Neuropsychopharmacotherapy 489

Ramanathan L, Gulyani S, Nienhuis R, et al. Sleep deprivation decreases superoxide dismutase

activity in rat hippocampus and brainstem. Neuroreport. 2002;13(11):1387–90. https://doi.org/
10.1097/00001756-200208070-00007.
Ramirez K, Shea DT, McKim DB, et al. Imipramine attenuates neuroinflammatory signaling and
reverses stress-induced social avoidance. Brain Behav Immun. 2015;46:212–20. https://doi.org/
10.1016/j.bbi.2015.01.016.
Rao CV, Verma AR, Vijayakumar M, Rastogi S. Gastroprotective effect of standardized extract of
Ficus glomerata fruit on experimental gastric ulcers in rats. J Ethnopharmacol. 2008;115
(2):323–6. https://doi.org/10.1016/j.jep.2007.09.019.
Rathore P, Dohare P, Varma S, et al. Curcuma oil: reduces early accumulation of oxidative product
and is anti-apoptogenic in transient focal ischemia in rat brain. Neurochem Res, 2008;33
(11):2376–2376. https://doi.org/10.1007/s11064-008-9787-5.
Rawdin BJ, Mellon SH, Dhabhar FS, et al. Dysregulated relationship of inflammation and oxidative
stress in major depression. Brain Behav Immun. 2013;31:143–52. https://doi.org/10.1016/j.bbi.
2012.11.011.
Réus GZ, Dos Santos MA, Abelaira HM, et al. Imipramine reverses alterations in cytokines and
BDNF levels induced by maternal deprivation in adult rats. Behav Brain Res. 2013;242:40–6.
https://doi.org/10.1016/j.bbr.2012.11.044.
Rinwa P, Kumar A. Piperine potentiates the protective effects of curcumin against chronic
unpredictable stress-induced cognitive impairment and oxidative damage in mice. Brain Res.
2012;1488:38–50. https://doi.org/10.1016/j.brainres.2012.10.002.
Rojas P, Serrano-García N, Medina-Campos ON, et al. Antidepressant-like effect of a Ginkgo
biloba extract (EGb761) in the mouse forced swimming test: role of oxidative stress.
Neurochem Int. 2011 Oct;59(5):628–36. https://doi.org/10.1016/j.neuint.2011.05.007.
Ruan J, Liu L, Shan X, et al. Anti-depressant effects of oil from fructus gardeniae via PKA-CREB-
BDNF signaling. Biosci Rep. 2019;39(4):BSR20190141. Published 2019 Apr 26. https://doi.
org/10.1042/BSR20190141
Sandhu AK, Gray DJ, Lu J, et al. Effects of exogenous abscisic acid on antioxidant capacities,
anthocyanins, and flavonol contents of muscadine grape (Vitis rotundifolia) skins. Food Chem.
2011;126(3):982–8. https://doi.org/10.1016/j.foodchem.2010.11.105.
Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen
Psychiatry. 2000;57(10):925–35. https://doi.org/10.1001/archpsyc.57.10.925.
Sarris J, Panossian A, Schweitzer I, Stough C, Scholey A. Herbal medicine for depression, anxiety
and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsycho-
pharmacol. 2011;21(12):841–60. https://doi.org/10.1016/j.euroneuro.2011.04.002.
Schulz V. Clinical trials with hypericum extracts in patients with depression – results, comparisons,
conclusions for therapy with antidepressant drugs. Phytomedicine. 2002;9(5):468–74. https://
doi.org/10.1078/09447110260571742.
Scott LV, Dinan TG. Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis func-
tion: implications for the pathophysiology of depression. Life Sci. 1998;62(22):1985–98.
https://doi.org/10.1016/s0024-3205(98)00027-7.
Scripnikov A, Khomenko A, Napryeyenko O, GINDEM-NP Study Group. Effects of Ginkgo
biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomised
controlled trial. Wien Med Wochenschr. 2007;157(13–14):295–300. https://doi.org/10.1007/
s10354-007-0427-5.
Seifritz E, Hatzinger M, Holsboer-Trachsler E. Efficacy of Hypericum extract WS( ®) 5570
compared with paroxetine in patients with a moderate major depressive episode – a subgroup
analysis [published correction appears in Int J Psychiatry Clin Pract. 2017 Jun;21(2):160]. Int
J Psychiatry Clin Pract. 2016;20(3):126–132.https://doi.org/10.1080/13651501.2016.
1179765.
Shafiee M, Arekhi S, Omranzadeh A, Sahebkar A. Saffron in the treatment of depression, anxiety
and other mental disorders: current evidence and potential mechanisms of action. J Affect
Disord. 2018;227:330–7. https://doi.org/10.1016/j.jad.2017.11.020.
490 Y. Wang and J. Li

Shim JS, Song MY, Yim SV, Lee SE, Park KS. Global analysis of ginsenoside Rg1 protective
effects in β-amyloid-treated neuronal cells. J Ginseng Res. 2017;41(4):566–71. https://doi.org/
10.1016/j.jgr.2016.12.003.
Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from Panax ginseng. J
Ginseng Res. 2015;39(4):287–98. https://doi.org/10.1016/j.jgr.2014.12.005.
Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor
produces antidepressant effects in behavioral models of depression. J Neurosci. 2002;22
(8):3251–61. https://doi.org/10.1523/JNEUROSCI.22-08-03251.2002.
Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. Ursolic acid inhibits nuclear factor-kappaB
activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65
phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix meta-
lloproteinase 9, and cyclin D1. Cancer Res. 2003;63(15):4375–83.
Shukla Y, Arora A, Taneja P. Antimutagenic potential of curcumin on chromosomal aberrations in
Wistar rats. Mutat Res. 2002;515(1–2):197–202. https://doi.org/10.1016/s1383-5718(02)00016-5.
Solanki I, Parihar P, Mansuri ML, et al. Flavonoid-based therapies in the early management of
neurodegenerative diseases. Adv Nutr. 2015;6(1):64–72. Published 2015 Jan 15. https://doi.org/
10.3945/an.114.007500
Soleymani S, Bahramsoltani R, Rahimi R, Abdollahi M. Clinical risks of St John’s Wort (Hyper-
icum perforatum) co-administration. Expert Opin Drug Metab Toxicol. 2017;13(10):1047–62.
https://doi.org/10.1080/17425255.2017.1378342.
Song X, Zhang W, Wang T, et al. Geniposide plays an anti-inflammatory role via regulating TLR4
and downstream signaling pathways in lipopolysaccharide-induced mastitis in mice. Inflamma-
tion. 2014;37(5):1588–98. https://doi.org/10.1007/s10753-014-9885-2.
Stout SC, Owens MJ, Nemeroff CB. Regulation of corticotropin-releasing factor neuronal systems
and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment.
J Pharmacol Exp Ther. 2002;300(3):1085–92. https://doi.org/10.1124/jpet.300.3.1085.
Su GL, Liu G, Liu YC, Dong HR. Progress on extraction and purification of liquiritin and its
pharmacological effects. Mod Chin Med. 2011;13(10):48–51.
Sun T, Wang X, Xu H. Ginkgo biloba extract for angina pectoris: a systematic review. Chin J Integr
Med. 2015;21(7):542–50. https://doi.org/10.1007/s11655-015-2070-0.
Sung JY, Goo JS, Lee DE, et al. Learning strategy selection in the water maze and hippocampal
CREB phosphorylation differ in two inbred strains of mice. Learn Mem. 2008;15(4):183–188.
Published 2008 Mar 19. https://doi.org/10.1101/lm.783108
Tabeshpour J, Sobhani F, Sadjadi SA, et al. A double-blind, randomized, placebo-controlled
trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate
postpartum depression. Phytomedicine. 2017;36:145–52. https://doi.org/10.1016/j.
phymed.2017.10.005.
Takei S, Morinobu S, Yamamoto S, et al. Enhanced hippocampal BDNF/TrkB signaling in response
to fear conditioning in an animal model of posttraumatic stress disorder. J Psychiatr Res.
2011;45(4):460–8. https://doi.org/10.1016/j.jpsychires.2010.08.009.
Tan MS, Yu JT, Tan CC, et al. Efficacy and adverse effects of Ginkgo biloba for cognitive
impairment and dementia: a systematic review and meta-analysis. J Alzheimers Dis. 2015;43
(2):589–603. https://doi.org/10.3233/JAD-140837.
Tang J, Xue W, Xia B, et al. Involvement of normalized NMDA receptor and mTOR-related
signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice.
Sci Rep. 2015;5:13573. Published 2015 Aug 28. https://doi.org/10.1038/srep13573
Tao W, Zhang H, Xue W, et al. Optimization of supercritical fluid extraction of oil from the fruit of
Gardenia jasminoides and its antidepressant activity. Molecules. 2014;19(12):19350–19360.
Published 2014 Nov 25. https://doi.org/10.3390/molecules191219350
Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake
inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry.
2006;63(11):1217–23. https://doi.org/10.1001/archpsyc.63.11.1217.
Teng GL, Zhang YX, Wu QG, Chen Z, Huang XW, et al. Chinese Materia Medica. Beijing:
People’s Medical Publishing House; 2019.
TCM Substances in Neuropsychopharmacotherapy 491

Tóth B, Hegyi P, Lantos T, et al. The efficacy of saffron in the treatment of mild to moderate
depression: a meta-analysis. Planta Med. 2019;85(1):24–31. https://doi.org/10.1055/a-0660-9565.
Tsai SJ. Effects of interleukin-1beta polymorphisms on brain function and behavior in healthy and
psychiatric disease conditions. Cytokine Growth Factor Rev. 2017;37:89–97. https://doi.org/10.
1016/j.cytogfr.2017.06.001.
Tsai YM, Chien CF, Lin LC, et al. Curcumin and its nano-formulation: the kinetics of tissue
distribution and blood-brain barrier penetration. Int J Pharm. 2011;416(1):331–8. https://doi.
org/10.1016/j.ijpharm.2011.06.030.
Tulsulkar J, Glueck B, Hinds TD Jr, et al. Ginkgo biloba extract prevents female mice from
ischemic brain damage and the mechanism is independent of the HO1/Wnt pathway. Transl
Stroke Res. 2016;7(2):120–31. https://doi.org/10.1007/s12975-015-0433-7.
Venigalla M, Gyengesi E, Münch G. Curcumin and Apigenin – novel and promising therapeutics
against chronic neuroinflammation in Alzheimer’s disease [published correction appears in
Neural Regen Res. 2015 Dec;10(12):2017]. Neural Regen Res. 2015;10(8):1181–1185.
https://doi.org/10.4103/1673-5374.162686.
Voehringer DW. BCL-2 and glutathione: alterations in cellular redox state that regulate apoptosis
sensitivity. Free Radic Biol Med. 1999;27(9–10):945–50. https://doi.org/10.1016/s0891-5849
(99)00174-4.
Wahlström B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol
(Copenh). 1978;43(2):86–92. https://doi.org/10.1111/j.1600-0773.1978.tb02240.x.
Wang P, Wang WP, Sun-Zhang, et al. Impaired spatial learning related with decreased expression of
calcium/calmodulin-dependent protein kinase IIα and cAMP-response element binding protein
in the pentylenetetrazol-kindled rats. Brain Res. 2008;1238:108–17. https://doi.org/10.1016/j.
brainres.2008.07.103.
Wang J, Gao W, Zhang L, Huang L. Establishment and quality assessment of tissue cultures in
Glycyrrhiza uralensis Fisch. Appl Biochem Biotechnol. 2013;169(2):588–94. https://doi.org/
10.1007/s12010-012-0012-2.
Wang J, Jing L, Toledo-Salas JC, Xu L. Rapid-onset antidepressant efficacy of glutamatergic system
modulators: the neural plasticity hypothesis of depression. Neurosci Bull. 2015a;31(1):75–86.
https://doi.org/10.1007/s12264-014-1484-6. Epub 2014 Dec 6.
Wang Z, Wei G, Ma S. Chemical and pharmacological effects of Rehmanniae Radix polysaccha-
rides. Chin J Exp Tradit Med Formulae. 2015b;21(16):231–5.
Wang GL, He ZM, Zhu HY, et al. Involvement of serotonergic, noradrenergic and dopaminergic
systems in the antidepressant-like effect of ginsenoside Rb1, a major active ingredient of Panax
ginseng C.A. Meyer. J Ethnopharmacol. 2017a;204:118–24.
Wang XR, Hao HG, Chu L. Glycyrrhizin inhibits LPS-induced inflammatory mediator production
in endometrial epithelial cells. Microb Pathog. 2017b;109:110–3. https://doi.org/10.1016/j.
micpath.2017.05.032.
Wise K, Selby-Pham S, Bennett L, Selby-Pham J. Pharmacokinetic properties of phytochemicals in
Hypericum perforatum influence efficacy of regulating oxidative stress. Phytomedicine.
2019;59:152763. https://doi.org/10.1016/j.phymed.2018.11.023.
Woelk H, Burkard G, Grünwald J. Benefits and risks of the hypericum extract LI 160: drug
monitoring study with 3250 patients. J Geriatr Psychiatry Neurol. 1994;7(Suppl 1):S34–8.
https://doi.org/10.1177/089198879400700110.
Wu A, Ying Z, Gomez-Pinilla F. The interplay between oxidative stress and brain-derived neurotrophic
factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J
Neurosci. 2004;19(7):1699–707. https://doi.org/10.1111/j.1460-9568.2004.03246.x.
Wu PS, Wu SJ, Tsai YH, Lin YH, Chao JC. Hot water extracted Lycium barbarum and Rehmannia
glutinosa inhibit liver inflammation and fibrosis in rats. Am J Chin Med. 2011;39(6):1173–91.
https://doi.org/10.1142/S0192415X11009482.
Wu R, Zhu D, Xia Y, et al. A role of Yueju in fast-onset antidepressant action on major depressive
disorder and serum BDNF expression: a randomly double-blind, fluoxetine-adjunct, placebo-
controlled, pilot clinical study. Neuropsychiatr Dis Treat. 2015;11:2013–2021. Published 2015
Aug 6. https://doi.org/10.2147/NDT.S86585
492 Y. Wang and J. Li

Wu R, Tao W, Zhang H, et al. Instant and persistent antidepressant response of gardenia yellow
pigment is associated with acute protein synthesis and delayed upregulation of BDNF expres-
sion in the hippocampus. ACS Chem Neurosci. 2016;7(8):1068–76. https://doi.org/10.1021/
acschemneuro.6b00011.
Xia X, Pan Y, Zhang WY, et al. Ethanolic extracts from Curcuma longa attenuates behavioral,
immune, and neuroendocrine alterations in a rat chronic mild stress model. Biol Pharm Bull.
2006;29(5):938–44. https://doi.org/10.1248/bpb.29.938.
Xiao Q, Xiong Z, Yu C, et al. Antidepressant activity of crocin-I is associated with amelioration of
neuroinflammation and attenuates oxidative damage induced by corticosterone in mice. Physiol
Behav. 2019;212:112699. https://doi.org/10.1016/j.physbeh.2019.112699.
Xu Y, Ku B, Tie L, et al. Curcumin reverses the effects of chronic stress on behavior, the HPA axis,
BDNF expression and phosphorylation of CREB. Brain Res. 2006;1122(1):56–64. https://doi.
org/10.1016/j.brainres.2006.09.009.
Xue W, Zhou X, Yi N, et al. Yueju pill rapidly induces antidepressant-like effects and acutely
enhances BDNF expression in mouse brain. Evid Based Complement Alternat Med.
2013;2013:184367. https://doi.org/10.1155/2013/184367.
Xue W, Wang W, Gong T, et al. PKA-CREB-BDNF signaling regulated long lasting antidepressant
activities of Yueju but not ketamine. Sci Rep. 2016;6:26331. Published 2016 May 20. https://
doi.org/10.1038/srep26331
Yallapu MM, Jaggi M, Chauhan SC. Curcumin nanoformulations: a future nanomedicine for cancer.
Drug Discov Today. 2012;17(1–2):71–80. https://doi.org/10.1016/j.drudis.2011.09.009.
Yamada N, Araki H, Yoshimura H. Identification of antidepressant-like ingredients in ginseng root
(Panax ginseng C.A. Meyer) using a menopausal depressive-like state in female mice: partic-
ipation of 5-HT2A receptors. Psychopharmacology. 2011;216(4):589–99. https://doi.org/10.
1007/s00213-011-2252-1.
Yan YX, Liu YQ, Li M, et al. Development and evaluation of a questionnaire for measuring
suboptimal health status in urban Chinese. J Epidemiol. 2009;19(6):333–41. https://doi.org/10.
2188/jea.je20080086.
Yang L, Dong X. Inhibition of inflammatory response by crocin attenuates hemorrhagic shock-
induced organ damages in rats. J Interf Cytokine Res. 2017;37(7):295–302. https://doi.org/10.
1089/jir.2016.0137.
Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid β oligomers and fibrils,
binds plaques, and reduces amyloidin vivo. J Biol Chem. 2004;280(7):5892–901. https://doi.
org/10.1074/jbc.m404751200.
Yang R, Wang LQ, Yuan BC, Liu Y. The pharmacological activities of licorice. Planta Med.
2015;81(18):1654–69. https://doi.org/10.1055/s-0035-1557893.
Yosri H, Elkashef WF, Said E, Gameil NM. Crocin modulates IL-4/IL-13 signaling and ameliorates
experimentally induced allergic airway asthma in a murine model. Int Immunopharmacol.
2017;50:305–12. https://doi.org/10.1016/j.intimp.2017.07.012.
Zahner C, Kruttschnitt E, Uricher J, et al. No clinically relevant interactions of St. John’s Wort
extract Ze 117 low in Hyperforin with cytochrome P450 enzymes and P-glycoprotein. Clin
Pharmacol Ther. 2019;106(2):432–40. https://doi.org/10.1002/cpt.1392.
Zhang YL, Meng FJ, Tian Y, et al. Study on chemical composition and pharmacological action of
licorice. Chem Eng. 2009;8:60–63, 66
Zhang L, Xu T, Wang S, et al. Curcumin produces antidepressant effects via activating MAPK/
ERK-dependent brain-derived neurotrophic factor expression in the amygdala of mice. Behav
Brain Res. 2012;235(1):67–72. https://doi.org/10.1016/j.bbr.2012.07.019.
Zhang L, Luo J, Zhang M, et al. Effects of curcumin on chronic, unpredictable, mild, stress-induced
depressive-like behaviour and structural plasticity in the lateral amygdala of rats. Int J
Neuropsychopharmacol. 2014a;17(5):793–806. https://doi.org/10.1017/S1461145713001661.
Zhang W, Men X, Lei P. Review on anti-tumor effect of triterpene acid compounds. J Cancer Res
Ther. 2014b;10(Suppl 1):14–9. https://doi.org/10.4103/0973-1482.139746.
TCM Substances in Neuropsychopharmacotherapy 493

Zhang L, Wang Y, Yang D, et al. Platycodon grandiflorus – an ethnopharmacological, phytochem-

ical and pharmacological review. J Ethnopharmacol. 2015a;164:147–61. https://doi.org/10.
1016/j.jep.2015.01.052.
Zhang H, Xue W, Wu R, et al. Rapid antidepressant activity of ethanol extract of Gardenia
jasminoides Ellis is associated with upregulation of BDNF expression in the hippocampus. Evid
Based Complement Alternat Med. 2015b;2015:761238. https://doi.org/10.1155/2015/761238.
Zhang L, Fang Y, Xu Y, et al. Curcumin improves amyloid β-peptide (1-42) induced spatial memory
deficits through BDNF-ERK signaling pathway. PLoS One. 2015c;10(6):e0131525. https://doi.
org/10.1371/journal.pone.0131525. PMID: 26114940; PMCID: PMC4482657
Zhang L, Liu J, Ge Y, Liu M. Ginkgo biloba extract reduces hippocampus inflammatory responses,
improves cardiac functions and depressive behaviors in a heart failure mouse model.
Neuropsychiatr Dis Treat. 2019;15:3041–3050. Published 2019 Oct 29. https://doi.org/10.
2147/NDT.S229296
Zhao ZY, Wang WX, Guo HZ, Zhou DF. The effect of liquiritin on body weight and behavior of
depressive rats. Chin Ment Health J. 2006a;20(12):787–90.
Zhao ZY, Wang WX, Guo HZ. The symposium 7th annual conference of Chinese Society of
Psychiatry. In: Chinese society of psychiatry. Effects of liquiritin on depressive model and its
anti-depressive mechanism. Beijing, The 7th annual conference of Chinese Society of Psychi-
atry. 2006b. p. 23–24
Zhao ZY, Wang WX, Guo HZ, Guan ZQ, Zhou DF. Anti-depressive effect of liquiritin on chronic
stress depression in rats. Chin J Clin Rehab. 2006c;10(27):69–72.
Zhao Z, Wang W, Guo H, Zhou D. Antidepressant-like effect of liquiritin from Glycyrrhiza
uralensis in chronic variable stress induced depression model rats. Behav Brain Res.
2008;194(1):108–13. https://doi.org/10.1016/j.bbr.2008.06.030.
Zheng XY. Pharmacopoeia of the People’s Republic of China. Chemical Industry Press Co., Ltd.
Beijing, Chinese ed., vol 1. 2005.
Zheng X, Liang Y, Kang A, et al. Peripheral immunomodulation with ginsenoside Rg1 ameliorates
neuroinflammation-induced behavioral deficits in rats. Neuroscience. 2014;256:210–22. https://
doi.org/10.1016/j.neuroscience.2013.10.023.
Zheng M, Xin Y, Li Y, et al. Ginsenosides: a potential neuroprotective agent. Biomed Res Int.
2018;2018:8174345. Published 2018 May 8. https://doi.org/10.1155/2018/8174345
Zhou J, Xu G, Ma S, et al. Catalpol ameliorates high-fat diet-induced insulin resistance and adipose
tissue inflammation by suppressing the JNK and NF-κB pathways. Biochem Biophys Res
Commun. 2015a;467(4):853–8. https://doi.org/10.1016/j.bbrc.2015.10.054.
Zhou J, Xu G, Yan J, et al. Rehmannia glutinosa (Gaertn.) DC. polysaccharide ameliorates
hyperglycemia, hyperlipemia and vascular inflammation in streptozotocin-induced diabetic
mice. J Ethnopharmacol. 2015b;164:229–38. https://doi.org/10.1016/j.jep.2015.02.026.
Zhou XL, Xiao BY, Wang HL, Tan T. Effect of Baihe Dihuang decoction (百合地黄汤) on IL-1β
and neurotransmitter 5-HT in depression model rats. Guiding J Tradit Chin Med Pharm. 2018;24
(16):30–3.
Zhou XD, Shi DD, Zhang ZJ. Ameliorative effects of Radix rehmanniae extract on the anxiety- and
depression-like symptoms in ovariectomized mice: a behavioral and molecular study.
Phytomedicine. 2019;63:153012. https://doi.org/10.1016/j.phymed.2019.153012.
Zirak N, Shafiee M, Soltani G, Mirzaei M, Sahebkar A. Hypericum perforatum in the treatment of
psychiatric and neurodegenerative disorders: current evidence and potential mechanisms of
action. J Cell Physiol. 2019;234(6):8496–508. https://doi.org/10.1002/jcp.27781.
Zou Z, Chen Y, Shen Q, Guo X, Zhang Y, Chen G. Neural plasticity associated with hippocampal
PKA-CREB and NMDA signaling is involved in the antidepressant effect of repeated low dose of
Yueju Pill on chronic mouse model of learned helplessness. Neural Plast. 2017;2017:9160515.
https://doi.org/10.1155/2017/9160515.
D-Serine: Basic Aspects with a Focus
on Psychosis

Toru Nishikawa, Asami Umino, and Masakazu Umino

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
Evidence for NMDA Receptor Hypofunction in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
NMDA Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
Anti-NMDA Receptor Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
NMDA Receptor Hypofunction and Onset of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
NMDA Receptor System in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Dopaminergic Transmission Under NMDA Receptor Hypofunction . . . . . . . . . . . . . . . . . . . . . . 502
NMDA Receptor Function Enhancement Therapy for Schizophrenia: Rationale
for Application of D-Serine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Issues and Improvement of NMDA Receptor Function Enhancement Therapy . . . . . . . . . . . 506
Modulation of Brain D-Serine Signaling for Development of Next Generation
Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
Detection and Distribution of Endogenous D-Serine in Mammalian Brains . . . . . . . . . . . . . . . 507
Biosynthesis of D-Serine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
Storage of D-Serine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
Extracellular D-Serine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510
Uptake of D-Serine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Degradation of D-Serine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
D-Serine Action on GluD2 and GluN1/GluN3 Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . 514
D-Serine Systems in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

T. Nishikawa (*) · A. Umino · M. Umino

Department of Pharmacology, School of Medicine, and Pharmacological Research Center, Showa
University, Tokyo, Japan
e-mail: torunishi@med.showa-u.ac.jp; npsdserotbc@springer.com; npsdser@springer.com

© Springer Nature Switzerland AG 2022 495

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_470
496 T. Nishikawa et al.

Abstract
Based on the glutamate hypothesis of schizophrenia postulating hypofunction of
the N-methyl-D-aspartate type glutamate receptor (NMDA receptor) consisting of
GluN1 and GluN2 subunits, D-serine has been selected as a candidate agent that
is expected to satisfy an unmet need to ameliorate antipsychotic-resistant negative
and cognitive symptoms in schizophrenia by recovering the NMDA receptor
disturbance as one of its coagonists. Meta-analyses of randomized controlled
trials of D-serine given with currently available antipsychotic drugs in patients
with schizophrenia have consistently shown a significant reduction in the rating
scores of their negative symptoms although D-serine has not yet been approved
for clinical use. This chapter begins with verification of the evidence for the
involvement of diminished NMDA receptor-mediated transmission in the patho-
physiology of schizophrenia, accumulated data illustrating the plausible mecha-
nisms from the hypofunction to the positive, negative, and cognitive symptoms
and the relationships between the NMDA dysfunction and the well-established
dopamine hypothesis assuming cerebral hyperdopaminergic activities. The con-
secutive parts verify the rationales for application of D-serine and other agonists
acting at the glycine site of the NMDA receptor for development of NMDA
receptor activity-enhancing therapy of schizophrenia and outline the preclinical
and clinical studies using these agonists. The NMDA receptor targeting strategy
is challenged by the results that the add-on treatments with augmentation of the
extracellular glycine concentrations have failed to improve the antipsychotic-
refractory symptoms of schizophrenia patients. To address this issue, the latter
parts raise the possibility to restore functioning of the forebrain NMDA receptor
by upregulating endogenous D-serine signaling at the synapses by modifying the
molecules that compose the metabolic pathways and regulatory systems of the
extracellular levels of D-serine.

Introduction

Schizophrenia is a serious brain disorder with a high prevalence of about 1%, which
causes a variety of mental and behavioral disturbances leading to a chronic disability
in individuals and social life such as a very low rate of full employment (Bouwmans
et al. 2015; McCutcheon et al. 2020). The characteristic disturbances fall into three
major categories positive, negative, and cognitive symptoms (Fig. 1).
Of these, the currently used antipsychotic-resistant negative and cognitive symp-
toms are attributed to the difficult prognosis (Fig. 1). An urgent unmet need in
schizophrenia, thus, is to develop a highly effective treatment for these two symptom
groups including blunted affect, alogia, social withdrawal, avolition, anhedonia,
executive dysfunction, working memory, attention deficits, etc. However, in contrast
to the ameliorating actions of antipsychotics on the positive symptoms, which have
been shown to occur through dopamine receptor blockade, pharmacotherapeutic
clues to improve these refractory symptoms were not available for a long time until
D-Serine: Basic Aspects with a Focus on Psychosis 497

Fig. 1 Treatment strategies for hypothetical molecular pathophysiology underlying the positive,
negative, and cognitive symptoms of schizophrenia and drug-induced schizophrenia-like psychosis
The neurotransmitter and neuromodulator mechanisms underlying the positive, negative, and
cognitive symptoms of schizophrenia and substance-induced psychosis, as inferred from clinical
and molecular pharmacological data, are described. Conventional pharmacotherapy by antipsy-
chotics with dopamine antagonist properties ameliorates the positive symptoms of schizophrenia
and novel pharmacotherapy by NMDA receptor glycine site agonists and D-serine signaling
enhancers is expected to possess efficacies on both of its antipsychotic-responsive and -resistant
symptoms.
Abbreviations: AMP amphetamine, D-Ser D-serine, GABA γ-aminobutyric acid, KET ketamine, MAP
methamphetamine, NMDAR N-methyl-D-aspartate type glutamate receptor, PCP phencyclidine

the 1980s. The discovery in 1983 that phencyclidine (PCP), which had been known
to induce schizophrenia-like negative and cognitive symptoms as well as positive
symptoms, is a noncompetitive antagonist for the N-methyl-D-aspartate
(NMDA)-type glutamate receptor (NMDA receptor) (Anis et al. 1983) (Fig. 1) has
made this receptor a target for the development of agents possessing therapeutic
efficacy on the intractable schizophrenic symptoms.
This section outlines the evidence for the involvement of the NMDA receptor
hypofunction in the pathophysiology of schizophrenia stemming from the basic and
clinical research on PCP, the road by which NMDA receptor function-enhancing
drugs, including D-serine, were introduced as novel therapeutic agents for this
disorder, and their clinical effects (Nishikawa 2011). In addition, the process from
these studies to the uncovering of the presence of endogenous D-serine in mamma-
lian brains, and the molecular mechanisms underlying the brain D-serine metabolism
and dynamics will be reviewed. Finally, the possible application of the molecules
498 T. Nishikawa et al.

that regulate the D-serine signaling for the creation of new methods for the recovery
of the NMDA receptor hypofunction in schizophrenia will be discussed.

Evidence for NMDA Receptor Hypofunction in Schizophrenia

The similarity of PCP psychosis to schizophrenia is illustrated by a reported case

in the United States in the 1970s in that psychiatrists misdiagnosed the psychi-
atric symptoms of PCP abusers as schizophrenia, resulting in an approximately
tripling of the usual incidence of schizophrenic patients who responded only
partially to antipsychotics (Petersen and Stillman 1978). This case is consistent
with the schizophrenomimetic effects of PCP, which were pointed out when it
was first developed as a dissociative anesthetic in the 1950s. Since then, PCP
psychosis has been compared to amphetamine-induced psychosis, with the for-
mer being a comprehensive model of the entire spectrum of symptoms seen in
schizophrenia (Petersen and Stillman 1978) and the latter being a model confined
to its hallucinatory-paranoid states (Connel 1958) (Fig. 1). These symptomatic
features fit with a partial response to treatment with antipsychotics, i.e., D2
dopamine receptor antagonists, in PCP psychosis and schizophrenia, and the
overall response in psychosis caused by amphetamines, well known dopamine
agonists (Fig. 1).
Great progress in the research fields of glutamate neurotransmission since the
1970s has led to the elucidation of the direct action of the schizophrenomimetic drug,
PCP, on the NMDA receptor, opening an avenue to analyze the NMDA receptor
function in schizophrenia and to develop its new treatments with NMDA receptor
activators.

NMDA Receptor Antagonists

In 1983, PCP and ketamine were revealed to noncompetitively and selectively

disrupt the NMDA receptor-mediated glutamate transmission by binding to the
PCP site within the ion channel of the NMDA receptor (Fig. 2) without significant
influences on the neuronal excitation by the alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) type glutamate receptor (AMPA receptor)- or
kainite glutamate receptor-selective agonists (Anis et al. 1983). Subsequent studies
have shown that this type of NMDA receptor is a heteromeric receptor consisting of
GluN1 and GluN2 subunits (Fig. 2).
The close relationships between the NMDA receptor hypofunction and schizophre-
nia are supported by the following clinical pharmacological facts (Fig. 1): (i) a wide
variety of competitive and noncompetitive NMDA receptor antagonists including PCP
and ketamine have been reported to induce schizophrenia-like psychotic symptoms
without exception, which embrace the positive and negative symptoms and cognitive
dysfunction (Lahti et al. 1999), and (ii) their potency of schizophrenomimetic action
parallels their affinity for the NMDA receptors (Lahti et al. 1999) as exemplified by the
D-Serine: Basic Aspects with a Focus on Psychosis 499

Fig. 2 Schematic representation of the relationships among D-serine and kynurenic acid metabolic
pathways and GluN1/GluN2-type NMDA receptor in mammalian brains
The regulatory sites of the GluN1/GluN2-type NMDA receptor and the candidate molecules and
cells for the metabolic or functional processes of D-serine and kynureate in the mammalian brains
are illustrated. The NMDA receptor complex has the multiple binding sites for L-glutamate
(L-GLU), glycine/D-serine (GLY), magnesium ion (Mg++), phencyclidine (PCP), zing ion (Zn++),
and polyamines (POLY). The heteromeric NMDA receptor forms a tetrameric ligand-gated channel
comprising two copies each of the GluN1 and GluN2 subunits. D-Serine has been demonstrated to
be mainly synthesized by SRR and to act as a coagonist for the NMDA receptor. Kynurenate occurs
via the kynurenine pathway and attenuates the NMDA receptor activity by blocking the glycine-
binding site. The interaction of D-serine with the NMDA receptor containing the GluN1 and GluN3
subunits and δ2 glutamate receptor are not shown in this scheme
Abbreviations: AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, Asc-1
Na+-independent alanine-serine-cysteine transporter 1, ASCT1 Na+-dependent broad-spectrum
neutral amino acid transporter 1, ASCT2 Na+-dependent broad-spectrum neutral amino acid trans-
porter 2, Bergmann Bergmann glia, DAO D-amino acid oxidase, D-Ser D-serine, GABAAR
γ-aminobutyric acid A receptor, Gly glycine, L-Glu L-glutamate, Müller Müller cells, NMDAR N-
methyl-D-aspartate type glutamate receptor, KYNA kynurenate, PAT1 proton/amino acid transporter
1, PCP phencyclidine, POLY polyamines, SNARE soluble N-methylmaleimide susceptibility factor
attachment protein receptor, SNAT2 sodium-coupled neutral amino acid transporter 2, SRR serine
racemase
Symbols: dotted square and line, antagonist; solid squares and lines, agonists

observations that in the stereoisomers of ketamine, the S form of ketamine, which has
a higher affinity for the NMDA receptors, is more potent to cause psychotic symptoms
than the R form, which has a lower affinity (Vollenweider et al. 1997). Furthermore, a
single challenge of small doses of PCP (Luby et al. 1959) or ketamine (Malhotra et al.
1997) has been found to elicit higher degrees and longer durations of induced
psychotic symptoms in schizophrenia patients than in healthy volunteers, suggesting
a lower level of the NMDA receptor function in schizophrenia.
500 T. Nishikawa et al.

Anti-NMDA Receptor Antibodies

The plausible implication of diminished activity of the NMDA receptor in the

pathophysiology of schizophrenia has been further affirmed by the fact that a
psychotic state resembling schizophrenia is observed in patients with encephalitis
caused by autoantibodies against NMDA receptor that disturb NMDA receptor
activity.
The anti-NMDA receptor encephalitis that was first reported by Dalmau et al.
(2007) has been depicted to manifest delusion, hallucination, disorganized thoughts,
bizarre behavioral expressions, personality changes, emotional instability, asociability
and blunted affect with aggressive and combative attitudes (Kayser and Dalmau 2011).
They are also observed in the NMDA receptor antagonist-induced psychosis and
contain positive, negative, and cognitive symptoms (Fig. 1) that meet the DSM-5
criteria of schizophrenia, whereas the difference from schizophrenia is that aggression
and violent attitudes are far more common than in schizophrenia (American Psychi-
atric Association 2013). The anti-NMDA receptor antibodies have been proved to
interact with the GluN1 subunit (Fig. 2), which is essential for the constitution of all
heteromeric NMDA receptors, thereby inducing NMDA receptor internalization and
disturbing the receptor function by preventing the binding of synaptic glutamate to the
NMDA receptors (Castillo-Gómez et al. 2017).
This series of clinical and basic findings draw the assumption that a part of the
heterogeneous psychiatric disorder defined as schizophrenia is caused by certain
anti-NMDA receptor antibodies. Indeed, patients initially diagnosed with schizo-
phrenia represent a higher positive rate for various NMDA receptor antibodies than
those with other psychiatric disorders (Steiner et al. 2013). However, Chen et al.
(2017) detected no anti-NMDA receptor antibodies in plasma samples from 78 and
234 patients with first-episode and chronic schizophrenia, respectively, rendering the
assumption debatable.

NMDA Receptor Hypofunction and Onset of Schizophrenia

Schizophrenia and the psychotic states provoked by antagonists and antibodies of

the NMDA receptor share a developmental period of onset as well as the properties
of symptomatologies. Ketamine, a noncompetitive NMDA receptor antagonist, has
long been safely employed for anesthesia in children (Kidd et al. 2016) because it
rarely produces psychotic symptoms in childhood (Reich and Silvay 1989; White
et al. 1982). Nevertheless, this drug is not utilized as an anesthetic in adolescence and
later, when the onset of schizophrenia is observed (American Psychiatric Associa-
tion 2013), because of its schizophrenomimetic action. Correspondingly, young
children or infants with the accidental intake of PCP were portrayed to incur
neurological, but not psychiatric problems (Schwartz and Einhorn 1986; Welch
and Correa 1980). As for anti-NMDA receptor encephalitis, many adult and adoles-
cent patients manifest psychiatric symptoms, while prepubertal children typically
give rise to neurological symptoms (Dalmau et al. 2019; Scheer and John 2016).
D-Serine: Basic Aspects with a Focus on Psychosis 501

The similar development-dependent expression of symptoms of schizophrenia

and NMDA receptor antagonist-induced schizophrenia-like psychosis implies that
there is a critical period (onset critical period) around puberty when the neural
information processing system of the brain, which is impaired in schizophrenia,
undergoes a change or maturation to become affected by decreased NMDA receptor-
mediated transmission (Sato et al. 1997; Hiraoka et al. 2010). The hypothesis of
NMDA receptor hypofunction in schizophrenia may, thus, also be valuable in
understanding the onset mechanism of the disorder.

NMDA Receptor System in Schizophrenia

Though the NMDA receptor hypofunction hypothesis of schizophrenia has been

tested by analysis of the genomic DNA and other biomolecules in postmortem brain
tissues, cerebrospinal fluid, and blood samples and by means of brain imaging
techniques in schizophrenia patients, the exact functional status of the NMDA
receptors and their regulatory systems in schizophrenia remains to be elucidated.
The main determinants of the NMDA receptor function are thought to be (i) the
genome DNA structure of the subunits that compose the NMDA receptor, (ii) the
functional control mechanisms of the glutamate, PCP, glycine, polyamine, zinc, and
magnesium regulatory site of the NMDA receptor (Fig. 2), and (iii) the endogenous
ligands that act on each regulatory site and their metabolism and synaptic concen-
tration control systems (Fig. 2), some of which have been reported to be altered in
schizophrenia.
No schizophrenia-specific structural abnormality has been discovered in the gene,
transcription product, or protein of the NMDA receptor subunits, but a significant
linkage was unveiled between GRIN2A (gene for GluN2A subunit) and schizophre-
nia in a recent large-scale genome-wide association study of single nucleotide
polymorphism (GWAS)(Schizophrenia Working Group of the Psychiatric Genomics
Consortium 2014). This GWAS study added a statistically meaning association of
schizophrenia with other genes encoding molecules related to glutamate neurotrans-
mission, which include GRM3 (glutamate metabotropic receptor), CLCN3 (chloride
voltage-gated channel 3), SLC38A7 (Solute Carrier Family 38 Member 7), and SRR
(serine racemase). However, their odds ratios were less than 1.15, indicating that
none of them independently contributes to the risk of developing schizophrenia.
Expressional changes in the NMDA receptor regulation site binding and subunit
mRNAs have been found in the frontal, temporal, and occipital cortices, and/or
thalamus (Hu et al. 2015; Ibrahim et al. 2000). Their regional variation proposes that
certain thalamocortical, corticothalamic, or cortico-cortical glutamate neurons could
be dysfunctional at each NMDA receptor-containing synapse. L-Glutamate amounts
determined in CSF, blood, and postmortem brain tissue of schizophrenia patients
have so far been inconclusive. The concentrations of glutamate as measured in vivo
by MRS (magnetic resonance spectroscopy) have been described to be unchanged in
the medial prefrontal cortex, dorsolateral prefrontal cortex, frontal white matter,
occipital lobe, basal ganglia, hippocampus/medial temporal lobe, and thalamus in
502 T. Nishikawa et al.

medication-free patients with schizophrenia (Iwata et al. 2018). The glycine modu-
latory site has been recognized to play a critical role in the physiological functioning
of the GluN1/GluN2 type NMDA receptor (Fig. 2), as the glycine site agonists, such
as glycine, D-serine, and D-alanine, are essential for activation of the glutamate
receptor without provoking EPSPs alone (Danysz and Parsons 1998). Accordingly,
insufficient stimulation of the glycine site following reduced or increased concen-
trations of its endogenous agonist or antagonist, respectively, may be a factor that
attenuates the NMDA receptor activity. Kynurenic acid, which is biosynthesized by
the kynurenine pathway from tryptophan and acts as an antagonist at the glycine
regulatory site (Fig. 2), has been reported in meta-analyses to be increased in the
cerebrospinal fluid of schizophrenia patients (Plitman et al. 2017). The findings
concerning the intrinsic glycine site agonists, glycine and D-serine, in biological samples
obtained from patients with schizophrenia are discussed later in section “D-Serine
Systems in Schizophrenia.”

Dopaminergic Transmission Under NMDA Receptor Hypofunction

The important question then arises as to the relationships between the NMDA
receptor hypofunction and cerebral hyperdopaminergic activity that has been well
established to be involved in the pathophysiology of schizophrenia. A body of
evidence has been accumulated arguing that disruption of the GluN1/GluN2 type
NMDA receptor-mediated glutamate transmission is accompanied by accelerated
dopaminergic transmission in the cerebrum.
Early animal studies have shown that noncompetitive antagonists for the NMDA
receptor, such as PCP and MK-801 (dizocilpine), which bind to the PCP site of the
receptor (Fig. 2), and competitive antagonists that act on the glutamate site (Fig. 2)
augment dopamine metabolism in the cerebral cortex and limbic regions including
the nucleus accumbens and olfactory tubercle (Deutch et al. 1987; Hata et al. 1990;
Rao et al. 1990; Umino et al. 1998). Furthermore, in vivo dialysis experiments have
revealed that both of these types of antagonists elicit an increase in the extracellular
dopamine concentrations in the frontal cortex and striatum in a nerve impulse-
dependent manner (Kashiwa et al. 1995; Nishijima et al. 1994, 1996). Interestingly,
the GABAA receptor agonists blocked the ability of PCP to produce an upregulation
of the extracellular dopamine levels accompanied by reduction in the extracellular
GABA concentrations in the frontal cortex (Yonezawa et al. 1998) (Fig. 1). In
conjunction with the expression of NMDA receptors on GABAergic interneurons
(Belforte et al. 2010), these results suggest the pathological changes in the cortical
neuron circuits in that blockade of NMDA receptors interrupts the tonic facilitatory
influence of glutamate transmission on the GABAergic interneurons, resulting in an
enhancement of dopaminergic activity by attenuation of the inhibitory GABAergic
transmission on the dopamine neurons (disinhibition) in the frontal cortex (Fig. 1).
In agreement with these observations, an in vivo human study using PET
(positron emission tomography) (Aalto et al. 2005), healthy subjects treated with
ketamine showed decreased radioligand binding to dopamine receptors in the
D-Serine: Basic Aspects with a Focus on Psychosis 503

posterior cingulate gyrus, retrosplenial cortex, and striatum, which indicated an

enhanced dopamine transmission (Fig. 1). This decrease correlated with the severity
of the schizophrenia-like symptoms. Moreover, the increased extracellular (synaptic)
dopamine release in the striatum after a challenge dose of amphetamine in schizo-
phrenia patients (Laruelle 1998) is also seen in the frontal cortex and striatum of rats
treated with a daily PCP injection for 3 months (Javitt et al. 2004).
These data are consistent with the concept that the NMDA receptor is implicated
in a tonic and neuronal activity-dependent inhibitory control over dopaminergic
transmission in the brain. Together with clinical observations that antipsychotics, at
least partially, attenuate the positive symptoms in PCP psychosis (Petersen and
Stillman 1978), the NMDA receptor-dopamine interactions agree with the hypoth-
esis that positive symptoms in PCP- and ketamine-induced psychosis and in schizo-
phrenia could be provoked by the NMDA receptor hypofunction (Fig. 1).

NMDA Receptor Function Enhancement Therapy

for Schizophrenia: Rationale for Application of D-Serine

Given the above data from the animal and human studies, an impaired NMDA
receptor function may elicit positive symptoms by indirectly increasing dopamine
transmission, and the negative and cognitive symptoms by affecting the extra-
dopamine systems in the brain of schizophrenia patients (Fig. 1). This assumption
is supported by observations that the NMDA receptor antagonists, PCP (Luby et al.
1959) and ketamine (Vollenweider et al. 1997), exacerbate all symptom groups
(positive, negative, and cognitive) in schizophrenia patients, whereas the dopamine
agonist, amphetamine (Luby et al. 1959), aggravates only the positive symptoms
(Fig. 1).
From this point of view, it is rationale to postulate that recovery of the NMDA
receptor function by its agonistic drugs may improve both the antipsychotic-respon-
sive positive symptoms and pharmacotherapy-resistant negative and cognitive
symptoms in schizophrenia. To this end, for a method to facilitate the NMDA
receptor function, glycine-binding site agonists (Fig. 2) were selected from agents
acting on various regulatory sites of the glutamate receptor because overstimulation
of the glutamate-binding site, but not the glycine site, has been found to induce
cytotoxicity and convulsions (Johnson and Jones 1990).

Preclinical Studies

To perform animal experiments for the development of NMDA receptor function

enhancement therapy for schizophrenia, PCP-induced abnormal behavioral changes
are used as models for the antipsychotic-resistant schizophrenic symptoms since
they have been depicted to be minimally antagonized by antipsychotic drugs with
potent D2 and 5HT-2 receptor blocking actions. The NMDA receptors of the GluN1/
GluN2 type are equipped with regulatory sites for the control of their activity, such as
504 T. Nishikawa et al.

L-glutamate- and zinc-binding sites in the GluN2 subunit, glycine-binding sites in

the GluN1 subunit, and PCP-, magnesium-, and polyamine-binding sites in the ion
channel (Fig. 2). Among these, the glycine-binding site is unique in that stimulation
by agonists acting on this site does not activate the NMDA receptor alone, but is
required for physiological activation by the neurotransmitter L-glutamate as intro-
duced in section “NMDA Receptor System in Schizophrenia” (Danysz and Parsons
1998). Due to these features, the glycine site agonists are referred to as coagonists for
the NMDA receptor (Danysz and Parsons 1998). The glycine site is distinct from the
strychnine-sensitive inhibitory glycine receptor and is also called the strychnine-
insensitive glycine site.
Facilitation of the NMDA receptor activity has been achieved by D-serine and
D-alanine as agents acting on the glycine modulatory site because: (i) glycine itself
also potently acts at the inhibitory glycine receptor; and (ii) the two D-amino acids
display highly stereoselective actions at the glycine site with much more potent
enhancing effects on the NMDA receptor-mediated transmission than the
corresponding L-isomers, being considered to be useful in determining the specific-
ity of their efficacies on the NMDA receptors (Contreras 1990; Danysz and Parsons
1998; Tanii et al. 1991, 1994). Another reason was that when the aforementioned
research was initiated, it was believed that D-amino acids were absent in the
mammalian tissues, so exogenously administered D-serine and D-alanine would
not be easily broken down due to the lack of a specific metabolic system, and their
influences were expected to be sustained (Tanii et al. 1991, 1994).
The intraventricular administration of D-serine and/or D-alanine, but not the
respective L-forms, have been demonstrated to inhibit hyperactivity, stereotypy,
and ataxia induced by the schizophrenomimetic NMDA receptor antagonist, PCP,
in a dose-related manner independently by two different research groups (Contreras
1990; Tanii et al. 1991, 1994). The glycine site-mediated nature of the anti-PCP
effects is verified by the stereoselectivity to the D-forms and significant attenuation
by the selective competitive antagonists for the glycine site of the NMDA receptor,
7-chlorokynureate and 5,7-dichlorokynureate (Tanii et al. 1994). The fact that
D-serine and D-alanine exhibit a minimum displacement on the D2 and 5HT-2
receptor-binding sites (Tanii et al. 1994) further differentiates the effects of these
D-amino acids from those of conventional antipsychotic drugs. D-Serine and other
agonists for the glycine site of the NMDA receptor have been revealed to possess
therapeutic effects on animal models of cognitive dysfunctions that are thought to be
related to schizophrenia, such as impairments in a working memory task of social
recognition, conditioned freezing response, executive function, and novel object
recognition (Fone et al. 2020).
The potential therapeutic efficacy of facilitation of the NMDA receptor function
on the positive symptoms has also been examined in dopamine agonist-injected
animals as their models. D-Alanine and D-serine intraventricularly applied have
been reported to lower hyperlocomotion evoked by an indirect dopamine agonist,
methamphetamine (Hashimoto et al. 1991). Accelerated dopamine transmission by
PCP as estimated by dopamine utilization after dopamine synthesis inhibition has
been shown to be diminished by intraventricularly infused D-alanine, but not
D-Serine: Basic Aspects with a Focus on Psychosis 505

L-alanine (Umino et al. 1998). Daily intra-nucleus accumbens supplementation of

exogenous D-serine prevents development of behavioral sensitization, a model for
relapse of positive symptoms, by daily systemic administration of cocaine, another
indirect dopamine agonist (Curcio et al. 2013). This set of results suggest that
agonists for the glycine site of the NMDA receptor could treat the positive symptoms
of schizophrenia (Fig. 2).
Accordingly, the effects of stimulation of the NMDA receptor glycine modulatory
site on distinct animal models of schizophrenic symptoms illustrate that the allosteric
agonists or coagonists for the NMDA receptor acting at the glycine site alone have
the potential to improve the overall positive, negative, and cognitive symptoms of
schizophrenia (Fig. 1).

Clinical Studies

With reference to the above data of animal experiments, randomized double-blind

clinical trials were conducted in which agonists of the NMDA receptor glycine
regulatory site, such as glycine, D-serine, D-alanine, D-cycloserine, sarcosine
(a glycine transporter inhibitor), and sodium benzoate, were add-ons administered
to schizophrenia patients treated with conventional antipsychotics whose positive
symptoms were improved. These trials included the positive results that glycine
site agonists including D-serine significantly reduced the scores of the negative
and/or cognitive symptoms (Chang et al. 2020; Goh et al. 2021; Singh and Singh
2011; Tsai and Lin 2010). It deserves attention that D-serine also remedies abnor-
malities in the mismatch negativity of event-related potentials, which are illus-
trated to be closely related to information processing involved in auditory
cognitive functions and NMDA receptor activity and are seen in schizophrenia
and its animal models (Featherstone et al. 2018).
As for glycine and D-serine, which are full agonists for the NMDA receptor
glycine site, and a glycine transporter inhibitor, sarcosine, meta-analyses also
report significant improvements in the negative symptoms and/or cognitive symp-
toms (Chang et al. 2020; Goh et al. 2021; Singh and Singh 2011; Tsai and Lin
2010). However, D-cycloserine described in these reports failed to have a signif-
icant efficacy on any of the three major symptom domains of schizophrenia
(Kuppili et al. 2021), being due to the partial agonist nature of D-cycloserine for
the receptor site. Therefore, it can be inferred that enhancement of the NMDA
receptor function reduces the antipsychotic-resistant symptoms through extra-
dopamine transmission systems.
It is of note that no such additional improvement was observed in schizophrenia
patients receiving clozapine with D-cycloserine (Goff et al. 1999), glycine (Potkin
et al. 1999), D-serine (Tsai et al. 1999), or sarcosine (Lane et al. 2006), which hints
that clozapine may have an NMDA receptor function-activating effect. In contrast, a
more recent study depicted that sodium benzoate (1 or 2 g for 6 weeks) plus
clozapine produced greater ameliorating effects on the negative symptoms than
placebo plus clozapine (Lin et al. 2018).
506 T. Nishikawa et al.

Since the previously mentioned test drugs have problems, such as poor
peripheral-to-brain transferability (need for excessive peripheral doses), side effects
from long-term continuous use, nonselectivity or low potency of action on the
glycine modulatory site, they are not suitable for long-term clinical use and the
creation of new drugs is awaited. To overcome these concerns, bitopertin, a blood–
brain barrier (BBB)-permeable and selective type I glycine transporter inhibitor, was
developed and large add-on double-blind randomized placebo-controlled trials were
conducted (Bugarski-Kirola et al. 2017). However, they failed to prove any statis-
tically significant improvement in the negative and/or cognitive symptoms of
schizophrenia patients with antipsychotic medication, challenging the NMDA recep-
tor disfunction hypothesis of schizophrenia (Bugarski-Kirola et al. 2017)

Issues and Improvement of NMDA Receptor Function Enhancement

Therapy

Taking into account the lack of the ameliorating effects of the selective glycine
transporter inhibitor, the below data extrapolate that it is more rationale to upregulate
the extracellular concentrations of D-serine as a mean of facilitating the NMDA
receptor function than to increase those of glycine: (i) glycine requires about
30 times the dose of D-serine to improve the schizophrenic symptoms (Goh et al.
2021; Singh and Singh 2011) despite a similar BBB permeability and ED50s for the
GluN1/GluN2 heteromeric NMDA receptor function-enhancing effects between the
two NMDA receptor coagonists (Matsui et al. 1995), (ii) it has been suggested that
D-serine and glycine binds to the synaptic and extrasynaptic NMDA receptors,
respectively (Papouin et al. 2012), (iii) glycine, unlike D-serine, is a selective agonist
for the inhibitory glycine receptor (Danysz and Parsons 1998), (iv) D-serine, but not
bitopertin, amended in schizophrenia patients the impairment of mismatch negativity
that has been indicated to be related to the NMDA receptor dysfunction and
disturbed information processing (Kantrowitz et al. 2016, 2017, 2018).
Since long-term administration of high doses of D-serine itself in the periphery poses
a risk of nephrotoxicity and since D-serine, but not glycine, has been shown to be an
intrinsic coagonist for the NMDA receptor as described in the next section, one of the
future strategies for developing drugs for augmentation of the NMDA receptor function
is to search for their target molecules that regulate the amount of D-serine at the
synapses.

Modulation of Brain D-Serine Signaling for Development of Next

Generation Antipsychotics

It had generally been believed that D-amino acids and L-sugars do not occur in nature.
The homochirality theories were challenged by the fact that D-amino acid oxidase
(DAO)activity was uncovered in mammalian tissues in 1935 by Krebs et al. This
intriguing discovery suggested the existence of certain D-optimal isomers of amino
D-Serine: Basic Aspects with a Focus on Psychosis 507

acids as substrates for the enzyme. D-Serine is one of the substrates with a high affinity
for this DAO, and was observed in free form in high concentrations in the earthworm
(Rosenberg and Ennor 1960) and silkworm (Srinivasan et al. 1962) tissues. However,
the free D-isomer of serine was not found in mammals for a long time afterward. The
coagonist action of D-serine on the NMDA receptor, thus, had been considered to be
an artificial phenomenon under in vitro experimental conditions until the detection of
endogenous D-serine in mammalian brains in 1992 (Hashimoto et al. 1992a, b). The
presence of D-serine raises the possibility that the metabolic processes of D-serine and
control pathways of synaptic D-serine signaling to the NMDA receptor may be
suitable targets for the creation of agents that ameliorate the schizophrenic symptoms
by positive modulation of the NMDA receptor function (Fig. 1).

Detection and Distribution of Endogenous D-Serine in Mammalian

Brains

The author’s research group first proved the natural occurrence of D-serine in
mammals by using gas chromatography-mass spectrometry in 1992 (Hashimoto
et al. 1992a, b) during the course of investigation in the rat to develop a novel
treatment for schizophrenia with enhancers of the NMDA receptor function includ-
ing D-serine and D-alanine that bind to the NMDA receptor glycine site as men-
tioned in the previous section “NMDA Receptor Function Enhancement Therapy for
Schizophrenia: Rationale for Application of D-Serine” (3.1~3.3). These D-amino
acids are highly polar and do not readily cross the BBB, making them unsuitable for
peripheral administration as therapeutic agents. Therefore, their fatty acid com-
pounds, N-myristoyl-D-serine and N-myristoyl-D-alanine, were prepared and their
efficacy as potential therapeutic agents for schizophrenia was indicated by their anti-
PCP properties in the rat (Tanii et al. 1991). The glycine site antagonist-reversible
nature of their anti-PCP properties and the lack of their direct binding to the glycine
site (Tanii et al. 1991) pointed out the plausibility that the fatty acid compounds
could liberate free D-serine and D-alanine in the brain, which stimulate the glycine
site. To examine this assumption, the author’s research group established the gas-
chromatgraphic method and HPLC with fluorometric detection for separation and
quantitation of chiral amino acids and discovered the presence of a large amount of
D-serine in the forebrain regions of the control rats without peripheral injections of
(0.2~0.3 μ mol/g wet weight) (Hashimoto et al. 1992a, b, 1993a, b).
The concern that D-serine could be an artifact product by nonspecific procedures
(e.g., nonenzymatic conversion of L- to D-serine during sample manipulation) may
be negated because: (i) the D-serine concentrations vary markedly among tissues and
brain regions or in the same brain portion at different developmental stages, and
(ii) the measured values are alike even though sample processing differs among the
detection methods (Hashimoto et al. 1992a, b, 1993a, b; Nishikawa et al. 1994).
Endogenous D-serine is enriched in the brain and at low or trace levels in the
peripheral organs and blood (Hashimoto et al. 1993b). In the brain of the adult
period, the concentrations of D-serine are high in the forebrain portions including the
508 T. Nishikawa et al.

cerebral cortex, hippocampus, striatum, and limbic system (containing the olfactory
tubercle, nucleus accumbens, and septum), moderate in the diencephalon and mid-
brain, and marginal in the pons-medulla and cerebellum (Hashimoto et al. 1993b).
The uneven distribution of D-serine is closely correlated with those of the radio-
ligand binding densities to L-glutamate, glycine, and PCP site of the NMDA
receptor (Hashimoto et al. 1993b). In contrast, the D-serine levels in each brain
region are almost homogeneous at birth (Hashimoto et al. 1995). The developmental
changes in the distribution patterns of D-serine are especially similar to those of the
GRIN2B mRNA expression in the brain (Hashimoto et al. 1993b, 1995, Nishikawa
2011). Together with the fact that D-serine is a selective agonist of the glycine
regulatory site (Fig. 2) that is indispensable for NMDA receptor activation, the very
similar distribution patterns throughout postnatal development between D-serine and
NMDA receptors agrees with the prediction that D-serine is an intrinsic coagonist of
the NMDA receptors.

Biosynthesis of D-Serine

In mammalian brains, endogenous D-serine has been considered not to originate from
enteric bacteria because the tissue D-serine concentrations are similar between normal
and germ-free rats (Hashimoto et al. 1993b). Early studies of D-serine synthesis
clarified in the rat that (i) the intraperitoneal administration of L-serine elevated the
D-serine level in the cerebral neocortex in 8-day-old rats, and vice versa (Takahashi
et al. 1997), and (ii) in the experiments using radioactive tracers, brain D-serine was
converted from L-serine applied intraventricularly whereas D-glucose and glycine
administered centrally or L-serine loaded peripherally failed to become D-serine
(Dunlop and Neidle 1997). These phenomena suggest that serine racemase (SRR),
which is involved in the interconversion of D- and L-serine, is present and important
for the D-serine synthesis (Fig. 2). Subsequently, the SRR protein and its cDNA were
identified and isolated by Wolosker et al. (1999a, b). Four types of prepared SRR gene-
knockout mice consistently display that the D-serine levels in various forebrain brain
regions decreased to 9~22 % of the level in the corresponding wild-type mice (Basu
et al. 2009; Horio et al. 2011; Labrie et al. 2009; Miyoshi et al. 2012), indicating that
SRR is the main D-serine-synthesizing enzyme in the D-serine-rich brain areas. SRR
is predominantly localized in the neurons under physiological conditions (Balu et al.
2014; Miya et al. 2008). However, brain injury by controlled cortical impact causes
enhanced expression of SRR in the astroglia (Perez et al. 2017).
The D-serine concentrations in both tissues and extracellular fluid are drastically
reduced in parallel in the SRR knockout mice (Horio et al. 2011) and the distribution
pattern of SRR is similar to that of the GluN2B subunit of the NMDA receptor
throughout life (Miya et al. 2008). These observations support the idea that drugs
that increase the SRR activity could augment the NMDA receptor function by
elevating the extracellular D-serine levels in the brain.
On the other hand, in the brain of mice in which D-3-phosphoglycerate
dehydrogenase, involved in the L-serine synthesis, was selectively knocked out
D-Serine: Basic Aspects with a Focus on Psychosis 509

in the glial fibrillary acidic protein (GFAP)-expressing cells (mainly astroglia), the
brain D-serine concentrations markedly decreased with a depletion in the L-serine
levels (Yang et al. 2010). This finding accords the view that D-serine in the brain is
dependent on L-serine supplied by the GFAP-expressing cells. The glycine cleav-
age system may also participate in the regulation and/or synthesis of brain
D-serine because the neocortical D-serine concentrations were downregulated in
the patients with non-ketotic hyperglycinemia deficient in the cleavage system
activity and rats treated with the inhibitor of the glycine degrading system (Iwama
et al. 1997). Consequently, facilitatory agents for the D-3-phosphoglycerate dehy-
drogenase and glycine cleavage system could be candidates as enhancers of the
NMDA receptor function by their possible increasing effects on the extracellular
D-serine levels.

Storage of D-Serine

The localization of D-serine in the mammalian brain tissues remains a major

debatable matter. The first examination by a specific antibody against D-serine
detected the D-serine immunoreactivity chiefly in the astroglia (Schell et al. 1995)
(Fig. 2). Indeed, D-serine was reported to be stored in a cytosolic pool or secretory
vesicles in the cortical astroglia (Martineau et al. 2013). However, other subsequent
immunocytochemical studies have found the immunostaining of D-serine as well as
its synthesizing enzyme, SRR, mainly in neurons (Balu et al. 2014; Benneyworth
et al. 2012; Kartvelishvily et al. 2006; Miya et al. 2008) (Fig. 2). These observations
coincide with the results that the conditional deletion of the SRR gene in the
CaMKII-expressing forebrain neurons caused a significant reduction in the tissue
and extracellular D-serine concentrations in the hippocampus (Ishiwata et al. 2015).
More recent work using immunohistochemistry and electron microscopy (Wong
et al. 2020) has revealed that D-serine and SRR are localized in the dendrites and
postsynaptic density in the hippocampal neurons. The detection of the D-serine-like
immunoreactivity in the Bergmann glia, Müller cells, microglia, and oligodendroglia
awaits further verification (Nishikawa 2011) (Fig. 2).
The intracellular storage sites for D-serine could be related to the Golgi apparatus
because SRR has been depicted to be co-localized with a Golgi body-linked protein,
Golga3, at the perinuclear Golgi area, cytosol, and the process of neurons and glia
cultured from the rat cerebral cortex (Dumin et al. 2006). Golga 3 has been found to
elevate the amounts of SRR by attenuationg ubiquitination of the enzyme. The rat
orthologue of human 30 -phosphoadenosine 50 -phosphosulfate transporter-1 (PAPST-1),
which influences the D-serine incorporation and liberation in the Xenopus oocyte gene
expression system, has also been found to have a punctiform distribution in the
cytoplasm partly associated with the Golgi apparatus and a denseness near the nucleus
(Shimazu et al. 2006).
Taken together, D-serine might, at least in part, be synthesized in the neuronal
perinuclear Golgi region and translocated by PAPST-1 across organella mem-
branes to cytoplasmic storage sites for extracellular release. Molecular systems
510 T. Nishikawa et al.

specific for these intracellular metabolic processes of D-serine could be included in

the target candidates for development of a D-serine signal modifier useful for the
treatment of schizophrenia.

Extracellular D-Serine

In vivo microdialysis experiments in the medial frontal cortex of freely moving

animals has proved substantial concentrations of D-serine in the extracellular fluid
(approximately 7 μM), indicating that, physiologically, D-serine directly acts on the
glycine-binding site of the NMDA receptor in the synaptic cleft (Hashimoto et al.
1995) (Fig. 2). The extracellular D-serine levels vary among the brain regions and
are positively correlated with the tissue D-serine levels and the binding densities of
the NMDA receptor glutamate, glycine, and PCP site (Hashimoto et al. 1993b,
1995).

Involvement of Neurons and Glia in Extracellular D-Serine Regulation

The NMDA receptor-associated regional variation of the extracellular concentra-
tions of D-serine suggests its neurotransmitter properties. However, when a
depolarizing agent, veratridine, is injected into the medial frontal cortex through a
dialysis probe, the extracellular fluid levels of the neurotransmitters, L-glutamate and
glycine, are remarkably elevated, but those of D-serine significantly decrease
(Hashimoto et al. 1995; Ishiwata et al. 2018; Umino et al. 2017). The effects of
depolarization are completely eliminated by simultaneous local perfusion of the
nerve impulse blocker, tetrodotoxin (Hashimoto et al. 1995). Tetrodotoxin alone
rapidly reduces the concentrations of the neurotransmitter, dopamine, in the extra-
cellular fluid to an undetectable level, as previously reported (Nishijima et al. 1996),
but causes a slight increase in the D-serine levels. After chelating calcium ions in the
dialysis tube, the extracellular dopamine levels promptly become undetectable while
the D-serine concentrations slightly increase (Hashimoto et al. 1995).
These findings uncover a difference in the mode of regulation by neurons
between D-serine and the classical neurotransmitters. The lack of the neuronal
activity-dependent increase and the calcium chelation-induced reduction in the
extracellular D-serine concentrations may reflect the control system for the synaptic
D-serine equipped with unknown types of molecular and cellular mechanisms, such
as non-vesicular and neuron–glia interaction-mediated release.
In fact, release of D-serine from synaptic vesicles purified from the rat cerebral
cortex was insensitive to a potent blocker of vesicular neurotransmitter uptake
(bafromycine A1) (Kartvelishvily et al. 2006). Moreover, involvement of the glial
activity in the regulation of the extracellular D-serine concentrations has been
consistently shown by in vivo dialysis and in vitro brain slice experiments by their
decline following application of fluorocitrate, a selective and reversible glial toxin
(Kanematsu et al. 2006; Henneberger et al. 2010; Ishiwata et al. 2018; Umino et al.
2017). Also, the NMDA receptor activity has been described to be tuned by the
extracellular D-serine released through the neutral amino acid transporter, Asc-1,
D-Serine: Basic Aspects with a Focus on Psychosis 511

expressed in the SRR-harboring neurons that synthesize D-serine from L-serine

produced by astroglial D-3-phosphoglycerate dehydrogenase (Neame et al. 2019).

Regulatory Molecules for Extracellular D-Serine Signaling

The exact organelles and molecular machinery essential for storage and release of
the extracellular D-serine are still unknown although Martineau et al. (2013)
suggested the possible involvement of the SNARE (soluble N-ethylmaleimide-
sensitive factor attachment protein receptor) complex and calcium-dependent vesic-
ular exocytosis in the D-serine liberation. On the one hand, synaptic receptors for the
excitatory and inhibitory neurotransmitters are found to regulate the extracellular
D-serine concentrations in mammalian brains.
The AMPA receptor has been demonstrated to be implicated in the phasic
attenuating influence on the extracellular D-serine signaling based upon the follow-
ing observations using an in vivo dialysis technique (Ishiwata et al. 2013b, 2018)
(Fig. 2): (i) the selective AMPA receptor agonist, s-AMPA, given into the intra-
medial frontal cortex via the dialysis tubing cause a concentration-dependent
decrease in the extracellular D-serine levels, which is augmented by cyclothiazide
that prevents AMPA receptor desensitization, and (ii) the reducing effects of
s-AMPA are inhibited by a general AMPA/kainate receptor antagonist, 2,3-dioxo-
6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, and a
calcium-permeable AMPA receptor antagonist, 1-naphthyl acetyl spermine.
The blockade of the calcium-permeable AMPA receptor may, therefore, contrib-
ute to repair of the presumed NMDA receptor dysfunction in schizophrenia by
restoring the reduced D-serine signaling under the overactivation of the AMPA
receptor. An experimental approach to this potential clinical application is instanced
in section “Treatment of Schizophrenia by Modulating Extracellular D-Serine
Signaling.”
The GABAA receptor has, in turn, been pointed out to exert a tonic elevating
regulation of the extracellular D-serine concentrations in the medial frontal cortex by
an in vivo dialysis study (Umino et al. 2017) (Fig. 2). Intra-medial frontal perfusion
of a selective GABAA receptor antagonist, bicuculline, results in a dose-dependent
reduction in the extracellular D-serine levels in the cortical portion, which is reversed
by a selective agonist for the GABAA receptor, muscimol. The reducing effect is
mimicked by another GABAA receptor antagonist, gabazine, but by none of the
GABAB and GABAA-rho receptor agents, including saclofen, baclofen, and
(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid. The bicuculline-induced
decrease in the D-serine levels in the cortical extracellular fluid leads to hypo-
function of the NMDA receptor as revealed by diminution of the increased responses
of the extracellular taurine concentrations to NMDA, supporting the coagonist role
of D-serine in NMDA receptor functioning.
Hence, certain GABAA agonists could facilitate the NMDA receptor activity by
enhancing the extracellular D-serine concentrations. In order to develop such
drugs, it is necessary to identify the unknown cell types that regulate the amounts
of D-serine at the synapse and the types of GABAA receptor subunits expressed
therein.
512 T. Nishikawa et al.

D-Serine As an Endogenous Coagonist for the NMDA Receptor

Compelling evidence has been accumulated indicating that physiological activation
of the NMDA receptor requires as its coagonist D-serine, rather than glycine, in the
glutamate synapses of the neocortex, hippocampus, and cerebellum. Selective elim-
ination of the intrinsic D-serine by means of application of DAO that does not
significantly degrade glycine attenuates the NMDA-provoked increase in the nitric
oxide activity and cGMP formation in cerebellar slices, and spontaneous NMDA
receptor-mediated synaptic excitatory postsynaptic currents in cultured hippocampal
neurons (Mothet et al. 2000). Furthermore, D-serine removal by DAO inhibits the
induction of the long-term potentiation that is sensitive to antagonists for the
L-glutamate and glycine site of the NMDA receptor in the cultured neurons and
slices prepared from the hippocampus (Yang et al. 2003). In agreement with these
data, in vivo dialysis studies demonstrate the NMDA receptor hypofunction as
assessed by the rate of increase in the extracellular taurine concentration by
NMDA and a significant reduction in the extracellular levels of D-serine, but not
glycine, in the hippocampus of mice lacking SRR in the CaMKII-expressing neu-
rons (Ishiwata et al. 2015) or in the medial frontal cortex perfused with bicuculline
(Umino et al. 2017), However, it cannot be totally denied that either D-serine or
glycine as the coagonist varies depending on the brain regions because sole depletion
of glycine by glycine oxidase weakened the NMDA receptor-associated excitatory
currents in the perforant path–dentate gyrus, but not the medial Schaffer collaterals,
in the hippocampal slice preparations (Le Bail et al. 2015).
Although the exact mechanisms for the selection of D-serine or glycine as the
NMDA receptor coagonist are unclear, the results that D-serine and glycine act on
the synaptic and extrasynaptic NMDA receptor, respectively, by the above-
mentioned enzymatic exclusion of either of the two amino acids (Papouin et al.
2012) suggest the specific cellular and molecular setups for control of the respective
intrinsic allosteric agonists. The distinct modulations of the extracellular D-serine
and glycine levels by the AMPA or GABAA receptor (Ishiwata et al. 2013b, 2018;
Umino et al. 2017) favor the idea that these receptors consist of the putative setups
for the D-serine signaling.

Treatment of Schizophrenia by Modulating Extracellular D-Serine

Signaling
In terms of the coagonist nature of D-serine for the NMDA receptor, optimizing the
extracellular D-serine levels by tuning their synaptic modulators, such as AMPA and
GABAA receptors (see the two prefious sections entitled “Regulatory Molecules for
Extracellular D-Serine Signaling”), could be another rational approach to normalize
the putative dysfunction of the NMDA receptor in schizophrenia.
From this point of view, the possible development of pharmacotherapy for
schizophrenia that restores D-serine signaling by blockade of the calcium-permeable
AMPA receptor is under investigation (Umino et al. 2018), focusing on the follow-
ing points: (a) calcium-permeable AMPA receptors exert an inhibitory influence on
the extracellular D-serine signaling (Ishiwata et al. 2013b), and (b) inhibition of the
NMDA receptor activity has been shown to be compensated by increased
D-Serine: Basic Aspects with a Focus on Psychosis 513

extracellular L-glutamate release (Moghaddam and Adams 1998), which could

overstimulate the calcium-permeable AMPA receptors and reduce D-serine signal-
ing, leading to a vicious cycle of further loss of the NMDA receptor function.
Subcutaneous injection of a selective calcium-permeable AMPA receptor antagonist
did not induce activity changes alone, but suppressed the abnormal behavior in a
schizophrenia model induced in animals treated with NMDA receptor antagonists
(PCP and dizocilpine (MK-801)) or dopamine agonist (methamphetamine) without
significantly affecting the behavior by itself (Umino et al. 2018), supporting the
concept that calcium permeable-AMPA receptor blockade may improve both the
antipsychotic-resistant and -responsive schizophrenia symptoms.

Uptake of D-Serine

Saturated uptake of D-serine (Fig. 2) was observed in in vitro experiments in which

radioactive D-serine accumulation was investigated in cultured C6 glioma cells
(Hayashi et al. 1997) and brain homogenates (Yamamoto et al. 2001). However,
no D-serine-specific transporters have been identified to date. Various amino acid
transporters including Na+-dependent broad-spectrum neutral amino acid transporter
1 (ASCT1), ASCT2, Na+-independent alanine-serine-cysteine transporter 1 (Asc-1),
proton/amino acid transporter 1 (PAT1), and sodium-coupled neutral amino acid
transporter 2 (SNAT2) retain affinity for D-serine on the micromolar order (Bodner
et al. 2020; Nishikawa 2011) (Fig. 2).
Since D-serine is a coagonist, its extracellular fluid level should be maintained
within a specific range in which the NMDA receptor is appropriately activated,
whereas classic transmitters need to be rapidly eliminated from the synaptic cleft to
terminate their stimulations of the corresponding receptors. Accordingly, D-serine-
incorporating molecules are assumed to have characteristics that differ from those of
neurotransmitters.
In the perspective of therapeutic drug development, the inhibitors of trans-
porters with a relatively high affinity for D-serine are expected to increase the
synaptic D-serine levels and enhance the NMDA receptor function. S-Methyl-L-
cysteine, a nonspecific Asc-1 inhibitor, elevated the extracellular D-serine levels
by around 40% in vivo (Ishiwata et al. 2013a). However, no studies have examined
the effects of S-methyl-L-cysteine or other Asc-1 inhibitors on animal models of
schizophrenia.

Degradation of D-Serine

Degradation of brain D-serine by D-amino acid oxidase (DAO) has been demon-
strated by the experiments revealing that the cerebellar tissue concentrations of D-
serine and D-alanine, which are proved to be stereoselective substrates for DAO
(Konno and Yasumura 1984), markedly increase in mature mutant mice with
deficiency of the enzyme activity (Hashimoto et al. 1993a) (Fig. 2). DAO was
514 T. Nishikawa et al.

initially found by Krebs in 1935 and later disclosed to be inhibited by chlorprom-

azine, a classical antipsychotic, in the diencephalon (Yagi et al. 1956). The substrate
property of D-serine for DAO interacting with the pioneering antipsychotic drug
have intimated that DAO inhibitors could improve a wide range of schizophrenic
symptoms by D-serine-mediated facilitation of the NMDA receptor (Lane et al.
2013; Lin et al. 2018).
From the decomposition of D-serine by DAO, it is speculated that DAO
inhibitors may increase the concentration of D-serine acting on the NMDA recep-
tors in the brain. However, this idea seems to be argued against by the facts that the
activity of this enzyme is extremely low in the forebrain areas, where brain
dysfunction in schizophrenia is presumed to occur, and that even in mice lacking
this enzyme activity, the increase in the neocortical D-serine concentrations has
been shown to be minimal or insignificant (Nishikawa 2011) as compared to the
wild-type mice. Indeed, the DAO inhibitors, 5-chlorobenzo[d]isoxazol-3-ol and
sodium benzoate, have been documented to not cause an increase in the plasma or
brain levels of D-serine, attenuation of PCP-induced abnormal behavior as an
animal model of schizophrenic symptoms, or NMDA glycine site antagonist-
sensitive amelioration of the behavioral change (Matsuura et al. 2015; Sershen
et al. 2016). These results suggest that improvement by add-on administration
studies of sodium benzoate of negative symptoms and cognitive impairment in
schizophrenia (Lane et al. 2013) could be produced by a mechanism other than
DAO inhibition.
G72 is a primate-specific gene identified in the chromosomal region 13q33 of the
schizophrenia susceptibility locus, being assumed to encode the DAO activator
protein (Chumakov et al. 2002). Although it is an interesting molecule that has
been reported to be associated with schizophrenia (Chumakov et al. 2002;
Nishikawa 2011), there is still much debate about the function, physiological and
pathophysiological significance of its transcript and protein (Ishiwata et al. 2017).

D-Serine Action on GluD2 and GluN1/GluN3 Glutamate Receptors

Not only the GluN1/G luN2A~2D heteromeric NMDA receptor but also the GluD2
glutamate receptor (Naur et al. 2007; Kakegawa et al. 2011) and GluN1/
GluN3A~3B type NMDA receptor (Danysz and Parsons 1998; Pérez-Otaño et al.
2016) have been shown to harbor physiological binding sites of intrinsic D-serine
with KD values in the 107 and 104 M ranges, respectively. The GluD2 receptor-D-
serine interaction has been demonstrated to regulate the cerebellar LTD and motor
coordination in mice (Kakegawa et al. 2011). The GluN1/GluN3 receptors are
manifested to take part in control of the LTP formation and synaptic maturation
although the exact electrophysiological properties of action of D-serine on the
glutamate-insensitive receptors are still elusive due to the reports that they are
excitatory, inhibitory, or have no significant influence (Pérez-Otaño et al. 2016).
On the basis of these data, D-serine could be expected to display therapeutic
efficacies on certain cognitive deficits in schizophrenia by the regulation of glutamate
D-Serine: Basic Aspects with a Focus on Psychosis 515

synaptic plasticity through the actions on the GluD2 and GluN1/GluN3 receptors.
To obtain evidence for these relationships requires further experimental and clinical
investigations.

D-Serine Systems in Schizophrenia

The coagonist property of D-serine intimates that the assumed NMDA receptor dys-
function in schizophrenia could be caused by reduced D-serine signaling in the brain. In
support of this idea, a recent GWAS study on big data has disclosed a significant
association with schizophrenia of the chromosomal locus encoding the SRR gene
(Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014).
Indeed, SRR gene knockout mice, in which the tissue and extracellular D-serine
levels markedly decreased in the brain, exhibit various changes serving as schizo-
phrenia models. These changes include the NMDA receptor hypofunction as
revealed by a diminished inward current and LTP formation via the receptor,
augmentation of NMDA receptor blockade-induced abnormal behavior, and distur-
bance of prepulse inhibition (Basu et al. 2009; Labrie et al. 2009). Furthermore, the
electrophysiological and behavioral impairments, at least in part, were improved by
D-serine or antipsychotic drugs.
In the postmortem brains of schizophrenia patients, however, no studies have so far
reported significant changes in the tissue D-serine concentrations in the prefrontal,
temporal, and parietal cortical areas (Kumashiro et al. 1995; Bendikov et al. 2007).
The expression amounts of proteins and mRNAs for the D-serine metabolic enzymes,
SRR and DAO, in the postmortem brain tissues are controversial among research
groups (Hu et al. 2015; Bendikov et al. 2007; Keller et al. 2018; Steffek et al. 2006).
The blood and cerebrospinal fluid D-serine levels in schizophrenia are also debatable
matters (Brouwer et al. 2013; Cho et al. 2016). Some investigations have cast doubt on
the significance of the blood D-serine levels as an index of the brain D-serine
pathology. The D-serine concentrations in the blood have been demonstrated not to
reflect those in the brain tissues by the experiments that brain-specific depletion of the
L-serine synthesizing enzyme resulted in a marked decrease in brain, but not blood,
D-serine levels in the adult genetically modified mice (Yang et al. 2010). Deletion of
the SRR gene yields a drastic reduction in the D-serine levels in various brain portions
without affecting those in the serum of the mouse (Miyoshi et al. 2012)
Despite the lack of direct evidence for D-serine signal deficit in biological samples
of schizophrenia patients, it is of interest to note that an increase in the density of the
NMDA receptor glycine-binding site, on which D-serine selectively acts, was observed
in various regions, such as the somatosensory and prefrontal cortices, supramarginal
and angular gyri, and visual cortex of postmortem schizophrenia brains (Ishimaru et al.
1994) because this phenomenon could be a consequence of the compensatory
upregulation of the NMDA receptor to inadequate D-serine signaling. This assumption
is in line with the recent PET observations indicating the reduced frequency of D-
serine-induced channel opening of the NMDA receptor that the binding ability of [123I]
CNS-1261, a ligand selectively binding to the PCP site of the NMDA receptor ion
516 T. Nishikawa et al.

channel significantly decreased in the hippocampus of schizophrenia patients

(Pilowsky et al. 2006). These findings further corroborate the value of the new strategy
that elevates or restores the extracellular D-serine concentrations by creating agents
targeted for their regulatory molecular pathways as discussed in this section.

Conclusions

Attenuated transmission via the NMDA receptor in the brain of patients with
schizophrenia has been corroborated by the previous observations that
schizophrenia-like positive, negative, and cognitive symptoms are caused by com-
petitive and noncompetitive NMDA receptor antagonists, and anti-NMDA receptor
autoantibodies with internalizing NMDA receptors from the cell surface. This
concept is further supported by the hypersensitivity of schizophrenia patients to
the psychotomimetic action of the NMDA receptor antagonist as compared to
healthy volunteers, suggesting reduced basal activity levels of the NMDA receptor
in the patients. Moreover, the NMDA receptor blockade results in overactivation of
the cortico-limbic dopaminergic neurons that have been considered to produce
antipsychotic-sensitive positive symptoms in an NMDA receptor glycine site
agonist-reversible manner. Taken together, functional restoration of the NMDA
receptor by stimulation of its glycine site has been expected to improve not only
antipsychotic-responsive positive symptoms but also antipsychotic-resistant nega-
tive and cognitive symptoms in schizophrenia patients. Among the glycine site
agonists, the intrinsic NMDA receptor coagonists glycine and D-serine have been
shown to ameliorate the negative symptoms in the meta-analyses of relatively large-
scale data of add-on clinical trials of each amino acid in schizophrenia patients
treated with conventional antipsychotic drugs except clozapine. The greater potent
therapeutic efficacy of D-serine than glycine and lack of significant palliation by a
glycine transporter inhibitor in the RCT raise the future direction for the develop-
ment of NMDA receptor potentiating therapy targeting molecules that participate in
the regulation of the metabolic pathways and synaptic concentrations of D-serine.

Cross-References

▶ D-Serine in the Treatment of Psychosis

References
Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H, et al. Cortical glutamate-
dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology
(Berl). 2005;182:375–83.
American Psychiatric Association. Schizophrenia spectrum and other psychotic disorders. In:
American Psychiatric Association, editor. Diagnostic and statistical manual of mental disorders
(DSM-5 ®). 5th ed. Washington, DC: Amer Psychiatric Pub Inc; 2013. p. 87–122.
D-Serine: Basic Aspects with a Focus on Psychosis 517

Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencycli-
dine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J
Pharmacol. 1983;79:565–575.
Balu DT, Takagi S, Puhl MD, Benneyworth MA, Coyle JT. D-serine and serine racemase are localized
to neurons in the adult mouse and human forebrain. Cell Mol Neurobiol. 2014;34:419–35.
Basu AC, Tsai GE, Ma CL, Ehmsen JT, Mustafa AK, Han L, et al. Targeted disruption of serine
racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry. 2009;14:
719–27.
Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, et al. Postnatal NMDA receptor ablation in
corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci. 2010;13:76–83.
Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, et al. A CSF and
postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr Res.
2007;90:41–51.
Benneyworth MA, Li Y, Basu AC, Bolshakov VY, Coyle JT. Cell selective conditional null
mutations of serine racemase demonstrate a predominate localization in cortical glutamatergic
neurons. Cell Mol Neurobiol. 2012;32:613–24.
Bodner O, Radzishevsky I, Foltyn VN, Touitou A, Valenta AC, Rangel IF, et al. D-serine signaling
and NMDAR-mediated synaptic plasticity are regulated by system A-type of glutamine/D-
serine dual transporters. J Neurosci. 2020;40:6489–502.
Bouwmans C, de Sonneville C, Mulder CL, Hakkaart-Van RL. Employment and the associated
impact on quality of life in people diagnosed with schizophrenia. Neuropsychiatr Dis Treat.
2015;11:2125–42.
Brouwer A, Luykx JJ, van Boxmeer L, Bakker SC, Kahn RS. NMDA-receptor coagonists in serum,
plasma, and cerebrospinal fluid of schizophrenia patients: a meta-analysis of case-control studies.
Neurosci Biobehav Rev. 2013 Sep;37(8):1587–96. https://doi.org/10.1016/j.neubiorev.2013.
Bugarski-Kirola D, Blaettler T, Arango C, Fleischhacker WW, Garibaldi G, Wang A, et al.
Bitopertin in negative symptoms of schizophrenia-results from the phase III FlashLyte and
DayLyte studies. Biol Psychiatry. 2017;82:8–16.
Castillo-Gómez E, Oliveira B, Tapken D, Bertrand S, Klein-Schmidt C, Pan H et al. All naturally
occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential
irrespective of epitope and immunoglobulin class. Mol Psychiatry. 2017;22:1776–1784.
Chang CH, Lin CH, Liu CY, Chen SJ, Lane HY. Efficacy and cognitive effect of sarcosine
(N-methylglycine) in patients with schizophrenia: a systematic review and meta-analysis of
double-blind randomised controlled trials. J Psychopharmacol. 2020;34:495–505.
Chen CH, Cheng MC, Liu CM, Liu CC, Lin KH, Hwu HG. Seroprevalence survey of selective anti-
neuronal autoantibodies in patients with first-episode schizophrenia and chronic schizophrenia.
Schizophr Res. 2017;190:28–31.
Cho SE, Na KS, Cho SJ, Kang SG. Low d-serine levels in schizophrenia: a systematic review and
meta-analysis. Neurosci Lett. 2016;634:42–51.
Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, et al. Genetic
and physiological data implicating the new human gene G72 and the gene for D-amino acid
oxidase in schizophrenia. Proc Natl Acad Sci U S A. 2002;99:13675–80.
Connel PH. Amphetamine Psychosis. Maudsley monographs number five. London: Chapman &
Hall Ltd; 1958. p. 123.
Contreras PC. D-serine antagonized phencyclidine- and MK-801-induced stereotyped behavior and
ataxia. Neuropharmacology. 1990;29:291–3.
Curcio L, Podda MV, Leone L, Piacentini R, Mastrodonato A, Cappelletti P, et al. Reduced D-serine
levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-
dependent synaptic plasticity. Brain. 2013;136:1216–30.
Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. Paraneoplastic anti-N-methyl-D-
aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25–36.
Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, et al. An update on
anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models.
Lancet Neurol. 2019;18:1045–57.
518 T. Nishikawa et al.

Danysz W, Parsons CG. Glycine and N-methyl-D-aspartate receptors: physiological significance

and possible therapeutic applications. Pharmacol Rev. 1998;50:597–664.
Deutch AY, Tam SY, Freeman AS, Bowers MB Jr, Roth RH. Mesolimbic and mesocortical
dopamine activation induced by phencyclidine: contrasting pattern to striatal response. Eur
J Pharmacol. 1987;134:257–64.
Dumin E, Bendikov I, Foltyn VN, Misumi Y, Ikehara Y, Kartvelishvily E, et al. Modulation of
D-serine levels via ubiquitin-dependent proteasomal degradation of serine racemase. J Biol
Chem. 2006;281(29):20291–302.
Dunlop DS, Neidle A. The origin and turnover of D-serine in brain. Biochem Biophys Res
Commun. 1997;235:26–30.
Featherstone RE, Melnychenko O, Siegel SJ. Mismatch negativity in preclinical models of schizo-
phrenia. Schizophr Res. 2018;191:35–42.
Fone KCF, Watson DJG, Billiras RI, Sicard DI, Dekeyne A, Rivet JM, et al. Comparative
pro-cognitive and neurochemical profiles of glycine modulatory site agonists and glycine
reuptake inhibitors in the rat: potential relevance to cognitive dysfunction and its management.
Mol Neurobiol. 2020;57:2144–66.
Goff DC, Henderson DC, Evins AE, Amico E. A placebo-controlled crossover trial of D-cycloserine
added to clozapine in patients with schizophrenia. Biol Psychiatry. 1999;45:512–4.
Goh KK, Wu TH, Chen CH, Lu ML. Efficacy of N-methyl-D-aspartate receptor modulator
augmentation in schizophrenia: a meta-analysis of randomised, placebo-controlled trials.
J Psychopharmacol. 2021;35:236–52.
Hashimoto A, Nishikawa T, Oka T, Takahashi K. D-alanine inhibits methamphetamine-induced
hyperactivity in rats. Eur J Pharmacol. 1991;202:105–7.
Hashimoto A, Nishikawa T, Hayashi T, Fujii N, Harada K, Oka T, et al. The presence of free
D-serine in rat brain. FEBS Lett. 1992a;296:33–6.
Hashimoto A, Nishikawa T, Oka T, Takahashi K, Hayashi T. Determination of free amino acid
enantiomers in rat brain and serum by high-performance liquid chromatography after derivati-
zation with N-tert.-butyloxycarbonyl-L-cysteine and o-phthaldialdehyde. J Chromatogr.
1992b;582:41–8.
Hashimoto A, Nishikawa T, Konno R, Niwa A, Yasumura Y, Oka T, et al. Free D-serine,
D-aspartate and D-alanine in central nervous system and serum in mutant mice lacking
D-amino acid oxidase. Neurosci Lett. 1993a;152:33–6.
Hashimoto A, Nishikawa T, Oka T, Takahashi K. Endogenous D-serine in rat brain: N-methyl-D-
aspartate receptor-related distribution and aging. J Neurochem. 1993b;60:783–6.
Hashimoto A, Oka T, Nishikawa T. Extracellular concentration of endogenous free D-serine in the
rat brain as revealed by in vivo microdialysis. Neuroscience. 1995;66:635–43.
Hata N, Nishikawa T, Umino A, Takahashi K. Evidence for involvement of N-methyl-D-aspartate
receptor in tonic inhibitory control of dopaminergic transmission in rat medial frontal cortex.
Neurosci Lett. 1990;120:101–4.
Hayashi F, Takahashi K, Nishikawa T. Uptake of D- and L-serine in C6 glioma cells. Neurosci Lett.
1997;239:85–88.
Henneberger C, Papouin T, Oliet SH, Rusakov DA. Long-term potentiation depends on release of
D-serine from astrocytes. Nature. 2010;463:232–6.
Hiraoka S, Kajii Y, Kuroda Y, Umino A, Nishikawa T. The development- and phencyclidine-
regulated induction of synapse-associated protein-97 gene in the rat neocortex. Eur Neuropsy-
chopharmacol. 2010;20:176–86.
Horio M, Kohno M, Fujita Y, Ishima T, Inoue R, Mori H, et al. Levels of D-serine in the brain and
peripheral organs of serine racemase (Srr) knock-out mice. Neurochem Int. 2011;59:853–9.
Hu W, MacDonald ML, Elswick DE, Sweet RA. The glutamate hypothesis of schizophrenia:
evidence from human brain tissue studies. Ann N Y Acad Sci. 2015;1338:38–57.
Ibrahim HM, Hogg AJ Jr, Healy DJ, Haroutunian V, Davis KL, Meador-Woodruff JH. Ionotropic
glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia.
Am J Psychiatry. 2000;157:1811–23.
D-Serine: Basic Aspects with a Focus on Psychosis 519

Ishimaru M, Kurumaji A, Toru M. Increases in strychnine-insensitive glycine binding sites in

cerebral cortex of chronic schizophrenics: evidence for glutamate hypothesis. Biol Psychiatry.
1994;35:84–95.
Ishiwata S, Ogata S, Umino A, Shiraku H, Ohashi Y, Kajii Y, et al. Increasing effects of S-methyl-L-
cysteine on the extracellular D-serine concentrations in the rat medial frontal cortex. Amino
Acids. 2013a;44:1391–5.
Ishiwata S, Umino A, Umino M, Yorita K, Fukui K, Nishikawa T. Modulation of extracellular
d-serine content by calcium permeable AMPA receptors in rat medial prefrontal cortex as
revealed by in vivo microdialysis. Int J Neuropsychopharmacol. 2013b;16:1395–406.
Ishiwata S, Umino A, Balu DT, Coyle JT, Nishikawa T. Neuronal serine racemase regulates
extracellular D-serine levels in the adult mouse hippocampus. J Neural Transm (Vienna).
2015;122:1099–103.
Ishiwata S, Hattori K, Sasayama D, Teraishi T, Miyakawa T, Yokota Y, et al. Plasma and
cerebrospinal fluid G72 protein levels in schizophrenia and major depressive disorder. Psychi-
atry Res. 2017;254:244–50.
Ishiwata S, Umino A, Nishikawa T. Involvement of neuronal and glial activities in control of the
extracellular d-serine concentrations by the AMPA glutamate receptor in the mouse medial
prefrontal cortex. Neurochem Int. 2018;119:120–5.
Iwama H, Takahashi K, Kure S, Hayashi F, Narisawa K, Tada K, et al. Depletion of cerebral
D-serine in non-ketotic hyperglycinemia: possible involvement of glycine cleavage system in
control of endogenous D-serine. Biochem Biophys Res Commun. 1997;231:793–6.
Iwata Y, Nakajima S, Plitman E, Mihashi Y, Caravaggio F, Chung JK, et al. Neurometabolite levels
in antipsychotic-naïve/free patients with schizophrenia: A systematic review and meta-analysis
of 1H-MRS studies. Prog Neuropsychopharmacol Biol Psychiatry. 2018;86:340–52.
Javitt DC, Balla A, Burch S, Suckow R, Xie S, Sershen H. Reversal of phencyclidine-induced
dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists. Neuropsy-
chopharmacology. 2004;29:300–7.
Johnson KM, Jones SM. Neuropharmacology of phencyclidine: basic mechanisms and therapeutic
potential. Annu Rev Pharmacol Toxicol. 1990;30:707–50.
Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, et al. D-serine regulates
cerebellar LTD and motor coordination through the δ2 glutamate receptor. Nat Neurosci.
2011;14:603–11.
Kanematsu S, Ishii S, Umino A, Fujihira T, Kashiwa A, Yamamoto N, et al. Evidence for
involvement of glial cell activity in the control of extracellular D-serine contents in the rat
brain. J Neural Transm (Vienna). 2006;113:1717–21.
Kantrowitz JT, Epstein ML, Beggel O, Rohrig S, Lehrfeld JM, Revheim N, et al. Neurophysiolog-
ical mechanisms of cortical plasticity impairments in schizophrenia and modulation by the
NMDA receptor agonist D-serine. Brain. 2016;139(Pt 12):3281–95.
Kantrowitz JT, Nolan KA, Epstein ML, Lehrfeld N, Shope C, Petkova E, et al. Neurophysiological
effects of bitopertin in schizophrenia. J Clin Psychopharmacol. 2017;37:447–51.
Kantrowitz JT, Epstein ML, Lee M, Lehrfeld N, Nolan KA, Shope C, et al. Improvement in
mismatch negativity generation during d-serine treatment in schizophrenia: correlation with
symptoms. Schizophr Res. 2018;191:70–9.
Kartvelishvily E, Shleper M, Balan L, Dumin E, Wolosker H. Neuron-derived D-serine release provides
a novel means to activate N-methyl-D-aspartate receptors. J Biol Chem. 2006;281:14151–14162.
Kashiwa A, Nishikawa T, Nishijima K, Umino A, Takahashi K. Dizocilpine (MK-801) elicits a
tetrodotoxin-sensitive increase in extracellular release of dopamine in rat medial frontal cortex.
Neurochem Int. 1995;26:269–79.
Kayser MS, Dalmau J. Anti-NMDA receptor encephalitis in psychiatry. Curr Psychiatry Rev.
2011;7:189–93.
Keller S, Punzo D, Cuomo M, Affinito O, Coretti L, Sacchi S, et al. DNA methylation landscape of
the genes regulating D-serine and D-aspartate metabolism in post-mortem brain from controls
and subjects with schizophrenia. Sci Rep. 2018;8:10163.
520 T. Nishikawa et al.

Kidd LR, Lyons SC, Lloyd G. Paediatric procedural sedation using ketamine in a UK emergency
department: a 7 year review of practice. Br J Anaesth. 2016;116:518–23.
Konno R, Yasumura Y. Brain and kidney D-amino acid oxidases are coded by a single gene in the
mouse. J Neurochem. 1984;42:584–6.
Krebs HA. Metabolism of amino-acids: The synthesis of glutamine from glutamic acid and ammonia,
and the enzymic hydrolysis of glutamine in animal tissues. Biochem J. 1935;29:1951–69.
Kumashiro S, Hashimoto A, Nishikawa T. Free D-serine in post-mortem brains and spinal cords of
individuals with and without neuropsychiatric diseases. Brain Res. 1995;681:117–25.
Kuppili PP, Menon V, Sathyanarayanan G, Sarkar S, Andrade C. Efficacy of adjunctive
D-Cycloserine for the treatment of schizophrenia: a systematic review and meta-analysis of
randomized controlled trials. J Neural Transm (Vienna). 2021;128:253–62.
Labrie V, Fukumura R, Rastogi A, Fick LJ, Wang W, Boutros PC, et al. Serine racemase is
associated with schizophrenia susceptibility in humans and in a mouse model. Hum Mol
Genet. 2009;18:3227–43.
Lahti AC, Holcomb HH, Gao X-M, Tamminga CA. NMDA-sensitive glutamate antagonism: a
human model for psychosis. Neuropsychopharmacol. 1999;21:S158–69.
Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, et al. Glycine transporter I inhibitor,
N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol
Psychiatry. 2006;60:645–9.
Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of
benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino
acid oxidase inhibitor. JAMA Psychiatry. 2013;70:1267–75.
Laruelle M. Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J
Nucl Med. 1998;42:211–21.
Le Bail M, Martineau M, Sacchi S, Yatsenko N, Radzishevsky I, Conrod S, et al. Identity of the
NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocam-
pus. Proc Natl Acad Sci U S A. 2015;112:E204–13.
Lin CH, Lin CH, Chang YC, Huang YJ, Chen PW, Yang HT, et al. Sodium benzoate, a D-amino
acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized,
double-blind, placebo-controlled trial. Biol Psychiatry. 2018;84:422–32.
Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R. Study of a new schizophrenomimetic
drug; sernyl. AMA Arch Neurol Psychiatry. 1959;81:363–9.
Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, et al. Ketamine-induced
exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizo-
phrenics. Neuropsychopharmacology. 1997;17:141–50.
Martineau M, Shi T, Puyal J, Knolhoff AM, Dulong J, Gasnier B, et al. Storage and uptake of
D-serine into astrocytic synaptic-like vesicles specify gliotransmission. J Neurosci. 2013;33:
3413–23.
Matsui T, Sekiguchi M, Hashimoto A, Tomita U, Nishikawa T, Wada K. Functional comparison of
D-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular
concentration. J Neurochem. 1995;65:454–8.
Matsuura A, Fujita Y, Iyo M, Hashimoto K. Effects of sodium benzoate on pre-pulse inhibition
deficits and hyperlocomotion in mice after administration of phencyclidine. Acta
Neuropsychiatr. 2015;27:159–67.
McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia – an overview. JAMA Psychiatry.
2020;77:201–10.
Miya K, Inoue R, Takata Y, Abe M, Natsume R, Sakimura K, et al. Serine racemase is predomi-
nantly localized in neurons in mouse brain. J Comp Neurol. 2008;510:641–54.
Miyoshi Y, Konno R, Sasabe J, Ueno K, Tojo Y, Mita M, et al. Alteration of intrinsic amounts of
D-serine in the mice lacking serine racemase and D-amino acid oxidase. Amino Acids. 2012;43:
1919–31.
Moghaddam B, Adams BW. Reversal of phencyclidine effects by a Group II metabotropic
glutamate receptor agonist in rats. Science. 1998;281:1349–52.
D-Serine: Basic Aspects with a Focus on Psychosis 521

Mothet JP, Parent AT, Wolosker H, Brady RO Jr, Linden DJ, Ferris CD et al. D-serine is an
endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci
U S A. 2000;97:4926–4931.
Naur P, Hansen KB, Kristensen AS, Dravid SM, Pickering DS, Olsen L, et al. Ionotropic
glutamate-like receptor delta2 binds D-serine and glycine. Proc Natl Acad Sci U S A.
2007;104:14116–21.
Neame S, Safory H, Radzishevsky I, Touitou A, Marchesani F, Marchetti M, et al. The NMDA
receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent
serine shuttle. Proc Natl Acad Sci U S A. 2019;116:20736–42.
Nishijima K, Kashiwa A, Nishikawa T. Preferential stimulation of extracellular release of dopamine
in rat frontal cortex to striatum following competitive inhibition of the N-methyl-D-aspartate
receptor. J Neurochem. 1994;63:375–8.
Nishijima K, Kashiwa A, Hashimoto A, Iwama H, Umino A, Nishikawa T. Differential effects of
phencyclidine and methamphetamine on dopamine metabolism in rat frontal cortex and striatum
as revealed by in vivo dialysis. Synapse. 1996;22:304–12.
Nishikawa T. Analysis of free D-serine in mammals and its biological relevance. J Chromatogr
B Analyt Technol Biomed Life Sci. 2011;879:3169–83.
Nishikawa T, Hashimoto A, Tanii Y, Umino A, Kashiwa A, Kumashiro S, et al. Disturbed
neurotransmission via the N-methyl-D-aspartate receptor and schizophrenia. In: Moroji T,
Yamamoto K, editors. The biology of schizophrenia. Development of psychiatry series. Amster-
dam: Elsevier; 1994. p. 197–207.
Papouin T, Ladépêche L, Ruel J, Sacchi S, Labasque M, Hanini M, et al. Synaptic and extrasynaptic
NMDA receptors are gated by different endogenous coagonists. Cell. 2012;150:633–46.
Perez EJ, Tapanes SA, Loris ZB, Balu DT, Sick TJ, Coyle JT, et al. Enhanced astrocytic d-serine
underlies synaptic damage after traumatic brain injury. J Clin Invest. 2017;127:3114–25.
Pérez-Otaño I, Larsen RS, Wesseling JF. Emerging roles of GluN3-containing NMDA receptors in
the CNS. Nat Rev Neurosci. 2016;17:623–35.
Petersen RC, Stillman RC, editors. Phencyclidine (PCP) abuse: an appraisal. National Institute on
Drug Abuse Research Monographs, superintendent of documents. Washington, DC: U. S.
Government Printing Office; 1978. p. 313.
Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH, et al. First in vivo
evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychi-
atry. 2006;11:118–9.
Plitman E, Iwata Y, Caravaggio F, Nakajima S, Chung JK, Gerretsen P, et al. Kynurenic acid in
schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2017;43:764–77.
Potkin SG, Jin Y, Bunney BG, Costa J, Gulasekaram B. Effect of clozapine and adjunctive high-
dose glycine in treatment-resistant schizophrenia. Am J Psychiatry. 1999;156:145–7.
Rao TS, Kim HS, Lehmann J, Martin LL, Wood PL. Interactions of phencyclidine receptor
agonist MK-801 with dopaminergic system: regional studies in the rat. J Neurochem. 1990;54:
1157–62.
Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can
J Anaesth. 1989;36:186–97.
Rosenberg H, Ennor AH. Occurrence of free D-serine in the earthworm. Nature. 1960;187:617–8.
Sato D, Umino A, Kaneda K, Takigawa M, Nishikawa T. Developmental changes in distribution
patterns of phencyclidine-induced c-Fos in rat forebrain. Neurosci Lett. 1997;239:21–4.
Scheer S, John RM. Anti-N-methyl-D-aspartate receptor encephalitis in children and adolescents.
J Pediatr Health Care. 2016;30:347–58.
Schell MJ, Molliver ME, Snyder SH. D-Serine, an endogenous synaptic modulator: localization to
astrocytes and glutamate-stimulated release. Proc Natl Acad Sci U S A. 1995;92:3948–52.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from
108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
Schwartz RH, Einhorn A. PCP intoxication in seven young children. Pediatr Emerg Care. 1986;2:
238–41.
522 T. Nishikawa et al.

Sershen H, Hashim A, Dunlop DS, Suckow RF, Cooper TB, Javitt DC. Modulating NMDA
receptor function with D-amino acid oxidase inhibitors: understanding functional activity in
PCP-treated mouse model. Neurochem Res. 2016;41:398–408.
Shimazu D, Yamamoto N, Umino A, Ishii S, Sakurai S, Nishikawa T. Inhibition of D-serine
accumulation in the Xenopus oocyte by expression of the rat ortholog of human 30 -phosphoa-
denosine 50 -phosphosulfate transporter gene isolated from the neocortex as D-serine modulator-
1. J Neurochem. 2006;96:30–42.
Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in
chronic schizophrenia. CNS Drugs. 2011;25:859–85.
Srinivasan NG, Corrigan JJ, Meister A. D-Serine in the blood of the silkworm Bombyx mori and
other lepidoptera. J Biol Chem. 1962;237:3844–5.
Steffek AE, Haroutunian V, Meador-Woodruff JH. Serine racemase protein expression in cortex and
hippocampus in schizophrenia. Neuroreport. 2006;17:1181–5.
Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, et al. Increased prevalence of
diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis
of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-
aspartate glutamate receptor encephalitis. JAMA Psychiatry. 2013;70:271–8.
Takahashi K, Hayashi F, Nishikawa T. In vivo evidence for the link between L- and D-serine
metabolism in rat cerebral cortex. J Neurochem. 1997;69:1286–90.
Tanii Y, Nishikawa T, Hashimoto A, Takahashi K. Stereoselective inhibition by D- and L-alanine of
phencyclidine-induced locomotor stimulation in the rat. Brain Res. 1991;563:281–4.
Tanii Y, Nishikawa T, Hashimoto A, Takahashi K. Stereoselective antagonism by enantiomers of
alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia in the rat.
J Pharmacol Exp Ther. 1994;269:1040–8.
Tanii Y, Nishikawa T, Hibino H, Takahashi K. Effects of allosteric agonists for N-methyl-D-
aspartate receptor and their derivatives on phencyclidine-induced abnormal behavior in the
rat. Brain Sci Mental Disord (Present: Jpn J Biol Psychiatry), 1991b; 2:497–502 (in Japanese
with English abstract). Erratum in: Jpn J Biol Psychiatry. 2010;21:126.
Tsai GE, Lin PY. Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission
in schizophrenia, a critical review and meta-analysis. Curr Pharm Des. 2010;16:522–37.
Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT. D-serine added to clozapine for the
treatment of schizophrenia. Am J Psychiatry. 1999;156:1822–5.
Umino A, Takahashi K, Nishikawa T. Characterization of the phencyclidine-induced increase in
prefrontal cortical dopamine metabolism in the rat. Br J Pharmacol. 1998;124:377–85.
Umino A, Ishiwata S, Iwama H, Nishikawa T. Evidence for tonic control by the GABAA receptor of
extracellular D-Serine concentrations in the medial prefrontal cortex of rodents. Front Mol
Neurosci. 2017;10:240.
Umino M, Umino A, Nishikawa T. Effects of selective calcium-permeable AMPA receptor block-
ade by IEM 1460 on psychotomimetic-induced hyperactivity in the mouse. J Neural Transm
(Vienna). 2018;125:705–11.
Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J. Differential psychopathology and patterns
of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using
positron emission tomography (PET). Eur Neuropsychopharmacol. 1997;7:25–38.
Weimar WR, Neims AH. The development of D-amino acid oxidase in rat cerebellum.
J Neurochem. 1977;29:649–56.
Welch MJ, Correa GA. PCP intoxication in young children and infants. Clin Pediatr (Phila).
1980;19:510–4.
White PF, Way WL, Trevor AJ. Ketamine – its pharmacology and therapeutic uses. Anesthesiology.
1982;56:119–36.
Wolosker H, Blackshaw S, Snyder SH. Serine racemase: a glial enzyme synthesizing D-serine to
regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci U S A. 1999a;96:
13409–14.
D-Serine: Basic Aspects with a Focus on Psychosis 523

Wolosker H, Sheth KN, Takahashi M, Mothet JP, Brady RO Jr, Ferris CD, et al. Purification of serine
racemase: biosynthesis of the neuromodulator D-serine. Proc Natl Acad Sci U S A. 1999b;96:721–5.
Wong JM, Folorunso OO, Barragan EV, Berciu C, Harvey TL, Coyle JT, et al. Postsynaptic serine
racemase regulates NMDA receptor function. J Neurosci. 2020;40:9564–75.
Yagi K, Nagatsu T, Ozawa T. Inhibitory action of chlorpromazine on the oxidation of d-amino-acid
in the diencephalon part of the brain. Nature. 1956;177:891–2.
Yamamoto N, Tomita U, Umino A, Nishikawa T. Uptake of D-serine by synaptosomal P2 fraction
isolated from rat brain. Synapse. 2001;42:84–6.
Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, et al. Contribution of astrocytes to hippocampal long-
term potentiation through release of D-serine. Proc Natl Acad Sci U S A. 2003;100:15194–9.
Yang JH, Wada A, Yoshida K, Miyoshi Y, Sayano T, Esaki K, et al. Brain-specific Phgdh deletion
reveals a pivotal role for L-serine biosynthesis in controlling the level of D-serine, an N-methyl-
D-aspartate receptor co-agonist, in adult brain. J Biol Chem. 2010;285:41380–90.
Yonezawa Y, Kuroki T, Kawahara T, Tashiro N, Uchimura H. Involvement of gamma-aminobutyric
acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal
cortex. Eur J Pharmacol. 1998;341:45–56.
Amine Precursors in Depressive Disorders
and the Blood-Brain Barrier

Hari Shanker Sharma and Aruna Sharma

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
Biogenic Amines and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
Serotonin Precursor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
Dopamine Precursor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
Histamine Precursor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
Pathophysiology of Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Traumatic Brain Injury and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Concussive Head Injury and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
Depression in Military . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Depression in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
Depression in Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
Psychostimulant Abuse and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
Stress and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
Neurotrophins and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
BDNF and Serotonin Interaction in the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
Cytokines and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
Unifying Concepts of Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
Monoamines and Neurotrophin Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
Monoamine and Cytokine Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
Blood-Brain Barrier Is the Gateway of Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
Conclusion and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548

Abstract
Depression caused by either genetic factors or environmental stimulates such as
chronic psychological or physiological stress, traumatic or sports-related brain
injuries, neurodegenerative diseases, and/or substance abuse and drug
H. S. Sharma (*) · A. Sharma
International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of
Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital,
Uppsala University, Uppsala, Sweden
e-mail: sharma@surgsci.uu.se; aruna.sharma@surgsci.uu.se

© Springer Nature Switzerland AG 2022 525

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_423
526 H. S. Sharma and A. Sharma

dependence leads to serious neurological manifestation and affects mortality and

morbidity since ages. Stress is one of the powerful stimulants to induce disruption
of the blood-brain barrier (BBB). In all the above cases breakdown of the BBB
occurs resulting in abnormal neuronal functions and precipitating brain pathol-
ogy. Disruption of BBB could be one of the leading factors affecting thought
processes and mental health leading to depression. Accordingly, depressive
episodes often lead to suicide that is estimated to be around 40 k individuals
per year in the USA. About 10–15% of these individuals were on antidepressant
therapy at that time. These antidepressants adversely affect the BBB breakdown.
Thus, although our knowledge on depression expanded in recent years, the
biological mechanisms of depression and suitable treatment strategies are still
obscure. In depressive episodes alterations in the metabolism of biogenic amines
in the brain formed the basis of treatment with amine precursors in clinic.
However, these treatments are only helping up to some extent in clinics, indicat-
ing the involvement of further agents beyond the amine mechanisms in depres-
sion. It appears that today’s view on depression is not only genetics and
environmental but rather an integrative etiopathogenetic and biopsychological
phenomena. In this review the potential role of amine precursors in depression is
discussed in the light of recent development in relation to the new developing
clinical strategies and mechanisms to treat depression.

Introduction

Depression. . . so mysteriously painful and elusive. . . remains nearly incomprehensible to

those who have not experienced it in its extreme mood, although the. . .“blues” which people
go through occasionally. . . are of such prevalence that they do give many individuals a hint
of the illness in its catastrophic form.
William Styron, Darkness Visible – A Memoir of Madness, 1990 (1, p. 7), Random House

Depression is one of the most severe diseases resulting in mortality and morbidity
among population (Blazer 2003). A rough estimate suggests that about 40 k people
die every year in the USA caused by either self-inflicted injury or suicide related to
depressive illness (Read et al. 2017). At the time of suicidal activity in depressive
illness, about 30% of victims are on antidepressive treatments (Brent 2016). This
suggests that treatment strategies for depression prescribed so far are still not quite
effective in containing the disease. In spite of recent progresses in depressive
therapy, the basic mechanisms or causes of depressive illnesses are not well
known. Thus, new avenues for treating depression beyond current strategies of
therapeutic advice are needed.
Available evidences now suggest that depression is not caused by any single
neurotransmitter such as serotonin or a group of closely related neurochemicals
like biogenic amines comprising dopamine, norepinephrine, epinephrine, and hista-
mine metabolism in the brain (Birkmayer et al. 1972; Ménard et al. 2016). There are
reasons to believe that several other agents and factors also contribute to the
mechanism of depressive illness. Thus, involvement of cytokines such as tumor
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 527

necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) is adversely affecting depres-

sive illnesses. Likewise, endogenous depletion of neurotrophins such as brain-
derived neurotrophic factor (BDNF), glia cell line-derived neurotrophic factor
(GDNF), and other excitatory and inhibitory amino acid transmitters and their
receptor modulation plays key roles in depression (Duman et al. 2016; Ménard
et al. 2016).
The central nervous system (CNS) homeostasis is strictly maintained by the
blood-brain barrier (BBB) that regulates the entry of several agents into the brain
from blood to maintain the fluid microenvironment and health of the neurons and
glial cells (Sharma and Westman 2004; Sharma 2009a; Sharma and Sharma 2010).
The BBB resides into the cerebral endothelial cells that are connected with the tight
junctions and also lack vesicular transport regulating intracellular transport (Sharma
2004a). Thus, in general, the BBB appears to be an extended plasma membrane
between blood and brain whose permeability properties are very similar to that of a
protein-lipid-protein structure (Sharma 1999, 2004a, 2009).
However, the endothelial cells have receptors of several neurochemicals and trans-
porters that regulate the passage of essential nutrients and lipid-soluble agents from
blood to the brain with transporters helping to efflux unwanted substances or metab-
olites from the brain to blood compartments (Nation et al. 2019; Dudek et al. 2020).
The BBB permeability is compromised following several psychological, mental,
or environmental stressors leading to the passage of large molecules from the blood
to brain resulting in perturbation of fluid microenvironment of the CNS (Sharma
2004a, 2009a; Sharma et al. 2009; 2010). Since neurons and glial cells are suspended
in the brain fluid microenvironment, any untoward alterations affect their function
and impair the health of the CNS (Sharma and Westman 2004). Several evidences
suggest that the BBB is also compromised in depression (Welcome and Mastorakis
2020; Dudek et al. 2020; Nation et al. 2019). The ABCB1 gene that encodes
p-glycoprotein (P-gp) at the BBB seems to be an important regulator for the control
of uptake of the antidepressants (O’Brien et al. 2012). This suggests that the BBB
plays a crucial role in depressive illnesses.
At the BBB interface the rate of serotonin synthesis depends on brain tryptophan
concentration (Curzon 1981; Fernstrom and Wurtman 1971, 1972). It also depends
on the simultaneous transport of other neutral amino acids (NAA) (Pardrige 1979;
Pardrige and Oldendorf 1975). Tryptophan enters into the brain through the BBB
transporter located on the cerebral endothelium that is also responsible for other
large neutral amino acid (NAA) transport, e.g., tryptophan, tyrosine, phenylalanine,
leucine, isoleucine, and valine (Fernstrom and Wurtman 1972). These amino acid
transporters are competitive; thus, an increase in the concentration of one NAA
lowers the transport of the other NAA (Young et al. 1976). These factors are crucial
for increased serotonin levels in the brain following 5-HTP administrations in
clinical cases in treating depression (Lehmann 1973; Birkmayer et al. 1972, 1984).
Several lifetime stress situations caused by psychological or physiological factors
precipitate depression (Dudek et al. 2020). Substance abuse, social stress of defeat,
inferiority complexes, and other irritating episodes that could be beyond one’s
control lead to frustration and culminate into depression (Ménard et al. 2017).
528 H. S. Sharma and A. Sharma

Several lines of evidences suggest that in most of these conditions, the BBB is
compromised (Sharma 2004a). Thus, the need of the hour is to restore the BBB
function in depression to maintain a healthy brain and mind (Dudek et al. 2020;
Shalev et al. 2009).
In clinics, depression is treated with several biogenic amine precursor agents that
seem to control the episode of depression for some time but not completely (Hamon
and Blier 2013). Thus, the current treatment strategy using amine precursors in
depression requires further investigation. Alternatively, the root cause of depressive
illnesses requires to be investigated in detail so that development of suitable thera-
peutic strategies to treat depression may be worked out more effectively.
This review discusses the role of amine pressures in depression in relation to the
BBB disturbances. In addition, other possible therapeutic angles of depression are
explored to develop suitable strategies to treat the disease more effectively in clinics.

Biogenic Amines and Depression

Depression known as melancholy (pathological aspect of depression) originated

from prolonged fear, sorrow, or sadness (Burton 1621; Freud 1917) as described
by Hippocrates (460–377 BC) about more than 2,500 years ago that exactly met the
criteria of modern medical definition of the disease (Hippocrates 1923–1931, Vol.
IV, p. 185). This description is certified by the First Diagnostic and Statistical
Manual of Mental disorders (DSM I) in 1952 by the American Psychiatric Associ-
ation (Horwitz et al. 2016).
With enhanced knowledge and clinical perspective in depression, a connection
between monoamines and depressive illness has emerged (see Reiderer et al. 1973;
Birkmayer and Riederer 1975; Knott and Curzon 1972; Mendels et al. 1975; Curzon
1981). This is evident from the findings in clinical cases when patients suffering from
chronic schizophrenia were given several amino acids together with monoamine oxi-
dase inhibitor (MAOI) that improved the symptoms (Pollin et al. 1961). It was later
found that only tryptophan, the precursor the monoamine 5-hydroxytryptamine, was
responsible for the elevation of mood. On the basis of these observations, patients
suffering from severe depression were given MAOI and/or D, L-tryptophan (214 mg/
kg) for 1 week. It was observed that patients who received both MAOI and tryptophan
recovered rapidly compared to those who received MAOI alone (Coppen et al. 1963).
These results were interpreted that both MAOI and tryptophan increased the amount of
5-hydroxytrypytamine (serotonin, 5-HT) in the brain, and this effect was responsible for
the therapeutic effect. This indicates that the 5-HT levels are low in depressed patients
and combinations of amine precursor and enzyme inhibitor brought back the 5-HT
levels to normal (Prange Jr 1964; Schildkraut 1965a, b; Coppen 1967; Murray 1996;
Meyerson et al. 1982; Davis 1970).
Later it was suggested that depression is associated with functional deficiencies of
norepinephrine (NE) or 5-HT in the brain (Schildkraut 1965; see Mendels et al.
1975). However, direct proof for the involvement of biogenic amines in depression is
difficult, as the amines do not cross the BBB. Thus, an alternate way of enhancing
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 529

the biogenic amines in the brain of depressive patients is the administration of amine
precursors that after entering into the brain endogenously converted into amines.
That amine precursors are working to elevate the amine in question physiologically
inside the brain is supported by the success of catecholamine precursor
l-dihydroxyphenylalanine (levodopa) in successfully treating Parkinson’s disease
(PD) (Birkmayer and Hornykiewicz 1961). This finding has revolutionized interest
in amine precursors as potential treatment in depressive illnesses.

Serotonin Precursor

To consolidate serotonin theory of depression, measurement of the amine was

performed at postmortem of depression-related suicide victims (Meyerson et al.
1982; Murray 1996). The findings suggest that the serotonin level was indeed
lower in depressed victims as compared to the non-depressed cases. This strength-
ened treatment strategies of amine precursors in depression.

L-Tryptophan
Results from several investigators suggest that L-tryptophan treatment is very
effective as an antidepressant in comparison to imipramine hydrochloride or elec-
troconvulsive therapy (Coppen et al. 1967, 1972; Bowers Jr. 1970; Kline and Shah
1973). However, large doses of L-tryptophan were found ineffective in depression
(Carroll et al. 1970; Bunney Jr et al. 1971; Gayford et al. 1973; Murphy et al. 1973;
Mendlewicz and Youdim 1980).
Studies further show that L-tryptophan potentiated the antidepressant effects of
MAOI as compared to MAOI alone (Coppen 1967; Pare and Sandler 1959; Pare
1963; Coppen et al. 1963; Gutierrez and Alino 1971). However, the combination of
L-5hydroxytryptamine with tricyclic antidepressant was ineffective as compared to
tricyclic alone (Pare 1973; Glassman and Platman 1969; Shaw et al. 1972). Inter-
estingly, L-tryptophan exerted anti-manic effects in two double-blind investigations,
indicating the interrelationship between mania and depression (Whybrow et al.
1969; Mendels and Stinnett 1973).

5-Hydroxytryptophan
The use of the immediate serotonin precursor 5-hydroxytryptophan (5-HTP) is
recommended for the treatment of depression either alone or in combination with
MAOI (Pare and Sandler 1959; Kline and Sacks 1963; Kline et al. 1964; Persson
and Roos 1967; Sano 1972; Brodie et al. 1973). However, it appears that 5-HTP is
definitely superior than placebo regarding its antidepressant effects; the effects are
weak on rating scales of mood elevation and psychiatric rated depression scale
(Mendels et al. 1975). Interestingly, when probenecid was given before 5-HTP
administration, the CSF accumulation of 5-hydroxyindoleacetic acid (5-HIAA)
was significantly reduced. This suggests that 5-HTP has reduced the serotonin
deficiency in these patients (Fuxe et al. 1971). However, 5-HTP administration not
only resulted in 5-HT production in serotoninergic neurons but also seen in the
530 H. S. Sharma and A. Sharma

dopaminergic neurons as well (Lynn-Bullock et al. 2004). These results suggest

that 5-HTP-induced serotonin production in the brain may not induce normal
physiological function of the amine leading to variable results in depression
(Kitahama et al. 2002). Thus, further research on 5-HTP-induced serotonin pro-
duction in the brain and its physiological effects in the CNS requires additional
investigation.

Dopamine Precursor

Catecholamine precursor levodopa has been extensively studied for the treatment of
depressive illnesses (Goodwin et al. 1971; Matussek 1971; Persson and Walinder
1971; Náhunek et al. 1972). Studies in 22 depressive patients receiving either
levodopa alone or in combination with alpha-methyldopahydrazine, an inhibitor of
the enzyme l-aromatic amino acid decarboxylase, showed improved conditions in
6 patients (Goodwin et al. 1971; Bunney Jr et al. 1970). The alpha-methylhydrazine
does not cross the BBB and prevents the peripheral conversion of levodopa to
dopamine. This will result in more levodopa to cross the BBB, indicating a potential
role of levodopa in treating depression. The results suggest that only the retarded
depressive patients and not agitated depressive cases were benefitted by combined
treatment with levodopa and alpha-methylhydrazine (Goodwin et al. 1971). How-
ever, the hydrazine compounds were shown to be liver toxic (Riederer et al. 1973;
Fernstrom 1979).
Further study showed that levodopa treatment resulted in hypomania in seven of
the depressed patients with levodopa treatment (Murphy et al. 1971; Goodwin et al.
1971). Studies by Matussek (1971) showed self-improvement score on depression in
36 retarded depressive patients with levodopa and benserazide hydrochloride, a
decarboxylase inhibitor. However, the differences between levodopa treated and
placebo were not significantly different (Matussek 1971).

Histamine Precursor

Histamine is another biogenic amine that is synthesized by the amino acid histidine
using histamine decarboxylase present in histaminergic neurons in the CNS (Panula
and Nuutinen 2013; Simons 2004). Although several indications suggest a role of
histamine receptors in the pathology of depression, histamine precursors have not
been systematically examined as possible therapy for depressive illness.
Previous report suggests that histidine, the precursor of histamine in the CNS,
reduces immobility time during forced swimming (FS) in mice, indicating a role of
histamine precursor in depression (Lamberti et al. 1998). In addition, animals fed on
histidine-free diet exhibit low histamine content in the brain and show several
symptoms of depression such as fatigue, sleeplessness, and other anxiety-related
behaviors, indicating a clear role of histamine precursor in depression (Yoshikawa
et al. 2014).
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 531

The role of histamine precursor histidine in depression is further strengthened by

a clinical study performed on 20 subjects with depressive illnesses (Sasahara et al.
2015). In this study the subjects were fed with histidine-rich diet of traditional
Japanese food “dashi” (Japanese fish broth) for 2 weeks and significantly improved
their well-being and ameliorated their disturbances in mood, feelings, and cognitive
health as compared to placebo. Since histidine can cross the BBB, feeding them with
histidine-rich diet can easily enhance histamine levels in the brain (Watanabe et al.
1984; Panula et al. 1998).
These observations support further investigations on the role of histamine pre-
cursor in treating depression, a subject currently being examined in our laboratory
(Sharma HS unpublished observation).

Pathophysiology of Depression

Apart from psychological origins of depression, several factors such as

neuroinflammation and/or neurodegeneration caused by a variety of agents severely
affect or precipitate depressive illnesses (Hurley and Tizabi 2013; Rakel 1999;
Blazer 2003; Ménard et al. 2016). A brief description of pathological aspect of
depression is given below.

Traumatic Brain Injury and Depression

Traumatic brain injury (TBI) is one of the leading causes of depression that
progresses with severity and duration of the insult (Fann et al. 2009). The
depressive illness is further aggravated in TBI by associated anxiety and alcohol
abuse in victims (Hibbard et al. 1998; Seel and Kreutzer 2003). More than 30% of
TBI cases show major depressive disorder (MDD) or organic defective disorder
ICD-10, F06.3 (mood disorder due to known physiological condition)
(Schoenhuber and Gentilini 1988; van Zomeren and van den Burg 1985).
According to rough estimate MDD is seen following TBI in 33% to 42% follow-
ing first year of insult and developed in more than 61% after 7 years of injury
(Jorge et al. 2004; Hibbard et al. 1998). Recent data shows that out of 559 subjects
hospitalized for TBI, 52% develop MDD within the first year of primary insult
(Fann et al. 2003). Interestingly the increased risk of MDD following TBI is not
limited to mild TBI as there were no subtle differences between severe cases or
mild TBI in precipitating MDD (Hoge et al. 2008). Apart from MDD in cases of
TBI, increased risk of suicide is also prevalent in 10% of cases 1 year post-injury
and about 15% 5 years post-injury (Brooks et al. 1986). Depressed TBI patients
are also susceptible to enhanced post-injury symptoms such as memory impair-
ment, blurred vision, headache, and dizziness as compared to non-depressed
patients (Fann et al. 1995).
There are reasons to believe that depression in TBI cases occurs due to a direct or
indirect secondary injury to brain tissues (Fann et al. 2009; Merritt et al. 2018).
532 H. S. Sharma and A. Sharma

TBI depression is linked to either injured or depressed frontal lobe and basal ganglia
circuit together with ascending monoaminergic pathways (Levin and Kraus 1994;
Rosenthal et al. 1998). Furthermore, the diffused or focal injury after TBI affected
the frontal and temporal lobe circuitry and reduced metabolism (Mayberg 1994). The
MDD can further be affected adversely depending on the post-TBI socioeconomic
factors (Seel et al. 2003).
Recent reports suggest that treatment with selective serotonin reuptake inhibitor
(SSRIs) or serotonin-norepinephrine reuptake inhibitor (SNRIs) could be the first
line of treatment of MDD associated with TBI (Warden et al. 2006). However,
further research is needed to enhance a combination of different drug combinations
including MAOI (DeRubeis et al. 2005).

Concussive Head Injury and Depression

Patients with concussion caused by sports injury such as either football and rugby or
amateur horse riding develop depression at a higher rate than the average population
(Yrondi et al. 2017). Concussion induces sudden trauma to the head caused by a
blow that transmits string inertial forces to the brain distorting memory and cognitive
and mental state (Brooks et al. 1986; Carman et al. 2015; Holm et al. 2005; Sharma
et al. 2016a, b).
Rough estimate suggests that incidences of concussion could occur in American
football players ranging from 0.2 per 1000 h and 4.1 to 8 per 1000 h in rugby players
as compared to 95 per 1000 h in amateur horse riding or training (Hollis et al. 2012;
Kemp et al. 2008; Koh et al. 2003; McCrory et al., 2017; Tommasone and Valovich
McLeod 2006). Several studies show that these repetitive concussions lead to the
development of depressive episodes associated with neurodegeneration and other
psychiatric diseases (Young et al. 2016; Omalu et al. 2005; Lehman et al. 2012;
McKee et al. 2013). In such concussive episodes MDD could occur in about 14% to
77% of cases that account for immediate after blow and also associated with longer-
term survival (Solomon et al. 2016). This suggests a clear link between MDD and
sports-related repetitive concussions (Yrondi et al. 2017).
Short-term concussion and development of MDD studies show that about 20% of
17 concussed athletes exhibited depressive symptoms within 5 days as compared to
non-concussed players (Vargas et al. 2015). Another study demonstrated 19.8%
incidences of depressive illness in concussed athletes, among which 33.8% have
both depression and anxiety (Yang et al. 2015a, b). In young high school athletes,
concussion-induced depressive symptoms appear within 1 week in more than 9% of
subjects as compared to non-concussed group (Roiger et al. 2015). In a study of
collegiate versus high school athletes 2 weeks after concussion, MDD was apparent
that is greater in collegiate students as compared to high school athletes (Kontos
et al. 2012).
Several lines of incidences suggest that concussion-induced depressive illnesses
are about 77% higher in rugby players as compared to other players. Likewise
American football players exhibited MDD that is 2 to 3 times higher than the general
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 533

population (Makdissi 2010; Makdissi et al. 2014; McCrory et al. 2013). It has also
emerged that lifetime repetitive concussion, e.g., 77 in rugby players versus
13 non-rugby players, exhibited higher degree of MDD associated with other
psychiatric and anxiety problems (Decq et al. 2016). It was found that athletes
who suffer at least three concussions are susceptible to develop three times higher
MDD as compared to those without any concussion. The magnitude and severity of
MDD in concussion is further exacerbated by alcohol intake, other co-morbidity
factors such as ligament injury, and anxiety-related disorders prior to concussion
(Guskiewicz et al. 2007, Guskiewicz and Broglio 2015).
There are evidences that sports concussion and neuroinflammation play key roles
associated with stress factors that are responsible for the increase in circulating
cytokines (Dowlati et al. 2010; Leonard and Maes 2012). Among the cytokines,
tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are particularly
involved in MDD caused by concussion (Plata-Salaman 2002). These cytokines
modulate the regulation of monoaminergic neurotransmitters including serotonin
(Hasse and Brown 2015). This suggests that neuropsychotherapy of depression
requires treatment needs regulating cytokines and monoamines together for effective
therapy in clinics.

Depression in Military

Traumatic brain injury (TBI) caused by either penetrating forces or concussive head
injury (CHI) by blunt forces inflicted in military is one of the most leading causes of
post-trauma cognitive, behavioral, and affective disorders (Kennedy et al. 2019).
According to the US Defense Medical Surveillance System data, about 384 k
service members received mild to severe brain injury in the last 18 years (2000–
2018), out of which more than 25% of cases showed chronic disorders ranging from
neurological to neuropsychiatric dysfunction (DoD Worldwide Numbers for TBI,
http://dvbic.dcoe.mil/).
Military personnel after TBI are prone to significantly higher episodes (40% to
77%) of developing MDD (Perry et al. 2016) as compared to personnel without
brain injury (Swanson et al. 2017). Symptoms of depression in TBI cases appear
within 2 weeks after trauma and progressing up to 6 months after the insult (Hou
et al. 2012).
The depression rate after brain injury was significantly higher in female service
members (57.9%) as compared to their male counterparts (Kennedy et al. 2019). The
rate of depression is further exacerbated in military personnel who are depleted to
combat operations more than three times (Shen et al. 2012).
Treatment with SSRI like sertraline is able to partially help depressive episodes in
these service members (Jorge et al. 2016). Since MDD could be a great risk of
suicide, it is important to treat MDD cases with TBI in military (Kambe et al. 2018).
Thus, TBI associated with military in relation to MDD should be identified earlier to
decrease cases of suicide and given suitable treatment to cope with these unwanted
psychiatric diseases.
534 H. S. Sharma and A. Sharma

Depression in Alzheimer’s Disease

Alzheimer’s disease (AD) is one of the prominent neurodegenerative diseases associ-

ated with MDD and other psychiatric ailments such as apathy, psychosis, anxiety,
agitation, and sleep disturbances (Orgeta et al. 2017). Several lines of evidences show
that TBI is one of the major risk factors of AD (see Sharma et al. 2018, 2019a, b,
2020). Military personnel are thus vulnerable to AD-induced MDD as the incidences
of TBI are quite frequent in service members (Kennedy et al. 2019).
About 50% of AD cases show MDD as compared to the general population
showing 20% to 30% cases of depressive illness (Starkstein et al. 2005).
The best clinical strategies to treat AD patients with MDD are to use SSRIs
because this will not interfere with other medications. In a clinical study of
311 patients, 147 participants were treated with SSRI and 164 with placebo. The
outcome suggests very minimal differences of improvements based on the depres-
sion scale analyzed between placebo and SSRI. This leads us to believe that
AD-induced depression may involve other pathways, e.g., glutamatergic transmis-
sion apart from monoaminergic mechanism (Banerjee et al. 2011; Hendricksen et al.
2004; Thomas et al. 2006). Thus, additional research using the combination of
drugs or nanodelivery of drugs in MDD associated with AD is needed. However,
this is a feature that is currently being examined in our laboratory (Sharma et al.
2019, 2020a, b).

Depression in Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disease in which loss of dopami-

nergic neurons predominates (Cacabelos 2017). However, loss of serotoninergic
neurons also occurs in PD (Politis and Niccolini 2015). Thus, loss of serotonin
and dopamine together leads to the development of depression in PD (Ryding et al.
2008). There are also reports that depressive symptoms may appear much earlier
than the clinical diagnosis of PD (Marsh 2013). This suggests that neurodegenerative
changes before motor symptoms could occur that are primarily responsible for
depression and anxiety-related disorders (Galts et al. 2019; Ryan et al. 2019).
About 40% to 50% of PD patients exhibit cases of MDD; however, in some cases
mild depression also prevails (Reijnders et al. 2008). The symptoms of depression in
PD cases may appear 4 to 6 years before motor symptoms could be seen (Global
Parkinson’s disease Survey (GPDS) Screening Committee 2002).
The mechanisms of depression in PD are not fully established yet. However,
available evidences suggest that degeneration of dopaminergic neurons with the
presence of Lewy bodies within the interneurons in substantia nigra pars compacta
(SNpC) is the classical neuropathological lesion in PD (Aarsland et al. 2012).
However, PD is not limited to SNpC, but neurodegeneration could be seen in remote
areas of the brain apart from midbrain where serotoninergic neurons are also lost
(Ishihara and Brayne 2006). These dopaminergic and serotoninergic neurons are
responsible for mood and reward system leading to anxiety and stress (Marsh 2013).
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 535

Degeneration of mesocortical and mesolimbic dopaminergic neurons results in

frontal dysfunction leading to disruption of serotoninergic neurons in the dorsal
raphe nucleus (Mayberg and Solomon 1995). All these disruptions and dysfunctions
lead to prominent depression in PD (Matsui et al. 2006; Mayberg et al. 1990;
Weintraub et al. 2005).
These studies support treatment with depression in PD with SSRIs (Devos et al.
2008; Richard et al. 2012; Peña et al. 2016; Mills et al. 2018; Ryan et al. 2019).
Several clinical studies show that SSRIs are not only safe but also improve the PD
symptoms other than depression (Barone et al. 2010; Andersen et al. 1980; Menza
et al. 2009). In some cases SNRIs also showed good response in clinic; however,
SSRIs seems to be superior (Skapinakis et al. 2010; Seppi et al. 2011). Other
treatments include MAOI and dopamine agonists; however, they were not so
successful to treat depression for a long time in PD (Imamura et al. 2011; Leentjens
et al. 2011, Barone et al. 2006).
In conclusion, treatment of MDD in PD requires further study to find a combi-
nation of agents in reducing anxiety and other motor symptoms together including
nanodelivery of drugs in future.

Psychostimulant Abuse and Depression

Psychostimulants used as recreational agents and some clinically prescription drugs

are well known to induce depression. A number of psychostimulants are clinically
prescribed for treating psychiatric disorders. Both kinds of psychostimulants induce
anxiety and depressive behavior (Sharma 2004b; Pary et al. 2015; Barr and Markou
2005; Qian et al. 2019).
The term psychostimulants loosely refers to a wide range of psychoactive sub-
stances affecting the CNS by either activating or inhibiting behaviors (Rasmussen
et al. 1996; Kosten et al. 1998; Barr et al. 2002). In general, psychostimulants
enhance the central activity of monoaminergic neurons and cholinergic activity
(Coury et al. 1992; Fibiger and Phillips 1988) and normally, in low doses, enhance
attention and mood while in high doses result in euphoria (Mattay et al. 2000).
Some of the key psychostimulants are used for recreation including cocaine
(Sharma et al. 2009), methamphetamine, and substituted methamphetamine, e.g.,
3.4-methylenedioxymethamphetamine (MDMA, ecstasy), that act primarily as
monoamine agonists (Vollenweider et al. 2002; Verhoeff et al. 2003; Sharma and
Ali 2008; Sharma et al. 2015). However, these drugs also create dependence after
repeated use as counter-production occurs in opposition to their primary rewarding
effects (Solomon and Corbit 1974; Koob et al. 1997). At the stages either continu-
ation of these drugs or withdrawal induces MDD in which depressed mood and
anhedonia are quite common (Schildkraut et al. 1971, Malison et al. 1998; Diag-
nostic and Statistical Manual of Mental Disorders, DSM IV; American Psychiatric
Association 1994).
The withdrawal or abstinence from psychostimulants creates several psychiatric
illnesses that are often treated with dopamine agonists either alone or together with
536 H. S. Sharma and A. Sharma

other tricyclic antidepressants (Giannini and Billett 1987; Barbosa Méndez and
Salazar-Juárez 2019; Ru et al. 2019;Shabani et al. 2019; Quin et al. 2019). The
dopamine D2 receptor agonist apomorphine also rapidly reduces withdrawal symp-
toms of psychostimulants (Hollander et al. 1990; Kampman et al. 2000).
Morphine also induces dependence in individuals using it to suppress either
pain or pleasure. Morphine dependence and withdrawal both cause severe MDD
symptoms (Schulteis et al. 1995). However, morphine withdrawal affecting both
opiates and monoaminergic pathways play significant role. Accordingly, naloxone,
an opiate antagonist, and serotonin 5-HT3 receptor antagonist ondansetron are
capable to alleviate morphine withdrawal symptoms (Schulteis et al. 1995; Sharma
et al. 2019).
These observations suggest that psychostimulant-induced MDD is mediated
through monoaminergic and opioid mechanisms. Further studies on the use of
combination drugs and nanodelivery may improve the clinical efficacy in these
areas.

Stress and Depression

Acute or chronic stressors induce depressive behaviors in human or in animals (Yang

et al. 2015; Sharma et al. 2011). Stress-induced depression includes irritability,
helplessness, anhedonia, mood disturbances, sleep deprivation, altered cognitive
function, and anxiety-related disorders (Rawson et al. 2010, 2015; Selye 1955;
Sharma et al. 2013).
In general, stress leads to MDD in about 20% to 25% women and 7–12% in men
(Belmaker and Agam 2008). However, our understanding on the mechanisms of
stress-induced MDD is far from clear. Likewise the treatment strategies of MDD in
stress are not well investigated (Svenningsson et al. 2013). For treating stress-
induced depression, antidepressants and SSRIs are commonly employed in the clinic
to enhance extracellular levels of serotonin that activates multiple pre- and postsyn-
aptic serotonin receptors (Svenningsson et al. 2006; Warner-Schmidt et al. 2009).
The 5-HT receptors interact with a protein p11 that is expressed in the brains in
prefrontal cortex, amygdala, and hippocampus and regulates serotonin levels
(Svenningsson et al. 2013). The p11 protein that interacts with several serotonin
receptors and ion channels is actively involved in depression-like behaviors and/or
antidepressant-like actions (Oh et al. 2013; Warner-Schmidt et al. 2009). It is present
in cholinergic neurons in nucleus accumbens, mossy fibers, and basket cells in the
dentate gyrus of the hippocampus, as well as in corticostriatal projection neurons
(Schmidt et al. 2012; Seo et al. 2017, 2018).
Several lines of evidences suggest that the level of p11 mRNA and protein is
downregulated in depressed human and animal cases and increased after treatment
with monoaminergic antidepressants and SSRIs (Anisman et al. 2008; Warner-
Schmidt et al. 2011; Seo et al. 2017). Likewise mice overexpressing p11 exhibit
antidepressant-like behaviors (Warner-Schmidt et al. 2010; Seo et al. 2018). Anti-
depressants including SSRIs and TCA all require p11 protein for their therapeutic
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 537

activity (Svenningsson et al. 2006, 2013). However, it is still unclear whether

MAOIs could also require p11 protein for their antidepressant effects (Seo et al.
2017, 2018).
Medial prefrontal cortical neurons project to several brain regions such as nucleus
accumbens, hippocampus, lateral habenula, amygdala, and hypothalamus involved
in the pathophysiology of stress-induced depression (de Kloet et al. 2005; Joëls et al.
2007; McEwen 2007; Popoli et al. 2012; Arnsten 2009).
These studies show that monoaminergic mechanisms are involved in stress-
induced depression. However, additional investigations are needed to explore
novel drugs or their combination in effectively regulating depression in stress
situations.

Neurotrophins and Depression

Apart from monoaminergic mechanisms of depression, the CNS network intricate

with several neurotransmitters and agents in any disease process of homeostasis of
the CNS. Thus, there are evidences that depressive patients show severe reductions
in the brain-derived neurotrophic factor (BDNF in postmortem brains). Interestingly,
treatment with antidepressants enhances BDNF expressions in the hippocampus
(Nibuya et al. 1996). This observation suggests that neurotrophins are involved in
depression in both human subjects and animal models. Further postmortem studies
of human-depressed brains show that the BDNF mRNA and protein are reduced in
the hippocampus, prefrontal cortex, and amygdala in suicide cases (Dwivedi et al.
2003; Karege et al. 2005; Guilloux et al. 2012). In addition, antidepressant treatment
significantly increased BDNF protein levels in several areas of the hippocampus
(Chen et al. 2001).
Further evidence of neurotrophins in depression came from reduced BDNF levels
in serum or in plasma of depressed patients, and this reduction in BDNF was
normalized after antidepressant treatment (Karege et al. 2002, 2005;Yoshida et al.
2012; Lee et al. 2007; Li et al. 2008; Shimizu et al. 2003; Deuschle et al. 2013). This
suggests that BDNF in plasma could be a potential biomarker of depression in
healthy human cases (Klein et al. 2011).
Neurotrophins belong to a family of growth factors maintaining survival,
growth, and differentiation of CNS neurons (Lewin and Barde 1996; Huang and
Reichardt 2001; Sharma et al. 1998; Sharma 2007). Various neurotrophins includ-
ing BDNF, nerve growth factor (NGF), and neurotrophin 3 and 4/5 (NT-3; 4/5)
influence cell signaling through tyrosine kinase (TrK) and/or p75 receptors
(Barbacid 1995).
Animal studies clearly show that stressors such as immobilization (Sharma and
Dey 1988), heat stress or hyperthermia (Sharma 2006; Sharma and Hoops 2003;
Sharma and Johanson 2007; Sharma and Sharma 2007; Sharma et al. 2015b)
restraint, forced swimming, foot electroshock, social isolation, or social defeat
downregulate BDNF mRNA and protein levels particularly in the hippocampus
inducing depressive-like behaviors (Smith et al. 1995; Ueyama et al. 1997;
538 H. S. Sharma and A. Sharma

Rasmusson et al. 2002; Pizarro et al. 2004; Greenwood et al. 2007). This down-
regulation of BDNF at mRNA and/or protein level was restored following antide-
pressant treatment (Tsankova et al. 2006). This suggests that BDNF mechanisms
are somehow involved in the development of depressive behaviors (Jiang and
Salton 2013).

BDNF and Serotonin Interaction in the CNS

Several lines of evidences suggest that BDNF promotes the development and
functioning of serotoninergic neuromas (see Martinowich and Lu 2008). Serotonin
is phylogenetically the oldest neurotransmitter in the CNS and has the highest
number of receptors compared to any neurotransmitters (Bockaert et al. 2006).
BDNF and its TrK receptor are co-expressed in serotoninergic neurons in the dorsal
and median raphe (Mamounas et al. 2000). The BDNF is retrogradely transported
from the serotonin terminals in the striatum and hippocampus to the cell bodies
located in the raphe nuclei (Anderson et al. 1995). The BDNF promotes expression
of serotoninergic expression in raphe neurons (Siuciak et al. 1996).
Likewise, serotoninergic neurotransmission exerts powerful control on BDNF
expression. This effect is one of the key mechanisms underlying the therapeutic
effects of BDNF enhancement following antidepressant therapy (Szapacs et al.
2004). This is supported by the fact that administration of SSRIs increases the
extracellular concentration of serotonin that could enhance the BDNF level probably
via cAMP response-binding protein (CREB) phosphorylation (Szapacs et al. 2004;
Martinowich and Lu 2008).
Although nearly all antidepressants increase BDNF mRNA levels and enhance
BDNF expression controlling depression, the underlying mechanisms are still not
well known and require further investigation. It appears that the genetic mechanisms
are involved in the BDNF and serotonin interaction (Rybakowski et al. 2007). This is
an interesting feature of research that needed additional investigation.

Cytokines and Depression

There is a close link between neuroinflammation and depressive behaviors (Troubat

et al. 2021). Cytokines play key roles in the regulation between immune responses
and infection (Estcourt et al. 1998). However, involvement of cytokines in psychi-
atric disorders especially MDD was first described by Smith (1991) in a provocative
theory on “macrophage theory of depression.” According to this theory depression
results in imbalances of cytokines leading to activation of monocyte/macrophage
and inhibition of leucocyte functions. Immune activation was confirmed after mea-
surement of cytokines in the plasma of depressed patient and/or treatment resistance
depression (Maes 1995). In line with this idea, higher levels of iterleukin-1 beta
(IL-1β) with lower levels of IL-6 while unchanged tumor necrosis factor-alpha
(TNF-α) levels were found in the CSF of 13 hospitalized depressed patients (Levine
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 539

et al. 1999). Further studies show that antidepressants are able to reduce the activated
immune system in depressive illness (Castanon et al. 2001; Yirmiya et al. 2001).
Cytokines induce downregulation of serotonin synthesis and influence dopami-
nergic system in basal ganglia (Lestage et al. 2002). The hippocampus is highly
innervated by serotoninergic nerve terminals (Hensler 2006). Also the density of
IL-1β, IL-6, IL-2, and TNF-α, the pro-inflammatory cytokines, is highest in the
hippocampus (Wilson et al. 2002). BDNF and TrK levels are downregulated in the
prefrontal cortex that is heavily innervated by serotoninergic neurons (Autry and
Monteggia 2012). This suggests that serotonin regulation of immune modulators
actively plays key roles in depression. Serotonin receptors are actively involved in
immune modulation (Baganz and Blakely 2013; Ahern 2011). Serotonin receptor
5-HT7 induces activation of cytokines in astrocytes (Lieb et al. 2005). These
observations indicate an intricate relationship between serotonin, cytokines, and
the neurotrophins in depression.

Unifying Concepts of Depression

The etiology of depression is largely due to monoaminergic mechanisms especially

serotoninergic neurotransmission playing key roles. In this regard serotonin trans-
porter (SERT) that regulates serotonin levels in the brain is responsible for all the
antidepressant actions of SSRIs. However, some drug-resistant depressive illness and
long time is needed for antidepressant action leads to new theories of psychiatric
disorders. Accordingly, interaction among monoamines, neurotrophins, glutamatergic
synapse, and cytokines is important in depressive illnesses and therapy.

Monoamines and Neurotrophin Interaction

The monoamine theory is based on the fact that decreased availability of neurotrans-
mitters serotonin and noradrenaline in the CNS is responsible for the pathogenesis of
depression (Krishnan and Nestler 2008). This theory gets support from the results
based on the antidepressant drugs SSRIs and SNRIs that alleviate depression in
patients (Trivedi et al. 2006). However, not all patients respond to these treatments.
This indicates that monoamines could be a part of the depression process. Additional
research showed that synaptic plasticity and neurogenesis are other important
aspects of depressive illness (Lee and Kim 2010; Eisch and Petrik 2012). The
antidepressive action of the N-methyl-D-aspartate (NMDA) receptor antagonist
ketamine indicates the involvement of glutamatergic receptors in depression
(Berman et al. 2000). However, serotonin is actively involved in the pathology of
depression because the monoamine neurotransmitters interact with several other
agents in the CNS to regulate mood, psychology, and behavioral functions.
Studies in clinics and in animal models of depression show that SSRIs enhance
neurogenesis and reverse hippocampal atrophy (Malberg et al. 2000). BDNF mRNA
and protein levels in the hippocampus increased after SSRI treatment (Autry and
540 H. S. Sharma and A. Sharma

Monteggia 2012). These observations clearly indicate the strong interaction between
BDNF, depression, and serotoninergic neurotransmission (Martinowich and Lu
2008; Hasse and Brown 2015). In addition, extracellular serotonin levels influence
BDNF expression and BDNF regulates serotonin levels through SERT activity
(Daws et al. 2007). These results suggest that reciprocal regulatory mechanisms
are operating between serotonin and BDNF as a feedback loop to maintain both
agents in balance (Hasse and Brown 2015).

Monoamine and Cytokine Interaction

Several lines of evidences suggest that pro-inflammatory cytokines are involved in

mood symptoms following acute or chronic stress-induced depression and inflam-
matory responses (Barrientos et al. 2003; Koo et al. 2010). The inflammatory
symptoms alone are inducing stress leading to the development of depressive illness
(Audet and Anisman 2013).
Elevated levels of cytokines are seen in animal models of depression (Couch et al.
2013; Goshen et al. 2008; You et al. 2011). Since microglia are the primary source of
pro-inflammatory cytokine activation of microglia in chronic stress or depressive
models indicates their role in neuronal plasticity (Walker et al. 2013). Although the
BDNF is largely produced in neurons and only very small amounts are produced in
astrocytes and microglia in healthy conditions, BDNF upregulation can occur in glial
cells in pathological situations (Dougherty et al. 2000). Activation of microglia is the
primary response of neuroinflammation and BDNF production is dependent on
microglial activity. This suggests that microglial activation has both neurotoxic
and neuroprotective effects on neuronal plasticity (Kettenmann et al. 2011; Kohman
and Rhodes 2013). BDNF levels, however, are negatively affected by the high
concentration of pro-inflammatory cytokines (Eyre and Baune 2012). Furthermore,
in astrocytes pro-inflammatory cytokines activate BDNF expression (Saha et al.
2006). This suggests that the balance between neuroprotective neurotrophins and
neurotoxic cytokines is playing a crucial role in depression.
Cytokines could regulate SERT activity as first described by Ramamoorthy et al.
(1995). Upregulation of SERT by IL-β is dependent on IL-1β receptor through
transcription of NFκB (Kekuda et al. 2000). Both TNF-α and IL-1β induced transient
upregulation of SERT activity in raphe neurons and in brain synaptosomes (Zhu et al.
2006). Pro-inflammatory activity induced enhanced SERT correlates with increased
serotonin turnover (van Heesch et al. 2014). Likewise intraperitoneal TNF-α admin-
istration causes depression-like behavior associated with increased serotonin and
dopamine turnover due to increased SERT activity (van Heesch et al. 2013a, 2013b).
However, it is still unclear whether pro-inflammatory-induced SERT activity comes
from neurons, astrocytes, or microglia (Huang and Pickel 2002).
As mentioned earlier, SERT activity and BDNF levels mutually regulate each
other (Kettenmann et al. 2011). This suggests that SERT mechanisms of
pro-inflammatory cytokine-induced BDNF expression induce neurochemical alter-
ations influencing neuroplasticity in depression (Hasse and Brown 2015).
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 541

Taken together it appears that monoamines, neurotrophins, and cytokine interac-

tion play a leading role in the pathophysiological mechanisms of depression. It
would be thus interesting to see whether a combination of approaches with
neurotrophins, anticytokine agents, and SSRIs together may have superior effects
in treating MDD in clinics.

Blood-Brain Barrier Is the Gateway of Depression

There are reasons to believe that cerebrovascular reactions play key roles in the
development of depressive illnesses following stress-induced neuroinflammation
following neurotransmitter release (Selye 1976). Stressors induce the release of
several neurotransmitters in the circulation as well as in the brain microenvironment
leading to cerebrovascular alteration in blood flow and disrupt BBB function (Mora
et al. 2012; Sharma et al. 1990; Shalev et al. 2009; Sharma and Westman 2004). In
this process monoaminergic neurotransmission, harmful cytokines, and other factors
play key roles (Elenkov and Chrousos 2006). Neurotrophins and other molecules are
also released to counteract the harmful vascular response (Smith et al. 1995). Thus, a
balance between neuroprotective and neurodestructive elements finally regulates the
state of the BBB leading to disease formation (Sharma 2009).
Recently, clinical and preclinical studies showed that neuroinflammation and
cerebrovascular dysfunction play key roles in the pathology of MDD (Dudek et al.
2020). It is well known that chronic stress alters the BBB permeability (Fig. 1,
Table 1) probably by enhancing the vesicular transport as well as by disrupting tight
junctional proteins (Sharma 2004b, 2009; Sharma and Sharma 2010). Disruption of
the BBB following stress allows circulating pro-inflammatory cytokines in the brain
resulting in depression-like behaviors, e.g., social avoidance, anhedonia, and help-
lessness (Dudek et al. 2020). One of the main mechanisms of stress-induced BBB
breakdown appears to be mediated by loss of claudin-5 present in the tight junction
of the cerebral endothelial cell (Ménard et al. 2017). Interestingly, the claudin-5
expression is severely reduced in depressive patients in nucleus accumbens region
(Ménard et al. 2017; Dudek et al. 2020).
Experiments from our laboratory showed that various stressors induce the
breakdown of the BBB to protein tracers leading to vasogenic edema formation
associated with depressive behaviors (Table 1, Sharma 1999; Sharma and Westman
2004; Sharma 2005; Sharma and Sharma 2010). At the ultrastructural level
increased vesicular permeability to lanthanum is clearly seen without widening
of the tight junctions (Figs. 2 and 3) (Sharma 2004a, 2009a; Sharma and Sharma
2010). This suggests that endothelial cell membrane forming the tight junctions is
permeable in stress allowing the passage of lanthanum across the tight junctions
without widening them (Sharma 2009a, b; Sharma and Sharma 2010). This effect is
seen in almost all cases of BBB leakage at the ultrastructural level (Figs. 2 and 3).
Stress is also capable to increase blood-cerebrospinal fluid barrier (BCSFB)
breakdown (Fig. 4) allowing cytokines and other immunologic elements to enter
542 H. S. Sharma and A. Sharma

Fig. 1 Showing stages of stress (a) and relation of stress severity with brain pathology (b). There
are three stages of stress, namely, alarm reaction, followed by state of resistance and after that stress-
induced exhaustion (Selye 1976). There are reasons to believe that blood-brain barrier (BBB)
permeability occurs during alarm reaction to the state of resistance (a). Brain pathology following
stress depends on the magnitude and duration of stress (b). It is likely that when moderate to severe
stress prolonged for some time, the BBB disruption occurs. Further continuation of stress results in
alteration of synaptic plasticity and brain pathology that could be irreversible in nature. Depression
may occur after BBB breakdown and alteration in synaptic plasticity associated with cerebrovas-
cular alteration and brain pathology (Sharma 1999, 2004a, 2009a). (Data modified after Sharma
1999, 2004a, 2009a, b; Sharma and Sharma 2010)

into the CSF and affect depressive behaviors (Dudek et al. 2020; Sharma 2009a, b;
Sharma and Sharma 2010).
When the serotonin precursor 5-HTP was injected acutely, the BBB disruption
occurs in several brain regions (Sharma et al. 2019a, b). This suggests that 5-HTP
by enhancing the serotonin levels in the brain and plasma is responsible for the
breakdown of the BBB (Sharma et al. 1990). These observations in part may
explain that 5-HTP treatment alone alters the BBB breakdown; therefore, this
treatment has mixed effects in treating depression-like behaviors in some
patients.
Treating stressful situations with cerebrolysin, a balanced composition of several
neurotrophic factors and/or neurotrophins, e.g., BDNF or IGF-1, significantly
reduced the BBB leakage resulting in attenuation of depressive symptoms
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 543

Table 1 Blood-brain barrier breakdown by stressors induce depression as evaluated using

immobility features
BBB
Stressors Species breakdown Depressiona Edema References
Immobilization 8-14 h Rat Yes Yes Yes Sharma and Dey
(1986a)
Heat stress 4 h 38
C Rat Yes Yes Yes Sharma and Dey
(1986b, 1987)
Forced swimming Rat Yes Yes Yes Sharma et al.
30 min (1991, 1995)
Sleep deprivation Rat Yes Yes Yes Sharma et al.
48-72 h (2015, 2018,
2019)
Morphine dependence Rat Yes Yes Yes Sharma et al.
10 days (2004)
Morphine withdrawal Rat Yes Yes Yes Sharma and Ali
48-72 h (2006), Sharma
et al. (2006)
Methamphetamine 4 h Mice Yes Yes Yes Sharma and Ali
(2006)
Methamphetamine 3 h Rat Yes Yes Yes Kiyatkin et al.
(2007)
Sharma and
Kiyatkin (2009)
MDMA 4 h Mice Yes Yes Yes Sharma and Ali
(2008)
Cocaine 4 h Rat Yes Yes Yes Sharma (2012)
Alzheimer’s disease Rat Yes Yes Yes Sharma et al.
(2012, 2016,
2018, 2019)
Parkinson’s disease Mice/rat Yes Yes Yes Ozkizilcik et al.
(2018, 2019);
Sharma et al.
(2019)
Traumatic brain injury Rat Yes Yes Yes Sharma et al.
(2004, 2006)
Concussive head Rat/mice Yes Yes Yes Sharma et al.
injury (2006, 2007,
2016, 2018)
Spinal cord injury Rat Yes Yes Yes Sharma (2004b,
2009, 2018,
2019)
Diabetes Rat Yes Yes Yes Sharma et al.
(2007)
Hypertension Rat Yes Yes Yes Muresanu and
Sharma (2006)
5-HTP Rat Yes Yes Yes Sharma et al.
(2019)
a
unpublished observation
544 H. S. Sharma and A. Sharma

Fig. 2 High-power transmission electron micrograph of cerebral capillaries showing tight junc-
tional permeability in stress-induced depression. In control tight junction (a) is closely apposed
endothelial cells that are tight to small molecule lanthanum (molecular diameter 12 Å) is very tight
(arrowhead). The dark black particles are lanthanum present exclusively in the lumen (L). Follow-
ing heat stress-induced depression, the endothelial cell is permeable to lanthanum and could be seen
within the endothelial cell cytoplasm (b, d) without widening of the tight junction (arrows). In (b)
lanthanum is seen penetrating into the endothelial cells around the tight junction (arrows) without
widening them. In (d) the tight junction stops the passage of lanthanum into the basal lamina
(arrowhead) while the endothelial cell cytoplasm is filled with lanthanum. The tight junction is not
widened. That lanthanum could penetrate without widening of the tight junction is clearly seen in
(e) where the cell membrane apposing the tight junction is permeable to lanthanum but the tight
junctions are not widened in heat stress-induced depressive episode (arrows). The tight junctions
between the cerebral capillaries in immobilization (c) and forced swimming (f) are intact and not
widened. The passage of lanthanum was stopped at the tight junctions (arrowheads) while the
cerebral endothelium shows infiltration of lanthanum. Bar 500 nm. (Data adapted from Sharma
et al. 1998; Sharma 2004a, 2009a; Sharma and Sharma 2010)

(Table 2, Sharma HS, unpublished observation; Sharma 1982, 1999, 2004a, 2009a, b).
We have used TiO2-nanowired cerebrolysin and related drugs to induce the
superior neuroprotective effects on the BBB breakdown and brain pathology. Thus,
the need of the hour is to investigate the effects of SSRIs and SNRIs using nano-
delivery in depression. However, these observations are in line with the idea that
depression results from the breakdown of the BBB and restoration of the BBB
structure and the function is likely to alleviate depressive illnesses (Dudek et al.
2020; Nation et al. 2019).
 Amine Precursors in Depressive Disorders and the Blood-Brain Barrier

Fig. 3 Low-power transmission electron micrograph (TEM) showing cerebral capillary alterations at the ultrastructural level in depressive episodes following
545

heat stress (a, b, f), immobilization stress (c), and forced swimming (e) as compared to control (d). The microvessel collapse following heat stress in the
546 H. S. Sharma and A. Sharma

Fig. 4 Light microscopy images showing neuronal loss and damages in stress-induced depressive
episode following heat stress (HS, a, b), immobilization (IMZ, c, e, f, g), and forced swimming (FS,
d, h). Hippocampus degeneration (b) in dentate gyrus and CA-4 regions (arrowheads) with
edematous swelling and sponginess (*) is clearly seen as compared to control (a). Following
immobilization (IMZ) induced depressive episodes lead to neuronal damages showing dark neurons
(arrows) with perineuronal edema, and expansion of the neuropil in the cerebral cortex (c) and in the
dorsal thalamus (arrows, g). Immobilization stress also affected blood-cerebrospinal fluid-barrier
(BCSFB) showing degeneration of choroidal epithelial cells and ependymal cells (arrows, f) as
compared to control (e). Likewise forced swimming (FS)-induced depression also resulted in
neuronal damages in the cerebral cortex (d) and ventral thalamus (h) showing dark and distorted
neurons (arrows) with perineuronal edema and expansion of the neuropil (d, h). The BCSFB is also
compromised in FS (k) as evident in the degeneration of choroidal epithelial cells and ependymal
cells (arrows) in FS. (Data modified from Sharma 2004a; Sharma and Sharma 2010. Paraffin
sections H&E stain (a, b); Nissl stain (c-k). Bar ¼ 30 μm)

Fig. 3 (continued) hippocampus (a) and cerebral cortex (f) with perivascular edema and sponginess
is quite apparent. In the thalamic region (b), two microvessels are partially collapsed, showing
lanthanum extravasation across the endothelial cells (arrows) following depression in heat stress.
Membrane vacuolation and edema (*) are clearly seen around the perivascular areas after heat stress
(a, b, f). Immobilization stress (c) and forced swimming (e)-induced microvascular alteration
showed partially collapsed cerebral capillary with perivascular edema (*) with dark and altered
pericytes (arrow) and membrane vacuolation. Bar ¼ 1 μm. (Data modified after Sharma 2004a,
2009; Sharma and Sharma 2010)
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 547

Table 2 Reduction in blood-brain barrier breakdown in stress by drugs reduced depressive

symptoms as evaluated using immobility features
Stressors Drug BBB Depressiona Edema References
breakdown
Immobilization Cerebrolysina, Reduced No Reduced Sharma
stress 8 h BDNFa (2004a)
Heat stress 4 h Cerebrolysin, Reduced No Reduced Sharma
38
C ondansetrona, (2004a)
Sharma and
Dey
(1986b)
Sharma and
Dey (1987)
Forced swimming Reduced No No Sharma
30 min et al. (1991,
1995)
Sleep deprivation Cerebrolysin, Reduced No Reduced Sharma
48-72 h ondansetron et al. (2015,
2018, 2019)
Morphine Cerebrolysin Reduced Reduced Reduced Sharma
dependence et al. (2004,
10 days 2007)
Morphine Cerebrolysin, Reduced No Reduced Sharma and
withdrawal 48-72 h ondansetron Ali (2006)
Sharma
et al. (2006)
Methamphetamine Cerebrolysin Reduced No No Sharma
4h et al. (2004)
(Sharma
and
Kiyatkin
2009;
Sharma
et al. 2015a)
Alzheimer’s Cerebrolysin Reduced No Reduced Sharma
disease et al. (2012,
2016, 2018,
2019)
Parkinson’s disease Cerebrolysin Reduced No Reduced Ozkizilcik
et al. (2018,
2019)
Sharma
et al. (2019)
Traumatic brain Cerebrolysin Reduced No Reduced Sharma
injury et al. (2004,
2006)
Concussive head Cerebrolysin Reduced No Reduced Sharma
injury et al. (2006,
2007, 2016,
2018)
(continued)
548 H. S. Sharma and A. Sharma

Table 2 (continued)
Spinal cord injury Cerebrolysin, Reduced No Reduced Sharma
BDNF (2004a,
2009, 2018,
2019)
IGF-1, Growth
hormone
Diabetes Cerebrolysin, Reduced No Reduced Sharma
MSCs et al. (2007,
2015b)
MSCc, mesenchymal stem cells
a
unpublished observation

Conclusion and Future Perspectives

There are reasons to believe that BBB is a gateway of depression and drugs that are
capable to restore BBB function are suitable therapy in treating depression in
clinic. Amine precursors are used for treating depression and work for some time
and then its effects are dwindling. To this end a combination of drugs antagonizing
pro-inflammatory cytokines and enhancing neurotrophins in the brain could be
used in addition to antidepressants for better clinical efficacy. Alternatively, with
the recent advancement in nanobiotechnology, these drugs may be delivered using
nanoformulation for enhanced therapeutic value in treating depressive illnesses.
The currently using available drugs or their combinations may be used as nano-
formulation in depression or superior effects. This is a new feature in depressive
therapy that is being examined in our laboratory currently.

Acknowledgments The authors’ research reported here are supported in part by grants from the
Air Force Office of Scientific Research (EOARD, London, UK) and Air Force Materiel Command,
USAF, under grant number FA8655-05-1-3065; Swedish Medical Research Council
(Nr 2710-HSS); Göran Gustafsson Foundation, Stockholm, Sweden (HSS); and Astra Zeneca,
Mölndal, Sweden (HSS/AS). We thank Suraj Sharma, Blekinge Institute of Technology, Karls-
krona, Sweden, for computer and graphic support. The US Government is authorized to reproduce
and distribute reprints for Government purpose notwithstanding any copyright notation thereon.
The views and conclusions contained herein are those of the authors and should not be interpreted as
necessarily representing the official policies or endorsements, either expressed or implied, of the Air
Force Office of Scientific Research or the US Government.

References
Aarsland D, Pahlhagen S, Ballard CG, et al. Depression in Parkinson disease -epidemiology,
mechanisms, and management. Nat Rev Neurol. 2012;8:35–47.
Ahern GP. 5-HT and the immune system. Curr Opin Pharmacol. 2011;11(1):29–33.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders.
Washington, DC: American Psychiatric Association; 1952.
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 549

American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV).
Washington, DC: American Psychiatric Association; 1994.
Andersen J, Aabro E, Gulmann N, et al. Anti-depressive treatment in Parkinson’s disease.
A controlled trial of the effect of nortriptyline in patients with Parkinson's disease treated with
L-DOPA. Acta Neurol Scand. 1980;62:210–9.
Anderson KD, Alderson RF, Altar CA, DiStefano PS, Corcoran TL, Lindsay RM, Wiegand
SJ. Differential distribution of exogenous BDNF, NGF, and NT-3 in the brain corresponds to
the relative abundance and distribution of high-affinity and low-affinity neurotrophin receptors.
J Comp Neurol. 1995;357(2):296–317.
Anisman H, et al. Serotonin receptor subtype and p11 mRNA expression in stress-relevant brain
regions of suicide and control subjects. J Psychiatry Neurosci. 2008;33:131–41.
Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev
Neurosci. 2009;10(6):410–22.
Audet MC, Anisman H. Interplay between pro-inflammatory cytokines and growth factors in
depressive illnesses. Front Cell Neurosci. 2013;7:68.
Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders.
Pharmacol Rev. 2012;64:238–58.
Baganz NL, Blakely RD. A dialogue between the immune system and brain, spoken in the language
of serotonin. ACS Chem Neurosci. 2013;4:48–63.
Banerjee S, Hellier J, Dewey M, Romeo R, Ballard C, Baldwin R, Bentham P, Fox C, Holmes C,
Katona C, Knapp M, Lawton C, Lindesay J, Livingston G, McCrae N, Moniz-Cook E,
Murray J, Nurock S, Orrell M, O’Brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Burns
A. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multi-
centre, double-blind, placebo-controlled trial. Lancet. 2011;378:403–11.
Barbacid M. Neurotrophic factors and their receptors. Curr Opin Cell Biol. 1995;7(2):148–55.
Barbosa Méndez S, Salazar-Juárez A. Mirtazapine attenuates anxiety- and depression-like behav-
iors in rats during cocaine withdrawal. J Psychopharmacol. 2019;33(5):589–605. https://doi.
org/10.1177/0269881119840521. Epub 2019 Apr 23
Barone P, Scarzella L, Marconi R, Antonini A, Morgante L, Bracco F, Zappia M, Musch B,
Depression/Parkinson Italian Study Group. Pramipexole versus sertraline in the treatment of
depression in Parkinson’s disease: a national multicenter parallel-group randomized study.
J Neurol. 2006;253(5):601–7.
Barone P, Poewe W, Albrecht S, et al. Pramipexole for the treatment of depressive symptoms in
patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet
Neurol. 2010;9:573–80.
Barr AM, Markou A. Psychostimulant withdrawal as an inducing condition in animal models of
depression. Neurosci Biobehav Rev. 2005;29(4–5):675–706.
Barr AM, Markou A, Phillips AG. A ‘crash’ course on psychostimulant withdrawal as a model of
depression. Trends Pharmacol Sci. 2002;23(10):475–82.
Barrientos RM, Sprunger DB, Campeau S, Higgins EA, Watkins LR, Rudy JW, Maier
SF. Brain-derived neurotrophic factor mRNA downregulation produced by social isolation
is blocked by intrahippocampal interleukin-1 receptor antagonist. Neuroscience.
2003;121(4):847–53.
Belmaker RH, Agam G. N Major depressive disorder. Engl J Med. 2008;358(1):55–68.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant
effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4.
Birkmayer W, Hornykiewicz O. The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-
akinesia. Wien Klin Wochenschr. 1961;73:787–8.
Birkmayer W, Riederer P. Biochemical post-mortem findings in depressed patients. J Neural
Transm. 1975;37:95–109. https://doi.org/10.1007/BF01663627.
Birkmayer W, Danielczyk W, Neumayer E, Riederer P. The balance of biogenic amines as condition
for normal behavior. J Neural Transm. 1972;33:163–78.
Birkmayer W, Riederer P, Linauer W, et al. L-deprenyl plus l-phenylalanine in the treatment of
depression. J Neural Transm. 1984;59:81–7. https://doi.org/10.1007/BF01249880.
550 H. S. Sharma and A. Sharma

Blazer DG. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci.
2003;58(3):249–65.
Bockaert J, Claeysen S, Bécamel C, Dumuis A, Marin P. Neuronal 5-HT metabotropic receptors:
fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res.
2006;326(2):553–72. https://doi.org/10.1007/s00441-006-0286-1. Epub 2006 Aug 1.
Bowers MB Jr. Cerebrospinal fluid 5-hydroxyindoles and behavior after L-tryptophan and pyri-
doxine administration to psychiatric patients. Neuropharmacology. 1970;9(6):599–604.
Brent DA. Antidepressants and suicidality. Psychiatr Clin North Am. 2016;39(3):503–12.
Brodie HKH, Sack R, Siever L. Clinical studies of L-5-hydroxytryptophan in depression. In:
Barchas J, Usdin E, editors. Serotonin and behavior. New York: Academic; 1973. p. 549–59.
Brooks N, Campsie L, Symington C, Beattie A, McKinlay W. The five year outcome of severe blunt
head injury: a relative’s view. J Neurol Neurosurg Psychiatry. 1986;49(7):764–70. https://doi.
org/10.1136/jnnp.49.7.764.
Bunney WE Jr, Murphy DL, Brodie HKH, et al. L-DOPA in depressed patients. Lancet.
1970;1:352.
Bunney WE Jr, Brodie HK, Murphy DL, Goodwin FK. Studies of alpha-methyl-para-tyrosine,
L-dopa, and L-tryptophan in depression and mania. Am J Psychiatry. 1971;127(7):872–81.
Burton, R. (1621/2001). The anatomy of melancholy. New York: New York Review Books.
Cacabelos R. Parkinson’s disease: from pathogenesis to pharmacogenomics. Int J Mol Sci.
2017;18(3):551.
Carman AJ, Ferguson R, Cantu R, Comstock RD, Dacks PA, DeKosky ST, et al. Expert consensus
document: mind the gaps – advancing research into short-term and long-term neuropsycholog-
ical outcomes of youth sports-related concussions. Nat Rev Neurol. 2015;11:230–44.
Carroll BJ, Mowbray RM, Davies B. L-tryptophan in depression. Lancet. 1970;2(7676):776.
Castanon N, Bluthé RM, Dantzer R. Chronic treatment with the atypical antidepressant tianeptine
attenuates sickness behavior induced by peripheral but not central lipopolysaccharide and
interleukin-1beta in the rat. Psychopharmacology. 2001;154(1):50–60.
Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased hippocampal BDNF
immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry.
2001;50(4):260–5.
Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967;113:1237–64.
Coppen A, Shaw DM, Farrell JP. Potentiation of the antidepressive effect of a monoamine-oxidase
inhibitor by tryptophan. Lancet. 1963;1:79–81.
Coppen A, Shaw DM, Herzberg B, et al. Tryptophan in the treatment of depression. Lancet. 1967;2:
1178–80.
Coppen A, Whybrow PC, Noguera R, et al. The comparative antidepressant value of L-tryptophan
and imipramine with and without attempted potentiation by liothyronine. Arch Gen Psychiatry.
1972;26:234–41.
Couch Y, Anthony DC, Dolgov O, Revischin A, Festoff B, Santos AI, Steinbusch HW, Strekalova
T. Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-
altered behaviour in mice susceptible to anhedonia. Brain Behav Immun. 2013;29:136–46.
Coury A, Blaha CD, Atkinson LJ, Phillips AG. Cocaine induced changes in extracellular levels of
striatal dopamine measured concurrently by microdialysis with HPLC-EC and chronoam-
perometry. Ann N Y Acad Sci. 1992;654:424–7.
Curzon G. Influence of plasma tryptophan on brain 5HT synthesis and serotonergic activity. In:
Haber B, Gabay S, Issidorides MR, Alivisatos SGA, editors. Serotonin. Advances in experi-
mental medicine and Biology, vol. 133. Boston: Springer; 1981. https://doi.org/10.1007/978-1-
4684-3860-4_11.
Davis JM. Theories of biological etiology of affective disorders. In: Pfeiffer CC, Smythies JR,
editors. International review of neurobiology, vol. 12. New York: Academic; 1970. p. 145–75.
Daws LC, Munn JL, Valdez MF, Frosto-Burke T, Hensler JG. Serotonin transporter function, but
not expression, is dependent on brain-derived neurotrophic factor (BDNF): in vivo studies in
BDNF-deficient mice. J Neurochem. 2007;101(3):641–51.
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 551

de Kloet ER, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev
Neurosci. 2005;6(6):463–75.
Decq P, Gault N, Blandeau M, Kerdraon T, Berkal M, ElHelou A, et al. Long-term con- sequences
of recurrent sports concussion. Acta Neurochir. 2016;158:289–300.
DeRubeis RJ, Hollon SD, Amsterdam JD, Shelton RC, Young PR, Salomon RM, O’Reardon JP,
Lovett ML, Gladis MM, Brown LL, Gallop R. Cognitive therapy vs. medications in the
treatment of moderate to severe depression. Arch Gen Psychiatry. 2005;62:409–16.
Deuschle M, Gilles M, Scharnholz B, Lederbogen F, Lang UE, Hellweg R. Changes of serum
concentrations of brain-derived neurotrophic factor (BDNF) during treatment with venlafaxine
and mirtazapine: role of medication and response to treatment. Pharmacopsychiatry. 2013;46(2):
54–8.
Devos D, Dujardin K, Poirot I, Moreau C, Cottencin O, Thomas P, Destée A, Bordet R, Defebvre
L. Comparison of desipramine and citalopram treatments for depression in Parkinson’s
disease: a double-blind, randomized, placebo-controlled study. Mov Disord. 2008;23(6):
850–7.
Dougherty KD, Dreyfus CF, Black IB. Brain-derived neurotrophic factor in astrocytes, oligo-
dendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol Dis. 2000;7
(6 Pt B):574–85.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of
cytokines in major depression. Biol Psychiatry. 2010;67:446–57.
Dudek KA, Dion-Albert L, Lebel M, LeClair K, Labrecque S, Tuck E, Ferrer Perez C, Golden SA,
Tamminga C, Turecki G, Mechawar N, Russo SJ, Menard C. Molecular adaptations of the
blood-brain barrier promote stress resilience vs. depression. Proc Natl Acad Sci U S
A. 2020;117(6):3326–36.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new
insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238–49.
Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN. Altered gene
expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem
brain of suicide subjects. Arch Gen Psychiatry. 2003;60(8):804–15.
Eisch AJ, Petrik D. Depression and hippocampal neurogenesis: a road to remission? Science.
2012;338(6103):72–5.
Elenkov IJ, Chrousos GP. Stress system–organization, physiology and immunoregulation.
Neuroimmunomodulation. 2006;13(5–6):257–67.
Estcourt MJ, Ramshaw LA, Ramsay AJ. Cytokine responses in virus infections: effects on
pathogenesis, recovery and persistence. Curr Opin Microbiol. 1998;1(4):411–8.
Eyre H, Baune BT. Neuroplastic changes in depression: a role for the immune system. Psychoneur-
oendocrinology. 2012;37(9):1397–416.
Fann JR, Katon WJ, Uomoto JM, Esselman PC. Psychiatric disorders and functional disability in
outpatients with traumatic brain injuries. Am J Psychiatry. 1995;152:1493–9.
Fann JR, Bombardier CH, Temkin NR, Esselman P, Pelzer E, Keough M, Romero H, Dikmen
S. Incidence, severity, and phenomenology of depression and anxiety in patients with moderate
to severe traumatic brain injury. Psychosomatics. 2003;44:161.
Fann JR, Hart T, Schomer KG. Treatment for depression after traumatic brain injury: a systematic
review. J Neurotrauma. 2009;26:2383–402.
Fernstrom JD. Hydrazine compounds were shown to be liver toxic. J Neural Transm. 1979;15:55.
Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological dependence on plasma trypto-
phan levels. Science. 1971;173:149.
Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological regulation by plasma neutral
amino acids. Science. 1972;178:414.
Fibiger HC, Phillips AG. Mesocorticolimbic dopamine systems and reward. Ann N Y Acad Sci.
1988;537:206–15.
Freud, S. (1917/1957). Mourning and melancholia. In J. Strachey (Ed. & Trans.), Standard edition
of the complete works of Sigmund Freud (Vol. 14, pp. 237–258). London: Hogarth Press.
552 H. S. Sharma and A. Sharma

Fuxe K, Butcher LL, Engel J. DL-5-Hydroxytryptophan-induced changes in central monoamine

neurons after peripheral decarboxylase inhibition. J Pharm Pharmacol. 1971;23:420–4.
Galts CPC, Bettio LEB, Jewett DC, Yang CC, Brocardo PS, Rodrigues ALS, Thacker JS,
Gil-Mohapel J. Depression in neurodegenerative diseases: Common mechanisms and current
treatment options. Neurosci Biobehav Rev. 2019;102:56–84.
Gayford JJ, Parker AL, Phillips EM, et al. Whole blood 5-hydroxy-tryptamine during treatment of
endogenous depressive illness. Br J Psychiatry. 1973;122:597–8.
Giannini AJ, Billett W. Bromocriptine-desipramine protocol in treatment of cocaine addiction.
J Clin Pharmacol. 1987;27(8):549–54.
Glassman AH, Platman SR. Potentiation of a monoamine oxidase inhibitor by tryptophan.
J Psychiatr Res. 1969;7(2):83–8.
Goodwin FK, Murphy DL, Brodie HKH, et al. Levodopa: alterations in behavior. Clin Pharmacol
Ther. 1971;12:383–96.
Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, Yirmiya R. Brain
interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation
and hippocampal neurogenesis suppression. Mol Psychiatry. 2008;13(7):717–28.
GPDS Steering Committee. Factors impacting on quality of life in Parkinson’s disease: results from
an international survey. Mov Disord. 2002;17:60–7.
Greenwood BN, Strong PV, Foley TE, Thompson RS, Fleshner M. Learned helplessness is
independent of levels of brain-derived neurotrophic factor in the hippocampus. Neuroscience.
2007;144(4):1193–208.
Guilloux JP, Douillard-Guilloux G, Kota R, Wang X, Gardier AM, Martinowich K, Tseng GC,
Lewis DA, Sibille E. Molecular evidence for BDNF- and GABA-related dysfunctions in the
amygdala of female subjects with major depression. Mol Psychiatry. 2012;17(11):1130–42.
Guskiewicz KM, Broglio SP. Acute sports- related traumatic brain injury and repetitive concussion.
Handb Clin Neurol. 2015;127:157–72.
Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Harding HP, Matthews A, et al. Recurrent
concussion and risk of depression in retired professional football players. Med Sci Sports Exerc.
2007;39:903–9.
Gutierrez JLA, Alino JJL. Tryptophan and a MAOI (nialamide) in the treatment of depression. Int
Pharmacopsychiatry. 1971;6:92–7.
Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog
Neuro-Psychopharmacol Biol Psychiatry. 2013;45:54–63.
Hasse J, Brown E. Integrating the monoamine, neurotrophin and cytokine hypothesis of depression
– a central role of the serotonin transporter. Pharmacol Ther. 2015;147:1–11.
Hendricksen M, Thomas AJ, Ferrier IN, Ince P, O’Brien JT. Neuropathological study of the dorsal
raphe nuclei in late-life depression and Alzheimer’s disease with and without depression. Am
J Psychiatry. 2004;161:1096–102.
Hensler JG. Serotonergic modulation of the limbic system. Neurosci Biobehav Rev. 2006;30(2):203–14.
Hibbard MR, Uysal S, Kepler K, Bogdany J, Silver J. Axis I psychopathology in individuals with
traumatic brain injury. J Head Trauma Rehabil. 1998;13:24–39.
Hippocrates. (1923–1931). Works of Hippocrates, Vol. I–IV. (Trans. W. H. S. Jones & E. T.
Withington). Cambridge, MA: Harvard University Press.
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in
U.S. soldiers returning from Iraq. N Engl J Med. 2008;358:453–63.
Hollander E, Nunes E, DeCaria CM, et al. Dopaminergic sensitivity and cocaine abuse: response to
apomorphine. Psychiatry Res. 1990;33(2):161–9.
Hollis SJ, Stevenson MR, McIntosh AS, Shores EA, Finch CF. Compliance with return-to-play
regulations following concussion in Australian schoolboy and community rugby union players.
Br J Sports Med. 2012;46:735–40.
Holm L, Cassidy JD, Carroll LJ, Borg J, Neurotrauma Task Force on Mild Traumatic Brain Injury
of the WHO Collaborating Centre. Summary of the WHO collaborating centre for neurotrauma
task force on mild traumatic brain injury. J Rehabil Med. 2005;37:137–41.
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 553

Horwitz AV, Wakefield JC, Lorenzo-Luaces L. History of depression. In: RJ DR, Strunk RD,
editors. Oxford handbooks; 2016. https://doi.org/10.1093/oxfordhb/9780199973965.013.2.
https://www.oxfordhandbooks.com/. Visited on Feb 02, 2021.
Hou R, Moss-Morris R, Peveler R, Mogg K, Bradley BP, Belli A. When a minor head injury results
in enduring symptoms: a prospective investigation of risk factors for postconcussional syn-
drome after mild traumatic brain injury. J Neurol Neurosurg Psychiatry. 2012;83(2):217–23.
Huang J, Pickel VM. Serotonin transporters (SERTs) within the rat nucleus of the solitary tract:
subcellular distribution and relation to 5HT2A receptors. J Neurocytol. 2002;31(8–9):667–79.
Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev
Neurosci. 2001;24:677–736.
Hurley LL, Tizabi Y. Neuroinflammation, neurodegeneration, and depression. Neurotox Res.
2013;23(2):131–44.
Imamura K, Okayasu N, Nagatsu T. The relationship between depression and regional cerebral
blood flow in Parkinson’s disease and the effect of selegiline treatment. Acta Neurol Scand.
2011;124(1):28–39.
Ishihara L, Brayne C. A systematic review of depression and mental illness preceding Parkinson’s
disease. Acta Neurol Scand. 2006;113:211–20.
Jiang C, Salton SR. The role of neurotrophins in major depressive disorder. Transl Neurosci.
2013;4(1):46–58.
Joëls M, Karst H, Krugers HJ, Lucassen PJ. Chronic stress: implications for neuronal morphology,
function and neurogenesis. Front Neuroendocrinol. 2007;28(2–3):72–96.
Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S. Major depression
following traumatic brain injury. Arch Gen Psychiatry. 2004;61:42–50.
Jorge RE, Acion L, Burin DI, Robinson RG. Sertraline for preventing mood disorders following
traumatic brain injury: a randomized clinical trial. JAMA Psychiat. 2016;73(10):1041–7.
Kambe T, Yasuda A, Kinoshita S, Shigeta M, Kinoshita T. Severity of depressive symptoms and
Volume of Superior Temporal Gyrus in People who visit a memory clinic unaccompanied.
Dement Geriatr Cogn Dis Extra. 2018;8(2):207–13. https://doi.org/10.1159/000489008.
eCollection 2018 May-Aug
Kampman KM, Rukstalis M, Pettinati H, et al. The combination of phentermine and fenfluramine
reduced cocaine withdrawal symptoms in an open trial. J Subst Abus Treat. 2000;19(1):77–9.
Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived
neurotrophic factor levels in major depressed patients. Psychiatry Res. 2002;109(2):143–8.
Karege F, Bondolfi G, Gervasoni N, Schwald M, Aubry JM, Bertschy G. Low brain-derived
neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered
platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry. 2005;57(9):1068–72.
Kekuda R, Leibach FH, Furesz TC, Smith CH, Ganapathy V. Polarized distribution of interleukin-1
receptors and their role in regulation of serotonin transporter in placenta. J Pharmacol Exp Ther.
2000;292(3):1032–41.
Kemp SPT, Hudson Z, Brooks JHM, Fuller CW. The epidemiology of head injuries in English
professional rugby union. Clin J Sport Med. 2008;18:227–34.
Kennedy JE, Lu LH, Reid MW, Leal FO, Cooper DB. Correlates of depression in U.S. military
service members with a history of mild traumatic brain injury. Mil Med. 2019;184(3/4):148–54.
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev.
2011;91(2):461–553.
Kitahama K, Jouvet A, Fujimiya M, Nagatsu I. Arai R.5-Hydroxytryptophan (5-HTP) uptake and
decarboxylation in the kitten brain. J Neural Transm (Vienna). 2002;109(5–6):683–9.
Kiyatkin EA, Brown PL, Sharma HS. Brain edema and breakdown of the blood-brain barrier during
methamphetamine intoxication: critical role of brain hyperthermia. Eur J Neurosci. 2007;26(5):
1242–53.
Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM, Aznar
S. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int
J Neuropsychopharmacol. 2011;14(3):347–53.
554 H. S. Sharma and A. Sharma

Kline NS, Sacks W. Relief of depression within one day using an M.A.O. inhibitor and intravenous
5-HTP. Am J Psychiatry. 1963;120:274–5.
Kline NS, Shah BK. Comparable therapeutic efficacy of tryptophan and imipramine: average
therapeutic ratings versus “true” equivalence: an important difference. Curr Ther Res.
1973;15:484–7.
Kline NS, Sacks W, Simpson GM. Further studies on one day treatment of depression with 5-HTP.
Am J Psychiatry. 1964;121:379–81.
Knott P, Curzon G. Free tryptophan in plasma and brain tryptophan metabolism. Nature. 1972;239:
452–3. https://doi.org/10.1038/239452a0.
Koh JO, Cassidy JD, Watkinson EJ. Incidence of concussion in contact sports: a systematic review
of the evidence. Brain Inj. 2003;17:901–17.
Kohman RA, Rhodes JS. Neurogenesis, inflammation and behavior. Brain Behav Immun.
2013;27(1):22–32.
Kontos AP, Covassin T, Elbin RJ, Parker T. Depression and neurocognitive performance after
concussion among male and female high school and collegiate athletes. Arch Phys Med Rehabil.
2012;93:1751–6.
Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS. Nuclear factor kappaB is a critical mediator
of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci U S A. 2010;107:
2669–74.
Koob GF, Caine SB, Parsons L, Markou A, Weiss F. Opponent process model and psychostimulant
addiction. Pharmacol Biochem Behav. 1997;57(3):513–21.
Kosten TR, Markou A, Koob GF. Depression and stimulant dependence: neurobiology and
pharmacotherapy. J Nerv Ment Dis. 1998;186(12):737–45.
Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):
894–902.
Lamberti C, Ipponi A, Bartolini A, Schunack W, Malmberg-Aiello P. Antidepressant-like effects of
endogenous histamine and of two histamine H1 receptor agonists in the mouse forced swim test.
Br J Pharmacol. 1998;123(7):1331–6.
Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression and in
antidepressant treatment. Psychiatry Investig. 2010;7(4):231–5.
Lee BH, Kim H, Park SH, Kim YK. Decreased plasma BDNF level in depressive patients. J Affect
Disord. 2007;101(1–3):239–44.
Leentjens AF, Dujardin K, Marsh L, et al. Symptomatology and markers of anxiety disorders in
Parkinson's disease: a cross-sectional study. Mov Disord. 2011;26:484–92.
Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired
National Football League players. Neurology. 2012;79:1970–4.
Lehmann J. TRYPTOPHAN MALABSORPTION IN LEVODOPA-TREATED PARKINSONIAN
PATIENTS. Effect of tryptophan on mental disturbances. Acta Med Scand. 1973;194(3):181–9.
https://doi.org/10.1111/j.0954-6820.1973.tb19428.x.
Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation
and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in
the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012;36:764–85.
Lestage J, Verrier D, Palin K, Dantzer R. The enzyme indoleamine 2,3-dioxygenase is induced in
the mouse brain in response to peripheral administration of lipopolysaccharide and super-
antigen. Brain Behav Immun. 2002;16(5):596–601.
Levin H, Kraus MF. The frontal lobes and traumatic brain injury. J Neuropsychiatr Clin Neurosci.
1994;6:443–54.
Levine J, Barak Y, Chengappa KN, Rapoport A, Rebey M, Barak V. Cerebrospinal cytokine levels
in patients with acute depression. Neuropsychobiology. 1999;40:171–6.
Lewin GR, Barde YA. Physiology of the neurotrophins. Annu Rev Neurosci. 1996;19:289–317.
Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG, et al. TrkB regulates hippocam-
pal neurogenesis and governs sensitivity to antidepressive treatment. Neuron. 2008;59:
399–412.
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 555

Lieb K, Biersack L, Waschbisch A, Orlikowski S, Akundi RS, Candelario-Jalil E, Hüll M, Fiebich

BL. Serotonin via 5-HT7 receptors activates p38 mitogen-activated protein kinase and protein
kinase C epsilon resulting in interleukin-6 synthesis in human U373 MG astrocytoma cells.
J Neurochem. 2005;93(3):549–59.
Lynn-Bullock CP, Welshhans K, Pallas SL, Katz PS. The effect of oral 5-HTP administration on
5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats. J Chem Neuroanat.
2004;27(2):129–38.
Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog
Neuro-Psychopharmacol Biol Psychiatry. 1995;19(1):11–38.
Makdissi M. Sports related concussion – management in general practice. Aust Fam Physician.
2010;39:12–7.
Makdissi M, Davis G, McCrory P. Updated guidelines for the management of sports- related
concussion in general practice. Aust Fam Physician. 2014;43:94–9.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases
neurogenesis in adult rat hippocampus. J Neurosci. 2000;20(24):9104–10.
Malison RT, Price LH, Berman R, et al. Reduced brain serotonin transporter availability in major
depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and
single photon emission computed tomography. Biol Psychiatry. 1998;44(11):1090–8.
Mamounas LA, Altar CA, Blue ME, Kaplan DR, Tessarollo L, Lyons WE. BDNF promotes the
regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain.
J Neurosci. 2000;20(2):771–82.
Marsh L. Depression and Parkinson’s disease: current knowledge. Curr Neurol Neurosci Rep.
2013;13:409–17.
Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsy-
chopharmacology. 2008;33(1):73–83. https://doi.org/10.1038/sj.npp.1301571. Epub 2007 Sep
19.
Matsui H, Nishinaka K, Oda M, et al. Minor depression and brain perfusion images in Parkinson’s
disease. Mov Disord. 2006;21:1169–74.
Mattay VS, Callicott JH, Bertolino A, et al. Effects of dextroamphetamine on cognitive perfor-
mance and cortical activation. NeuroImage. 2000;12(3):268–75.
Matussek N. L-DOPA in the treatment of depression. In: Vinar O, Votva Z, Bradley PB, editors.
Advances in neuropharmacology. Amsterdam: North-Holland Publishing Co; 1971. p. 111–9.
Mayberg HS. Frontal lobe dysfunction in secondary depression. J Neuropsychiatr Clin Neurosci.
1994;6:428–42.
Mayberg HS, Solomon DH. Depression in Parkinson’s disease: a biochemical and organic view-
point. Adv Neurol. 1995;65:49–60.
Mayberg HS, Starkstein SE, Sadzot B, et al. Selective hypometabolism in the inferior frontal lobe in
depressed patients with Parkinson’s disease. Ann Neurol. 1990;28:57–64.
McCrory P, Meeuwisse WH, Aubry M, Cantu RC, Dvorak J, Echemendia RJ, et al. Consensus
statement on concussion in sport: the 4th international conference on concussion in sport,
Zurich, November 2012. J Athl Train. 2013;48:554–75.
McCrory P, Meeuwisse W, Dvorak J, Aubry M, Bailes J, Broglio S, et al. Consensus statement on
concussion in sport-the 5(th) international conference on concussion in sport held in Berlin,
October 2016. Br J Sports Med. 2017;51(11):838–847. https://doi.org/10.1136/bjsports-2017-
097699. Epub 2017 Apr 26.
McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain.
Physiol Rev. 2007;87(3):873–904.
McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, et al. The spectrum of
disease in chronic traumatic encephalopathy. Brain J Neurol. 2013;136:43–64.
Ménard C, Hodes GE, Russo SJ. Pathogenesis of depression: insights from human and rodent
studies. Neuroscience. 2016;321:138–62.
Ménard C, Pfau ML, Hodes GE, Russo SJ. Immune and neuroendocrine mechanisms of stress
vulnerability and resilience. Neuropsychopharmacology. 2017;42(1):62–80.
556 H. S. Sharma and A. Sharma

Mendels J, Stinnett J. Biogenic amine metabolism, depression and mania. In: Mendels J, editor.
Biological psychiatry. New York: Interscience-John Wiley & Sons Inc; 1973. p. 99–131.
Mendels J, Stinnett JL, Burns D, Frazer A. Amine precursors and depression. Arch Gen Psychiatry.
1975;32(1):22–30.
Mendlewicz J, Youdim MBH. Antidepressant potentiation of 5-hydroxytryptophan by L-deprenil in
affective illness. J Affect Disord. 1980;2(2):137–46. https://doi.org/10.1016/0165-0327(80)
90013-0.
Menza M, Dobkin RD, Marin H, et al. The impact of treatment of depression on quality of life,
disability and relapse in patients with Parkinson’s disease. Mov Disord. 2009;24:1325–32.
Merritt VC, Clark AL, Sorg SF, Evangelista ND, Werhane M, Bondi MW, Schiehser DM, Delano-
Wood L. Apolipoprotein E ε4 Genotype Is Associated with Elevated Psychiatric Distress in
Veterans with a History of Mild to Moderate Traumatic Brain Injury. J Neurotrauma. 2018;35
(19):2272–2282. https://doi.org/10.1089/neu.2017.5372. Epub 2018 Jun 7.
Meyerson LR, Wennogle LP, Abel MS, Coupet J, Lippa AS, Rauh CE, Beer B. Human brain
receptor alterations in suicide victims Pharmacol Biochem Behav 1982;17(1):159–63. https://
doi.org/10.1016/0091-3057(82)90279-9.
Mills KA, Greene MC, Dezube R, Goodson C, Karmarkar T, Pontone GM. Efficacy and tolerability
of antidepressants in Parkinson’s disease: A systematic review and network meta-analysis. Int J
Geriatr Psychiatry. 2018;33(4):642–651. https://doi.org/10.1002/gps.4834. Epub 2017 Dec 13.
Mora F, Segovia G, Del Arco A, de Blas M, Garrido P. Stress, neurotransmitters, corticosterone and
body-brain integration. Brain Res. 2012;1476:71–85.
Murphy DL, Brodie HK, Goodwin FK, Bunney WE Jr. Regular induction of hypomania by L-dopa
in “bipolar” manic-depressive patients. Nature. 1971;229(5280):135–6. https://doi.org/10.1038/
229135a0.
Murphy DL, Baker M, Kotin J, et al. Behavioral and metabolic effects of L-tryptophan in unipolar
depressed patients. In: Barchas J, Usdin E, editors. Serotonin and behavior. New York: Aca-
demic Press Inc; 1973. p. 529–37.
Murray JB. Depression in Parkinson’s disease. The Journal of Psychology. 1996;130(6):659–667.
https://doi.org/10.1080/00223980.1996.9915039.
Náhunek K, Svestka J, Kamenická V, Rodová A. Preliminary clinical experience with L-dopa in
endogenous depressions. Act Nerv Super (Praha). 1972;14(2):101–2.
Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, Sepehrband F,
Nelson AR, Buennagel DP, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM,
Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV. Blood-brain barrier
breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270–6.
Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression
of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci. 1996;16:
2365–72.
O’Brien FE, Dinan TG, Griffin BT, Cryan JF. Interactions between antidepressants and P-glyco-
protein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. Br J
Pharmacol. 2012;165(2):289–312. https://doi.org/10.1111/j.1476-5381.2011.01557.x.
Oh YS, Gao P, Lee KW, Ceglia I, Seo JS, Zhang X, Ahn JH, Chait BT, Patel DJ, Kim Y, Greengard
P. SMARCA3, a chromatin remodeling factor, is required for p11-dependent antidepressant
action. Cell. 2013;152(4):831–43. https://doi.org/10.1016/j.cell.2013.01.014.
Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic traumatic
encephalopathy in a National Football League player. Neurosurgery. 2005;57:128–34. [Discus-
sion 128–34]
Orgeta V, Tabet N, Nilorooshan R, Howard R. Efficacy of antidepressants for depression in
Alzheimer’s disease: systematic review and meta-analysis. J Alzheimer Disease. 2017;58:
725–33.
Ozkizilcik A, Sharma A, Muresanu DF, Lafuente JV, Tian ZR, Patnaik R, Mössler H, Sharma
HS. Timed release of cerebrolysin using drug-loaded titanate nanospheres reduces brain pathology
and improves behavioral functions in Parkinson’s disease. Mol Neurobiol. 2018;55(1):359–69.
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 557

Ozkizilcik A, Sharma A, Lafuente JV, Muresanu DF, Castellani RJ, Nozari A, Tian ZR, Mössler H,
Sharma HS. Nanodelivery of cerebrolysin reduces pathophysiology of Parkinson’s disease. Prog
Brain Res. 2019;245:201–46.
Panula P, Nuutinen S. The histaminergic network in the brain: basic organization and role in disease.
Nat Rev Neurosci. 2013;14(7):472–87.
Panula P, Rinne J, Kuokkanen K, Eriksson KS, Sallmen T, Kalimo H, Relja M. Neuronal histamine
deficit in Alzheimer’s disease. Neuroscience. 1998;82(4):993–7.
Pardridge WM. Tryptophan transport through the blood-brain barrier: in vivo measurement of free
and albumin-bound amino acid. Life Sci. 1979;25:1519.
Pardridge WM, Oldendorf WH. Kinetic analyses of blood-brain barrier transport of amino acids.
Biochem Biophys Acta. 1975;401:128.
Pare CM. Potentiation of monoamine-oxidase inhibitors by tryptophan. Lancet. 1963;2(7306):527–8.
Pare CM. Psychiatric complications of everyday drugs. Practitioner 1973;210(255):120–6.
Pare CMB, Sandler M. A clinical and biochemical study of a trial of iproniazid in the treatment of
depression. J Neurol Neurosurg Psychiatry. 1959;22:247–51.
Pary R, Scarff JR, Jijakli A, Tobias C, Lippmann S. A review of psychostimulants for adults with
depression. Fed Pract. 2015;32(Suppl 3):30S–7S.
Peña E, Mata M, López-Manzanares L, Kurtis M, Eimil M, Martínez-Castrillo JC, Navas I, Posada
IJ, Prieto C, Ruíz-Huete C, Vela L, Venegas B. en nombre del grupo de trastornos del
movimiento de la Asociación Madrileña de NeurologíaAntidepressants in Parkinson’s disease.
Recommendations by the movement disorder study group of the Neurological Association of
Madrid. Neurologia. 2016;19:S0213–4853(16)00055-4. https://doi.org/10.1016/j.nrl.2016.02.
002.
Perry DC, Sturm VE, Peterson MJ, et al. Association of traumatic brain injury with subsequent
neurological and psychiatric disease: a meta-analysis. J Neurosurg. 2016;124(2):511–26.
Persson T, Roos BE. 5-Hydroxytryptophan for depression. Lancet. 1967;2:987–8.
Persson T, Walinder J. L-DOPA in the treatment of depressive symptoms. Br J Psychiatry.
1971;119:277–8.
Pizarro JM, Lumley LA, Medina W, Robison CL, Chang WE, Alagappan A, Bah MJ, Dawood MY,
Shah JD, Mark B, Kendall N, Smith MA, Saviolakis GA, Meyerhoff JL. Acute social defeat
reduces neurotrophin expression in brain cortical and subcortical areas in mice. Brain Res.
2004;1025(1–2):10–20.
Plata-Salaman CR. Brain cytokines and dis-ease. Acta Neuropsychiatr. 2002;14:262–78.
Politis M, Niccolini F. Serotonin in Parkinson’s disease. Behav Brain Res. 2015;277:136–45.
Pollin W, Cardon PV Jr, Kety SS. Effects of amino acid feedings in schizophrenic patients treated
with iproniazid. Science. 1961;133(3446):104–5.
Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and
glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2012;13:22–37.
Prange AJ Jr. The pharmacology and biochemistry of depression. Dis Nerv Syst. 1964;25:217–21.
Qian Z, Wu X, Qiao Y, Shi M, Liu Z, Ren W, Han J, Zheng Q. Downregulation of mGluR2/3
receptors during morphine withdrawal in rats impairs mGluR2/3- and NMDA receptor-
dependent long-term depression in the nucleus accumbens. Neurosci Lett. 2019;690:76–82.
https://doi.org/10.1016/j.neulet.2018.10.018. Epub 2018 Oct 11.
Rakel RE. Depression. Prim Care. 1999;26(2):211–24.
Ramamoorthy S, Ramamoorthy JD, Prasad PD, Bhat GK, Mahesh VB, Leibach FH, Ganapathy
V. Regulation of the human serotonin transporter by interleukin-1 beta. Biochem Biophys Res
Commun. 1995;216(2):560–7.
Rasmussen K, Kendrick WT, Kogan JH, Aghajanian GK. A selective AMPA antagonist, LY293558,
suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs
of morphine withdrawal. Neuropsychopharmacology. 1996;15(5):497–505.
Rasmusson AM, Shi L, Duman R. Downregulation of BDNF mRNA in the hippocampal dentate
gyrus after re-exposure to cues previously associated with footshock. Neuropsychophar-
macology. 2002;27(2):133–42.
558 H. S. Sharma and A. Sharma

Rawson KA, Gunstad J, Hughes J, Spitznagel MB, Potter V, Waechter D, Rosneck J. The METER:
a brief, self-administered measure of health literacy. Gen Intern Med. 2010;25(1):67–71.
Rawson KS, Dixon D, Nowotny P, Ricci WM, Binder EF, Rodebaugh TL, Wendleton L, Doré P,
Lenze EJ. Association of functional polymorphisms from brain-derived neurotrophic factor and
serotonin-related genes with depressive symptoms after a medical stressor in older adults. PLoS
One. 2015;10(3):e0120685. https://doi.org/10.1371/journal.pone.0120685. eCollection 2015.
PMID: 25781924
Read JR, Sharpe L, Modini M, Dear BF. Multimorbidity and depression: a systematic review and
meta-analysis. J Affect Disord. 2017;221:36–46.
Reijnders JS, Ehrt U, Weber WE, et al. A systematic review of prevalence studies of depression in
Parkinson’s disease. Mov Disord. 2008;23:183–9. quiz 313
Richard IH, McDermott MP, Kurlan R, et al. A randomized, double-blind, placebo-controlled trial
of antidepressants in Parkinson disease. Neurology. 2012;78:1229–36.
Riederer P, Birkmayer W, Neumayer E. The tyrosine-tryptophan-diagram in a longtime study with
depressed patients. J Neural Transm. 1973;34(1):31–48. https://doi.org/10.1007/BF01244825.
PMID: 4714592
Roiger T, Weidauer L, Kern B. A longitudinal pilot study of depressive symptoms in con-cussed
and injured/nonconcussed National Collegiate Athletic Association Division I student-athletes.
J Athl Train. 2015;50:256–61.
Rosenthal M, Christensen BK, Ross TP. Depression following traumatic brain injury. Arch Phys
Med Rehabil. 1998;79:90–103.
Ru Q, Xiong Q, Zhou M, Chen L, Tian X, Xiao H, Li C, Li Y. Withdrawal from chronic treatment
with methamphetamine induces anxiety and depression-like behavior in mice. Psychiatry Res.
2019;271:476–83. https://doi.org/10.1016/j.psychres.2018.11.072. Epub 2018 Dec 3
Ryan M, Eatmon CV, Slevin JT. Drug treatment strategies for depression in Parkinson disease.
vExpert Opin Pharmacother. 2019;20(11):1351–1363. https://doi.org/10.1080/14656566.2019.
1612877. Epub 2019 May 23.
Rybakowski JK, Suwalska A, Skibinska M, Dmitrzak-Weglarz M, Leszczynska-Rodziewicz A,
Hauser J. Response to lithium prophylaxis: interaction between serotonin transporter and BDNF
genes. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(6):820–3.
Ryding E, Lindström M, Träskman-Bendz L. The role of dopamine and serotonin in suicidal
behaviour and aggression. Prog Brain Res. 2008;172:307–15.
Saha RN, Liu X, Pahan K. Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the
neuroprotective role of cytokine. J NeuroImmune Pharmacol. 2006;1(3):212–22.
Sano I. L-5-hydroxytryptophan(L-5-HTP) therapy in endogenous depression. 1. Munch Med
Wochenschr. 1972;114(40):1713–6.
Sasahara I, Fujimura N, Nozawa Y, Furuhata Y, Sato H. The effect of histidine on mental fatigue and
cognitive performance in subjects with high fatigue and sleep disruption scores. Physiol Behav.
2015;147:238–44.
Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting
evidence. Am J Psychiatry. 1965a;112:509–22.
Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting
evidence. Am J Psychiatry. 1965b;122(5):509–22.
Schildkraut JJ, Watson R, Draskoczy PR. Amphetamine withdrawal: depression and
M.H.P.G. excretion. Lancet. 1971;2(7722):485–6.
Schmidt EF, et al. Identification of the cortical neurons that mediate antidepressant responses. Cell.
2012;149:1152–63.
Schoenhuber R, Gentilini M. Anxiety and depression after mild head injury: a case control study.
J Neurol Neurosurg Psychiatry. 1988;51:722–4.
Schulteis G, Markou A, Cole M, Koob GF. Decreased brain reward produced by ethanol with-
drawal. Proc Natl Acad Sci U S A. 1995;92(13):5880–4.
Seel RT, Kreutzer JS. Depression assessment after traumatic brain injury: an empirically based
classification method. Arch Phys Med Rehabil. 2003;84:1621–8.
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 559

Seel RT, Kreutzer JS, Rosenthal M, Hammond FM, Corrigan JD, Black K. Depression after
traumatic brain injury: a National Institute on Disability and Rehabilitation Research Model
Systems multicenter investigation. Arch Phys Med Rehabil. 2003;84(2):177–84. https://doi.org/
10.1053/apmr.2003.50106.
Selye H. Stress and disease. Science. 1955;122(3171):625–31.
Selye H. Forty years of stress research: principal remaining problems and misconceptions. Can Med
Assoc J. 1976;115(1):53–6.
Seo JS, Wei J, Qin L, Kim Y, Yan Z, Greengard P. Cellular and molecular basis for stress-induced
depression. Mol Psychiatry. 2017;22(10):1440–7.
Seo JS, Zhong P, Liu A, Yan Z, Greengard P. Elevation of p11 in lateral habenula mediates
depression-like behavior. Mol Psychiatry. 2018;23(5):1113–9.
Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society evidence-based medicine
review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord.
2011;26(Suppl 3):S42–80.
Shabani S, Schmidt B, Ghimire B, Houlton SK, Hellmuth L, Mojica E, Phillips TJ. Depression-like
symptoms of withdrawal in a genetic mouse model of binge methamphetamine intake. Genes
Brain Behav. 2019;18(3):e12533. https://doi.org/10.1111/gbb.12533. Epub 2018 Nov 26
Shalev H, Serlin Y, Friedman A. Breaching the blood-brain barrier as a gate to psychiatric disorder.
Cardiovasc Psychiatry Neurol. 2009;2009:278531.
Sharma HS. Blood-brain barrier in Stress, Ph D Thesis, May 1982, Banaras Hindu University Press,
Varanasi, India.
Sharma HS. Pathophysiology of blood-brain barrier, brain edema and cell injury following hyper-
thermia: new role of heat shock protein, nitric oxide and carbon monoxide. an experimental
study in the rat using light and electron microscopy. Acta Universitatis Upsaliensis. 1999;830:1–
94. Sharma 2004a,b,c
Sharma HS. Blood-brain and spinal cord barriers in stress. In: Sharma HS, Westman J, editors. The
blood-spinal cord and brain barriers in health and disease. San Diego: Elsevier Academic Press;
2004a. p. 231–98.
Sharma HS. Histamine influences the blood-spinal cord and brain barriers following injuries to the
central nervous system. In: Sharma HS, Westman J, editors. The blood-spinal cord and brain
barriers in health and disease. San Diego: Elsevier Academic Press; 2004b. p. 159–90.
Sharma HS. Pathophysiology of blood-spinal cord barrier in traumatic injury and repair. Curr
Pharm Des. 2005;11(11):1353–89. Review.
Sharma HS. Hyperthermia influences excitatory and inhibitory amino acid neurotransmitters in the
central nervous system. An experimental study in the rat using behavioural, biochemical,
pharmacological, and morphological approaches. J Neural Transm (Vienna). 2006;113(4):
497–519.
Sharma HS. Neurotrophic factors in combination: a possible new therapeutic strategy to influence
pathophysiology of spinal cord injury and repair mechanisms. Curr Pharm Des. 2007;13(18):
1841–74.
Sharma HS. Blood–central nervous system barriers: the gateway to neurodegeneration,
neuroprotection and neuroregeneration. In: Lajtha A, Banik N, Ray SK, editors. Handbook of
neurochemistry and molecular neurobiology: brain and spinal cord trauma. Berlin, Heidelberg,
New York: Springer; 2009a. p. 363–457.
Sharma HS. New concepts of psychostimulants induced neurotoxicity. Int Rev Neurobiol. vol. 89.
San Diego, USA, Oxford, UK: Academic Press. 2009b; pp. 1–435.
Sharma HS. A combination of tumor necrosis factor-alpha and neuronal nitric oxide synthase
antibodies applied topically over the traumatized spinal cord enhances neuroprotection and
functional recovery in the rat. Ann N Y Acad Sci. 2010;1199:175–85.
Sharma HS. New perspectives of central nervous system injury and neuroprotection. Int Rev
Neurobiol. 2012;102:1–424. https://doi.org/10.1016/B978-0-12-386986-9.00013-2.
Sharma HS, Ali SF. Alterations in blood-brain barrier function by morphine and methamphetamine.
Ann N Y Acad Sci. 2006;1074:198–224.
560 H. S. Sharma and A. Sharma

Sharma HS, Ali SF. Acute administration of 3,4-methylenedioxymethamphetamine induces pro-

found hyperthermia, blood-brain barrier disruption, brain edema formation, and cell injury. Ann
N Y Acad Sci. 2008;1139:242–58.
Sharma HS, Dey PK. Influence of long-term immobilization stress on regional blood-brain barrier
permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats.
J Neurol Sci. 1986a;72(1):61–76. https://doi.org/10.1016/0022-510x(86)90036-5.
Sharma HS, Dey PK. Probable involvement of 5-hydroxytryptamine in increased permeability of
blood-brain barrier under heat stress in young rats. Neuropharmacology. 1986b;25(2):161–7.
Sharma HS, Dey PK. Influence of long-term acute heat exposure on regional blood-brain barrier
permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats. Brain
Res. 1987;424(1):153–62.
Sharma HS, Dey PK. EEG changes following increased blood-brain barrier permeability under
long-term immobilization stress in young rats. Neurosci Res. 1988;5(3):224–39.
Sharma HS, Hoopes PJ. Hyperthermia induced pathophysiology of the central nervous system. Int
J Hyperth. 2003;19(3):325–54.
Sharma HS, Johanson CE. Blood-cerebrospinal fluid barrier in hyperthermia. Prog Brain Res.
2007;162:459–78.
Sharma HS, Sharma A. Nanoparticles aggravate heat stress induced cognitive deficits, blood-
brain barrier disruption, edema formation and brain pathology. Prog Brain Res. 2007;162:
245–73.
Sharma HS, Sjöquist PO, Ali SF. Drugs of abuse-induced hyperthermia, blood-brain barrier
dysfunction and neurotoxicity: neuroprotective effects of a new antioxidant compound H-290/
51. Curr Pharm Des. 2007;13(18):1903–23. https://doi.org/10.2174/138161207780858375.
Sharma HS, Sharma A. Breakdown of the blood-brain barrier in stress alters cognitive dysfunction
and induces brain pathology: new perspectives for neuroprotective strategies. In: Ritsner MS,
editor. Brain protection in schizophrenia, mood and cognitive disorders, vol. 3; 2010. p. 243–
304. https://doi.org/10.1007/978-90-481-8553-5. Springer Science+Business Media B.V. 2010,
New York, USA.
Sharma HS, Westman J. The blood-spinal cord and brain barriers in health and disease. San Diego:
Academic; 2004. p. 1–617. (Release date: Nov. 9, 2003).
Sharma HS, Olsson Y, Dey PK. Early accumulation of serotonin in rat spinal cord subjected to
traumatic injury. Relation to edema and blood flow changes. Neuroscience. 1990a;36(3):725–
30. https://doi.org/10.1016/0306-4522(90)90014-u.
Sharma HS, Olsson Y, Dey PK. Changes in blood-brain barrier and cerebral blood flow following
elevation of circulating serotonin level in anesthetized rats. Brain Res. 1990b;517(1–2):215–23.
https://doi.org/10.1016/0006-8993(90)91029-g.
Sharma HS, Cervós-Navarro J, Dey PK. Acute heat exposure causes cellular alteration in cerebral
cortex of young rats. Neuroreport. 1991;2(3):155–8.
Sharma HS, Westman J, Nyberg F. Pathophysiology of brain edema and cell changes following
hyperthermic brain injury. Prog Brain Res. 1998;115:351–412.
Sharma HS, Patnaik R, Ray AK, Dey PK. Blood-central nervous system barriers in morphine
dependence and withdrawal. In: Sharma HS, Westman J, editors. The blood-spinal cord and
brain barriers in health and disease. San Diego: Elsevier Academic Press; 2004. p. 299–328.
Sharma HS, Lundstedt T, Boman A, Lek P, Seifert E, Wiklund L, Ali SF. A potent serotonin-
modulating compound AP-267 attenuates morphine withdrawal-induced blood-brain barrier
dysfunction in rats. Ann N Y Acad Sci. 2006a;1074:482–96. https://doi.org/10.1196/annals.
1369.049.
Sharma HS, Duncan JA, Johanson CE. Whole-body hyperthermia in the rat disrupts the blood-
cerebrospinal fluid barrier and induces brain edema. Acta Neurochir Suppl. 2006b;96:426–31.
https://doi.org/10.1007/3-211-30714-1_88.
Sharma HS, Muresanu D, Sharma A, Patnaik R. Cocaine-induced breakdown of the blood-brain
barrier and neurotoxicity. Int Rev Neurobiol. 2009;88:297–334. https://doi.org/10.1016/S0074-
7742(09)88011-2.
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 561

Sharma HS, Zimmermann-Meinzingen S, Johanson CE. Cerebrolysin reduces blood-cerebrospinal

fluid barrier permeability change, brain pathology, and functional deficits following traumatic
brain injury in the rat. Ann N Y Acad Sci. 2010;1199:125–37.
Sharma HS, Ali SF, Patnaik R, Zimmermann-Meinzingen S, Sharma A, Muresanu DF. Cerebrolysin
attenuates heat shock protein (HSP 72 KD) expression in the rat spinal cord following morphine
dependence and withdrawal: possible new therapy for pain management. Curr Neuropharmacol.
2011;9(1):223–35.
Sharma HS, Castellani RJ, Smith MA, Sharma A. The blood-brain barrier in Alzheimer's disease:
novel therapeutic targets and nanodrug delivery. Int Rev Neurobiol. 2012;102:47–90.
Sharma HS, Muresanu DF, Patnaik R, Sharma A. Exacerbation of brain pathology after partial restraint
in hypertensive rats following SiO2 nanoparticles exposure at high ambient temperature. Mol
Neurobiol. 2013;48(2):368–79. https://doi.org/10.1007/s12035-013-8502-y. Epub 2013 Jul 6.
Sharma HS, Kiyatkin EA, Patnaik R, Lafuente JV, Muresanu DF, Sjöquist PO, Sharma
A. Exacerbation of methamphetamine neurotoxicity in cold and hot environments:
neuroprotective effects of an antioxidant compound H-290/51. Mol Neurobiol. 2015a;52(2):
1023–33. https://doi.org/10.1007/s12035-015-9252-9. Epub 2015 Jun 26.
Sharma HS, Feng L, Lafuente JV, Muresanu DF, Tian ZR, Patnaik R, Sharma A. TiO2-nanowired
delivery of mesenchymal stem cells thwarts diabetes- induced exacerbation of brain pathology
in heat stroke: an experimental study in the rat using morphological and biochemical
approaches. CNS Neurol Disord Drug Targets. 2015b;14(3):386–99. https://doi.org/10.2174/
1871527314666150318114335.
Sharma A, Menon P, Muresanu DF, Ozkizilcik A, Tian ZR, Lafuente JV, Sharma HS. Nanowired
drug delivery across the blood-brain barrier in central nervous system injury and repair. CNS
Neurol Disord Drug Targets. 2016a;15(9):1092–117. https://doi.org/10.2174/
1871527315666160819123059.
Sharma HS, Muresanu DF, Lafuente JV, Nozari A, Patnaik R, Skaper SD, Sharma A. Pathophysiology
of Blood-brain barrier in brain injury in cold and hot environments: novel drug targets for
neuroprotection. CNS Neurol Disord Drug Targets. 2016b;15(9):1045–71. https://doi.org/10.2174/
1871527315666160902145145.
Sharma HS, Muresanu DF, Lafuente JV, Patnaik R, Tian ZR, Ozkizilcik A, Castellani RJ,
Mössler H, Sharma A. Co-administration of TiO2 nanowired mesenchymal stem cells with
cerebrolysin potentiates neprilysin level and reduces brain pathology in Alzheimer’s disease.
Mol Neurobiol. 2018;55(1):300–11.
Sharma HS, Muresanu DF, Castellani RJ, Nozari A, Lafuente JV, Tian ZR, Ozkizilcik A,
Manzhulo I, Mössler H, Sharma A. Nanowired delivery of cerebrolysin with neprilysin and
p-Tau antibodies induces superior neuroprotection in Alzheimer’s disease. Prog Brain Res.
2019a;245:145–200.
Sharma A, Castellani RJ, Smith MA, Muresanu DF, Dey PK, Sharma HS. 5-Hydroxytryptophan: a
precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow,
brain edema formation, and neuropathology. Int Rev Neurobiol. 2019b;146:1–44.
Sharma A, Muresanu DF, Ozkizilcik A, Tian ZR, Lafuente JV, Manzhulo I, Mössler H, Sharma
HS. Sleep deprivation exacerbates concussive head injury induced brain pathology:
neuroprotective effects of nanowired delivery of cerebrolysin with alpha-melanocyte-stimulat-
ing hormone. Prog Brain Res. 2019c;245:1–55.
Sharma A, Patnaik R, Sharma HS. Neuroprotective effects of 5-HT(3) receptor antagonist
ondansetron on morphine withdrawal induced brain edema formation, blood-brain barrier
dysfunction, neuronal injuries, glial activation and heat shock protein upregulation in the
brain. Int Rev Neurobiol. 2019d;146:209–28.
Sharma A, Muresanu DF, Sahib S, Tian ZR, Castellani RJ, Nozari A, Lafuente JV, Buzoianu AD,
Bryukhovetskiy I, Manzhulo I, Patnaik R, Wiklund L, Sharma HS. Concussive head injury
exacerbates neuropathology of sleep deprivation: superior neuroprotection by co-administration
of TiO(2)-nanowired cerebrolysin, alpha-melanocyte-stimulating hormone, and mesenchymal
stem cells. Prog Brain Res. 2020a;258:1–77.
562 H. S. Sharma and A. Sharma

Sharma A, Muresanu DF, Castellani RJ, Nozari A, Lafuente JV, Sahib S, Tian ZR, Buzoianu AD,
Patnaik R, Wiklund L, Sharma HS. Mild traumatic brain injury exacerbates Parkinson’s disease
induced hemeoxygenase-2 expression and brain pathology: neuroprotective effects of
co-administration of TiO2 nanowired mesenchymal stem cells and cerebrolysin. Prog Brain
Res. 2020b;258:157–231.
Shaw DM, Johnson AL, MacSweeney DA. Tricyclic antidepressants and tryptophan in unipolar
affective disorder. Lancet. 1972;2:1245.
Shen YC, Arkes J, Williams TV. Effects of Iraq/Afghanistan deployments on major depression and
substance use disorder: analysis of active duty personnel in the US military. Am J Public Health.
2012;102(Suppl 1):S80–7.
Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H,
Shinoda N, Okada S, Iyo M. Alterations of serum levels of brain-derived neurotrophic factor
(BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70–5.
Simons FE. Advances in H1-antihistamines. N Engl J Med. 2004;351(21):2203–17.
Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM. BDNF increases monoaminergic activity
in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res.
1996;710(1–2):11–20.
Skapinakis P, Bakola E, Salanti G, Lewis G, Kyritsis AP, Mavreas V. Efficacy and acceptability of
selective serotonin reuptake inhibitors for the treatment of depression in Parkinson’s disease: a
systematic review and meta-analysis of randomized controlled trials. BMC Neurol. 2010;10:49.
Smith RS. The macrophage theory of depression. Med Hypotheses. 1991;35:298–306.
Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of
brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci.
1995;15:1768–77.
Solomon RL, Corbit JD. An opponent-process theory of motivation. I. Temporal dynamics of
affect. Psychol Rev. 1974;81(2):119–45.
Solomon GS, Kuhn AW, Zuckerman SL. Depression as a modifying factor in sport- related
concussion: a critical review of the literature. Phys Sportsmed. 2016;44:14–9.
Starkstein SE, Jorge R, Mizrahi R, Robinson RG. The construct of minor and major depression in
Alzheimer’s disease. Am J Psychiatry. 2005;162:2086–93.
Svenningsson P, et al. Alterations in 5-HT1B receptor function by p11 in depression-like states.
Science. 2006;311:77–80.2006.
Svenningsson P, Kim Y, Warner-Schmidt J, Oh YS, Greengard P. p11 and its role in depression and
therapeutic responses to antidepressants. Nat Rev Neurosci. 2013;14(10):673–80.
Swanson TM, Isaacson BM, Cyborski CM, French LM, Tsao JW, Pasquina PF. Traumatic brain
injury incidence, clinical overview, and policies in the US military health system since 2000.
Public Health Rep. 2017;21(9):1–9.
Szapacs ME, Mathews TA, Tessarollo L, Ernest Lyons W, Mamounas LA, Andrews AM. Exploring
the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF
protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression.
J Neurosci Methods. 2004;140(1–2):81–92.
Thomas AJ, Hendriksen M, Piggott M, Ferrier IN, Perry E, Ince P, O’Brien JT. A study of the
serotonin transporter in the prefrontal cortex in late-life depression and Alzheimer’s disease with
and without depression. Neuropathol Appl Neurobiol. 2006;32:296–303.
Tommasone BA, Valovich McLeod TC. Contact sport concussion incidence. J Athl Train. 2006;41:
470–2.
Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA,
Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ, STAR*D Study Team.
Medication augmentation after the failure of SSRIs for depression. N Engl J Med.
2006;354(12):1243–52.
Troubat R, Barone P, Leman S, Desmidt T, Cressant A, Atanasova B, Brizard B, El Hage W,
Surget A, Belzung C, Camus V. Neuroinflammation and depression: a review. Eur J Neurosci.
2021;53(1):151–71.
Amine Precursors in Depressive Disorders and the Blood-Brain Barrier 563

Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal
chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci.
2006;9(4):519–25.
Ueyama T, Kawai Y, Nemoto K, Sekimoto M, Toné S, Senba E. Immobilization stress reduced the
expression of neurotrophins and their receptors in the rat brain. Neurosci Res. 1997;28(2):
103–10.
van Heesch F, Prins J, Korte-Bouws GA, Westphal KG, Lemstra S, Olivier B, Kraneveld AD, Korte
SM. Systemic tumor necrosis factor-alpha decreases brain stimulation reward and increases
metabolites of serotonin and dopamine in the nucleus accumbens of mice. Behav Brain Res.
2013a;253:191–5.
van Heesch F, Prins J, Konsman JP, Westphal KGC, Olivier B, Kraneveld AD, Korte
SM. Lipopolysaccharide-induced anhedonia is abolished in male serotonin transporter knockout
rats: an intracranial self-stimulation study. Brain Behav Immun. 2013b;29:98–103.
van Heesch F, Prins J, Konsman JP, Korte-Bouws GA, Westphal KG, Rybka J, Olivier B, Kraneveld
AD, Korte SM. Lipopolysaccharide increases degradation of central monoamines: an in vivo
microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice. Eur
J Pharmacol. 2014;725:55–63.
van Zomeren AH, van den Burg W. Residual complaints of patients two years after severe head
injury. J Neurol Neurosurg Psychiatry. 1985;48:21–8.
Vargas G, Rabinowitz A, Meyer J, Arnett PA. Predictors and prevalence of postconcussion
depression symptoms in collegiate athletes. J Athl Train. 2015;50:250–5.
Verhoeff NP, Christensen BK, Hussey D, et al. Effects of catecholamine depletion on D2 receptor
binding, mood, and attentiveness in humans: a replication study. Pharmacol Biochem Behav.
2003;74(2):425–32.
Vollenweider FX, Liechti ME, Gamma A, Greer G, Geyer M. Acute psychological and neurophys-
iological effects of MDMA in humans. J Psychoactive Drugs. 2002;34(2):171–84.
Walker FR, Nilsson M, Jones K. Acute and chronic stress-induced disturbances of microglial
plasticity, phenotype and function. Curr Drug Targets. 2013;14(11):1262–76.
Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, Bruns J, Drake A, Gentry T, Jagoda A,
Katz DL, Kraus J, Labbate LA, Ryan LM, Sparling MB, Walters B, Whyte J, Zapata A, Zitnay
G. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain
injury. J Neurotrauma. 2006;23:1468–501.
Warner-Schmidt JL, et al. Role of p11 in cellular and behavioral effects of 5-HT4 receptor
stimulation. J Neurosci. 2009;29:1937–46.
Warner-Schmidt JL, et al. A role for p11 in the antidepressant action of brain-derived neurotrophic
factor. Biol Psychiatry. 2010;68:528–35.
Warner-Schmidt JL, et al. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs)
are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S
A. 2011;108:9262–7.
Watanabe T, Taguchi Y, Shiosaka S, Tanaka J, Kubota H, Terano Y, Tohyama M, Wada
H. Distribution of the histaminergic neuron system in the central nervous system of rats; a
fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res.
1984;295(1):13–25.
Weintraub D, Newberg AB, Cary MS, et al. Striatal dopamine transporter imaging correlates with
anxiety and depression symptoms in Parkinson’s disease. J Nucl Med. 2005;46:227–32.
Welcome MO, Mastorakis NE. Stress-induced blood brain barrier disruption: molecular mecha-
nisms and signaling pathways. Pharmacol Res. 2020;157:104769.
Whybrow PC, Prange AJ Jr, Treadway CR. Mental changes accompanying thyroid gland dysfunc-
tion. A reappraisal using objective psychological measurement. Arch Gen Psychiatry.
1969;20(1):48–63.
Wilson AA, Ginovart N, Hussey D, Meyer J, Houle S. In vitro and in vivo characterisation of [11C]-
DASB: a probe for in vivo measurements of the serotonin transporter by positron emission
tomograph. Nucl Med Biol. 2002;29(5):509–15.
564 H. S. Sharma and A. Sharma

Yang J, Peek-Asa C, Covassin T, Torner JC. Post-concussion symptoms of depression and anxiety
in division I collegiate athletes. Dev Neuropsychol. 2015a;40:18–23.
Yang L, Zhao Y, Wang Y, Liu L, Zhang X, Li B, Cui R. The effects of psychological stress on
depression. Curr Neuropharmacol. 2015b;13(4):494–504.
Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M, Weihe E, Weidenfeld J. Effects of
antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS)
in rodents. Neuropsychopharmacology. 2001;24(5):531–44.
Yoshida T, Ishikawa M, Niitsu T, Nakazato M, Watanabe H, Shiraishi T, Shiina A, Hashimoto T,
Kanahara N, Hasegawa T, Enohara M, Kimura A, Iyo M, Hashimoto K. Decreased serum levels
of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients
with major depressive disorder. PLoS One. 2012;7(8):e42676.
Yoshikawa T, Nakamura T, Shibakusa T, Sugita M, Naganuma F, Iida T, Miura Y, Mohsen A,
Harada R, Yanai K. Insufficient intake of L-histidine reduces brain histamine and causes
anxiety-like behaviors in male mice. J Nutr. 2014;144(10):1637–41.
You Z, Luo C, Zhang W, Chen Y, He J, Zhao Q, et al. Pro- and antiinflammatory cytokines
expression in rat's brain and spleen exposed to chronic mild stress: involvement in depression.
Behav Brain Res. 2011;225:135–41.
Young SN, Lal S, Feldmuller F, Sourkes TL, Ford RM, Kiely M, Martin JB. Parallel variation of
ventricular CSF tryptophan and free serum tryptophan in man. J Neurol Neurosurg Psychiatry.
1976;39:61–5.
Young JS, Hobbs JG, Bailes JE. The impact of traumatic brain injury on the aging brain. Curr
Psychiatry Rep. 2016;18:81.
Yrondi A, Brauge D, LeMen J, Arbus C, Pariente J. Depression and sports-related concussion: a
systematic review. Presse Med. 2017;46:890–902.
Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor
necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 2006;31(10):
2121–31.
The Endocannabinoid System in the Central
Nervous System: Emphasis on the Role
of the Mitochondrial Cannabinoid Receptor
1 (mtCB1R)

Marisol Maya-López, Cecilia Zazueta, Socorro Retana-Márquez,

Syed F. Ali, Cimen Karasu, Emmanuel S. Onaivi, Michael Aschner,
and Abel Santamaría

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
The Endocannabinoid System (ECS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
Historical Background of the ECS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
Endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
Receptors for Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
The ECS and the Modulation of Functions in the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
Regulation of Mitochondrial Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
The Cannabinoid 1 Mitochondrial Receptor (mtCB1R) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
Effects of Cannabinoids on Mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583

Abstract
The study of the endocannabinoid system (ECS) emerges formally from the
chemical characterization of the psychoactive component of Cannabis sativa,

M. Maya-López
Posgrado en Ciencias Biológicas y de la Salud, DCBS, Universidad Autónoma Metropolitana-
Iztapalapa, Ciudad de México, Mexico
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel
Velasco Suárez, Ciudad de México, Mexico
C. Zazueta
Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez,
Ciudad de México, Mexico
S. Retana-Márquez
Departamento de Biología de Reproducción, Universidad Autónoma Metropolitana-Iztapalapa,
Ciudad de México, Mexico
S. F. Ali
Division of Neurotoxicology, National Center for Toxicological Research, United States Food and
Drug Administration, Jefferson, AR, USA

© Springer Nature Switzerland AG 2022 565

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_461
566 M. Maya-López et al.

Δ9-tetrahydrocannabinol (Δ9-THC). The ECS consists of genes encoding two

well-characterized cannabinoid receptors (CB1Rs and CB2Rs), endo-
cannabinoids (eCBs), and metabolic enzyme machinery responsible for their
synthesis and degradation. The study of the ECS is of great interest for understand-
ing CNS function due to its role in the regulation of several physiological functions.
Furthermore, ECS implication in antiexcitotoxic, antioxidant, anti-inflammatory,
and neuroprotective mechanisms suggests therapeutic potential for some neurolog-
ical and psychiatric disorders. It is noteworthy that the presence of CB1R in the
outer membrane of mitochondria seems to modulate mitochondrial energy metab-
olism. The high-energy demand of neurons is needed to maintain cellular homeo-
stasis, the membrane potential, and synaptic transmission; therefore, a broad
distribution of mitochondria can be found throughout the neuronal body. In
addition, ATP synthesis is necessary for axonal growth and regulation of axonal
transport. The characterization of a CB1R-regulated Gi/Go signaling pathway at
the mitochondrial level has led to a controversial and yet not well understood
finding in terms of the physiological significance and the regulated reduction in
ATP levels. Although the precise physiological role that cannabinoids play in
mitochondria is to be elucidated, some reports using isolated mitochondria suggest
that cannabinoids may prevent the mitochondrial damage through this pathway.
Here we review, update, and discuss evidence collected on the relevance of the ECS
to optimal CNS function and specifically the role that mtCB1R and cannabinoids
play in the regulation of mitochondrial/neuronal function.

Introduction

The endocannabinoid system (ECS) is responsible for the regulation of several

signaling pathways at the cytoplasmic, nuclear, and organelle levels. Consequently,
this complex system affords therapeutic properties comprising antiexcitotoxic, anti-
nociceptive, antiproliferative, antioxidant, and anti-inflammatory responses
(reviewed by Joshi and Onaivi 2019), which combined orchestrate homeostatic

C. Karasu
Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine,
Department of Medical Pharmacology, Gazi University, Ankara, Turkey
E. S. Onaivi
Department of Biology, William Paterson University, Wayne, NJ, USA
M. Aschner
Albert Einstein College of Medicine, Bronx, NY, USA
IM Sechenov First Moscow State Medical University, Moscow, Russia
A. Santamaría (*)
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel
Velasco Suárez, Ciudad de México, Mexico
e-mail: absada@yahoo.com
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 567

and neuroprotective responses and prevent several mechanisms of cell death and
damage occurring in neurodegenerative disorders. In turn, these pathologies are
characterized by progressive neuronal loss in brain tissue, leading to metabolic
dysfunction accompanied by behavioral, cognitive, and motor alterations (Warby
et al. 2011; Domaradzki 2015; Ren et al. 2020). The neuroprotective mechanisms
evoked by the ECS may emerge, among several processes, from the inhibition of
excessive glutamatergic transmission, thereby reducing excitotoxicity through the
induction of hypofunction of the subtype of glutamatergic receptors N-methyl-D-
aspartate receptors (NMDAR) (Sánchez-Blázquez et al. 2014), favoring neuronal
survival via increased production of the brain-derived neurotrophic factor (BDNF)
(Blázquez et al. 2015) through the activation of cannabinoid receptors at the cell
membrane. It is noteworthy that only a few studies have paid attention to the
expression and regulation of mitochondrial cannabinoid 1 receptors (mtCB1R) and
the consequent reduction of the energetic metabolism (Bénard et al. 2012; Hebert-
Chatelain et al. 2016). In this chapter, we discuss the cumulative general knowledge
concerning the role of the ECS in the CNS and explore the contribution of mtCB1R
to the energetic metabolism as a physiological function in neurons, with emphasis on
whether this function can be considered as a mechanism accounting for the regula-
tion of mitochondrial activity linked to neuroprotection or is merely a triggering
signal for pathophysiological events. Thus, the aim of this chapter is to provide an
overview on the role of the ECS in optimal CNS since its first descriptions and up to
the present, with emphasis on those reports exploring the modulation of mitochon-
drial energetic metabolism and signaling by mtCB1R.

The Endocannabinoid System (ECS)

The endocannabinoid system (ECS) is a complex neuromodulatory system involved

in the regulation of several major physiological functions throughout the body. The
ECS can be found in different tissues and organs and consists of a series of
endocannabinoids, receptors, and enzymes for the synthesis and degradation of
endogenous ligands. The wide distribution of diverse elements of the ECS through-
out the body suggests that this system is required at several physiological levels in
different organs, with a predominant role in the CNS. In recent years, the intense
exploration of this system has revealed its regulatory role in the maintenance of
homeostasis in several mammalian species. Among the key functions regulated by
the ECS are blood flow pressure, body temperature, respiratory frequency, immu-
nological responses, appetite, nociception, sleep cycles, neuronal excitability, etc.
The discovery of an expanded ECS with several mediators that are related biochem-
ically is known as the endocannabinoidome (Cristino et al. 2020) and described later.

Historical Background of the ECS

Since ancient times, the presence of cannabis in different civilizations has shown the
utility of this plant for several purposes, including the fabrication of ropes and cloths,
568 M. Maya-López et al.

the preparation of food, and its use as a substrate for preparation de medicinal
infusions and rituals. The characterization of the psychoactive components of the
plant began in the XIX century with the lipophilic extraction of the plant compo-
nents. In 1964, Raphael Mechoulam and Yechiel Gaoni isolated Δ9-tetrahydrocan-
nabinol (Δ9-THC), the main psychoactive compound of cannabis (Mechoulam and
Gaoni 1965), and other components such as cannabidiol (CBD), which combined
were termed as “cannabinoids.” The characterization of the effects of Δ9-THC
catapulted the study of a considerable number of effects of other components of
cannabis, leading to a most recent description of an endogenous regulatory system
activated by phytocannabinoids.
In 1988, this story took a step forward when the Allyn Howlett’s group charac-
terized brain receptors located on the surface of the cell membrane which were
activated by THC in rats (Devane et al. 1988). Once cloned, the receptor was named
of cannabinoid receptor 1 (CB1R), which is one of the most abundant receptors
coupled to G proteins (GPCR) in the brain. Further studies revealed that CB1R is
also present in the skin and several other organs. Then, a key question emerged: why
does the body possess receptors capable of responding to phytocannabinoids?
Reflections on this topic led to the conclusion on the existence of endogenous
compounds similar to THC referred to as endocannabinoids (eCBs), as discussed
below.
N-arachidonoylethanolamine (anandamide or AEA) was discovered in 1992 by
Raphael Mechoulam’s group (Devane et al. 1992) and formally identified as the first
endogenous cannabinoid neurotransmitter that can bind to CB1R. Later on, AEA
and THC were found to bind CB1R and generate similar effects. Both are ligands
capable of triggering cascades of intracellular events regulating several physiolog-
ical processes, including appetite, glucose metabolism, mood, nociception, and
fertility, among several others. AEA is produced by the body upon demand and is
known to facilitate neurogenesis and neuroprotection.
Later, in 1993, a second type of cannabinoid receptor, CB2R, was identified.
These receptors are mainly located in the immunological system, the peripheral
nervous system (PNS), and in metabolic tissue and inner organs, suggesting, for the
first time, an active role of cannabinoids in the modulation of inflammatory events in
autoimmune alterations (Munro et al. 1993). Nowadays, CB2R is known to be
located in immune cells in the CNS, including microglia and astrocytes. In this
regard, AEA was shown to exhibit low affinity for CB2R, suggesting the existence
yet of another endocannabinoid capable of activating this receptor.
2-Arachidonoylglycerol (2-AG) was simultaneously identified for the first time in
1995 by Raphael Mechoulam’s group (Mechoulam et al. 1995) and by a Japanese
group (Sugiura et al. 1995). This compound is more widely synthesized than AEA
throughout the body, showing higher content in the brain and exhibiting affinity for
both CB1R and CB2R. Both AEA and 2-AG are considered lipidic neurotransmit-
ters capable of maintaining homeostasis and reducing oxidative stress, though only
2-AG can reduce directly the expression of proinflammatory cytokines.
Endocannabinoids possess a well-defined cell metabolism which is orchestrated
by several synthesis and degradative enzymes, acting upon demand. While AEA is
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 569

degraded by the enzyme characterized by Ben Cravatt’s group in 1997, fatty acid
amide hydrolase (FAAH) (Giang and Cravatt 1997), 2-AG is catabolized by the
enzyme described by Di Marzo’s group in 1997, monoacylglycerol lipase (MAGL)
(Bisogno et al. 1997). It is noteworthy that the partial inhibition of these enzymes
may be responsible for augmenting the circulating levels of these molecules, which
may afford neuroprotection in some neurodegenerative processes.
The formal characterization of the endocannabinoids AEA and 2-AG and other
lipid derivatives, as well as of CB1R and CB2R and the synthesis and degradative
enzymes for these agents, established the basis for the concept of a canonical
endocannabinoid system (ECS), a complex neurotransmitter system responsible
for the regulation of several major physiological functions.
Taking advantage of CB1R antagonists, evidence emerged demonstrating that not
all the effects of AEA are mediated by these receptors. In 2000, a British group
(Smart et al. 2000) described the role of AEA as agonist of the vanilloid receptors
TRPV1. Such receptors have been related to the regulation of body temperature
and inflammatory pain and are mainly activated by 2-AG. In addition, it is
known that TRP channels can be modulated by both endocannabinoids and
phytocannabinoids.
On the other hand, the concept of retrograde signaling, through which AEA and
2-AG – in contrast to typical neurotransmitters – cross the synaptic cleft from the
postsynaptic terminal to bind to their receptors at the presynaptic terminal, emerged
from observations of several groups in the early 2000s (Wilson et al. 2001; Yoshida
et al. 2002). Their actions as retrograde messengers allow endocannabinoids to
modulate excitatory and inhibitory neurotransmission and reduce excessive
glutamatergic excitation and the subsequent neuronal inflammation; however, at this
point it is pertinent to mention that for the case of AEA, this endocannabinoid can also
be released from presynaptic terminals to bind postsynaptic receptors for regulating
the activity of glutamatergic receptors (reviewed by Joshi and Onaivi 2019).
In 2004, Ethan Russo formally established the concept of “clinical deficiency of
endocannabinoids” based on observations suggesting that disorders such as
migraine, irritable colon, fibromyalgia, and clinical depression share the condition
abovementioned (Russo 2004). Nowadays, the number of disorders sharing this
deficiency has been broadened to include epilepsy, autism, and several neurodegen-
erative diseases.
Another mechanism of action of cannabinoids occurring independently of CB1R
and CB2R was described in 2005. It involves direct activation of the nuclear
receptors known as peroxisome proliferator-activated receptor gamma (PPARγ),
which regulate the lipidic metabolism, genetic expression, and inflammatory
responses (Bouaboula et al. 2005). Both AEA and 2-AG can activate these receptors.
In this regard, cumulative evidence demonstrating these actions led to consider the
existence of a transporting mechanism responsible for conducting endocannabinoids
to the nucleus to bind this nuclear receptor. In 2009, a group from New York
identified a fatty-acid-binding protein (FABP) endowed with transporting endo-
cannabinoids from the cytoplasmic domain to the nucleus or to other intracellular
structures (Kaczocha et al. 2009).
570 M. Maya-López et al.

A few years later, in 2012, a French group described the presence of CB1R on the
mitochondrial membranes (Bénard et al. 2012), suggesting that cannabinoids might
regulate mitochondrial functions such as the energetic metabolism, neurotransmis-
sion, and redox activity.
Considering the mechanistic elements that have been added to the conventional
concept of the canonical ECS, several groups have suggested the adoption of a new
concept, the “extended ECS,” which includes other lipid derivatives besides AEA
and 2-AG. Given this cumulative amount of evidence in favor of a more complex
ECS, in 2013 Vincenzo Di Marzo’s group established the concept of “endo-
cannabinoidome” in direct reference to a complex hypersystem including the
lipidome and microbiome since the ECS signaling facilitates a cross-talk between
the gut bacteria and the brain (Maione et al. 2013).
Therapies based on cannabinoids are gaining relevance and attention in modern
medicine. Specifically, phytocannabinoids have emerged as the first source of
neuroactive compounds producing a broad therapeutic spectrum in the CNS through
their interactions with the ECS. Although several of these effects remain unclear, this
broad efficacy spectrum may be mostly attributed to the pharmacological properties
of these compounds as modulators of the ECS (Rohleder and Müller 2020). Among
these promising phytocompounds, Δ9-THC, cannabidiol (CBD), cannabigerol
(CBG), and cannabidivarin (CBDV) have shown notorious effects on pain percep-
tion, energy homeostasis, appetite, lipid metabolism, cardiovascular functions, ther-
moregulation, immune response, sleep-wake rhythm, psychomotor activity,
memory, and stress response, though their differential effects might be linked to
diverse mechanisms mediated by interactions with specific molecular targets and a
variety of receptors and ion channels (Rohleder and Müller 2020) that will be revised
in this chapter.

Endocannabinoids

The most studied endocannabinoids, on the bases of their levels, distribution, and
physiological relevance, are AEA, 2-AG, and oleamide (ODA). AEA and ODA are
considered fatty acid amides (FAA). The chemical name of AEA is N-arachidonoy-
lethanolamine, which describes an N-acylethanolamine (NAE) composed by an acyl
group and ethanol group and an amino group. The physiological responses evoked
by AEA in the CNS are commonly associated to a positive mental status, which is
implicit in its composed name, combining the Sanskrit term “Ananda,” equivalent to
happiness or plenitude, with the generic term amide. AEA has been shown to exert
similar effects to those of Δ9-THC, the first molecule extracted from Cannabis
sativa. It is also known that AEA exhibits affinity for both CB1R and CB2R, as
well as for TRPV, modulating the Ca2+ exchange (McKinney and Cravat 2005).
ODA is one of the fatty acid primary amides (FAPAs). It is an unsaturated amide
of 18 carbon groups derived from oleic acid. Its chemical name is cis-9-10-octa-
decenamide. ODA is also considered as endocannabinoid due to its affinity for
CB1R, as well as for other receptors for neurotransmitters, such as the GABA-A
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 571

receptor and serotonin receptor. This amide has also affinity for GAP junctions to
antagonize cellular communication (McKinney and Cravatt 2005). ODA was found
for the first time in the cerebrospinal fluid of cats subjected to sleep deprivation
(Mueller and Driscoll 2009; Tripathi 2020).
In turn, 2-AG is a lipid derivative from the cell membrane which is synthesized
from the activation of phospholipase C and diacylglycerol lipase. This endo-
cannabinoid is an ester formed from omega-6 arachidonic acid and glycerol and
has been characterized as a ligand for CB1R and CB2R in the CNS, the PNS, and the
immunological system (Mechoulam et al. 1995). 2-AG is accumulated in neurons in
response to Ca2+ mobilization stimuli – in contrast to AEA which presents increased
levels in the brain of mammals – being the most abundant endocannabinoid in the
CNS (Piomelli et al. 1998).

Synthesis and Degradation of Endocannabinoids

AEA is synthesized by Ca2+-dependent enzymes, transacylase and phospholipase D.
Transacylase transfers the acyl group of phosphatidylcholine to phosphatidyletha-
nolamine to form the precursor N-acyl phosphatidylethanolamine, which is further
hydrolyzed by phospholipase D to separate AEA from phosphatidic acid (McKinney
and Cravatt 2005).
ODA requires oleic acid as substrate for its synthesis through the enzyme acyl-
CoA synthetase; this substrate binds coenzyme A to form oleoyl-CoA as its main
precursor. Through cytochrome c and an aminotransferase, ODA is directly
obtained, although it can also be synthesized in the presence of glycine and cyto-
chrome c to form N-oleoylglycine, requiring the enzyme PAM (peptidyl glycine-α-a-
midating monooxygenase) commonly found in the neuroendocrine region of the
brain (Mueller and Driscoll 2009).
The degradation of AEA and ODA is catalyzed by FAAH, an enzyme present in
the inner part of intracellular membranes, in the outer mitochondrial membrane, and
in the smooth endoplasmic reticulum. The binding site for the enzyme is hydropho-
bic, surrounded by positively charged amino acids interacting with negatively
charged phospholipids (McKinney and Cravatt 2005; Tripathi 2020).
On the other hand, 2-AG is synthesized by the activation of phospholipase C
(PLC) to form 2-acylglycerol and 2-oleoylglycerol (2-OG), or alternatively by the
activation of diacylglycerol lipase. 2-AG is catabolized by hydrolysis, forming
glycerol and arachidonic acid by the action of MAGL or α-β hydrolase (Mechoulam
et al. 1995).

Receptors for Cannabinoids

Endocannabinoids, phytocannabinoids, and synthetic cannabinoids sometimes exert

their effects in selective manners through the activation of several transmembrane
proteins located both on cellular and organelle membranes. These receptors can be
metabotropic or ionotropic, and their activation generates signaling cascades in the
cytoplasmic domain facilitating the modulation of several processes of the cellular
572 M. Maya-López et al.

function in the CNS (Joshi and Onaivi 2019). Cannabinoid receptors are known to
be widely distributed throughout the body, consisting of receptor subtypes
which most of them are coupled to G proteins, with CB1R and CB2R being the
most studied. There is also a wide variety of endocannabinoids which can be
considered as retrograde messengers since they are synthesized and released from
postsynaptic terminals to complete their function at presynaptic terminals as
described above.

CB1 Receptor (CB1R)

CB1Rs are receptors coupled to Gi/o proteins (RCPG) which are codified by the
CNR1 gene on chromosome 6; these receptors are located in the CNS, mostly in
neurons from brain regions such as the basal ganglia, the hippocampus, the brain
cortex, and the hypothalamus (Console-Bram et al. 2012). These receptors are also
located in organelles such as the mitochondria. CB1Rs possess seven transmem-
brane domains connected by three extracellular loops and three intracellular loops
(Shao et al. 2016). CB1R is involved in behavioral processes such as the response to
fear, anxiety, stress, learning, and memory (Djeungoue-Petga and Hebert-Chatelain
2017). The receptors can be found at the presynaptic level as homodimers, hetero-
dimers, or oligomers forming complexes with other receptors coupled to G proteins
(Shao et al. 2016). Upon activation, CB1R decreases the intracellular concentration
of cAMP by inhibiting its production, modifying adenylate cyclase activity, and
increasing the concentration of MAP kinases (Pertwee 2006); this mechanism, in
turn, increases the intracellular presynaptic K+ levels and reduces Ca2+ levels,
inhibiting the neurotransmitter release in different brain regions.

CB2 Receptor (CB2R)

CB2Rs, similar to CB1R, are receptors coupled to G proteins that are codified by the
CNR2 gene on chromosome 1. CB2R and CB1R share similitude in their amino acid
sequence. In fact, both proteins are tightly related and share different ligands (Munro
et al. 1993), with 2-AG being their main endogenous ligand as full agonist. In
contrast to the 473 amino acid residues that are inherent to CB1R, the CB2R chain
is composed of only 360 amino acids (Cabral and Griffin-Thomas 2009). Similar to
CB1R, CB2R contains seven transmembrane domains. The receptors are less con-
served among species and are found densely expressed in immunological response
cells, regulating actions in the CNS through the activation of microglial cells (Cabral
et al. 2008). These functions are regulated by CB2R through a mechanism similar to
that of CB1R, by inhibiting adenylate cyclase via activation of Gi/o subunits, also
activating the MAPK-ERK pathway, and stimulating several physiological pro-
cesses such as the immunological response and cell migration (Bouaboula et al.
1996; Cabral et al. 2008; Saroz et al. 2019).
CB2R activation is known to regulate several physiological processes such as the
immunological response, cell migration, neuroinflammation inhibition, reduction of
oxidative stress, and stimulation of neuronal regeneration. CB2R is also involved in
the modulation of motor functions and memory improvement (Xin et al. 2020; Joshi
and Onaivi 2019). Therefore, since its location in glial cells, CB2R plays a critical
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 573

role in the CNS, triggering neuroprotective, anti-inflammatory, and antiexcitotoxic

responses by activating Gβγ subunits from GPCR. These responses afford
neuroprotection in neurons from regions such as the substantia nigra, the hippocam-
pus, and the brain cortex, complementing the function of CB1R through Gi/o
signaling. These combined effects support the wide distribution of these receptors
along the CNS, highlighting the relevance of the ECS for the maintenance of cell
homeostasis and neuromodulatory responses. CB2R also activates the β-arrestin
signaling pathway to modulate physiological functions at the mitochondrial level
through CREB signaling (Xin et al. 2020; Joshi and Onaivi 2019).
In regard to the functional neuronal expression of CB2R, there is limited and
controversial evidence. For several years, it has been accepted that CB2R is not
widely expressed in neuronal cells; however, recent evidence suggest that CB2R
might be expressed in neurons. While little trace of one isoform of CB2R originally
identified in the spleen has been observed in neurons, another isoform more
prevalent in the testes and brain more detectable with selective antibodies may
reveal a wide expression of these proteins in neurons (Liu et al. 2009). If these
findings are confirmed, the design of therapeutic approaches for neurological
disorders based on CB2R agonists will gain relevance. In the interim, the expres-
sion of CB2R in neurons remains under intense controversy (Ghose 2009; Liu
et al. 2020).

Vanilloid Receptor (TRPV1)

The transient receptor potential cation channel subfamily V member 1 (TRPV1),
also known as vanilloid receptor 1 (or capsaicin receptor), is a membrane ionotropic
receptor codified by the TRPV1 gene on chromosome 17. This receptor belongs to a
large family of ionic channels/transient receptor potential channels which are per-
meable to Ca2+, modulating inward currents in neurons for excitatory responses
(Clapham et al. 2005). TRPV1 is considered as an integral part of the ECS given its
affinity and sensitivity to several endocannabinoids. Among its main physiological
functions is its regulatory role for the control of pain (nociception) and body
temperature (Cui et al. 2006; Everaerts et al. 2011).

Nuclear PPAR-γ Receptor

The peroxisome proliferator-activated receptor gamma (PPAR-γ), also known as the
glitazone receptor, is a type II nuclear receptor codified by the PPARG gene involved
in genetic regulation (Elbrecht et al. 1996). Two major physiological functions are
regulated by PPAR-γ: the lipidic metabolism linked to adipogenesis (Ahmadian et al.
2013) and the activation of anti-inflammatory responses in macrophages, microglia,
and other cell types (Peluso et al. 2012), thus reducing the transcriptional activity of
NFκB and limiting the production of pro-inflammatory cytokines. Among the most
abundant ligands of PPARγ are poly-unsaturated fatty acids, arachidonic acid and
derivatives, and several phytocannabinoids and endocannabinoids (Dreyer et al.
1993; Liu et al. 2003; O’Sullivan et al. 2005). Through these processes, PPARγ
activation may also inhibit growing of several types of cancer cells (Krishnan et al.
2007).
574 M. Maya-López et al.

Other Receptors
Cannabinoids may interact with several other receptors, thus generating a variety of
effects. For instance, CBG has been shown to activate α2-adrenoceptors and block G
protein-coupled CB1R and 5-HT1A receptors (Cascio et al. 2010; reviewed by De
Petrocellis et al. 2011). Additional studies are needed to elucidate whether other
cannabinoids might also act on α2-adrenoceptors and which kind of effects can be
derived from these interactions, since these GPCR receptors are commonly related to
sedation, muscle relaxation, and analgesia. In addition, an interaction of CBD with
the 5-hydroxytriptamine (5-HT)1A receptor led to propose this cannabinoid as a
serotoninergic agonist (Russo et al. 2005), which might support a role of CBD in
relief of anxiety, pain, headache, and thermoregulation through the activation of
these receptors. It is noteworthy that the regulatory role of CBD on nausea and
vomiting via 5-HT1A receptor activation can be suppressed by an interaction
between CBD and CGB (Rock et al. 2011), suggesting complex pharmacological
effects of these compounds at the serotonergic level.
The G protein-coupled receptor (GPCR) 55 regulates the triggering of intracel-
lular Ca2+ mobilization, playing a crucial role in neurotransmitter release in hippo-
campal CA3-CA1 synapses. It has been shown that CBD, acting as an antagonist on
GPR55, inhibits Ca2+ release from the presynaptic stores, thus modulating the effects
of this receptor and contributing to the regulation of hippocampal functions
(Sylantyev et al. 2013). The impact of this evidence has been extended to other
levels, since CBD has also been demonstrated to reduce seizures and autistic-like
social deficits in a mouse model of Dravet syndrome through the recovery of the
function of inhibitory interneurons in the hippocampal dentate gyrus, with CDB
acting as a GPR55 antagonist (Kaplan et al. 2017).
Endogenous and exogenous cannabinoids have been shown to allosterically
modulate glycine receptors (GlyRs) (Xiong et al. 2012). Both AEA and Δ9-THC
increased glycine-activated currents in spinal-cultured neurons through α1 and α3
subunits, potentiating GlyRs. Such receptors are ligand-gated chloride ion channels
mediating inhibitory transmission in the spinal cord and brainstem. They are also
involved in motor activity and pain perception (Avila et al. 2013). GlyR regulation
by cannabinoids suggests a role of these molecules not only in the mentioned
functions but also in cellular and molecular mechanisms controlling the brain
development.
Collectively, the role of cannabinoids (either phyto-, endo- or synthetic com-
pounds) as ligands of several receptors located in the CNS needs more detailed
characterization in light of the broad regulatory functions that these complex inter-
actions might exert at the central level.

The ECS and the Modulation of Functions in the CNS

Recent research on the role of the ECS in the CNShas generated a considerable
interest in its physiological functions and its promising therapeutic potential through
the use of drugs interacting with several of its elements (Robson 2014). Among its
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 575

several functions, the ECS is involved in neuroprotection, the modulation of

nociception, the regulation of motor activity, neurogenesis, synaptic plasticity, and
the control of specific phases of the memory processing (Skaper and Di Marzo
2012). In addition, the ECS modulates immune and inflammatory responses,
maintaining a positive energetic balance. The protective effects generated by the
stimulation of the ECS also involve the modulation of glutamatergic excitability via
the postsynaptic inhibition of glutamatergic receptors such as the NMDAR through
the CB1R activation at the cytoplasmic membrane, reducing the glutamatergic
neurotransmission by co-internalization of subunit NR1 of the NMDAR in a process
regulated by the histidine triad nucleotide-binding protein 1 (HINT1); this process
induces the internalization of the complexed proteins into the cytoplasmic domain,
where the NR1 subunit will be released by proteasome (Sánchez-Blázquez et al.
2013; Chiarlone et al. 2014; Aguilera-Portillo et al. 2019). The described mechanism
has helped to explain in part the antiexcitotoxic and neuroprotective effect evoked by
several CB1R agonists such as the synthetic cannabinoid WIN 55,212-2, the endo-
cannabinoid ODA, or the increased levels of endocannabinoids (AEA and others)
induced by the inhibitor of the enzyme FAAH, URB597. It has been reported that
these agents are able to prevent toxicity in neurotoxic models induced by the
mitochondrial toxin 3-nitropropionic acid (3-NP) and the excitotoxin quinolinic
acid (QUIN), both of which trigger pathophysiological mechanisms leading to
neurodegeneration via the stimulation of excitotoxicity, oxidative stress, inflamma-
tion, mitochondrial dysfunction, and apoptotic/necrotic cell death. The induction of
these models in Wistar rats in vivo and in striatal cell cultures, brain slices, and
synaptosomal fractions in vitro has served to demonstrate the efficacy of the ECS in
modulating neuroprotection (Rangel-López et al. 2015; Maya-López et al. 2017;
Aguilera-Portillo et al. 2019; Maya-López et al. 2020). Consequently, regulatory and
neuroprotective effects mediated by several components of the ECS may be induced
via activation CB1R, CB2R, PPARγ, TRPV1, and other receptors or by receptor-
independent mechanisms such as direct antioxidant and anti-inflammatory effects
(Elmazoglu et al. 2020).

Regulation of Mitochondrial Function

Regulation of mitochondrial respiration at the neuronal level constitutes a physio-

logical process needed for the coordination of neurotransmission and other events;
this process is stimulated by metabolites such as lactate, which are released from
astrocytes for the eventual generation of ATP, the main source of cellular energy.
Neurons are highly enriched with mitochondria which are distributed throughout
their whole structure: in the terminal, axon, soma, and dendrites. This wide distri-
bution is due to the high energetic demand that neurons exhibit to maintain cell
survival, to generate the action potential, to maintain ion gradients, to activate
synaptic transmission, and to regulate plasticity processes. In turn, the physiological
meaning of ATP synthesis depletion and the increase in intracellular ADP is yet to be
fully elucidated: under physiological conditions, it is necessary to reduce the
576 M. Maya-López et al.

mitochondrial motility in the case of axonal transport to maintain mitochondria in a

stationary state for recruiting these organelles in specific neuronal subdomains, such
as dendrites and axons; this transitory process assures optimal energy production and
Ca2+ recruitment in situ when synaptic transmission is increased or axonal ramifi-
cation is required (MacAskill and Kittler 2009). In turn, mitochondrial immobiliza-
tion is regulated by increased concentrations of nitric oxide and Ca2+ (MacAskill and
Kittler 2009; Sheng 2013). In addition, mitochondrial mobility may be regulated via
cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) through the inter-
action of A-kinase anchoring proteins (AKAPs) with β-tubulin, the acidic protein
isoform conforming microtubules, where mitochondrial axonal transport takes place
(Livigni et al. 2006). The phosphorylated PKA pathway regulates critical cell
functions, and as it is present in the outer mitochondrial membrane, it improves
the transmission of several signals for cell survival. Such signaling pathway has been
demonstrated in GC2 cells (Cardone et al. 2002). The AKAP-tubulin interaction
contributes to cell development, maintaining, division, and the axonal transport
characterizing neuronal functions.
On the other hand, during mitochondrial respiration, which is necessary to
generate energy in the form of ATP, the process of reactive oxygen species (ROS)
formation is activated from mitochondrial complexes and the enzyme monoamine
oxidase (MAO). The latter is present in the mitochondrial outer membrane (Nolfi-
Donegan et al. 2020). Complex I (NADH-dehydrogenase) induces ROS formation
in mitochondrial matrix from different sources, including fully reduced FMN and the
reversed electron transport (RET).
Upon NADH oxidation, the FMN site is reduced, favoring its reaction with
oxygen to form superoxide anion (O2•-); the production of this radical upon phys-
iological conditions by this process is relatively low but necessary to regulate
signaling processes. In contrast, upon pathological conditions, NADH/NAD+
increases, resulting in decreased activity of the electron transport, leading to
increased formation of O2• due to reduction of the FMN site (Nolfi-Donegan
et al. 2020).
The RET is activated when quinol (QH2) formation is increased by over-
reduction of quinone (Q), simultaneously occurring with an increased proton-motive
force to revert electrons to complex I (NADH:dehydrogenase), thus reducing NAD+
to NADH, stimulating O2•– formation in the mitochondrial matrix. This
RET-mediated mechanism may occur during pathological events such as ischemia-
reperfusion; however, in general terms, this physiological process is commonly
involved in signaling pathways and activation of protective mechanisms (Nolfi-
Donegan et al. 2020). Although the process of ROS formation ensues in toxic
outcomes, upon physiological conditions it is known to be part of several physio-
logical events, such as the activation of the transcription factor nuclear factor kappa
B (NF-kB), the nuclear receptors such as PPAR, and enzymes such as the
AMP-activated protein kinase (AMPK). It has been considered that this process
plays an active role in the regulation of the cell bioenergetics for ATP synthesis and
for maintaining the basal functioning of the antioxidant system in a Ca2+-dependent
manner (Taylor and Moncada 2010; Sanz 2016). The RET mechanism reverts
electrons to the Q-binding site at complex I; this site is also known as NADH
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 577

Table 1 Reports on the use of cannabinoids (agonists of CB1R) in isolated mitochondria and other
biological preparations in studies about the function of mitochondrial cannabinoid receptor
1 (mtCB1R)
Experimental Cannabinoid Effect
Source model use Concentrations (summary)
Hebert- Mice post-natal WIN 55,212-2 2 μM Decreased cellular
Chatelain fibroblasts respiration
et al. Mice post-natal HU210 1 μM Reduced mitochondrial
(2016) primary mobility
hippocampal
neurons
In vivo model in WIN 55,212-2 5 mg/kg, i.p. Reduced performance in the
mice NOR test
Hippocampal Δ9-THC 800 nM Decreased adenylate cyclase
mitochondria and cellular respiration
isolated from Decreased expression of
mice NDUFS2 subunit of
complex I
Mice HU210 2.5 μM Reduced fEPSP
hippocampal
slices
Bénard Hippocampal WIN 55,212-2 20–100 nM Decreased mitochondrial
et al. mitochondria respiration in a
(2012) isolated from concentration-dependent
mice manner
100 nM Decreased complex I
activity, cAMP, and PKA
Δ9-THC 400–800 nM Reduced mitochondrial
respiration, cAMP, and PKA
In vivo model in Δ9-THC 5 mg/kg, i.p. Decreased activity of the
C57BL6/N mice mitochondrial respiratory
chain
In these studies, the presence of CB1R in mitochondria isolated from the hippocampus was
demonstrated, and the signaling pathway involved in their activity was explored, providing
evidence of a reduced activity in mitochondrial electron transport chain
Abbreviations: NOR, novel object recognition; fEPSP, field excitatory postsynaptic potentials;
cAMP, cyclic AMP; PKA, protein kinase A; NDUFS2, NADH dehydrogenase [ubiquinone] iron-
sulfur protein 2

dehydrogenase [ubiquinone] iron-sulfur protein 2 (NDUFS2) (Wolin et al. 2019).

Accordingly, it has been suggested that RET-mediated ROS formation might be
modulated by several regulatory mechanisms, including the activation of cannabi-
noid receptors (see Table 1).

The Cannabinoid 1 Mitochondrial Receptor (mtCB1R)

Advances in cannabinoid research have demonstrated that CB1Rs are located in

intracellular compartments, including in the mitochondria, beyond the classical
notion of CB1R localization in plasma membrane of cells (Bénard et al. 2012;
578 M. Maya-López et al.

Hebert-Chatelain et al. 2016). The discovery of cannabinoid 1 mitochondrial recep-

tor (mtCB1R) has significantly contributed to the understanding of the complexity
characterizing this organelle. With mitochondria as key organelles providing cellular
energy for vital functions, new insights reveal the impact of mtCB1R modulation of
bioenergetic cellular processes (Djeungoue-Petga and Hebert-Chatelain 2017).
Therefore, the detection and functional analysis of mtCB1R in the CNS indicate
that cannabinoids can regulate intramitochondrial signaling, cellular aerobic respi-
ration, and other bioenergetic processes that can influence the behavioral effects of
cannabinoids and eCB ligands (Xu et al. 2016; Harkany and Horvath 2017). As the
brain is one of the most energy consuming organs in the body, mitochondrial activity
is important for brain function and dysfunction. Therefore, the presence of CB1R in
mitochondria seems to be related to the modulation of neuronal functions for
energetic metabolism, axonal and mitochondrial mobility, and synaptic transmission
(Djeungoue-Petga and Hebert-Chatelain 2017). The modulation of energetic metab-
olism is directly related with the activation of this receptor through the regulation of
an inhibitory signaling pathway at the intermembrane mitochondrial domain. This
process resembles the function of GPCRs in the cytoplasmic membrane by
inhibiting adenylate cyclase, coordinating the activity of cAMP, and inhibiting
protein kinase A (PKA), thereby interrupting the electron transport system (ETS),
the oxygen consumption, and the ATP production. The apparent physiological
“purpose” of this regulatory program might be related to a decreased excitatory
transmission, the modulation of Ca2+ homeostasis, and ATP production for the
downregulation of memory at the hippocampal level (Djeungoue-Petga and
Hebert-Chatelain 2017), although other functions in the CNS have yet to be char-
acterized. Specifically, this pathway preferentially reduces the activity of the mito-
chondrial complex I (NADH dehydrogenase). The decreased expression of the
specific subunit of complex NDUFS2 mediates the inhibition of oxidative phos-
phorylation through this signaling pathway, thus reducing ATP production and
activity (Djeungoue-Petga and Hebert-Chatelain 2017). These signaling processes
have been described on the basis of experimental studies carried out by Bénard et al.
(2012) and Hebert-Chatelain et al. (2016), who employed several cannabinoids at
different concentrations (Table 1). It is noteworthy; these groups demonstrated that
this pathway is not dependent on oxidative phosphorylation, since the use of
inhibitors for the same signaling cascade downstream the mtCB1R did not affect
mitochondrial respiration. Therefore, the regulation of this pathway might represent
an alternative for the reduction of synaptic transmission, at least in the hippocampus,
affecting in this manner memory processes, as demonstrated in mice administered
with the synthetic agonist of CB1R, WIN 55,212-2, in tasks such as the novel object
recognition (NOR) test. This event may also be related to a decrease in the hippo-
campal field excitatory postsynaptic potential (fEPSP). Combined, these findings
suggest that, being a brain region with high density of CB1R, including mtCB1r, the
hippocampus requires these receptors for regulating the intense glutamatergic and
GABAergic activity via cannabinoid modulation (Bénard et al. 2012; Hebert-
Chatelain et al. 2016).
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 579

However, the downregulation of mitochondrial functions through mtCB1R acti-

vation under “normal” physiological conditions constitutes a concept that remains to
be understood and controversial, although this mechanism seems to be of great
physiological relevance. The loss of cellular energy by a decreased mitochondrial
activity linked to cannabinoid signaling might suggest in the first place the genera-
tion of noxious events as a physiological component of the CNS. In this regard, it has
been shown that the activation of these receptors and the subsequent decrease in
excitatory synaptic transmission and energy metabolism are involved in the loss of
memory by dysfunction of hippocampal neurons, leading to episodic amnesia and
the reduction of synaptic plasticity (Hebert-Chatelain et al. 2016). Similarly, this
process might account for the redox dysfunction and consequent formation of high
amounts of ROS and the disruption of axonal transport. Furthermore, these events
might affect the synthesis of neurotransmitters such as glutamate and GABA
(Djeungoue-Petga and Hebert-Chatelain 2017). It is accepted that mitochondria
contribute to Ca2+ storage for modulating the levels of this ion in the cytoplasmic
domain while decreasing the exocytotic process during the neurotransmitter release.
The major directing force in maintaining Ca2+ homeostasis is the membrane poten-
tial. The bidirectional transport in mitochondria is crucial for ATP supply in active
sites. In this regard, mitochondrial downregulation by cannabinoids is responsible
for modulation of neuronal activity (Harkany and Horvath 2017). Up to this point,
collectively, this evidence suggests that the signaling linked to mtCB1R per se might
be noxious for the baseline functions of the CNS; however, even though the real
physiological nature of these receptors has yet to be characterized, it makes more
sense to consider that mtCB1R activation might serve as a fine modulatory function
in mitochondria, possibly compensating for the continuous activation of mitochon-
drial complexes, thus coordinating mitochondrial plasticity. At this point, it is not
possible to discard that a signal designed to decrease mitochondrial function in a
transitory manner, such as cannabinoid signaling activating mtCB1R, might consti-
tute a physiological strategy to regulate mitochondrial fission/fusion cycles, or at the
cellular level, to stimulate inhibitory processes controlling synaptic transmission. We
therefore hypothesize that the physiological role that these receptors play in mito-
chondrial physiology is related to the modulation of mitochondrial mobility,
maintaining the mitochondria in a “stationary” state for an adequate energy supply
during synaptic transmission. We advance this hypothesis on the basis of evidence
demonstrating that the ADP/ATP balance is involved in mitochondrial motility and
plasticity (Mironov 2007; Sheng 2013). Since changes in the ADP/ATP balance are
required for mitochondrial mobilization during normal neuronal activity, the modu-
lation in ADP and ATP production linked to activation of mtCB1R might provide
mitochondria with signals oriented to regulate their activity. Another possible key
role for these receptors might lie in the fact that their activation is required for the
coordination of neuronal activity: the most common protein in mitochondria, the
translocase of the outer membrane (TOM), allows the reorganization of the
N-terminal sequence of mtCB1R in the membrane, and such N-terminal sequence
is reorganized by an interface of the outer mitochondrial membrane (Mim1)
580 M. Maya-López et al.

(Chacinska et al. 2009); in turn, this process implies the cooperation with chaperons
and the assembly of molecular complexes to direct mitochondrial proteins to their
final destinations. Other functions linked to mtCB1R are yet to be fully characterized
in order to establish the precise role of these receptors in the physiology of the CNS.
In regard to NDUFS2, it has been demonstrated that a decrease in the levels of
mitochondrial hydrogen peroxide (H2O2) may be mediated by inhibition of this
subunit from the mitochondrial complex I due to the lack of oxygen (O2) under
hypoxic conditions, as it has been shown in pulmonary artery smooth muscle cells
(PASMC), as well as by rotenone, which binds this subunit to inhibit the activity of
NADH dehydrogenase complex. This evidence has been collected from a study
where the expression of NDUFS2 was inhibited through the use of small interfering
RNA (siRNA). It is known that H2O2 formation is important for lung vasodilation.
This radical is formed in the mitochondrial matrix by the reduction of O2•– through
the activity of superoxide dismutase 2 (SOD2) (Dunham-Snary et al. 2019; Wolin
et al. 2019). Through this mechanism, we hypothesize that mitCB1R might exert
relevant physiological functions in the mitochondria from the CNS since the inhibi-
tion of the subunit NDUFS2 reduces the respiratory chain, thus decreasing quinone
over-reduction to prevent RET and modulate harmful ROS formation in mitochon-
dria. Figure 1 summarizes the series of events underlying mtCB1R activation.

Effects of Cannabinoids on Mitochondria

There are a limited number of reports addressing the effects of cannabinoids on

isolated mitochondria. It has been demonstrated that endocannabinoids such as AEA
modify the translation signals dependent of mitochondria, thereby controlling cel-
lular events such as apoptosis. When these molecules regulate mitochondrial swell-
ing, they reduce the Ca2+-dependent release of cytochrome c, thereby contributing to
the inhibition of apoptosis (Catanzaro et al. 2009). The same group also found that
AEA decreased mitochondrial membrane potential and augmented membrane fluid-
ity, and these effects were independent of cannabinoid or vanilloid receptors. It was
concluded that AEA reduced the mitochondrial sensitivity to Ca2+ through receptor-
independent processes, which constitutes an important mechanism for mitochondrial
regulation; however, this work did not contribute to our knowledge on mitochondrial
cannabinoid regulation in the CNS since it was performed in liver mitochondria.
Thus, the question arose: how to explain the cannabinoid-induced modulatory
effects in mitochondria in a receptor-independent manner? In part, a clue to answer
this question might lie in the findings of Velez-Pardo et al. (2010), who studied the
effects of the synthetic cannabinoids CP55,940 and JWH-015 in mitochondria
isolated from the brain of rats exposed to the toxin paraquat. Both molecules
attenuated the mitochondrial damage produced by the toxin by scavenging super-
oxide radical and hydrogen peroxide, maintaining the mitochondrial membrane
potential and inhibiting swelling. The protective properties of compounds were
attributed to their capacity to act as free radical scavengers, suggesting that canna-
binoids might use such properties to evoke mechanisms of mitochondrial redox
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 581

Fig. 1 Schematic representation of a neuronal mitochondrion anchored to microtubules at the

axon. A decreased synthesis of ATP mediated by inhibition of the mitochondrial respiratory chain
(red lines) may contribute to reduce/stop mitochondrial mobility through a protein kinase A (PKA)-
dependent pathway modulated negatively by the mitochondrial cannabinoid 1 receptor (mtCB1R),
located at the mitochondrial outer membrane. When mtCB1R inhibits the PKA activity, it blocks the
activity of the NADH dehydrogenase [ubiquinone] iron-sulfur protein subunit 2 (NDUFS2) of
complex I in a reversible manner to reduce the ATP synthesis (inhibited pathway appears
represented by red lines) (Bénard et al. 2012; Hebert-Chatelain et al. 2016). PKA is transported
to mitochondria by A-kinase anchoring proteins (AKAPs) which are bound to microtubules through
β-tubulin. In this manner, PKA plays a major role in modulating the mitochondrial transport, also
regulating the cAMP pathway to participate in the control of cell survival, development, axonal
transport, and axonal and dendritic plasticity (Mironov 2007; MacAskill and Kittler 2009; Sheng
2013). NDUFS2 also plays a crucial role in reactive oxygen species (ROS) formation (yellow
arrow) when the reversed electron transport (RET) mechanism is activated due to a quinol (QH2)
increase due to over-reduction of quinone following an increased electron transport chain (Wolin
et al. 2019). Therefore, NDUFS2 inhibition via the mtCB1R-dependent blockade of PKA might
reduce ROS formation

regulation independently of the activation of receptors in brain tissue. Unfortunately,

the major limitation in this study lies in the fact that no endocannabinoids were tested
nor antagonists for cannabinoid receptors. In addition, an experimental study probing
the ligand binding kinetics and correlating affinity and function of endocannabinoids
on mtCB1R has yet to be performed. Though the findings by these groups are
promising in terms of the information provided on the regulation of the mitochondrial
function by the ECS under physiological and pathophysiological conditions, a more
detailed characterization of the role of the ECS (including endocannabinoids and
mitochondrial receptors) on mitochondrial function is required.
582 M. Maya-López et al.

Conclusion

Since the first description of THC in 1964 by Raphael Mechoulam, and the ensuing
characterization of receptors with affinity for THC by Allyn Howlett’s group, the
ECS has been intensely investigated, revealing so far an unexpected complexity
linked to its broad distribution throughout the body, particularly in the brain. Such
level of complexity is enriched by a considerable amount and diversity of receptors
and endogenous ligands (endocannabinoids), the many pathways for their synthesis
and degradation, and the molecular and cellular mechanisms regulated by the
membrane receptors CB1R, CB2R, and TRPV1, as well as by activation of nuclear
receptors PPAR-γ, for the coordination of various physiological, neuroprotective,
and antineoplastic events. This chapter aims to update the reader on the state-of-the-
art knowledge about the many faces of the ECS by providing a brief description of
key findings on the functions of this complex system, highlighting the presence and
function of CB1R on the membranes of organelles in charge of the cellular bioen-
ergetics, the mitochondria. This relatively novel field of research deserves consider-
able attention given the wide distribution of mitochondria in neurons, which are
responsible for maintaining several functions such as cell survival, synaptic com-
munication, cell plasticity, and axonal growth, to name a few. Thus, the regulation of
the energetic metabolism depends on constant ATP availability, and mitochondria
are not only in charge of this process, but also of the regulated ROS production for an
adequate cellular signaling. Through the formal description of the signaling pathway
linked to the activation of mtCB1R by Bénard and Hebert-Chatelain, we have
learned that these receptors activate inhibitory oxidative phosphorylation signals
through the inhibition of adenylate cyclase in hippocampal mitochondria, thus
potentially reducing cognitive skills; however, based on evidence discussed in this
chapter, we suggest that, while the contributions made by these groups are essential
for the comprehension of mtCB1R functions, these findings remain limited to the
extent that they only address hippocampal function, thereby lacking broader support
to explain the full complexity of functions that may be elicited by these receptors in
other brain regions, as well as justifying their real physiological role. So far, it seems
that these receptors are abundant in glutamatergic and GABAergic neurons and their
activity contributes to regulatory processes yet poorly explored, also participating in
deleterious events such as episodic amnesia in rodents. These findings are of major
relevance, as they link the function of these receptors to pathophysiological events,
partially supporting the concept that cannabinoids, mostly those with psychoactive
properties, may alter cognitive functions through the described mechanism. None-
theless, several questions remain in regard to the function of mtCB1Rs, necessitating
an integrative approach to characterizing their function and brain distribution, as
well as the development of binding studies with endogenous ligands to establish
specific regional pharmacological criteria such as affinity and potency. In addition,
this chapter highlights the need to explore the distribution of these receptors, not
only in neurons but also in other cell types such as glia, exploring their physiological
contribution and therapeutic potential. Combined, these concerns remain as perspec-
tives to be explored in a near future.
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 583

Cross-References

▶ Cannabinoid Drugs in Mental Health Disorders

Acknowledgments E.S.O is supported by William Paterson University and NIAAA-NIH grant

AA027909. M.A. was supported by the National Institute of Environmental Health Sciences’ grants
R01ES03771 and R01ES10563.

Declaration of Interest
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this chapter. The authors are responsible
for content and writing of the manuscript and do not necessarily reflect the position of the US Food
and Drug Administration nor do mention of trade names and commercial products constituting
endorsement or recommendation for use and do not represent agency position or policy.

References
Aguilera-Portillo G, Rangel-López E, Villeda-Hernández J, Chavarría A, Castellanos P,
Elmazoglu Z, Karasu Ç, Túnez I, Pedraza G, Königsberg M, Santamaría A. The pharmacolog-
ical inhibition of fatty acid amide hydrolase prevents excitotoxic damage in the rat striatum:
possible involvement of CB1 receptors regulation. Mol Neurobiol. 2019;56:844–56.
Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM. PPARγ signaling and
metabolism: the good, the bad and the future. Nat Med. 2013;19:557–66.
Avila A, Nguyen L, Rigo J-M. Glycine receptors and brain development. Front Cell Neurosci.
2013;7:184.
Bénard G, Massa F, Puente N, Lourenço J, Bellocchio L, Soria-Gómez E, Matias I, Delamarre A,
Metna-Laurent M, Cannich A, Hebert-Chatelain E, Mulle C, Ortega-Gutiérrez S, Martín-
Fontecha M, Klugmann M, Guggenhuber S, Lutz B, Gertsch J, Chaouloff F, López-Rodríguez
ML, Grandes P, Rossignol R, Marsicano G. Mitochondrial CB1 receptors regulate neuronal
energy metabolism. Nat Neurosci. 2012;15:558–64.
Bisogno T, Sepe N, Melck D, Maurelli S, De Petrocellis L, Di Marzo V. Biosynthesis, release and
degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in
mouse neuroblastoma cells. Biochem J. 1997;322:671–7.
Blázquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, García-Rincón D, Sendtner M,
Timmusk T, Lutz B, Galve-Roperh I, Guzmán M. The CB1 cannabinoid receptor signals striatal
neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death Differ. 2015;22:
1618–29.
Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrié B, Rinaldi-Carmona M, Calandra B,
Le Fur G, Casellas P. Signaling pathway associated with stimulation of CB2 peripheral
cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of
Krox-24 expression. Eur J Biochem. 1996;237:704–11.
Bouaboula M, Hilairet S, Marchand J, Fajas L, Le Fur G, Casellas P. Anandamide induced
PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J
Pharmacol. 2005;517:174–81.
Cabral GA, Griffin-Thomas L. Emerging role of the cannabinoid receptor CB2 in immune regula-
tion: therapeutic prospects for neuroinflammation. Exp Rev Mol Med. 2009;11:e3.
Cabral GA, Raborn ES, Griffin L, Dennis J, Marciano-Cabral F. CB2 receptors in the brain: role in
central immune function. Br J Pharmacol. 2008;153:240–51.
Cardone L, de Cristofaro T, Affaitati A, Garbi C, Ginsberg MD, Saviano M, Varrone S, Rubin CS,
Gottesman ME, Avvedimento EV, Feliciello A. A-kinase anchor protein 84/121 are targeted to
584 M. Maya-López et al.

mitochondria and mitotic spindles by overlapping amino-terminal motifs. J Mol Biol. 2002;320:
663–75.
Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG. Evidence that the plant cannabi-
noid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A
receptor antagonist. Br J Pharmacol. 2010;159:129–41.
Catanzaro G, Rapino C, Oddi S, Maccarrone M. Anandamide increases swelling and reduces
calcium sensitivity of mitochondria. Biochem Biophys Res Commun. 2009;388:439–42.
Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N. Importing mitochondrial pro-
teins: machineries and mechanisms. Cell. 2009;138:628–44.
Chiarlone A, Bellocchio L, Blázquez C, Resel E, Soria-Gómez E, Cannich A, Ferrero JJ,
Sagredo O, Benito C, Romero J, Sánchez-Prieto J, Lutz B, Fernández-Ruiz J, Galve-Roperh I,
Guzmán M. A restricted population of CB1 cannabinoid receptors with neuroprotective activity.
Proc Natl Acad Sci U S A. 2014;111:8257–62.
Clapham DE, Julius D, Montell C, Schultz G. International Union of Pharmacology. XLIX.
Nomenclature and structure-function relationships of transient receptor potential channels.
Pharmacol Rev. 2005;57:427–50.
Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological
principles. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;38:4–15.
Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in
neurological disorders. Nat Rev Neurol. 2020;16:9–29.
Cui M, Honore P, Zhong C, Gauvin D, Mikusa J, Hernandez G, Chandran P, Gomtsyan A,
Brown B, Bayburt EK, Marsh K, Bianchi B, McDonald H, Niforatos W, Neelands TR,
Moreland RB, Decker MW, Lee C-H, Sullivan JP, Faltynek CR. TRPV1 receptors in the CNS
play a key role in broad-spectrum analgesia of TRPV1 antagonists. J Neurosci. 2006;26:9385–93.
De Petrocellis L, Ligresti A, Moriello AS, Allara M, Bisogno T, Petrosino S, Stott CG, Di Marzo
V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and
endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163:1479–94.
Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and character-
ization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–13.
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A,
Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to the
cannabinoid receptor. Science. 1992;258:1946–9.
Djeungoue-Petga M-A, Hebert-Chatelain E. Linking mitochondria and synaptic transmission: the
CB1 receptor. BioEssays 2017;1700126.
Domaradzki J. The impact of Huntington disease on family carers: a literature overview. Psychiatr
Pol. 2015;49:931–44.
Dreyer C, Keller H, Mahfoudi A, Laudet V, Krey G, Wahli W. Positive regulation of the peroxi-
somal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-
activated receptors (PPAR). Biol Cell. 1993;77:67–76.
Dunham-Snary KJ, Wu D, Potu F, Sykes EA, Mewburn JD, Charles RL, Eaton P, Sultanian RA,
Archer SL. Ndufs2, a core subunit of mitochondrial complex I, is essential for acute oxygen-
sensing and hypoxic pulmonary vasoconstriction. Circ Res. 2019;124:1727–46.
Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz MD, Moller DE, Berger J. Molecular
cloning, expression and characterization of human peroxisome proliferator activated receptors
gamma 1 and gamma 2. Biochem Biophys Res Comm. 1996;224:431–7.
Elmazoglu Z, Rangel-López E, Medina-Campos ON, Pedraza-Chaverri J, Túnez I, Aschner M,
Santamaría A, Karasu Ç. Cannabinoid-profiled agents improve cell survival via reduction of
oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hypergly-
cemia+Aβ1-42 peptide in rat hippocampal neurons. Neurochem Int. 2020;140:104817. https://
doi.org/10.1016/j.neuint.2020.104817.
Everaerts W, Gees M, Alpizar YA, Farre R, Leten C, Apetrei A, Dewachter I, van Leuven F,
Vennekens R, De Ridder D, Nilius B, Voets T, Talavera K. The capsaicin receptor TRPV1 is a
crucial mediator of the noxious effects of mustard oil. Curr Biol. 2011;21:316–21.
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 585

Ghose T. Cannabinoid controversy. Scientist. 2009; http://www.the-scientist.com/news/print/55969/

Giang DK, Cravatt BF. Molecular characterization of human and mouse fatty acid amide hydro-
lases. Proc Natl Acad Sci U S A. 1997;94:2238–42.
Harkany T, Horvath TL. (S)pot on mitochondria: cannabinoids disrupt cellular respiration to limit
neuronal activity. Cell Metab. 2017;25:8–10.
Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A,
Christian Pagano Zottola AC, Delamarre A, Cannich A, Vincent P, Varilh M, Robin LM,
Terral G, García-Fernández MD, Colavita M, Mazier W, Drago F, Puente N, Reguero L,
Elezgarai I, Dupuy J-W, Cota D, Lopez-Rodriguez M-L, Barreda-Gómez G, Massa F,
Grandes P, Bénard G, Marsicano G. A cannabinoid link between mitochondria and memory.
Nature. 2016;539:555–9.
Joshi N, Onaivi ES. Endocannabinoid system components: overview and tissue distribution. Adv
Exp Med Biol. 2019;1162:1–12.
Kaczocha M, Glaser ST, Deutsch DG. Identification of intracellular carriers for the endo-
cannabinoid anandamide. Proc Natl Acad Sci U S A. 2009;106:6375–80.
Kaplan JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social
deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci. 2017;114:11229–34.
Krishnan A, Nair SA, Pillai MR. Biology of PPAR gamma in cancer: a critical review on existing
lacunae. Curr Mol Med. 2007;7:532–40.
Liu J, Li H, Burstein SH, Zurier RB, Chen JD. Activation and binding of peroxisome proliferator-
activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol Pharmacol. 2003;63:
983–92.
Liu Q-R, Pan C-H, Hishimoto A, Li C-Y, Xi Z-X, Llorente-Berzal A, Viveros M-P, Ishiguro H,
Arinami T, Onaivi ES, Uhl GR. Species differences in cannabinoid receptor 2 (CNR2 gene):
identification of novel human and rodent CB2 isoforms, differential tissue expression and
regulation by cannabinoid receptor ligands. Genes Brain Behav. 2009;8:519–30.
Liu Q-R, Canseco-Alba A, Liang Y, Ishiguro H, Onaivi ES. Low basal CB2R in dopamine neurons
and microglia influences cannabinoid tetrad effects. Int J Mol Sci. 2020;21:9763.
Livigni A, Scorziello A, Agnese S, Adornetto A, Carlucci A, Garbi C, Castaldo I, Annunziato L,
Avvedimento EV, Feliciello A. Mitochondrial AKAP121 links cAMP and src signaling to
oxidative metabolism. Mol Biol Cell. 2006;17:263–71.
MacAskill AF, Kittler JT. Control of mitochondrial transport and localization in neurons. Trends
Cell Biol. 2009;20:102–12.
Maione S, Costa B, Di Marzo V. Endocannabinoids: a unique opportunity to develop multitarget
analgesics. Pain. 2013;154:S87–93.
Maya-López M, Colín-González AL, Aguilera G, De Lima ME, Colpo A, Rangel-López E, Villeda-
Hernández J, Rembao-Bojórquez D, Túnez I, Luna-López A, Lazzarini-Lechuga R, González-
Puertos VY, Posadas-Rodríguez P, Silva-Palacios A, Königsberg M, Santamaría
A. Neuroprotective effect of WIN 55,212-2 against 3-nitropropionic acid-induced toxicity in
the rat brain: involvement of CB1R and NMDA receptors. Am J Transl Res. 2017;9:261–74.
Maya-López M, Rubio-López L, Rodríguez-Alvarez IV, Orduño-Piceno J, Flores-Valdivia Y,
Collonelo A, Rangel-López E, Túnez I, Prospero-García O, Santamaría A. A cannabinoid
receptor-mediated mechanism participates in the effects of oleamide against excitotoxic damage
in rat brain synaptosomes and cortical slices. Neurotox Res. 2020;37:126–35.
McKinney MK, Cravatt BF. Structure and function of fatty acid amide hydrolase. Annu Rev
Biochem. 2005;74:411–32.
Mechoulam R, Gaoni Y. A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of
hashish. J Am Chem Soc. 1965;87:3273–5.
Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A,
Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel
Z. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to
cannabinoid receptors. Biochem Pharmacol. 1995;50:83–90.
Mironov S. ADP regulates movements of mitochondria in neurons. Biophys J. 2007;92:2944–52.
586 M. Maya-López et al.

Mueller GP, Driscoll WJ. Biosynthesis of oleamide. Vitam Horm. 2009;81:55–78.

Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for
cannabinoids. Nature. 1993;365:61–5.
Nolfi-Donegan D, Braganza A, Shiva S. Mitochondrial electron transport chain: oxidative phos-
phorylation, oxidant production, and methods of measurement. Redox Biol. 2020;37:101674.
https://doi.org/10.1016/j.redox.2020.101674.
O’Sullivan SE, Tarling EJ, Bennett AJ, Kendall DA, Randall MD. Novel time-dependent vascular
actions of Delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor
gamma. Biochem Biophys Res Comm. 2005;337:824–31.
Peluso I, Morabito G, Urban L, Ioannone F, Serafini M. Oxidative stress in atherosclerosis
development: the central role of LDL and oxidative burst. Endocrine Metab Immune Disord
Drug Targets. 2012;12:351–60.
Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J
Obesity. 2006;30:S13–8.
Piomelli D, Beltramo M, Giuffrida A, Stella N. Endogenous cannabinoid signaling. Neurobiol Dis.
1998;5:462–73.
Rangel-López E, Colín-González AL, Paz-Loyola AL, Pinzón E, Torres I, Serratos IN,
Castellanos P, Wajner M, Souza DO, Santamaría A. Cannabinoid receptor agonists reduce the
short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat
brain. Neuroscience. 2015;285:97–106.
Ren SY, Wang Z, Zhang Y, Chen N. Potential application of endocannabinoid system agents in
neuropsychiatric and neurodegenerative diseases – focusing on FAAH/MAGL inhibitors. Acta
Pharmacol Sin. 2020;41:1263–71.
Robson PJ. Therapeutic potential of cannabinoid medicines. Drug Test Anal. 2014;6:24–30.
Rock EM, Goodwin JM, Limebeer CL, Breuer A, Pertwee RG, Mechoulam R, Parker
LA. Interaction between non-psychotropic cannabinoids in marihuana: effect of cannabigerol
(CBG) on the anti-nausea or anti-emetic effects of cannabidiol (CBD) in rats and shrews.
Psychopharmacology. 2011;215:505–12.
Rohleder C, Müller JK. Pharmakologie von cannabis und cannabinoiden. Psychopharma-
kotherapie. 2020;27:105–13.
Russo ER. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic
benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-
resistant conditions? Neuro Endocrinol Lett. 2004;25:31–9.
Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors.
Neurochem Res. 2005;30:1037–43.
Sánchez-Blázquez P, Rodríguez-Muñoz M, Vicente-Sánchez A, Garzón J. Cannabinoid receptors
couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced
by glutamate. Antioxid Redox Signal. 2013;19:1766–82.
Sánchez-Blázquez P, Rodríguez-Muñoz M, Garzón J. The cannabinoid receptor 1 associates with
NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizo-
phrenia. Front Pharmacol. 2014;4:169.
Sanz A. Mitochondrial reactive oxygen species: do they extend or shorten animal lifespan. Biochim
Biophys Acta. 2016;1857:1116–26.
Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL. Cannabinoid receptor 2 (CB2) signals via G-
alpha-s and induces IL-6 and IL-10 cytokine secretion in human primary leukocytes. ACS
Pharmacol Transl Sci. 2019;2:414–28.
Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, Rosenbaum DM. High-resolution
crystal structure of the human CB1 cannabinoid receptor. Nature. 2016;540:602–6.
Sheng Z-H. Mitochondrial trafficking and anchoring in neurons: new insight and implications. J
Cell Biol. 2013;204:1087–98.
Skaper SD, Di Marzo V. Endocannabinoids in nervous system health and disease: the big picture in
a nutshell. Philos Trans R Soc Lond Ser B Biol Sci. 2012;367:3193–200.
The Endocannabinoid System in the Central Nervous System: Emphasis on the. . . 587

Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, Chambers JK, Randall AD, Davis
JB. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1).
Br J Pharmacol. 2000;129:227–30.
Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku
K. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain.
Biochem Biophys Res Commun. 1995;215:89–97.
Sylantyev S, Jensen TP, Ross RA, Rusakov DA. Cannabinoid- and lysophosphatidylinositol-
sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad
Sci. 2013;110:5193–8.
Taylor CT, Moncada S. Nitric oxide, cytochrome C oxidase, and the cellular response to hypoxia.
Arterioscler Thromb Vasc Biol. 2010;30:643–7.
Tripathi RKP. A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential
therapeutic agents. Eur J Med Chem. 2020;188:111953.
Velez-Pardo C, Jimenez-Del-Rio M, Lores-Arnaiz S, Bustamante J. Protective effects of the
synthetic cannabinoids CP55,940 and JWH-015 on rat brain mitochondria upon paraquat
exposure. Neurochem Res. 2010;35:1323–32.
Warby SC, Visscher H, Collins JA, Doty CN, Carter C, Butland SL, Hayden AR, Kanazawa I, Ross
CJ, Hayden MR. HTT haplotypes contribute to differences in Huntington disease prevalence
between Europe and East Asia. Eur J Hum Genet. 2011;19:561–6.
Wilson RI, Kunos G, Nicoll RA. Presynaptic specificity of endocannabinoid signaling in the
hippocampus. Neuron. 2001;31:453–62.
Wolin MS, Alruwaili N, Sharath K. Studies on hypoxic pulmonary vasoconstriction detect a novel
role for the mitochondrial complex I subunit Ndufs2 in controlling peroxide generation for
oxygen-sensing. Circ Res. 2019;124:1683–5.
Xin Q, Xu F, Taylor DH, Zhao J, Wu J. The impact of cannabinoid type 2 receptors (CB2Rs) in
neuroprotection against neurological disorders. Acta Pharmacol Sin. 2020;41:1507–18.
Xiong W, Wu X, Li F, Cheng K, Rice KC, Lovinger DM, Zhang L. A common molecular basis for
exogenous and endogenous cannabinoid potentiation of glycine receptors. J Neurosci. 2012;32:
5200–8.
Xu Z, Lv XA, Dai Q, Ge YQ, Xu J. Acute upregulation of neuronal mitochondrial type-1
cannabinoid receptor and its role in metabolic defects and neuronal apoptosis after TBI. Mol
Brain. 2016;9:75.
Yoshida T, Hashimoto K, Zimmer A, Maejima T, Araishi K, Kano M. The cannabinoid CB1
receptor mediates retrograde signals for depolarization-induced suppression of inhibition in
cerebellar Purkinje cells. J Neurosci. 2002;22:1690–7.
Experimental Psychopharmacology

Nicola Simola

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
Use of Instrumental Techniques in Experimental Psychopharmacology . . . . . . . . . . . . . . . . . . . . . . . 590
Use of Animal Models in Experimental Psychopharmacology: General Considerations . . . . . 593
Overview of Animal Models Used in Experimental Psychopharmacology . . . . . . . . . . . . . . . . . . . . 600
Animal Models Used to Evaluate the Antidepressant Potential of Drugs . . . . . . . . . . . . . . . . . . . . . 600
Animal Models Used to Evaluate the Anxiolytic Potential of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Animal Models Used to Evaluate Rewarding and Addictive Properties of Drugs . . . . . . . . . . . . 604
Animal Models Used to Evaluate the Antimanic Potential of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 606
Animal Models Used to Evaluate the Antipsychotic Potential of Drugs . . . . . . . . . . . . . . . . . . . . . . 607
Animal Models Used to Evaluate the Effects of Drugs on Cognitive and Executive
Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
Animal Models Used to Evaluate New Drugs for the Treatment of Neurodegenerative
Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
Towards Improved Behavioral Animal Models: The Example of Ultrasonic Vocalizations . . . 612
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614

Abstract
Studies of psychopharmacology in experimental animals are a major source of
information on the effects that drugs elicit on superior brain functions. Moreover,
studies of psychopharmacology are a key step in the refinement of existing drugs
and development of new drugs for the treatment of psychiatric diseases, such as
anxiety, depression, and psychosis. The present chapter provides an overview of
the techniques and animal models that can be used in studies of experimental
psychopharmacology and discusses their strengths and limitations.

N. Simola (*)
Department of Biomedical Sciences, University of Cagliari, Monserrato University Campus,
Monserrato, Italy
e-mail: nicola.simola@unica.it; nicola.simola@gmail.com

© Springer Nature Switzerland AG 2022 589

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_3
590 N. Simola

Introduction

Psychopharmacology is the field of pharmacology that investigates the effects of

drugs on superior brain functions, such as cognition, emotion, ideation, and mood.
When performed in the clinical setting, studies of psychopharmacology allow to
evaluate the effects of drugs on emotional state and behavior in healthy individuals
and/or patients suffering from psychiatric or neurological diseases. Evaluation of
psychoactive drugs in humans can rely on interviews, behavioral tests, and rating
scales (Bech 2006), used alone or combined with electrophysiological and/or neu-
roimaging techniques. The latter techniques represent a powerful research tool, as
they can provide valuable information on how drugs modulate neuronal activity,
neurotransmitter release, and other molecular targets in the brain (Coull 2014; Jobert
et al. 2012). Moreover, electrophysiological and neuroimaging techniques can be
used in studies of pharmacokinetics, to investigate how drugs diffuse in and are
eliminated from the brain (Jobert et al. 2012; Moresco and Fazio 2005). Even though
clinical studies are necessary to understand the effects of psychoactive drugs in
humans, they cannot be considered the strategy of choice in psychopharmacology,
due to ethical constraints (Gutheil 2012) and high costs, particularly when neuroim-
aging techniques are involved (Yousem 2014). Accordingly, experimental psycho-
pharmacology remains a first-choice strategy in deciphering the effects of drugs on
superior brain functions.
Studies of experimental psychopharmacology use instrumental techniques and
animal models of disease, alone or in combination, to elucidate how drugs modulate
neurotransmission, neuronal activity, and behavior. Studies of experimental phar-
macology may be performed to obtain preliminary data on the beneficial and/or toxic
effects of drugs, which may serve as basis for subsequent clinical investigations.
Moreover, studies of experimental psychopharmacology may be helpful in elucidat-
ing the mechanism(s) of action of drugs that are already used in human pharmaco-
therapy. Finally, experimental psychopharmacology remains a major strategy in the
development of new drugs for the treatment of anxiety, dementia, depression, and
schizophrenia (Hendriksen and Groenink 2015). Nevertheless, studies of experi-
mental psychopharmacology are not devoid of limitations, mainly because animal
models often fail to adequately and/or exhaustively reproduce human disease.
Indeed, these limitations are reflected in the high drop-off rate that is observed in
phase III clinical trials of new drugs for the treatment of psychiatric and neurological
disorders (Hendriksen and Groenink 2015). The present chapter provides an over-
view of the techniques and animal models that can be used in studies of experimental
psychopharmacology and discusses their strengths and limitations.

Use of Instrumental Techniques in Experimental

Psychopharmacology

Instrumental techniques may be used to investigate the modifications in neurochem-

istry and/or brain function that are induced by psychoactive drugs, and to correlate
those modifications to drugs’ effects on emotional state and behavior in health and
Experimental Psychopharmacology 591

disease. Some instrumental techniques have long been utilized in experiments of

psychopharmacology, whereas others are emerging as promising tools with which to
study the effects of drugs in the brain.
The effects of drugs on the release and turnover of neurotransmitters can be
investigated in experimental animals by means of cerebral microdialysis (Kennedy
2013). Cerebral microdialysis is carried out by implanting in the brain region of
interest sampling probes provided with a semipermeable membrane that can be
crossed by molecules with low molecular weight, such as neurotransmitters and
their metabolites. Sampling probes are then perfused by buffers of varying compo-
sition, and equilibration of concentration gradients drives neurotransmitters from the
extracellular space to the inner side of the semipermeable membrane. Samples are
then collected, and their content is evaluated by means of analytical techniques (i.e.,
high-performance liquid chromatography). Microdialysis can also be used in studies
of pharmacokinetics, in order to evaluate the levels of cerebral metabolites and
disposition of drugs from the brain. Such an evaluation can be performed in both
experimental animals and humans (Shannon et al. 2013). Cerebral microdialysis has
some limitations, since it can usually monitor only one neurotransmitter at a time and
has low spatiotemporal resolution. Nevertheless, technological refinements of
microdialysis have been recently implemented in order to overcome the limitations
of the technique (Kennedy 2013).
Fast-scan cyclic voltammetry (FSCV) is another technique that can be used to
evaluate how drugs affect neurotransmitter release (Rodeberg et al. 2017). In FSCV,
the brain of experimental animals is implanted with carbon-fiber microelectrodes
that are used to induce rapid changes in electric potential, in order to cyclically
oxidize and reduce the compound of interest. This redox cycle results in the
movement of electrons in solution that can be ultimately plotted as a function of
time to generate “voltammograms” which are highly specific and allow to identify
the molecule(s) of interest (Rodeberg et al. 2017). FSCV has some advantages over
microdialysis, since carbon-fiber microelectrodes have rapid scan rates, enabling
measurements on a sub-second time scale. Moreover, small size of microelectrodes
enhances spatial resolution and reduces tissue damage, compared with microdialysis
probes. However, FSCV can only detect molecules that are electro-active (Rodeberg
et al. 2017), which may limit the usefulness of the technique to the study of certain
classes of psychoactive drugs.
Modulation of neuronal activity by psychoactive drugs can also be evaluated in
experimental animals by using techniques of immunochemistry, molecular biology,
and electrophysiology. All those techniques allow to study the effects of acute and
repeated drug administration and may also reveal the occurrence of neuroplasticity
phenomena. Techniques of immunochemistry and molecular biology evaluate how
drugs modify the levels of proteins and/or nucleic acids (i.e., mRNA). Several of
those techniques exist which are commonly used in experiments of psychopharma-
cology, just to mention western blotting, immunoreactivity in tissue slices, in situ
hybridization, and polymerase chain reaction. Techniques of electrophysiology
evaluate the electric properties of neuronal membranes and ion channels and can
be performed either in vitro or in vivo. Use of electrophysiology in awake and
behaving animals is highly relevant to experimental psychopharmacology, as it
592 N. Simola

allows to correlate the behavioral effects of drugs to modifications of electric activity

in the brain. In this regard, it is worth mentioning pharmaco-electroencephalography
(pharmaco-EEG), an electrophysiology-based technique that has greatly contributed
to experimental pharmacology (Drinkenburg et al. 2015).
Pharmaco-EEG consists in the recording of rhythmic electrical activity from the
brain of living organisms treated with drugs and may provide qualitative and
quantitative information about the effects of drugs on the central nervous system.
Moreover, pharmaco-EEG has translational value, since it can also be performed in
humans. Use of pharmaco-EEG in experimental animals, especially rodents, is now
resurgent after a period of decline, since the technique has some notable strengths
(Drinkenburg et al. 2015). Thus, pharmaco-EEG allows the investigation of several
electrophysiological parameters at the preclinical level, such as spectral power,
sleep-wake parameters, and advanced connectivity parameters. Extensive database
from pharmaco-EEG studies are available, which allow to predict the clinical effects
of psychoactive drugs, also regarding pharmacokinetics, interactions with other
drugs, and toxicity (Jobert et al. 2012). Moreover, pharmaco-EEG is easy to imple-
ment, is highly reproducible, and has a more favorable cost/benefit ratio, compared
with neuroimaging techniques (Drinkenburg et al. 2015). Nevertheless, use of
pharmaco-EEG in experimental animals does also have some limitations that should
be carefully considered when translating the results obtained into clinical research.
Thus, animals cannot be instructed to stay awake during recordings, and changes in
arousal are a major confounder in studies of pharmaco-EEG. Moreover, translatabil-
ity of preclinical findings to humans may vary according to the class of drugs
evaluated. For example, preclinical studies of pharmaco-EEG that evaluate anxio-
lytic drugs have a translational value that is high in the case of benzodiazepines and
low in the case of partial agonists of 5HT1A receptors. Time of drug administration
may also affect the translational value of preclinical results obtained with pharmaco-
EEG. Thus, many studies are performed during the day in rodents, which are
nocturnal animals, and this may not adequately reproduce the timing of drug dosing
in the human circadian cycle. Furthermore, differences in cortical development and
thickness may affect the parameters obtained from pharmaco-EEG recordings in
animals, especially when surface electrodes are used (Drinkenburg et al. 2015).
Additional variables that may potentially limit the translational value of preclinical
studies of pharmaco-EEG are age, living conditions, species, sex, strain of animals,
study design, and data analysis. Nevertheless, it is possible to reduce the impact of all
the abovementioned factors on preclinical studies of pharmaco-EEG by ensuring
standardization of procedures across laboratories and by taking into account the
influence of sleep-wake cycle and chronopharmacology on the results obtained
(Drinkenburg et al. 2015).
Studies of experimental psychopharmacology are also continuously exploring the
potential of novel techniques of molecular and cellular biology, as well as of
metabolomics, proteomics, and neuroimaging in experimental animals. Indeed,
using those techniques may allow to thoroughly characterize molecular pathways
of disease, which may be instrumental in setting up effective translational animal
models for psychiatric disorders. Optogenetics is another emerging technique that
Experimental Psychopharmacology 593

appears highly relevant for experimental psychopharmacology, which uses light to

activate selected populations of neurons. Combination of optogenetics and genomics
may offer the possibility to map neural substrates and identify cellular and molecular
pathways involved in pathological processes. Achieving this target may be a key
step in the development of new effective drugs for the treatment of psychiatric
diseases. Nevertheless, the potential of optogenetics in the field of drug discovery
is somehow limited by current technical limitations concerning instrumentation as
well as acquisition and analysis of data (Zhang and Cohen 2017).

Use of Animal Models in Experimental Psychopharmacology:

General Considerations

Several animal models can be used in studies of experimental psychopharmacology.

However, choosing the best animal model is complex, since each model has poten-
tial strengths and limitations that must be considered in order to allow reliability and
reproducibility of results (McGonigle 2014).
A major limitation inherent in animal models is the inability to reproduce some of
the effects that psychoactive drugs may induce in humans, such as modifications in
verbal function and ideation. Besides, animal models of psychiatric and neurological
disorders often fail to accurately and/or exhaustively mimic the features of human
disease (Sarnyai et al. 2011). In this regard, it should be considered that the etiology
of psychiatric and neurological disorders is often unknown and/or multifactorial,
involving interactions among environment, gender, genetic background, and life-
styles. Hence, it may be difficult for an animal model to recapitulate all the factors
that trigger and sustain human brain disease. Moreover, it is noteworthy that
diagnosis of psychiatric and neurological diseases is complex, and many subcate-
gories of these diseases exist which may even feature mutually opposed symptoms
(i.e., agitation or catatonia in the case of schizophrenia). Furthermore, experimental
animals in many cases do not display the same behavioral and emotional responses
that are observed in humans. Accordingly, several animal models of neurological
and psychiatric disease use readouts that have limited translational value. In other
words, certain behavioral changes that are measured in animal models (i.e., modi-
fication in exploratory activity) indicate that modifications have occurred in brain
function and emotional state of animals, but do not necessarily reproduce the
behavioral and emotional symptoms of human disease.
Generally, animal models used in experiments of psychopharmacology should
fulfill certain validating criteria, which were originally defined by Willner (1984) and
have later been refined. Those criteria indicate how accurately a model can repro-
duce the etiology and symptoms of human disease and how much a model is suited
for evaluating and validating new drugs. Ideally, animal models should possess the
so-called face validity, predictive validity, and construct validity. However, most of
the available animal models fulfill only one or two of those criteria, even in part.
Such a limitation does not necessarily prevent an animal model from being used in
594 N. Simola

experiments of psychopharmacology, but requires that the results obtained are

interpreted with caution.
Animal models can be said to possess face validity in the first instance when they
reproduce in animals one or more symptoms of a specific human disease. In this
regard, an animal model with marked face validity is the prepulse inhibition (PPI)
model of schizophrenia, which reproduces in animals the deficits in an operational
measure of sensorimotor gating, the PPI, that can be observed in schizophrenic
patients (Geyer et al. 2001). Moreover, animal models can be said to possess face
validity when they use readouts that are thought to reproduce the behavioral symp-
toms and/or neurochemical changes featuring a given disease. However, this defini-
tion is necessarily subjective, as it is based on the assumption, yet not provable, that
what is observed in animals reflects what happens in human disease. In this regard,
an example of animal model with face validity may be locomotor sensitization
observed in rodents repeatedly treated with drugs of abuse. Locomotor sensitization
is thought to reflect an increase in the appetitive and incentive properties of drugs
with repeated experience, which has been proposed as a key mechanism in addiction
(Robinson and Berridge 2000). However, the occurrence of behavioral sensitization
in human addicts and its involvement in drug dependence are disputed
(Vanderschuren and Pierce 2010).
Predictive validity is the criterion defining animal models that can detect drugs
that either act by means of established mechanisms or are clinically effective on the
disease that is reproduced by the specific model. An exemplary model that evaluates
drugs acting by means of established mechanisms is the catalepsy rodent model used
in the screening of typical antipsychotics (Hoffman and Donovan 1995). Typical
antipsychotics exert their therapeutic effects by antagonizing dopamine D2 receptors
in limbic and cortical regions of the brain (Lidow et al. 1998). However, typical
antipsychotics also antagonize dopamine D2 receptors in the nigrostriatal system,
which causes extrapyramidal side effects (Lidow et al. 1998). In rodents, extrapyra-
midal effects of typical antipsychotics may be manifested as catalepsy, a condition
featuring freezing, muscular stiffness, and immobility (Hoffman and Donovan
1995). Drugs that antagonize dopamine D2 receptors all induce catalepsy in rodents,
provided they possess pharmacokinetic properties that allow their penetration in the
brain. Accordingly, the catalepsy model is commonly used to detect the “typical”
profile of novel antipsychotic drugs (Hoffman and Donovan 1995). On the other
hand, examples of predictive models that recognize the effects of drugs on human
disease are the forced swim test (FST) and the tail suspension test (TST), which are
used in the screening of novel antidepressants (Porsolt et al. 1977; Steru et al. 1985).
Indeed, the FST and TST can detect a wide array of molecules with supposed
antidepressant activity, irrespective of the chemical class and mechanisms of action.
Animal models with predictive validity have significantly contributed to the devel-
opment of new drugs for the treatment of psychiatric disorders. At the same time, it
should be considered that experiments performed in animal models with predictive
validity may have low levels of specificity, which may lead to considerable rates of
Experimental Psychopharmacology 595

false-negative or false-positive findings. Even in this case, the catalepsy rodent

model is exemplary, since it may not easily detect drugs that are effective as
antipsychotics but primarily act by means of mechanisms other than the antagonism
of dopamine D2 receptors (i.e., clozapine) (Hoffman and Donovan 1995). Besides, it
should be noted that catalepsy may be induced in rodents also by drugs that neither
have antipsychotic potential nor act as dopamine D2 receptor antagonists (i.e.,
morphine) (Fischer et al. 2002).
Animal models are said to have construct validity when they share, or are
assumed to, common pathological mechanisms with human disease and reproduce
at least one clinical feature of disease. The criterion of construct validity can
straightforwardly be applied to models that reproduce in animals human diseases
with known etiology. A striking example in this regard are mouse models of
Huntington’s disease, which is a genetic neurodegenerative disorder caused by a
trinucleotide repeat expansion mutation in the coding region of the gene for the
protein called “huntingtin” (Brooks et al. 2012). However, most animal models used
in studies of experimental psychopharmacology can fulfill the criterion of construct
validity only partially, since the etiology of psychiatric and neurological diseases is
largely unknown. An example of an animal model of psychiatric disease with
appreciable construct validity is the chronic mild stress (CMS) rodent model of
depression (Willner 1997). In the CMS model, rodents manifest a series of behaviors
that are reminiscent of symptoms featuring human depression, most notably a
generalized decrease in responsiveness to rewards which is comparable to anhedo-
nia, the core symptom of the melancholic subtype of major depressive disorder.
Moreover, in the CMS model, rodents may eventually develop a depressive-like
phenotype after repeated exposure to stressful stimuli, and repeated stress experience
is regarded as a possible causative factor in human depression (Willner 1997).
In addition to validity criteria, some practical aspects concerning animal models
should be carefully considered when setting up experiments of psychopharmacol-
ogy. Those aspects may be interconnected and involve the type of information the
models can provide in terms of drug effects on behavior and/or neurochemistry, ease
of model implementation, reproducibility of results, animal welfare, and overall
costs of experimentation. Another crucial aspect to be considered in experiments
of psychopharmacology concerns the type of animals, since the effects of drugs may
significant differ across species and strains. Moreover, species differences in brain
structure and connectivity exist, which may eventually impact the repertoire of
behaviors evaluated in animal models. For example, rodents can all perform a variety
of tasks that are based on exploratory behavior, nose-poking, lever-pressing, object
recognition, and platform location, but inter- and intraspecies differences in some of
these behaviors may exist. Finally, it is noteworthy that factors like age, body weight,
gender, and nourishment may all influence behaviors that are evaluated in animal
models of neurological and psychiatric diseases (D’Hooge and De Deyn 2001;
Bogdanova et al. 2013; Kokras and Dalla 2014). Table 1 summarizes the strengths
and limitations of the experimental models discussed in the present chapter.
596 N. Simola

Table 1 Strengths and limitations of some animal models commonly used in studies of
psychopharmacology
Disease Model Major strengths Major limitations
Anxiety Conditioned models Modifications in the May not always
(i.e., conditioned foot experimental protocol discriminate between
shocks) may allow to study anxiety and fear
different types of
anxiety (i.e.,
anticipatory anxiety,
discomfort caused by
an aversive event)
Reproducible
Anxiety Conflict models (i.e., Reproducible Employ deprivation
Vogel test) of food or water
which may interfere
with the emotional
state of the animals
and with the effects
of the drugs
evaluated
Anxiety Maze-based models - Cost-effective - Are based on
(i.e., elevated plus - Easy to implement exploratory drive
maze; elevated zero - Reproducible - Should not be
maze) replicated in the
same animal to
preserve accuracy
of results
Anxiety Models based on - Cost-effective The specificity of
defensive burying (i. - Easy to implement these models to
e., conditioned probe - Reproducible anxiety is questioned
burying; marble
burying)
Depression Chronic mild stress - Induces behavioral - May be time-
changes reminiscent consuming and
of the symptoms of difficult to
human depression implement
that are reverted by - Results may have
chronic, but not low reproducibility
acute, treatment with across laboratories
antidepressants
- Fulfills all the
validity criteria of
animal models
- May reproduce the
anhedonia observed
in human depression
(continued)
Experimental Psychopharmacology 597

Table 1 (continued)
Disease Model Major strengths Major limitations
Depression Learned helplessness May reproduce certain - May be sensitive to
aspects of the so- acute antidepressants
called stress-coping - The results obtained
depression may be significantly
affected by the
individual variability
in developing the
learned helplessness
behavior and/or by
the individual
sensitivity to pain
induced by foot
shocks
Depression Models based on - Cost-effective - Are sensitive to the
acute stress (i.e., - Easy to implement acute administration
forced swim test, tail - Reproducible of antidepressant
suspension test) drugs
- The readout of these
models (immobility)
is based on motor
activity
- The significance of
the immobility
measured in these
models is disputed
Depression Olfactory bulbectomy Induces behavioral - Is based on the
changes that are induction of
reverted by chronic, hyperactivity,
but not acute, which is not a
treatment with symptom of human
antidepressants depression
- The neurobiological
mechanisms of
hyperactivity
measured in this
model are unknown
Depression Social defeat - Induces behavioral - Results may have
changes reminiscent low reproducibility
of the symptoms of across laboratories
human depression - Specificity of the
that are reverted by model to depression
chronic, but not is questioned
acute, treatment with
antidepressants
- Induces modifications
in the hypothalamic-
pituitary-adrenal axis
reminiscent of those
featuring human
depression
(continued)
598 N. Simola

Table 1 (continued)
Disease Model Major strengths Major limitations
Drug addiction Conditioned models - Cost-effective Drugs that induce
(i.e., conditioned - Easy to implement conditioning may not
place preference; - Reproducible necessarily have
conditioned taste addiction potential
aversion)
Drug addiction Locomotor - Cost-effective Specificity of the
sensitization - Easy to implement model to drug
- Reproducible addiction is
questioned
Drug addiction Models based on - Drug self- - Interpretation of
operant behavior (i.e., administration results may be
drug self- predicts the abuse affected by
administration; drug potential of drugs differences in
discrimination) - Drug self- preclinical and
administration clinical endpoints
reproduces in used to define drug
animals several addiction,
stages of human abstinence, and
addiction relapse
- Drug discrimination - May be time-
allows to study the consuming and
subjective effects of difficult to
drugs implement
- Possess marked
translational value
Impairment in Models based on non- - Allow to measure - Are influenced by
cognitive and operant behavior learning, nonspatial exploratory drive
executive functions (i.e., object memory, and spatial and/or lateralization
recognition, memory of animals
exploration of mazes) - Cost-effective - May require the use
- Easy to implement of stressful stimuli
- Reproducible (i.e., food
deprivation,
swimming) that may
interfere with the
emotional state of
the animals
- Use readouts that
may have limited
translational value
Impairment in Models based on - Allow to measure - Implementation may
cognitive and operant behavior (i.e., attention, motivation, be complex and
executive functions go/no-go, stop-signal, and impulsivity time-consuming
five-choice serial - Are analogous to or - Require extensive
reaction time task) derived from tests training of animals
that are used to - The predictive
measure cognitive validity of these
and executive models may greatly
functions in humans vary according to
- Possess marked the class of drugs
translational value studied
(continued)
Experimental Psychopharmacology 599

Table 1 (continued)
Disease Model Major strengths Major limitations
Mania Environmental - May induce in - In the sleep
models (i.e., resident- animals behavioral deprivation model
intruder; sleep alterations observed animals are exposed
deprivation) in human mania (i.e., to stressful stimuli
aggressiveness, (i.e., isolation) that
agitation) may affect the
- The mania-like emotional state
phenotype can be - Sleep deprivation
reverted by chronic does not induce
treatment with manic-like states in
clinically effective healthy humans
antimanic drugs
Mania Pharmacological - Easy to implement - Are based solely on
models (i.e., - Sensitive to the acute hyperactivity
amphetamine, administration of - Limited and
ouabain, quinpirole) clinically effective contrasting evidence
antimanic drugs exists on the effects
of chronic treatment
with antimanic
drugs in these
models
Neurodegenerative Toxin-based models - Easy to implement Neurodegeneration
diseases - Cost-effective obtained in these
- Induce phenotypes in models is usually
animals that based on a single
effectively mimic one mechanism of
or more symptoms of toxicity
human disease
- Reproducible
Psychosis Catalepsy model - Easy to implement - Does not reproduce
- Cost-effective in animals any
- Reproducible symptoms of
human psychosis
- Possesses only
predictive validity
that allows to
identify the “typical
profile” of
antipsychotic drugs
Psychosis Neurodevelopmental - Are consistent with - Difficult to
models (i.e., the hypothesis that implement
hippocampal neonatal schizophrenia is a - Low reproducibility
lesion; perinatal disorder of of results
insults) neurodevelopment - Specificity of these
- Reproduce in models to psychosis
animals anatomical is questioned
and behavioral
deficits that mimic
the abnormalities
featuring human
schizophrenia
(continued)
600 N. Simola

Table 1 (continued)
Disease Model Major strengths Major limitations
Psychosis Pharmacological - Easy to implement Are based on
models (i.e., - Cost-effective behavioral readouts
dopaminomimetic - Reproducible that reproduce in
drugs, glutamate animals
receptor antagonists) predominantly the
“positive” symptoms
of human
schizophrenia

Overview of Animal Models Used in Experimental

Psychopharmacology

Experimental models used in studies of preclinical psychopharmacology aim to

reproduce human disease in animals by means of various strategies, for example,
exposure to stress and administration of drugs or toxins. A wealth of genetic animal
models of disease also exist which are widely used in experiments of psychophar-
macology. However, genetic animal models do also have some limitations, such as
differences in genetic background among species and strains, as well as manifesta-
tion of compensatory adaptive changes (Cryan and Mombereau 2004). These lim-
itations may complicate the interpretation of behavioral results; accordingly, the
validity of many genetic animal models of brain disease is questioned. This section
provides an overview of the animal models most commonly used in experiments of
psychopharmacology and discusses their strengths and limitations. For the sake of
conciseness, genetic animal models of disease are not discussed, given their high
number and potential inherent limitations.

Animal Models Used to Evaluate the Antidepressant Potential of

Drugs

The most common animal models used for studying the antidepressant potential of
drugs are based on the exposure of rodents to stress, either acute or repeated, in order
to induce changes in behavior that are thought to reproduce certain symptoms
featuring human depression.
Experimental models of depression that use acute exposure to stress are the FST
and the TST. In the FST, rats or mice are placed in a water cylinder (Porsolt et al.
1977), whereas in the TST mice are hung by the tail upside down (Steru et al. 1985).
In either model, the animal will initially try to escape from the stressful situation, but
it will eventually keep an immobile posture as soon as it realizes that the situation is
inescapable. Immobile posture of rodents in the FST and TST is often referred to as
“behavioral despair” and can be attenuated by clinically effective antidepressant
Experimental Psychopharmacology 601

drugs (Porsolt et al. 1977; Steru et al. 1985). On this basis, drugs that reduce
immobility in the FST and TST are envisaged as potential antidepressants (Cryan
et al. 2005; McGonigle 2014). Both the FST and TST are easy to implement,
cost-effective, and allow reproducibility of results but do also have some limitations
(Cryan et al. 2005; McGonigle 2014). Thus, the FST and TST use a readout that is
based on decreased motor activity. Accordingly, drugs that increase or decrease
motor activity may lead to false-positive or false-negative results in those models.
Moreover, the significance of immobility observed in the FST and TST is disputed.
Immobility has originally been proposed to mimic symptoms of despair that may be
observed in human depression (Porsolt et al. 1977; Steru et al. 1985). However,
others have questioned this hypothesis and have suggested that immobility may be
a strategy that rodents use to cope with stressful stimuli (Cryan et al. 2005).
Additionally, it has been hypothesized that immobility may be analogous to reluc-
tance of depressed patients to maintain sustained expenditure of effort, rather than
to despair (Cryan et al. 2005). Furthermore, immobility observed in the FST and
TST can be reversed by the acute administration of antidepressants, which contrasts
with clinical evidence showing that the therapeutic effects of antidepressants
emerge only after repeated treatment (Cryan et al. 2005). Finally, the FST and
TST may have varying sensitivity towards different classes of antidepressants. For
example, in mice the TST may be more effective in detecting the efficacy of
selective serotonin reuptake inhibitors (SSRI), compared with the FST (Cryan
et al. 2005).
Experimental models of depression that use repeated exposure to stress are the
CMS and the chronic social stress. In the CMS model, rodents are exposed for a
period of 3–4 consecutive weeks to unpredictable stressful stimuli of mild intensity
and various nature (i.e., temporary food or water deprivation, soiled cage, small
modifications in light or temperature) (Willner 1997). Rodents subjected to the CMS
model eventually manifest a series of behavioral changes that are thought to mimic
symptoms of human depression, for example, reduction in grooming, exploratory,
and sexual behaviors (Willner 1997). Moreover, rodents subjected to the CMS
model display a decreased responsiveness to rewards, which is thought to model
anhedonia observed in major depression (Willner 1997). For example, rodents
subjected to CMS drink lower amounts of solutions containing 1% sucrose, com-
pared with non-stressed animals. Moreover, rats subjected to the CMS and treated
with amphetamine emit lower numbers of 50-kHz ultrasonic vocalizations (USVs),
a behavioral marker of positive emotional states (Brudzynski 2013), compared with
amphetamine-treated rats not exposed to stress (Kõiv et al. 2016). Finally, behavioral
changes observed in the CMS model can be effectively reversed by repeated, but not
acute, administration of antidepressant drugs with clinical efficacy. Based on all the
above considerations, CMS is considered a highly valuable animal model of depres-
sion, since it shows construct validity, face validity, and predictive validity (Willner
1997). Nevertheless, the potential of the CMS model in the study of antidepressant
drugs may be limited by time-demanding implementation and difficulties in
reproducing results across laboratories (Micale et al. 2013). Changes in behavior
similar to those featuring the CMS model can also be observed in rodents subjected
602 N. Simola

to repeated and short exposures to a dominant conspecific in a resident-intruder

paradigm, which is known as the social defeat (or social stress) model of depression
(Keeney and Hogg 1999). Interestingly, the social defeat model of depression may
also induce modifications in the function of the hypothalamic-pituitary-adrenal axis
reminiscent of those that may be observed in depressed patients (Page et al. 2016).
Behavioral changes featuring the social defeat model can be reversed by repeated
treatment with antidepressants (Venzala et al. 2012). However, the potential of the
social defeat model in studies of experimental psychopharmacology may be limited
by issues related to implementation and reproducibility of results, similar to the CMS
model (McGonigle 2014). Finally, the specificity of social defeat as a model of
depression has been questioned, and it has been proposed that social defeat also
recapitulates behavioral aspects relevant to anxiety-related disorders (Venzala et al.
2012).
The learned helplessness (LH) and the olfactory bulbectomy (OBX) are two other
popular animal models used to study antidepressant drugs. The LH model
is performed in rodents and includes two phases: in the first phase, the animal is
exposed to inescapable foot shocks, whereas in the second phase the animal is
exposed to escapable shocks of same intensity. The LH model is based on the
principle that animals quickly learn the inevitability of inescapable shocks, and do
not attempt to escape from shocks when subsequently put in a situation that allows
them to do so (Seligman and Beagley 1975). The LH model is thought to reproduce
in animals a situation of “stress-coping depression,” which may be triggered by
exposure to unpredictable and uncontrollable events that may lead to unwanted
consequences (Micale et al. 2013). Acute and/or repeated treatment with clinically
effective antidepressant drugs increases the number of escapes in the LH model.
Accordingly, drugs are considered to have antidepressant potential if they elevate the
number of escapes in the LH model (Micale et al. 2013). However, it should be noted
that results obtained in the LH model may be affected by interindividual variability
in the development of LH behavior and by sensitivity to pain induced by foot shocks
(Micale et al. 2013).
The OBX model consists in the surgical ablation of olfactory bulbs in rodents,
which induces a series of behavioral changes, like reduced sexual activity in males,
reduced fostering activity in females, cognitive decline, and hyperactivity
(Hendriksen et al. 2015). Several classes of clinically effective antidepressants
reduce hyperactivity in the OBX model, which suggests that the model may be
suited for the screening of novel antidepressants (Hendriksen et al. 2015). Moreover,
counteraction of hyperactivity can be observed after repeated but not acute treatment
with antidepressants, which gives the OBX model high translational value
(Hendriksen et al. 2015). Nevertheless, it should be noted that hyperactivity
observed in the OBX model is not a symptom of depression in humans. Moreover,
using the OBX model in the screening of antidepressants may lead to false-negative
findings, since the mechanism(s) by which antidepressants reduce hyperactivity are
not known. Hence, new drugs that have antidepressant potential but do not act on the
same circuits that regulate hyperactivity could be erroneously dismissed (Hendriksen
et al. 2015).
Experimental Psychopharmacology 603

Animal Models Used to Evaluate the Anxiolytic Potential of Drugs

Experimental models of anxiety are all based on the induction of a state of conflict in
animals, which can be defined as the condition where an organism is both attracted
and repelled by the same stimulus (Ito and Lee 2016). Nevertheless, experimental
models of anxiety use different strategies to induce conflict in animals and can be
broadly categorized into ethological models, conflict-based models properly defined,
and models based on conditioned learning (McGonigle 2014).
Ethological models of anxiety evaluate spontaneous behaviors that animals
perform either in normal conditions or in the presence of natural aversive stimuli.
Very popular ethological models of anxiety are the elevated plus maze, the elevated
zero maze, the open field, and the light-dark compartment test. Those models
measure the reduction in the exploratory drive of rodents for novel environments
under conditions of bright light and/or elevation from the floor that may ultimately
cause an anxiety-like state of conflict (reviewed in Harro 2018). Two other popular
ethological models used in the screening of anxiolytic drugs are the social interaction
test and the defensive burying (reviewed in Harro 2018). The social interaction test
evaluates the time spent in nonaggressive contacts by two unfamiliar rats that are
placed together in a novel environment under bright light, whereas the defensive
burying measures the tendency of rodents to bury objects (i.e., marbles) that do not
have any emotional values. A conditioned version of the defensive burying model
also exists which evaluates the tendency of rodents to bury a non-electrified probe
that was previously associated with the delivery of shocks. However, the signifi-
cance of defensive burying is disputed, since the model has been suggested to better
recapitulate the features of obsessive-compulsive disorder rather than anxiety
(Albelda and Joel 2012). Differently from ethological models, conflict models of
anxiety do not evaluate the animals’ spontaneous behavior but rather performance of
motivated behaviors that are punished by mild electric shocks. The most common
model in this category is the Vogel test, which measures the suppression of drinking
in water-deprived rodents with free access to a bottle provided with an electrified
spout (Vogel et al. 1971). Finally, conditioned models of anxiety are based on the
Pavlovian association between a neutral stimulus, such as a light, and an aversive
stimulus, usually an electric shock (reviewed in Harro 2018). Animals that are
trained in conditioned paradigms of anxiety and subsequently exposed to the
formerly neutral stimulus display anticipatory behaviors which are thought to
indicate an anxiety-like state, such as increased levels of freezing behavior, startle
response, and emission of 22-kHz USVs, a behavioral marker of negative emotional
states in rats (Brudzynski 2013).
Several classes of drugs with clinical efficacy on anxiety attenuate behavioral
abnormalities in most of the abovementioned models, which makes those models
suited for the development of new anxiolytic agents. Nevertheless, animal models of
anxiety may have varying sensitivity for different classes of drugs with putative
anxiolytic potential. For example, the defensive burying test may disclose the
anxiolytic potential of SSRIs more effectively than other tests, like the elevated
plus maze (McGonigle 2014). Hence, a careful selection of animal models should be
604 N. Simola

done when evaluating novel anxiolytic agents, in order not to dismiss drugs that
may be potentially effective. Finally, caution is advisable when using conflict and
conditioned animal models which rely on procedures such as delivery of foot shocks,
presentation of visual or audio stimuli, and deprivation of water or food. In fact,
drugs that interfere with one or more sensorial processes may lead to false-positive or
false-negative findings in those models.

Animal Models Used to Evaluate Rewarding and Addictive

Properties of Drugs

Studies in experimental animals are still a major source of information about the
subjective effects of drugs that possess rewarding and addictive properties. Animal
models used in this respect can be based on the evaluation of locomotor, condi-
tioned, or operant behavior.
Several drugs that possess rewarding properties stimulate locomotor activity in
experimental animals after acute administration, an effect that depends on the
activation of striatal and limbic dopaminergic transmission (Wise 1987). Moreover,
rodents repeatedly and intermittently treated with addictive drugs eventually develop
the so-called locomotor sensitization, which consists in the progressive increase of
locomotor activity in response to escalating administrations of the same dose of a
given drug. Locomotor sensitization has been envisaged as a behavioral correlate of
the neuroadaptive changes that addictive drugs induce in the dopaminergic circuits
that regulate reward and motivation (Robinson and Berridge 2000). On this basis,
locomotor sensitization has long been used as an animal model with which to study
drug addiction and its neurobiological mechanisms. However, it is still unclear
whether human addicts develop sensitization to the behavioral effects of drugs and
whether behavioral sensitization plays a role in drug dependence (Vanderschuren
and Pierce 2010). Moreover, it should be considered that locomotor sensitization
may also reflect the psychotomimetic and/or manic potential of drugs, particularly
when psychostimulants are administered (Seeman 2009a; Logan and McClung
2016). In fact, rodents that develop sensitization to the locomotor stimulating effects
of psychostimulants also display neurochemical changes similar to those observed in
experimental models of schizophrenia (Seeman 2009a).
Another popular rodent model that is used to study the rewarding and addictive
properties of drugs is the conditioned place preference (CPP), which is based on
drug-induced conditioning. The CPP model is performed in an apparatus made of
two compartments with different visual and/or tactile characteristics and involves a
conditioning phase and an expression phase. In the conditioning phase, whose
duration varies according to the drug tested, rodents are confined on alternate days
in either compartment of the apparatus and treated with the drug or its vehicle,
respectively. In the expression phase, rodents are left free to explore the whole
apparatus and should spend more time in the compartment previously paired with
drug administration. The preference of rodents for the drug-paired compartment in
the CPP model depends on the conditioning properties of drugs and is considered
Experimental Psychopharmacology 605

a behavioral marker of the positive effects that drugs may induce on the emotional
state (Tzschentke 1998). Nevertheless, it should be noted that drugs that induce CPP
definitively possess rewarding properties but do not necessarily have addiction poten-
tial (Tzschentke 1998). Conditioned behavior of rodents can also be used to study the
aversive properties of drugs in the conditioned place aversion model, which is similar
to CPP but evaluates avoidance of rodents for the drug-paired compartment
(Tzschentke 1998). Another popular rodent model used to evaluate the aversive
properties of drugs is the conditioned taste aversion, which evaluates the avoidance
of palatable fluids (i.e., solutions containing saccharin) that were previously paired
with the administration of drugs with aversive properties (Davis and Riley 2010).
Rewarding and addictive properties of drugs can also be evaluated by means of
paradigms of operant behavior, and a very reliable model in this regard is drug self-
administration. Several studies have demonstrated that rodents and primates may
perform drug self-administration, which can be based either on the principle of
operant reinforcement or on non-operant behavior (i.e., in the case of ethanol)
(reviewed in Sanchis-Segura and Spanagel 2006). The drug self-administration
model may reproduce in animals several stages of drug dependence observed in
human addicts and may predict the abuse potential of drugs. In fact, experimental
animals readily self-administer drugs that are highly addictive in humans (i.e.,
cocaine) but scarcely self-administer drugs that have a negligible abuse potential
(i.e., caffeine). The drug discrimination model is also widely used to evaluate the
rewarding and addictive properties of drugs (Stolerman et al. 2011) and involves a
training phase and a testing phase. In the training phase, animals must learn to
discriminate between the subjective effects of drugs and saline in a reinforced lever-
pressing procedure, where food is usually used as reinforcer. In the testing phase,
animals will press the lever associated with food in response to the injection of a drug
that possesses subjective effects similar to those of the drug used in the training
phase. Animals readily discriminate rewarding drugs from saline, and drugs with
similar subjective properties (i.e., amphetamine and cocaine) fully substitute for each
other in the drug discrimination model (Stolerman et al. 2011). Another model of
operant behavior that is widely used in studies of the rewarding and addictive
properties of drugs is the intracranial self-stimulation. In that model, rodents are
trained to self-administer electric pulses in brain regions that regulate reward and
motivated behavior. Pretreatment of animals with drugs that possess rewarding and/
or addictive properties reduces the intensity of pulses that sustain intracranial self-
stimulation behavior (reviewed in Sanchis-Segura and Spanagel 2006).
Animal models have greatly contributed to elucidate the neurobiological bases of
goal-directed behavior and drug addiction, and novel animal models are being
developed in order to investigate non-pharmacological human addictions, such as
pathological gambling (van den Bos et al. 2014). In addition, it is noteworthy that the
drug discrimination and drug self-administration models can be implemented in
humans, which confers them high translational value. Finally, animal models have
been extensively used to investigate new therapeutics for drug addiction although
with limited success, likely due to differences in preclinical and clinical endpoints
used to define drug addiction, abstinence, and relapse (Paterson 2011).
606 N. Simola

Animal Models Used to Evaluate the Antimanic Potential of Drugs

Experimental models used to reproduce mania in animals can be broadly categorized

in pharmacological and environmental (reviewed in Logan and McClung 2016).
The first and most widely used pharmacological model of mania is the evaluation
of hyperactivity in rodents treated with amphetamine. The model was developed on
the basis of the clinical evidence that amphetamine and other psychostimulants may
induce a state that resembles mania in healthy subjects, and that amphetamine may
induce or exacerbate manic episodes in bipolar patients (reviewed in Logan and
McClung 2016). Amphetamine can be administered either acutely or repeatedly in
order to reproduce a mania-like state in rodents. In the acute model, amphetamine-
induced hyperactivity can be attenuated by single administration of lithium or
tamoxifen, two drugs that are clinically effective as mood stabilizers (Cechinel-
Recco et al. 2012). However, others have reported that chronic administration of
lithium does not reduce hyperactivity in rats treated with acute amphetamine
(Cappeliez and Moore 1990), which is in contrast with the clinical evidence that
chronic treatment with lithium stabilizes mood in bipolar patients. Moreover, valid-
ity of acute amphetamine administration as a model of mania is disputed, since the
paradigm reproduces in animals the hyperactivity but not the other symptoms
observed in bipolar patients. It has also been suggested that locomotor sensitization
induced by repeated treatment with amphetamine may be a better model of mania,
compared with acute amphetamine administration. Thus, repeated administration of
amphetamine may induce neuroplastic changes in dopamine systems, and aberrant
dopaminergic neuroplasticity has been envisaged as an etiological mechanism of
mania (de Bartolomeis et al. 2014). Moreover, locomotor sensitization in rats
repeatedly treated with amphetamine may be attenuated by acute administration of
drugs that are clinically effective as mood stabilizers, such as carbamazepine,
lamotrigine, and lithium (Dencker and Husum 2010). However, limited evidence
is available on the effects that repeated administration of antimanic drugs has on
locomotor sensitization induced by amphetamine. Other pharmacological models of
mania have been proposed, such as combined administration of amphetamine and
chlordiazepoxide, intracerebroventricular administration of ouabain, and acute
administration of quinpirole. However, the validity of those models is disputed,
since they merely evaluate hyperactivity and may be sensitive to drugs that are not
clinically effective as mood stabilizers or even induce manic episodes (reviewed in
Logan and McClung 2016).
A mania-like state can be induced in rodents also by means of environmental
manipulations. The sleep deprivation model of mania has been developed based on
the clinical evidence that sleep deprivation may trigger manic episodes in bipolar
patients (reviewed in Logan and McClung 2016). In order to induce sleep depriva-
tion, rodents are individually placed on a narrow platform surrounded by water for
72 consecutive hours (Gessa et al. 1995). When on the platform, animals must stay
awake in order to avoid falling into the water, which eventually results in sleep
deprivation. Rodents subjected to sleep deprivation display a series of behavioral
abnormalities reminiscent of symptoms observed in bipolar patients, such as
Experimental Psychopharmacology 607

aggressive behavior, hyperactivity, and insomnia, that can be attenuated by chronic

treatment with lithium (Gessa et al. 1995). Taken together, these findings suggest
that the sleep deprivation model is highly relevant in the study of mania, as it may
fulfill the criteria of construct validity, face validity, and predictive validity.
Nevertheless, the sleep deprivation model has some inherent limitations. First,
sleep deprivation does not induce long-lasting manic episodes in healthy humans.
Moreover, rodents subjected to the sleep deprivation model are also exposed to
stressors, like isolation and immobilization, which could themselves modify the
emotional state and behavior (reviewed in Logan and McClung 2016). Another
animal model of mania based on environmental manipulations is the variant of the
resident-intruder model of depression that evaluates aggressive behavior in the
dominant rodent, instead of social defeat in the submissive rodent (Einat 2007).
The resident-intruder model may recapitulate the agitation and aggressive behavior
that can be observed in bipolar patients. Moreover, validity of the resident-intruder
model in the preclinical study of mania may be substantiated by the finding that
repeated treatment with lithium or valproate reduces aggressive behavior in the
dominant rodent without affecting nonaggressive social interactions (Einat 2007).

Animal Models Used to Evaluate the Antipsychotic Potential of

Drugs

Animal models used to evaluate the antipsychotic potential of drugs can be broadly
subdivided in pharmacological and developmental (reviewed in Jones et al. 2011).
Pharmacological models of psychosis rely on the use of drugs that act on
dopaminergic or glutamatergic receptors, in order to reproduce in animals certain
behavioral abnormalities that are reminiscent of the symptoms of human psychosis.
This approach has both a theoretical and an empirical rationale. Thus, it has been
hypothesized that schizophrenia may stem from hyperfunction of the dopaminergic
mesolimbic system and hypofunction of the glutamatergic system (Seeman 2009b).
Besides, overt psychotic episodes have been consistently documented in healthy
humans after the intake of either dopaminomimetic psychostimulants (i.e., amphet-
amines, cocaine) or phencyclidine (PCP), an antagonist of glutamate N-methyl-D-
aspartate (NMDA) receptors (Steinpreis 1996). Models of psychosis that rely on
dopaminomimetic drugs use acute or repeated administration of either amphetamine
or apomorphine in rodents, in order to induce hyperactivity and stereotyped behavior
and/or to impair associative learning and avoidance behavior (reviewed in Jones
et al. 2011). Similar to what observed in models based on dopaminomimetic agents,
acute or repeated administration of PCP may induce hyperactivity in rodents, which
is envisaged to reproduce the hyperactivity and agitation featuring human psychosis
(Steinpreis 1996; Bubeníková-Valesová et al. 2008). Hyperactivity has also been
observed in rodents treated with other NMDA receptor antagonists, like dizocilpine
and ketamine (Bubeníková-Valesová et al. 2008). Moreover, administration of either
dopaminomimetic drugs or NMDA receptor antagonists to experimental animals
induces deficits in PPI, providing an experimental model with marked face validity
608 N. Simola

that reproduces a deficit in sensorimotor gating that may be observed in patients with
schizophrenia (reviewed in Jones et al. 2011). Experimental models of psychosis
based on dopaminomimetics or NMDA receptor antagonists are very popular but are
thought to reproduce in animals only the “positive” symptoms of schizophrenia.
However, administration of PCP to rodents has also been shown to induce behav-
ioral deficits that could reproduce the “negative” symptoms of schizophrenia. For
example, a recent study has demonstrated that PCP reduced the emission of 50-kHz
USVs in rats that engaged in heterospecific play with a familiar human, a procedure
known as “tickling” (Boulay et al. 2013). Since 50-kHz USVs are thought to mark
positive emotional states in rats (Brudzynski 2013), suppression of calling behavior
by PCP has been proposed to model the social withdrawal that may be observed in
schizophrenic patients (Boulay et al. 2013). Animal models of psychosis that rely on
dopaminomimetics or NMDA receptor antagonists can disclose the effects of anti-
psychotic drugs that have either a “typical” or “atypical” profile (reviewed in Jones
et al. 2011). Another pharmacological model exists that is widely used in the
screening of antipsychotic drugs and consists in the evaluation of drug-induced
catalepsy (Hoffman and Donovan 1995). In the catalepsy model, antipsychotic
drugs to be tested are not supposed to correct psychotic-like behavioral abnormal-
ities that are induced by previous pharmacological treatment. Conversely, an anti-
psychotic that is effective in the catalepsy model should induce in animals a
behavioral phenotype characterized by muscular stiffness and immobility, termed
as catalepsy, which stems from the antagonism of dopaminergic receptors in the
nigrostriatal tract. Accordingly, the catalepsy model is used to screen antipsychotic
drugs that are thought to possess a “typical” profile of action or, alternatively, to
clarify whether antipsychotic drugs effective in other animal models possess a
“typical” profile of action. The catalepsy model has neither face validity nor con-
struct validity for psychosis but is still widely used in drug discovery because it is
easy to implement, allows high reproducibility of results, has predictive validity, and
is cost-effective.
Neurodevelopmental animal models of psychosis have been characterized in
recent years starting from the evidence obtained in epidemiological and imaging
studies which suggests that schizophrenia may be a neurodevelopmental disorder
caused by the interaction between inherited factors and factors acquired during the
pre- and perinatal phases of development (reviewed in Mouri et al. 2013). Popular
neurodevelopmental models of psychosis are the lesion of the ventral hippocampus
in neonatal rodents, the treatment of pregnant rodents with the mitotic inhibitor
methylazoxymethanol, which reduces the proliferation of neuroblasts, and post-
weaning isolation of rodents. Other neurodevelopmental models of psychosis that
have recently emerged are the administration of polyriboinosinic-polyribocytidilic
acid or lipopolysaccharide to pregnant rodents (reviewed in Jones et al. 2011). The
latter models are thought to recapitulate in the offspring the neurochemical and
behavioral effects elicited by systemic viral or bacterial infection during pregnancy,
which has been suggested to be an environmental factor that may favor the mani-
festation of schizophrenia (reviewed in Mouri et al. 2013). Neurodevelopmental
models of psychosis all reproduce in animals enduring anatomical and behavioral
Experimental Psychopharmacology 609

deficits that mimic abnormalities featuring schizophrenia, such as altered synaptic

connectivity in cortical and limbic regions, reduction in PPI, and impaired social
behavior (Mouri et al. 2013; McGonigle 2014). However, the validity of neurodeve-
lopmental models of psychosis is questioned, and use of those models in drug
discovery is hampered by difficult implementation, high mortality rate of animals,
and limited reproducibility of results (McGonigle 2014).

Animal Models Used to Evaluate the Effects of Drugs on Cognitive

and Executive Functions

Animal models used to study how drugs affect cognitive and executive functions can
be broadly subdivided in models based on non-operant or operant behavior.
Animal models based on non-operant behavior allow to study several aspects of
cognition, such as general cognitive function, acquisition and retention of spatial and
nonspatial memory, and learning. In detail, those models evaluate behaviors that are
readily performed by animals and that may be either spontaneous or motivated by
obtaining a reward or escaping from an unpleasant situation. For example, a model
commonly used to evaluate episodic memory in rodents is the novel object recog-
nition test, which is based on the innate exploratory drive that rodents have for
objects. In that test, the inability of rodents to discriminate between a novel object
and a familiar object previously encountered is thought to reflect deficits in episodic
memory (Ennaceur 2010). Models commonly used to study general cognitive
function evaluate the sequence of arm entries that rodents perform in Y-shaped or
T-shaped mazes; these models may also provide information about the integrity of
spatial memory and learning (Hughes 2004; van der Staay et al. 2011). Furthermore,
spatial learning and retention of spatial memory may be studied by means of the
radial arm maze or the Morris water maze, two models that evaluate the ability of
rodents to recognize baited arms previously visited or to locate and retrieve an
escape platform in a water tank, respectively (Morris 1984; van der Staay et al.
2011). Animal models for the study of cognition that evaluate non-operant behaviors
can be easily implemented in rats and mice, are cost-effective, and allow reproduc-
ibility of results across laboratories.
Animal models based on operant behavior may be used to study certain aspects of
executive functions, such as inhibitory control of behavior and impulsivity. Popular
models in this respect are the go/no-go, the stop-signal, the five-choice serial reaction
time (5-CSRT) tasks, and the delay discounting (reviewed in Bari and Robbins
2013). In all those models, rodents are requested to make lever-pressing or nose-
poking in order to obtain a reward and to adjust their behavior according to the
stimuli that are delivered during trials. The go/no-go task consists in a series of trials
where animals are exposed to stimuli that must either promote or inhibit response. In
some of the trials only the “go” signal is presented, which prompts animals to
respond. Conversely, in the remaining trials, the “go” signal is either presented
simultaneously with or preceded by another stimulus, the “no-go” signal that should
prevent animals from responding. Inability of animals to adjust responding after the
610 N. Simola

presentation of the “no-go” signal is considered an index of impulsivity (reviewed in

Bari and Robbins 2013). The stop-signal task is designed similarly to the go/no-go
task, but the “stop” (no-go) signal is presented after the “go” signal. Accordingly,
animals are requested to abort responding when the “stop” signal is presented.
Inability in doing so is considered an index of impulsivity, and the closer the
presentation of the “stop” signal is to the initiation of responding, the harder it is
for the animals to abort responding (reviewed in Bari and Robbins 2013). The 5-
CSRT is another model widely used to study impulsivity in rodents and is derived
from the continuous performance task that is utilized in humans to monitor atten-
tional functions (Carli et al. 1983). The 5-CSRT is run in an apparatus that contains
five adjoining holes, and rodents undergo a series of trials where they must respond
only in the hole illuminated by a light stimulus. Trials are separated by an inter-trial
interval during which light stimuli are turned off and animals must not respond.
Responding during the inter-trial interval is considered an index of impulsivity.
Notably, the 5-CSRT may also measure aspects of cognitive performance other
than impulsivity, such as attention, motivation, and speed of responding (reviewed
in Bari and Robbins 2013). Finally, impulsivity can also be studied in animals by
means of the so-called delay discounting paradigms, which measure how subjects
devaluate rewards whose delivery is delayed. In other words, animals subjected to
delay discounting models must decide whether a small but immediate reward is
worth more or less work than a large but delayed reward (Monterosso and Ainslie
1999). In the delay discounting model, impulsivity is defined as the selection of the
small immediate reward.
Animal models have greatly contributed to elucidating the neurobiological bases
of cognitive and executive functions, as well as of the alterations in these functions
that feature neurodegenerative diseases (i.e., Alzheimer’s disease) and neuropsychi-
atric diseases (i.e., attention deficit hyperactivity disorder, depression, drug addic-
tion, obsessive-compulsive disorder, schizophrenia). Moreover, certain animal
models used to evaluate cognitive and executive functions have marked translation
value, as they can be implemented also in humans with appropriate methodological
corrections. This may be the case of the go/no-go and stop-signal tasks. Furthermore,
several animal models used to study cognitive and executive functions are respon-
sive to drugs that possess clinical efficacy, such as acetylcholinesterase inhibitors,
atomoxetine, memantine, methylphenidate, and modafinil (Robbins 2017).
However, caution should be exercised when animal models are used to develop
drugs that may affect cognition. Thus, tests that evaluate non-operant behaviors may
use readouts that have limited translational value and that are significantly influenced
by the exploratory drive of animals. Accordingly, drugs affecting locomotor behav-
ior may influence the results obtained in those tests. Moreover, there is still no
enough evidence to determine whether drug effects observed in animal models of
impulsivity reliably translate to humans (Winstanley 2011; Robbins 2017). Besides,
the predictive validity of animal models of impulsivity may greatly vary according to
the class of drugs evaluated (Winstanley 2011). Finally, it must be remarked that
implementing animal models of impulsivity is complex, is time-consuming, and
Experimental Psychopharmacology 611

requires considerable expertise, which may somehow limit the use of those models
across different laboratories.

Animal Models Used to Evaluate New Drugs for the Treatment of

Neurodegenerative Diseases

Animal models can be used to investigate the mechanisms that promote and sustain
the neuronal demise underlying neurodegenerative diseases. Moreover, animal
models can allow to reproduce at the preclinical level some of the cardinal behav-
ioral symptoms observed in patients suffering from neurodegenerative diseases, such
as the memory deficits featuring Alzheimer’s disease or the motor impairment
featuring Parkinson’s disease. Popular models used in preclinical studies of neuro-
degenerative diseases are based on the induction of damage in specific neuronal
populations of the animal brain, in order to reproduce the neurodegeneration featur-
ing human disease. For example, these models include the use of dopaminergic
neurotoxins, such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP), in the case of Parkinson’s disease, or the use of
either toxins or peptides that induce cholinergic dysfunction (i.e., β-amyloid,
streptozotocin) in the case of Alzheimer’s disease (Duty and Jenner 2011; Iqbal
et al. 2013; Salkovic-Petrisic et al. 2013; Simola et al. 2007). Several genetic models
of Alzheimer’s, Huntington’s, and Parkinson’s disease have also been developed
(Harvey et al. 2011). Although a detailed description of the numerous animal models
used in preclinical research on neurodegenerative diseases falls outside the aims of
the present chapter, it is relevant to mention that experimental models have recently
been developed which allow to study the neuropsychiatric-like behavioral abnor-
malities that may precede and/or accompany neurodegenerative diseases. For exam-
ple, new models have utilized discrete and bilateral neurotoxic lesions of the
nigrostriatal dopaminergic system induced by 6-OHDA in order to reproduce in
rodents the motivational deficits, anxiety-like, and depression-like behavioral abnor-
malities that may be observed in Parkinson’s disease (Magnard et al. 2016). Notably,
rodents subjected to discrete dopaminergic denervation do not display the overt
motor impairment featuring classic animal models of Parkinson’s disease that are
based on complete and unilateral denervation of the nigrostriatal tract (Magnard et al.
2016). Hence, rodent models based on discrete dopaminergic lesions may allow to
study non-motor symptoms of Parkinson’s disease at the preclinical level without the
interference of motor impairment. Indeed, the presence of motor deficits may
significantly affect the interpretation of results in preclinical studies of non-motor
symptoms of Parkinson’s disease that are performed in classic animal models of
dopaminergic denervation (Magnard et al. 2016). New animal models that reproduce
neuropsychiatric-like abnormalities associated with neurodegenerative diseases
appear highly relevant to experimental psychopharmacology. In fact, those models
may allow to study the cognitive and emotional symptoms of disease that are often
neglected and may also help to develop new drugs for treating those symptoms.
612 N. Simola

Towards Improved Behavioral Animal Models: The Example of

Ultrasonic Vocalizations

As discussed in the previous paragraphs, a major limitation common to several

animal models employed in studies of psychopharmacology is the use of behavioral
readouts that have limited translational value. Accordingly, there is growing interest
in expanding the repertoire of behaviors that may be evaluated in experimental
animals (Millan et al. 2015). A notable example in this regard is the increasing use
of rat USVs in experiments of psychopharmacology (reviewed in Simola 2015). Rat
USVs are envisaged as markers of affect and emotion (Brudzynski 2013); accord-
ingly, evaluation of calling behavior may allow to directly appreciate the effects that
drugs may elicit on the emotional state. Rat USVs are classified according to their
average frequency in the three families of 22-kHz, 40-kHz, and 50-kHz USVs
(Portfors 2007). Rat pups emit 40-kHz USVs when separated from litter. Conversely,
young and adult rats emit 22-kHz or 50-kHz USVs in response to a wide range of
aversive or rewarding stimuli, respectively. Notably, emission of USVs in rats may
be affected by psychoactive drugs of different classes and is modulated by various
neurotransmitters (Costa et al. 2015; Simola 2015; Simola and Brudzynski 2018;
Simola et al. 2016, 2018). On this basis, rat USVs may be a valuable tool in
experiments of psychopharmacology and can be used either as self-standing tech-
nique or combined with other validated models that reproduce neurological or
psychiatric diseases.
Emission of 40-kHz USVs and emission of 22-kHz USVs are envisaged as a
correlate of distress and anxiety in isolated rat pups or in young/adult rats, respec-
tively (Portfors 2007), and have therefore been widely used as a behavioral model
with which to study the anxiolytic potential of drugs. In pups, spontaneous emission
of 40-kHz USVs is evaluated immediately after separation from the litter.
Conversely, in young/adult rats, evaluation of calling behavior is usually performed
by exposing animals to inescapable foot shocks in a novel environment; emission of
conditioned 22-kHz USVs is then measured upon re-exposure of rats to the envi-
ronment where they previously received the shocks. The validity of 22-kHz USVs as
a model of anxiety is strengthened by the evidence that young/adult rats conditioned
to foot shocks also display other behaviors that are thought to indicate the presence
of an anxiety-like state (i.e., freezing) (Sánchez 2003). Notably, several classes of
drugs with clinical efficacy on anxiety, such as benzodiazepines, serotonin 5-HT1A
receptor agonists, and SSRIs, reduce either the number of 40-kHz USVs emitted by
isolated rat pups, or the number of 22-kHz USVs emitted by young/adult rats
conditioned to foot shocks (reviewed in Simola 2015). Moreover, it has been
proposed that the emission of 22-kHz USVs in rats conditioned to foot shocks
may provide a model with which to study panic disorder. In fact, in that paradigm,
rats are exposed to an environment that acquires aversive properties and may
subsequently trigger anxiety, similar to what happens in situational panic disorder
in humans (Molewijk et al. 1995). Support to this view may also come from the
evidence that alprazolam and SSRIs, which are the first-choice treatments for panic
disorder, are more effective than classic benzodiazepines in suppressing the emission
Experimental Psychopharmacology 613

of 22-kHz USVs in rats conditioned to foot shocks (Molewijk et al. 1995). Measur-
ing 22-kHz USVs may also have relevance in the preclinical study of analgesic
drugs, since calling behavior could provide an experimental model with which to
study the affective dimension of pain (Oliveira and Barros 2006).
Emission of 50-kHz USVs is thought to be a marker of positive affect in young/
adult rats (Brudzynski 2013). Previous studies have demonstrated that drugs with
rewarding and addictive properties, such as amphetamines, cocaine, morphine, and
nicotine, may modify the number and acoustic parameters (bandwidth, duration,
maximum frequency) of 50-kHz USVs in rats (Barker et al. 2015; Costa et al. 2015;
Knutson et al. 1999; Simola et al. 2010, 2012, 2014, 2016; Simola and Morelli 2015;
Wright et al. 2010). Emission of 50-kHz USVs is increasingly being used to study
the motivational effects of drugs, either alone or combined with CPP or drug self-
administration paradigms (reviewed in Simola 2015). Notably, evaluating 50-kHz
USVs during self-administration procedures is a promising strategy that may dis-
close the emotional components inherent in drug abuse and the factors that may
promote relapse and reinstatement of drug taking (Barker et al. 2015). Moreover, it is
noteworthy that measuring 50-kHz USVs may disclose effects of drugs on the
emotional state that are not, or are only partially, revealed by other paradigms that
are classically used to study addiction (Barker et al. 2015; Simola and Morelli 2015).
Emission of 50-kHz USVs may also be relevant to fields of experimental psycho-
pharmacology other than drug addiction. Thus, it has been demonstrated that rats
selectively bred for low levels of 50-kHz USV emission showed blunted affectivity
and emitted fewer 50-kHz USVs in response to tickling by a familiar human,
compared with rats that had normal affectivity. This finding was thought to indicate
impairment in social communication and has led to a novel model of autism-like
social withdrawal (Harmon et al. 2008). Notably, the model has been shown to have
predictive validity, since it was able to detect the beneficial effects of the NDMA
receptor partial agonist GLYX-13, a drug that was reported to ameliorate social
withdrawal in autistic individuals (Moskal et al. 2011). Furthermore, as discussed in
the paragraph on animal models of psychosis, a reduced emission of 50-kHz USVs
has been observed in rats subjected to tickling that were treated with PCP (Boulay
et al. 2013). Deficits in calling behavior displayed by PCP-treated rats have been
proposed to model social withdrawal and could be useful to study the negative
symptoms of schizophrenia at the preclinical level. This hypothesis may be strength-
ened by the finding that buspirone, a drug that may attenuate the negative symptoms
of schizophrenia when added to antipsychotic therapy, restored calling behavior in
PCP-treated rats subjected to tickling (Boulay et al. 2013). Moreover, emission of
50-kHz USVs may be useful in studies of the modifications in the emotional state of
rats subjected to models of depression, as suggested by recent findings showing that
rats previously exposed to CMS emitted low numbers of 50-kHz USVs in response
to amphetamine administration (Kõiv et al. 2016).
Use of rat USVs as a marker of emotional states in experiments of psychophar-
macology is not devoid of limitations. For example, certain aspects related to the
behavioral significance of rat USVs and their relevance to the subjective effects of
psychoactive drugs are still to be elucidated (Simola and Costa 2018). Moreover,
614 N. Simola

certain drugs that possess clinically relevant effects may have a negligible influence
on the emission of USVs. Nevertheless, the evidence obtained in studies concerned
with rat USVs supports the idea that expanding the repertoire of behaviors that are
evaluated in animals is an urgent need in experimental psychopharmacology. This
approach shall hopefully be combined with other emerging techniques (i.e., set up of
developmental models, omics techniques, optogenetics), in order to obtain models
that adequately reproduce human disease in animals and that increase the reliability
and translational validity of results obtained in experiments of psychopharmacology.

Cross-References

▶ Anti-dementia Medications: Pharmacology and Biochemistry

▶ Antidepressants: Pharmacology and Biochemistry
▶ Antipsychotics/Neuroleptics: Pharmacology and Biochemistry
▶ Mood Stabilizers: Pharmacology and Biochemistry
▶ Psychopathology: Rating Scales for the Assessment of Mental Status
▶ Tranquilizers/Anxiolytics: Pharmacology and Biochemistry of Anxiolytic Drugs
Acting via GABAergic Mechanisms

References
Albelda N, Joel D. Animal models of obsessive-compulsive disorder: exploring pharmacology and
neural substrates. Neurosci Biobehav Rev. 2012;36:47–63.
Bari A, Robbins TW. Inhibition and impulsivity: behavioral and neural basis of response control.
Prog Neurobiol. 2013;108:44–79.
Barker DJ, Simmons SJ, West MO. Ultrasonic vocalizations as a measure of affect in preclinical
models of drug abuse: a review of current findings. Curr Neuropharmacol. 2015;13:193–210.
Bech P. Rating scales in depression: limitations and pitfalls. Dialogues Clin Neurosci.
2006;8:207–15.
Bogdanova OV, Kanekar S, D’Anci KE, Renshaw PF. Factors influencing behavior in the forced
swim test. Physiol Behav. 2013;118:227–39.
Boulay D, Ho-Van S, Bergis O, Avenet P, Griebel G. Phencyclidine decreases tickling-induced 50-
kHz ultrasound vocalizations in juvenile rats: a putative model of the negative symptoms of
schizophrenia? Behav Pharmacol. 2013;24:543–51.
Brooks SP, Jones L, Dunnett SB. Comparative analysis of pathology and behavioural phenotypes in
mouse models of Huntington’s disease. Brain Res Bull. 2012;88:81–93.
Brudzynski SM. Ethotransmission: communication of emotional states through ultrasonic vocali-
zation in rats. Curr Opin Neurobiol. 2013;23:310–7.
Bubeníková-Valesová V, Horácek J, Vrajová M, Höschl C. Models of schizophrenia in humans and
animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev. 2008;32:1014–23.
Cappeliez P, Moore E. Effects of lithium on an amphetamine animal model of bipolar disorder. Prog
Neuro-Psychopharmacol Biol Psychiatry. 1990;14:347–58.
Carli M, Robbins TW, Evenden JL, Everitt BJ. Effects of lesions to ascending noradrenergic
neurones on performance of a 5-choice serial reaction task in rats; implications for theories of
dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res.
1983;9:361–80.
Experimental Psychopharmacology 615

Cechinel-Recco K, Valvassori SS, Varela RB, Resende WR, Arent CO, Vitto MF, Luz G,
de Souza CT, Quevedo J. Lithium and tamoxifen modulate cellular plasticity cascades in animal
model of mania. J Psychopharmacol. 2012;26:1594–604.
Costa G, Morelli M, Simola N. Involvement of glutamate NMDA receptors in the acute, long-term,
and conditioned effects of amphetamine on rat 50 kHz ultrasonic vocalizations. Int J Neuropsy-
chopharmacol. 2015;18:pyv057.
Coull JT. Getting the timing right: experimental protocols for investigating time with functional
neuroimaging and psychopharmacology. Adv Exp Med Biol. 2014;829:237–64.
Cryan JF, Mombereau C. In search of a depressed mouse: utility of models for studying depression-
related behavior in genetically modified mice. Mol Psychiatry. 2004;9:326–57.
Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing antidepressant
activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev.
2005;29:571–625.
D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and
memory. Brain Res Rev. 2001;36:60–90.
Davis CM, Riley AL. Conditioned taste aversion learning: implications for animal models of drug
abuse. Ann N Y Acad Sci. 2010;1187:247–75.
de Bartolomeis A, Buonaguro EF, Iasevoli F, Tomasetti C. The emerging role of dopamine-
glutamate interaction and of the postsynaptic density in bipolar disorder pathophysiology:
implications for treatment. J Psychopharmacol. 2014;28:505–26.
Dencker D, Husum H. Antimanic efficacy of retigabine in a proposed mouse model of bipolar
disorder. Behav Brain Res. 2010;207:78–83.
Drinkenburg WH, Ahnaou A, Ruigt GS. Pharmaco-EEG studies in animals: a history-based
introduction to contemporary translational applications. Neuropsychobiology. 2015;72:139–50.
Duty S, Jenner P. Animal models of Parkinson’s disease: a source of novel treatments and clues to
the cause of the disease. Br J Pharmacol. 2011;164:1357–91.
Einat H. Establishment of a battery of simple models for facets of bipolar disorder: a practical
approach to achieve increased validity, better screening and possible insights into endo-
phenotypes of disease. Behav Genet. 2007;37:244–55.
Ennaceur A. One-trial object recognition in rats and mice: methodological and theoretical issues.
Behav Brain Res. 2010;215:244–54.
Fischer DA, Ferger B, Kuschinsky K. Discrimination of morphine- and haloperidol-induced
muscular rigidity and akinesia/catalepsy in simple tests in rats. Behav Brain Res.
2002;134:317–21.
Gessa GL, Pani L, Fadda P, Fratta W. Sleep deprivation in the rat: an animal model of mania.
Eur Neuropsychopharmacol. 1995;5:89–93.
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse
inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psycho-
pharmacology. 2001;156:117–54.
Gutheil TG. Reflections on ethical issues in psychopharmacology: an American perspective. Int J
Law Psychiatry. 2012;35:387–91.
Harmon KM, Cromwell HC, Burgdorf J, Moskal JR, Brudzynski SM, Kroes RA, Panksepp J.
Rats selectively bred for low levels of 50 kHz ultrasonic vocalizations exhibit alterations in early
social motivation. Dev Psychobiol. 2008;50:322–31.
Harro J. Animals, anxiety, and anxiety disorders: how to measure anxiety in rodents and why.
Behav Brain Res. 2018;352:81–93.
Harvey BK, Richie CT, Hoffer BJ, Airavaara M. Transgenic animal models of neurodegeneration
based on human genetic studies. J Neural Transm. 2011;118:27–45.
Hendriksen H, Groenink L. Back to the future of psychopharmacology: a perspective on animal
models in drug discovery. Eur J Pharmacol. 2015;759:30–41.
Hendriksen H, Korte SM, Olivier B, Oosting RS. The olfactory bulbectomy model in mice and rat:
one story or two tails? Eur J Pharmacol. 2015;753:105–13.
Hoffman DC, Donovan H. Catalepsy as a rodent model for detecting antipsychotic drugs with
extrapyramidal side effect liability. Psychopharmacology. 1995;120:128–33.
616 N. Simola

Hughes RN. The value of spontaneous alternation behavior (SAB) as a test of retention in
pharmacological investigations of memory. Neurosci Biobehav Rev. 2004;28:497–505.
Iqbal K, Bolognin S, Wang X, Basurto-Islas G, Blanchard J, Tung YC. Animal models of the
sporadic form of Alzheimer’s disease: focus on the disease and not just the lesions. J Alzheimers
Dis. 2013;37:469–74.
Ito R, Lee AC. The role of the hippocampus in approach-avoidance conflict decision-making:
evidence from rodent and human studies. Behav Brain Res. 2016;313:345–57.
Jobert M, Wilson FJ, Ruigt GS, Brunovsky M, Prichep LS, Drinkenburg WH. IPEG Pharmaco-
EEG Guidelines Committee. Guidelines for the recording and evaluation of pharmaco-EEG data
in man: the International Pharmaco-EEG Society (IPEG). Neuropsychobiology.
2012;66:201–20.
Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. Br J Pharmacol.
2011;164:1162–94.
Keeney AJ, Hogg S. Behavioural consequences of repeated social defeat in the mouse: preliminary
evaluation of a potential animal model of depression. Behav Pharmacol. 1999;10:753–64.
Kennedy RT. Emerging trends in in vivo neurochemical monitoring by microdialysis. Curr Opin
Chem Biol. 2013;17:860–7.
Knutson B, Burgdorf J, Panksepp J. High-frequency ultrasonic vocalizations index conditioned
pharmacological reward in rats. Physiol Behav. 1999;66:639–43.
Kõiv K, Metelitsa M, Vares M, Tiitsaar K, Raudkivi K, Jaako K, Vulla K, Shimmo R, Harro J.
Chronic variable stress prevents amphetamine-elicited 50-kHz calls in rats with low positive
affectivity. Eur Neuropsychopharmacol. 2016;26:631–43.
Kokras N, Dalla C. Sex differences in animal models of psychiatric disorders. Br J Pharmacol.
2014;171:4595–619.
Lidow MS, Williams GV, Goldman-Rakic PS. The cerebral cortex: a case for common site of action
of antipsychotics. Trends Pharmacol Sci. 1998;19:136–40.
Logan RW, McClung CA. Animal models of bipolar mania: the past, present and future.
Neuroscience. 2016;321:163–88.
Magnard R, Vachez Y, Carcenac C, Krack P, David O, Savasta M, Boulet S, Carnicella S. What can
rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson’s
disease? Transl Psychiatry. 2016;6:e753.
McGonigle P. Animal models of CNS disorders. Biochem Pharmacol. 2014;87:140–9.
Micale V, Kucerova J, Sulcova A. Leading compounds for the validation of animal models of
psychopathology. Cell Tissue Res. 2013;354:309–30.
Millan MJ, Goodwin GM, Meyer-Lindenberg A, Ove Ögren S. Learning from the past and looking
to the future: emerging perspectives for improving the treatment of psychiatric disorders.
Eur Neuropsychopharmacol. 2015;25:599–656.
Molewijk HE, van der Poel AM, Mos J, van der Heyden JA, Olivier B. Conditioned ultrasonic
distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic
drugs. Psychopharmacology. 1995;117:32–40.
Monterosso J, Ainslie G. Beyond discounting: possible experimental models of impulse control.
Psychopharmacology. 1999;146:339–47.
Moresco RM, Fazio F. SPET in psychopharmacology. Q J Nucl Med Mol Imaging.
2005;49:205–14.
Morris R. Developments of a water-maze procedure for studying spatial learning in the rat.
J Neurosci Methods. 1984;11:47–60.
Moskal JR, Burgdorf J, Kroes RA, Brudzynski SM, Panksepp J. A novel NMDA receptor glycine-
site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism. Neurosci
Biobehav Rev. 2011;35:1982–8.
Mouri A, Nagai T, Ibi D, Yamada K. Animal models of schizophrenia for molecular and pharma-
cological intervention and potential candidate molecules. Neurobiol Dis. 2013;53:61–74.
Oliveira AR, Barros HM. Ultrasonic rat vocalizations during the formalin test: a measure of the
affective dimension of pain? Anesth Analg. 2006;102:832–9.
Experimental Psychopharmacology 617

Page GG, Opp MR, Kozachik SL. Sex differences in sleep, anhedonia, and HPA axis activity in a rat
model of chronic social defeat. Neurobiol Stress. 2016;3:105–13.
Paterson NE. Translational research in addiction: toward a framework for the development of novel
therapeutics. Biochem Pharmacol. 2011;81:1388–407.
Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant
treatments. Nature. 1977;266:730–2.
Portfors CV. Types and functions of ultrasonic vocalizations in laboratory rats and mice. J Am
Assoc Lab Anim Sci. 2007;46:28–34.
Robbins TW. Cross-species studies of cognition relevant to drug discovery: a translational
approach. Br J Pharmacol. 2017;174:3191–9.
Robinson TE, Berridge KC. The psychology and neurobiology of addiction: an incentive-sensiti-
zation view. Addiction. 2000;95(Suppl 2):S91–S117.
Rodeberg NT, Sandberg SG, Johnson JA, Phillips PE, Wightman RM. Hitchhiker’s guide to
voltammetry: acute and chronic electrodes for in vivo fast-scan cyclic voltammetry. ACS
Chem Neurosci. 2017;8:221–34.
Salkovic-Petrisic M, Knezovic A, Hoyer S, Riederer P. What have we learned from the
streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic
strategies in Alzheimer’s research. J Neural Transm. 2013;120:233–52.
Sánchez C. Stress-induced vocalisation in adult animals. A valid model of anxiety? Eur J
Pharmacol. 2003;463:133–43.
Sanchis-Segura C, Spanagel R. Behavioural assessment of drug reinforcement and addictive
features in rodents: an overview. Addict Biol. 2006;11:2–38.
Sarnyai Z, Alsaif M, Bahn S, Ernst A, Guest PC, Hradetzky E, Kluge W, Stelzhammer V,
Wesseling H. Behavioral and molecular biomarkers in translational animal models for neuro-
psychiatric disorders. Int Rev Neurobiol. 2011;101:203–38.
Seeman P. Dopamine D2High receptors measured ex vivo are elevated in amphetamine-sensitized
animals. Synapse. 2009a;63:186–92.
Seeman P. Glutamate and dopamine components in schizophrenia. J Psychiatry Neurosci.
2009b;34:143–9.
Seligman ME, Beagley G. Learned helplessness in the rat. J Comp Physiol Psychol.
1975;88:534–41.
Shannon RJ, Carpenter KL, Guilfoyle MR, Helmy A, Hutchinson PJ. Cerebral microdialysis in clinical
studies of drugs: pharmacokinetic applications. J Pharmacokinet Pharmacodyn. 2013;40:343–58.
Simola N. Rat ultrasonic vocalizations and behavioral neuropharmacology: from the screening of
drugs to the study of disease. Curr Neuropharmacol. 2015;13:164–79.
Simola N, Brudzynski SM. Rat 50-kHz ultrasonic vocalizations as a tool in studying neurochemical
mechanisms that regulate positive emotional states. J Neurosci Methods. 2018;310:33–44.
Simola N, Costa G. Emission of categorized 50-kHz ultrasonic vocalizations in rats repeatedly
treated with amphetamine or apomorphine: possible relevance to drug-induced modifications in
the emotional state. Behav Brain Res. 2018;347:88–98.
Simola N, Morelli M. Repeated amphetamine administration and long-term effects on 50-kHz
ultrasonic vocalizations: possible relevance to the motivational and dopamine-stimulating
properties of the drug. Eur Neuropsychopharmacol. 2015;25:343–55.
Simola N, Morelli M, Carta AR. The 6-hydroxydopamine model of Parkinson’s disease. Neurotox
Res. 2007;11:151–67.
Simola N, Ma ST, Schallert T. Influence of acute caffeine on 50-kHz ultrasonic vocalizations in
male adult rats and relevance to caffeine-mediated psychopharmacological effects. Int J
Neuropsychopharmacol. 2010;13:123–32.
Simola N, Fenu S, Costa G, Pinna A, Plumitallo A, Morelli M. Pharmacological characterization of
50-kHz ultrasonic vocalizations in rats: comparison of the effects of different psychoactive
drugs and relevance in drug-induced reward. Neuropharmacology. 2012;63:224–34.
Simola N, Frau L, Plumitallo A, Morelli M. Direct and long-lasting effects elicited by repeated drug
administration on 50-kHz ultrasonic vocalizations are regulated differently: implications for the
618 N. Simola

study of the affective properties of drugs of abuse. Int J Neuropsychopharmacol.

2014;17:429–41.
Simola N, Costa G, Morelli M. Activation of adenosine A2A receptors suppresses the emission of
pro-social and drug-stimulated 50-kHz ultrasonic vocalizations in rats: possible relevance to
reward and motivation. Psychopharmacology. 2016;233:507–19.
Simola N, Paci E, Serra M, Costa G, Morelli M. Modulation of rat 50-kHz ultrasonic vocalizations
by glucocorticoid signaling: possible relevance to reward and motivation. Int J Neuropsycho-
pharmacol. 2018;21:73–83.
Steinpreis RE. The behavioral and neurochemical effects of phencyclidine in humans and animals:
some implications for modeling psychosis. Behav Brain Res. 1996;74:45–55.
Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening
antidepressants in mice. Psychopharmacology. 1985;85:367–70.
Stolerman IP, Childs E, Ford MM, Grant KA. Role of training dose in drug discrimination: a review.
Behav Pharmacol. 2011;22:415–29.
Tzschentke TM. Measuring reward with the conditioned place preference paradigm: a comprehen-
sive review of drug effects, recent progress and new issues. Prog Neurobiol. 1998;56:613–72.
van den Bos R, Koot S, de Visser L. A rodent version of the Iowa Gambling Task: 7 years of
progress. Front Psychol. 2014;5:203.
van der Staay FJ, Rutten K, Erb C, Blokland A. Effects of the cognition impairer MK-801 on
learning and memory in mice and rats. Behav Brain Res. 2011;220:215–29.
Vanderschuren LJ, Pierce RC. Sensitization processes in drug addiction. Curr Top Behav Neurosci.
2010;3:179–95.
Venzala E, García-García AL, Elizalde N, Delagrange P, Tordera RM. Chronic social defeat stress
model: behavioral features, antidepressant action, and interaction with biological risk factors.
Psychopharmacology. 2012;224:313–25.
Vogel JR, Beer B, Clody DE. A simple and reliable conflict procedure for testing anti-anxiety
agents. Psychopharmacologia. 1971;21:1–7.
Willner P. The validity of animal models of depression. Psychopharmacology. 1984;83:1–16.
Willner P. Validity, reliability and utility of the chronic mild stress model of depression: a 10-year
review and evaluation. Psychopharmacology. 1997;134:319–29.
Winstanley CA. The utility of rat models of impulsivity in developing pharmacotherapies for
impulse control disorders. Br J Pharmacol. 2011;164:1301–21.
Wise RA. The role of reward pathways in the development of drug dependence. Pharmacol Ther.
1987;35:227–63.
Wright JM, Gourdon JC, Clarke PB. Identification of multiple call categories within the rich
repertoire of adult rat 50-kHz ultrasonic vocalizations: effects of amphetamine and social
context. Psychopharmacology. 2010;211:1–13.
Yousem DM. The economics of functional magnetic resonance imaging: clinical and research.
Neuroimaging Clin N Am. 2014;24:717–24.
Zhang H, Cohen AE. Optogenetic approaches to drug discovery in neuroscience and beyond.
Trends Biotechnol. 2017;35:625–39.
 Part II
General Aspects

Peter Riederer
Psychopharmacology: A Brief Overview of
Its History

Paul Foley

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
The Ancient and Medieval Periods: Opium, Hellebore, and Chandra . . . . . . . . . . . . . . . . . . . . . . . . 622
The Nineteenth Century: First Attempts at Scientific Pharmacology, and
the Need for Restraint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
Tentative Explorations During the First Half of the Twentieth Century . . . . . . . . . . . . . . . . . . . . . . . 627
Chlorpromazine and Reserpine: The Beginning of the 1950s Psychopharmacology
Revolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
Haloperidol and Depot Antipsychotic Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
After Haloperidol: The Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
The Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Mood Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
Anxiolytics and Minor Tranquilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
Hypnotica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Nootropics (Cognitive Enhancers) and Anti-dementia Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645
Antiparkinsonian Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
Psychopharmacology and the Emergence of Modern Neurochemistry . . . . . . . . . . . . . . . . . . . . . . . . 647
Assessing the Effects of Modern Psychopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653

Abstract
People have used diverse types of drugs and other preparations to ease their
physical pain and mental distress for thousands of years. The search for new,
more effective drugs gathered pace during the nineteenth century, before a
confluence of factors culminated in the birth of modern psychopharmacology
in the early 1950s, heralded by the discovery of the first neuroleptic and

P. Foley (*)
Medical Journal of Australia, Sydney, NSW, Australia
e-mail: pfoley@mja.com.au

© Springer Nature Switzerland AG 2022 621

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_12
622 P. Foley

antidepressant agents. The rapid expansion of the number of options for

psychopharmacotherapy, particularly between 1950 and 1980, has radically
transformed both basic and clinical neuroscience.

Introduction

Psychopharmacology in sensu stricto – the systematic, experimental investigation of

drugs that modulate mood, perception, and cognitive and other mental functions –
may be relatively young, but psychotropic agents have been employed since prehis-
toric times. People have been aware for thousands of years that their mental state
could be altered by beverages prepared from fermented grains, fruits, or honey; the
Greeks, for example, spoke frankly of wine moistening the mind (phrenes), altering
its character (Onians 1988, pp. 30–34). Humans have availed themselves of what-
ever nature provided to raise their spirits, to relieve the harshness of life, in religious
ceremonies, and as medicines for body and soul, commencing with attempts to
reduce the physical and mental pain that encumbers all conscious beings.
This chapter is a concise overview of the history of psychotropic agents for
treating psychiatric disorders, broadly defined. It will not be possible to explore all
the details and controversies that comprise this history, nor to discuss the broader
cultural context of psychopharmacology, or the non-medical uses of psychotropic
agents. My account focuses on the threads of the story most relevant to current
psychopharmacology, and must also forgo discussing the major differences between
older and more recent concepts of mental function and dysfunction.
Throughout history, psychotropic agents have been discovered with a fluid combi-
nation of systematic search and serendipity; empiricism – learning through experience,
good or bad – has often been a more steadfast guide than rational considerations. This
applies to an even greater degree to psychopharmacotherapy than general pharmaco-
therapy: the targets of psychotropic drugs have always been less tangible than
infections or organ failure. The psychotropic properties of many agents were discov-
ered by accident, while others were introduced for reasons that later proved erroneous;
further, cultural and economic factors have often played roles as important as scientific
considerations. Anything that alters perception or mood has, at some point, been co-
opted by psychopharmacotherapy, and whether a rationale was proffered in advance or
in retrospect, physicians – as limited and fallible as any of their contemporaries – have
generally acted to the best of their knowledge and capacity.

The Ancient and Medieval Periods: Opium, Hellebore, and

Chandra

Pain has been eased and sleep facilitated in the Middle East and Europe by the juice
of the opium poppy since the Neolithic period, roles that opium and its chemical
derivatives have never completely surrendered. Its effects on mood were also noticed
Psychopharmacology: A Brief Overview of Its History 623

early; it has been suggested, for instance, that the drug Helen added to her guests’
wine in the Odyssey (in an early instance of polypharmacy!) to raise their spirits,
nepenthe (“without sorrow”), was opium. Wine and opium were consistently
recommended by Greek doctors for similar purposes, but also as calmatives,
reflecting their bivalent effects on mood. The most respected physician of classical
antiquity, Galen (c. AD 129–216), recognized that drugs could both cause (as
excitants) and lessen mental symptoms (as sedatives), and endorsed opium, man-
drake, and henbane as effective in some cases, but placed a greater emphasis on
dietary approaches to modifying mental states (Siegel 1973, pp. 275f.). Mandrake
(Mandragora) and henbane (Hyoscyamus), both members of the Solanaceae family,
continued to be used alongside the related belladonna as intoxicants or hallucinogens
and as medications until the early twentieth century. St John’s wort, on the other
hand, was long included in composita (theriacs) for treating wounds, but also as a
sedative and antidepressant (Tschupp 2004).
Galen also mentioned the most eminent psychoactive substance of the period,
hellebore, the popular reputation of which was so great that the adjective elleborosus
– literally, “in need of hellebore” – was used for “mad”; poets, satirists, and
philosophers frequently referred to the plant that grew especially well in Antikyra
on the Gulf of Corinth (Oppenheimer 1928, pp. 330f.). Two types were distin-
guished: black (various Helleborus species) and the unrelated white hellebore
(Veratrum album), the latter preferred for treating the symptoms of madness, partic-
ularly hallucinations, gloomy thoughts, and agitation. Hellebore, also used to reduce
fever and to slow the pulse, retained a place in the therapy of mental disorders until
the nineteenth century, when the first of a range of alkaloids were isolated from the
plant, many of which are now known to activate neuronal sodium channels (Barroso
2015).
The persistent humoral model of disease was long invoked to justify herbal
therapy for mental disorders; as it assumed the unity of mind and body, this model
did not distinguish between psychiatric and somatic disorders. Such therapies were
retained for centuries not, however, because they were rational, but because their
effects were convincing. Their perceived efficacy consequently provided no insights
into the nature of mental function and disturbances.
Of herbal preparations used outside Europe, the most relevant to later develop-
ments was Sarpagandha, or snakeroot (Rauvolfia serpentina), used in India, among
other purposes, for calming excited patients (Somers 1958). The root contains a
range of alkaloids that were isolated by Indian researchers in the twentieth century,
one of which – reserpine – played a major role in Western psychopharmacology
during the 1950s, as will be discussed below.
The psychotropic effects of naturally occurring substances were all too clear to
those who consumed grain contaminated by the ergot fungus (Claviceps purpurea),
particularly prominent in Europe from the early Middle Ages. Ergotism has been
held responsible for a range of bizarre epidemics, including outbreaks characterized
by manic or psychotic symptoms now attributed to the serotonergic actions of its
alkaloids, which include lysergic acid (Eadie 2003). It is also relevant that German
beer purity laws (including the Bavarian regulation of 1516) were partly motivated
624 P. Foley

by the desire to prevent brewers adulterating their products with psychotropic plants,
such as henbane (supplanted by the safer hops).

The Nineteenth Century: First Attempts at Scientific

Pharmacology, and the Need for Restraint

At the beginning of the nineteenth century, French alienist and reformer Philippe
Pinel (1745–1826) argued that prescribing drugs should not be the primary approach
to treating psychiatric patients, because “. . . waiting, assisted by a moral or physical
regime, often suffices, and in other cases the problem is beyond all help.” The doctor
should “reserve for extreme cases, hitherto regarded as incurable, the application of
certain active remedies, which other circumstances would render superfluous, harm-
ful, or reckless” (Pinel 1809, pp. 343f.). Pharmacological approaches were often
defended by practitioners by appeal to systems regarded by Pinel as outdated or
misguided, and the pharmacopeia of the early nineteenth century was indeed little
changed since Dioscorides had composed his Materia medica in the first century, a
limited catalog of sedatives, stimulants, purgatives, and emetics (Weber 1999).
The popularity of hellebore was in decline, but opium retained its place as an
antidepressant, supplied from the sixteenth century as a component of laudanum, a
composite of varying constitutions taken for a broad range of somatic and mental
indications, including pain, insomnia, and restlessness, and as a general panacea
(Dormandy 2012). Italian psychiatrist and reformer Vincenzo Chiarugi (1759–1820)
had employed opium as a sedative for asylum patients but was aware that long
term use entailed the risk of mental dulling (Schmitz 1925). In Germany, Friedrich
Engelken (1744–1815) treated agitated patients with opium in his private sanatorium
near Bremen, with an approach that his successors kept secret until Hermann
Engelken (1807–1881) finally published details of their increasing dose strategy in
1844. Mid-century, German psychiatrist Albrecht Erlenmeyer (1849–1926) classed
opium as the most valuable of the psychopharmaca, and it was widely used to treat
depression (including postnatal melancholy), mania, and hyperactivity in children
(Schmitz 1925; Weber 1987). By the end of the century, tinctures of opium were the
preferred forms of the drug, and they remained popular for early depression well into
the twentieth century, although in his 1925 review Bremen Nervenarzt Hans Schmitz
concluded that unpleasant side effects were common and cures not achieved
(Schmitz 1925). Hashish, digitalis, and alcohol also found applications as sedative
medications in psychiatry, as did ether and chloroform, solanaceous plant extracts,
and prussic acid (cyanide), while camphor, musk, and ammonia salts were employed
as “excitants” (see, for instance, Schneider 1824; Griesinger 1861, pp. 481–495).
Alcohol (as spirits, wine, or beer), on the other hand, lost favor in medicine, both
because of its unpredictable mixture of stimulating and sedative effects and because
of growing recognition of the deleterious social and mental effects of its misuse.
But a new era was beginning, one in which specific chemical substances were
preferred to herbal preparations, in the hope that more specific and controllable
effects could be achieved. In 1804, German pharmacist Friedrich Sertürner isolated
Psychopharmacology: A Brief Overview of Its History 625

morphine (from “Morpheus,” the god of dreams; Sertürner 1806) from the opium
poppy plant, the first of the alkaloids that would increasingly supplant less consistent
vegetable extracts, particularly for treating states of excitation and restlessness.
Morphine was used both for sedation and analgesia, as well as for treating opium
and alcohol addiction, until its own addictive properties were recognized. From the
late 1870s, cocaine, first isolated from the coca plant in 1855, was in turn employed
to treat morphinism until cocainism was decried as even more pernicious (Maier
1926). Morphine was soon joined by the belladonna alkaloids – hyoscyamine,
hyoscine (scopolamine), and atropine – which replaced their corresponding plant
preparations as mental and motor calmatives (Debreyne 1852; Harley 1869;
Kalischer 1910).
A series of further drugs were introduced during the nineteenth century for
reducing agitation and inducing sleep. Bromides were discovered to have sedative
(first major report: Behrend 1864) and anti-epileptic properties mid-century (Eadie
2012). Potassium bromide enjoyed massive popularity as an hospital and over-the-
counter sedative even after the deleterious effects of chronic intake (“bromism”)
were recognized in the 1870s (Sourkes 1991); it has been estimated that 40% of all
prescriptions by British general practitioners between the World Wars were for
bromides (Balme 1976). Bromides were also combined with other substances, as
in the treatment for epilepsy introduced by German psychiatrist Paul Flechsig
(1847–1929), in which bromide therapy was preceded by several weeks of slowly
elevated opium treatment (Flechsig 1893).
The first synthetic drug used in psychiatry was also a sedative, chloral hydrate.
First synthesized in 1832, Berlin pharmacologist Oscar Liebreich (1839–1908)
described its hypnotic properties in 1869, erroneously believing it could be
converted in vivo to chloroform (Butler 1970). Its ease of use and reliability led to
its quickly displacing opiates in both psychiatric and general practice, but it was in
turn largely displaced by morphine as a sedative after the 1870s and by barbiturates
for overcoming insomnia in the early twentieth century, although it was retained in
asylums into the 1940s because it was both effective and inexpensive (Sourkes
1992). Wilhelm Griesinger (1817–1868), the German Nervenarzt who famously
declared that mental disorders were essentially brain disorders, noted that patients
recovering from ether or chloroform narcosis often experienced remission of mel-
ancholia or mania, but also that the effect diminished with repeated attempts, ruling
out regular use of this early sleep therapy (Griesinger 1861, p. 489).
Inspired by insights gained during his 1836–1840 voyage thérapeutique through
the Middle East, French psychiatrist Jacques-Joseph Moreau (1804–1884) investi-
gated hashish both as a neuropsychiatric drug and as a tool for simulating the
symptoms of insanity – the first model psychosis, in which he related drug-induced
delirium to “mental pathogeny” – including self-experimentation that allowed him to
experience these symptoms from within. He reported some success in displacing
pathologic or disordered thoughts in patients with mania with more governable drug-
induced symptoms, but his limited supply of hashish limited his studies (Moreau de
Tours 1845). Moreau’s systematic investigations and his foundation of the Annales
médico-psychologiques as a forum for medical investigations of mental disorders
626 P. Foley

underlie his recognition as a pioneer of experimental psychopharmacology

(Ledermann 1988).
Throughout the nineteenth century, individual doctors further explored the effects
of drugs in people with mental disorders, including Scottish psychiatrist Thomas
Clouston (1840–1915) in Edinburgh (Clouston 1887), and in self-experiment, such
as the work of Bohemian physiologist Jan Evangelista Purkyně (1787–1869)
(Hanzlik 1938), but the investigations by German psychiatrist Emil Kraepelin
(1856–1926), published in 1892 as On the influence of certain drugs on basic mental
processes, were the most extensive and systematic. During the 1880s, Kraepelin had
introduced into psychiatry the methods of experimental psychology, pioneered in
Germany since the 1870s by philosopher-psychologist Wilhelm Wundt
(1832–1920). Kraepelin assessed, for example, the effects on reaction time of
“Arzneimittel” ranging from tea and coffee to chloral hydrate and morphine, both
in himself and others. He described this work as Pharmakopsychologie, with his
primary aim the quantification of the effects of external agents upon normal mental
processes that “can otherwise only be described in broad outline with the deceptive
assistance of self-observation”:

My goal was exclusively to formulate methods for precisely measuring the mental effects of
drugs in certain respects, and to show the possibility of their practical application, as well as
the usefulness of their results, with selected examples. (Kraepelin 1892, pp. 229f.)

Kraepelin’s efforts, however, were frustrated by differences between experimental

subjects in the quality and quantity of their responses, compounded by the effects
of practice and fatigue on individual performance. His original aim of establishing
a Patho-Psychophysik as the basis of a nosologic-diagnostic system was conse-
quently unfulfilled, but his recognition that the idiosyncrasy of the individual was
as important as the properties of psychotropic agents was a critical insight that
has not always been taken into account when testing such drugs (Müller et al.
2006).
The first steps towards a chemical model of brain function were also taken in the
nineteenth century, quite independently of clinical practice. Investigations of brain
chemistry in Paris were reported at the turn of the century by Antoine François de
Fourcroy (1755–1809) and Nicolas-Louis Vauquelin (1763–1829). By 1856, Julius
Eugen Schlossberger (1819–1860), who introduced the term “Nervenchemie ,” was
searching for correspondences between local chemical (Chemismus) and electrical
properties in nerve tissue (Foley 2008). In his comprehensive 1884 Treatise on the
chemical constitution of the brain, German-British chemist and oenologist Johann
Ludwig Wilhelm Thudichum (1829–1901) presaged the practical consequences of
brain chemistry:

. . . many derangements of the brain and mind, which are at present obscure, will become
accurately definable and amenable to precise treatment, and what is now an object of anxious
empiricism will become one for the proud exercise of exact science. (Thudichum 1884,
pp. 259f.)
Psychopharmacology: A Brief Overview of Its History 627

At about the same time, Kraepelin emphasized the probable role of metabolic
disturbances in the development of psychiatric disorders (for instance, Kraepelin
1899, p. 40); in 1914, Bleuler conceived schizophrenia as a “somatic, anatomic, or
chemical disorder” in which no significant brain lesion was evident (Bleuler 1914).
In 1904, Swedish-American chemist Otto Folin (1867–1934) wrote of the “wide-
spread hope that chemical investigations will, perhaps, sooner or later yield a clearer
understanding of [mental diseases] than can be looked for from the other sciences
that have been brought to bear on them” (Folin 1904). These and similarly minded
authors were, however, aware that knowledge in this area was as yet inadequate to
understand the chemistry of mental processes, let alone to provide insights into
rational therapies for dysfunctions. With few exceptions, the nascent field of neuro-
chemistry would remain largely restricted to separate chemo-anatomic and physio-
logical analyses until the mid-twentieth century. The first major textbook on
“neurochemistry,” by American Irvine Page in 1937, was, apart from a speculative
final chapter, one of general physiological chemistry (Page 1937).

Tentative Explorations During the First Half of the Twentieth

Century

Hypnagogic agents lacking the cardio-circulatory side effects of chloral hydrate were
identified during the final quarter of the nineteenth century, including paraldehyde,
urethane (ethyl carbamide), sulfonmethane, and their derivatives. Of greatest signif-
icance was the synthesis by Emil Fischer (1852–1919) and Josef von Mering
(1849–1908) of barbital (Veronal) in 1902, the comparative safety and tolerability
of which rapidly won it popularity in psychiatry, quickly displacing alternatives. The
potential for dependence and misuse of barbital (including for suicide, albeit at much
larger than therapeutic doses) were, however, also quickly recognized; during the
1950s, chlorpromazine was initially used primarily to facilitate withdrawal from
barbiturates or morphine. Barbital also served as the prototype for a range of
commercialized derivatives, including phenobarbital (Luminal; 1912), pentobarbital
(Neodorm, Nembutal; 1915), and amobarbital (sodium amytal, “truth serum”; 1923),
thereby presaging the post-Second World War approach to finding new agents
(Dundee and McIlroy 1982; López-Muñoz et al. 2004b).
Until the 1950s, barbiturate infusions roused patients from catatonic immobility
for hours, but with declining effectiveness as tolerance developed (Fink 2009). A
more radical use for barbiturates was in the “prolonged sleep therapies” introduced
during the early twentieth century, most famously the method of Swiss psychiatrist
Jakob Klaesi (1883–1980) in Bleuler’s Zürich clinic. In 1922, he described treating
patients with schizophrenia with a combination of Somnifen (barbital/
diallylbarbituric acid) and morphine, with the aim of providing a respite that might
allow stabilization of nervous function that promoted openness to psychotherapy on
waking, what might be termed today “re-booting the soul”; 12 of 30 patients
improved, but 7 died (Haenel 1979). In Europe, the approach was soon regarded
628 P. Foley

as unacceptably dangerous (Walther-Buël 1953) and was supplanted by the various

forms of shock therapy, but sleep therapies practiced by individual clinicians in
English-speaking countries as late as the 1970s, most notoriously at the Chelmsford
Private Hospital in Sydney, where 26 deaths over 16 years were attributed to the
treatment before it was discontinued in 1979 (Walton 2013).
The mechanism of action of the barbiturates was long unknown. During the
1950s their depression of CNS excitability was described, as was the possibility
that γ-aminobutyric acid (GABA) was involved, confirmed from the 1970s by
studies that barbiturates potentiate inhibitory GABAA receptors (at different binding
sites to the benzodiazepines) and inhibit excitatory AMPA receptors (Löscher and
Rogawski 2012).
Hyoscine, alone or in combination with morphine or apomorphine, remained
current as a calmative throughout the inter-War period, as did opium as a treatment
for depression. However, the first restrictions on the use of opium, legally
distinguishing between “pharmaceutical agent” and “recreational drug,” had been
introduced before the First World War in the United States (Food and Drug Act 1906,
Harris Act 1914), Australia (1908), Germany (1912), and internationally (Interna-
tional Opium Convention, 1912).
The effects in patients with melancholy and manic depression of the photo-
sensitizing molecule hematoporphyrin were explored, with limited success, from
1929 until the 1950s, with peak interest during the 1930s. One view was that the
drug increased tissue sensitivity to light and therefore stimulation of the vegetative
nervous system, but consensus about its mechanism in psychiatry was not reached
during its heyday (Huehnerfeld 1936).
Amphetamine was first synthesized in Berlin in 1887, but attracted attention
only a quarter of a century later as the similarity of its structure to that of the
catecholamines was recognized. It was noted that amphetamine elicited euphoria
and insomnia in patients who had received it intranasally to induce vasoconstriction,
and by 1931 it was being recommended for patients with narcolepsy. Its central
stimulant effects and its antagonism of subcortical hypnotica were established in
animal studies, culminating in the 1935 publication by Americans Prinzmetal
and Bloomberg that raised public awareness of the drug. It was initially released
commercially (as a decongestant) in an inhaler (Benzedrine), but as users quickly
learned how to access the depot, the drug was soon also released in tablet form.
Alongside its derivatives methamphetamine (Pervitin; first synthesized, 1893; in
crystal form, 1919) and D-amphetamine (Dexedrine), it quickly gained fame as the
first commercial stimulant, and the energizing effect of “pep pills” was valued both
by the general public and by the armed forces of all sides during the Second
World War. It also quickly earned notoriety for the attendant risks of dependence,
psychosis, and mortality. As early as 1937, it was additionally found that the drug
improved school performance in children with attention deficits (Foley 2014). Hopes
that amphetamine might be useful for treating depression, however, were soon
abandoned (review: Rasmussen 2015).
“Psychopharmacology” and similar terms were used more frequently after the First
World War (Macht 1920; Freeman 1931; Thorner 1935), but the field was still quite
Psychopharmacology: A Brief Overview of Its History 629

fallow. Russian-American pharmacologist David Macht (1882–1961), reporting his

own investigations of the effects of opium alkaloids on mental functions, commented:

The effect of drugs on psychological functions has been the subject of remarkably little
investigation on the part of either psychologists or pharmacologists . . . the number of
contributions to what we may be permitted to call “psychopharmacology” is certainly very
meagre. (Macht 1920)

In the following decade, psychopharmacology was, however, invigorated as hallu-

cinogenic agents became popular objects of enquiry, especially the alkaloids of
psychoactive plants, such as harmine and mescaline. Kurt Beringer (1893–1949),
in particular, interpreted their effects as possible models of disturbed thought
processes in psychosis (Beringer 1927; also Lewin 1924). German psychiatrist
Hans Berger (1873–1941), whose main interest – establishing correlations between
mental activity and measurable changes in the brain – ultimately led to his develop-
ment of electroencephalography, reported the apparently hallucinatory effects of
cocaine on dogs in 1921. He subsequently examined the effect of the drug in patients
with mental disorders; although it was tried by others for treating asylum patients
with schizophrenia or melancholy, it was soon abandoned because it achieved little
more than temporary acceleration of mental processes (Berger 1921). Such research
was in tune with the then widespread interest in exogenous causes of mental disease;
psychiatrist and philosopher Karl Jaspers (1883–1969) recommended the “thor-
oughly interesting literature” on the phenomena of the “model psychoses,” including
self-reports (Jaspers 1946, pp. 389f.).
Neurochemistry was similarly embryonic at this point. German neuropathologists
Cécile (1875–1962) and Oskar Vogt (1870–1959) proposed, for example, that
specific chemical characteristics (Chemismus) of certain brain regions determined
their liability to injury (Pathoklise): with respect to the striatal system, “[we] have
thereby also laid the necessary basis for chemotherapy, which we believe promises
more success for controlling striatal disorders than any other therapeutic approach”
(Vogt and Vogt 1920). In the USSR, Aleksandr Paladin (1885–1972) identified
biochemical changes during brain development and in different functional brain
states, such as excitation and inhibition (Paladin 1934). Recognition of the full
import of these and similar findings was hampered by technical, conceptual, and
political considerations; “brain chemistry” lacked a synthesis for explaining specific
neural functions or disorders and had no major impact in the clinic. Occasional
forays into neurochemical approaches were undertaken, such as the use of manga-
nese to treat schizophrenia in the late 1920s, partly because of its presumed anti-
bacterial properties but later because of the suggestion that central hypoxia and
“deficient oxidative processes” were involved in the disorder (Reiter 1929).
In 1908, French psychiatrist Maxime Laignel-Lavastine (1875–1953) discussed
the role of endocrine disturbances in the etiology of psychopathy (Laignel-Lavastine
1908) and organotherapy (treatment with glandular and other tissue extracts) were
vigorously promoted from the 1890s until the 1930s, with limited clinical benefit.
Kraepelin advocated thyroid extract treatment for patients with dementia praecox,
630 P. Foley

suspecting an underlying sex gland-related autointoxication (Noll 2007), while

Norwegian psychiatrist Rolv Gjessing (1887–1959) treated periodic catatonia with
large doses of thyroid extracts from 1929 (Gjessing 1939).
Pharmacology of the mind thus remained a poorly developed branch of psychi-
atry until pharmacologic empiricism began to emerge in some psychiatric depart-
ments from the 1940s. The limitations of the available pharmacopeia – tranquilizers
and the new stimulants, but nothing with a specific effect on the symptoms or course
of mental disorders – did not induce, as sometimes asserted, a mood of therapeutic
nihilism, but rather one of realistic recognition of the boundaries of what could be
achieved (Barbara 2015). The situation prior to the Second World War was remark-
ably similar to that before the First, as described by Jena psychiatrist Max Seige:

The torrent of sedative and hypnotic drugs that have flooded the market over the past decade
shows no sign of abating, and new ones are constantly commended under cleverly
constructed names, while others are already forgotten. Even of those that have held their
place in medical practice, few have been able to gain more general recognition; in almost
every case we see the same pattern in the literature: the initial news was extremely favorable
in every respect, but it soon became clear that they did not satisfy the old requirements of
cito, tuto et jucunde; that even in small doses they elicited all sorts of unpleasant or harmful
side effects. (Seige 1912)

From the 1930s until the 1950s, the somatic or shock therapies attracted broader
attention than pharmacological therapy for treating serious mental disorders. The
alleged benefits of sharp physical interventions for mental health had been described
since ancient times, but modern shock therapy commenced with Julius Wagner-
Jauregg (1857–1940) systematically exploiting the long recognized influence of
acute febrile disease on mood by artificially inducing fever, initially with tuberculin
and later with malaria parasites, in patients with syphilitic psychoses; his success
was recognized by the Nobel Prize committee in 1927. In 1933, Austrian-American
psychiatrist Manfred Sakel (1900–1957) described insulin coma therapy for treating
the symptoms of psychosis, depression, and morphine dependence: insulin-induced
hypoglycemia led to altered consciousness (not necessarily genuine coma) and
convulsions until terminated a few minutes later by the administration of glucagon.
A short time later, Hungarian psychiatrist Ladislas von Meduna (1896–1964)
induced convulsions in patients with schizophrenia with camphor, then with
pentetrazol (Cardiazol), motivated by the perceived antagonism between epilepsy
and schizophrenia (Fink 1984; Braslow 1999).
Chemical shock therapies were always controversial because of the risks of
permanent nervous or physical injury, including death (particularly in insulin coma
therapy), and because it was unclear whether the claimed success rates in terms of
the alleviation of mental symptoms were justified. Critics argued that the physical
exhaustion associated with these methods could explain short term symptomatic
improvements in behavior, while the nature of psychiatric disease meant that spon-
taneous remission was always a possibility. That these risky options were abandoned
in the mid-1950s (but not the successor technique, electroconvulsive therapy) was
attributable less to dismay with their undesirable effects as to the fact that the new
Psychopharmacology: A Brief Overview of Its History 631

antipsychotic and antidepressant agents rendered them superfluous. As David Healy

has noted, however, a clinical trial in 1957 found that insulin therapy was as effective
as chlorpromazine for managing psychosis; further, the fact that amphetamine could
restore patients to consciousness as effectively as glucose suggests that the neuro-
chemical basis of the treatment was perhaps more complex than assumed, a suspi-
cion consistent with current views of the mechanism of electroconvulsive therapy
(Healy 2002, pp. 53–55). If nothing else, the shock therapies showed that psychiatric
symptoms were accessible to treatment by physical means, paving the way for the
development of pharmacotherapy.

Chlorpromazine and Reserpine: The Beginning of the 1950s

Psychopharmacology Revolution

The Second World War facilitated the rise of large commercial chemical and
pharmaceutical firms, with a string of achievements during the 1940s (antibiotics,
steroids, anti-tuberculosis drugs) fostering confidence that the industrial approach to
the systematic development of new agents would dominate future advances rather
than ad hoc investigations by individual researchers. Nevertheless, individual phy-
sicians and researchers and chance naturally played critical roles in the post-War
revolution in psychopharmacology. Even should developments during this period
not constitute a scientific revolution in the Kuhnian sense (Baumeister and Hawkins
2005), the seismic shifts in both theory and practice were undoubtedly revolutionary
by any other measure. It was during this period that the term “psychopharmacology”
entered both scientific and popular discourse as an everyday word, with a sharp rise
in the number of publications indexed under this word in MEDLINE, peaking in
1965 before slowing until a second rise from 1976, a rise that has not yet reached its
peak. The authors of an early review confessed that the “task of reviewing the
development of psychopharmacology is a formidable one, which only dedicated,
highly involved, or foolhardy individuals undertake. The problem arises from the
thousands of reports which have appeared in the past five years or so on the effects of
drugs as related to some aspect of behavior” (Ross and Cole 1960).
The roots of the revolution reach back to the first flowering of industrial organic
chemistry in the nineteenth century, particularly the interest in synthetic dyes. In
1876, methylene blue was synthesized at the German chemical giant BASF, its core
structure the phenothiazine nucleus (itself synthesized in 1886). The dye stained
several cell types, including nerve cells, and was also vasoconstrictive, prompting
investigation of its analgesic, hypnagogic, and psychotropic effects; Pietro Bodoni in
Genoa, for instance, reported the value of intramuscular injections of the dye for
calming patients with mania. Overshadowed by the new barbiturates, methylene
blue and phenothiazine were both largely forgotten by human medicine for many
years, although in 1938 the oxidative effects of methylene blue were reported to
ameliorate catatonic symptoms. More recently identified interesting features of the
dye have led to investigations of its usefulness for treating bipolar and neurodegen-
erative disorders (Howland 2016).
632 P. Foley

Methylene blue was mildly anti-parasitic, and French pharmaceutical firm

Rhône-Poulenc tested several phenothiazine derivatives during the 1930s in the
search for more effective agents. In vain: but the new drugs were also assessed for
antihistaminic properties, as these were of particular interest in Paris at this time.
Research at the Institut Pasteur and from the 1940s at Rhône-Poulenc were moti-
vated by findings regarding the role of histamine in allergic reactions and shock,
commencing with Dale discerning a link between histamine release and anaphylaxis
in 1910 (Ring et al. 2014). Interestingly, people taking the first commercial antihis-
tamines, such as phenbenzamine (Antergan; 1942) and diphenhydramine (Benadryl;
1946), had noticed their sedative effects and, more remarkably, the mental indiffer-
ence they induced, exemplified by the story of a truck driver taking Antergan who
noticed but ignored red traffic lights. Their psychotropic effects, however, were of no
value for the treatment of psychiatric disorders (Weber 1999, pp. 138f.). Non-
phenothiazine antihistamines continued to be used as antipsychotics in Eastern
Europe until the 1970s (Healy 2002, p. 78).
The first phenothiazine antihistamine, promethazine (Phenergan; 1947), also had
sedative properties and was tried in sleep therapies for psychosis. Rhône-Poulenc,
however, was more interested in a different application: the amelioration of the
shock associated with major surgery. French surgeon Henri Laborit (1914–1995),
who had noted in 1938 that methylene blue potentiated the effects of narcotics,
reported during 1949 that a “lytic cocktail” containing promethazine and pethidine
reduced mental distress before and after surgery, by vegetative stabilization through
“artificial hibernation” and sedation of the patient, but without loss of consciousness.
He urged Rhône-Poulenc to optimize the antihistaminic component of the
cocktail, initiating a further round of molecular modifications (López-Muñoz et al.
2005).
In 1950, chlorpromazine was synthesized, a compound with a complex combi-
nation of actions consistent with the “ganglioplegic” or general “nerve-paralyzing”
activity that Laborit thought necessary for preventing the process of surgical shock:
anti-adrenergic and anticholinergic, it also potentiated the effects of narcotics; it
paralyzed thermoregulation. In one of the first industrial applications of an animal
model in psychotropic drug testing, the effects of chlorpromazine on rats in Macht’s
1920 rope-climbing test suggested that their poor performance was explained more
by indifference to unpleasant stimuli than by sedation or lack of coordination (Healy
2002, pp. 77–101; López-Muñoz et al. 2005).
With a name reflecting its pleasingly diverse actions – a truly “dirty drug” –
chlorpromazine was commercially released in Europe in 1953 as Largactil. The
psychotropic effects of chlorpromazine, particularly the psychomotor indifference to
stimuli – likened by some authors to “pharmacologic lobotomy” – soon attracted
attention, and the beneficial effects for patients with delirium, mania, or psychosis
were reported from various hospitals in France and Switzerland. The series of reports
by Jean Delay (1907–1987), Pierre Deniker (1917–1998), and colleagues on its
effectiveness for treating mania and schizophrenia in patients of the psychiatric
Hôpital Sainte-Anne in Paris were of particular consequence, including their pro-
posed designation for this new class of drug, “neuroplegic”:
Psychopharmacology: A Brief Overview of Its History 633

The results of our treatment of 38 patients were thoroughly encouraging. For most, a rapid
and spectacular effect could be achieved. And several cures or solid remissions were
observed within periods comparable with those of shock therapy. (Delay and Deniker 1952)

Restlessness, excitation, and hallucinations were all ameliorated, although “negative

symptoms” were less amenable to therapy.
The effects of the drug on delirium and psychotic symptoms were as dramatic as
those of penicillin had been for infectious diseases, and enthusiasm only increased
when it became available in capsules, removing the need for intramuscular injection.
The staff (and neighbors) of psychiatric units were impressed by the reduction in
noise, aggression, and chaos the new pill achieved: “doors were unlocked, staff
morale increased, and the hospital was transformed” (Healy 2002, p. 95). It was clear
that the sedation chlorpromazine induced differed from that achieved by narcotics,
very much resembling the sleep of encephalitis lethargica (Foley 2018, pp.
193–198). Chlorpromazine could, in fact, rouse patients who had been silent and
immobile for years, if only provisionally (Healy 2002, pp. 85–93; López-Muñoz
et al. 2005; Ban 2007).
Despite its clearly unique qualities, a degree of skepticism lingered, essentially
because the liberating effects of chlorpromazine were unprecedented; being the first
antipsychotic agent, it could not be easily categorized and was indeed initially
licensed in the United States as an antiemetic. Even in France, its initial use in
psychiatry was technically off-label. In 1953, German-Canadian psychiatrist Heinz
Lehmann (1911–1999) reported promising results, finally leading to its 1955 release
in North America as Thorazine, which was prescribed in much higher doses than
Largactil in Europe, and typically for out- rather than inpatients. Major conferences
on the therapy and its implications were organized in Basel in 1953 and Paris in
1955, followed by a broader meeting in the United States in 1956 devoted to
psychopharmacology and its assessment, with a call for multicenter trials. Only
one year later, the new situation was reflected in the formation of the Collegium
Internationale Neuro-psychopharmacologium (CINP) in Milan (Lehmann 1993;
Healy 2002, pp. 96–101; Barbara 2015).
It soon became clear, however, that chlorpromazine did not cure psychosis, and
that ongoing medication and psychotherapy would be required if patients were to be
released into the community. Individual differences in response were also noted very
early (Freyhan 1956). Further, the extrapyramidal motor effects of the drug could not
be overlooked, although these could be managed with the usual anticholinergic
therapies for patients with parkinsonism, including new synthetic anticholinergics,
particularly biperiden (Foley 2003, pp. 217–250). Lausanne psychiatrist Hans Steck
(1891–1980), who had written extensively on the psychiatric symptoms of enceph-
alitis lethargica and had noted the apparent antagonism between the disorder and
schizophrenia, reported that chlorpromazine elicited in a subset of patients a post-
encephalitic parkinsonism-like syndrome that included rigidity, akinesia, seborrhea,
and drooling (tremor was less typical), but which developed more rapidly, “as if a
film were being wound more rapidly than usual” (Steck 1954). The symptoms
appeared about 2 weeks into therapy and, in most cases, then receded, but in 10%
634 P. Foley

of patients, it proved persistent. The close association of extrapyramidal signs with

antipsychotic agents was such that clinicians often regarded them as indicating
effective treatment, and chlorpromazine-treated patients were referred to as
“shakers.”
Another agent, as effective as chlorpromazine but less expensive, attracted at least
as much attention during the 1950s. Rauvolfia preparations had long been used in
India to treat psychosis (and its parkinsonian side effects noted), but in the West it
was patients taking the Rauvolfia alkaloid reserpine (Serpasil) to reduce blood
pressure who identified its value as a “tranquilizer” (the term introduced at Ciba to
describe the action of its product Serpasil): “Many patients become positively lyrical
about their sense of well-being on the drug” (Wilkins 1954). It was found to exert
similar effects to chlorpromazine, although tremor developed at lower doses; reser-
pine (and, to a lesser extent, phenothiazines), also elicited the psychomotor restless-
ness of akathisia, first described at the turn of the century but unusual until it surfaced
as a symptom of encephalitis lethargica (Foley 2018, p. 325). The disinterested state
of reserpine-treated patients was sometimes interpreted as depression, although
reserpine was also used to treat this symptom (Baumeister et al. 2003). Leo Hollister
(1920–2000) undertook an ad hoc single blind study in California that returned
impressive results for its effects as an antipsychotic, drawing media attention to the
changing face of psychiatry (Healy 2002, pp. 101–107). The molecular structure of
reserpine was much more complex than that of chlorpromazine, hindering the
development of modified versions and reducing its longer term commercial signif-
icance. But the discovery that it depleted biogenic amine stores in the brain led to its
playing a critical role in neurochemistry research from the mid-1950s, including
chemical models of psychiatric and neurologic disorders (Foley 2003, pp. 350–362;
López-Muñoz et al. 2004a; Baumeister 2013).
Chlorpromazine and reserpine initiated a major change in the management of
psychosis: they were not sedatives for managing crises or chemical straitjackets à la
scopolamine, but tools that made patients more accessible to psychotherapy and
ultimately facilitated their return to living in the community. The advance was
naturally accompanied by therapeutic, financial and administrative, and social
challenges:

A patient who has been in restraint for two or three years continuously, only out for the legal
number of minutes per day under very close supervision, does not need restraint any more,
and yet he is not a well individual. He needs a great deal of extra attention from the
occupational therapy department, from the rehabilitation service, possibly from teachers
and other people who can reeducate him into useful channels. (Duval and Goldman 1956)

Sedation without sleepiness, less excited but not benumbed, inner peace without
paralysis: the optimism engendered by the initial experiences with neuroleptic
agents encouraged the search for further psychotropic phenothiazines. Pro-
chlorperazine (Stemetil; 1955) was much more potent as an antipsychotic than
chlorpromazine, but was not sedative. This first example of an “incisive agent,” as
psychiatrists in Lyon termed them, suggested that drugs with a more restricted set of
Psychopharmacology: A Brief Overview of Its History 635

specific effects were possible. But prochlorperazine also elicited excitomotor reac-
tions (dyskinesias) that could be influenced by mood and attention, reminiscent of
signs attributed to hysteria, thereby blurring the line assumed to divide psychiatry
from neurology (Lambert and Revol 1960; Brouillot et al. 2000).
This phenomenon, and growing recognition of the similarities of encephalitis
lethargica and phenothiazine therapy, led Delay and Deniker in 1955 to denote the
phenothiazine drugs (and reserpine) as “neuroleptic” agents; that is, drugs that
produce psychomotor indifference, useful for treating excitement and agitation, but
which also elicit extrapyramidal symptoms, with both the desired and “side” effects
explained by their action on the basal ganglia (Deniker 1989). “Neuroleptic”
was preferred to alternative suggestions (“tranquilizer,” “ataraxic”) at the Second
International Congress of Psychiatry in Zürich in 1957 and was adopted in Europe;
North Americans, however, favored “(major) tranquilizers” (King and Voruganti
2002).
Further phenothiazine neuroleptics soon followed, including perphenazine
(Trilafon; marketed 1957) and trifluoperazine (Stelazine, 1958), and in the 1960s
by the related thioxanthene antipsychotic agents, including clopenthixol (Sordinol;
1961), flupenthixol (Fluanxol; 1965), and thiothixene (Navane; 1967).

Haloperidol and Depot Antipsychotic Medications

Attempting to improve on the potency of pethidine, Belgian pharmacologist Paul

Janssen (1926–2003) produced a series of derivatives that, like chlorpromazine,
blocked the effects of amphetamines and induced catatonia in laboratory rats,
culminating in 1958 in haloperidol (Haldol). The stereotypies exhibited by profes-
sional cyclists taking amphetamine, in particular, suggested that blocking response
to amphetamine might signal an antipsychotic effect. Haloperidol appeared to be
potently antipsychotic in one treated patient with suspected schizophrenia; wonder-
ing whether the drug effect was real, Janssen discontinued treatment 7 years later,
and the patient relapsed into an acute psychotic state. Haloperidol soon proved
effective for treating states of agitation without sedating patients, and was more
effective than chlorpromazine for resolving hallucinations; it was also useful for
managing “odd” patients, such as those who qualified for institutionalization by
having Tourette syndrome. It elicited extrapyramidal side effects to a greater extent
than chlorpromazine, but by 1959 this quality was considered the mark of an
effective neuroleptic. Haloperidol was soon accepted as the first-line antipsychotic
in Europe, but for a variety of reasons, it was not approved in the United States until
1967 (Granger and Albu 2005; López-Muñoz and Alamo 2009).
Janssen’s firm subsequently prepared a series of further butyrophenone (including
trifluperidol [1959], benperidol [1961; the most potent neuroleptic currently sold in
Europe, now primarily prescribed for sex offenders], pipamperone [1961]) and
diphenylbutylpiperidine antipsychotic drugs (pimozide [1963], fluspirilene [1963],
penfluridol [1968]). These newer antipsychotics were more potent than the
636 P. Foley

phenothiazines and incisive in terms of their lower propensity for sedating patients;
haloperidol consequently displaced chlorpromazine during the 1960s as the bench-
mark for antipsychotic efficacy.
Depot preparations for simplifying antipsychotic therapy, particularly for patients
with poor compliance, were explored during the early 1960s. The first commercially
available items were fluphenazine enanthate (Moditen) in 1963 and fluphenazine
decanoate (Prolixin) in 1965; a depot form of haloperidol became available in 1981.
Zuclopenthixol, the cis-isomer of the typical antipsychotic clopenthixol (introduced
1961), was itself introduced in 1978; it was supplied as a regular depot preparation
(Clopixol) from the 1980s, but also as a shorter acting formulation (2–4 days)
(Clopixol-Acuphase) for treating acute psychotic states (Healy 2002, pp. 231–234).
On the other hand, the dopamine hypothesis of schizophrenia and the apparent high
tolerance of many patients for antipsychotic drugs encouraged some psychiatrists to
administer very large doses of haloperidol, particularly as extrapyramidal reactions
could cease beyond a certain drug level. This approach was largely discredited in 1988
by separate reports that D2 dopamine receptors were effectively completely blocked at
low drug doses, and that clinical benefits were not increased beyond daily dosages of
600 mg chlorpromazine or 30 mg haloperidol (Healy 2002, pp. 234–238).

After Haloperidol: The Atypical Antipsychotics

Clozapine, with an imipramine-like structure, was synthesized by Swiss firm Wander

in 1958, but was not effective as an antidepressant; it blocked apomorphine-induced
climbing but not stereotypies in test animals and did not induce catalepsy, so screening
did not identify it as a candidate neuroleptic. It was made available in 1961 as an
experimental drug, but a mixture of disappointing and alarming results included 4
deaths among 14 patients in Paris, including 3 with agranulocytosis. Nevertheless, a
multicenter trial in Germany, Switzerland, and Austria in 1966 found that it was of
benefit for patients with long standing schizophrenia, if not remarkably more effica-
cious than existing neuroleptics; it was released commercially in Europe in 1972 (as
Leponex). Acceptance across the Atlantic was hindered by skepticism, but it was
eventually licensed in the United States in 1990 after the 16-site, double-blind Sandoz
Clozapine Study #30 reported the most dramatic responses to a psychotropic agent
since the introduction of chlorpromazine (Crilly 2007).
German psychiatrist Hanns Hippius (1925), among others, noted that clozapine
was atypical in that it could elicit akathisia but was not associated with traditional
extrapyramidal problems (the “neuroleptic threshold” of Hans-Joachim Haase
[1922–1997]: hence the designation “atypical neuroleptic”) and could even reduce
the degree of existing tardive dyskinesias; on the other hand, it could cause convul-
sions at high doses. Not only was it well tolerated, it appeared particularly useful for
patients refractory to older options. Its rising popularity was abruptly interrupted in
1975 when 16 cases of agranulocytosis (eight fatal) were reported in Finland, leading
to its immediate withdrawal in several countries and mandatory blood monitoring
elsewhere. Despite the (low) risks of often transient agranulocytosis during the first
Psychopharmacology: A Brief Overview of Its History 637

months of therapy and of neuroleptic malignant syndrome, the possibility of cho-

linergic rebound effects on withdrawal, and its relatively high cost, the absence of
extrapyramidal side effects justified the continued use of clozapine (Crilly 2007).
Two untoward phenomena associated with neuroleptic therapy were seen less
frequently in patients treated with atypical antipsychotics. Tardive dyskinesia dur-
ing neuroleptic therapy, but more especially after discontinuing treatment had been
seen during the late 1950s, but was more broadly discussed and recognized as a
problem that could be worse than the disease during the 1960s, particularly after the
Danes Uhrbrand and Faurbye published a detailed, illustrated report about some-
times irreversible dyskinesias linked with perphenazine, chlorpromazine, reserpine,
and electroconvulsive therapies (Tarsy 1983; Wolf et al. 1993; Paulson 2005). As
discussed by Healy (Healy 2002, pp. 245–251), tardive dyskinesia had become a
legal problem by the 1970s, for which reason the arrival of clozapine was more than
welcome. Valbenazine, tetrabenazine, and deutetrabenazine have recently been used
to treat the symptom, as have dopamine receptor agonists, but with less than optimal
results. Moreover, longer term analyses have cast doubt on the belief that atypical
antipsychotic agents are associated with significantly lower rates than the older
neuroleptics (D’Abreu et al. 2018).
Neuroleptic malignant syndrome, a life-threatening condition characterized by
rigidity, fever, and autonomic nervous system instability, was noted as early as 1956
as an adverse effect of neuroleptic therapy (Ayd 1956) but was first described in
detail by Delay and colleagues in 1959 (Delay et al. 1960). The condition, however,
remained neglected despite rising numbers of deaths during the era of high-dose
therapy, until reports accumulated during the 1970s, culminating in the 1980 review
by Stanley Caroff (1980). It is relatively rare, affecting about 1% of patients, and
usually develops during the first weeks of treatment; it can be alleviated with
dopamine agonists but also with benzodiazepines or barbiturates. Contrary to initial
impressions, the atypical neuroleptics can also induce neuroleptic malignant syn-
drome, although it is generally less severe than with older agents (Murri et al. 2015).
By the 1990s, the major advantage of clozapine was not that it averted tardive
dyskinesia, but that it effectively treated the negative symptoms of psychosis,
promoting sociability and “warming of the personality,” But as the effects of
clozapine were being compared with those of high-dose chlorpromazine, it has
been argued that the atypical antipsychotic was simply shown to be better than
excessive dosing with typical agents (chemical lobotomy!); that is, the “treatment-
resistant schizophrenia” improved by clozapine was actually drug-induced negativ-
ity (Healy 2002, pp. 267–269).
Clozapine analogs soon followed, including olanzapine (marketed 1996) and
quetiapine (1997), as well as by further types of atypical antipsychotic, including
risperidone (1993) and sertindole (1996), but none have proved clinically superior to
clozapine. Pipamperone was synthesized in 1961 as an early attempt to block the
effects of both amphetamines and serotonin, but it was found to be less potent than
haloperidol. In the 1980s, however, Janssen – with the benefit of receptor-binding
techniques – revived this approach, designing the butyropiperidine risperidone
(Risperdal; introduced 1993) as a combined D2/5HT2A receptor antagonist, a
638 P. Foley

combination that came to be regarded as the pharmacologic hallmark of atypical

antipsychotics (Awouters and Lewi 2007). Ironically, receptor-binding studies indi-
cated that some typical antipsychotics (for instance: chlorprothixene, flupentixol)
shared this feature to some degree. Risperidone analogs include ziprasidone (2002)
and paliperidone (2007).
More recently, the partial D2 dopamine receptor agonist aripiprazole (Abilify;
marketed 2002) has found use as an atypical antipsychotic agent and for treating
bipolar disorder (Costentin 2009), as has cariprazine (D3/D2 partial agonist), intro-
duced in 2015. The D2 receptor partial agonist brexpiprazole, also introduced in
2015, is similarly employed as an atypical antipsychotic and for treating major
depression (López-Muñoz et al. 2018; Corponi et al. 2019).
The atypical antipsychotics are much “dirtier” than the first generation agents in
terms of their receptor-related activity; particularly marked is their antagonism of 5-
HT2A receptors. In fact, the atypical antipsychotics are defined more by their complex
receptor binding patterns than by the absence of extrapyramidal side effects, as it has
been found that they can indeed elicit them under certain conditions. Generally
regarded as efficacious in patients with intransigent schizophrenia, particularly for
treating negative symptoms, each atypical antipsychotic has a distinct pattern of side
effects (Shen 1999; Weiden 2007; Carpenter and Davis 2012; Nucifora et al. 2017).
The benzamide sulpiride is usually also classified as an atypical antipsychotic, but
its receptor activity is less diverse (selective antagonism of presynaptic D2 and D3
dopamine receptors and of γ-hydroxybutyrate receptors at therapeutic doses). It was
synthesized in the mid-1960s from the antiemetic metoclopramide, which induced
parkinsonian symptoms in some patients, suggesting a neuroleptic derivative was
possible. Sulpiride was indeed antipsychotic, albeit not as potent as chlorpromazine,
but it did not induce catalepsy in animals, nor did it induce parkinsonism or tardive
dyskinesia. These features were rather curious once the dopamine hypothesis of
schizophrenia had gained ground, given its potency as a D2 receptor antagonist. As it
also had antidepressant and disinhibiting properties, it has been used alone and as
adjunctive therapy for treating psychosis and depression since its commercial release
in 1972. Its derivative amisulpride, introduced in the 1990s, has a receptor profile
more like that of other atypical antipsychotics, and its efficacy has been ranked as
second only to that of clozapine (Angrist 1982; Colonna 1994; Leucht et al. 2013).
Finally, the view that atypical antipsychotics are invariably superior to the classic
neuroleptics is no longer unchallenged as the focus shifts from potency to overall
quality of life. The responses, good and bad, to specific agents need to be carefully
assessed when deciding the best choice for an individual patient. Clozapine, how-
ever, retains the best reputation in terms of the balance between efficacy and adverse
effects (Jones et al. 2006; Leucht et al. 2013; Haddad and Correll 2018).

The Antidepressants

Opium and alcohol had long found favor for raising spirits; “nerves” might be treated
with laudanum, tonics such as strychnine, or anticholinergic alkaloids, especially
hyoscine; cocaine and (later) amphetamines could be used to boost mental energy.
Psychopharmacology: A Brief Overview of Its History 639

But these remedies were hardly antidepressants as the term is now understood
(Moncrieff 2008).
At about the same time that chlorpromazine was being discovered, Ernst Zeller
(1907–1987) and his Chicago colleagues reported that the anti-tuberculosis drug
isoniazid and an analog, iproniazid, each inhibited liver and kidney amine oxidases.
In the same year (1952), it was found that iproniazid markedly improved mood in
tuberculosis patients: they were more vivacious (“dancing in the halls tho’ there were
holes in their lungs”; Robitzek et al. 1952), their appetite, sleep, and sociability
improved – if in some cases to a more than desirable degree, causing psychomotor
agitation, hypersexuality, and psychotic symptoms. Clinical and public attention on
both sides of the Atlantic grew, and in 1958 chlorpromazine was marketed as
Marsilid. Cincinnati psychiatrist Max Lurie, one of the early investigators of isoni-
azid, had termed the new type of drug “antidepressant,” but Nathan S. Kline
(1916–1983), the head of research at Rockland State Hospital in New York who
had already shared the 1957 Lasker Clinical Medical Research Award for his
neuroleptic work and would win the 1964 prize for his antidepressant research,
initially achieved more traction with “psychic energizer” (López-Muñoz and Álamo
2009). Iproniazid, however, was withdrawn in many countries only a few years later
because of its hepatotoxicity. By this time, more potent but safer alternatives had
become available, including phenelzine (Nardil; described 1959) and isocarboxazid
(Marplan; 1960).
The monoamine oxidase (MAO)-inhibiting properties of tranylcypromine
(Parnate), a substituted amphetamine first synthesized in 1948, were not recognized
until 1959. It was first marketed in 1960, but was temporarily withdrawn a few years
later after a number of deaths were attributed to its use. It had also been found that
therapy with MAO inhibitors required avoiding tyramine-containing foods, includ-
ing red wine and aged cheese, as the accumulation of tyramine could lead to
potentially fatal hypertensive crises (“cheese effect”). As a result, and because of
their interactions with several other medications, MAO inhibitors lost favor as
antidepressants. But in the 1980s, it was discovered that MAO occurs in two
forms, and that the antidepressant effect is primarily associated with inhibition
of type A MAO. Reversible inhibitors of this isozyme not requiring stringent
dietary restrictions, such as moclobemide (Aurorix) – originally examined in 1972
as a lipid-lowering or antibiotic drug – have recently been investigated (Yáñez et al.
2012).
Reservations about MAO inhibitors were exacerbated by an alternative class of
antidepressants developed at about the same time. In 1956, Swiss psychiatrist
Roland Kuhn (1912–2005), searching for a medication more effective than opium
for “vital depressive mood disorders,” discovered the value of imipramine (Tofranil)
as a “thymoleptic.” Imipramine, the first tricyclic antidepressant, was originally
developed by Geigy (Basel) as an antihistamine, then as a neuroleptic (it includes
the chlorpromazine side chain, and its dibenzazepine nucleus resembles phenothia-
zine). Like opium, imipramine had some depressive effects, but Kuhn was satisfied
in 1958 that it specifically elevated mood in patients with depression of any etiology,
consistent with his view of depression as a “psychophysical phenomenon” that was
part of various conditions, although the effects of imipramine were less reliable in
640 P. Foley

patients with schizophrenia or brain damage than in cases of endogenous or exog-

enous depression (Bossong 2008; Brown and Rosdolsky 2015).
Imipramine served as the prototype for a string of tricyclic antidepressants –
including desipramine (1959), amitriptyline (1960), and clomipramine (described
1964) – that were increasingly used to treat depression outside institutions, as well as
anxiety states and obsessive-compulsive disorder. They each inhibit norepinephrine
and serotonin reuptake to varying degrees and have complex transmitter receptor
binding patterns, features that probably explain why individual drugs are preferred
for specific clinical indications. Imipramine ultimately led also to the tetracyclic
antidepressants, which generally do not inhibit serotonin reuptake, including
mianserin (described 1967/marketed 1975) and mirtazapine (1989/1994), which
are antagonists of α2-adrenergic and certain serotonin receptors, and maprotiline
(1966/1974), a norepinephrine reuptake inhibitor and potent antagonist of the
histamine H1 and serotonin 5-HT7 receptors (overview: Fangmann et al. 2008).
That the tricyclic antidepressants are mixed inhibitors of synaptic serotonin and
noradrenaline reuptake was established during the 1960s, and this contributed to
competing catecholamine and serotonin deficit models of depression (Schildkraut
1965; Coppen 1967). This in turn motivated the search for more specific reuptake
inhibitors in the hope that they would not have the undesirable side effects of the
tricyclic agents, an early example of rational drug design on a neurochemical basis.
The first specific serotonin reuptake inhibitor (SSRI), the antihistamine derivative
zimelidine, was marketed in 1982, but withdrawn shortly afterward because of cases
of Guillain-Barré syndrome. Fluoxetine (Prozac) was first synthesized from diphen-
hydramine (Benadryl) in 1972, but, despite its specificity, it was not marketed until
1986, but then with spectacular success. This paved the way for further SSRIs during
the late 1980s, including citalopram (Celexa), fluvoxamine (Luvox), and sertraline
(Zoloft). The rise of the SSRIs was paralleled by an expansion in the indications for
antidepressants to encompass various anxiety, pain, and obsessive-compulsive syn-
dromes (Wong et al. 2005; Perez-Caballero et al. 2014).
The SSRIs, pharmacologically cleaner than the tricyclic antidepressants, require
greater consideration of the individual when prescribing and setting dosage. There is
even some suggestion that SSRIs are more efficacious for treating obsessive-com-
pulsive disorder, anxiety, or social phobia than depression, and that their classifica-
tion as antidepressants may have had as much to do with market needs (and
neurochemical expectations) as with what they actually achieve (Healy 2002,
pp. 62–65).
In the search for a broader spectrum of action, serotonin/norepinephrine reup-
take inhibitors (SNRIs) for treating major depressive disorder were examined in
the 1990s, the first marketed being venlafaxine (Effexor) in 1993, followed in 2004
by duloxetine (synthesized 1986; Cymbalta); these agents are also used for treating
people with general anxiety disorder, social phobia, and panic disorder. More
recently, so-called atypical antidepressants, such as trazodone (a potent 5-HT2A
and α1-adrenergic receptor antagonist and a weak serotonin reuptake inhibitor;
described 1960s/marketed 1981), the atypical μ-opioid receptor agonist and
Psychopharmacology: A Brief Overview of Its History 641

glutamatergic transmission modulator tianeptine (Stablon; 1960s/2012), the nor-

epinephrine/dopamine reuptake inhibitor bupropion (Wellbutrin; 1969/1985;
methylphenidate is also reckoned to this class), and the melatonin receptor agonist
agomelatine (Valdoxan; marketed in Europe, 2009), have been added to
the options for treating affective disorders (overviews: Cipriani et al. 2018;
Mandrioli et al. 2018). Antagonists of the NK1 receptor for neuropeptide substance
P (such as the anti-emetic aprepitant) showed interesting properties as atypical
antidepressants, but development stalled during phase 3 testing (Rupniak and
Kramer 2017).

Mood Stabilizers

The primary aim of a mood stabilizing agent is to reduce the severity of the mood
shifts in manic-depressive disorder, but they are also employed to manage borderline
personality and schizo-affective disorders. They are more effective for treating
mania than depression, but their mechanisms of action remain controversial.
The first (and hitherto only) specialist mood stabilizer was lithium. In 1886,
Danish psychologist Carl Lange (1834–1900) recommended lithium salts for
patients with manic-depressive illness on the basis that they suffered “cerebral
gout,” the effects of uric acid accumulation on nervous function, and lithium had
been found to dissolve urate stones (Schioldann 2011). Mineral spas including
lithium-containing waters had been increasingly praised for their health-promoting
effects through the nineteenth century. Lange’s treatment was as effective as any, but
was abandoned after its rationale lost favor, although the soft drink 7 Up was still
promoted as a “lithiated lemon-lime soda” when launched in 1929, and included
lithium citrate until 1948 (Aita et al. 1990). Lithium was still used for treating gout
until its sometimes fatal cardiac effects led to its being banned in the United States in
1949. In the same year, Australian psychiatrist John Cade (1912–1980) treated
people with schizophrenia and mania with the metal salt, having observed the
sedating effect of lithium urate in laboratory animals and of lithium carbonate in
himself. Danish psychiatrist Mogens Schou (1918–2005) undertook further studies,
including the first double-blind, placebo-controlled trial of a psychotropic agent,
which revived interest in the usefulness of lithium for treating mania. Schou and
colleagues later also provided evidence that lithium had prophylactic effects, but
these findings were more controversial. Nevertheless, the US Food and Drug
Administration (FDA) approved lithium for long-term therapy in 1974, and it is
recognized as effective for treating bipolar disorder, despite the original rationale
being discredited (Schou 2001).
A range of other agents have been employed as mood stabilizers, including
atypical antipsychotic agents also employed for treatment-resistant depression
(aripiprazole, risperidone and its analogs, olanzapine, quetiapine) and anti-convul-
sants (valproate, lamotrigine, carbamazepine) (overviews: Denicoff et al. 1998;
López-Muñoz et al. 2018).
642 P. Foley

Anxiolytics and Minor Tranquilizers

The minor tranquilizers – so termed in contrast to the neuroleptics, which in North

America were termed (major) tranquilizers – for treating neurotic states and anxiety
were ultimately derived from muscle relaxants used in surgery. The glycerin ether
mephenesin, originally destined to be an antibiotic, proved more effective in reduc-
ing muscle tone in mice without sedating them or inducing excitement (in contrast to
the barbiturates). This “tranquilizing” effect seemed useful for treating patients with
increased muscle tone, spasm, or tremor, but during the late 1940s its calmative
effects in anxiety, psychosis, and alcohol withdrawal were also examined. In
1954/55, Czechoslovakian pharmacologist Frank Berger (1913–2008) found that
meprobamate, synthesized from mephenesin in 1950, acted on the nucleus ventralis
of the thalamus to reduce anxiety without affecting other mental or physical func-
tions. The following year it was launched with great fanfare in the United States as
Miltown and soon achieved massive popularity for reducing nervousness, stress, and
anxiety. In contrast to barbiturates, hitherto the normal option for treating these
symptoms, meprobamate had no apparent effect upon people without these symp-
toms (Ramchandani et al. 2006).
In the United States, meprobamate seemed ideal for the accelerated but politically
uncertain world of the 1950s; Aldous Huxley was moved to muse on “the ethical,
religious, and social implications of psychopharmacology.” Initially meprobamate
competed here with chlorpromazine for treating psychoses. Huge numbers of pre-
scriptions were written in mental institutions and in the community, and reports of
dependence and other longer term effects did little to dampen enthusiasm until the
mid-1960s, when more stringent controls were imposed before it was proscribed
altogether in 1970 (Speaker 1997).
The first benzodiazepine, chlordiazepoxide (Librium), had been synthesized at
Hoffmann La Roche by Polish-Swiss chemist Leo Sternbach (1908–2005) in 1955,
but its sedative, muscle relaxant, and anxiolytic effects were not immediately
recognized – the benzodiazepine research program was, in fact, being closed for
lack of interesting results – and it was not commercially released until 1960; it was
followed by diazepam (Valium; 1963), lorazepam (Ativan; 1977), and alprazolam
(Xanax; 1981). Diazepam, in particular, supplanted meprobamate as a presumptively
safer agent for managing anxiety and tension. By the 1980s, however, the potential
for dependence and addiction had become clear (although this is reportedly not the
experience in Japan). Diazepam continues to be used extensively for relieving
anxiety in the short term and can assist in the management of compulsive behaviors,
but has largely been displaced by SSRIs for most indications (Sternbach 1983;
Williams 1990; Lader 1991; López-Muñoz et al. 2011).
Apart from their popularity as anxiolytics, various benzodiazepines have proved
useful as hypnotics (including nitrazepam [Mogadon; 1965] and temazepam
[Restoril; 1969]), anti-convulsants, muscle relaxants, and amnesics. Clonazepam
(Klonopin; synthesized 1964/marketed 1975) is employed to treat panic disorders
and akathisia. The antihistamines hydroxyzine (Atarax), first marketed in 1956, and
captodiamine (Covatix; 1958) have been employed as anxiolytics not burdened by
Psychopharmacology: A Brief Overview of Its History 643

the dependence problems of the benzodiazepines, as has the anti-convulsant pre-

gabalin (synthesized 1990/marketed 2004) (Baldwin et al. 2014).

Hypnotica

Barbiturates were the mainstay of hypnotic therapy until the 1960s; glutethimide
(introduced 1954) and meprobamate were regarded as safer alternatives until their
potential for misuse was also recognized (Hollister 1983). Methaqualone, originally
an antimalarial drug, was introduced in 1965 as Quaalude (in the United States; also
as Mandrax elsewhere), but its misuse (as “ludes,” “mandies”) led to benzodiaze-
pines being preferred for medical purposes from the late 1970s (Herzberg 2011).
Several quinazolinone analogs of methaqualone, all positive allosteric modulators of
GABAA receptors, have been marketed for the treatment of insomnia. Benzodiaze-
pines themselves have considerable misuse potential, and the risk of dependence is
great. The desire for safer alternatives led to development during the late 1980s of
non-benzodiazepines with similar effects on GABAA receptors and efficacy, but with
lower propensity for inducing tolerance and dependence: the “Z-drugs” zopiclone
(Imovane; marketed 1989), zolpidem (Ambien; 1992), and zaleplon (Sonata; 1999)
(Becker and Somiah 2015).
The orexin receptor antagonist suvorexant (Belsomra) has been available for
treating insomnia in Japan and the United States since 2014; orexin is a hypotha-
lamic neuropeptide involved in arousal and wakefulness. The pineal hormone
melatonin (discovered 1958) is critical to the regulation of circadian rhythms,
including the sleep-wake cycle; it has been reported to reduce time to sleep onset
without increasing total sleep time and to ameliorate the effects of shift work and jet
lag. Melatonin (and the melatonin receptor agonist ramelteon) may have greater
benefits for sleep in specific populations, such as children with neurodevelopmental
problems (Auld et al. 2017; Abdelgadir et al. 2018). The sedative effects of other
drug types have also been exploited as mild hypnotics, including antidepressants
(such as mirtazapine), atypical antipsychotics, antihistamines (particularly diphen-
hydramine), the α2 receptor agonist clonidine, and gabapentinoids (such as pre-
gabalin) (Atkin et al. 2018).

Psychostimulants

Stimulant substances have long been used informally in most cultures to improve
mood, endurance, and alertness, including tea, coffee, cocaine, khat, and tobacco.
Until the mid-twentieth century, stimulants also played a major role in psychophar-
macology, including “tonics” for alleviating melancholy (such as St John’s wort),
reducing nervousness, stimulating the appetite, or increasing mental energy. Since
the 1950s, they have largely fallen into disfavor because of misuse (amphetamines,
for instance) but also because they have been supplanted by agents directed at
specific symptoms, although these have also changed with time: in the Western
644 P. Foley

world, the neurasthenia of the nineteenth century became the nervousness of the
early twentieth; anxiety then dominated the post-Second World War, before depres-
sion became more common in the 1980s, followed by burnout in the early twenty-
first century. These conditions were absolute synonyms neither clinically nor
socially, but all would once have been indications for agents that stimulate the
nervous system.
Apart from their general stimulatory effects, amphetamines had been employed to
treat narcolepsy and as appetite suppressants since the 1920s. The first controlled
psychopharmacologic trial found in 1939 that amphetamines were efficacious for
treating depression (Dub and Lurie 1939; Rasmussen 2015), and they were used to
treat depression until the 1970s, but were ineffective in this regard for institutional-
ized patients and those with pychoses (Rasmussen 2006, 2015). It has been noted
that the same applies to later agents defined as being specifically antidepressant,
including the most recent SSRIs, whereas more sedative drugs can be effective in
these patients (Schatzberg 2003); indeed, it was noted as early as 1962 that it was
“well known that antidepressant drugs are of most use in the mild-to-moderate
degrees of depression” (Pare et al. 1962). As late as the 1980s, the usefulness of
amphetamines and methylphenidate for treating intransigent depression was advo-
cated by some authors (Chiarello and Cole 1987), but more recently doubt has been
cast on the evidence for their efficacy (Malhi et al. 2016).
A more surprising and enduring role for stimulants has been their use for
managing hyperactivity and improving attention, particularly in children and ado-
lescents. In 1937, American physician Charles Bradley (1902–1979) reported that
“a single dose of Benzedrine [could] produce a greater improvement in school
performance than the combined efforts of a capable staff working in a most
favorable setting,” but noted that the child’s environment and psychotherapy
were still critical. Concern about the effects of amphetamines was already suffi-
cient to prevent immediately pursuing this direction further. In 1944, methylphe-
nidate (Ritalin) was synthesized, and was used from the early 1950s for treating
depression, narcolepsy, and parkinsonism, before Bradley’s approach was resumed
in the 1960s by administering it to children then designated as having “minimal
brain dysfunction,” roughly equivalent to the attention deficit/hyperactivity disor-
ders defined in the DSM-III in 1980. Prevalence of this latter diagnosis rose
rapidly, particularly in the United States, from the 1990s, and correspondingly
the prescribing of methylphenidate. Its effectiveness for this indication is generally
accepted (and was tested in one of the first controlled drug trials in children), but
the question of whether the diagnosis is too broadly applied remains the subject of
ongoing discussion in medical, educational, and lay circles. Methylphenidate
occurs in four distinct stereoisomers, of which D-threo-methylphenidate
(dexmethylphenidate) is the pharmacologically active form of the norepineph-
rine/dopamine reuptake inhibitor (commercially available as Focalin) (Heal et al.
2013; Foley 2014). Lisdexamfetamine, an amphetamine prodrug with longer
action and lower abuse potential than standard amphetamines, has been approved
for treating attention deficit/hyperactivity disorder and binge eating in adults
(Roncero and Álvarez 2014).
Psychopharmacology: A Brief Overview of Its History 645

Drinamyl was an interesting product marketed by Smith, Kline and French from
1950 until the 1970s for relieving depression and anxiety. The combination of its two
components, amobarbital (50 mg) and D-amphetamine (5 mg), was designed to
balance their effects, but it was regarded as more stimulating than amphetamine
alone (for which reason it was popular with British mods as “purple hearts”).
Drinamyl was as effective as imipramine for treating depression in a controlled
trial, leading the authors to conclude that imipramine itself was not specifically
effective in this regard (Hare et al. 1964).

Nootropics (Cognitive Enhancers) and Anti-dementia Agents

The newest category of psychotropic agent is also the most controversial. In 1972,
Romanian psychologist and pharmacologist Corneliu Giurgea (1923–1995) intro-
duced the concept of the “nootropic” as a drug that directly activated integrative
brain functions, enhancing cognitive performance by acting on the highest cortical
regions (Margineanu 2011). Giurgea applied the term to a drug he had synthesized in
the early 1960s, piracetam, the prototype for the racetam group, which includes
oxiracetam and aniracetam. Their nootropic properties are disputed, and sale of
piracetam as a nootropic is permitted in Europe but not in the United States. Its
mechanism of action is unclear, but increased cholinergic function in the prefrontal
cortex may be involved (Winblad 2005; Malykh and Sadaie 2010).
Claims of cognitive enhancement properties have been made for a diverse range
of other medicinal agents (Froestl et al. 2014). For example, modafinil (1998) and
armodafinil (2007), which promote wakefulness and alertness (eugeroics) and are
therefore primarily prescribed for treating narcolepsy, have been reported to improve
cognitive function (Battleday and Brem 2015). Recent analyses suggest that low
doses of amphetamine or methylphenidate may improve cognitive functions, includ-
ing inhibitory control, memory, and aspects of attention, as well as increase moti-
vation (Ilieva et al. 2015; Marraccini et al. 2016).
The various nootropic candidates exhibit a diverse range of pharmacologic
properties, and their effectiveness is contentious. A recent meta-analysis found
some evidence of mild benefits in certain cognitive domains, but the authors noted
that the number of investigations has been limited by ethical considerations regard-
ing “brain doping,” and that many studies have returned negative results (Fond et al.
2015).
Other putative nootropics achieve some degree of symptomatic cognitive
improvement for patients with Alzheimer dementia, but none slow the course of
the disease (reviewed: Aisen et al. 2012):

• acetylcholinesterase inhibitors: tacrine (Cognex; now discontinued because of its

potential hepatotoxicity), donepezil (Aricept; 1996), and rivastigmine (Exelon;
1997), as well as galantamine (a naturally occurring alkaloid originally isolated
from the Caucasian snowdrop) (for the cholinergic hypothesis of Alzheimer
disease: Contestabile 2011; Douchamps and Mathis 2017).
646 P. Foley

• NMDA receptor antagonist: memantine (Axura; 1989 [synthesized 1968, initially

viewed as an anti-diabetic drug]).
• Atomoxetine (Strattera), a weak antidepressant, inhibits prefrontal cortex norepi-
nephrine reuptake and is an NMDA receptor antagonist. It has available since
2002 for treating people with attention deficit disorders, and its potential for
improving cognitive performance in other conditions is being explored (Robbins
2019).

Several other targets for symptomatic or preventive pharmacotherapy are cur-

rently being explored, including therapies directed at aspects of metabolic and
vascular function implicated in the pathophysiology of dementia (reviewed: Loera-
Valencia et al. 2019).

Antiparkinsonian Drugs

Until the mid-twentieth century, the pharmacotherapy of Parkinson disease was

dominated by preparations of solanaceous plants (such as belladonna) and by
alkaloids extracted from these plants (atropine, hyoscyamine, scopolamine,
“duboisine”). These preparations were employed for their general calmative and
sedative properties and were also exploited in psychiatric institutions; their major
benefit in patients with parkinsonism was the relief of tremor. Harmine, later found
to be a monoamine oxidase type A inhibitor, found favor in Germany at the end of
the 1920s as it also relieved akinesia, albeit at doses that also elicited hallucinations.
After the Second World War, the traditional agents were superseded by an array of
synthetic anticholinergic (including benzhexol [Artane], biperiden [Akineton],
benztropine [Cogentin]) and antihistaminergic preparations (such as diphenhydra-
mine [Benadryl] and orphenadrine [Disipal]; reviewed: Foley 2003).
In 1958, Swedish pharmacologist Arvid Carlsson had proposed on the basis of
animal experiments that parkinsonism might be ameliorated by raising central
dopamine levels with L-DOPA; 2 years later, Oleh Hornykiewicz and Herbert
Ehringer (Vienna) and Isamu Sano (Osaka) reported that dopamine levels in the
striatum were markedly reduced in parkinsonism. In 1961, Hornykiewicz and
Walther Birkmayer infused parkinsonian patients with L-DOPA, achieving remark-
able amelioration of all symptoms, particularly akinesia. Despite confirmation of
their findings in Osaka and Montréal, and subsequently in several European hospi-
tals, the reported effects of an amino acid in a neurodegenerative disease were met
with skepticism until George Cotzias reported similar effects (with oral racemic
DOPA) in the United States at the end of the 1960s. By the early 1970s, L-DOPA was
recognized as the gold standard medication for treating parkinsonism, usually in
combination with a decarboxylase inhibitor (benserazide, carbidopa) to minimize
peripheral metabolism of the amino acid (reviewed: Foley 2003).
Sympathomimetic agents, including apomorphine, amphetamine, and methylphe-
nidate, had been tried as antiparkinsonian agents during the 1950s, but the success of
L-DOPA and acceptance of the dopamine deficiency hypothesis of parkinsonism
established dopamine replacement therapy as the dominant paradigm for the
Psychopharmacology: A Brief Overview of Its History 647

treatment of parkinsonism. Most subsequent additions to treatment accordingly fall

into three major groups:

• Dopamine receptor agonists were initially employed, from the mid-1970s, as

adjuncts to L-DOPA therapy, but are now typically used as monotherapy soon
after diagnosis, delaying the need for L-DOPA:
– ergot-derived D2 receptor agonists, such as bromocriptine, lisuride, pergolide,
and cabergoline;
– non-ergoline D2 receptor agonists, such as pramipexole, ropinirole,
quinagolide, and piribedil;
– D3 receptor agonists, such as talipexole.
• Inhibitors of monoamine oxidase type B extend the benefit of L-DOPA treatment
by inhibiting dopamine metabolism. The two major members of this class are the
irreversible MAO-B inhibitors deprenyl (or selegiline), the antiparkinsonian
properties of which were described by Birkmayer and colleagues in 1975, and
rasagiline, developed in Israel and licensed for use as an antiparkinsonian agent in
2005. The reversible MAO-B inhibitor safinamide has been approved for this
purpose since 2015. It is possible that MAO-B inhibitors may also be
neuroprotective for neurons susceptible to degeneration in parkinsonism
(reviewed: Szökő et al. 2018; Müller and Möhr 2019).
• Inhibitors of catecholamine-O-methyltransferase (COMT) increase L-DOPA
availability by inhibiting its peripheral metabolism and reducing dopamine
metabolism in the brain. The COMT inhibitors entacapone and tolcapone were
introduced in the late 1990s, but were soon withdrawn in many countries because
of their potential hepatotoxicity; where now permitted, regular monitoring of liver
function is required. A more recent addition to this group is opicapone,
recommended for managing the end-of-dose motor fluctuations that vex
L-DOPA therapy (Castro Caldas et al. 2018).

At the end of the 1960s, Robert Schwab discovered that amantadine, an antiviral
agent used for treating influenza, was also antiparkinsonian. Only much later was it
established that amantadine is an NMDA glutamate receptor antagonist; it also
increases dopamine release and blocks its reuptake. It has found particular use as
an adjunct to L-DOPA in later stage disease and for relieving akinetic crises.
Budipine is a further antiparkinsonian agent that antagonizes NMDA receptors,
but amantadine may also be anticholinergic and enhance dopamine release. The
potential role of NMDA receptor antagonists in managing the psychiatric symptoms
of Parkinson disease has also been recently explored (Vanle et al. 2018).

Psychopharmacology and the Emergence of Modern

Neurochemistry

The introduction of the neuroleptics, the beginning of modern psychopharmacology,

was marked by a number of important features. Firstly, chlorpromazine was not the
product of a specific search for psychotropic agents, but the by-product of research
648 P. Foley

motivated by the problem of surgical shock. The corollary of this circumstance was
that the neuroleptics were accepted because they worked, not because they fitted
with concepts of how psychiatric disorders develop; nor was it known how drugs
modulated brain processes, let alone mental functions. Whatever their mechanism,
there was renewed hope that specific psychiatric processes might be amenable to
pharmacologic modulation beyond the traditional poles of sedation and stimulation,
a possibility entertained by Freud toward the end of his life:

Here we are concerned with therapy only with respect to its use of psychological means: at
the moment we have no alternatives. The future may teach us how to directly influence
energy resources and their distribution in the psychic apparatus by means of particular
chemical substances. (Freud 1940, p. 44)

On the other hand, antihistamine research had shown that new agents could be
systematically sought by modifying the structures of existing agents and screening
the results for interesting properties.
Another gradual but key change throughout the slow revolution initiated by
chlorpromazine was the shift in emphasis from the safety to the efficacy of psycho-
tropic drugs; for a new agent to be sanctioned by industry, clinicians, and regulatory
authorities, it was no longer sufficient that it do no harm: it must effectively improve
specific aspects of mood and behavior. This was reflected by the move from ad hoc
testing of new agents in single institutions to multicenter controlled trials. In the
United States, the National Institute of Mental Health created the Psychopharma-
cology Research Center in 1956 to formalize clinical testing of psychotropic agents,
leading to several investigations during the early 1960s that confirmed their efficacy,
including the 1964 nine-hospital, double-blind controlled trial of chlorpromazine
therapy (Healy 2002, pp. 99f.).
Further, rather than reflecting neurochemical models of the brain, the new drugs
informed the development of such models. For example, reports that chlorpromazine
could resolve the psychosis-like states induced by hallucinogens validated model
psychoses based on these effects, including transmethylation and serotonin hypoth-
eses, while amine depletion by reserpine provided clues about the roles played by
chemical modulators in mood (Baumeister et al. 2003; Baumeister and Hawkins
2005). The psychopharmacology revolution was stoked by an interaction between
basic and applied biomedical research that was unprecedented in the history of
psychiatry. The combination of initial serendipity exploited by perceptive observers
with systematic assessment and follow-up studies provided short term successes in
the clinic, but also longer term insights that would eventually reform psychophar-
macology by providing a rational (if incomplete) basis for its endeavors.
That neurochemistry and psychopharmacology should both blossom during the
1950s partially reflected their conceptual cross-fertilization. Two concepts were key to
their interaction: that mental processes were somehow related to chemical transmis-
sion in the brain (not accepted by all pharmacologists or physiologists at the start of the
decade), and that the effects of psychotropic agents on mental and cognitive function
provided clues about how chemical transmission operated in health and in disease.
Psychopharmacology: A Brief Overview of Its History 649

Throughout most of the 1950s, psychopharmacology was undertaken in the clinic

without knowing how psychotropic drugs worked. Some early antidepressants were
known to be MAO inhibitors, but how this explained their sometimes dramatic
effects in patients was a mystery. At the same time, physiologists were finding that
monoamines, acetylcholine, and other molecules were concentrated in certain brain
regions; by the mid-1950s, an at least limited role in the brain for chemical trans-
mission was avidly discussed, with acetylcholine, histamine, and substance P ini-
tially the likeliest candidates. Progress in the new field that spanned pharmacology,
physiology, and biochemistry was determined by the available tools for experimen-
tation, and the new psychotropic agents were critical in this regard. American
biochemist Bernard Brodie (1907–1989), for example, pioneered the investigation
of serotonin in the brain with the aid of reserpine, lysergic acid diethylamide, and
iproniazid, and his findings led him to ponder whether pharmacological manipula-
tion of serotonin levels might be clinically useful. Swedish pharmacologist Arvid
Carlsson (1923–2018) entertained similar thoughts about the catecholamines, par-
ticularly dopamine (review: Foley 2008).
During the early 1960s, Carlsson, Nils-Åke Hillarp (1916–1965), and Kjell Fuxe
(1938) introduced techniques for visualizing monoamines with the fluorescence
microscope, a major step in establishing neurochemistry as the dominant research
paradigm in the investigation of brain function and disease:

The 1960s were the golden age of the monoamine transmitters, so much enthusiasm, so
much hope. Many tools were developed and much knowledge accumulated, with rapid
progress on all frontiers — pharmacology (virtually every step of monoamine transmission
could be influenced by a drug), pathology (Parkinson’s disease, schizophrenia, depression),
metabolites in cerebrospinal fluid and, not least, the histochemistry. (Hökfelt 2010)

Insights provided by this revolution underlay neurochemical models of mental

dysfunction. In 1952, Abram Hoffer (1917–2009) proposed, for example, the “trans-
methylation hypothesis” of schizophrenia, in which the metabolism of aberrantly
methylated catecholamines produced endogenous psychotogens, linking it with
hallucinogen models of psychosis (mescaline, LSD). The results of clinical trials
of nicotinic acid (administered to sequester donor methyl groups) provided some
support for the hypothesis, as did the fact that methionine (a methyl donor) exacer-
bated major psychoses. Attempts to identify the psychotogenic molecule in body
fluids, however, were unsuccessful (despite brief excitement about a urinary “pink
spot” in the early 1960s), and by the 1970s the Hoffer model had lost importance
(Wyatt and Gillin 1976; Healy 2002, pp. 182–191).
A major example of the interaction between clinical and theoretical psychophar-
macology was the emergence of the dopamine hypothesis of schizophrenia. In 1963,
Carlsson and Margit Lindqvist (1924–1978) proposed that neuroleptics may act by
blocking monoamine receptors (whereby the concept of “receptors” was still con-
tentious at this point). In 1966, Jacques van Rossum (1930) hypothesized in his
article on the “significance of dopamine-receptor blockade for the mechanism of
action of neuroleptic drugs” that psychosis reflected overactivity in certain
650 P. Foley

dopaminergic pathways, a model boosted by the psychotomimetic properties of

amphetamine. New agents had initially been screened for their antagonism of
amphetamine and apomorphine and for their induction of catalepsy in laboratory
animals, but the development of techniques for labelling dopamine D2 receptors in
the 1970s allowed in vitro assessment of candidate compounds. This approach
confirmed that classic neuroleptics bound D2 receptors with high affinity, and this
was interpreted as explaining both their beneficial and extrapyramidal effects. It was
consequently assumed that D2 receptor antagonists should be selective antipsy-
chotics and that receptor binding would streamline the screening of candidate
molecules; it also reinforced the impression that the antipsychotic and extrapyrami-
dal effects of these agents could not be separated (Seeman 1987; Bennett 1998;
Baumeister and Francis 2002; Kendler and Schaffner 2011).
The “atypical” receptor-binding profile of clozapine indicated, however, that the
matter was more complicated. The dopamine hypothesis had already been criticized
for being overly simplistic, not accounting, for instance, for the negative symptoms
of the disorder. Carlsson, among others, argued that the value of clozapine perhaps
lay in its dirtiness, but that its overall impact was not simply the sum of its effects in
multiple transmitter systems, as these effects were mutually modifying. Equally
importantly, it was probable that the neurochemistry (and hence pharmacology) of
schizophrenia might be as individual as the people who had the condition (Carlsson
and Carlsson 1990). Reflecting the fact that the typical antipsychotics were relatively
ineffective against the negative symptoms of schizophrenia, the original hypothesis
was modified to propose that dopaminergic transmission in schizophrenia was
reduced in some brain regions: “schizophrenia is characterized by abnormally low
prefrontal dopamine activity (causing deficit symptoms) leading to excessive dopa-
mine activity in mesolimbic dopamine neurons (causing positive symptoms)” (Davis
et al. 1991). Once again, neurochemical findings based on the effects of existing
drugs informed models of psychosis, thereby directing the search for better medica-
tions. Pharmaceutical regulation and prevailing models had favored specificity over
polyvalency since the early 1960s, but perhaps polyvalency was precisely what was
needed. By the late 1990s, a new form of polypharmacy was now reputable, one that
took into account the complexity of both the normal brain and psychiatric disease
(Toda and Abi-Dargham 2007).
A catecholamine hypothesis of affective disorders was similarly proposed in 1965
by American psychiatrist Joseph Schildkraut (1934–2006), largely based on the
effects of antidepressants and reserpine; 2 years later, British psychiatrist Alec
Coppen (1923) published his alternative serotonin hypothesis. With technical
developments, the focus moved to monoamine receptors, but, as Schildkraut
commented on his own proposal, it was “undoubtedly, at best, a reductionist
oversimplification of a very complex biological state.” Supporters of the two
hypotheses could point to logical failings in the other, including the fact that not
all agents which enhance serotonergic or noradrenergic transmission are antidepres-
sant; on the other hand, the antidepressants are also useful for treating a range of
other conditions, including obsessive-compulsive disorder, anxiety, and eating dis-
orders. As with the dopamine hypothesis of schizophrenia, the multisystem nature of
Psychopharmacology: A Brief Overview of Its History 651

depression – in itself a less well-defined condition than psychosis – is now generally

recognized by pharmacologists and clinicians, and the potential for therapies
directed at, for example, cholinergic and glutamatergic transmission is being
explored (Mulinari 2012; Dale et al. 2015). Even more complicated is accounting
for the cycling of affect in bipolar disorder, but models involving dopamine and
other transmitters have been discussed since the mid-1970s (van Enkhuizen et al.
2015; Ashok et al. 2017).
Despite criticisms of the deficiencies of models of psychiatric disease, their
adaptability and heuristic value mean that the cross-fertilization of neurochemistry
and psychopharmacology will continue. As Healy commented, “the history of
psychopharmacology makes it clear that having a theory is scientifically useful
primarily because having a theory leads to action. The skill lies in detecting what
actually happened during tests rather than what the theory suggests must have
happened” (Healy 2002, p. 118).

Assessing the Effects of Modern Psychopharmacology

The changes in the possibilities for the pharmacologic management of psychiatric

illness and mental problems, combined with the rapid increase in knowledge about
the neurochemistry of brain function that began about 1950, radically transformed
both basic and clinical neuroscience. The focus of psychopharmacology has shifted
from the hospital to helping people live happier lives in their own communities. The
change in culture and practice was never without controversy, with (not always
baseless) concerns about drugs as “chemical straitjackets” for patients, concerns felt
by both physicians and members of the public since the late nineteenth century. The
benefits of psychotherapeutic agents have always been accompanied by unintended
motor and vegetative effects that can make their use unpleasant or even unendurable;
moreover, their very nature means that they have profound effects on consciousness
and personality that may also be regarded as disagreeable or even invalid assaults on
the person.
Skepticism about the place of pharmaceuticals in psychotherapy has also been
constant. Prominent British psychiatrist Aubrey Lewis (1900–1975) remarked in
1959 that, “If we had to choose between abandoning the new psychotropic drugs and
abandoning the industrial rehabilitation units and other social facilities available to
us, there would be no hesitation about the choice: the drugs would go” (cited by
Healy 2002, p. 133). The opposing view in professional circles was not that chemical
therapies would replace psychological and social therapies, but that, in many cases,
psychotropic drugs made the patient accessible to other forms of therapy. The
differences in climate on psychiatric wards and the increased opportunities for
treating patients without restraining or even hospitalizing them cannot be seen as
anything but major steps forward, not to mention the autonomy restored to many
people who would previously have struggled to live independent or fulfilling lives.
This view does not overlook the potential for misusing psychopharmacology,
employing it for motives other than careful and compassionate clinical reasons, or
652 P. Foley

even as a means of social control. The aim must be to constantly improve how
psychoactive drugs are deployed rather than to damn them altogether, to apply the
same careful clinical acuity and care that initiated the rapid advance of psychophar-
macology in the first place.
Marked differences between the effects experienced by people taking a particular
medication mean that listening to the individual taking them is critical. Personalized
medicine is a higher priority when treating patients with mental or cognitive
problems than in other areas of medicine; as Roland Kuhn reflected in 2005:

Instead of large statistical analyses with numerous patients and always applying the same
methods and asking the same questions, a return to the individual patient is needed. This
happens in open conversation between the patient and doctor who asks about past symptoms
and the effects of treatments already tried . . . In this manner, a unity of pharmacologic and
psychological therapy can be achieved that allows the selection, dosing and administration
of drugs to be evaluated in as short a time as possible. The more accurately the patient is
examined, the greater are the chances of success with minimal disturbing side effects. (Kuhn
2005)

A particular problem of psychopharmacology is that, even in the era of model-

directed drug design, we can never be as clear about the target of a psychotropic
agent as, for example, for an antibiotic. Knowing which receptors or enzymes are
modified by a psychotropic agent is not the same as understanding how the drug
modifies consciousness, thought patterns, or mood: there is no known pathogen to be
slain, no toxin to be expelled. Nor is even a desired effect always simple to define, as
German-American psychiatrist Fritz Freyhan (1912–1982) noted for the effects of
imipramine:

Strangely enough, [its impact] is often difficult to define, although most observers —
doctors, nurses and, last not least, the patient — agree that a change has occurred. The
essence of the transformation, it seems, is not so much reflected in what the patient
experiences in a novel manner as in what ceases to disturb him; not the spontaneous
expression of new thoughts and feelings, but the attenuation of depressive self-concern is
indicative of the pharmacotherapeutic effect. Conversely, if [imipramine] fails, the patient
remains as he was. (Freyhan 1959)

Symptoms, not diseases, are treated in psychiatry: there are no genuinely “anti-
schizophrenia” or “anti-anxiety” drugs; a medication from one class will probably be
useful for some patients with other problems. The exercise is complicated by the
importance of individual differences in set and setting, of the psychology and
physiology of the person taking a drug and the circumstances in which they are
taking it. Further, a drug that benefits “only” a small number of patients in a clinical
trial may not be a failure, but rather a tool that identifies people with a specific
treatable dysfunction. We have learned a great deal about the brain and the mind
from the effects of psychotropic agents in patients, but they may also point to
shortcomings of the Kraepelinian nosology of psychiatric disorders or the concept,
for instance, of “depressive illness.” Re-examination of older concepts of syndromes
or symptom complexes in psychiatry, rather than diseases, may be rewarding.
Psychopharmacology: A Brief Overview of Its History 653

The central problems of psychopharmacology are that the effects of psychotropic

drugs are more difficult to delimit than those of an antibiotic, for example, and that
their modulation of mentation or mood cannot be immediately explained by its
molecular actions. For these reasons, it is also more difficult to model their effects
in laboratory animals; Freiburg psychiatrist Rudolf Degkwitz (1920–1990) even
opined that “the intrinsic psychopharmacologic effect of [psychotropic drugs] can
only be investigated in mentally healthy people” (Degkwitz 1967, p. 28), for which
reason he had tried many of the new agents himself. While the validity of such an
approach might be questioned – do psychoactive agents necessarily have similar
effects in “healthy controls” and in those with mental problems? – this philosophy
had long played a role in psychopharmacology, as investigators strove to understand
the effects of psychotropic drugs from within.
For the same reasons, serendipity has also played a major role in psychopharma-
cology: not blind fortune, but the intersection of astute openness to the implications
of unexpected observations, favored by an environment or Zeitgeist that values these
insights, and the intellectual, institutional, and economic interest in following new
paths in laboratory and clinical research that motivates systematic testing and pro-
vides intellectual and financial support. Rational drug design can be very useful in
psychopharmacology, but it should be remembered that the neurochemical models of
mental dysfunction were founded on findings with psychopharmacologic agents, not
vice versa. The founding scientific director of the National Institute of Mental
Health, Seymour Kety (1915–2000), remarked during the height of the slow
revolution:

One of the speakers yesterday mentioned that the court of last appeal is the practical effect on
patients. We must not forget, however, that basic research can also be done in man, and
clinical studies can contribute a great deal to a fundamental understanding of how these
agents act and what are the roles of the monoamines in the brain. (Kety 1962)

Too stringent a focus on pursuing what is already unknown can divert attention from
what lies just outside one’s field of view. Goal-directed development is indubitably
valuable, but breakthroughs and radically new insights usually come from unex-
pected quarters.

References
Abdelgadir IS, Gordon MA, Akobeng AK. Melatonin for the management of sleep problems in
children with neurodevelopmental disorders: a systematic review and meta-analysis. Arch Dis
Child. 2018;103:1155–62.
Aisen PS, Cummings J, Schneider LS. Symptomatic and nonamyloid/tau based pharmacologic
treatment for Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:a006395.
Aita JF, Aita JA, Aita VA. 7-Up anti-acid lithiated lemon soda or early medicinal use of lithium.
Nebr Med J. 1990;75:277–80.
Angrist BM. The neurobiologically active benzamides and related compounds: some historical
aspects. In: Rotrosen J, Stanley M, editors. The benzamides: pharmacology, neurobiology, and
654 P. Foley

clinical effects (Advances in biochemical psychopharmacology; 35). New York: Raven Press;
1982. pp. 1–6.
Ashok AH, Marques TR, Jauhar S, Nour MM, Goodwin GM, Young AH, Howes OD. The
dopamine hypothesis of bipolar affective disorder: the state of the art and implications for
treatment. Mol Psychiatry. 2017;22:666–79.
Atkin T, Comai S, Gobbi G. Drugs for insomnia beyond benzodiazepines: pharmacology, clinical
applications, and discovery. Pharmacol Rev. 2018;70:197–245.
Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL. Evidence for the efficacy of melatonin in
the treatment of primary adult sleep disorders. Sleep Med Rev. 2017;34:10–22.
Awouters FH, Lewi PJ. Forty years of antipsychotic drug research – from haloperidol to
paliperidone – with Dr. Paul Janssen. Arzneimittelforschung. 2007;57:625–32.
Ayd FJ. Fatal hyperpyrexia during chlorpromazine therapy. J Clin Exp Psychopathol.
1956;17:189–92.
Baldwin DS, Anderson IM, Nutt DJ, Christer A, Bandelow B, den Boer JA, Christmas DM, Davies
S, Fineberg N, Lidbetter N, Malizia A, McCrone P, Nabarro D, O’Neill C, Scott J, van der Wee
N, Wittchen H-U. Evidence-based pharmacological treatment of anxiety disorders, post-trau-
matic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from
the British Association for Psychopharmacology. J Psychopharmacol. 2014;28:403–39.
Balme R. Early medicinal uses of bromides. J R Coll Physicians Edinb. 1976;10:205–8.
Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat.
2007;3:495–500.
Barbara J-G. History of psychopharmacology: from functional restitution to functional enhance-
ment. In: Clausen J, Levy N, editors. Handbook of neuroethics. Dordrecht: Springer; 2015.
pp. 489–504.
Barroso MS. The hellebore, the plant beloved by the Greeks: the reasons behind a myth. Vesalius.
2015;21:30–7.
Battleday RM, Brem AK. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived
subjects: a systematic review. Eur Neuropsychopharmacol. 2015;25:1865–81.
Baumeister AA. The chlorpromazine enigma. J Hist Neurosci. 2013;22:14–29.
Baumeister AA, Francis JL. Historical development of the dopamine hypothesis of schizophrenia.
J Hist Neurosci. 2002;11:265–77.
Baumeister AA, Hawkins MF. Continuity and discontinuity in the historical development of
modern psychopharmacology. J Hist Neurosci. 2005;14:199–209.
Baumeister AA, Hawkins MF, Uzelac SM. The myth of reserpine-induced depression: role in the
historical development of the monoamine hypothesis. J Hist Neurosci. 2003;12:207–20.
Becker PM, Somiah M. Non-benzodiazepine receptor agonists for insomnia. Sleep Med Clin.
2015;10:57–76.
Bennett MR. Monoaminergic synapses and schizophrenia: 45 years of neuroleptics.
J Psychopharmacol. 1998;12:289–304.
Berger H. Zur Pathogenese des katatonischen Stupors. Münch med Wschr. 1921;68:448–50.
Beringer K. Der Meskalinrausch: Seine Geschichte und Erscheinungsweise. Berlin: Julius Springer;
1927.
Bleuler E. Die Kritiken der Schizophrenien. Zschr f d ges Neurol u Psychiat. 1914;22:19–44.
Bossong F. Erinnerung an Roland Kuhn (1912–2005) und 50 Jahre Imipramin. Nervenarzt.
2008;79:1080–6.
Braslow JT. History and evidence-based medicine: lessons from the history of somatic treatments
from the 1900s to the 1950s. Ment Health Serv Res. 1999;1:231–40.
Brouillot P, Broussolle P, Greffe J, Guyotat J, Lambert P, Lemoine P. The birth of
psychopharmacotherapy: explorations in a new world 1952–1968. In: Healy D, editor. The
psychopharmacologists, vol. 3. London: Arnold; 2000. pp. 1–54.
Brown WA, Rosdolsky M. The clinical discovery of imipramine. Am J Psychiatr. 2015;172:426–9.
Butler TC. The introduction of chloral hydrate into medical practice. Bull Hist Med.
1970;44:168–72.
Psychopharmacology: A Brief Overview of Its History 655

Carlsson M, Carlsson A. Interactions between glutamatergic and monoaminergic systems within the
basal ganglia – implications for schizophrenia and Parkinson’s disease. Trends Neurosci.
1990;13:272–6.
Caroff SN. The neuroleptic malignant syndrome. J Clin Psychiatry. 1980;41:79–83.
Carpenter WT, Davis JM. Another view of the history of antipsychotic drug discovery and
development. Mol Psychiatry. 2012;17:1168–73.
Castro Caldas A, Teodoro T, Ferreira JJ. The launch of opicapone for Parkinson’s disease: negatives
versus positives. Expert Opin Drug Saf. 2018;17:331–7.
Chiarello RJ, Cole JO. The use of psychostimulants in general psychiatry: a reconsideration.
Arch Gen Psychiatry. 1987;44:286–95.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG,
Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A,
Ioannidis JPA, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for
the acute treatment of adults with major depressive disorder: a systematic review and network
meta-analysis. Lancet. 2018;391:1357–66.
Clouston TS. Clinical lectures on mental diseases. London: J. & A. Churchill; 1887.
Colonna L. Antideficit properties of neuroleptics. Acta Psychiatr Scand. 1994;89(Suppl.
380):77–82.
Contestabile A. The history of the cholinergic hypothesis. Behav Brain Res. 2011;221:334–40.
Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967;113:1237–64.
Corponi F, Fabbri C, Bitter I, Montgomery S, Vieta E, Kasper S, Pallanti S, Serretti A. Novel
antipsychotics specificity profile: a clinically oriented review of lurasidone, brexpiprazole,
cariprazine and lumateperone. Eur Neuropsychopharmacol. 2019;29:971–85.
Costentin J. Une nouvelle approche de la prise en charge de la schizophrénie: les agonistes partiels
des récepteurs D2 de la dopamine. Ann Pharm Fr. 2009;67:310–9.
Crilly J. The history of clozapine and its emergence in the US market: a review and analysis. Hist
Psychiatry. 2007;18:39–60.
D’Abreu A, Akbar U, Friedmanac JH. Tardive dyskinesia: epidemiology. J Neurol Sci.
2018;389:17–20.
Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond
SSRIs and SNRIs. Biochem Pharmacol. 2015;95:81–97.
Davis KL, Kahn R, Ko G, Davidson M. Dopamine in schizophrenia: a review and
reconceptualization. Am J Psychiatr. 1991;148:1474–86.
Debreyne. Des vertus thérapeutiques de la belladone. Paris: J.-B. Ballière; 1852.
Degkwitz R. Leitfaden der Psychopharmakologie für Klinik und Praxis. Stuttgart:
Wissenschaftliche Verlags-Gesellschaft; 1967.
Delay J, Deniker P. Trente-huit cas de psychoses traitées par la cure prolongée et continue de 4560
R. P. C. R. In: Congrès des médecins aliénistes et neurologistes de France et des pays de langue
française, Le session, Luxembourg, 21–27 juillet 1952. Paris: Masson & Cie; 1952. pp. 503–13.
Delay J, Pichot P, Lemperiere T, Glissalde B, Peigne F. Le neuroleptique majeur non
phenothiazinique et non reserpinique, l’haloperidol, dans le traitement es psychoses [Séance
du 21 Decembre 1959]. Annales médico-psychologiques (Paris). 1960;118:145–52.
Denicoff KD, Frye MA, Dunn RT, Leverich GS, Osuch E, Speer A. A history of the use of
anticonvulsants as mood stabilizers in the last two decades of the 20th century. Neuropsychobiology.
1998;38:152–66.
Deniker P. From chlorpromazine to tardive dyskinesia (brief history of the neuroleptics). Psychiatr
J Univ Ott. 1989;14:253–9.
Dormandy T. Opium: reality’s dark dream. New Haven: Yale University Press; 2012.
Douchamps V, Mathis C. A second wind for the cholinergic system in Alzheimer’s therapy. Behav
Pharmacol. 2017;28:112–23.
Dub LA, Lurie LA. Use of benzedrine in the depressed phase of the psychotic state. Ohio State Med
J. 1939;35:39–45.
Dundee JW, McIlroy PDA. The history of the barbiturates. Anaesthesia. 1982;37:726–34.
656 P. Foley

Duval AM, Goldman D. The new drugs (chlorpromazine & reserpine): administrative aspects.
Ment Hosp. 1956:7, 30–34. (reprinted: Psychiatric Services 2000; 2051:2327–2331)
Eadie MJ. Convulsive ergotism: epidemics of the serotonin syndrome? Lancet Neurol.
2003;2:429–34.
Eadie MJ. Sir Charles Locock and potassium bromide. J R Coll Physicians Edinb. 2012;42:274–9.
Fangmann P, Assion H-J, Juckel G, González CÁ, López-Muñoz F. Half a century of antidepressant
drugs. On the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics.
Part II: tricyclics and tetracyclics. J Clin Psychopharmacol. 2008;28:1–4.
Fink M. Meduna and the origins of convulsive therapy. Am J Psychiatr. 1984;141:1034–41.
Fink M. Catatonia: a syndrome appears, disappears, and is rediscovered. Can J Psychiatr Rev Can
Psychiatr. 2009;54:437–45.
Flechsig P. Über eine neue Behandlungsmethode der Epilepsie. Neurol Centralbl. 1893;12:229–31.
Foley PB. Beans, roots and leaves. A history of the chemical therapy of parkinsonism. Marburg:
Tectum Verlag; 2003.
Foley P. Succi nervorum: a brief history of neurochemistry. J Neural Transm Suppl. 2008;72:5–15.
Foley PB. Sons and daughters beyond your control: episodes in the prehistory of the attention
deficit/hyperactivity syndrome. Atten Defic Hyperact Disord. 2014;6:125–51.
Foley PB. Encephalitis lethargica. The mind and brain virus. New York: Springer; 2018.
Folin O. Some metabolism studies. With special reference to mental disorders. Am J Insanity.
1904;60:699–732.
Fond G, Micoulaud-Franchi J-A, Brunel L, Macgregor A, Miot S, Lopez R, Richieri R, Abbar M,
Lancon C, Repantis D. Innovative mechanisms of action for pharmaceutical cognitive
enhancement: a systematic review. Psychiatry Res. 2015;229:12–20.
Freeman W. Psychochemistry: some physicochemical factors in mental disorders. J Am Med Assoc.
1931;97:293–6.
Freud S. Abriß der Psychoanalyse (aus dem Nachlaß). Internationalen Zeitschrift für Psychoanalyse
und Imago. 1940;25:7–67.
Freyhan FA. Comments on the biological and psychopathological basis of individual variation in
chlorpromazine therapy. L’Encéphale. 1956;45:913–9.
Freyhan FA. Clinical effectiveness of Tofranil in the treatment of depressive psychoses.
Can Psychiatr Assoc J. 1959;4(Suppl):S86–99.
Froestl W, Pfeifer A, Muhs A. Cognitive enhancers (nootropics). Update 2014. J Alzheimers Dis.
2014;42:1–68,961–1019,1079–1149
Gjessing R. Beiträge zur Kenntnis der Pathophysiologie periodisch katatoner Zustände. IV.
Mitteilung. Versuch einer Ausgleichung der Funktionsstörungen. Arch Psychiatr Nervenkr.
1939;109:525–95.
Granger B, Albu S. The haloperidol story. Ann Clin Psychiatry. 2005;17:137–40.
Griesinger W. Die Pathologie und Therapie der psychischen Krankheiten für Ärzte und Studirende.
2nd ed. Stuttgart: Adolph Krabbe; 1861.
Haddad PM, Correll CU. The acute efficacy of antipsychotics in schizophrenia: a review of recent
meta-analyses. Ther Adv Psychopharmacol. 2018;8:303–18.
Haenel T. Jakob Klaesi: Schlafkur und Antieidodiathese. Gesnerus. 1979;36:246–65.
Hanzlik PJ. Purkinje’s pioneer self-experiments in psychopharmacology. Cal West Med.
1938;49:140–2.
Hare EH, McCance C, McCormick WO. Imipramine and “Drinamyl” in depressive illness: a
comparative trial. Br Med J. 1964;1:818.
Harley J. The old vegetable neurotics. Hemlock, opium, belladonna and henbane. Their
physiological action and therapeutical use alone and in combination. Being the Gulstonian
lectures of 1868, extended and including a complete examination of the active constituents of
opium. London: Macmillan and Co.; 1869.
Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present – a pharmacological and
clinical perspective. J Psychopharmacol. 2013;27:479–96.
Healy D. The creation of psychopharmacology. Cambridge, MA: Harvard University Press; 2002.
Psychopharmacology: A Brief Overview of Its History 657

Herzberg D. Blockbusters and controlled substances: Miltown, Quaalude, and consumer demand
for drugs in postwar America. Stud Hist Phil Biol Biomed Sci. 2011;42:415–26.
Hökfelt T. Looking at neurotransmitters in the microscope. Prog Neurobiol. 2010;90:101–18.
Hollister LE. The pre-benzodiazepine era. J Psychoactive Drugs. 1983;15:9–13.
Howland RH. Methylene blue: the long and winding road from stain to brain. J Psychosoc Nurs
Ment Health Serv. 2016;10(9):21–4, (10) 21–26
Huehnerfeld J. The hematoporphyrin treatment of melancholia and endogenous depression.
Am J Psychiatr. 1936;92:1323–30.
Ilieva IP, Hook CJ, Farah MJ. Prescription stimulants’ effects on healthy inhibitory control, working
memory, and episodic memory: a meta-analysis. J Cogn Neurosci. 2015;27:1069–89.
Jaspers K. Allgemeine Psychopathologie. 4th ed. Berlin/Heidelberg: Springer; 1946.
Jones PB, Barnes TRE, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A,
Lewis SW. Randomized controlled trial of the effect on quality of life of second- vs first-
generation antipsychotic drugs in schizophrenia: Cost Utility of the latest Antipsychotic Drugs
in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006;63:1079–87.
Kalischer S. Medikamentöse Therapie. In: Lewandowsky M, editor. Handbuch der Neurologie.
Erster Band: Allgemeine Neurologie, zweiter Teil. Berlin: Julius Springer; 1910. pp. 1481–515.
Kendler KS, Schaffner KF. The dopamine hypothesis of schizophrenia: an historical and
philosophical analysis. Philos Psychiatry Psychol. 2011;18:41–63.
Kety SS. Résumé: I. Biochimie. In: de Ajuriaguerra J, editor. Monoamines et système nerveux
central. Symposium Bel-Air, Genève, Septembre 1961. Genève: Georg et Cie; 1962. pp. 263–8.
King C, Voruganti LNP. What’s in a name? The evolution of the nomenclature of antipsychotic
drugs. J Psychiatry Neurosci. 2002;27:168–75.
Kraepelin E. Über die Beeinflussung einfacher psychischer Vorgänge durch einige Arzneimittel.
experimentelle Untersuchungen. Jena: Gustav Fischer; 1892.
Kraepelin E. Klinische Psychiatrie. Psychiatrie: ein Lehrbuch für Studirende und Ärzte. Bd. 2.
Leipzig: Barth; 1899.
Kuhn R. Psychopharmakologie gestern – heute – morgen. Vortrag zur Verleihung der Hans-
Prinzhorn-Medaille in Berlin am 28. Oktober 2004. Schweiz Arch Neurol Psychiatr.
2005;156:267–9.
Lader M. History of benzodiazepine dependence. J Subst Abus Treat. 1991;8:53–9.
Laignel-Lavastine M. Des troubles psychiques par perturbations des glandes à sécrétion interne.
Congrès des aliénistes et neurologistes de France et des pays de langue française, XVIIIe
session, Dijon, août 1908. Paris: G. Masson; 1908.
Lambert PA, Revol L. Classification psychopharmacologique et clinique des différents
neuroleptiques. Indications thérapeutiques générales dans les psychoses. Presse Med.
1960;68:1509–11.
Ledermann F. Pharmacie, médicaments et psychiatrie vers 1850: le cas de Jacques-Joseph Moreau
de Tours. Rev Hist Pharm. 1988;35:67–76.
Lehmann HE. Before they called it psychopharmacology. Neuropsychophrmacology.
1993;8:291–303.
Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, Samara M, Barbui C, Engel RR,
Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM. Comparative efficacy and
tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.
Lancet. 2013;382:951–62.
Lewin L. Phantastica: die betäubenden und erregenden Genussmittel, für Ärzte und Nichtärzte.
Berlin: Georg Stilke; 1924.
Loera-Valencia R, Cedazo-Minguez A, Kenigsberg PA, Page G, Duarte AI, Giusti P, Zusso M,
Robert P, Frisoni GB, Cattaneo A, Zille M, Boltze J, Cartier N, Buee L, Johansson G, Winblad
B. Current and emerging avenues for Alzheimer’s disease drug targets. J Intern Med.
2019;86:398–437.
López-Muñoz F, Alamo C. The consolidation of neuroleptic therapy: Janssen, the discovery of
haloperidol and its introduction into clinical practice. Brain Res Bull. 2009;79:130–41.
658 P. Foley

López-Muñoz F, Álamo C. Monoaminergic neurotransmission: the history of the discovery of

antidepressants from 1950s until today. Curr Pharm Des. 2009;15:1563–86.
López-Muñoz F, Bhatara VS, Álamo C, Cuenca E. Aproximación histórica al descubrimiento de la
reserpina y su introducción en la clinica psiquiátrica. Actas Espanolas de Psiquiatria.
2004a;32:387–95.
López-Muñoz F, Ucha-Udabe R, Álamo-González C. Un siglo de barbitúricos en neurología.
Rev Neurol. 2004b;39:767–75.
López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and
clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005;17:113–35.
López-Muñoz F, Álamo C, García-García P. The discovery of chlordiazepoxide and the clinical
introduction of benzodiazepines: half a century of anxiolytic drugs. J Anxiety Disord.
2011;25:554–62.
López-Muñoz F, Shen WW, D’Ocon P, Romero A, Álamo C. A history of the pharmacological
treatment of bipolar disorder. Int J Mol Sci. 2018;19:2143.
Löscher W, Rogawski MA. How theories evolved concerning the mechanism of action of barbiturates.
Epilepsia. 2012;53(Suppl. 8):12–25.
Macht DI. Contributions to psychopharmacology. Johns Hopkins Hosp Bull. 1920;31:167–73.
Maier HW. Der Kokainismus: Geschichte, Pathologie, Medizinische und behördliche Bekämpfung.
Leipzig: Georg Thieme; 1926.
Malhi GS, Byrow Y, Bassett D, Boyce P, Hopwood M, Lyndon W, Mulder R, Porter R, Singh A,
Murray G. Stimulants for depression: on the up and up? Aust N Z J Psychiatry.
2016;50:203–7.
Malykh AG, Sadaie MR. Piracetam and piracetam-like drugs. From basic science to novel clinical
applications to CNS disorders. Drugs. 2010;70:287–312.
Mandrioli R, Protti M, Mercolini L. New-generation, non-SSRI antidepressants: therapeutic drug
monitoring and pharmacological interactions. Part 1: SNRIs, SMSs, SARIs. Curr Med Chem.
2018;25:772–92.
Margineanu DG. A weird concept with unusual fate: nootropic drug. Revue des Questions
Scientifiques. 2011;182:33–52.
Marraccini ME, Weyandt LL, Rossi JS, Gudmundsdottir BG. Neurocognitive enhancement or
impairment? A systematic meta-analysis of prescription stimulant effects on processing speed,
decision-making, planning, and cognitive perseveration. Exp Clin Psychopharmacol.
2016;24:269–84.
Moncrieff J. The creation of the concept of an antidepressant: an historical analysis. Soc Sci Med.
2008;66:2346–55.
Moreau de Tours J. Du hachisch et de l’aliénation mentale. Études psychologiques. Paris: Fortin,
Masson & Cie; 1845.
Mulinari S. Monoamine theories of depression: historical impact on biomedical research. J Hist
Neurosci. 2012;21:366–92.
Müller T, Möhr JD. Pharmacokinetics of monoamine oxidase B inhibitors in Parkinson’s disease:
current status. Expert Opin Drug Metab Toxicol. 2019;15:429–35.
Müller U, Fletcher PC, Steinberg H. The origin of pharmacopsychology: Emil Kraepelin’s
experiments in Leipzig, Dorpat and Heidelberg (1882–1892). Psychopharmacology (Berlin).
2006;184:131–8.
Murri MB, Guaglianone A, Bugliani M, Calcagno P, Respino M, Serafini G, Innamorati M, Pompili
M, Amore M. Second-generation antipsychotics and neuroleptic malignant syndrome: systematic
review and case report analysis. Drugs R&D. 2015;15:45–62.
Noll R. Kraepelin’s ‘lost biological psychiatry’? Autointoxication, organotherapy and surgery for
dementia praecox. Hist Psychiatry. 2007;18:301–20.
Nucifora FC, Mihaljevic M, Lee BJ, Sawa A. Clozapine as a model for antipsychotic development.
Neurotherapeutics. 2017;14:750–61.
Onians RB. The origins of European thought about the body, the mind, the soul, the world, time,
and fate. Cambridge, MA: Cambridge University Press; 1988.
Psychopharmacology: A Brief Overview of Its History 659

Oppenheimer H. Medical and allied topics in Latin poetry. London: John Bale, Sons & Danielson;
1928.
Page IH. Chemistry of the brain. Springfield/Baltimore: Charles C. Thomas; 1937.
Paladin A. Recherches sur la biochimie du cerveau. Bull Soc Chim Biol. 1934;16:1193–210.
Pare CMB, Rees L, Sainsbury MJ. Differentiation of two genetically specific types of depression by
the response to anti-depressants. Lancet. 1962;2:1340–3.
Paulson GW. Historical comments on tardive dyskinesia: a neurologist’s perspective. J Clin
Psychiatry. 2005;66:260–4.
Perez-Caballero L, Torres-Sanchez S, Bravo L, Mico JA, Berrocoso E. Fluoxetine: a case history of
its discovery and preclinical development. Expert Opin Drug Discovery. 2014;9:567–78.
Pinel P. Traité medico-philosophique sur l’aliénation mentale. Paris: J. Ant. Brosson; 1809.
Ramchandani D, López-Muñoz F, Álamo C. Meprobamate: tranquilizer or anxiolytic? A historical
perspective. Psychiatry Q. 2006;77:43–53.
Rasmussen N. Making the first anti-depressant: amphetamine in American medicine, 1929–1950.
J Hist Med Allied Sci. 2006;61:288–323.
Rasmussen N. Amphetamine-type stimulants: the early history of their medical and non-medical
uses. Int Rev Neurobiol. 2015;120:9–25.
Reiter PJ. Behandlung von Dementia praecox mit Metallsalzen a. m. Walbum. I. Mangan.
Vorläufige Mitteilung. Zschr f d ges Neurol u Psychiat. 1929;108:464–80.
Ring J, Grosber M, Brockow K, Bergmann K-C. Anaphylaxis. In: Bergmann K-C, Ring J, editors.
History of allergy. Basel: Karger; 2014. pp. 54–61.
Robbins TW. Pharmacological treatment of cognitive deficits in nondementing mental health
disorders. Dialogues Clin Neurosci. 2019;21:301–8.
Robitzek EH, Selikoff IJ, Ornstein GG. Chemotherapy of human tuberculosis with hydrazine
derivatives of isonicotinic acid. Q Bull Sea View Hosp. 1952;13:27–51.
Roncero C, Álvarez FJ. The use of lisdexamfetamine dimesylate for the treatment of ADHD and
other psychiatric disorders. Expert Rev Neurother. 2014;14:849–65.
Ross S, Cole JO. Psychopharmacology. Annu Rev Psychol. 1960;11:415–38.
Rupniak NMJ, Kramer MS. NK1 receptor antagonists for depression: why a validated concept was
abandoned. J Affect Disord. 2017;223:121–5.
Schatzberg AF. New approaches to managing psychotic depression. J Clin Psychiatry. 2003;64
(Suppl. 1):19–23.
Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting
evidence. Am J Psychiatr. 1965;509:509–22.
Schioldann J. ‘On periodical depressions and their pathogenesis’ by Carl Lange (1886). Hist
Psychiatry. 2011;22:108–30.
Schmitz H. Die Opiumbehandlung bei Geisteskrankheiten, insbesondere bei Melancholie, ihre
Geschichte, ihr heutiger Stand und eigene Erfahrungen. Allg Zschr Psychiat psych-gerichtl
Med. 1925;83:92–112.
Schneider PJ. Entwurf zu einer Heilmittellehre gegen psychische Krankheiten, oder Heilmittel in
Beziehung auf psychische Krankheitsformen. Tübingen: Heinrich Laupp; 1824.
Schou M. Lithium treatment at 52. J Affect Disord. 2001;67:21–32.
Seeman P. Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse.
1987;1:133–52.
Seige M. Klinische Erfahrungen mit Neuronal. Dtsch Med Wochenschr. 1912;38:1828–30.
Sertürner F. Darstellung der reinen Mohnsäure (Opiumsäure) nebst einer chemischen Untersuchung
des Opiums mit vorzüglicher Hinsicht auf einen darin neu entdeckten Stoff und die dahin
gehörigen Bemerkungen. Journal der Pharmacie für Ärzte, Apotheken und Chemisten.
1806;14:47–93.
Shen WW. A history of antipsychotic drug development. Compr Psychiatry. 1999;40:407–14.
Siegel RE. Galen on psychology, psychopathology, and function and diseases of the nervous
system. Basel: S. Karger; 1973.
Somers K. Notes on rauwolfia and ancient medical writings of India. Med Hist. 1958;2:87–91.
660 P. Foley

Sourkes TL. Early clinical neurochemistry of CNS-active drugs. Bromides. Mol Chem
Neuropathol. 1991;14:131–42.
Sourkes TL. Early clinical neurochemistry of CNS-active drugs. Chloral hydrate. Mol Chem
Neuropathol. 1992;17:21–30.
Speaker SL. From “happiness pills” to “national nightmare”: changing cultural assessment of minor
tranquilizers in America, 1955–1980. J Hist Med Allied Sci. 1997;52:338–76.
Steck H. Le syndrome extrapyramidal et diencéphalique au cours de traitements au largactil et ou
serpasil. Ann Med Psychol. 1954;112:737–43.
Sternbach LH. The benzodiazepine story. J Psychoactive Drugs. 1983;15:15–7.
Szökő É, Tábi T, Riederer P, Vécsei L, Magyar K. Pharmacological aspects of the neuroprotective
effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease.
J Neural Transm. 2018;125:1735–49.
Tarsy D. History and definition of tardive dyskinesia. Clin Neuropharmacol. 1983;6:91–9.
Thorner MW. Psycho-pharmacology of sodium amytal. J Nerv Ment Dis. 1935;81:161–7.
Thudichum JLW. A treatise on the chemical constitution of the brain. London: Ballière, Tindall &
Cox; 1884.
Toda M, Abi-Dargham A. Dopamine hypothesis of schizophrenia: making sense of it all.
Curr Psychiatry Rep. 2007;9:329–36.
Tschupp C. Johanniskraut, Hypericum perforatum L.: vom Hexenkraut zum modernen Arzneimittel
(Veröffentlichungen der Schweizerischen Gesellschaft für Geschichte der Pharmazie; 26).
Brugg: Schweizerischen Gesellschaft für Geschichte der Pharmazie; 2004.
van Enkhuizen J, Janowsky DS, Olivier B, Minassian A, Perry W, Young JW, Geyer MA. The
catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited. Eur J
Pharmacol. 2015;753:114–26.
Vanle B, Olcott W, Jimenez J, Bashmi L, Danovitch I, IsHak WW. NMDA antagonists for treating
the non-motor symptoms in Parkinson’s disease. Transl Psychiatry. 2018;8:117.
Vogt C, Vogt O. Zur Lehre der Erkrankungen des striären Systems. J Psychol Neurol. 1920;25
(Suppl 3):627–846.
Walther-Buël H. Drei Dezennien Narkotherapie. Monatsschr Psychiatr Neurol. 1953;125:718–31.
Walton M. Deep sleep therapy and Chelmsford private hospital: have we learnt anything? Australas
Psychiatry. 2013;21:206–12.
Weber MM. Die „Opiumkur” in der Psychiatrie: Ein Beitrag zur Geschichte der
Psychopharmakotherapie. Sudhoffs Arch. 1987;71:31–61.
Weber MM. Die Entwicklung der Psychopharmakologie im Zeitalter der naturwissenschaftlichen
Medizin Ideengeschichte eines psychiatrischen Therapiesystems. München: Urban und Vogel;
1999.
Weiden PJ. EPS profiles: the atypical antipsychotics are not all the same. J Psychiatr Pract.
2007;13:13–24.
Wilkins RW. Clinical usage of Rauwolfia alkaloids, including reserpine (Serpasil). Ann N Y Acad
Sci. 1954;59:36–44.
Williams M. Antianxiety agents: a historical perspective. In: Meldrum BS, Williams M, editors.
Current and future trends in anticonvulsant, anxiety, and stroke therapy: proceedings of a
symposium held at Princeton, New Jersey, May 21–23, 1989 (Progress in clinical and biological
research, 361). New York: Wiley-Liss; 1990. pp. 131–44.
Winblad B. Piracetam: a review of pharmacological properties and clinical uses. CNS Drug Rev.
2005;11:169–82.
Wolf MA, Yassa R, Llorca PM. Complications extrapyramidales induites par les neuroleptiques.
Perspectives historiques. Encephalé. 1993;19:657–61.
Wong DT, Perry KW, Bymaster FP. The discovery of fluoxetine hydrochloride (Prozac). Nat Rev
Drug Discov. 2005;4:764–74.
Wyatt RJ, Gillin JC. The transmethylation hypothesis: a quarter of a century later. Psychiatr Ann.
1976;6:33–49.
Yáñez M, Padín JF, Arranz-Tagarro JA, Camina M, Laguna R. History and therapeutic use of
MAO-A inhibitors: a historical perspective of MAO-A inhibitors as antidepressant drug. Curr
Top Med Chem. 2012;12:2275–82.
Historical Overview of Psychiatric
Diagnostics in Japan

Toshiyuki Someya and Satoshi Hoya

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
Psychiatric Diagnostics Before DSM-III in Japan (Conventional Psychiatric Diagnostics) . . . 662
Problems of Conventional Psychiatric Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
Turning Point of Psychiatric Diagnostics in Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
Psychiatric Diagnostics After Introduction of DSM in Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
Reaffirming the Basic Idea of DSM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
Domestic Opinion About DSM-5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
Major Depressive Disorder Versus Bereavement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
Neurocognitive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Toward Future Development of Psychiatric Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669

Abstract
When Japanese psychiatry was in its infancy, the disease concepts held by
individual physicians varied, and even the same diagnosis could sometimes
refer to a completely different group of symptoms. Based on such reliability
problems of psychiatric diagnostics, DSM-III (Diagnostic and Statistical Manual
of Mental Disorders – Third Edition) was introduced to Japan in 1982. Since then,
the reliability of psychiatric diagnostics has increased. Fields such as clinical
practice, education, and research in Japan have also benefited from DSM. How-
ever, it is also true that the misuse of DSM by inexperienced users has caused
adverse effects. The misuse of DSM is attributed mainly to the misunderstanding

T. Someya (*) · S. Hoya

Department of Psychiatry, Niigata University Graduates School of Medicine and Dental Science,
Niigata, Japan
e-mail: psy@med.niigata-u.ac.jp; houya-nii@umin.ac.jp

© Springer Nature Switzerland AG 2022 661

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_21
662 T. Someya and S. Hoya

that “it’s a disease simply because it’s specified in DSM diagnostic criteria.” DSM
diagnostic criteria have been created to stipulate the core of each disease. Thus, in
using those criteria, sufficient understanding of the ideal type of the disease, the
characteristics and symptoms including those not stated in DSM, is a prerequisite.
Attempting to extract a homogeneous population based on such an appropriate
use has been a challenge of DSM to date. Reaffirming this basic idea of DSM is
necessary for the future development of psychiatric diagnostics. In addition, we
must not forget that psychiatric diagnostics strive not only to provide diagnosis of
a disease but also to understand human beings from a multifaceted viewpoint,
bearing in mind each patient’s personality as well as the social and environmental
background.

Introduction

The DSM (Diagnostic and Statistical Manual of Mental Disorders) and ICD (Inter-
national Classification of Diseases) are both taught in Japanese medical schools in
addition to traditional psychiatry, and both DSM and ICD are widely used in
psychiatric care in Japan. The DSM in particular has widely permeated clinical
practice, education, and research in Japan, and virtually all clinical research and
clinical trials reference it for the definition of the target disease (Kuroki et al. 2016).
In this chapter, we summarize the changes in psychiatric diagnostics in Japan,
focusing on the DSM and clarifying the important points for moving forward with
future diagnostic development.

Psychiatric Diagnostics Before DSM-III in Japan (Conventional

Psychiatric Diagnostics)

In Japan, the systematic study of psychiatry is said to have begun in 1886, with the
establishment of Japan’s first psychiatry course in the Medical College of the
Imperial University (currently the Faculty of Medicine, University of Tokyo).
With the landing of the United States Navy East India Fleet (in Japan, this is
commonly known as the Black Ships) commanded by Perry in 1853, there ended
215 years of national isolation (a self-imposed policy prohibiting transport and trade
between Japan and other countries), and henceforth the Japanese government rapidly
introduced modern Western technology. In particular, it was officially announced
that German medicine would be introduced into Japan. Hajime Sasaki, the first
lecturer appointed to teach psychiatry in the Medical College of the Imperial
University, had studied in Germany, and German army surgeons were also recruited
as professors at the same university. Doctors who studied psychiatry in this course
were subsequently appointed to psychiatry departments in university medical facul-
ties newly established in various regions throughout Japan. Thus, German psychiatry
strongly influenced the emerging field of psychiatry in Japan (Omata 2005).
Historical Overview of Psychiatric Diagnostics in Japan 663

Specifically, the concept proposed by Kraepelin of two distinct forms of psychiatric

disease (schizophrenia and manic depression), and a classification method based on
categorizing etiology as exogenous, psychogenic, or endogenous, formed the basis
of Japanese psychiatry. Jaspers’s concept of understanding was used to deduce
etiology.
Later, Japan developed its own specific psychopathology, based on German
psychopathology, motivated by the necessity of treatment and prognosis prediction
suited to actual conditions in Japan. One of the results of this development can be
seen in the invention of a Japanese depression classification. The Japanese-specific
depression classification, by Kasahara and Kimura (Kasahara and Kimura 1975), is
characterized by evaluating premorbid personality, premorbid condition, clinical
picture, therapeutic responsiveness, and prognosis together as a set. The practicality
of this classification system is highly rated in Japan, but unfortunately it is virtually
unknown in other countries. The reason for this could be that the classification was
adapted to the conditions in Japan at the time, and as the assessment items are not
independent, there are no criteria for determining which items should be applied to
determine the disease type. Thus, ultimately, the classification was based on the
experience and subjective views of individual doctors.

Problems of Conventional Psychiatric Diagnostics

Thus, conventional psychiatric diagnostics in Japan was largely based on the

experience of individual physicians. Not only for depression but also for other
diseases, individual physicians formed disease concepts based on their own experi-
ence and their own belief. However, the disease concepts held by physicians varied,
and even the same diagnosis could sometimes refer to a completely different group
of symptoms. It was common for the diagnoses to not be consistent. Another
problem was that physicians did not engage in discussion about diseases with each
other. About the same time as the US-UK study (Cooper 1972) in the 1960s and
1970s, researches on the concordance rate of diagnosis were also conducted in Japan
(Kitamura et al. 1989a, b), which raised multiple questions about the science behind
psychiatric diagnoses.
In order for diagnostics to be scientific, it is necessary for reliability and validity
to be guaranteed. It has been proven in mathematics that the upper limit of the
reliability coefficient regulates the upper limit of the validity coefficient. To make
diagnostics scientific, the reliability of diagnosis must first be increased.
There are five well-known factors that reduce reliability, that is, subject variance,
situation variance, information variance, observation/interpretation variance, and
criterion variance (Spitzer et al. 1975). In order to minimize these factors, attempts
are made that presents the information necessary for diagnosis, explains the obser-
vation and interpretation clearly, and defines a kind of rule for diagnosis from the
obtained information, that is, the diagnostic criteria. When considering the criterion
variance, it is necessary to set clear operational definition. This is the operational
diagnostic criteria, and these are defined as clear criteria such as “Three (or more) of
664 T. Someya and S. Hoya

the following criteria exist in the past 12 months in order to make a diagnosis.” By
doing this, presentation of symptom list is inevitably carried out, and information
variance is greatly improved at the same time. On the other hand, for observation/
interpretation variance, sufficient training for symptomatology is necessary.

Turning Point of Psychiatric Diagnostics in Japan

In addition to globally increasing concerns about the reliability and validity of

psychiatric diagnosis, and the need to develop diagnostic criteria, empirical research
based on the RDC (Spitzer et al. 1978) and Feighner criteria (Feighner et al. 1972)
was reported. Iowa 500 study (Morrison et al. 1973) gathered information on
additional factors including family history; suicide rate, as well as outcome; and
response to therapy for the three diseases of schizophrenia, mania, and depression. In
addition to making all that data available, this study allowed us to establish a
diagnostic framework, share cases, and accumulate data, which had an extremely
large impact on the usefulness of epidemiological research. Based on RDC, Feighner
criteria, DSM-III was created. Saburo Takahashi came to know about DSM-III
clinical trials when studying in Canada, and after his return to Japan, he acquired
the final document and introduced the concept in a Japanese academic journal, which
became the impetus for publication of the Japanese version of DSM-III in 1982
(American Psychiatric Association 1980). The impact of DSM-III in Japan was seen
as revolutionary, likened to the landing of Commander Perry with the Black Ships
in 1853.
On the other hand, ICD, which had been previously published by the World
Health Organization (WHO), prepared diagnostic guidelines for psychiatric diseases
from the publication of ICD-10 in 1992. While ICD-10 follows the configuration of
DSM-III, it differs from DSM in that it takes into consideration the incorporation of
the guidelines into the health systems and policies of the various countries that
belong to the WHO, which means the description is highly flexible, and it allows for
culture-based differences. In Japan from this point on, official statistics and the
criteria for questions in the National Medical Practitioners Qualifying Examination
were based on ICD-10.

Psychiatric Diagnostics After Introduction of DSM in Japan

With a principle of descriptive methods, DSM adopted clear operational diagnostic

criteria based on symptoms, signs, and courses. From this, the core of the disease
was indicated, the reliability was secured in psychiatric diagnosis, and diagnostic
category was commonly shared among psychiatrists. Psychiatry was able to apply
medical models like physical medicine, and psychiatrists were able to utilize diag-
nostic inferences and share the information of treatment including drug therapies. As
a result, DSM was widely used throughout the field of psychiatry and resulted in
Historical Overview of Psychiatric Diagnostics in Japan 665

many benefits to fields such as clinical practice, education, and research in Japan
(Kuroki 2012).
In the clinical practice, using DSM as a common language enabled experts in
the different areas of psychiatry to engage in discussion. Additionally, it allowed
psychiatry to utilize diagnostic inference methods such as the algorithmic
approach, the pattern recognition method, and the hypothetical-deductive method
(Kitamura 2016).
DSM also served an important purpose in education. DSM outlines the core
symptoms of each disease, allowing beginners to learn about psychiatric diseases in
a systematic way. Furthermore, it also allowed beginners to study a precise diagnos-
tic process.
DSM also contributed significantly to research. The clear disease categories,
coupled with the progress in imaging technology and molecular genetic techniques,
contributed to the acceleration of both epidemiological and biological research into
psychiatric disease.
Nonetheless, due to the usefulness of DSM and its multifarious dissemination, the
misunderstanding that “it’s a disease simply because it’s specified in DSM diagnostic
criteria” became common among users who had not acquired sufficient training in
psychiatric diagnostics. As a result, adverse effects arose in every field where DSM
had been used. For example, in the clinical practice, DSM was used as a bible, and
the abundant descriptions of diseases and symptoms for which psychopathology had
been cultivated up to that time came to be unfortunately neglected. In education, it
became common for students to simply memorize DSM diagnostic criteria without
studying the disease concepts. Additionally, this kind of flawed use made it impos-
sible to extract homogeneous populations. It is possible that the negative effects
arising from misuse of DSM were one reason why research aimed at clarifying the
pathology of psychiatric disease was not advancing.

Reaffirming the Basic Idea of DSM

Based on the misunderstanding that occurred in Japan after introducing DSM, I

would like to reaffirm the basic idea of DSM.
Again, in conventional diagnoses, individual physicians diagnosed psychiatric
illnesses on the basis of their respective disease concepts. This created issues
regarding the reliability of diagnoses. To address this problem, DSM diagnostic
criteria were created to stipulate the core of each disease. Thus, in using those
criteria, sufficient understanding of the disease concept, the ideal type of the disease,
is a prerequisite. If we do not recognize the ideal type of the disease, and just observe
each individual diagnostic criteria, we lose sight of what the diagnostic criteria
should be regulating. In using DSM, understanding of the basic idea of DSM and
the circumstances in which DSM was created, as well as considering the ideal type of
the disease regulated by the diagnostic criteria, is essential. Attempting to extract a
homogeneous population based on such an appropriate use of the criteria has been a
challenge of DSM to date.
666 T. Someya and S. Hoya

The purpose of extracting homogeneous population is not only to elucidate the

pathology but also to compare the treatment response and outcomes among medical
doctors and institutions and to facilitate epidemiological investigation. Thus, in a
nutshell, it can be said that the diagnostic criteria were not originally created to
accurately diagnose individual patients. As a basic requirement, all diagnostic
criteria must possess certain characteristics such as concise expression, reliability,
and disease-specific factors (Kendler 2016). Diagnostic criteria have been created
specifically to include characteristics of the disease that serve as easy-to-use identi-
fiers from abundant description of the disease that can be used for diagnosis. Hence,
the diagnostic criteria themselves are not the disease. They should be used only after
understanding the important characteristics and symptoms of a disease that are not
included in the diagnostic criteria.
Even excluding this kind of misunderstanding of DSM, it cannot be denied that
there are some structural problems in DSM itself. As a basic requirement for a
categorical diagnosis to be effective, it is necessary that the classified group be
uniform, the boundary between classifications be clear, and one classification must
mutually conflict with other classifications. Therefore, from the start, there have been
limitations on the use of DSM in psychiatric disease. In actual clinical practice, a
diagnosis of a “not otherwise specified.... disorder” is unfortunately common.

Domestic Opinion About DSM-5

The DSM-5, which is the most recent revision of the manual for psychiatric
diagnostics, was published in May of 2013 and is already receiving criticism for
different reasons. The most common reason pertains to concern about overdiagnosis
as a result of the current revisions. In particular, elimination of the bereavement
exclusion from major depression has frequently been the target of criticism (Fried-
man 2012). In addition to depression, there are also concerns about overdiagnosis of
conditions such as mild cognitive impairment and substance use disorders.
Let’s see what kind of opinions in Japan about some diagnoses of DSM-5.

Major Depressive Disorder Versus Bereavement

DSM considers a condition to be major depressive disorder if the criteria for major
depressive disorder are met from the points of severity, duration, and functional
impairment, even in the case of a major life event, such as bereavement. As the
positive opinion, this would decrease the amount of missed diagnoses. On the
contrary, as the negative opinions, there is a concern regarding overdiagnosis,
resulting in unnecessary drug therapy.
It is important to note that the aim of outlining the characteristics of major
depressive episode in DSM is established on the basis of the prerequisite of “careful
consideration is given to the delineation of normal sadness and grief from a major
depressive episode.” As such, there is a note in DSM-5 regarding discrimination
Historical Overview of Psychiatric Diagnostics in Japan 667

between grief and major depressive episode. As described in the note, investigating
the characteristics of the symptoms and of the progression in detail was the
natural approach in traditional psychiatry, which determined the cause by using
the concept of understanding. In light of the basic idea of DSM, if diagnostic criteria
are applied appropriately in this kind of approach, the extraction of a uniform major
depressive disorder group can be expected, even from among patients with the
experience of loss.

Neurocognitive Disorder

From the viewpoint of detailed examination of the symptoms, the abundant expla-
nation of neurocognitive disorders is also worth noting. On the contrary, as a
disadvantage, there is a concern regarding insufficient introduction of biological
indicators to the diagnostic criteria.
For diagnosis of a neurocognitive disorder using DSM-5, detailed evaluation of
the cognitive domains defined as complex attention, executive function, learning and
memory, language, perceptual-motor function, and social cognition is required
(Sachdev et al. 2014). And the practical guidelines are provided, outlining what
kinds of episodes in daily life can be observed in case of the impairment of the
various domains, as well as concrete assessment methods to evaluate these episodes.
Similar to the note for major depressive disorder, review of details regarding the
nature of symptoms, and an attempt to extract a homogeneous neurocognitive
disorder population using those particular details, conform to the basic idea of DSM.

Autism Spectrum Disorder

In light of the limitations of categorical disease classification, DSM-5 introduces the

concepts of dimensional models and spectrums within some limited areas. Here, I
would like to address autism spectrum disorders. There are many positive opinions
regarding the introduction of a spectrum concept based on a dimensional assessment
of severity. However, an important concern raised is the difficulty in grasping an
image of the disease with just the disease name. Many clinicians are still not
accustomed to quantitative evaluation and its interpretation, and perhaps, training
in this area will be a worthwhile future endeavor.

Toward Future Development of Psychiatric Diagnostics

Based on the current state of psychiatric diagnostics in Japan, I would like to

describe four points that seem to be important for the future development of
diagnostics.
The first is reaffirming the basic idea of DSM. Many people have come to use
DSM erroneously based on “the misunderstanding that it’s a disease simply because
668 T. Someya and S. Hoya

it’s specified in DSM diagnostic criteria.” However, it must be remembered that

diagnostic criteria are nothing more than indices or tools for diagnosis. Perhaps it is
necessary to re-establish the fact that diagnostic criteria only provide the framework
for forming the ideal type of a disease. Recognizing and correcting this approach to
DSM should help us enjoy the many benefits our increasingly research-based criteria
can afford to our field while diminishing its negative effects of reduced interest in our
rich descriptive heritage and of excessive diagnostic literalism and reification.
The second is proficiency in a new evaluation style. With appropriate use of
diagnostic criteria as a prerequisite, DSM has progressed to this point and will likely
continue to progress. Specifically, a transition from categorical diagnosis to dimen-
sional diagnosis and the advancement of the introduction of biological indices are
expected. Mastery of multilayered diagnosis that utilizes biological indices as
intermediate phenotypes and assesses symptoms dimensionally, all while focusing
on the underlying pathology, is necessary.
As the diagnostic modalities evolve, the description of DSM will have to be
further enhanced. Specifically, in describing symptomatology, it is to enrich the
contents about the difference of psychopathology. Dimensional assessment is effec-
tive for pathology situated at the periphery of traditional categories or for diseases
that cross over conventional categories. Therefore, in order to make use of dimen-
sional evaluation, the importance of recognizing the core of the conventional
category, that is, the ideal type, is increasing. Descriptions of detailed symptom
analysis that psychopathology has accumulated for grasping the ideal type will be
helpful once again.
As a final recommendation, I would like to emphasize the perspective of human
understanding in psychiatric diagnostics. Even if one correctly applies DSM and
provides a correct diagnosis, it does not necessarily indicate that the patient’s true
condition has been understood. We must not forget that psychiatric diagnostics strive
not only to understand the brain pathology and diagnosis of a disease but also to
understand human beings from a multifaceted viewpoint, bearing in mind each
patient’s personality as well as the social and environmental background.

Conclusion

So far, I described the transition of psychiatric diagnostics in Japan, current situation,

and future.
The important point is, in diagnostic criteria for mental disorders, where there are
almost no objective tests and no other choice but to depend only on clinical
symptoms and course, high reliability is required for each of them. In order to
improve the reliability and then validity, we have to strive for accumulation of
various information on individual diseases. Even if it is not the best diagnostic
criteria, we have to pursue better ones at that time.
In other words, the diagnostic criteria for mental disorders of unknown origin are
in fate to evolve to new diagnostic criteria at the time when new information on not
only etiology/pathology but also therapeutic reactivity, outcome, epidemiology, etc.
Historical Overview of Psychiatric Diagnostics in Japan 669

are sufficiently obtained. It is important for psychiatrists to not merely follow the
diagnostic criteria but to understand the essence of them and to use them
therapeutically.

References
American Psychiatric Association. Quick reference to the diagnostic criteria from DSM-III.
Washington, DC: American Psychiatric Association; 1980. (Translated into Japanese by
Takahashi S, Hanada K and Fujinawa A. Tokyo: Igaku Shoin; 1982.)
Cooper JE. Psychiatric diagnosis in New York and London. Maudsley monograph no. 20. London:
Oxford University Press; 1972.
Feighner JP, Robins E, Guze SB, et al. Diagnostic criteria for use in psychiatric research. Arch Gen
Psychiatry. 1972;26:57–63.
Friedman RA. Grief, depression, and the DSM-5. N Engl J Med. 2012;366:1855–7.
Kasahara Y, Kimura B. Utsu jōtai no rinshōteki bunrui ni kansuru kenkyū (Study on clinical
classification of depressive state). Seishin Shinkeigaku Zasshi. 1975;77:715–73.
Kendler KS. Phenomenology of schizophrenia and the representativeness of modern diagnostic
criteria. JAMA Psychiat. 2016;73:1082–92.
Kitamura H. DSM recommendation to refine psychiatric diagnosis. Arch Psychiatr Diagn Clin Eval.
2016;9:46–52.
Kitamura T, Shima S, Sakio E, et al. Psychiatric diagnosis in Japan. I. A study on diagnostic labels
used by practitioners. Psychopathology. 1989a;22:239–49.
Kitamura T, Shima S, Sakio E, et al. Psychiatric diagnosis in Japan. II. Reliability of conventional
diagnosis and discrepancies with RDC diagnosis. Psychopathology. 1989b;22:250–9.
Kuroki T. DSM to gendai no seishin igaku – Doko kara kite, doko e mukau no ka (DSM and modern
psychiatry – where do we come from and where are we going). In: Kanba S, Matsuhita M,
editors. Senmoni no tame no seishinka ryumiēru 30 (Psychiatric Lumière for specialists 30).
Tokyo: Nakayama Shoten; 2012. p. 123–36.
Kuroki T, Ishitobi M, Kamio Y, et al. Current viewpoints on DSM-5 in Japan. Psychiatry Clin
Neurosci. 2016;70:371–93.
Morrison J, Winokur G, Crowe R, Clancy J. The Iowa 500. The first follow-up. Arch Gen
Psychiatry. 1973;29:678–82.
Omata W. Seishin igaku no rekishi (History of psychiatry). Tokyo: Daisan Bunmeisha; 2005.
Sachdev PS, Blacker D, Blazer DG, et al. Classifying neurocognitive disorders: the DSM-5
approach. Nat Rev Neurol. 2014;10:634–42.
Spitzer RL, Endicott J, Robins E. Clinical criteria for psychiatric diagnosis and DSM-III.
Am J Psychiatry. 1975;132:1187.
Spitzer RL, Endicott J, Robins E. Research diagnostic criteria: rationale and reliability. Arch Gen
Psychiatry. 1978;35:773–82.
Neuro-psychopharmacotherapy and the
Differential Diagnostic Approaches in
Europe

Richard Musil and Peter Falkai

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
Differential Diagnostic Approach to Establish the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
Neuro-psychopharmacological Recommendations According to Treatment Phases . . . . . . . . . . 674
Treatment Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Differential Diagnostic Approach According to Predominant Symptomatology and
Subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
Differential Diagnostic Approach According to Special Circumstances . . . . . . . . . . . . . . . . . . . . . . . 690
Summary and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698

Abstract
At present there are no Pan-European guidelines regarding the differential diag-
nostic approach for most psychiatric diseases. Exceptions are guidelines for the
diagnosis of Tourette syndrome or Alzheimer’s disease published by European
societies. By contrast, national guidelines give recommendations on how to
approach the patient with initial or recurrent presentation of, e.g., psychotic
symptoms, which diagnostic measures to take or which kind of first-line treatment
to choose for common clinical scenarios.
In this chapter we focus on the differential diagnostic approach to the patient
with psychotic symptoms and have chosen the guidelines of the World Federation
of Societies for Biological Psychiatry for schizophrenia as a reference and
compared these to six national guidelines available in German or English. Tables
summarize commonalities and disparities on how to establish a diagnosis, of
neuro-psychopharmacotherapeutical recommendations according to different

R. Musil (*) · P. Falkai

Klinik für Psychiatrie und Psychotherapie des Klinikums der Universität München, Munich,
Germany
e-mail: Richard.musil@med.uni-muenchen.de; Peter.falkai@med.uni-muenchen.de

© Springer Nature Switzerland AG 2022 671

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_367
672 R. Musil and P. Falkai

treatment phases or treatment resistance, and on how to approach different kinds

of symptomatology, subtypes, and specific clinical situations.
We found that the six national guidelines each focus on different aspects of
schizophrenia in particular. While recommendations for the initial approach were
found to be most consistent, details of diagnostic measures differed as well as
suggestions on how to deal with certain clinical situations or comorbidities.
Although we only focused on the differential diagnostic approach for schizo-
phrenia, we hope that our elaboration may serve as a model for a differential
diagnostic approach for other psychiatric diseases as well.

Introduction

Psychiatric diagnoses in Europe are usually based upon the International Classification
of Diseases (ICD) in its current version, which is the tenth revision at the moment
(Akiskal and Benazzi 2005). In 2012 the European Psychiatric Association founded
the “Guidance Project,” which should fill the gap of clinically important situations and
other aspects of treatment not covered in national or international guidelines (Gaebel
and Moller 2012). The differential diagnostic approach is not yet covered by any of the
guidelines published (European Psychiatric Association 2018).
For most of the psychiatric disorders, there is no Pan-European guideline.
Exceptions are, e.g., the guidelines for the diagnosis of Tourette syndrome from
the European Society for the Study of Tourette Syndrome (ESSTS) (Cath et al. 2011)
or guidelines for diagnosis and treatment of Alzheimer’s disease from the European
Federation of Neurological Societies (EFNS) (Hort et al. 2010).
In the late 1990s, European societies promoted development of European guide-
lines for diagnosis and management of dementias and harmonization of European
approaches with those of the United States and Japan (Harvey et al. 1998).
Since then, identification of factors influencing early diagnosis of dementia
(Vernooij-Dassen et al. 2005), developing screening guidelines for early detection
(Visser et al. 2008), and computer-based educational programs to train diagnosis and
treatment in dementia (Degryse et al. 2009) were in the focus of European harmo-
nization processes.
Nowadays, European recommendations exist for the use of neuroimaging in the
diagnostic approach of dementias (Filippi et al. 2012), early diagnosis for dementia
(Brooker et al. 2014), and assessment of dementia of patients from ethnic minorities
(Nielsen et al. 2011), and currently researchers are making efforts to create European
guidelines for outcome parameters in Alzheimer’s prevention under the Horizon
2020/IMI European Prevention of Alzheimer’s Dementia (EPAD) project (Ritchie
et al. 2017).
Although in 1986 a survey of the different approaches toward the assessment of
schizophrenia was published (Berner et al. 1986) and expert recommendations from
European researchers followed focusing on treatment of schizophrenia (Altamura et al.
2000) or use of antipsychotic depot medication throughout Europe (Kane et al. 1998),
there is still no European guideline for diagnosis and treatment of schizophrenia.
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . . 673

In this chapter we therefore compared the recommendations of six national

guidelines: Austrian (Kasper et al. 2016), DGPPN S3 (Germany; DGPPN e.V.
(Hrsg.) für die Leitliniengruppe 2019, DGPPN e.V. 2019), Danish (Baandrup et al.
2016), NICE (British; National Institute for Health and Care Excellence 2014),
SIGN (Scottish; SIGN 2013), and Spanish (Catalan Agency for Health Technology
Assessment and Research 2009) with the approach of the WFSBP (World Federation
of Societies for Biological Psychiatry) guideline (Hasan et al. 2017) as a reference
point. Due to language restrictions, we could only rely on those guidelines published
either in English or German.
As part of the guideline project, in 2015 recommendations for early detection
(Schultze-Lutter et al. 2015) and interventions (Schmidt et al. 2015) in clinical high-
risk states of psychoses were published and will therefore not be covered by this chapter.
We chose schizophrenia as a complex psychiatric disorder for a detailed analysis
and assume that the differential diagnostic approach might be generalizable to other
disease entities as well. Differentiating diagnostic approaches for all psychiatric
disorders would have been beyond the scope of this chapter; however, we will
highlight some aspects of other diseases as well.

Differential Diagnostic Approach to Establish the Diagnosis

Most psychiatric diseases are diagnosed based on clinical assessment and not on any
laboratory, imaging, or other biological marker. However, ruling out any somatic causes
of the symptomatology presented by the patient is crucial, and this will be one of the first
steps to the differential diagnostic approach in any country. An exception might be the
differential diagnostic approach to establish a diagnosis of dementia, as neuroimaging
and laboratory findings are largely approaching a useful state to be incorporated into
clinical practice. The reader is kindly asked to refer to the abovementioned European
guidelines of diagnosis and treatment of Alzheimer’s disease and other dementias.
After any somatic causes have been established to be very unlikely, the next
important step is to gain a clearer picture of the psychiatric symptoms themselves
and to group these symptoms according to defined syndromes. Together with time
criteria, a psychiatric diagnosis can be made.
In Table 1 recommendations of the six national guidelines for the approach to the
patient with first psychotic symptoms and investigations to rule out organic brain
disorders are presented as well as initial setup after establishing a diagnosis.
Not all national guidelines cover recommendations for ruling out organic brain
disorders. And some go into a lot of detail, including individual lab values, whereas
others remain superficial. Not surprisingly, the most comprehensive one is the latest
published national guideline, the current version of the S3 DGPPN guideline, which
was published only a few months ago and thus incorporates all the latest data.
This guideline also provides a dedicated differential diagnostic algorithm to
establish a diagnosis of schizophrenia or other related disorders and to rule out
somatic diseases as secondary causes for psychotic symptoms. Furthermore, it lists
in detail organic diseases that may mimic schizophrenia-like symptoms such as
674 R. Musil and P. Falkai

inflammatory processes (e.g., multiple sclerosis, toxoplasmosis, HIV encephalitis),

cerebral vascular disorders, as well as disturbances of endocrine and metabolic
functioning. Medications that may induce psychotic symptoms are presented in
table form. The entity of autoimmune encephalitis with psychotic features is pre-
sented in detail together with common antibodies and their clinical features.
Some guidelines were clearly developed with a certain focus (e.g., Danish
national guidelines; focus on pre-defined questions not covered by most other
guidelines). The NICE guideline in its updated edition of 2014 takes a different
approach and does not provide recommendations for the fields gathered in Table 1,
respectively. As this guideline follows a different structure, we did not extract
recommendations that may fit one of the cells in our table. No recommendations
are given on specific diagnostic procedures to establish the diagnosis. The emphasis
is on comparative evaluation of specific interventions (pharmacologic treatment,
psychological therapy, and psychosocial interventions) on the one hand, and on the
other, recommendations to reduce the burden of carers reflect specific needs of
people in at-risk mental states or aspects of health economics.
It stresses the need for a management plan and provision for a supportive and
optimistic treatment setting in partnership with the patients and their supporters. It
further covers needs of patients with different ethnical and cultural backgrounds and
impaired physical health.
In summary, physical examination and laboratory investigation stand at the core
of the differential diagnostic approach. Some recommend brain imaging as a stan-
dard procedure, while others only include it as a second step upon more specific
suspicion of an organic disorder. CSF (cerebrospinal fluid) tests are only
recommended as a second step.
After the diagnosis has been established, development of a treatment plan includ-
ing involvement of professional caregivers as well as family members, facilitating
access to healthcare system providers, and building a therapeutic alliance are crucial
components in most national guidelines. Furthermore, some offer recommendations
for diagnostic investigations in case of relapse.

Neuro-psychopharmacological Recommendations According to

Treatment Phases

Now we are reaching the point where first therapeutic decisions have to be made.
The diagnosis is established, a treatment plan worked out, and a therapeutic alliance
reached. The differential diagnostic approach will now separate between phases of a
disorder or according to specific symptomatology. This means that treatment will
most likely differ in a patient with a first episode of any disorder, with a recurrent
episode, or with a chronic condition.
In Table 2 treatment recommendations for patients with a first psychotic episode
are listed and followed by recommendations for a post-acute stabilization phase,
patients in remission, and relapsing cases. Although specific recommendations will
Table 1 Differential diagnostic approaches across European national guidelines for establishing a diagnosis of schizophrenia and initial approach
Danish
Austrian consensus national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
Approach “Careful • Diagnosis should • Physical and Not • Comprehensive • Perform At baseline
to the diagnostic be based on neurological covered multidisciplinary psychiatric and physical
patient evaluation”: operationalized examination assessment general medical monitoring
with first laboratory criteria • Lab (incl. complete should be history, should include
psychotic investigation, • Differentiation blood count, signs of performed psychosocial assessment of
symptoms screening for from other psychotic inflammation (CRP), including history and family individual and
drug abuse disturbance or liver and kidney psychiatric psychiatric history, family history
organic and function, thyroid comorbidities, examination of the of physical
substance-induced hormones, fasting medical history mental state, illness, smoking
disorders should be glucose, HbA1c, and full physical physical assessment history, BMI,
made cholesterin, HDL- examination, including weight, waist
• Perform physical cholesterin, lifestyle factors neurological circumference,
examination (incl. triglycerides, drug incl. smoking, examination, blood pressure,
weight, size, temp., screen weight, physical necessary HbA1c, fasting
RR, HR) • ECG activity, nutrition, complementary glucose, fasting
• Lab (incl. complete • MRT psychosocial examinations to rule lipids (prolactin,
blood count, liver • Lues serology situation, out other disorders ECG as
and kidney • HIV screen developmental • Differentiate clinically
functioning, CRP, • Waist circumference history, social symptomatology indicated)
TSH, drug screen, • Neuropsychological activities, from other
fasting glucose tests occupational psychiatric
• Structural imaging • Pregnancy tests situation, quality disorders (e.g.,
MRT (T1, T2, of life and mood disorders
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

FLAIR) (CT if MRT economic status with psychotic

is not available) features, etc.) or
organic medical
conditions
675

(continued)
 676

Table 1 (continued)
Danish
Austrian consensus national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
• Initial assessment
should include
MRI,
neurocognitive
assessment,
neurological exam,
ECG, height,
weight, illegal drug
screen
How to Imaging • CSF in case of Optional: ANA, Not Not covered • Consider Not covered
exclude techniques suspected coeruloplasmin, CSF, covered consumption of
organic (MRI, if not secondary causes EEG, X-ray thorax, drugs or specific
brain available for psychotic serum-cortisol levels, medications (e.g.,
disorders CCT); CSF symptoms drug plasma levels, steroids)
only if organic • Neuropsychology screen for toxins, • Lab should
brain disorders testing (attention, genetic testing, include toxicology
are clinically learning, memory, prolactin screen, general
expected executive function., biochemistry,
social cognition) complete
• EEG in case of hemogram and
suspected urine analysis
neurological • Consider
disorders pregnancy test,
R. Musil and P. Falkai
 • Screening for ECG, CT or MRI,
dementia in higher neuropsychological
ages assessment, and
• Lab: CK, general
antibodies, iron, psychometry
copper, vit. B1, B6,
B12, serological
screening (HIV,
Hep., Lues, etc.) in
case of suspected
secondary causes
After • Establish • At any new • At any new relapse: Not • Establish a care • Involve patient • Treatment
diagnosis therapeutic relapse, offer physical and covered plan in and family in the should be
has been alliance recommended neurological cooperation with treatment plan in an offered within
established • Formulate diagnostic steps for examination, lab primary service active collaboration the context of a
treatment plan initial presentation (complete blood providers • Develop an specialist early
• Reevaluate if not yet performed count, CRP, liver, and integrated and intervention
diagnosis and • Establish overall kidney function, coordinated model of care
treatment plan treatment plan with recheck pathological treatment plan involving
periodically participation of findings, ECG, fasting • Establish a assertive
• Involve patients and glucose, HbA1c, therapeutic alliance outreach
family and professionals in cholesterin, HDL- and stimulate approaches,
significant cooperation with cholesterin, treatment family
others with relatives and triglycerides, waist compliance involvement,
patients’ significant others circumference • Provide education access to
permission and involve • Optional: drug for patient and psychological
nonprofessional plasma levels, TDM, family interventions,
helping systems neuropsychological • Treat comorbid vocational
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

• All treatment steps tests, glucose diseases interventions,

should be integrated tolerance • Take social and access to
in the treatment
(continued)
677
 678

Table 1 (continued)
Danish
Austrian consensus national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
plan and offered on circumstances into antipsychotic
an individual and account medication
phase-specific
manner
(multiprofessional
and close to home)
• Facilitate access to
healthcare system
and providers
• Facilitate
empowerment
R. Musil and P. Falkai
Table 2 Differential diagnostic approaches across European national guidelines with respect to treatment phases
Austrian Danish
consensus national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
Acute • Beware of • Early intervention • Focus put on Not • Oral • Recommendations • Individual
treatment in EPS risk with antipsychotics treatment of covered antipsychotics of different prescribing
first episode • Gradual • Depending on positive together with international should consider
introduction psychopathology symptoms, psychological guidelines are given benefits and
of and patient agitation, and interventions, (e.g., Canadian harms
antipsychotic preferences, anxiety Treatment offer family guidelines, PORT, • Adverse effects
treatment watchful waiting of with SGAs interventions and TMAP, APA, and should be
• Aim at some days to combined with CBT, provide RANZCP: discussed in
lowest weeks can be additional regular antipsychotic detail
possible considered at first measures assessments of medication should • Medication
effective dose episode and should • Psychiatric and treatment plan, be prescribed in a should be
• Choose be integrated into somatic and monitor noncoercive manner continued for at
FGA or SGA overall treatment comorbidities symptoms combined with least 2 weeks
according to plan should be regularly psychosocial • In case of poor
patient’s • SGAs should be identified and • Decide upon interventions incl. response to
mental and preferred treated medication Aadherence- medication
somatic considering • SGAs should be together with the promoting adherence and
condition, substance-specific preferred patients strategies. inter-current
risk of EPS, side effects (considering side considering • A 24–48- h substance misuse
other side • Antipsychotics effect profile, possible side observation period is should be
effects, and should be used on patients‘ effects. Start with recommended assessed
comorbid lowest effective preferences, lower doses and • Choice of • After 4 weeks of
conditions dosage earlier gradual titrate medication should non-response and
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

• Choice of experiences, upward be guided by the despite dose

antipsychotic available forms of • Perform regular individual optimization, a
should be based on application) monitoring characteristics of change in
(continued)
679
 680

Table 2 (continued)
Austrian Danish
consensus national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
clinical symptoms • In patients with each patient medication
aimed at; first episode, • Weight and BMI should be
experiences with lower doses may should be measured, considered
prior treatments; be sufficient consultation with • Minimum
risk and benefits of • Once-daily dietitian is advisable, effective dose of
the specific agents; peroral physical activity either first- or
metabolic, motor, application is the should be second-
cardiovascular, and first choice encouraged generation
endocrine/sexual • Specific • Monitor fasting antipsychotics
adverse events; risk recommendations plasma glycemia, should be used
and benefits of for patients with lipid profiles
abstinence from first episode are • Antipsychotics
AP treatment; provided (citing should be initialized
preferences of the WFSBP and gradually after
patients and DGPPN careful explanation
gender-, age-, and guidelines) • SGAs are
comorbidity- recommended at first
specific aspects time
• Symptomatology
should be
monitored on a
regular basis using
disease-specific
rating scales
Treatment in • Antipsychotic • Psychoeducation • Encourage • In case of response • Following
post-acute treatment for should be offered patients to write to antipsychotic remission of the
R. Musil and P. Falkai
stabilization relapse prevention • Cognitive an account of their treatment, first episode,
phase should be offered remediation illness after each maintenance of duration of
in a continuous should be initiated acute episode 12 months and maintenance
form • Family members • Inform patients gradual decrease treatment with
should be about risk of thereafter is antipsychotics
involved relapse after recommended should be at least
cessation of • CBT, intensive 18 months
medication within case management, • All service users
first 1–2 years family, and should be offered
after acute episode community support a mental health
should be provided review at regular
• It is recommended intervals
that care be given in
least restrictive and
coercive settings
possible
Treatment • In case of stability • Sociotherapeutic • Offer • In case of non- • Maintenance
for patients and reasons against interventions opportunity to response to initial treatment with an
in remission continuing AP stand at the point return to primary treatment offer antipsychotic
treatment, stepwise of interest care facilities after switching to medication
reduction should be stabilization of (another) SGA should be offered
offered and symptoms • Provide (usually the one
intermittent psychosocial used during the
treatment with interventions (early last acute episode
early intervention intervention in case of efficacy
in case of programs, supported and tolerability)
prodromes of employment, for a minimum of
threatened relapse cognitive 2 years; for
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

aimed at rehabilitation, active maintenance

• Shared decision intensive amisulpride,
making is crucial in olanzapine, or
(continued)
681
 682

Table 2 (continued)
Austrian Danish
consensus national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
all treatment phases biopsychosocial risperidone
if discontinuation care) should be
of treatment is considered (low
wished by patients to moderate
• Regular dosing of
monitoring of 300–400 mg
symptoms for any chlorpromazine
relapse being part equivalents)
of an overall
treatment plan
should be offered
for at least 2 years
Treatment FGAs and • Antipsychotic • Last effective Not • Offer crisis • Immediately • In case of acute
for relapsing SGAs can be treatment for dose should be covered resolution and initiate exacerbation,
patients chosen relapse prevention aimed for home treatment pharmacological amisulpride,
according to should be offered teams as a first- treatment (inform olanzapine, or
patient’s • Antipsychotics line service and consult patient risperidone
previous previously leading • Crisis houses and family members should be offered
experience, to remission should and acute day on different agents • Chlorpromazine
treatment be offered for facilities should taking into account and other low-
effects, side relapse prevention be considered previous potency FGAs are
effects, unless tolerability • Consider the experiences) considered
patient’s was low impact of hospital • Consider SGAs in alternatives
preference, • Choice of interventions case of non-response • Previous
comorbid medication for • Offer oral to FGAs response to
disorders, and relapse prevention antipsychotics • Promote CBT individual
R. Musil and P. Falkai
potential should take together with • After remission is antipsychotic
interactions preferences, psychological achieved, continue medication and
with other previous interventions for 12 months, with relative adverse
medication experiences, and taking into gradual decrease of effect profiles
different adverse account several weeks should be
event profile recommendations thereafter considered
(tardive for starting • Medication
dyskinesias, treatment should be
sedation, cardial, continued for at
metabolic, least 4 weeks
endocrine, and • In partial
other effects) into remission
account medication should
be reassessed after
8 weeks (unless
significant adverse
effects)
• Patients, relatives,
and significant
others should be
informed about
higher relapse risks
with discontinuing
antipsychotic
treatment
• Duration of
treatment has to
take several aspects
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

into account
• Depot medication
should be offered
(continued)
683
 684

Table 2 (continued)
Austrian Danish
consensus national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
due to secure
application and
high bioavailability
• Choice of depot
medication should
be based on side
effects profile and
intended treatment
interval
R. Musil and P. Falkai
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . . 685

differ, this approach is similar in patients with other severe mental illnesses like
major depressive disorder or bipolar disorder.
As can be depicted, first choice of medication is in most cases a second-
generation antipsychotic given at the lowest effective dose and slowly up-titrated
if needed. Patients should be involved in a coercive manner, and choice of the
specific drug is based more on adverse event profiles than effects on any specific
symptomatology. Some guidelines highlight the possibility of watchful waiting
for some hours to a few weeks, and most give specific recommendations for
monitoring.
Differences are greater in the post-acute stabilization phase. Some guidelines
recommend continuous antipsychotic treatment for a specific time frame, while
others focus on additional interventions such as psychoeducation or cognitive
behavioral therapy. The same applies to the approach toward patients in remission.
While the latest S3 DGPPN guidelines get very specific about recommendations for
the process of discontinuing medication, other guidelines shift the focus on non-
medication strategies.
In the case of relapse, most guidelines recommend reinitiation of antipsychotic
treatment, some recommend specific compounds, while most stress the fact that
selection should be based on previous experiences and adverse event profiles. The
British guidelines put the focus on different kinds of early intervention programs.

Treatment Resistance

A very challenging “treatment phase” is an episode of treatment resistance. This will

be the case in a substantial number of patients. So the differential diagnostic
approach in this scenario is to first know the definition of treatment resistance for
any disease category. Most definitions take pharmacoresistance as the basis, usually
stating inadequate treatment effects toward at least two types of different medica-
tions in adequate dosing and time. As recommendations for treatment resistance do
get very specific and in most cases include other treatment modalities (e.g., electro-
convulsive therapy, certain forms of psychotherapy) or less tolerable types of
medication, the identification of treatment resistance is a crucial step.
Another important aspect is the ruling out of “pseudo-therapeutic resistance” as it
is called in the S3 guideline. This means that other causes such as lack of medical
adherence, substance abuse, interacting medication, comorbidities, etc. have to be
ruled out. So psychiatrists and other physicians are encouraged to rethink diagnosis
and reconsider any meaningful diagnostic steps (see Table 3).
For schizophrenia, most guidelines recommend using clozapine in case of treat-
ment resistance. The Danish guideline, not providing any recommendations for other
treatment phases, has a slightly different approach, including a trial of clozapine in
the definition of treatment resistance, and highlights the fact that, in case response
cannot be achieved with the current medication, a gradual decrease of any medica-
tion to reduce side effects has to be considered.
Table 3 Diagnostic approaches to schizophrenic patients with treatment resistance across European national guidelines
686

Austrian
consensus Danish national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
Treatment Def.: No significant Def.: Moderate • Clozapine is Def.: No In case of In case of no Failure to
resistance improvement with severity and < 20% recommended response to at inadequate response, low respond to an
two different symptom • Reevaluate least two response: adherence or adequate trial of
antipsychotics from improvement on diagnosis, different SGAs reconsider persistent suicide two different
two different standardized comorbidities and clozapine diagnosis risk, use of antipsychotics
chemical classes at symptom scale (substance • Maintaining • Revise clozapine is (including a
recommended (PANSS, BPRS, abuse), treatment with adherence to recommended SGA)
doses for at least SANS, or SAPS) compliance, and antipsychotics is medication, dose, • If there is no • Clozapine
2–8 weeks per drug during 6-week metabolism recommended for and duration of response to first should be offered
• Multidimensional treatment periods non-remitted antipsychotic choice of • Diagnosis and
evaluation of • Overall treatment patients with treatment antipsychotic, comorbidity
persisting positive duration was previous • Review consider switch should be
or negative 12 weeks incl. at least response to engagement with to (another) reviewed
symptoms, 6-week treatment antipsychotic psychological SGA; evaluate • Clozapine
cognitive periods with two treatment treatments, offer adherence; plasma levels
dysfunctions, different • In patients with interventions that switch to should be
bizarre behavior, antipsychotics no previous have not been clozapine in case monitored in
recurrent affective • Mean dosage was response to performed (CBT of non-response certain cases
symptoms, deficits 600 mg several or family to two adequate -Augmentation
in vocational and chlorpromazine antipsychotic intervention) trials of with a second
social functioning, equivalents, and at compounds • Consider any antipsychotic SGA (or
and a poor quality least 80% of dosage including comorbid treatment (at lamotrigine)
of life has been taken clozapine, a disorders or least one SGA) should be
• Ensure adherence, • Pseudotherapeutic gradual taper of substance use as considered with
consider clozapine resistance should be any ongoing causes for non- inadequate
as first choice, ruled out before antipsychotic response
R. Musil and P. Falkai
consider other treatment resistance treatment with • Offer clozapine response to
SGAs, is diagnosed: close monitoring in case of non- clozapine alone
augmentation consider adherence, for any relapse is response to a
strategies, use of illegal recommended to least two
combination of substances, severe reduce adverse adequate trials of
drugs, adverse events, events different drugs
electroconvulsive comorbidities, (at least one other
therapy effective dosage SGA)
• Consider (incl. plasma levels), • Consider
psychoeducation to and environmental measuring
ensure treatment factors (stress, high therapeutic drug
adherence expressed emotions) levels and wait
• In case of for an adequate
established treatment time in case of
resistance, clozapine any
should be offered augmentation
after risk benefit- strategy
evaluation, consent,
and accompanying
screening tests
• If clozapine is not
tolerated, olanzapine
and risperidone
should be considered
• Dose escalation
beyond
recommended use
should be avoided
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

• Monotherapy
should be preferred,
and combination of
two substances only
considered after
687

(continued)
 688

Table 3 (continued)
Austrian
consensus Danish national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
monotherapy with
three substances incl.
clozapine was not
successful
• Augmentation with
carbamazepine,
lamotrigine, or
valproic acid to
improve symptoms
should not be offered
on a routine basis
• ECT can be
considered in case of
pharmacotherapeutic
non-response
• rTMS should be
offered in case of
persisting acoustic
R. Musil and P. Falkai
hallucinations or
negative symptoms
• Treatment should be
continued for at least
10 weeks
• High-dose
antipsychotics should
only be considered
after adequate trials
of antipsychotic
monotherapy, and
augmentation,
including a trial of
clozapine, has failed
• ECT should only be
considered in those
individuals for whom
other approaches
have failed
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .
689
690 R. Musil and P. Falkai

Differential Diagnostic Approach According to Predominant

Symptomatology and Subtypes

Patients presenting with emergency conditions like suicidal or violent behavior,

overt aggression or stupor, and mutism impose a challenge for any treating physi-
cian. Per se none of these conditions is specific for any psychiatric diagnosis, and
patients might initially present in such a condition of emergency or develop it during
in- or outpatient treatment. These emergency conditions often require prompt reac-
tions, sometimes even before a diagnosis has been established. Still, in the case of
patients with a known psychiatric diagnosis, emergency conditions will be treated
differently compared to usual approaches. Therefore, most national guidelines have
sections on the approach toward the patient with severe symptoms (see Table 4).
As can be depicted, some guidelines focus on management of suicidal ideation,
while others stress treatment of aggression or violent behavior.
In major depression or bipolar disorder, severity of symptoms often corresponds
with the existence of psychotic features and will result in the addition of antipsy-
chotics, to a trial of antidepressants or even involvement of electroconvulsive therapy.
Therefore, awareness for severe symptoms will prompt physicians and other
caregivers toward a closer monitoring, intensification of treatment, or change in
treatment setting such as admission to hospital.
Apart from severe symptoms, some guidelines give specific recommendations for
certain subtypes. ICD-10 differentiates between catatonic, hebephrenic, and paranoid
subtypes and furthermore between the difficult-to-diagnose subtype schizophrenia
simplex and an unspecific subtype. In the six national guidelines chosen, none of
these subtypes is highlighted – instead, treatment of comorbidities like depression,
anxiety, or OCD is covered. Furthermore, persisting negative symptoms and their
differentiation and treatment are discussed in detail in some of the guidelines.
The six national guidelines show greatest diversity in this section, and a Pan-
European guideline or consensus statement for treatment of severe symptoms or
other predominant symptoms might help European physicians to gain certainty
about a specific approach.
The differentiation of subtypes is an important topic in other psychiatric diseases.
Apart from the different treatment modalities for vascular or Alzheimer’s type of
dementia, in major depression a melancholic or atypical subtype might respond to
different types of antidepressants. Therefore, depending on the psychiatric disease,
differentiation of subtypes or identification of certain predominant symptoms can
lead to a more specific treatment.

Differential Diagnostic Approach According to Special

Circumstances

Finally, national guidelines for schizophrenia provide recommendations for certain

circumstances requiring the attention of the caregivers and physicians. This involves
presence of substance abuse, poor treatment adherence, and cognitive or functional
impairment among others (see Table 5).
Table 4 Differential diagnostic approaches according to predominant symptomatology and subtypes across European national guidelines
Austrian
consensus Danish national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
Differential Special attention • Use • Combine SGAs Not covered In case of • Identify risk Medication for
treatment to the presence concomitant with immediate risk factors of violent the treatment of
according to of suicidal benzodiazepines benzodiazepines to themselves or behavior, irritability,
severe ideation and in case of in patients with others or risk of consider hostility, and
symptoms commanding agitation, anxiety, agitation, violence, rapid inpatient aggression
hallucinations anxiety, or inner or aggression tranquilization treatment should be based
• Lorazepam and restlessness in a • Aripiprazol i.m. should be • Consider on the preference
FGAs show time-restricted or FGAs should considered sedation with of service users,
comparable fashion be used in • Follow relevant benzodiazepines past experiences,
efficacy in • Frequently agitated patients NICE guidelines and restricted adverse effect
patients with check for • Lorazepam on these topics settings, consider profile, and
acute agitation suicidal should be • Encourage ethical concurrent
• Consider side ideations; preferred in discussion of regulations on medical history
effects in the use consider agitated patients experiences restrictive • For individuals
of intramuscular clozapine in case over other during rapid measures being with treatment-
formulations of continuous benzodiazepines tranquillization part of an resistant
• Restraint and suicidality and explain individualized schizophrenia
seclusion should decision for this treatment plan accompanied by
be reserved for approach • Pay attention to aggression/
exceptional suicidal ideations hostility, a trial
emergency and offer more of clozapine is
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

situations frequent indicated

outpatient visits
after discharge
(continued)
691
 692

Table 4 (continued)
Austrian
consensus Danish national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
• Optimize
pharmacological
treatment and
consider
inpatient
treatment if
needed
Differential Consider ECT in • Lorazepam can Regular Not covered Follow national Consider • Consider
treatment patients with be used in a evaluation for treatment comorbidity with sedative
according to catatonic time-restricted depressive and guidelines in other mental antipsychotic
subtypes features (when fashion (in manic features is case of suspected disorders (e.g., medication in
an initial combination recommended affective depression, individuals in
lorazepam trial with psychosis or OCD, remission with
fails) antipsychotics bipolar disorder dissociative comorbid
with low risk for symptoms, anxiety
malignant anxiety symptoms
neuroleptic symptoms, etc.) • Treatment in
syndrome) anxiety state
• ECT is the first- should be
choice treatment offered in
in case of accordance with
malignant CPG for anxiety
catatonia and panic
disorders
R. Musil and P. Falkai
 • Patients with
criteria of
depressive
disorder should
be treated in
accordance with
CPG for
depression incl.
use of
antidepressant
medication
• SGA treatment
should be
considered in
case of comorbid
depressive
symptoms
Differential • Differentiate • In patients with Standard • In patients • In stable phases In case of
treatment primary and predominant instruments for with persisting consider persistent
according to secondary negative evaluation of negative treatment for negative
predominant negative symptoms, use psychotic symptoms, depressive or symptoms
symptomatology symptoms amisulpride or symptoms, SSRIs/SNRIs OCD symptoms despite
• Consider SGAs olanzapine and clinical should only be • SGAs are adherence to
• Consider avoid strong D2 symptomatology, used cautiously recommended antipsychotic
treatment of blockade and cognitive • CBT should be for treatment of medication,
cognitive deficits • In case of non- functions are considered in depressive augmentation
• Consider response to listed without a patients with symptoms with an
administration of antipsychotic clear persisting • Use antidepressant,
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

antidepressants monotherapy, recommendation positive and/or antidepressants lamotrigine, or

with additional in which cases negative in stable phases sulpiride should
antipsychotics antidepressants these instruments symptoms be considered
(mirtazapine should be offered should be used
693

(continued)
 694

Table 4 (continued)
Austrian
consensus Danish national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines (CPG) guideline
Year 2012 2019 2016 2016 2014 2009 2013
should be • In case of
favored) persisting
negative
symptoms, high-
frequency rTMS
can be offered
• Regularly
check for
depressive
symptoms;
optimize
antipsychotic
medication in
case of
depressive
symptoms, offer
CBT, consider
use of
antidepressants
R. Musil and P. Falkai
Table 5 Differential diagnostic approaches for other factors in schizophrenic patients across European national guidelines
Austrian
consensus Danish national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines CPG guideline
Year 2012 2019 2016 2016 2014 2009 2013
Differential • Check drug • Offer • Antipsychotics • Consider use of • Consider • Maintenance
treatment in concentrations therapeutic drug in fluid or fast long-acting intensive case treatment with depot
patients with monitoring in dissolvable injectable management for antipsychotics should
poor case of assumed forms should be antipsychotics patients likely to be offered
adherence poor adherence preferred disengage from • Service users should
• Causes for non- treatment or be given the option of
compliance are services oral or depot
given in table • Consider depot/ medication in line
form long-acting with their preference
injectable
medication if
avoiding
nonadherence is a
clinical priority
Differential • SGAs • Cognitive • Acetylcholinesterase
treatment in should be remediation inhibitors may be
patients with favored should be offered considered as
cognitive in combination adjunctive therapies to
impairment with other antipsychotic
psychosocial and medication
rehabilitative • Cognitive
measurements remediation therapy
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . .

• Advantages of may be considered

different
antipsychotics on
cognitive
(continued)
695
Table 5 (continued)
696

Austrian
consensus Danish national Clinical practice SIGN Scottish
Guideline WFSBP DGPPN S3 statement guideline NICE guidelines CPG guideline
Year 2012 2019 2016 2016 2014 2009 2013
functions are
discussed
Differential • Explore use of • In patients with • Discuss the use of Patients should • Comorbid substance
treatment in addictive cannabis and/or alcohol, tobacco, receive specific misuse should not
patients with substances central stimulant and illicit drugs and treatment for exclude people with
comorbid • Use an abuse, CBT and their possible alcohol or drug schizophrenia from
substance integrative motivational effects abuse (harm services or
abuse approach in interviewing reduction, interventions
patients with should be abstinence, relapse • Management may
comorbid considered prevention, require a joint
substance abuse rehabilitation) consultive approach
• Use
antipsychotics
with low
anticholinergic
and EPMS
adverse events
risk
• Offer substance-
specific
psychotherapy
and psychosocial
interventions
• Consider
specific
guidelines for
treatment of
R. Musil and P. Falkai

comorbid
substance abuse
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . . 697

Again, the national guidelines show differences in their approach toward these
situations. Though cognitive impairment is known as one of the most important
factors hampering integration of affected patients into work and should be addressed
specifically, not all guidelines give specific recommendations for treatment. And the
diagnostic approach for these topics is mostly not explained in greater detail, and
some guidelines refer to other guidelines (like guidelines for substance abuse).
In the new version of the S3 guideline, common comorbidities of schizophrenia
are listed, namely, substance abuse or dependency, depression and suicidality,
obsessive-compulsive disorder, posttraumatic stress disorder, anxiety disorders,
agitation, and sleeping disorders. As such, screening for pertinent symptoms consti-
tutes an important aspect in the differential diagnostic approach to schizophrenia.

Summary and Discussion

To summarize this chapter on the differential diagnostic approach in Europe, we

discovered, firstly, that there are no Pan-European guidelines for most psychiatric
disorders. Secondly, no specific guideline or consensus paper exists for the differ-
ential diagnostic approach in schizophrenia. Thirdly, in our example of six national
guidelines for the treatment of schizophrenia, most guidelines cover aspects of the
differential diagnostic approach, while others focus mainly on some very specific
questions, which have not been addressed in greater detail in other publications.
Fourthly, guidelines show great agreement on the initial approach toward the patient
with first onset of psychotic features and on the approach toward the patient in the
different phases of disease including treatment resistance. Greater variation was
found in addressing severe symptoms and subtypes of the disorder, in dealing with
certain symptoms, and in addressing comorbidities.
What was not covered by the national guidelines is a clear recommendation on
how to differentiate certain symptom constellations within the spectrum of the
disorder. There is a long-standing debate as to whether psychiatric diseases should
be regarded as well-defined entities or whether symptoms and syndromes are better
placed on a continuum. In recent years it has become common to speak of schizo-
phrenia spectrum disorders, anxiety spectrum disorders, or autism spectrum disor-
ders, to name but a few.
Classification of symptoms in some patients of these spectra to one of the defined
subtypes can be quite challenging at times. How to obtain certainty and which
instruments to use thereby still depends on clinical expertise and is not standardized
to a greater extent at the moment in Europe.
We did not cover the differentiation of new symptoms occurring after initiation of
neuropsychopharmacological treatment which could be due to adverse events or
symptoms associated with the process of switching or discontinuing medication,
which is a subject on its own. The guidelines do provide recommendations for the
treatment of these adverse events to a differing extent, but a detailed discussion of
this aspect would have been beyond the scope of this chapter.
698 R. Musil and P. Falkai

Initiating pharmacotherapy usually involves a process based on shared decision

making and being part of an overall treatment plan. We did not cover details of this
process in this chapter yet want to stress that some of the summaries given in table
form may seem too shortened without paying attention to these important aspects.
Furthermore, some guidelines, such as the S3 guideline, list recommendations for
the use of CBT, family interventions, social skills training, facilitation of access to
the healthcare system, vocational training, and other interventions, yet we did not
cover this area and the scenarios leading to recommendation of these interventions.
Other important features to stratify are age and gender. For schizophrenia early
onset schizophrenia has unique features. At an early age, patients may also present
within the prodromal phase of the disease. Both age and gender are obviously easy to
recognize yet important to consider. In females pregnancy and breast feeding are
important aspects to consider and might change treatment modalities. The SIGN
guideline provides a chapter on perinatal issues. The specific problems of medication
during pregnancy or breast feeding are not covered in this chapter. However, we still
want to stress that assessment of pregnancy and family planning is crucial for all
situations involving psychopharmacological treatment.
Apart from differentiating and formulating specific treatment aims for acute, post-
acute, and remission phases, the S3 guideline furthermore mentions five important
aspects to take into account, namely, mortality, morbidity, health-related quality of
life, intervention- and disease-related efforts, and patient contentedness. In general,
this also holds true for other psychiatric diseases.
There is a plethora of ongoing scientific efforts to find new biomarkers to
differentiate patients’ symptoms. In the field of dementia, amyloid PET has emerged
as helpful to differentiate types of dementia together with findings in CSF. Neuro-
psychological assessment is chosen to separate patients with severe depression and
pseudodementia from patients with cognitive deficits due to dementia or to separate
patients with at-risk mental state and ADHD. Omic techniques like metabolomics,
genomics, and proteomics might be helpful in the future to delineate psychiatric
diseases or subtypes of disease entities. However, all these efforts have not yet led to
conclusive results that have found their way into guidelines, not to mention different
approaches across countries. New and advanced statistical methods such as machine
learning might help to stratify patients according to imaging findings or clinical
characteristics. Again, these new possibilities have not led to conclusive
recommendations.

References
Akiskal HS, Benazzi F. Atypical depression: a variant of bipolar II or a bridge between unipolar and
bipolar II? J Affect Disord. 2005;84(2–3):209–17.
Altamura AC, Bobes J, Owens DC, Gerlach J, Hellewell JS, Kasper S, et al. Principles of practice
from the European expert panel on the contemporary treatment of schizophrenia. Int J Psychi-
atry Clin Pract. 2000;4(1):1–11.
Neuro-psychopharmacotherapy and the Differential Diagnostic Approaches in. . . 699

Baandrup L, Ostrup Rasmussen J, Klokker L, Austin S, Bjornshave T, Fuglsang Bliksted V, et al.

Treatment of adult patients with schizophrenia and complex mental health needs – a national
clinical guideline. Nord J Psychiatry. 2016;70(3):231–40.
Berner P, Kieffer W, Musalek M, Pakesch G, Simhandl C, Wancata J. Approaches to the assessment
of schizophrenia in Europe. Pharmacopsychiatry. 1986;19(1):33–6.
Brooker D, La Fontaine J, Evans S, Bray J, Saad K. Public health guidance to facilitate timely
diagnosis of dementia: ALzheimer’s COoperative valuation in Europe recommendations. Int J
Geriatr Psychiatry. 2014;29(7):682–93.
Catalan Agency for Health Technology Assessment and Research. Clinical practice guideline for
schizophrenia and incipient psychotic disorder. Clinical Practice Guidelines in the NHS [Inter-
net]. Barcelona; 2009.
Cath DC, Hedderly T, Ludolph AG, Stern JS, Murphy T, Hartmann A, et al. European clinical
guidelines for Tourette syndrome and other tic disorders. Part I: assessment. Eur Child Adolesc
Psychiatry. 2011;20(4):155–71.
Degryse J, De Lepeleire J, Southgate L, Vernooij-Dassen M, Gay B, Heyrman J. An evaluation of a
computer based education program for the diagnosis and management of dementia in primary
care. An international study of the transcultural adaptations necessary for European dissemina-
tion. Med Teach. 2009;31(5):397–402.
DGPPN e.V., editor. für die Leitliniengruppe. S3-Leitlinie Schizophrenie. Langfassung. AWMF-
Register Nr 038-009. 2019 (Version 1.0).
European Psychiatric Association. 2018. https://www.europsy.net/publications/guidance-papers/
Filippi M, Agosta F, Barkhof F, Dubois B, Fox NC, Frisoni GB, et al. EFNS task force: the use of
neuroimaging in the diagnosis of dementia. Eur J Neurol. 2012;19(12):e131–40, 1487–501
Gaebel W, Moller HJ. European guidance: a project of the European psychiatric association. Eur
Psychiatry. 2012;27(2):65–7.
Harvey RJ, Whitehouse PJ, Rossor MN. Report of the European Working Group on dementia drug
guidelines meeting – Brussels, November 1997. Alzheimer Dis Assoc Disord. 1998;12
(4):259–61.
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophre-
nia – a short version for primary care. Int J Psychiatry Clin Pract. 2017;21(2):82–90.
Hort J, O’Brien JT, Gainotti G, Pirttila T, Popescu BO, Rektorova I, et al. EFNS guidelines for the
diagnosis and management of Alzheimer’s disease. Eur J Neurol. 2010;17(10):1236–48.
Kane JM, Aguglia E, Altamura AC, Ayuso Gutierrez JL, Brunello N, Fleischhacker WW, et al.
Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychophar-
macology consensus conference in Siena, Italy. Eur Neuropsychopharmacol. 1998;8(1):55–66.
Kasper S, Sachs GM, Bach M, Erfurth A, Frey R, Fruhwürth G, Geretsegger C, Gößler R, Hofer A,
Jagsch C, Kapfhammer H-P, Kienbacher C, Klier C, Lehofer M, Marksteiner J, Miller-Reiter E,
Psota G, Rados C, Rainer M, Willeit M, Windhager E. Schizophrenie Medikamentöse Therapie.
Konsensus-Statement – State of the art 2016. CliniCum neuropsy. 2016; Sonderausgabe
November.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: treatment
and management: updated edition 2014. London: National Institute for Health and Clinical
Excellence Guidance; 2014.
Nielsen TR, Vogel A, Riepe MW, de Mendonca A, Rodriguez G, Nobili F, et al. Assessment of
dementia in ethnic minority patients in Europe: a European Alzheimer’s disease consortium
survey. Int Psychogeriatr. 2011;23(1):86–95.
Ritchie K, Ropacki M, Albala B, Harrison J, Kaye J, Kramer J, et al. Recommended cognitive
outcomes in preclinical Alzheimer’s disease: consensus statement from the European prevention
of Alzheimer’s dementia project. Alzheimers Dement. 2017;13(2):186–95.
Schmidt SJ, Schultze-Lutter F, Schimmelmann BG, Maric NP, Salokangas RK, Riecher-Rossler A,
et al. EPA guidance on the early intervention in clinical high risk states of psychoses. Eur
Psychiatry. 2015;30(3):388–404.
700 R. Musil and P. Falkai

Schultze-Lutter F, Michel C, Schmidt SJ, Schimmelmann BG, Maric NP, Salokangas RK, et al. EPA
guidance on the early detection of clinical high risk states of psychoses. Eur Psychiatry. 2015;30
(3):405–16.
Scottish Intercollegiate Guidelines Network (SIGN). Management of schizophrenia. SIGN publi-
cation no. 131. Edinburgh; 2013. http://www.sign.ac.uk
Vernooij-Dassen MJ, Moniz-Cook ED, Woods RT, De Lepeleire J, Leuschner A, Zanetti O, et al.
Factors affecting timely recognition and diagnosis of dementia across Europe: from awareness
to stigma. Int J Geriatr Psychiatry. 2005;20(4):377–86.
Visser PJ, Verhey FR, Boada M, Bullock R, De Deyn PP, Frisoni GB, et al. Development of
screening guidelines and clinical criteria for predementia Alzheimer’s disease. The DESCRIPA
study. Neuroepidemiology. 2008;30(4):254–65.
Neuropsychopharmacotherapy
and the Differential Diagnostic Approaches
in China

Jie Li and Shen Li

Contents
Mental Health in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
Brief History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
Prevalence of Mental Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Lack of Qualified Staff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Diagnostic Classification CCMD System in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
Brief History and Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
CCMD-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
Diagnosis of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
Psychiatric Diagnosis Principles and Ideas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
Standardized and Diagnostic Mental Examination Tool . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711

Abstract
Mental health in China is a growing issue and has emerged as an important
specialty. Over the past four decades, China’s economic reforms have achieved
great success. However, rapid urbanization and economic growth are generating
new challenges for the country and its mental health system. The mental health
care system in China has undergone substantial changes during the last 40 years.
Most international experts have assessed China’s mental health system and
diagnostic approaches according to western standards. It is necessary to introduce

J. Li (*)
Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China
e-mail: jieli@tjmhc.com
S. Li
Department of Psychiatry, Tianjin Medical University, Tianjin, China
e-mail: lishen@tmu.edu.cn

© Springer Nature Switzerland AG 2022 701

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_366
702 J. Li and S. Li

the mental system and diagnostic classification in China. In this chapter, it

summarizes the metal health, diagnostic classification CCMD system, and diag-
noses of mental disorders in China; the history of the development of Chinese
mental health system; the current situation in mental field that China has to face
in; brief history of diagnostic classification CCMD system and CCMD-3; the
psychiatric diagnosis principles; and the standardized and diagnostic mental
examination tool in clinical work in China.

Mental Health in China

Mental health in China is a growing issue, with experts estimating that 173 million
people live with a mental disorder (Xiang et al. 2012). Social stigma related to
religious and cultural beliefs of upholding social harmony and maintaining personal
reputation contribute to a lack of desire to seek treatment. While the Chinese
government has committed to expanding mental health care services and legislation,
the country struggles with a lack of mental health professionals and access to
specialists in rural areas.

Brief History

China’s first mental institutions were introduced before 1849 by western missionar-
ies. Missionary and doctor John Kerr opened the first psychiatric hospital in 1898,
with the goal of providing care to people with mental illness and treating them in a
more humane way (Blum and Fee 2008).
In 1949, the country began developing its mental health resources by building
psychiatric hospitals and facilities for training mental health professionals. However,
many community programs were discontinued during the Cultural Revolution (Liu
et al. 2011).
In a 1999 meeting jointly held by Chinese ministries and the World Health
Organization, the Chinese government committed to creating a mental health action
plan and a national mental health law, among other measures, to expand and improve
care (Liu et al. 2011). The action plan, adopted in 2002, outlined China’s priorities of
enacting legislation, educating its people on mental illness and mental health
resources, and developing a stable and comprehensive system of care.
In 2000, the Minority Health Disparities Research and Education Act was
enacted. This act helped raised national awareness to health issues through research,
health education, and data collection.
Though China continues to develop its mental health services, it continues to
have a large number of untreated people with mental illness. Intense stigma
associated with mental illness, a lack of mental health professionals and special-
ists, and culturally specific expressions of mental illness may play a role in the
disparity.
Neuropsychopharmacotherapy and the Differential Diagnostic Approaches. . . 703

Prevalence of Mental Illness

In the past 30 years, China – with almost a fifth of the world’s population – has
undergone unprecedented economic development and social change. This transfor-
mation has led to tremendous changes in population structure, urbanization, migra-
tion, education, transportation, culture, leisure, social concepts, and disease
epidemiology. Researchers estimate that roughly 173 million people out of 1.4
billion people in China have a mental disorder (Xiang et al. 2012). Over 90% of
people with a mental disorder have never been treated. A lack of government data on
mental illness makes it difficult to estimate the prevalence of specific mental
disorders (Xiang et al. 2012).
Conducted between 2001 and 2005, a nongovernmental survey of 63,000 Chi-
nese adults found that 16% of the population had a mood disorder, including 6% of
people with major depressive disorder (Phillips et al. 2009). Thirteen percent of the
population had an anxiety disorder, and 9% had an alcohol use disorder. Women
were more likely to have a mood or anxiety disorder compared to men, but men were
significantly more likely to have an alcohol use disorder. People living in rural areas
were more likely to have major depressive disorder or alcohol dependence.
The suicide rate in China was approximately 23 per 100,000 between 1995 and
1999 (Xiang et al. 2012).Since then, the rate is thought to have fallen to roughly 7 per
100,000, according to government data. WHO states that the rate of suicide is
thought to be three to four times higher in rural areas than in urban areas.
Till now, it took more than 10 years for Chinese psychiatrists, related profes-
sionals, and the Chinese Government to set up the China Mental Health Survey
(CMHS) . Launched in 2012, the CMHS addressed the limitations of the previous
studies by using a consistent methodology to do a nationally representative survey,
which relied on coherent diagnostic nomenclature, fully structured diagnostic inter-
views, and sophisticated household survey technology (Huang et al. 2016; Liu et al.
2016).
The latest results were published in the Lancet Psychiatry. Huang et al. found the
prevalence of most mental disorders in China in 2013 is higher than in 1982 (point
prevalence 1.1% and lifetime prevalence 1.3%), 1993 (point prevalence 1.1% and
lifetime prevalence 1.4%), and 2002 (12-month prevalence 7.0% and lifetime
prevalence 13.2%), but lower than in 2009 (1-month prevalence 17.5%). The
evidence from this survey poses serious challenges related to the high burdens of
disease identified, but also offers valuable opportunities for policy makers and
healthcare professionals to explore and address the factors that affect mental health
in China (Huang et al. 2019).

Lack of Qualified Staff

China has 17,000 certified psychiatrists, which is 10% of that of other developed
countries per capita. China averages one psychologist for every 83,000 people, and
some of these psychologists are not board-licensed or certified to diagnose illness.
704 J. Li and S. Li

Individuals without any academic background in mental health can obtain a license
to counsel following several month of training through the National Exam for
Psychological Counselors (Huang 2015), even if most of them study psychology
for personal use and do not intend to pursue a career in counseling (Hizi 2017).
Patients leave the clinics with false diagnoses and often do not return for follow-up
treatments, which is detrimental to the degenerative nature of many psychiatric
disorders (Chen 2016).
The disparity between psychiatric services available between rural and urban
areas (Chen 2016) partially contributes to this statistic, as rural areas have tradition-
ally relied on barefoot doctors since the 1970s for medical advice. These doctors, one
of the few modes of healthcare able to reach isolated parts of rural China, are unable
to obtain modern medical equipment and, therefore, reliable diagnoses for psychi-
atric illness. Furthermore, the nearest psychiatric clinic may be hundreds of kilome-
ters away, and families may be unable to afford professional psychiatric treatment for
the afflicted.

Diagnostic Classification CCMD System in China

Brief History and Overview

Before the foundation of the People’s Republic of China in 1949, in China, there
wasn’t its own classification system for mental illness. In June 1958, the Ministry of
Health held the first national conference on the prevention and treatment of mental
illness in Nanjing, referring to the etiological classification of the Soviet Union;
mental illness was classified into 14 categories, including (1) infectious psychosis;
(2) toxic psychosis; (3) psychosis induced by physical diseases; (4) traumatic psy-
chosis; (5) psychosis induced by brain tumors; (6) cerebrovascular psychosis;
(7) mental illness in the early stage of old age or in old age; (8) epileptic psychosis;
(9) schizophrenia; (10) manic and depressive psychosis; (11) psychogenic psycho-
sis; (12) paranoia; (13) pathological personality; and (14) mental retardation. Among
these 14 categories, mental disorders due to brain organic diseases, physical dis-
eases, and mental retardation account for the majority, while the proportion of
“functional” mental disorders is less.
In July 1978, the second academic annual conference of the Chinese Society of
Neuropsychiatry was held in Nanjing, and a special group was set up to revise the
draft of classification (in 1958). In 1979, the Chinese Journal of Neuropsychiatry
published the revised Classification of Mental Diseases (trial draft), which classified
mental diseases into ten categories: (1) brain organic psychosis, (2) psychosis
induced by physical diseases, (3) schizophrenia, (4) affective psychosis, (5) reactive
psychosis, (6) other psychosis, (7) neuroses, (8) abnormal personality, (9) mental
retardation, and (10) childhood psychosis.
At the academic conference on schizophrenia held in Suzhou in 1981, the
diagnostic criteria for clinical work of schizophrenia in our country were discussed
and formulated, with more than 3 months as the course criterion. In the criteria of
Neuropsychopharmacotherapy and the Differential Diagnostic Approaches. . . 705

symptomatology, strong attention was paid to the diagnostic significance of negative

symptoms, especially in the 1984 revision criteria. It was considered that there were
two items of definite poor content including thinking and indifference of emotion,
which could establish the diagnosis. In 1984, an academic conference on affective
psychosis was held in Huangshan, and the diagnostic criteria of mania and depres-
sion in China were formulated. The Guiyang academic conference on neuroses in
1985 discussed and formulated the diagnostic criteria of neuroses in China, retaining
the diagnosis of hysteria, classifying it into hysterical mental disorder (separated
hysteria) and hysterical physical disorder (converted hysteria), and retaining the
status of depressive neuroses in the classification of neuroses, thus also retaining
the boundaries of neuroses and mental illness in taxonomy. And the diagnosis of
neurasthenia was reserved. This program can be regarded as the first edition of the
diagnostic classification of mental illness in China, namely, CCMD-1.
In June 1986, the third annual meeting of the national neuropsychiatric society of
the Chinese Medical Association decided to set up a working committee on diag-
nostic criteria for mental diseases to formulate diagnostic criteria and classification
schemes for mental diseases in China. This program referred to ICD-10 and DSM-III
and carried out a nationwide collaborative field test. In 1989, the field test of the draft
of diagnostic criteria for schizophrenia, affective disorder and neuroses were com-
pleted. At the enlarged meeting of the psychiatric standing committee of the Chinese
society of neuropsychiatry held in Xi’an in April 1989, the “second edition of
China’s classification scheme and diagnostic criteria for mental diseases” was
approved, namely, CCMD-2.
In May 1994, the first committee of the Chinese psychiatric society in Quanzhou
passed the CCMD-2-R version, which was published and implemented. CCMD-2-R
was as close as possible to ICD system, and the naming, classification, and diag-
nostic criteria of most diseases are as consistent as possible with ICD-10, and some
advantages of DSM system were also referred and adopted. This program increased
the classification and subtypes of mental disorders caused by some organic psycho-
sis, infectious toxic psychosis, and physical disorders. In the category of schizo-
phrenia and paranoid psychosis, the diagnosis and classification of some transient
mental disorders have been added, and the temporary and independent taxonomic
position of “mental disorders closely related to culture, i.e., mental disorders caused
by shrink phobia, Qigong, superstition and witchcraft” has been retained. The
taxonomic position of neurasthenia, hysteria, and depressive neurosis in neurosis
has been retained.

CCMD-3

In 1996, the psychiatric society of the Chinese Medical Association decided to

compile CCMD-3 at the standing committee in Beijing. The compilation principle
of CCMD-3 was following the principle of serving patients and meeting the needs of
patients and the society; with Chinese characteristics and in line with China’s
national conditions; inheriting the advantages of the first 2 versions of CCMD;
706 J. Li and S. Li

paying attention to international integration; and being concise and easy to operate.
The classification was mainly close to ICD-10, considering both etiological classi-
fication and symptomatology classification. The classification and ranking of mental
disorders in CCMD-3 were subject to hierarchical diagnosis and the classification
principle of ICD-10. CCMD-3 emphasizes the traditional, scientific, comprehensi-
ble, acceptable, operable, and relatively stable feature of classification diagnosis.
Large classes and small classes maintained a master-slave logical relationship. Some
categories considered being necessary by Chinese scholars have been retained or
added, including reservations of neuroses (but separating hysteria from neuroses),
recurrent mania, homosexuality, etc.; “Mental disorders closely related to culture,
i.e., mental disorders caused by Qigong, superstition and witchcraft, shrink phobia,
other or cultural related mental disorders to be classified” has been retained. In
China, the concept of simple subtype of schizophrenia was retained, and the
concepts of remission period, residual period, and decline period were still used in
the course of disease, which was different from the classification of remission type
and residual type of ICD-10. A more detailed classification of the mental disorders
caused by other encephalopathy in organic mental disorders reflects the importance
of the concept of etiological diagnosis. According to China's social and cultural
characteristics and traditional classification, some mental disorders were not
included in CCMD-3, such as in the ICD-10 (F 52.7 hypersexuality, F 60.31
borderline personality disorder, F 64.2 childhood gender identity disorder, F 66
some subtypes of psychological and behavioral disorders related to sexual develop-
ment and sexual orientation, F 68.0 rendering somatic symptoms for psychological
reasons, and F 93.3 sibling competition disorder).
Since 2002, China has officially used ICD-10 system for disease classification
statistics, and all kinds of disease codes reported to health administrative depart-
ments by psychiatric medical institutions have been required to use ICD-10 code. At
present, ICD and DSM classification systems have been basically adopted in clinical
and scientific research work.
In short, as mentioned earlier, the existing classification system, whether ICD,
DSM or CCMD, has many problems and is far from a strictly scientific classification.
Like other medical disciplines, the diagnostic classification system of mental disor-
ders also needs to be revised with the progress of medical research and clinical
practice.

Diagnosis of Mental Disorders

Clinical medicine (including internal medicine and surgery) and clinical psychiatry
belong to the same category of natural sciences. The common goal they explore is
for human health and development. Clinical medicine belongs to the practical
science system, and practical experience is of paramount importance. A qualified
clinician must have professional theoretical knowledge and must be a practicing
doctor with certain clinical experience and certain clinical skills and methods. Most
of the exact causes of mental disorders are still unknown, so far it has not been found
Neuropsychopharmacotherapy and the Differential Diagnostic Approaches. . . 707

that can help to clarify the diagnostic well and objective biological indicators.
Clinical psychiatrists also lack tools for assisted diagnosis such as physical diagno-
sis, chemical diagnosis, and imaging diagnosis as physicians and surgeons. Clinical
psychiatrists need to practice hard in their daily work to master the scientifically
correct and reliable skills and methods that are consistent with objective reality and
scientific thinking methods and then can make a correct diagnosis.

Psychiatric Diagnosis Principles and Ideas

Diagnosis refers to the inclusion of a specific patient’s condition in a project of

disease classification. The specific process is for the physician, by virtue of his or her
professional knowledge and skills, to conduct interviews, observations, and exam-
inations (including laboratory examinations) to make clinical assessments of a
person’s personal, family, social condition, potential health problems and major
events in the life process. Based on this, the physicians take the treatment procedure
as the framework and achieve treatment goals by partially or completely solving
these problems. Different classification systems have different diagnostic names, so
the classification of the disease should be mastered before diagnosis.

Principle of Diagnosis of Mental Disorders

The basic purpose of diagnosis is to select the appropriate treatment, to predict the
outcome of the disease, and of course to facilitate statistical analysis and communi-
cation. The treatment of diseases can be divided into two categories, namely,
etiological treatment and symptomatic treatment. The former treatment method is
more thorough than the latter, so the etiological diagnosis is more conducive to
treatment than the symptom diagnosis, and the classification according to the cause
is far more ideal than the symptom classification. Etiological diagnosis is the most
ideal medical diagnosis, but the cause of many mental illnesses has not been clearly
elucidated.
Therefore, the diagnostic process mainly starts with symptom analysis, the earlier
we recognize the symptoms, the earlier we can diagnose and treat them in time.
Experienced physicians, like sophisticated detectives, can find the basis for diagno-
sis from intricate clues or atypical symptoms. This kind of skill can’t be obtained
directly from books, but it needs to be learned through continuous summarization of
practical experience. Diagnostic clues need to be discovered not only by physicians
but also by clues provided by others. For psychiatrists, the clues related to mental
symptoms are generally not ignored, but they often do not attach much importance to
various clues related to physical symptoms, which is a status quo that needs us to
make great efforts to change.
The clinical thinking method refers to the process in which the clinician uses the
professional knowledge and experience according to the collected perceptual data,
analyzes and synthesizes according to objective laws, judges the reasoning to find
out the essential characteristics of the disease, and determines the principles of
diagnosis and disposal. The causes of misdiagnosis can be summarized as follows:
708 J. Li and S. Li

(1) the collection of medical history is not detailed and reliable; (2) the manifestation
of the disease is not sufficient; (3) the observation of the condition is not objective
enough, and the identification of symptoms is not correct; (4) the diagnostic criteria
used are not perfect or cannot be used correctly; (5) the process of diagnostic
thinking is unscientific, for example, adopting a fixed and exclusive way of thinking
about the initial diagnosis hypothesis, which makes oneself fall into the subjective
prejudice of “preemption”; and (6) the level of scientific development is limited, and
some diseases cannot be recognized well.
At present, the causes of mental disorders are complex and symptoms are diverse
and often rely on the diagnosis of symptom groups. However, there are often
overlaps between mild mental symptoms and normal mental activities, so the
diagnosis of some diseases is characterized by varying degrees of rigidity and
yardstick. Based on this fact, some scholars have put forward the characteristic
“diagnostic symptoms” for a disease, such as the “4A” fundamental symptoms
proposed by Eugen Bleuler and the “first rank symptoms” proposed by Kurt
Schneider when schizophrenia is diagnosed, although this view, once approved by
more experts, has not been widely used in clinical practice and is increasingly being
“challenged.” In view of this, WHO and APA of the United States have successively
formulated a unified diagnostic standard for each mental disorder in accordance with
the definition of disease and have continuously supplemented and revised it
according to the development of the discipline, becoming an internationally accepted
ICD and DSM diagnostic system.

Diagnostic Thinking of Mental Disorders

The diagnosis of mental disorders mainly follows the procedural thinking method of
“symptomatic syndrome-diagnosis” (SSD). The specific process is: firstly determine
the mental symptoms, then determine the syndrome according to the combination of
symptoms, and then comprehensively analyze the dynamic development trend of
mental symptoms or syndrome, combined with the pathogenesis, course of disease,
pre-illness personality, social function and other related data. Next various possible
diagnostic assumptions were put forward, according to the possibility from small to
great order to exclude one by one. Finally make a conclusive diagnosis, that is, to
make symptomatic diagnosis or to make etiological diagnosis combined with the
etiology. The diagnosis of mental disorders must follow the principles of practice,
cognition, repractice, and recognition. After the clinical diagnosis is confirmed, we
should continue to observe and follow up and verify the correctness of the diagnosis
by practice. In clinical work, the SSD diagnosis process of specific cases is generally
through the following four links: (1) onset basis, (2) onset and course of disease,
(3) clinical manifestations, and (4) etiology and incentives.

Basis of Disease
It included personal information, family disease history, pre-disease personality, past
disease history, and so on. These related factors often affect the clinical manifesta-
tion, progression, etiology, or incentive of the disease. The main points should be
noted:
Neuropsychopharmacotherapy and the Differential Diagnostic Approaches. . . 709

1. In terms of the occupation of the patient, attention should be paid to the patients’
exposure to harmful substances, the history of pesticide exposure by farmers, the
history of chemical exposure of workers, and so on.
2. Attention should be paid to the existence and progression of acute and chronic
somatic diseases in the history of past diseases, the relationship between physical
diseases and mental disorders, the characteristics of the course of disease, the
treatment situation, and the current curative effect. Sometimes physical symp-
toms before the onset of mental disorders, such as fever, oral herpes, and upper
respiratory tract infections may be prodromal symptoms of sporadic encephalitis.
3. Should pay attention to the influence of pre-illness personality, family, and school
education on the formation and development of patients’ personality. The healthy
personality or some bias often has a certain relationship with a certain disease.
4. The history of mental illness, epilepsy, mental retardation, and personality abnor-
mality in the family members can be used as a reference for the diagnosis and
analysis of mental disorders.

Onset and Course of Disease

There is no uniform definition of the timing of the onset and course of mental
disorders. According to the situation described in the American Research Diagnostic
Criteria (RDC), the onset time was acute within 2 weeks, subacute onset from
2 weeks to 3 months, subchronic onset from 3 months to 2 years, subchronic onset
from 3 months to 2 years, and chronic onset was more than 2 years. In general, acute
morbidity is more common in organic mental disorders (such as mental disorders
caused by poisoning, infections, etc.) or acute psychogenic disorders. So special
attention should be paid to finding the causes of these diseases. In addition, parox-
ysmal or recurrent course of disease is common in mood disorders, epilepsy, and
conversion disorders.

Clinical Manifestation
According to SSD thinking method, we should first determine the mental symptoms,
then determine the syndrome according to the combination of symptoms, and
compare each symptom or syndrome with similar phenomena to find out the
relationship among its nature, psychological background, and environment. Through
extensive and meticulous analysis, propose reasoning and then make it a diagnostic
basis. As such disturbance of consciousness or dementia (including the
corresponding syndrome) often suggests mental disorder caused by brain organic
disorder or somatic disease. Generally, a symptom or syndrome can be seen in a
variety of mental disorders. For example, the encephalasthenia syndrome may be an
early symptom of schizophrenia, a preexisting manifestation of cerebral arterioscle-
rosis, or just a neurosis. In order to understand the real connotation and essence of
the encephalasthenia syndrome through the external appearance, it is necessary to
repeatedly analyze the principal and secondary relationship from the clinical practice
and to identify according to the other characteristic manifestations of different
diseases.
710 J. Li and S. Li

Etiology and Inducement

Ideally, the diagnosis of mental disorders should try to make an etiological diagnosis,
same as the diagnosis of physical illnesses. When collecting medical history and
conducting mental examinations, physical examinations, and laboratory tests, psy-
chiatrists should try to discover the pathogeny as possible as by combining the
characteristics of the disease with various examination results to comprehensively
analyze and carefully compare. In general, the pathogenic factors of mental disorders
are roughly divided into biological factors and psychological factors. Mental disor-
ders are caused by general biological factors with associated clinical symptoms and
signs, which can't attain related abnormal results by physical examinations or
laboratory tests. There is obviously trauma or stress event before onset for mental
disorder caused by mental and society factors. A part of mental such as schizophre-
nia or mood disorder possibly is caused by the collective effects of personal factors
and the influence of environment. In this case, the pre-patient psychosocial factors
are usually attributed to incentives or accidents. We must carefully distinguish the
accurate association between onset and psychosocial factors, especially temporal
correlation between onset and psychological stimulation, whether there are obvious
or occasional inappropriate words and deeds before the stressful event.

Standardized and Diagnostic Mental Examination Tool

The World Health Organization has studied the reliability and consistency of mental
disorders in different social and cultural contexts. The study showed that there is
difference for diagnosis among doctors. Analyze the cause of the difference: the
source of the data collected is different; terminology that doctor used and under-
standing the terminology are different; and the methods of talking examinations,
disease classification, and diagnostic criteria are different. In order to improve the
diagnosis and reliability of the disease, while developing diagnostic criteria, foreign
psychiatrists have also developed standardized mental examination tools and com-
puter diagnostic systems for clinical diagnosis and research. This tool is designed by
a psychiatrist with clinical experience based on diagnostic criteria and diagnostic
criteria. This tool consists of a series of entries, each of which represents a symptom
or clinical variable, a prescribed examination procedure, a questioning method and a
scoring standard, with an explanation of the terms of the tool. This is a fixed or semi-
timed interview tool. The doctor or the researcher conducts inquiries and examina-
tions in strict accordance with the regulations. The results are scored according to the
definition of the entry to determine whether the symptoms exist and determine the
severity. Different doctors use this standardized inspection tool to check patients,
which greatly improves the consistency of diagnosis. Currently used diagnostic
mental examination tools are Composite International Diagnostic Interview-Core
Version (CIDI) and Structured Clinical Interview for DSM-IV (SCID), which is
fixed clinical examination. The former can separately infer the diagnosis of ICD-10
Neuropsychopharmacotherapy and the Differential Diagnostic Approaches. . . 711

and DSM-IV. The former can be operated by a non-psychiatrist, while the latter must
be operated by a trained psychiatrist.
In recent years, in some epidemiological studies, a more simplified diagnostic
tool has been adopted, namely, mini-international neuropsychiatric interview
(MINI). MINI is a simple, effective, and reliable structured interview tool developed
by Sheehan and Lecrubier. It is mainly used for screening and diagnosing 16 kinds of
axis mental illness and personality disorder in DSM-IV and ICD-10, including
130 questions. Like Structured Clinical Interview for DSM-IV-Patients (SCID-P)
and CIDI, each diagnosis in the MINI is a question group, and most diagnoses have
screening problems that exclude diagnosis. There have been studies comparing the
reliability and validity of MINI with SCID-P and CIDI, and the results show that
MINI has a very acceptable reliability and validity score. The MINI has been
translated into a variety of languages and is widely used in clinical trials and clinical
practice. In recent years, China has been participating more and more in international
clinical research. The English version 5.0.0 (2004) of MINI has been translated into
Chinese version, and the reliability and validity test has been carried out. The results
show that the MINI Chinese version has a high consistency in the diagnosis of
depressive episodes, anxiety disorders, substance dependence, psychotic disorders
and the diagnosis made by SCID-P. The use of MINI ensures the accuracy and
consistency of the diagnostic process and can reveal potential psychiatric
comorbidities. Due to the short interview process, the problem is concise and easy
to be accepted by patients, and it can be widely used in clinical practice.

References
Blum N, Fee E. The first mental hospital in China. Am J Public Health. 2008;98:1593.
Chen M. Abuse of mentally ill in China. Mental Health in China. Weekly; 2016.
Hizi G. “Developmental” therapy for a “modernised” society: the sociopolitical meanings of
psychology in urban China. China. 2017;15:98–119.
Huang H-Y. From psychotherapy to psycho-boom: a historical overview of psychotherapy in China.
Psychoanal Psychother China. 2015;1(1):1–30.
Huang Y, Liu Z, Wang H, Guan X, Chen H, Ma C, Li Q, Yan J, Yu Y, Kou C, Xu X, Lu J, Wang Z,
Liu L, Xu Y, He Y, Li T, Guo W, Tian H, Xu G, Xu X, Lv S, Wang L, Wang L, Yan Y, Wang B,
Xiao S, Zhou L, Li L, Tan L. The China mental health survey (CMHS): I. Background, aims and
measures. Soc Psychiatry Psychiatr Epidemiol. 2016;51:1559–69.
Huang Y, Wang Y, Wang H, Liu Z, Yu X, Yan J, Yu Y, Kou C, Xu X, Lu J, Wang Z, He S, Xu Y,
He Y, Li T, Guo W, Tian H, Xu G, Xu X, Ma Y, Wang L, Wang L, Yan Y, Wang B, Xiao S,
Zhou L, LI L, Tan L, Zhang T, Ma C, Li Q, Ding H, Geng H, Jia F, Shi J, Wang S, Zhang N,
Du X, Du X, Wu Y. Prevalence of mental disorders in China: a cross-sectional epidemiological
study. Lancet Psychiatry. 2019;6:211–24.
Liu J, Ma H, He YL, Xie B, Xu YF, Tang HY, Li M, Hao W, Wang XD, Zhang MY, Ng CH,
Goding M, Fraser J, Herrman H, Chiu HF, Chan SS, Chiu E, YU X. Mental health system in
China: history, recent service reform and future challenges. World Psychiatry. 2011;10:210–6.
Liu Z, Huang Y, Lv P, Zhang T, Wang H, Li Q, Yan J, Yu Y, Kou C, Xu X, Lu J, Wang Z, Qiu H,
Xu Y, He Y, Li T, Guo W, Tian H, Xu G, Xu X, Ma Y, Wang L, Wang L, Yan Y, Wang B, Xiao S,
712 J. Li and S. Li

Zhou L, Li L, Tan L, Chen H, Ma C. The China mental health survey: II. design and field
procedures. Soc Psychiatry Psychiatr Epidemiol. 2016;51:1547–57.
Phillips MR, Zhang J, Shi Q, Song Z, Ding Z, Pang S, Li X, Zhang Y, Wang Z. Prevalence,
treatment, and associated disability of mental disorders in four provinces in China during 2001-
05: an epidemiological survey. Lancet. 2009;373:2041–53.
Xiang YT, Yu X, Sartorius N, Ungvari GS, Chiu HF. Mental health in China: challenges and
progress. Lancet. 2012;380:1715–6.
Ethical Issues in
Neuropsychopharmacotherapy: US
Perspective

Michael Menconi Jr. and Veljko Dubljević

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
Autonomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
Beneficence and Nonmaleficence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
Justice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718
Iatrogenic Properties and Trust . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719
Nontherapeutic Use and Cosmetic Neuroenhancement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722
Socioenvironmental Determinants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
Fluoxetine (Prozac ®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
Clinical Indications and Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
Mechanism of Action of Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
Additional Ethical Considerations with Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
Modafinil (Provigil ®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
Clinical Indications and Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
Mechanism of Action of Modafinil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 730
Additional Ethical Considerations with Modafinil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735

Abstract
The patient rights movement has designated medical autonomy as the predomi-
nant principle within the contemporary biomedical ethics paradigm. The
principles that govern the clinical delivery of medicine and clinical research
have, as of late, elicited numerous ethical concerns within the realm of neuropsy-
chopharmacotherapy that can only be addressed by reviewing the principles of
M. Menconi Jr.
Bioethics and Public Health, Columbia University, New York, NY, USA
e-mail: m.menconi@columbia.edu
V. Dubljević (*)
Department of Philosophy and Religious Studies, and Science Technology and Society Program,
North Carolina State University, Raleigh, NC, USA
e-mail: veljko_dubljevic@ncsu.edu

© Springer Nature Switzerland AG 2022 713

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_380
714 M. Menconi Jr. and V. Dubljević

biomedical ethics through the lens of contemporary psychotherapeutic research,

practice, and healthcare delivery. In this chapter, we address three overarching
categories of emerging ethical questions in the field of neuropsychopharma-
cotherapy, namely (i) trust within the clinician–patient relationship, (ii) the non-
therapeutic acquisition and usage of psychotropics for neuroenhancement, and
(iii) the socioenvironmental factors that have contributed to the increase of
psychotropic drug use in society. We then contextualize these ethical consider-
ations by providing case studies of two of the most prolific and widely used
psychotropic medications – Fluoxetine (Prozac ®) and Modafinil (Provigil ®). We
conclude with a discussion on the future of neuropsychopharmacotherapy as it
continues to evolve in a global society that is characterized by exponential
increases in the prescription and use of psychotropic medications.

Introduction

Contemporary ethical debates surrounding the prescription and use of psychotropic

medications are nearly indistinguishable from those that captured public attention
throughout the 1980s. The patient rights movement – derived variously from modern
American social movements addressing civil rights, reproductive rights, human
rights, and a near-universal embrace of market driven healthcare delivery models –
has designated medical autonomy as the predominant principle within the contem-
porary biomedical ethics paradigm. Consequently, over the previous four decades,
principalism has emerged as the paradigmatic approach to the conceptualization and
practice of biomedical ethics. The four principles and pillars of biomedical ethics,
which healthcare providers, researchers, and other allied health professionals employ
in cases of moral and/or ethical uncertainty or conflict, include (1) respect for
autonomy, (2) beneficence, (3) nonmaleficence, and (4) justice (Beauchamp and
Childress 2013). These principles not only govern the clinical delivery of healthcare,
they also apply to the clinical research enterprise. This includes research, develop-
ment, and manufacturing of pharmaceuticals as well as emerging biotechnologies
(pharmacogenetic testing, for example). This phenomenon has been paralleled by
rapid advances in our understanding of neuroscience, psychopathology, and the
underlying socioenvironmental determinants of health associated with these fields.
As such, numerous vexing ethical concerns continue to challenge practitioners and
patients within the realm of neuropsychopharmacotherapy.
In an effort to competently address these complex challenges, it is necessary to
review the principles of biomedical ethics through the lens of contemporary psy-
chotherapeutic research, practice, and healthcare delivery. Following this brief
overview, we will address three overarching categories of emerging ethical questions
in the field of neuropsychopharmacotherapy. First, we will demonstrate how the
iatrogenic properties of psychotropic medications affect the crucial element of trust
within the clinician–patient relationship. Subsequently, we will present an analysis
of nontherapeutic acquisition and use of psychotropics for the purposes of cosmetic
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 715

neuroenhancement. Thirdly, we will identify the related socioenvironmental deter-

minants of health as they pertain to the ongoing increase in both therapeutic and
nontherapeutic use of psychotropic drugs in contemporary society. In this section,
we also postulate possible explanations for the increased incidence of mental illness
and the implications of this troubling trend for neuropsychopharmacotherapy. In an
effort to contextualize this complex array of ethical considerations, we provide case
studies of two of the most prolific and widely used psychotropic medications –
Fluoxetine (Prozac ®) and Modafinil (Provigil ®). We conclude with a discussion on
the future neuropsychopharmacotherapy as it continues to evolve in a society that is
characterized by exponentially increasing psychotropic medication use, with an
emphasis on the unfortunate reality that this demand will continue to overwhelm
the healthcare delivery system as it exists today.

Autonomy

Respect for autonomy refers to the right of the patient or individual to make personal
decisions regarding their own medical care, including the right to refuse unwanted
treatment (Beauchamp and Childress 2013). This right is recognized in medical and
legal contexts and is contingent on the patient’s ability to become fully informed of
proposed medical treatments and interventions. If a patient is to exercise their
medical autonomy directly, they must also hold the cognitive capacity – or compe-
tence – to understand the full array of risks and benefits of personal medical
decisions. If a patient is determined to lack this capacity by a medical provider, a
healthcare proxy or agent (typically a next of kin or family member) is appointed to
undergo the informed consent process for them. Today, the safeguard of medical
autonomy is informed consent, which constitutes a medicolegal contract (verbal or
written) between clinician and patient. A thorough and competent informed consent
process outlines the purpose of the proposed therapeutic intervention(s), relevant
risks, and expected therapeutic benefits. These are discussed between the clinician
and patient, during which time the patient may ask questions regarding the proposed
treatment. Once mutual understanding is reached, whether or not the proposed
intervention(s) are carried out is solely contingent on the patient’s explicitly stated
preferences.
The widespread integration of the informed consent process into the practice of
medicine and clinical research was the product of public and governmental
responses to the human rights violations observed in the Tuskegee Syphilis study.
In October 1932, poor black men in Tuskegee, Alabama were coerced into partic-
ipating in a study that sought to observe the effects of untreated Syphilis. Specifi-
cally, investigators sought to observe the neurological effects of untreated Syphilis.
There was no therapeutic purpose or motive for the study, which continued for over
40 years despite the discovery of penicillin as a curative treatment. The study
operated largely out of the public eye until a reporter published a whistleblowing
report on the front page of the Washington Star in 1972 (Brandt 1978). The
716 M. Menconi Jr. and V. Dubljević

consequent public outcry over such inhumane research resulted in the creation of a
federal ad hoc ethics committee to review the study. The review, led by the United
States Centers for Disease Control and Prevention (CDC), ultimately led to the
study’s termination in 1973. While aftermath of the Tuskegee Syphilis Study spurred
many of the informed consent standards used today and sparked an international
conversation on racial bias in medicine, the application of these standards to
contemporary healthcare delivery remains a complicated endeavor.
The Tuskegee Syphilis Study instigated national and international conversations
about patient rights, raising questions about what information – in the context of
clinical research or otherwise – individuals (or patients) seeking treatment are
entitled to receive. This marked the first time informed consent occupied a signifi-
cant platform in the medical ethics community. While the post-World War II
Nuremberg Trials elucidated important ethical guidelines surrounding the treatment
of human research subjects on a global scale, the domestic reality of Tuskegee
imparted crucial lessons that permeated the practice of clinical medicine and
research in the United States. In response to Tuskegee, the National Research Act
was passed by the U.S. Congress in 1973, in which autonomy – or “respect for
persons” as it is called in the law – was codified (Reverby 2011). The subsequent five
decades witnessed a monumental erosion of medical paternalism as a result. Since
the advent of primary care medicine, patients largely accepted physician recommen-
dations, including prognoses and treatment plans. Today however, between 20 and
40% of patients seek second opinions (Payne et al. 2014). As will be elucidated later
in this chapter, this newly empowered patient – a consumer of healthcare that is not
only acutely aware of their medical autonomy but chooses to maximize it – elicits
numerous ethical implications for neuropsychopharmacotherapy.
Unfortunately, the operationalization of the necessary elements of the informed
consent process is not always straightforward in the context of neuropsychopharma-
cotherapy. First, the side effects of psychotropic medications – particularly the
frequency, specificity, and risk of these side effects – are not always communicated
appropriately by the prescribing clinician. For example, many clinicians do not
disclose the well-documented risk of increased appetite that accompanies many
SSRIs, thus falsely implying that the risk of weight gain is insignificant (Gafoor
et al. 2018). However, even in instances where side effects and therapeutic expec-
tations are articulated properly by the prescribing clinician, clinicians and patients
frequently utilize data from industry-funded clinical trials to inform their decisions.
The use and interpretation of such data, sometimes published via misleading
industry-authored reports that minimize drug risks while exaggerating therapeutic
benefits, influence the clinician’s decision to offer and prescribe the medication, as
well as the patient’s decision to accept and comply with the proposed treatment. In
such instances where the information guiding medical decision-making is suspect,
medical autonomy is threatened because the patient’s consent, if offered, is not fully
and/or accurately informed.
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 717

Beneficence and Nonmaleficence

The principles of beneficence (do good) and nonmaleficence (do no harm) originate
from the earliest versions of the Hippocratic Oath authored many centuries ago.
Today, these elements guide clinicians in their administration of medical treatments
and interventions. While beneficence and nonmaleficence are presented in founda-
tional bioethics texts as separate principles, both principles jointly operate as a dyad
in clinical practice and research. For example, clinicians are obligated to present
treatment options to patients that stand to produce more benefit than harm. This is, of
course, if the treatments are administered correctly and unexpected complications
are avoided. In essence, this mode of reasoning involves ensuring the benefits of a
proposed medical intervention outweigh the known risks. However, all risk assess-
ments in the clinical environment remain highly contingent on the type of medical
intervention being considered. In the context of surgery, for example, surgeons
consider the complete array of possible complications that may arise during the
procedure, in addition to the predicted severity of the postoperative recovery course.
Patents are informed of these elements during the informed consent process. Alter-
natively, practitioners prescribing medication must be reasonably confident that a
drug’s potential side effects represent an acceptable harm. This determination is
made by weighing these potential harms against the drug’s expected therapeutic
benefits. This standard also holds for clinical trials. In all cases, the patient performs
their own risk-benefit analysis under the guidance of their clinician during the
informed consent process.
While this ethical analysis may appear elementary, it becomes vastly more
complicated in the context of psychotropic medications. For example, some studies
claim placebo effects are responsible for alleviating symptoms of depression and
anxiety in over 50% of patients that are prescribed SSRIs (Weimer et al. 2015).
However, side effects of the same medications, including sexual dysfunction and
suicidal ideation, are neither insignificant nor rare (Boseley 2000). Suppose a patient
experiences significant therapeutic relief as a result of a placebo effect (this phe-
nomenon is impossible to determine definitively outside of a randomized controlled
trial). If the clinician were able to determine that the placebo effect was producing
the symptom relief instead of the prescribed psychotropic, it would be unethical to
continue prescribing the drug if any possibility of serious side effects exists. In this
hypothetical case, since a transition to a harmless sugar pill would impart identical
therapeutic benefit with zero risk, the clinician would be obligated to transition the
patient to this zero-risk option. Of course, this would require that the patient be
blinded to the fact that the psychotropic drug they was originally prescribed is now in
fact a sugar pill. While such deception is not ethical or practical, the logic surround-
ing the risk-benefit analysis remains valid. Consequently, the outcome of a risk-
benefit analysis in this context is entirely contingent on the prescribing clinician’s
interpretation of risk, the data they employ to assess such risk, and the quality and
scope of relevant clinical training necessary to integrate these elements into practice.
718 M. Menconi Jr. and V. Dubljević

Problematically, these elements are neither universal nor standardized, thereby

calling into question the scientific and clinical rigor of prescribing practices in the
context of neuropsychopharmacotherapy.

Justice

The principle of justice – or the degree to which healthcare resources are fairly
distributed among society – is largely dictated by the economic environment in
which a healthcare delivery system operates. Notions and theories of justice vary
widely across academic and political disciplines, with the most polarizing differ-
ences deriving from libertarian and utilitarian spheres. Such debates often include
discussion of oppositional ideological forces (i.e., collectivism vs. individualism),
and what rights ought to be recognized (and thus protected) by government and
society. While the perennial (and important) international debate regarding the merit
and feasibility of codifying health as a fundamental human right lies outside the
scope of this discussion, it is necessary to acknowledge that in societies without
universal healthcare coverage (such as the USA), socioeconomic status often deter-
mines the degree to which, if at all, neuropsychopharmacotherapy is accessible.
Recall our previous discussion of the modern patient’s newfound affinity for
second opinions. In certain instances, this phenomenon is associated with “doctor
shopping,” a term used to describe patient attempts at seeking out physicians with
permissive prescribing practices. This phenomenon – which does not occur exclu-
sively in the context of clinician malpractice – often manifests via clinicians’ low
diagnostic threshold for diagnosing attention deficit hyperactivity disorder (ADHD).
For example, some clinicians may require (and administer) a comprehensive psy-
choanalytic assessment before diagnosing ADHD, while others may simply inter-
view the patient and screen for relevant symptoms. While inconsistency in
diagnostic approaches may be a result of the clinician’s personal preferences or
training, such variability may alternatively arise from the diagnostic manual
referenced by the clinician. For example, US clinicians utilize the Diagnostic and
Statistical Manual for Mental Disorders (DSM), while European practitioners and
others utilize the International Classification of Diseases (ICD). Diagnostic criteria
found in the DSM are associated with higher levels of specificity, thus allowing less
room for interpretation. Diagnostic criteria found in the ICD are considered to be
more inclusive and flexible, thus allowing more room for clinician judgment (Dalal
and Sivakumar 2009).
In cases where diagnostic criteria are less stringent and/or the clinician adopts an
approach characterized by a low diagnostic threshold, the possibility of exploitation
by drug seeking patients increases. This includes university students seeking
amphetamines for cognitive enhancement purposes. Currently, no research has
investigated the ability of psychiatric clinicians to detect dishonesty during ADHD
assessments, thus the extent of the problem is largely unknown. Regardless, “doctor
shopping” in the United States requires an expensive and comprehensive private
insurance plan, or the ability to pay out of pocket for multiple visits. Patients with
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 719

few resources, such as those enrolled in government insurance plans (i.e., Medicaid),
are assigned clinicians and therefore not afforded this flexibility. As such, the
socioeconomic status of the patient influences how, and to what degree, psychotropic
medications are accessed.
In addition to economic access barriers, the high level of subjectivity inherent in
diagnostic approaches to psychopathology raises concerns about establishing a
uniform standard of care. The standard of care is defined as what a “reasonable
clinician” with relevant specialty training considers a competent approach to a
particular clinical situation (Cohen et al. 2017). The DSM, currently in its fifth
edition, also exhibits subjectivity and variability through its constant revisions,
which continue to generate significant controversy among US practitioners (Amer-
ican Psychiatric Association 2013). For example, the American Psychiatric Associ-
ation is currently debating the introduction of new diagnostic revisions to the
DSM-V. Most notably, proposed additions include expanded “dimensional mea-
sures,” which allow clinicians to diagnose mental disorders on a spectrum based
on the severity and prevalence of symptoms (American Psychiatric Association
2020). It is unclear how clinicians will interpret and implement these new criteria,
thus future effects on prescribing patterns are difficult to predict. Such clinical
inconsistency, now poised to increase as a result of proposed expansions of the
less precise “dimensional” DSM criteria, raises significant justice-related ethical
concerns, namely fairness. For example, it increases the probability that a patient
presenting with identical symptoms to two different psychiatric clinicians will
receive disparate diagnoses and treatments. This reality is problematically charac-
terized by decreased clinical objectivity and leaves the treatment course (and patient)
more susceptible to clinician biases of all types (clinical, social, etc.). These concerns
are exacerbated for patients of low socioeconomic status who lack the ability to
choose their prescribing clinician.
While all four pillars of biomedical ethics are relevant to our discussion, the
principalist biomedical ethics paradigm as it operates today remains predominantly
driven by medical autonomy. The confluence of social, economic, and cultural forces
within the psychotherapeutic enterprise raises significant ethical questions for the
research and practice of neuropsychopharmacotherapy. These dilemmas – collec-
tively representing the ethical aspects of neuropsychopharmacotherapy – are most
logically taxonomized into three primary categories: iatrogenic properties and trust,
nontherapeutic use and cosmetic neuroenhancement, and socioenvironmental deter-
minants of health. Through this manner of organization, we seek to examine the
ethical implications of neuropsychopharmacotherapy as they affect patients, clini-
cians, and the public at large.

Iatrogenic Properties and Trust

The global history of medicine and clinical research has been consistently afflicted
with instances of gross human rights violations at the hands of clinicians. It is
therefore unsurprising that many of the same issues continue to plague the practice
720 M. Menconi Jr. and V. Dubljević

and delivery of neuropsychopharmacotherapy. Many of these instances, including

Tuskegee, disproportionately affected racial and ethnic minorities and thus continue
to represent a barrier to healthcare access for these populations. Deceit was the
predominant coercive method employed to commit these heinous deeds. Such
assaults on the therapeutic relationship continue to promulgate mistrust in the
context of psychotropic pharmaceuticals. Distrust and skepticism of psychotropic
medications – as well as of the prescribers of these drugs – have recently vaulted to
the forefront of bioethical debate. For example, symptoms of psychopathologies that
some psychotropics purport to treat are simultaneously listed as possible side effects
for the same medications. This is most infamously demonstrated with SSRIs. One
side effect of the most common SSRI includes suicidal ideation, a symptom of major
depressive disorder that the drug is aggressively marketed to treat (Wenthur et al.
2014). To the layperson, this glaring contradiction may call into question the motives
of the psychotherapeutic enterprise, especially in the context of the ongoing suicide
epidemic. Among Americans the suicide rate increased by 33% between 1999 and
2017 (Hedegaard et al. 2018).
Furthermore, the extensive time period that certain psychotropic medications
require to achieve therapeutic effect represents a serious barrier to patient trust. In
clinical practice, this timeframe is known as a drug’s “time-to-effect” (Machado–
Vieira et al. 2010). Patients seeking treatment from a mental health professional will
often be prescribed antidepressant medications. However, some antidepressants
require more than four weeks to take effect, with some studies reporting time-to-
effect of over six weeks for others (Wenthur et al. 2014). Evidence suggests that
patients struggle with medication compliance in the absence of demonstrable evi-
dence of therapeutic relief (Wenthur et al. 2014). In other words, patients that fail to
experience improvement of symptoms within what they perceive as a reasonable
timeframe are likely to stop treatment, even when advised against such actions by
their prescribing clinician. While the prescription of benzodiazepines (anti-anxiety
medications) have traditionally been used for the purposes of acute episode man-
agement (ameliorating symptoms in the short-term while the SSRI is initiated),
the highly addictive properties of these pharmaceuticals have instigated a significant
reduction in prescriptions. This is partly a byproduct of the ongoing global
opioid epidemic. As such, patients may not only wait four-plus weeks for SSRI-
induced therapeutic relief from debilitating conditions such as depression and
generalized anxiety disorder, the short-term anti-anxiety prescriptions used for
acute symptom management are under increased scrutiny and are thus prescribed
less frequently.
The seminal keeper of trust in all therapeutic endeavors – the informed consent
process – also becomes increasingly complicated in the context of psychotropic
medications. At the onset of all clinical interventions, the patient must be informed
by the clinician of the risks, benefits, and therapeutic purpose of the proposed
intervention (Beauchamp and Childress 2013). However, the degree to which
patients in acute emotional crisis internalize and understand the risks and side effects
communicated to them during the clinical encounter is unclear (Appelbaum 2007).
For some psychotropic medications, such as certain antidepressants, the side effects
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 721

are significant and require serious self-awareness on the part of the patient to ensure
that the onset of some side effects, such as suicidal thoughts, do not become
catastrophic (Appelbaum 2007). This raises serious medico-legal questions sur-
rounding the capacity of the psychiatric patient to undergo a proper informed
consent process in nonemergent contexts. For example, consider an instance in
which a patient in emotional turmoil presents to a psychiatrist following the loss
of a loved one. Whether or not this patient is able to properly internalize the risks of a
proposed course of psychotropic medication is up to the clinician’s sole discretion. If
this encounter is the clinician’s first with the patient, such an assessment is compli-
cated due to the clinician’s lack of familiarity with the patient’s baseline emotional
function and coping mechanisms.
The notion of capacity (used interchangeably in both legal and medical literature
with “competence”) is further complicated by the subjective nature of cognitive
evaluations. It is not uncommon for psychiatric clinicians to reach different conclu-
sions following capacity assessments of the same patient (Appelbaum 2007). These
assessments are less complex in instances where the patient presents with psychosis.
In these cases, clinicians are legally empowered to file for a medical hold (commonly
understood as civil commitment), effectively restraining and detaining the patient
until forced treatment restores the patient’s cognitive capacity.
Questions regarding criteria for determination of cognitive capacity (the degree to
which an individual is deemed competent to make personal healthcare decisions) in
clinical settings additionally raise ethical concerns. In extreme cases, psychiatric
practitioners are able to temporarily restrict medical autonomy entirely by forcing
treatment via state-specific civil commitment statutes if they determine patients are a
danger to themselves or others. In such cases, no informed consent process is
required, as the patient has been clinically determined to lack capacity (Appelbaum
2007). Regardless, the complexities and clinical inconsistencies surrounding the
informed consent process in the context of psychotropic medications provide
ammunition for those skeptical of the psychotherapeutic enterprise.
Furthermore, the questionable practices of corporate pharmaceutical advertising
of psychotropic medications have only furthered ethical concerns surrounding trust.
While recent public focus has revolved around the marketing of prescription opioids,
antidepressants were the most heavily marketed drug class in the mid 2000’s
(McHenry 2006). Significant levels of spending on direct-to-consumer advertising
and massive distributions of free samples to providers has been linked to increased
fluoxetine prescription for children, despite a lack of evidence of its efficacy in a
number of pediatric clinical trials (Boseley 2000). Specifically, experts and regula-
tory authorities have questioned the grounds on which pharmaceutical companies
such as Eli Lilly (the original manufacturer of Prozac) make claims of efficacy in
advertisements. Opposition to these claims of efficacy takes many forms, from direct
challenges to the neuroscience underlying various mechanisms of action (e.g., the
Serotonin hypothesis) to allegations of systemic rigging of the clinical trial process
and selective publication of subsequent trial results (McHenry 2006). The onslaught
of direct to consumer advertising in conjunction with the development of a powerful,
industry-dependent clinical research enterprise has led some critics to coin the
722 M. Menconi Jr. and V. Dubljević

umbrella term “corporate psychiatry” (McHenry 2006). Both of these elements will
be elucidated further in the specific discussion of fluoxetine.

Nontherapeutic Use and Cosmetic Neuroenhancement

In the context of neuropsychopharmacotherapy, non-therapeutic use refers to the

ingestion of psychotropic medications for the purposes of cosmetic
neuroenhancement, or the aim of gaining a cognitive advantage over one’s baseline
cognitive performance. Drugs used for these purposes may be acquired legally (via
online vendors, etc.) or illicitly. The illegal black market for psychotropic medica-
tions is most prominently demonstrated by the widespread dissemination of pre-
scription amphetamines by high school and university students, where students with
prescriptions often sell or trade pills to those without prescriptions. The ultimate aim
of those obtaining illicit amphetamines is to gain a competitive edge in the academic
environment. This phenomenon manifests against a backdrop of increased hysteria
surrounding the college admissions process, with increased pressure being placed on
students by schools and parents. It is therefore unsurprising that performance on
standardized tests, as well as other academic assessments related to conventional
classroom study, remain top reasons students illicitly seek amphetamines without
prescriptions.
The degree to which society currently values (and in many sectors, prioritizes)
high levels of productivity and education introduces the possibility of coercion. A
majority of cases in which students obtain prescription amphetamines illicitly are
instances where they experience anxiety about an upcoming project or exam, and
thus feel compelled to medicate themselves for the purposes of gaining a competitive
edge. It is therefore unsurprising that up to 35% of students pursuing an undergrad-
uate or graduate degree reported consuming stimulant medication to gain a compet-
itive edge in the classroom (DeSantis et al. 2008). In areas of high socioeconomic
status, it is common for parents to pay out-of-pocket for neuropsychological evalu-
ations in an effort to secure an ADHD diagnosis and thus a monthly prescription of
stimulants for their children. Currently, ADHD is diagnosed more frequently in
mid-high socioeconomic status (SES) communities than in low SES communities.
This is despite the fact that ADHD occurs more frequently in children living in
low-resource households. Consequently, serious justice concerns arise about access
to stimulant medication and the role of the psychotherapeutic enterprise in exacer-
bating such inequities.
Furthermore, workers in occupations that prize long work hours, such as the legal
and medical professions as well as many corporate sectors, report high rates of
amphetamine use. As such, the confluence of prescriber leniency and social forces
have produced an ethical dilemma of monumental proportions: do stimulants belong
within the realm of medicine solely for the therapeutic purposes of correcting
cognitive deficits, or should they be made available over the counter to meet the
cognitive demands of an increasingly skilled workforce?
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 723

Socioenvironmental Determinants

The previous two decades have produced an extensive body of public health
research that attempts to identify the underlying causes of disease, illness, and
mortality. In an attempt to focus on disease prevention, the field of public health
has integrated crucial elements of sociomedical science into its theory and practice.
As such, a paradigm shift has resulted that supplants the individualistic health
behavior model (i.e., focus on personal responsibility) with a holistic psychosocial
scheme that evaluates the patient’s environment for factors that instigate and rein-
force maladaptive health behaviors. Consequently, when examining trends in public
health such as increased use of psychotropic medications, we are simultaneously
obligated to seek out potential drivers of patient (or consumer) behavior, particularly
at the societal level. In the context of neuropsychopharmacotherapy, the socio-
environmental determinants that begin to explain the increased use of psychotropic
medications are found in two primary realms. First, the ways in which the market
economy affects and often dictates healthcare delivery provides insight into how the
concept of the “patient” has been reframed to meet market demands. This phenom-
enon has produced an environment that has readily increased the availability of
prescription psychotropic medications via licit and illicit means. Second, contem-
porary societal trends in academia and occupational productivity represent social
forces that encourage exploitation of their widespread availability.
The reduction from patient to consumer has promulgated resounding effects on
the credibility of the healthcare system. In the context of psychoactive pharmaceu-
ticals, an ongoing ethical debate persists – both in theory and clinical practice –
regarding whether or not the conceptualization of psychotropics merely includes
therapeutic interventions or if the scope includes cosmetic neuroenhancers (Jotterand
and Dubljević 2016). If the patient is primarily treated as a customer, the prescribing
provider’s fiduciary obligation to the patient now includes the subjective, market-
driven element of patient satisfaction as an aside to beneficent therapeutic care. It is
therefore unsurprising that over 40% of SSRI prescriptions issued to patients by
general practitioners are the result of patient requests (Mercier et al. 2014). Recent
efforts to combat financial abuse of the pay-per-service physician reimbursement
model have resulted in a nationwide increase in the use of patient satisfaction
surveys, the results of which are compiled by hospital administrators and used as a
performance benchmark. Physician compensation is either increased or decreased
based on these results.
This increased incentive for prescribers – including physicians and nurse practi-
tioners – to satisfy their patients has resulted in a decreased deterrence of requests for
medications patients believe they need. This phenomenon is evidenced by the
problematic over-prescription of antibiotics, where drugs like penicillin are pre-
scribed for antibiotic-resistant viral infections for the purposes of meeting the
patient’s conception of a successful medical appointment. This nearly universally
involves the expectation of receiving a prescription at the conclusion of the visit
(Smith 2012). This affront to medical paternalism has promulgated a public health
724 M. Menconi Jr. and V. Dubljević

crisis, as the prevalence of antibiotic-resistant infections continues to increase. As

such, a patient who is refused psychotropic medications may express dissatisfaction
on physician report cards and thus endanger the physician’s compensation. In
instances where physicians receive multiple unsatisfactory marks, their employment
contract with the hospital or practice may be endangered.
Increased administrative demand for prescribers to satisfy their patients has been
met with a simultaneous societal emphasis on career productivity and advancement.
For example, the under-35 birth rate has declined precipitously in the previous two
decades, a phenomenon that sociologists largely attribute to increased educational
and career focus among the population, particularly in women of childbearing age
(Marshall et al. 2009). Furthermore, while the unemployment rate is currently near
an all-time low in the United States, the student debt crisis and skyrocketing housing
prices have pushed recent college graduates into high-wage, high-pressure sectors.
Such increased entry into high-skill careers characterized by 50–60 hour-plus work
weeks is simultaneously met with increased participation in highly competitive
academic environments to obtain the necessary qualifications for these careers.
The result is a record demand for psychotropic medications that has reached
historical highs. The American Psychiatric Association (2017) reported that from
2016 to 2017, the number of adults who described themselves as more anxious than
the previous year rose 36%. Anxiety is one of the largest risk factors for depression.
In 2017, more than 17 million American adults had at least one major depressive
episode, as did three million adolescents aged 12–17 (National Institutes of Health
2019). Furthermore, 40 million individuals over the age of 18 currently suffer from
an anxiety disorder. This constitutes nearly 20% of the adult population (National
Alliance on Mental Illness 2017). Given the longstanding character of this ethical
debate, and the inherent limitations in space, in what follows we canvass the ethical
issues in two salient neuropsychopharmacotherapies: Fluoxetine (Prozac ®) and
Modafinil (Provigil ®). These are used as test cases of the past and present ethical
debates in neuropsychopharmacotherapy, which will facilitate a general understand-
ing of underlying contentious issues and serve as a useful resource for future ethical
debates.

Fluoxetine (Prozac ®)

Clinical Indications and Side Effects

Fluoxetine, commonly known by its brand name Prozac ®, is a selective serotonin

reuptake inhibitor (SSRI) prescribed for the treatment of major depressive disorder
(MDD), obsessive-compulsive disorder (OCD), Bipolar I disorder, bulimia nervosa,
and a number of other depression-related mood disorders (National Institutes of
Health 2019). Predominantly, it is prescribed for the purposes of treating MDD,
which currently affects over 120 million people worldwide and 1 in 10 Americans
(National Institutes of Health 2019). MDD, known among the public more generally
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 725

as depression, is a chronic psychopathology characterized by episodes of poor mood,

low self-esteem, and diminished pleasure and/or interest in daily activities. Fluoxe-
tine is prescribed specifically to relieve these symptoms. If left untreated, depression
is a debilitating condition that negatively impacts one’s personal and family relation-
ships, work productivity, sleep patterns, eating habits, and overall health (Wenthur
et al. 2014). In the United States, over 5% of patients diagnosed with depression
commit suicide. Furthermore, over 60% of suicides in the United States are carried
out by patients that are suffering from psychopathologies that Fluoxetine is pre-
scribed to treat (American Psychiatric Association 2017). For the treatment of
depression, doses begin at 20 mg and may be titrated up to 60 mg. For anxiety
and eating disorders, doses are generally higher and may also be titrated up to 60 mg
(Wenthur et al. 2014). All doses are taken daily in the form of tablet or capsule;
however, in certain cases it may be provided in liquid form or in a weekly 90 mg
capsule. Fluoxetine holds a half-life of 2–4 days and is only available by
prescription.
As with all SSRI’s, Fluoxetine has been found to cause a number of adverse side
effects. These include the low-to-moderate side effects such as nausea, headache,
diarrhea, drowsiness, tremors, and changes in appetite and weight. A plethora of
sexual dysfunction side effects have been observed as well, including erectile
dysfunction, diminished libido, and anorgasmia (Wenthur et al. 2014). More severe
side effects include increases in aggressive thoughts and behavior. Perhaps most
notably, fluoxetine is distributed with a black box warning for increased risk of
suicidal ideation. Consequently, fluoxetine is one of the few medications currently
on the market that holds the potential to inadvertently cause symptoms that the
medication was prescribed to treat. This risk exponentially increases in patients
under age 25 (Busch and Barry 2009). Such increased risk is particularly problematic
given the increased use of fluoxetine for the treatment of mild depression in pediatric
patients, despite the FDA’s issuance of the black box warning in 2004 (Wenthur et al.
2014). As a result, the relevant ethical considerations for mental healthcare providers
are numerous, particularly those involving the communication of potentially para-
doxical iatrogenic effects to patients and families.
While some SSRIs have been declared safe during pregnancy, fluoxetine is
generally not prescribed to pregnant women. This is due to the body of inconclusive
research on the drug’s toxic fetal effects (Yonkers et al. 2014). Such uncertainty has
concerned many in the field of obstetrics and gynecology because unlike some
medications, SSRIs are passed through the umbilical cord to the fetus once metab-
olized by the mother (Nulman et al. 2002). Other studies suggest that fluoxetine use
during pregnancy has no significant effect on child development, however these
studies only examined a narrow array of developmental indicators. Regardless, it is
not uncommon for women to become pregnant while undergoing pharmacotherapy
for depression, as depression is most likely to manifest in women during childbear-
ing age (Nulman et al. 2002). Consequently, current practice guidelines recommend
prescription of tricyclic antidepressants in lieu of fluoxetine, which have not been
associated with toxic fetal effects (Nulman et al. 2002).
726 M. Menconi Jr. and V. Dubljević

Mechanism of Action of Fluoxetine

Fluoxetine follows the conventional mechanism of action that characterizes all

SSRI’s, which involves blocking the monoamine serotonin transporter protein
SERT from transporting serotonin to presynaptic neurons (Wenthur et al. 2014).
As a result, the uptake of 5HT1 inhibitory autoreceptors is inhibited and the
concentration of serotonin increases. Such serotonin stimulation decreases 5HT1
production by serotonergic neurons, a phenomenon known as downregulation
(Wenthur et al. 2014). This is widely believed to explain the extensive time-to-effect
of SSRI medications. On average, Fluoxetine requires between 4 and 6 weeks to
achieve therapeutic effects following ingestion of the first dose (Wenthur et al.
2014). Such delays in onset of therapeutic effects means that the drug is not able
to relieve symptoms in patients experiencing acute crises (i.e., attempted suicide),
and thus faster-acting benzodiazepines (anti-anxiety psychotropics, i.e., Xanax) may
be prescribed to relieve acute anxiety and psychological stress. However, as men-
tioned above, this practice has been subject to recent scrutiny in light of the highly
addictive properties of benzodiazepines. In severe cases where the patient is deemed
a danger to themselves or others, the patient may be civilly committed and forcibly
administered fluoxetine under medical supervision until it begins to take effect or
until the patient is deemed capable of adhering to the dosing requirements and
related treatment plan.
However, fluoxetine’s complete mechanism of action and the process by which it
achieves its therapeutic purpose remains unknown. Some studies have demonstrated
efficacy rates of less than 50% in depressed patients following multiple treatment
regimens with fluoxetine (Weimer et al. 2015). This may explain why more than
50% of preclinical fluoxetine studies have failed to find elevated 5HT1 levels after
sustained administration of the drug. Such evidence indicates that other mechanisms
of action are likely but have not yet been identified. Furthermore, the single
mechanism of action that has been identified – inhibition of 5HT1 uptake via
SERT immobilization – occurs shortly after the first ingestion; however, the thera-
peutic effects of fluoxetine are not observed until a minimum of 3 weeks of sustained
ingestion. Consequently, while this mechanism of action has been conclusively
determined to be a contributing factor to fluoxetine’s biomechanical profile, it does
not represent a complete explanation of its efficacy. The extensive placebo effect
associated with the drug further complicates this investigation. As such, researchers
continue to explore the mechanistic profile of fluoxetine and other SSRIs (Andrews
2009).

Additional Ethical Considerations with Fluoxetine

Fluoxetine and some other SSRI’s have garnered attention for their unusually high
placebo effects. Knorr et al. (2019) completed a systematic literature review of SSRI
effects found in 51 clinical trials. Of the 249 outcome tests that were performed on
this data, only 4 revealed a statistically significant change in patient outcome
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 727

following SSRI intervention compared to effects with a placebo (Knorr et al. 2019).
The high placebo rate holds significant ethical implications for the risk-benefit
analysis that providers and patients are obligated to undertake prior to treatment. If
more than half of fluoxetine prescriptions are alleviating symptoms in patients via a
mere placebo effect, prescribers must question whether administering a drug with
such serious potential side effects (e.g., suicidal ideation) outweighs its benefits.
Additionally, placebo data is not included as part of the informed consent process in
conventional psychiatric treatment settings (outside of a clinical trial), and thus the
patient may be left with incomplete and/or misleading information with which to
guide their treatment decisions, including the option of in-person therapy – usually
cognitive behavioral therapy – as a first-line treatment option with minimal risk
before beginning fluoxetine.
Additionally, the prescription of fluoxetine has promulgated a series of scope of
practice issues among nonpsychiatric clinicians. Currently, general practitioners
(physicians or nurse practitioners who did not undergo specialty psychiatric training
post clinical degree) are responsible for 80% of SSRI prescriptions worldwide
(Mercier et al. 2014). This phenomenon coincides with a systematic over-
prescription of antidepressant medications; a recent analysis found that up to 18%
of fluoxetine prescriptions were for the purposes of off-label, nonpsychiatric condi-
tions (Mercier et al. 2014). While professional organizations such as the American
Psychiatric Association (APA) have not openly asserted that general practitioners
lack the specialized expertise for the prescription of psychotropic medications, there
is some evidence that prescriptions issued by general practitioners have not met the
standard of care. This includes instances of terminating treatment before therapeutic
effects may be realized and prescription of subtherapeutic dosages (Mercier et al.
2014). The APA has issued treatment guidelines for general practitioners to address
some of these issues. However, it remains unclear whether the primary care delivery
system is appropriately suited for neuropsychopharmacotherapy. Areas of concern
include short appointment times, limited psychosocial understanding of patients, and
high incidence of complex comorbidities. Furthermore, primary care clinicians are
not trained in non-pharmaceutical psychiatric therapies, which are frequently co-
indicated with fluoxetine and other SSRIs for the treatment of anxiety and depres-
sion. In many instances, anxiety and depression may be more appropriately treated
with cognitive behavioral therapy (CBT) or alternative non-pharmaceutical therapies
alone. However, such treatments often require access to a psychiatric or psycholog-
ical specialist, which is problematic for patients whose geographic location or
insurance status represent a barrier to access. Finally, the exponential increase in
fluoxetine prescription and use since the early 1990s may be at least partially
attributed to the extensive and aggressive corporate marketing campaigns commis-
sioned by Eli Lilly & Company, the original manufacturer of Prozac ®. For example,
in 2003 Eli Lilly was sued in a Florida court for invasion of privacy. The company
was accused of using confidential medical information from patient charts to send
unsolicited samples of Prozac ® to their homes without a prescription (Dyer 2003).
Ely Lilly later fired the company officials who contrived the scheme. Such aggres-
sive and unlawful marketing tactics were most frequent from 1996 to 2005, during
728 M. Menconi Jr. and V. Dubljević

which time pharmaceutical companies tripled spending on advertising for psycho-

tropic medications. The same period saw a fivefold increase in direct-to-consumer
advertising efforts (Smith 2012). Advertisements found in print and television
commercials often featured oversimplified depictions of depression and Prozac ®
effects. For example, such advertisements frequently invoked illustrations of clouds,
rain, and storms that were juxtaposed with illustrations of sun and rainbows in an
effort to communicate the effects of the drug. Several studies found that many of
these advertisements did not adequately explain the risk of side effects (Smith 2012).
They were also found to exaggerate and/or misrepresent therapeutic effects. Such
advertisements were banned in Canada, which may explain why American patients
are more than twice as likely to request advertised drugs such as Prozac ® from their
physicians than their Canadian counterparts (Smith 2012). This suggests such
predatory advertising has a measurable impact on the rate of SSRI prescription,
and thus problematically influences both physicians and patients.

Modafinil (Provigil ®)1

Clinical Indications and Side Effects

Modafinil is a wakefulness-inducing compound prescribed for treatment of exces-

sive daytime sleepiness as a consequence of sleep disturbances, such as shift-work,
sleep disorder, obstructive sleep apnea, restless leg syndrome, and narcolepsy
(Murillo-Rodriguez et al. 2017). However, modafinil has also been widely used by
healthy individuals as an off-label cognitive enhancer, particularly in populations of
students and professionals where cognitive enhancement is thought to be especially
beneficial (Dubljević et al. 2020). Franke and Lieb (2010) suggest that the growing
prevalence of the cognitive enhancer use such as modafinil is a result of factors akin
to pressure to perform at work or in private life, which are positively associated with
the use of prescription or illicit drugs for cognitive enhancement. In a poll conducted
by Maher (2008) in Nature, 44% of its readership reported using stimulants such as
modafinil as a study-aid, with most of these users falling in the age group of 18–25.
Such data is interpreted in the literature (Appel 2008, Dubljević 2012a, b, 2013a, b,
Dubljević et al. 2020, Hockenhull et al. 2019) as indicating that the use of cognitive
enhancers is popular in high-pressure environments such as the educational, finan-
cial, and medical sectors.
Modafinil’s accessibility is further enabled by the common misconception that it
lacks side effects. Unlike traditional stimulants, such as amphetamine (e.g., Adderall®)
and methylphenidate (Ritalin ®), which also confer similar benefits of wakefulness
and alertness to sleep-deprived individuals, modafinil does not induce some of these
drugs’ severe side effects, such as amphetamine psychosis (Dubljević and Ryan

1
In this section, we draw on Dubljević 2016. We are also grateful to Anirudh Nair for assisting
the corresponding author in the updated literature review of modafinil effects.
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 729

2015; Dubljević 2016). However, modafinil’s “lifespan” as a medication is relatively

short, and although it exhibits less potential for acute short-term effects, it is still too
early to discern whether or not there are any negative long-term effects (Dubljević
and Ryan 2015).
In February 2019, Health Canada was warned about the use of modafinil in
pregnant women by Teva Canada Innovation, a modafinil manufacturer. Health
Canada subsequently released this statement: “When used during pregnancy, Alertec
(modafinil) has been associated with cases of major fetal congenital malformations,
including congenital cardiac anomalies.” Similarly, product information on
modafinil in the United States warns of “fetal risks associated with human exposure
during pregnancy,” adding that “two cases of intrauterine growth retardation and one
case of [miscarriage] have been reported in association with armodafinil and
modafinil” (Warrer et al. 2014).
A majority of the discourse (ethical or otherwise) surrounding modafinil assumes
a range of benefits besides the intended effects of wakefulness and alertness prop-
erties. The first and most cited systematic review of available “enhancement”
studies, done by Repantis et al. (2010), has shown that non-sleep-deprived volun-
teers may also experience benefits in the domains of working memory, visual
recognition, planning performance, and executive inhibitory control (see Repantis
et al. 2010). However, when controlled for discrepancies among different cognitive
domains (see below), more recent reviews have found that the alleged benefits of
modafinil on cognition are neither as concrete nor as consistent as initially thought.
Despite the prominence of select positive findings in the literature, when the results
in various domains of cognition are evaluated across a large number of studies, the
efficacy of modafinil is limited (Kredlow et al. 2019). Given that the ethical
discussion has in large part been dominated by repeating assertions from Repantis
et al. (2010) that modafinil is “safe and effective,” in what follows, we will focus on
the results obtained from systematic reviews conducted by Kredlow et al. (2019) and
Battleday and Brem (2015) on the effectiveness of modafinil, tested across a variety
of cognitive domains on healthy, non-sleep deprived participants. Modafinil exhibits
different effects on sleep-deprived individuals, as well as individuals that tend to
perform on cognitive tasks in the below average range. Implications of that will also
be discussed in detail.
Most studies found modafinil’s effects on attention to be minimal. Battleday
and Brem (2015) reported that the majority of studies found no improvement in
tests of selective or sustained attention, and none of the studies observed any
improvements in divided attention. Kredlow et al. (2019) in their meta-analysis
found a minimal effect size of g ¼ 0.06 when comparing the results of attention
tests of studies investigating modafinil, further elucidating modafinil’s minimal
effect on attention in healthy, non-sleep-deprived individuals. Similarly, both
reviews failed to identify any noticeable improvements in working memory.
Kredlow et al. (2019) reported that improvements in working memory were
nonsignificant. Battleday and Brem (2015) found similar results; none of the
tests evaluating verbal-working memory demonstrated any improvements follow-
ing modafinil administration.
730 M. Menconi Jr. and V. Dubljević

Contrary to the results in the domain of attention and working memory, Kredlow
et al. (2019) noted that improvements in executive functioning and processing
speed were, in fact, significant (g ¼ 0.1, g ¼ 0.2). Battleday and Brem (2015)
adopted a much broader approach to executive functioning, evaluating tests involv-
ing complex tasks. Most of the studies reviewed for “complex tasks” involved
administering tests that demanded a range of abilities such as higher-order function-
ing, decision-making, creativity, and fluid intelligence. Firstly, Battleday and Brem
(2015) note that no improvement was found in their review of cognitive flexibility
tests, and participants actually performed worse following modafinil intake. How-
ever, they also found that in studies that tested for fluid intelligence, all showed
improvements in participants, particularly those involving medium difficulty tasks.
When examining studies that tested creativity, Battleday and Brem (2015) found that
for the most part, studies that tested convergent-thinking-based creativity, which
involves problem strategies, showed no improvements in performance.
Currently, modafinil requires a prescription to be obtained in theory, but clinician
involvement can be circumvented in practice. In fact, the ease with which it can be
obtained via online marketplaces has been the subject of ethical scrutiny. In part, this
may be a result of policy decisions: the U.S. Food and Drug Administration (FDA)
extended the modafinil label to help alleviate symptoms of sleepiness associated
with shift-work syndrome (Food and Drug Administration 2007), and the U.S. Drug
Enforcement Agency (DEA) classified it as a Schedule 4 drug, i.e., a drug with low
abuse potential. Increases in on-label prescriptions and policy designations ostensi-
bly based on safety contribute to the popularity of modafinil as a go-to stimulant. An
additional explanatory factor might be the unfettered availability for online purchase
and complete lack of enforcement. Hockenhull et al. (2019) reported that online
searches using popular search engines yielded 73 websites that sold modafinil in the
United Kingdom for the purpose of enhancement without the need for a prescription.
A majority of these websites listed possible desired effects such as increased
alertness, improved memory, increased concentration and productivity and perfor-
mance enhancement. Similarly, Dursun et al. (2019) found that 13 websites sold
modafinil to consumers in Australia without prescription, with a median price of
118 Australian dollars (81 USD) for 90,150 mg pills. Such availability of
unprescribed modafinil only fuels the already existing ethical controversy.

Mechanism of Action of Modafinil

Contrary to the relatively clear neurobiological picture of traditional stimulants such

as amphetamine, the exact molecular mechanism of modafinil’s action is unclear and
there are several possible explanations for its effects (AMS 2008, 2012; Franke and
Lieb 2010; Lieb 2010). Modafinil is thought to alter the balance of major inhibitory
(GABA) and excitatory (glutamate) neurotransmitters, leading to a cascade of
neurophysiological events, including the release of both histamine and orexin
(Ballon and Feifel 2006). Also, stimulation effects of modafinil may be related to
its weak dopamine (DA) reuptake inhibition properties, which means that it also
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 731

amplifies spontaneously released DA and noradrenaline (NA) in the brain, making

its danger profile similar to that of methylphenidate. Although modafinil is a weak
DA reuptake inhibitor, concentrations of the drug achieved after oral dosing are quite
high and sufficient enough to have a substantial action on DA reuptake, which might
explain the rare occasions of psychosis and mania connected with its use (Kanal et al.
2012; Mariani and Hart 2005). Enhancement of extracellular serotonin levels and
serotonin neurotransmission is another possible molecular mechanism of its action
(Kanal et al. 2012). All in all, the mechanisms underlying modafinil’s
neuromodulatory effects are complex and somewhat different from older stimulant
drugs such as methylphenidate and amphetamine, potentially incorporating extra-
cellular and intracellular effects (Gerrard and Malcolm 2007). Furthermore, they
seem to focus on hypothalamus-based wakefulness circuits rather than overall brain
activation (Ballon and Feifel 2006).
The wakefulness promoting properties of modafinil are also different than those
of traditional stimulants. Namely, subjects on modafinil have demonstrated the
ability to stay awake for periods of up to 64 h with little obvious decline in their
level of performance (Cahill 2005; Caldwell et al. 1999; Estrada et al. 2012). Estrada
et al. (2012) have summed up the available data from military studies on healthy
adults and report that three daily doses of 200 mg (given at 23:00, 03:00, and 07:00
during a 40-hour period of continuous wakefulness) maintained flight performance
at rested levels and attenuated the effects of 40 h of continuous wakefulness on
fatigue, confusion, and physiological arousal. No adverse behavioral effects were
noted; however, vertigo, nausea, and dizziness were reported as side effects by the
majority of subjects. Although amphetamine has similar effects on performance
during prolonged periods of sleep deprivation, it causes “sleep rebound”: the need
to “make up” for lost hours of sleep. Apparently, this occurs at a drastically lower
level with modafinil (Ballon and Feifel 2006; Cahill 2005; Lagarde et al. 1995).
Moreover, unlike amphetamine, modafinil does not create rapid effects (“rush”),
euphoric effects (“high”), or a subsequent decrease in mood and energy (“crash”).
All of these properties make modafinil much less likely to cause addiction (Cahill
2005; Deroche-Gamonet et al. 2002); however, addiction cannot be entirely
excluded (Mohamed 2012; Mohamed and Sahakian 2012; Volkow et al. 2009)
even though no cases of modafinil addiction have been reported (Kim 2012) and
psychiatric adverse events related to its use have been reported in only a few cases
(Kanal et al. 2012; Mariani and Hart 2005). The lower risk for addiction makes
modafinil appealing and may contribute to its rise in popularity as a go-to enhancer.
Also, unlike methylphenidate and amphetamine, modafinil is much less likely to
cause serious cardiovascular adverse events (Minzenberg and Carter 2008).

Additional Ethical Considerations with Modafinil

Modafinil first became ethically controversial when the pharmaceutical corporation

Cephalon (holder of the modafinil patent at the time) started promoting its use for
non-FDA approved conditions, such as general “excessive sleepiness” (Cahill
732 M. Menconi Jr. and V. Dubljević

2005). At first, Provigil (the first commercial brand of modafinil in the United States)
was approved to treat narcolepsy, but the label was subsequently expanded to
include treatment of sleep apnea and shift work sleep disorder. From 2001 through
2006, Cephalon allegedly promoted Provigil as a nonstimulant drug for the treatment
of sleepiness, tiredness, decreased activity, lack of energy and fatigue. In 2002, the
FDA sent Cephalon a letter, warning the company to cease and desist promoting
Provigil off-label. Cephalon apparently ignored this warning and continued to
undertake its promotional practices via a variety of techniques, such as training its
sales force to disregard or downplay restrictions of the FDA-approved label. The
activities of Cephalon resulted in a lawsuit which was settled in 2008 for 425 million
US$ (Department of Justice 2008). However, the government fine still did nothing to
curb Cephalon’s unethical practices. The effectiveness of these questionable promo-
tional strategies is evidenced in the steady rise of patients filling prescriptions for on-
and off-label uses of modafinil; 90% of all modafinil prescriptions are issued for
off-label purposes (Cahill 2005), and this rate continues to increase (Kasselheim
et al. 2012). In 2016, there were almost 1.5 million modafinil prescriptions in the
United States.2
The relatively permissive attitudes regarding modafinil are a result of its desig-
nation as “relatively safe,” especially compared to traditional stimulants. Indeed, the
wakefulness promoting properties of modafinil might be very beneficial for the
society at large by alleviating the effects of fatigue during work and even freeing
up more time for leisure activities (see Tannenbaum 2012). However, modafinil is
not without detrimental effects that may impact safety of patients (and other users).
In 2007, Health Canada – the health agency with historically the most cautious
approach toward the emergence of serious health issues associated with modafinil
use – warned about the possibility of severe allergic reactions to modafinil and a host
of associated skin problems, including rashes, hives, and sores (CBC 2007). The
probability of allergic and other types of dermatological reactions to modafinil seems
to be greater than for other comparable medications. Furthermore, the FDA findings
on the long-term side effects of modafinil use are inconclusive, yet the severity of
rashes and dermatological toxicity observed in younger patients fuels doubts as the
potential impact is uncertain (Kumar 2008). Life-threatening side effects were also
reported, including instances of extreme allergic reactions resulting in myocarditis
(Bauml et al. 2019). These concerns were corroborated in a study conducted by
Davies et al. (2013). They observed that incidences of skin conditions among
patients in the United Kingdom that were prescribed modafinil were responsible
for 33% of patients discontinuing treatment. Finally, sleep deprivation may be
exacerbated by the long-term use of modafinil, which may lead to immune system
failure as well as emotional and physical damage (Dubljević 2016; Eliyahu et al.
2007).
Evidence suggests that significant placebo effects are associated with modafinil.
Battleday and Brem (2015) comment on the “ceiling effects” they observed in their

2
See https://clincalc.com/DrugStats/Drugs/Modafinil
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 733

review, and they claim that “when these ceiling effects were lessened by only
analyzing data from low baseline performers, many studies actually did detect
significant differences between modafinil and placebo groups.” It is important to
note this recurring trend of selective efficiency of modafinil in low-baseline per-
formers. It would appear that any putative “enhancement” effects of modafinil are in
fact placebo effects or instances of “self-medication” with nonprescribed psychotro-
pics to handle social pressures or life-style choices. Arguably, the noticeable cogni-
tive benefits of modafinil observed in the “high-pressure” populations of students,
medical professionals, and shift workers are likely attributable to the prevalence of
sleep deprivation in those populations, which means that, in reality, they are typically
performing below their baseline. As Battleday and Brem (2015) note: “robust effects
on these same tasks are seen with sleep deprivation, when all participants effectively
become low baseline performers.” In light of this information, the purported benefits
of modafinil should not be considered proven, and the inconsistencies between
modafinil’s supposed enhancement effects raise the need to devise and implement
more innovative testing methods that account for these discrepancies and can
accurately ascertain the efficacy of modafinil in enhancing cognition in populations
of normal and high functioning individuals. It also highlights the importance of
conducting these tests on populations of healthy individuals who neither suffer from
cognitive impairments nor are suffering from any health issues when being tested,
including sleep deprivation.

Concluding Remarks

Collectively, the ethical aspects of neuropsychopharmacotherapy reflect the rapid

advancement in neurobiological science and related psychopharmacology. The
ethical, legal, clinical, and social implications of these advancements are clarified
via the application of contemporary biomedical ethics; however, such clarification,
while useful in addressing the questions raised in this chapter, hardly offer a static
conclusion given the tumultuous social, political, and economic (e.g., profit-driven)
environments that influence access, delivery, and innovation across the psychother-
apeutic enterprise. A normative understanding of these exogenous factors, which
this chapter aims to facilitate, will continue to play a vital role in informing the
regulation, legislation, and development (by both private and public actors) of
neuropsychopharmacotherapy. Moving forward, we predict that two primary areas
of ethical inquiry will dominate the debate as neurotechnologies and neuropharma-
ceuticals continue evolve and society continues to increasingly adopt them for both
therapeutic and cosmetic purposes. These areas of inquiry include existential ques-
tions of personal identity that hold significant implications for autonomy, as well as
concrete sociopolitical questions that hold significant implications for justice.
First, the question of personal identity, and the degree to which neuropsycho-
pharmacotherapy modifies such identity, has become a rising concern among
patients and consumers. For example, some question whether the artificial modifi-
cation of the brain’s neurochemistry draws them away from their authentic self
734 M. Menconi Jr. and V. Dubljević

(Klein et al. 2016). Such skepticism is only exacerbated by the reality that the
mechanisms of action responsible for the therapeutic effects of many psychotropic
medications remain unidentified or only partially explained. The traditional
approach to this question by practitioners and researchers within the psychothera-
peutic enterprise has involved designating the diagnosed mental illness (depression,
for example) as a departure from one’s authentic self, thus neuropsychopharma-
cotherapy is required to restore authenticity. While many patients accept this
approach to treatment, new neurotechnologies such as deep brain stimulation
(DBS) have resulted in patients expressing concern that manipulation of mood and
emotion is “artificial” and correspondingly results in an unacceptable loss of agency
(Klein et al. 2016). This is in contrast to those who licitly and illicitly obtain
amphetamines and other stimulants for the purposes of cosmetic neuroenhancement.
The large majority of these individuals embrace the notion of artificial optimization
of neurochemistry for the purpose of achieving a competitive edge in high cognitive
demand environments. By doing so, they implicitly acknowledge that their authentic
self is in need of enhancement and therefore little attention is paid to the potential
loss of agency or authenticity. Regardless of the existential position adopted in this
context, serious implications for autonomy lie in the balance.
Furthermore, the question of access to neuropsychopharmacotherapy continues to
vault to the forefront of national debate as U.S. healthcare remains a top priority for
voters. Currently, the United States is in the midst of a severe mental health services
shortage, with over three-quarters of counties meeting less than half of psychotropic
prescription demand (Thomas et al. 2009). While the shortage of prescribers is
substantial on its own, some studies estimate that the nonprescriber (those delivering
psychotherapy only) shortfall is ten times greater than the prescriber shortfall
(Thomas et al. 2009). As such, current rates of accessibility for neuropsychophar-
macotherapy are alarmingly low, signaling a healthcare delivery crisis in the arena of
mental health. Access rates are even lower for low SES populations in both urban
and rural areas. Such reduced provider numbers reflect only the status quo – if
current proposals for universal healthcare in the United States were to succeed,
addition of the anticipated 30 million newly insured beneficiaries to the healthcare
marketplace will likely have wide-ranging consequences, the effects of which may
disproportionately burden vulnerable populations. Even in the event the healthcare
system remains unchanged, solutions to the existing challenges continue to elude
experts. Such unfortunate realities promulgate serious questions of justice – how do
we distribute therapeutic mental health resources fairly?
There are no simple solutions to the ethical issues raised in this chapter – the
difficult conceptual work of balancing normative values with critical bioethical
reasoning will only grow more rigorous as neuropsychopharmacotherapy continues
to advance. However, with the lessons of history as guiding light, it is necessary that
we do not cede ground to the polarized hyperbole that characterizes much of the
contemporary public debate surrounding these issues. With the critical lens articu-
lated in this chapter, it is our sincere hope that current and future practitioners,
researchers, innovators, and consumers of neuropsychopharmacotherapy will be
more attuned to the ethics of their endeavors. In bringing these ethical implications
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 735

to light, there is reason to be cautiously optimistic about the future of neuropsycho-

pharmacotherapy as a fundamentally therapeutic enterprise.

References
Academy of Medical Sciences [AMA]. 2008. Brain science, addiction and drugs, An Academy of
Medical Sciences working group report chaired by Professor Sir Gabriel Horn FRS FRCP,
Available at: http://www.acmedsci.ac.uk/p99puid126.html. Accessed 5 Mar 2013.
Academy of Medical Sciences [AMA]. 2012. Human enhancement and the future of work. Joint
report of the Academy of Medical Sciences, the British Academy, the Royal Academy of
Engineering and the Royal Society, Available at: http://royalsociety.org/uploadedFiles/Royal_
Society_Content/policy/projects/human-enhancement/2012-11-06-Human-enhancement.pdf.
Accessed 10 Nov 2012.
American Psychiatric Association (Ed.). (2013). Diagnostic and statistical manual of mental
disorders Dsm-5. American Psychiatric Association.
American Psychiatric Association. 2017, April 27. APA Public Opinion Poll – Annual Meeting
2017. APA Newsroom. https://www.psychiatry.org/newsroom/apa-public-opinion-poll-annual-
meeting-2017
Andrews AM. Does chronic antidepressant treatment increase extracellular serotonin? Front
Neurosci. 2009;3:246–7. (n.d.).
Appel JM. When the boss turns pusher: a proposal for employee protections in the age of cosmetic
neurology. J Med Ethics. 2008;34(8):616–8.
Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med.
2007;357(18):1834–40.
Ballon JS, Feifel D. A systematic review of Modafinil: potential clinical uses and mechanisms of
action. J Clin Psychiatry. 2006;67(4):554–66.
Battleday RM, Brem A-K. Modafinil for cognitive neuroenhancement in healthy non-sleep-
deprived subjects: a systematic review. Eur Neuropsychopharmacol. 2015;25(11):1865–81.
https://doi.org/10.1016/j.euroneuro.2015.07.028.
Bauml M, Udi J, Klingel K, Bode C, Warnatz K, Zirlik A, et al. Severe eosinophilic myocarditis
associated with modafinil in a patient with normal peripheral eosinophil count. Clinical
Research in Cardiology: Official Journal of the German Cardiac Society. 2019,
August;108:963–6. https://doi.org/10.1007/s00392-019-01434-w.
Beauchamp TL, Childress JF. Principles of biomedical ethics. 7th ed. New York [u.a.]: Oxford
University Press; 2013.
Boseley S. Happy drug Prozac can bring on impulse to suicide, study says. The Guardian. 2000,
May 22. https://www.theguardian.com/science/2000/may/22/drugs.uknews
Brandt AM. Racism and research: the case of the Tuskegee syphilis study. Hast Cent Rep. 1978;8
(6):21. https://doi.org/10.2307/3561468.
Busch SH, Barry CL. Pediatric antidepressant use after the black-box warning. Health Aff. 2009;28
(3):724–33. https://doi.org/10.1377/hlthaff.28.3.724.
Cahill M. The ethical consequences of modafinil use. Penn Bioethics Journal. 2005;1(1):1–3.
Caldwell JA, Smythe NK, Caldwell JL et al. The Effects of Modafinil on Aviator Performance
During 40 Hours of Continuous Wakefulness: A UH-60 Helicopter Simulator Study, U.S. Army
Aeromedical Research Laboratory, Report No. 99–17. 1999.
Cohen IG, Lynch HF, Sepper E. Law, religion, and health in the United States: Cambridge
University Press; 2017.
Dalal PK, Sivakumar T. Moving towards ICD-11 and DSM-V: concept and evolution of psychiatric
classification. Indian J Psychiatry. 2009;51(4):310–9.
Davies M, Wilton L, Shakir S. Safety profile of modafinil across a range of prescribing indications,
including off-label use, in a primary care setting in England: results of a modified prescription-
736 M. Menconi Jr. and V. Dubljević

event monitoring study. Drug Saf. 2013;36(4):237–46. https://doi.org/10.1007/s40264-013-

0025-y.
Department of Justice. Biopharmaceutical Company, Cephalon, to pay $425 million & enter plea to
resolve allegations of off-label marketing. 2008. Available: http://www.justice.gov/opa/pr/2008/
September/08-civ-860.html. Accessed 1 June 2020.
Deroche-Gamonet V, Darnaudéry M, Bruins-Slot L, Piat F, Le Moal M, Piazza PV. Study of the
addictive potential of modafinil in naïve and cocaine-experienced rats. Psychopharmacology.
2002;161:387–95.
DeSantis AD, Webb EM, Noar SM. Illicit use of prescription ADHD medications on a college
campus: a multimethodological approach. J Am Coll Heal. 2008;57(3):315–24.
Dubljević V. Principles of justice as the basis for public policy on psychopharmacological cognitive
enhancement. Law Innov Technol. 2012a;4(1):67–83.
Dubljević V. Toward a legitimate public policy on cognition-enhancement drugs. Am J Bioeth
Neurosci. 2012b;3(3):29–33.
Dubljević V. Cognitive enhancement, rational choice and justification. Neuroethics. 2013a;
6(1):179–87.
Dubljević V. Prohibition or coffee-shops: regulation of amphetamine and methylphenidate for
enhancement use by healthy adults, Am J Bioeth. 2013b;13(7):23–33.
Dubljević V. Enhancement with Modafinil: benefiting or harming the society? In: Jotterand F,
Dubljević V, editors. Cognitive enhancement: ethical and policy implications in international
perspectives. New York: Oxford University Press; 2016. p. 259–74.
Dubljević V, Ryan CJ. Cognitive enhancement with methylphenidate and modafinil: conceptual
advances and societal implications. Neurosci Neuroecon. 2015;4:25–33.
Dubljević V, Coates McCall I, Illes J. Neuroenhancement at work: addressing the ethical, legal and
social implications. In: Trempe-Martineau J, Racine E, editors. Organizational Neuroethics.
Cham: Springer; 2020. p. 87–103.
Dursun S, Dunn M, McKay F The availability and acquisition of modafinil on the internet. Drug
Alcohol Rev. 2019;38. https://doi.org/10.1111/dar.12977.
Dyer O. Drug company and pharmacy send unsolicited samples of Prozac to Florida residents. BMJ
(Clinical research ed). 2003;327(7421):950. https://doi.org/10.1136/bmj.327.7421.950-a. (n.d.).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140346/?tool¼pmcentrez&report¼abstract
Eliyahu U, Berlin S, Hadad E, Heled Y, Moran D. Psychostimulants and military operations. Mil
Med. 2007;172(4):383–7.
Estrada A, Kelley AM, Webb CM, Athy JR, Crowley JS. Modafinil as a replacement for Dextro-
amphetamine for sustaining alertness in military helicopter pilots. Aviat Space Environ Med.
2012;83(6):556–64.
Food and Drug Administration. 2007. No Title. Retrieved from https://www.accessdata.fda.gov/
drugsatfda_docs/label/2007/020717s020s013s018lbl.pdf
Franke A, Lieb K. Pharmakologisches Neuroenhancement und „Hirndoping“: Chancen und
Risiken. Bundesgesundheitsblatt. 2010;53:853–860.
Gafoor R, Booth HP, Gulliford MC. Antidepressant utilisation and incidence of weight gain during
10 years’ follow-up: population based cohort study. BMJ. 2018:k1951. https://doi.org/10.1136/
bmj.k1951.
Gerrard P, Malcolm R. Mechanisms of modafinil: a review of current research. Neuropsychiatr Dis
Treat. 2007;3(3):349–64.
Hedegaard H, Curtin SC, Warner M. Suicide mortality in the United States, 1999–2017, vol.
330: National Center for Heatlh Statistics (Washington, DC). 2018. p. 8.
Hockenhull J, Wood DM, Dargan PI. The Availability of modafinil and methylphenidate purchased
from the Internet in the United Kingdom without a prescription. Substance Use & Misuse.
2019;1–10. https://doi.org/10.1080/10826084.2019.1654516. http://www.tradecommodities.
co.uk/commodities/. Accessed on 3 April 2013.
Jotterand F, Dubljević V, editors. Cognitive enhancement: ethical and policy implications in
international perspectives. New York: Oxford University Press; 2016.
Ethical Issues in Neuropsychopharmacotherapy: US Perspective 737

Kanal MG, Ozkan C, Doganavsargil O, Eryilmaz M. Late onset mania possibly related to modafinil
use: a case report. Bulletin of Clin Psychopharmacol. 2012;22(1):71–74.
Kasselheim AS, Myers JA, Solomon DH, Winkelmayer WC, Levin R, Avorn J. The prevalence and
cost of unapproved uses of top-selling orphan drugs. PLoS One. 2012;7(2):e31894. https://doi.
org/10.1371/journal.pone.0031894.
Kim D. Practical use and risk of Modafinil, a novel waking drug, Environ Health Toxicol. 2012.
https://doi.org/10.5620/eht.2012.27.e2012007.
Klein E, Goering S, Gagne J, Shea CV, Franklin R, Zorowitz S, Dougherty DD, Widge AS. Brain-
computer interface-based control of closed-loop brain stimulation: attitudes and ethical considerations.
Brain-Comput Interfaces. 2016;3(3):140–8. https://doi.org/10.1080/2326263X.2016.1207497.
Knorr U, Madsen JM, Kessing LV. The effect of selective serotonin reuptake inhibitors in healthy
subjects revisited: a systematic review of the literature. Exp Clin Psychopharmacol. 2019;
27(5):413–32. https://doi.org/10.1037/pha0000264.
Kredlow MA, Keshishian A, Oppenheimer S, Otto MW. The efficacy of Modafinil as a cognitive
enhancer: a systematic review and meta-analysis. J Clin Psychopharmacol. 2019;39(5).
Retrieved from https://journals.lww.com/psychopharmacology/Fulltext/2019/09000/The_Effi
cacy_of_Modafinil_as_a_Cognitive_Enhancer_.7.aspx
Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs.
2008;68(13):1803–39. https://doi.org/10.2165/00003495-200868130-00003.
Lagarde D, Batejet D, Van Beers P, Sarafian D, Pradella S. Interest of Modafinil, a new
psychostimulant, during a sixty-hour sleep deprivation experiment. Fundam Clin Pharmacol.
1995;9(3):271–9.
Lieb K. Hirndoping: Warum wir nicht alles schlucken sollten. Mannheim: Artemis & Winkler;
2010.
Machado-Vieira R, Baumann J, Wheeler-Castillo C, Latov D, Henter I, Salvadore G, Zarate C. The
timing of antidepressant effects: a comparison of diverse pharmacological and somatic treat-
ments. Pharmaceuticals. 2010;3(1):19–41. https://doi.org/10.3390/ph3010019.
Maher B. Poll results: look who’s doping. Nature. 2008;452(7188):674–5. https://doi.org/10.1038/
452674a.
Mariani JD, Hart CL. Psychosis associated with modafinil and shift work. Am J Psychiatr. 2005;
162(10):18.
Marshall KP, Georgievskava Z, Georgievsky I. Social reactions to valium and Prozac: a cultural lag
perspective of drug diffusion and adoption. Res Soc Adm Pharm. 2009;5(2):94–107. https://doi.
org/10.1016/j.sapharm.2008.06.005.
McHenry L. Ethical issues in psychopharmacology. J Med Ethics. 2006;32(7):405–10. https://doi.
org/10.1136/jme.2005.013185.
Mercier A, Auger-Aubin I, Lebeau J-P, Schuers M, Boulet P, Van Royen P, Peremans L. Why do
general practitioners prescribe antidepressants to their patients? A pilot study. Bio Psycho Soc
Med. 2014;8(1):17. https://doi.org/10.1186/1751-0759-8-17.
Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition.
Neuropsychopharmacology. 2008;33:1477–502.
Mohamed AD. Modafinil has the potential for addiction. AJOB Neurosci. 2012;3(2):36–8.
Mohamed AD, Sahakian BJ. The ethics of elective psychopharmacology. Int
J Neuropsychopharmacol. 2012;15:559–71.
Murillo-Rodriguez E, Veras A, Rocha N, Budde H, Machado S. An overview of the clinical uses,
pharmacology, and safety of Modafinil. ACS Chem Neurosci; 2017; 9. https://doi.org/10.1021/
acschemneuro.7b00374.
National Alliance on Mental Illness. 2017, December. Anxiety disorders. Mental health conditions.
https://www.nami.org/learn-more/mental-health-conditions/anxiety-disorders
National Institutes of Health. 2019, February. Major depression. Mental health information. https://
www.nimh.nih.gov/health/statistics/major-depression.shtml
Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G. Child development
following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective,
738 M. Menconi Jr. and V. Dubljević

controlled study. Am J Psychiatr. 2002;159(11):1889–95. https://doi.org/10.1176/appi.

ajp.159.11.1889.
Payne VL, Singh H, Meyer AND, Levy L, Harrison D, Graber ML. Patient-initiated second
opinions: systematic review of characteristics and impact on diagnosis, treatment, and satisfac-
tion. Mayo Clin Proc. 2014;89(5):687–96. https://doi.org/10.1016/j.mayocp.2014.02.015
Repantis D, Schlattmann P, Laisney O, Heuser I Modafinil and methylphenidate for
neuroenhancement in healthy individuals: a systematic review, Pharmacol Res. 2010. https://
doi.org/10.1016/j.phrs.2010.04.002.
Reverby SM. 2011. Examining Tuskegee: the infamous syphilis study and its legacy, University of
North Carolina Press, 2011. ProQuest Ebook Central. http://ebookcentral.proquest.com/lib/
columbia/detail.action?docID¼475201. (n.d.).
Smith B. Inappropriate prescribing. Monit Psychol. 2012, June;43(6):36.
Tannenbaum J. The promise and peril of the pharmacological enhancer modafinil. Bioethics. 2012.
https://doi.org/10.1111/bioe.12008.
Thomas KC, Ellis AR, Konrad TR, Holzer CE, Morrissey JP. County-level estimates of mental
health professional shortage in the United States. Psychiatric Services (Washington, DC).
2009;60(10):6.
Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, et al. Effects of modafinil on dopamine and
dopamine transporters in the male human brain. JAMA. 2009;301:1148–54.
Warrer P, Aagaard L, Hansen EH. Comparison of pregnancy and lactation labeling for attention-
deficit hyperactivity disorder drugs marketed in Australia, the USA, Denmark, and the
UK. Drug Saf. 2014;37(10):805–13. https://doi.org/10.1007/s40264-014-0215-2.
Weimer K, Colloca L, Enck P. Placebo effects in psychiatry: mediators and moderators. Lancet
Psychiatry. 2015;2(3):246–57. https://doi.org/10.1016/S2215-0366(14)00092-3.
Wenthur CJ, Bennett MR, Lindsley CW. Classics in chemical neuroscience: fluoxetine (Prozac).
ACS Chem Neurosci. 2014;5(1):14–23. https://doi.org/10.1021/cn400186j.
Yonkers KA, Blackwell KA, Glover J, Forray A. Antidepressant use in pregnant and postpartum
women. Annu Rev Clin Psychol. 2014;10(1):369–92. https://doi.org/10.1146/annurev-clinpsy-
032813-153626.
Ethics of Informed Consent: Coercive and
Preventive Medication

Hanfried Helmchen

Contents
The Normative Framework and Its Change Over Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
Capacity to Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
Coercive Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
Acute Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
Chronic Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
Preventive Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
Primary Prevention of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745
Primary Prevention of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749

Abstract
Acknowledgement of human rights and its translation into psychiatric action is an
increasingly extensive achievement of the past decades. Orientation towards the
individual patient means to recognize both his/her right and capacity of self-
determination as well as to consider his/her preferences. This is particularly valid
in the use of psychotropic medication in problematic situations such as in
coercive and in preventive medication. In view of coercive medication in life-
threatening psychiatric emergencies, psychiatrists must convert a seemingly
antagonism between respecting the autonomy of the mentally ill and their

H. Helmchen thanks Jane Helmchen, M.A. for optimisation of his English.

H. Helmchen (*)
Department of Psychiatry & Psychotherapy, CBF, Charité – University Medicine Berlin, Berlin,
Germany
e-mail: hanfried.helmchen@charite.de

© Springer Nature Switzerland AG 2022 739

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_404
740 H. Helmchen

obligation to care into an ethically acceptable complementary solution. Medica-

tion for primary prevention confronts the psychiatrist with difficulties of
informing an (almost) healthy individual in view of uncertainties of conversion
rates in schizophrenia as well as of lacking drugs with satisfying efficacy in
dementia. The application of psychotropic drugs in such cases is often only the
last choice due to their questionable or low efficiency, unwanted effects, and other
preferences of the comprehensively informed patient.

Keywords
Self-determination · Informed consent to medication · Preventive medication ·
Change of normative framework · Coercive medication · Dementia ·
Schizophrenia

The Normative Framework and Its Change Over Time

Two hundred years ago a dominating psychiatric conviction was that “the mentally
ill is under age as a child”; and this was the first sentence of the influential book Die
Irrenanstalt in allen ihren Beziehungen (The lunatic asylum in all its relationships);
it was published 1831 by Carl Friedrich Roller, the very influential founding director
of the then most modern asylum Illenau in south-west Germany (Roller 1831).
Today, psychiatry had implemented the principle of informed consent into clinical
practice and is on the way to recognize the right of self-determination of the mentally
ill as is required by the UN Convention on the Rights of Persons with Disabilities
(UN 2006); the CRPD is interpreted by the Central Ethics Committee at the German
Federal Board of Physicians as: “the assistant does not substitute the decisions of the
patient with his own decisions but assists him/her in the exercise of his/her right of
self-determination.” (Zentrale Ethikkommission bei der Bundesärztekammer 2016).
The British Supreme Court expressed this in a decision in 2016 as follows: “The UK
Supreme Court ruled that the standard for what physicians should inform patients
about the risks, benefits, and alternatives of treatment will no longer be determined
by what a responsible body of physicians deems important but rather by what a
reasonable patient deems important” (Spatz et al. 2016).
Such a change of the normative framework corresponds to a change of psychiatric
attitudes towards the patient (Helmchen 2019b). But it needs continuous educational
efforts across generations; for example, although the psychiatrist Wilhelm
Griesinger in 1845 had already written about the use of general human rights for
the mentally ill (Griesinger 1845), it was deemed necessary by the German Society
for Psychiatry and Psychotherapy, Psychosomatics and Neuroscience (DGPPN) to
publish a “plan of action” in 2018 in order to implement the CRPD into clinical
reality (DGPPN 2018a).
This understanding of the patient’s right of self-determination will be discussed
by the following aspects of psychopharmacotherapy: 1. Informed consent to medi-
cation, 2. Coercive medication, 3. Preventive medication.
Ethics of Informed Consent: Coercive and Preventive Medication 741

Informed Consent

In order to realize his right of self-determination, the patient must understand all
information that is relevant for his decision to accept or to reject the drug treatment
recommended by his psychiatrist. Accordingly it is the twofold responsibility of the
psychiatrist to provide to the patient all relevant evidence-based information as well
as to test whether the patient can use this information for a rational decision, that is,
the patient‘s capacity of self-determination (Capacity to consent is included in the
broader term capacity of self-determination; the latter term is clearer in implying also
the capacity to reject as well as being a human right).

Information

Respect for autonomy requires improving the patient’s understanding of the disorder
and of the benefits and risks of both the recommended and alternative therapeutic
interventions as well as the elucidation of their meaning for the patient’s personal
values, especially his expectations towards the therapy (Helmchen 2010). The infor-
mation must include the aim of psychotropic medication, that is, to mitigate the present
symptoms, or to prevent their recurrence – not the least in order to strengthen the
patient’s capacity to use psychotherapeutic and rehabilitative interventions (Helmchen
2018). Besides these intended benefits, the medication may also have unwanted effects
that must be named; the psychiatrist should explain that nevertheless he recommends
the medication because in his view its probable benefits will outweigh its possible
risks; in some situations also the timing will be of relevance: some unwanted effects of
drug treatment such as tardive hyperkinesias and a metabolic syndrome become
manifest only in long-term treatment; therefore, information about these risks must
be given at the latest when the acute treatment will proceed to maintenance treatment.
Of course, the psychiatrist must inform the patient also about alternative treatments,
and why he recommends them only as a second or additional or later choice. Also the
patient should be informed on the procedure of medication: how often, how long, as a
pill or by injection, mode of control (monitoring for efficiency, safety, and adherence),
and with regard to poor adherence not only about the risk of relapse but also about
withdrawal symptoms or “discontinuation syndromes” of antipsychotics (Buffo 2020;
Keks et al. 2019) as well as of antidepressants that could be prevented by a monitored
slow reduction over weeks (Henssler et al. 2019).
Recently a first schedule for measuring the quality of this information has been
published (Spatz et al. 2020). It seems to be a further step to the standardization of
medical procedures.

Capacity to Consent

If there are doubts about the patient’s capacity of self-determination the psychiatrist
should test it by asking the patient to repeat the given information, that is, what will
742 H. Helmchen

be done, why will it be done, and what it means for the patient him-/her self. In case
of questionable capacity of self-determination, the patient should be assisted to
improve his understanding and decision-making capacity (Zentrale
Ethikkommission bei der Bundesärztekammer 2016); (Szmukler and Rose 2014),
for example, by corrective feedback in case of misrepresenting the given information
(Prince et al. 2013), or by assistance in drawing up a “facilitated psychiatric advance
directive” (F-PAD (Swanson et al. 2006)). Information needs time and should not be
a single event but a process in which the patient should have time to consider and ask
again for clarification (Helmchen 2019a).

Coercive Medication

The psychiatrist is entitled to medicate the patient against his will only under two
conditions: first, if the patient lacks the capacity for self-determination, especially the
capacity to consent to the needed medication in question, and, second, if the patient‘s
violent or suicidal behavior leads to acute life-threatening situations. But the assess-
ment of the capacity for self-determination may be difficult and may lead only to a
questionable result; in such cases the physician’s obligation of caring for the best
interest of the patient (and the safety of others) may conflict with the physician’s
obligation to respect the autonomous will of the patient. Therefore, a consent of the
patient should be attempted at by all gentler measures, and coercion must be only the
last possibility, and according to the law controlled by a judge (DGPPN 2014)
(Deutsche Gesellschaft für Psychiatrie und Psychotherapie Psychosomatik und
Nervenheilkunde (DGPPN) (Task Force “Ethik in Psychiatrie und Psychotherapie”)
2018); (Steinert and Hirsch 2020). All measures of coercion should be fairly
balanced against their expected potential benefits (Appelbaum and Redlich 2006).

Acute Conditions

Commonly the patient voluntarily accepts the medication as help against his painful
experiences. However, sometimes he might not understand the reason for medica-
tion, especially in case his disturbed and dangerous behavior will be experienced
mainly by others and, therefore, he rejects any medication. Nevertheless, the psy-
chiatrist has the task to inform the patient about the negative or even dangerous
consequences of his behavior and that it can be controlled by the medication.
However, if the patient refuses a medication due to previously experienced unwanted
drug effects or other rational reasons, the psychiatrist has to accept the rejection in
case the patient has the capacity of self-determination.

Chronic Conditions

A related problem can be encountered in persons with chronic psychotic conditions

who isolate themselves from their social network or environment and are in danger
Ethics of Informed Consent: Coercive and Preventive Medication 743

either to neglect themselves, to become homeless and to starve, or to relapse

frequently and must repeatedly be admitted to the hospital. Relatives often urge
psychiatrists to act against such dangerous isolation; psychiatrists and social workers
look after such patients, for example, by various forms of outreach services or home
treatment. These highly specialized teams seek to contact severely psychically ill
persons in the community and to build-up and maintain a lasting supportive and
therapeutic relationship with those who do not make use of these services by
themselves. The service teams try to empower the mentally ill, that is, to discover
their own strengths and support them in finding their own way to an independent and
satisfactory life. The results of such outpatient or home treatments remain question-
able: some patients accept the offer of talks and help, but do not like a focus on
medication. The lack of improvement in such cases is contrasted by the finding that a
community treatment order, that is, an outpatient compulsory treatment, might
improve the adherence and reduce readmissions due to relapses (Muirhead et al.
2006; Rawala and Gupta 2014). The ethical implications of the risk-benefit-evalu-
ation of such interventions become clear in the controversial discussion about
strengthening the adherence to medication by various modes of leverage, for exam-
ple, whether financial incentives for appearing for appointments for injections is
acceptable, or which losses are confronted with the benefit of such incentivized or
purchased adherence (Priebe et al. 2010).
There is evidence that in people with such chronic psychotic conditions treatment
with long-acting depot antipsychotic medication improves the outcome in terms of
self-serving functioning and fewer readmissions (Leucht et al. 2011). It is also valid
that financial incentives improve patient‘s adherence to such treatment (Henderson
et al. 2015). However, this effect disappears after discontinuation of such treatment
regimen (Priebe et al. 2016b). This may indicate that such financially induced
treatment adherence implies some leverage or even coercion, and by this “it may
become more difficult for potential patients to seek or at least accept psychiatric
treatment. This may reduce the overall effectiveness of mental health care and
indirectly lead to even more coercion for ensuring that unwilling patients receive
care” (Claassen and Priebe 2010); this remark points to the complexity that the
benefit-risk-evaluation must consider. Moreover, according to most laws any mode
of coercion is forbidden for persons with capacity of self-determination. The finding
that “no strong or consistent associations were found between capacity and use of
leverage” (Appelbaum and Redlich 2006) demonstrates the need for two procedures:

(a) The assessment of the capacity of self-determination in order to avoid compulsory

medication in mentally ill persons who have this capacity. If competent patients
with an inclination to episodic relapses reject an antipsychotic medication it may
be a trust-building measure to inform them not only of the high risk of relapse
without antipsychotic medication but also that they would be welcomed and
offered treatment again in the case of a very probable relapse. However, this
situation implies not only a conflict between the ethical principles of respecting the
self-determination of the patient and his welfare, but also between the principle of
individual welfare and the principle of justice, that is, the common good, with
regard to possible high costs of avoidable repeated readmissions due to relapses.
744 H. Helmchen

(b) In every individual case, a careful benefit-risk-evaluation is needed. Particularly

in cases of questionable capacity to consent the risks of coerced medication such
as not only unwanted medication effects but also the experience of leverage on
the willingness to further cooperation must be considered as well as the risks of
the untreated disorder including the impact of strange or disturbed behavior on
the patient’s social environment with negative rebounds such as increasing the
risk of stigmatization or of compulsory admission. Thus, all efforts should be
undertaken to win the cooperation of even the unwilling chronic psychotic
outpatient for adherence to a relapse-preventing antipsychotic depot medication,
considering the preferences of the patient as far as possible as well as keeping
coercion as minimal as possible, for example (Szmukler and Rose 2014; DGPPN
2014, 2018b; Steinert and Hirsch 2020). More research is needed in order to base
a fair risk-benefit-evaluation on more evidence-based knowledge of individual
factors that might influence adherence (Priebe et al. 2016a).

Preventive Medication

Until now examples of medication under conditions of compulsion or leverage have

been given; this medication was directed against symptoms (secondary prevention)
or recurrence of symptoms (tertiary prevention). In contrast the following remarks
are related to primary prevention, that is, the intervention against the onset or
procrastination or attenuation of the very early first clinical symptoms of severe
mental illnesses such as schizophrenia or dementia.
The interest in prevention of mental disorders is not new (Caplan 1964; Ciompi
1984; Rudolf and Tlle 1984; Klosterkötter and Maier 2017); however, increasing
need as well as growing hope stimulate present activities. The need is given both by
the individual suffering of millions of people and the continuously increasing burden
of disease, particularly due to persisting disability from severe mental disorders
(World Health Organisation (WHO) 2019); and hope is stimulated by growing
knowledge about the predictive power of indicators of preclinical morbid processes
(Maier and Oertel 2014) as well as of risk factors for the onset of mental disorders
and new effective interventions for primary prevention. The latter are mainly
directed against social determinants (e.g., as support for change of life-style, unem-
ployment, homelessness) and concomitant somatic diseases (e.g., hypertension,
stroke, diabetes) or prodromal symptoms of mental disorders (e.g., transient single
symptoms of psychosis such as hallucinations or delusions as well as a low level of
(social) functioning). Furthermore, the availability of psychotropic drugs with effec-
tiveness against symptoms of severe mental disorders also fostered their preventive
utilization. Particularly for chronic disabling disorders such as schizophrenia and
dementia measures of social support and psychotherapeutic interventions are known
to become augmented or even applicable by psychotropic drugs in order to prevent
or to slow or to attenuate the onset of a mental disorder (Schmidt et al. 2015;
Helmchen 2018). Nevertheless, the application of drugs in primary prevention has
Ethics of Informed Consent: Coercive and Preventive Medication 745

been under discussion since the 2000s (Mcgorry 1998) especially due to ethical
questions with regard to the accuracy and validity of prediction: the probability of
transition from a clinically premorbid or mildly morbid state to a severe mental
disorder must be evaluated against the risk of unwanted drug effects in order to avoid
them particularly in patients who despite their high-risk state never will develop a
severe mental disorder. This will be explained by the examples of preventive
utilization of psychotropic drugs in early stages of schizophrenia and dementia.

Primary Prevention of Schizophrenia

Because of the early beginning in adolescence, the often progressive course, and the
perhaps lifelong duration of the disabling symptoms and lower functioning of
schizophrenia, it seems natural to start a treatment as early as possible. However,
the possible benefits of a preventive treatment, that is, the exclusion or postponing of
a transition from a high-risk state to a psychosis, or at least mitigation of disabling
symptoms, must be assessed against their possible risks (Klosterkoetter and
Schultze-Lutter 2010).

(a) Predictive intervention: The first step is to recognize people with the risk of
developing schizophrenia, for example, healthy persons with single psychotic
symptoms. A state-of-the-art review concluded that “clinical high-risk (CHR)
state for psychosis has evolved to capture the prepsychotic phase, describing
people presenting with potentially prodromal symptoms” (Fusar-Poli et al.
2013). According to fairly heterogeneous criteria of CHR and different follow-
up periods, a correct prediction of the manifestation of schizophrenia varies
between less than 20 and almost 90% (Ruhrmann et al. 2010), or 1/3 in 3 years
(Fusar-Poli et al. 2012), that is, almost 2/3 of people with high risk do not
develop a psychosis (Bechdolf et al. 2015). Even if the accuracy of prediction
will be further improved by combination of criteria for early and late clinical
high-risk stages and inclusion of biological and environmental risk factors
(Klosterkötter 2014), it may not reach 100%, at least on the individual level.
Therefore, early detection (ED) of healthy people at risk of schizophrenia
implies the risk of provoking unnecessary fears and stigmatization particularly
in those who never will get a manifest psychosis.
These psychological risks should be countered by starting such predictive
intervention as an offer of information and help in an individualized and
nonstigmatizing mode only for those seeking help (Bechdolf et al. 2015) who
are competent to consent after full information, particularly about the probabil-
ities of benefits and risks of preventive interventions (Helmchen 2014).
(b) Preventive intervention: The second step is to consider with regard to the
pharmacotherapeutic component of such preventive intervention not only pos-
sible unwanted drug effects but also the possibility that they may occur in
persons who would never have developed the psychosis even without any
746 H. Helmchen

pharmacotherapy; this means that this risk-benefit-assessment has to evaluate the

probabilities of side effects as well as of the rate of conversion from healthy state
to the manifestation of psychosis.

Specialized services have been developed to translate the new findings into
practice, e.g. associated centers for early intervention and therapy for young adults
with beginning psychosis (HÄfner et al. 2012). They provide early detection (ED) as
well as early intervention (EI) by a comprehensive offer of treatment, particularly
cognitive-behavioral psychotherapy, support of the patients dealing with their ail-
ments, promotion of stigma coping and empowerment, and medication as one
component (Schmidt et al. 2015).
Controlled studies show an improvement of symptoms and functioning of the
high-risk state as well as a reduction of conversion rates, for example, from 1/3 to
1/10 (Mcgorry et al. 2002) for both cognitive behavioral therapy and psychophar-
macotherapy, but no significant differences between them. Therefore, the benefit-
risk-assessment of preventive medication has to consider on the one hand that
psychotherapeutic interventions are more acceptable by patients and less stigmatiz-
ing, have less unwanted effects, and are first choice treatments for anxiety and
depressive disorders that are frequent in these patients (Bechdolf et al. 2015; Michel
et al. 2018); on the other hand, psychotropic drugs will be effective more quickly
than psychotherapy and are indicated in cases of rapid progression of symptoms or
acute suicidality or strong social disability in order to make psychosocial interven-
tions possible (Schmidt et al. 2015; Lambert and Correll 2015). The risk of unwanted
effects (body weight gain, tardive hyperkinesia) of antipsychotic drugs such as
Risperidon, Amisulprid, Aripiprazol, Olanzapin should be avoided by low doses
and tight monitoring (Lambert and Correll 2015).
In general people with high-risk for psychosis should be accompanied and
empowered to deal with their ailments and stress and be offered risk-adapted
(Klosterkötter 2014) preventive interventions, but due to the unsatisfying state of
phase-specific preventive interventions with convincing and unequivocal efficacy
“caution is required when making clinical recommendations for the prevention of
psychosis in individuals at risk” (Fusar-Poli et al. 2019).

Primary Prevention of Dementia

Dementia, prototypically of the Alzheimer type, is a slow but continuously progres-

sive psychopathological syndrome. Its underlying neuropathological process needs
probably one to two decades to become clinically manifest (Rujescu and Maul
2019). Therefore, it could be an ideal target for preventive interventions, that is, at
least for treating the preclinical course of the disease (“interception” (Frank and Bug
2019). The search for biomarkers as indicators of the Alzheimer disease process and
thereby as preclinical predictors of clinical dementia is slowly but increasingly
successful: different biomarkers (imaging and bodyfluids) are ß amyloid deposition,
pathologic tau, and neurodegeneration (AT(N)) (Jack et al. 2018). It is hoped that the
Ethics of Informed Consent: Coercive and Preventive Medication 747

biomarker-based validation, stratification, and staging of the neuropathological

Alzheimer disease (Wiltfang 2019) will enable researchers to define specific targets
for successful treatment. Because and despite immense investments into neurobio-
logical research and, based on it, for preclinical blocking of the Alzheimer disease
process, to date no effective treatment is available.
Against this background it is to be questioned whether it is justified to use the
increasing power of prediction (Rowe et al. 2013); (Jack et al. 2019) by combining
invasively obtained biomarkers with genetic (ApoE 4; Amyloid Precurser Protein
(APP), Proteins Presenilin 1 and 2) (Rujescu and Maul 2019) and clinical markers
(subjective cognitive decline (SCD) (Jessen 2014)) as well as MCI findings by
neuropsychological tests (Di Pucchio et al. 2018; Johnen 2016) in order to predict
dementia in clinical practice and care.

(a) Predictive intervention, that is, prognosis of the onset of dementia in a healthy or
at least nondemented person, must consider the expense and problems (risks of
taking body fluids or subjective discomfort by imaging procedures) of biologi-
cally based interventions. They may be necessary for research studies, but have
almost no or only very limited indication in practice and care. In any case the
concerned person must be competent to understand the comprehensive informa-
tion about the aim and risks and missing therapeutic consequences of this
predictive intervention. If a person is willing to defer to such predictive inter-
vention, he also should be informed about possibilities to write an advance
research directive for his willingness to participate in a future research study.
However, predictive intervention on a less invasive level is helpful for
counseling the patient. Less invasive are anamnestic (family and genetic) data
and findings of neuropsychological tests. Predicted high probability of clinical
dementia clearly indicates preventive interventions, as primary prevention on a
general level and as early secondary prevention on the individual level.
(b) Preventive interventions sensu interception with drugs are not available and
RCTs with new investigative drugs have to overcome methodological difficul-
ties (Rujescu and Maul 2019) and to apply specific ethical evaluations
(Helmchen 2017; Vollmann 2017; Winkler 2019).

However, in contrast to the lack of primary preventive medication for the

Alzheimer disease process several psychotropic drugs are used for early secondary
prevention. Authorized drugs against mild or moderate clinical symptoms of demen-
tia are acetylcholinesterase-inhibitors (Donepezil, Rivastigmin, Galantamin),
whereas the NMDA-receptor-antagonist Memantine is indicated only for severe
symptoms; this has a significant but only small positive influence on the cognitive
capacity and everyday competence of persons with dementia and may thereby delay
the progression of clinical symptoms for some months; however, it might have
unpleasant side-effects and cannot intercept the underlying neuropathological dis-
ease process (Tan et al. 2014). Such early preventive medication against symptoms
of dementia should be distinguished from medication against complications which
often arise later in the course of dementia; complications of dementia such as
748 H. Helmchen

restlessness or disturbing behavior can be controlled by antipsychotics like

aripiprazol, risperidone, clozapine; but they should be used only as a last resort if
otherwise removable reasons of such behavior (Cohen-Mansfield 2013) cannot be
found, and for only a short time because their sedating effect may amplify the
psychopathological dementia symptoms. Longterm sedation of demented patients
in nursing homes for old people is often a misuse and should be avoided as well as
oblivion of withdrawal of these initially indicated drugs. Likewise the use of
antidepressant drugs must consider that anticholinergic effects of some antidepres-
sant drugs (as amitriptyline) may trigger symptoms of dementia. Whereas the
application of antidepressant drugs against depression in demented patients can be
seen as secondary prevention, their use in nondemented patients with depression can
be seen as primary prevention of dementia, because depression is a risk factor for
dementia (Deckers et al. 2015).
There are many other risk factors the reduction or exclusion of which can
modulate the onset and course of dementia (Livingston Gill et al. 2017). Risk factors
such as manifest or silent somatic diseases, for example, cardiovascular diseases,
hypertonus, diabetes, hypothyreosis, or even indicated drugs, for example, such as
widely used proton-pump-inhibitors against overproduction of gastric acid
(Haenisch et al. 2014), can be treated, or unhealthy consumption of alcohol, tobacco,
drugs, and other consequences of an unfavorable life-style such as physical inactiv-
ity and overweight can be reduced or eliminated by a sustainable change of life-style
(Deckers et al. 2015). It is estimated that 1/3 of dementia cases are related to such
modifiable factors (Norton et al. 2014). Such change on a broader scale may be a
condition of recent signs of a slight reduction of dementia prevalence rates in
younger European cohorts (Matthews et al. 2013; Wu et al. 2015; Garre-Olmo
2018; Dhana et al. 2020) but not in some other regions as in China (Chan et al.
2013). This may point to the relevance of successful treatment of depression and
somatic diseases as well as particularly of risk-reduced lifestyles (physical activities,
Mediterranian diet) and increase of cognitive reserves (improved education).
Such findings stimulate interventions aiming at protecting early social develop-
ment (Danner et al. 2001) as well as strengthening stimulating social interactions and
subjectively meaningful activities. They may stimulate and use the ability to learn
that remains retained up to the highest age even in people with slight symptoms of
dementia (Lindenberger and Reischies 1999). It is hypothesized that such activities
stimulate build-up processes in the brain (neuroplasticity) and may counter the
predominance of involutional processes (Hüther 2017).
Thus, intensive information and assistance of a physician for a patient to decide to
participate in a primary predictive intervention of dementia is necessary, because to
date no primary preventive medication exists, not even a risk-reducing medication
against the neurodegenerative Alzheimer disease. However, there is a spectrum of
possibilities to prevent or at least to reduce the dementia syndrome the realization of
which is a task of public health (World Health Organisation (WHO) 2016).
To date early secondary preventive medication against the dementia syndrome in
individual patients plays only a minor role, due to its low efficiency and some
unwanted effects.
Ethics of Informed Consent: Coercive and Preventive Medication 749

Conclusion

The need to inform comprehensively an individual and to assist his decision-making

is exemplified by preventive interventions in schizophrenia and dementia. Consid-
erations are separated into predictive interventions and preventive interventions due
to their different risks and informational needs. Informing must take into account that
individuals may react differently with informations about

• The prediction of the risk to become ill (conversion rate)

• The progressive disabling nature of these diseases
• The currently limited efficiency of medication combined with risks of unwanted
effects
• Alternative interventions, particularly psychotherapeutic and social interventions
• Possible arrangements for worsening, for example, advance directives
• The evaluation of probabilities

The appraisal of this information and balancing according to the patient’s prefer-
ences may be difficult and needs assistance from the informing physician. Accord-
ingly his orientation towards the patient will be expressed by taking time enough for
listening and taking seriously the patient’s comments and questions, also giving time
for repeated questions.

Cross-References

▶ Anti-dementia Medications: Classification, Indications, and Differential

Indications
▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and
Resistance to Therapy
▶ Antipsychotics/Neuroleptics: Course and Duration of Therapy, Withdrawal
Symptoms, Resistance to Therapy, Side Effects, and Contraindications
▶ Anxiolytics: Misuse, Dependence, and Withdrawal Syndromes
▶ Compliance and Psychoeducation
▶ Ethical Issues in Neuropsychopharmacotherapy: US Perspective
▶ Evidence-Based Treatment with Antipsychotics in Schizophrenia: S3-Guideline
and Current References
▶ Memantine for Treatment of Dementia
▶ Neuropharmacology of Dementias

References
Appelbaum PS, Redlich A. Impact of decisional capacity on the use of leverage to encourage
treatment adherence. Community Ment Health J. 2006;42:121–30.
750 H. Helmchen

Bechdolf A, Laier S, Kallenbach M, Biester A, Leopold K. Sollen bei Prodromalstadien der

Schizophrenie Antipsychotika zur Psychoseprävention eingesetzt werden? Kontra. Nervenarzt.
2015;86:1424–6.
Buffo J. Antipsychotic withdrawal symptoms, signs, and detoxification. 2020. Available: https://
www.withdrawal.net/antipsychotic/
Caplan G. Principles of preventive psychiatry. New York: Basic Books; 1964.
Chan KY, Wang W, Wu JJ, Liu L, Theodoratou E, Car J, Middleton L, Russ TC, Deary IJ, Campbell
H, Wang W, Rudan I. Epidemiology of Alzheimer’s disease and other forms of dementia in
China, 1990–2010: a systematic review and analysis. Lancet. 2013;381:2016–23.
Ciompi L. Die Verhütung psychischer Krankheiten – Wunsch und Wirklichkeit. Ein Überblick. In:
Rudolf G, TÖlle R, editors. Prävention in der Psychiatrie. Heidelberg: Springer; 1984.
Claassen D, Priebe S. Ethics of deinstitutionalisation. In: Helmchen H, Sartorius N, editors. Ethics
in psychiatry. European contributions. Dordrecht: Springer; 2010.
Cohen-Mansfield J. Nonpharmacologic treatment of Behavioral disorders in dementia. Curr Treat
Options Neurol. 2013;15:765–85.
Danner DD, Snowdon DA, Friesen WV. Positive emotions in early life and longevity: findings from
the nun study. J Pers Soc Psychol. 2001;80:804–13.
Deckers K, Van Boxtel MPJ, Schiepers OJG, De Vugt M, Muñoz SÁnchez JL, Anstey KJ, Brayne
C, Dartigues J-F, Engedal K, Kivipelto M, Ritchie K, Starr JM, Yaffe K, Irving K, Verhey FRJ,
KÖhler S. Target risk factors for dementia prevention: a systematic review and Delphi consen-
sus study on the evidence from observational studies. Int J Geriatr Psychiatry. 2015;30:234–46.
Deutsche Gesellschaft für Psychiatrie und Psychotherapie Psychosomatik und Nervenheilkunde
(DGPPN) (Task Force „Ethik in Psychiatrie und Psychotherapie“) 2018. S3-Leitlinie
„Verhinderung von Zwang: Prävention und Therapie aggressiven Verhaltens bei Erwachsenen“.
AWMF-Register Nr. 038-022.
DGPPN. Achtung der Selbstbestimmung und Anwendung von Zwang bei der Behandlung von
psychisch erkrankten Menschen. Eine ethische Stellungnahme der DGPPN. Nervenarzt.
2014;85:1419–31.
DGPPN. Aktionsplan: Umsetzung der UN-BRK. In: DGPPN editor https://dgppn.de/
schwerpunkte/menschenrechte/aktionsplan-un-brk.html. Berlin: DGPPN; 2018a.
DGPPN. S3-Leitlinie„Verhinderung von Zwang: Prävention und Therapie aggressiven Verhaltens
bei Erwachsenen“(Langversion –Fassung vom 10.09.2018) AWMF-Register Nr. 038-022;
2018b.
Dhana K, Evans DA, Rajan KB, Bennett DA, Morris MC. Healthy lifestyle and the risk of
Alzheimer dementia. Findings from 2 longitudinal studies. Neurology. 2020;95:e374. https://
doi.org/10.1212/WNL.0000000000009816.
Di Pucchio A, Vanacore N, Marzolini F, Lacorte E, Di Fiandra T, Gasparini M. Use of neuropsy-
chological tests for the diagnosis of dementia: a survey of Italian memory clinics. BMJ Open.
2018;8:e017847.
Frank J, Bug C, editors. Disease Interception – Implikationen einer frühen Diagnose und Krankheit-
sunterbrechung für Medizin und Gesellschaft. Bonn: eRelation AG – Content in Health; 2019.
Fusar-Poli P, Bonoldi I, Yung AR, Borgwardt S, Kempton MJ, Valmaggia L, Barale F, Caverzasi E,
McGuire P. Predicting psychosis: meta-analysis of transition outcomes in individuals at high
clinical risk. Arch Gen Psychiatry. 2012;69:220–9.
Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-RÖssler A, Schultze-Lutter F,
Keshavan M, Wood S, Ruhrmann S, Seidman LJ, Valmaggia L, Cannon T, Velthorst E, De
Haan L, Cornblatt B, Bonoldi I, Birchwood M, Mcglashan T, Carpenter W, Mcgorry P,
Klosterkötter J, McGuire P, Yung A. The psychosis high-risk state: a comprehensive state-of-
the-art review. JAMA Psychiat. 2013;70:107–20.
Fusar-Poli P, Davies C, Solmi M, Brondino N, De Micheli A, Kotlicka-Antczak M, Shin JI, Radua
J. Preventive treatments for psychosis: umbrella review (Just the evidence). Front Psych.
2019;10:764.
Ethics of Informed Consent: Coercive and Preventive Medication 751

Garre-Olmo J. Epidemiology of Alzheimer’s disease and other dementias. Rev Neurol.

2018;66:377–86.
Gill L, Andrew S, Orgeta Vasiliki SG, Costafreda JH, Ames D, Ballard C, Banerjee S, Alistair
Burns JC-M, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K,
Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia
prevention, intervention, and care. Lancet. 2017;S0140-6736:31363-6.
Griesinger W. Die Pathologie und Therapie der psychischen Krankheiten für Ärzte und
Studierende. Stuttgart: Adolph Krabbe; 1845.
Haenisch B, Von Holt K, Wiese B, Prokein J, Lange C, Ernst A, Brettschneider C, KÖnig H-H,
Werle J, Weyerer S, Luppa M, Riedel-Heller S, Fuchs A, Pentzek M, Weeg D, Bickel H, Broich
K, Jessen F, Maier W, Scherer M. Risk of dementia in elderly patients with the use of proton
pump inhibitors. Eur Arch Psychiatry Clin Neurosci. 2014:1–10.
Häfner H, Bechdolf A, Klosterkötter J, Kurt M, editors. Psychosen – Früherkennung und
Frühintervention: Der Praxisleitfaden. Stuttgart: Schattauer; 2012.
Helmchen H. Informed consent in psychiatric practice. In: Helmchen H, Sartorius N, editors. Ethics
in psychiatry – European contributions. Dordrecht: Springer; 2010. p.139–146.
Helmchen H. Relationship of benefits to risks in psychiatric research interventions. In: Clausen J,
Levy N, editors. Handbook of neuroethics. Dordrecht: Springer Netherlands; 2014. p.907–928.
Helmchen H. Das Janusgesicht der Psychiatrie. Nutzen und Risiken psychiatrischen Handelns.
Stuttgart: Kohlhammer; 2017.
Helmchen H. Zur Rolle der Psychopharmakotherapie in der Entwicklung der Sozialpsychiatrie.
Nervenarzt. 2018;89:88–91.
Helmchen H. Die Entwicklung des Konzepts der Einwilligung nach Aufklärung in der
psychiatrischen Forschung. Ethik in der Medizin. 2019a;31:207–20.
Helmchen H. Zum Einfluss von Zeitgeist und Menschenrechten auf psychiatrisches Handeln.
Nervenarzt. 2019b;90:724–32.
Henderson C, Knapp M, Yeeles K, Bremner S, Eldridge S, David AS, O’connell N, Burns T, Priebe
S. Cost-effectiveness of financial incentives to promote adherence to depot antipsychotic
medication: economic evaluation of a cluster-randomised controlled trial. PLoS One.
2015;10:e0138816.
Henssler J, Heinz A, Brandt L, Bschor T. Antidepressant withdrawal and rebound phenomena.
Dtsch Arztebl Int. 2019;116:355–61.
Hüther G. Raus aus der Demenz-Falle! Wie es gelingen kann, die Selbstheilungskräfte des Gehirns
rechtzeitig zu aktivieren. München: Arkana Verlag; 2017.
Jack CR Jr, Wiste HJ, Therneau TM, Weigand SD, Knopman DS, Mielke MM, Lowe VJ, Vemuri P,
Machulda MM, Schwarz CG, Gunter JL, Senjem ML, Graff-Radford J, Jones DT, Roberts RO,
Rocca WA, Petersen RC. Associations of amyloid, tau, and Neurodegeneration biomarker
profiles with rates of memory decline among individuals without dementia Amyloid, Tau, and
Neurodegeneration Biomarker Profiles and Memory Decline In Individuals Without Dementia
Amyloid, Tau, and Neurodegeneration Biomarker Profiles and Memory Decline In Individuals
Without Dementia. JAMA. 2019;321:2316–25.
Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust
W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC,
Scheltens P, Siemers E, Snyder HM, Sperling R. NIA-AA research framework: toward a
biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–62.
Jessen F. Subjective and objective cognitive decline at the pre-dementia stage of Alzheimer’s
disease. Eur Arch Psychiatry Clin Neurosci. 2014;264:3–7.
Johnen A. Neuropsychologische Demenztests in der Praxis-Wann? Welche? Wie? 2016. https://
www.ukm.de/fileadmin/ukminternet/daten/kliniken/neurologie/Aktuelles/Praesentationen/
Demenzfortbildung_Oktober_2016/3_Demenztests_in_der_Praxis_-_Welche_Wann_Wie.pdf
Keks N, Schwartz D, Hope J. Stopping and switching antipsychotic drugs. Aust Prescr.
2019;42:152–7.
752 H. Helmchen

Klosterkoetter J, Schultze-Lutter F. Prevention and early treatment. In: Helmchen H, Sartorius N,

editors. Ethics in psychiatry. Dordrecht: Springer; 2010.
Klosterkötter J. Prädiktion von Psychosen. Nervenarzt. 2014;85:1238–48.
Klosterkötter J, Maier W, editors. Handbuch präventive psychiatrie: forschung – Lehre –
Versorgung. Stuttgart: Schattauer; 2017.
Lambert M, Correll C. Sollen bei Prodromalstadien der Schizophrenie Antipsychotika zur
Psychoseprävention eingesetzt werden? Pro. Nervenarzt. 2015;86:1420–3.
Leucht C, Heres S, Kane JM, Kissling W, Davis JM, Leucht S. Oral versus depot antipsychotic
drugs for schizophrenia – a critical systematic review and meta-analysis of randomised long-
term trials. Schizophr Res. 2011;127:83–92.
Lindenberger U, Reischies F. Limits and potentials of intellectual functioning in old age. In: Baltes
PB, Mayer K-U, editors. The Berlin Aging Study – Aging from 70 to 100. Cambridge, UK:
Cambridge University Press; 1999.
Maier W, Oertel W. Prädiktion neurologischer und psychiatrischer Erkrankungen. Nervenarzt.
2014;85:1231–2.
Matthews FE, Arthur A, Barnes LE, Bond J, Jagger C, Robinson L, Brayne C. A two-decade
comparison of prevalence of dementia in individuals aged 65 years and older from three
geographical areas of England: results of the cognitive function and ageing study I and II.
Lancet. 2013;382:1405–12.
Mcgorry P. “A stitch in time” . . . the scope for preventive strategies in early psychosis. Eur Arch
Psychiatry Clin Neurosci. 1998;248:22–31.
Mcgorry PD, Yung AR, Phillips LJ, Yuen HP, Francey S, Cosgrave EM, Germano D, Bravin J,
McDonald T, Blair A, Adlard S, Jackson H. Randomized controlled trial of interventions
designed to reduce the risk of progression to first-episode psychosis in a clinical sample with
subthreshold symptoms. Arch Gen Psychiatry. 2002;59:921–8.
Michel C, Ruhrmann S, Schimmelmann BG, Klosterkötter J, Schultze-Lutter F. Course of clinical
high-risk states for psychosis beyond conversion. Eur Arch Psychiatry Clin Neurosci.
2018;268:39–48.
Muirhead D, Harvey C, Ingram G. Effectiveness of community treatment orders for treatment of
schizophrenia with oral or depot antipsychotic medication: clinical outcomes. Aust N Z J
Psychiatry. 2006;40:596–605.
Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of
Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13:788–94.
Priebe S, Sinclair J, Burton A, Marougka S, Larsen J, Firn M, Ashcroft R. Acceptability of offering
financial incentives to achieve medication adherence in patients with severe mental illness: a
focus group study. J Med Ethics. 2010;36:463–8.
Priebe S, Bremner SA, Lauber C, Henderson C, Burns T. Financial incentives to improve adherence
to antipsychotic maintenance medication in non-adherent patients: a cluster randomised con-
trolled trial. Health Technol Assess. 2016a;20:1.
Priebe S, Bremner SA, Pavlickova H. Discontinuing financial incentives for adherence to antipsy-
chotic depot medication: long-term outcomes of a cluster randomised controlled trial. BMJ
Open. 2016b;6:e011673–e011673.
Prince M, Prina M, Guerchet M. World Alzheimer report 2013. Journey of caring. AN analysis of
long-term care for dementia. London: Alzheimer’s Disease International; 2013.
Rawala M, Gupta S. Use of community treatment orders in an inner-London assertive outreach
service. Psychiatr Bull (2014). 2014;38:13–8.
Roller CFW. Die Irrenanstalt nach allen ihren Beziehungen. Karlsruhe: Müller’sche
Hofbuchhandlung; 1831.
Rowe CC, Bourgeat P, Ellis KA, Brown B, Lim YY, Mulligan R, Jones G, Maruff P, Woodward M,
Price R, Robins P, Tochon-Danguy H, O’keefe G, Pike KE, Yates P, Szoeke C, Salvado O,
Macaulay SL, O’meara T, Head R, Cobiac L, Savage G, Martins R, Masters CL, Ames D,
Villemagne VL. Predicting Alzheimer disease with β-amyloid imaging: results from the Aus-
tralian imaging, biomarkers, and lifestyle study of ageing. Ann Neurol. 2013;74:905–13.
Ethics of Informed Consent: Coercive and Preventive Medication 753

Rudolf G, Tölle R. Prävention in der Psychiatrie. Berlin/Heidelberg: Springer; 1984.

Ruhrmann S, Schultze-Lutter F, Salokangas RKR, Heinimaa M, Linszen D, Dingemans P,
Birchwood M, Patterson P, Juckel G, Heinz A, Morrison A, Lewis S, Graf Von Reventlow H,
Klosterkotter J. Prediction of psychosis in adolescents and young adults at high risk: results
from the prospective European prediction of psychosis study. Arch Gen Psychiatry.
2010;67:241–51.
Rujescu D, Maul S. Perspektiven der Alzheimer-Therapie. In: Frank J, Bug C, editors. Disease
Interception. Implikationen einer frühen Diagnose und Krankheitsunterbrechung für Medizin
und Gesellschaft. Bonn: eRelation AG – Conzent in Health; 2019.
Schmidt SJ, Schultze-Lutter F, Schimmelmann BG, Maric NP, Salokangas RK, Riecher-RÖssler A,
Van Der Gaag M, Meneghelli A, Nordentoft M, Marshall M, Morrison A, Raballo A,
Klosterkötter J, Ruhrmann S. EPA guidance on the early intervention in clinical high risk states
of psychoses. Eur Psychiatry. 2015;30:388–404.
Spatz ES, Krumholz HM, Moulton BW. The new era of informed consent: getting to a reasonable-
patient standard through shared decision making. JAMA. 2016;315:2063–4.
Spatz ES, Suter LG, George E, Perez M, Curry L, Desai V, Bao H, Geary LL, Herrin J, Lin Z,
Bernheim SM, Krumholz HM. An instrument for assessing the quality of informed consent
documents for elective procedures: development and testing. BMJ Open. 2020;10:e033297.
Steinert T, Hirsch S. S3-Leitlinie Verhinderung von Zwang: Prävention und Therapie aggressiven
Verhaltens bei Erwachsenen. Nervenarzt. 2020;91:611–6.
Swanson JW, Swartz MS, Elbogen EB, Van Dorn RA, Ferron J, Wagner HR, McCauley BJ, Kim M.
Facilitated psychiatric advance directives: a randomized trial of an intervention to foster advance
treatment planning among persons with severe mental illness. Am J Psychiatry. 2006;163:1951.
Szmukler G, Rose D. Strengthening self-determination of persons with mental illness. In: Clausen J,
Levy N, editors. Handbook of Neuroethics. Dordrecht: Springer; 2014.
Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, Jiang T, Zhu XC, Tan L. Efficacy and safety
of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s
disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;41:615–31.
UN. Convention on the Rights of Persons with Disabilities (2006) (CRPD-06). 2006. http://www.
un.org/disabilities/convention/conventionfull.shtml. Access 7_6_16 [Online]
Vollmann J. Ethik in der Psychiatrie. Köln: Psychiatrie-Verlag; 2017.
Wiltfang J. Blutbasierte Diagnostik der präklinischen Alzheimerdemenz: Rekrutierungshilfe für
klinische Studien zur Disease Interception beim Morbus Alzheimer. In: Frank J, Bug C, editors.
Disease Interception. Implikationen einer frühen Diagnose und Krankheitsunterbrechung für
Medizin und Gesellschaft. Bonn: eRelation AG – Content in Health; 2019.
Winkler E. Ethische Überlegungen zur Disease Interception. In: Frank J, Christoph B, editors.
Disease Interception – Implikationen einer frühen Diagnose und Krankheitsunterbrechung für
Medizin und Gesellschaft. Bonn: BonneRelation AG – Content in Health; 2019.
World Health Organisation (WHO) 2016. Action Plan for the Prevention and Control of Non-
communicable Diseases in the WHO European Region.
World Health Organisation (WHO) 2019. Fact sheet: mental Disorders. https://www.who.int/news-
room/fact-sheets/detail/mental-disorders
Wu Y-T, Fratiglioni L, Matthews FE, Lobo A, Breteler MMB, Skoog I, Brayne C. Dementia in
western Europe: epidemiological evidence and implications for policy making. Lancet Neurol-
ogy. 2015;
Zentrale Ethikkommission bei der Bundesärztekammer. Stellungnahme „Entscheidungsfähigkeit
und Entscheidungsassistenz in der Medizin“. Deutsches Ärzteblatt 2016; 113.
Neuropsychopharmacotherapy: Aspects
of Placebo Effects

Petra Netter

Contents
Definition of Placebos and Areas of Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
Factors Involved in Drug and Placebo Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
Influences of Attributes of Medication, Accompanying Information, and “Ambiente”
(Factors c and S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
Factor “c” Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
Factor “S” Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
Target Variables of Placebo Responses and Their Methods of Assessment
(Factors R and m) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
Functions and Symptoms Responding to Placebo (Factor R) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
Methods of Assessment (Factor m) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
Factors Associated with Patient/Participant Variables (Factors Pi and Pj and Their
Interactions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
Considerations on General Placebo Response Rates in Psychiatric Drug Studies . . . . . . . . . . . . 764
Mechanisms Operating in Placebo Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Cognitive Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Biological Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
Use of Placebos for Therapy and the Role of Nocebo in Clinical Trials and
Medical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771
Nocebo Effects in Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773

Abstract
Clinical and experimental examples of placebo effects are presented. Placebo
effects including spontaneous remission are also part of response to active
treatment. Placebo effects result from complex interactions between accompany-
ing information about positive and negative (¼ nocebo) drug effects, character-
istics of the experimenter or physician, and experimental setting. They can be

P. Netter (*)
Department of Psychology, University of Giessen, Giessen, Germany
e-mail: petra.netter@psychol.uni-giessen.de

© Springer Nature Switzerland AG 2022 755

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_441
756 P. Netter

observed in any kind of psychiatric and somatic diseases or symptoms, as well as

in affective, behavioral, and somatic functions of the individual and may vary
with methods of assessment across time. Affective variables (anxiety/depression)
or pain-related diseases are most and laboratory parameters of body fluids are
least susceptible to placebo/nocebo effects. Personality traits, in particular sug-
gestibility and drug experiences, are most important modifiers of placebo/nocebo
responses. None of the personal attributes, including gender and age, can be
identified as predictors of a general placebo responder. Major underlying mech-
anisms, induction of expectations and conditioning, operate additively on con-
scious processes (perception and motor processes) whilew unconscious responses
(hormone or immunological responses), are merely mediated by conditioning.
Major biological mediators of placebo as well as nocebo responses detected by
neuroimaging techniques, positron emission tomography, and receptor antago-
nists are release of opioids and dopamine in pain and reward-related brain circuits
or inhibition of these transmitters as nocebo responses indicating that relief from
negative and induction of positive effects or vice versa also determine the
magnitude of responses. Aspects of placebo and nocebo effects in clinical
practice and consequences of obtaining informed consent are discussed.

Definition of Placebos and Areas of Use

The original translation of the term placebo means “I will please.” The first time the
word placebo appears in a medical context was in a dictionary of the eighteenth
century where placebo was defined as “an unspecific method which is meant to
please a patient for a while,” but phenomena of healing after some kind of “treat-
ment” which modern placebo researchers would term placebo effects have been
reported across many previous centuries (De Craen et al. 1999; Finniss 2018).
A later more specific definition given by Shapiro (1971) as “a therapeutic device
applied by a physician intentionally or without his information, exerting an effect on
a patient or a symptom, but without an objective effect” according to present
knowledge is not valid either anymore, since:

• Placebos are not only applied by physicians in patients or diseases but refer to any
kind of effects on emotional, performance, or social activity also in healthy
persons.
• Placebo is not only related to specific actions but may be effective with respect to
more global well-being as assessed after recreational or physiotherapy.
• Placebo does show objective biological effects in the autonomic as well as in the
central nervous system.

Interest in phenomena and mode of action of placebos has governed experimental

psychology as well as medical and therapeutic research for more than 150 years.
Placebo research received special attention since neuroscience and progress in
scientific studies on mind-body relationships have provided ways of searching for
Neuropsychopharmacotherapy: Aspects of Placebo Effects 757

biological mechanisms of placebo effects. This is documented in large handbook

contributions and review publications on the placebo effect (Benedetti 2020; Colloca
2018; Finniss et al. 2010; Schedlowski et al. 2015).
During the last decade, publications also increased on nocebo effects (Häuser
et al. 2012): negative treatment outcome induced by the physician or the patient’s
own negative expectations based on previous information or experiences.
Use of placebos is encountered

• in therapeutic contexts.
• as control conditions in clinical trials.
• as a device for elucidating underlying factors of placebo effects in research.

In the present chapter, the first two aspects will only be briefly touched, since they
may be partly covered by the chapters ▶ “Randomized Controlled Trials and the
Efficacy of Psychotropic Medications” and “Significance of and Attitude to Psy-
chopharmacological Agents.” Instead, the focus will be on the third aspect from a
more experimental approach. Since the factors of influence and mechanisms of
placebo and nocebo are principally the same, only examples for placebo will be
addressed. However, after briefly discussing aspects of placebo effects also in
clinical practice, a respective section on the role of nocebo effects in therapy will
be added.
Although placebo effects are also operating on non-pharmacological types of
therapy, this contribution will primarily illustrate aspects of placebos used in drug
studies.
The responses to a placebo do not only imitate the size of the active drug effect
(e.g., on reduction of pain) but also the inverted u-shape course of its effects
in observation periods across time after application (rise to a maximum and
consecutive decline), accumulation effects after consecutive drug applications, or
number of applications required according to severity of symptoms (Lasagna et al.
1958).
It has to be considered that a placebo response is also part of active drug responses
as nowadays emphasized in reviews on placebo (e.g., Colloca 2018; Evers et al.
2018). This is depicted in Fig. 1.
In both conditions, baseline levels of the outcome variable as well as elapse of
time (¼ “natural history,” spontaneous remission) largely contribute to therapeutic
effects. A meta-analysis on 37 controlled clinical trials on patients suffering from
different diseases of minor severity (phobia, insomnia, nausea, acute and chronic
pain) compared a placebo, a no treatment, and a treatment group represented in each
of the 37 trials with respect to standardized symptom reduction (Krogsbøll et al.
2009). The overall result across different psychological, physical, and pharmacolog-
ical treatments and across different diseases revealed that symptom reduction in the
no treatment group (representing the part ET of Fig. 1) was about half the size of the
placebo effect (part P of the figure) and that the relative contributions of spontaneous
improvement and of the placebo effect to that of the active interventions were 24%
and 20%, respectively.
758 P. Netter

Fig. 1 Composition of drug effects in active compounds and placebos. (Modified from
Klebelsberg (1974)

Part ET also comprises statistical bias like regression to the mean (the tendency of
a repeated measurement to be shifted to the population mean). Placebo effects (part
P), i.e., subjective factors involved in judgment (see later), are also adding to the true
pharmacodynamic effects of the active drug to a considerable degree. This aspect is
often neglected in controlled clinical trials as well as in clinical practice. A way to
subtract the placebo effect from the outcome of an active drug is, for instance,
achieved by hidden application (infusion) of the drug. The reported relief from pain
after open administration of an analgesic was considerably reduced when the drug
was infused (Amanzio et al. 2001). In order to judge the pure net effect of a placebo,
a control condition has to be run which only consists of a baseline and a repeated
measurement obtained at the same time point as assessment of the placebo effect.
Placebo and active treatment responses measured within the same individuals are
often correlated because the placebo parts as well as the baseline levels of a variable
in the treatment and the placebo group are correlated.

Factors Involved in Drug and Placebo Responses

A schematic representation of factors involved in drug and placebo responses is

depicted in Fig. 2 which follows a stimulus-response concept in experimental research.
These factors are equally relevant in experimental and clinical placebo research.
Neuropsychopharmacotherapy: Aspects of Placebo Effects 759

Fig. 2 Schematic representation of factors involved in drug and placebo responses (legend see
text)

Application of the medication of placebo (Mp) or active drug (Mx, My) is

accompanied by conditions (c) of, e.g., attributes of the drug (form, color, dose,
number, and mode of applications, information about action of drug, or possible
side effects) as well as situational environmental factors (S), e.g., general practice/
hospital/laboratory and attributes of experimenter or physician (rational/emo-
tional). An essential source of drug effects are variables of the patient or individual
characterized by a vast number of individual differences (Pi. . .Pj). Beyond age and
gender, primarily disease history and types of symptoms as well as attitudes and
expectations toward the drugs, and personality factors (like optimism, anxiety,
suggestibility) are modifiers of therapeutic or experimental outcome. Finally, there
are different outcome variables (responses (R)) of different types (symptom reduc-
tion, side effects, as well as changes in mood, performance, and somatic variables)
which again can be assessed by different methods (m) like self- or observer reports,
experimental tests, or laboratory analyses, often assessed across several points of
time (t1-tx).
These factors do not act additively but show first-, second-, or third-order
interactions in the statistical sense. Examples illustrating the isolated or interacting
influences of these factors will be given below.
760 P. Netter

Influences of Attributes of Medication, Accompanying

Information, and “Ambiente” (Factors c and S)

Factor “c” Effects

In the beginning of placebo research, it has been reported that color, shape, and
taste as well as mode of application of a placebo are relevant for the outcome, for
example, blue pills seemed to induce more sedative, red ones rather stimulating
effects, green ones were effective against states of anxiety, yellow ones against
depression, fluids were better in case of sleeplessness than solid pills, and the
number of pills showed a dose response curve (Buckalew and Ross 1981).
More important is the large number of publications concerned with effects of the
accompanying information provided along with drug application in clinical set-
tings as well as in drug experiments (Benedetti et al. 2003; Kaptchuk and Miller
2015); this concerns:

• Declaring a medication as active compound versus placebo

• Listing drug qualities (like sedative versus stimulating)
• Listing possible side effects of the active drug

In clinical settings, the placebo declared as the active drug (D) and the active drug
declared as the placebo (P) had similar effects on pain and attacks of migraine in the
conditions D and P, whereas the condition, in which the active drug was combined
with the information that it was a powerful analgesic, elicited significantly higher
success rates in pain reduction than the application without any concomitant infor-
mation or compared with conditions D and P (Colloca et al. 2004).
Similarly, in an experiment testing expected stimulating effects of caffeine on
performance in healthy participants, the placebo announced as caffeine elicited even
higher increases in mental performance than the reverse condition of an active
compound declared as a placebo (Lienert 1956).
Experiments declaring a placebo either as a tranquilizer or as a stimulant indicated
that a stimulating effect was experienced in 78% of 68 heathy participants and
tranquilizing effects in 38% (Janke 1967, unpublished). Comparisons of effects on
arousing versus relaxing emotional states revealed that changes after the “sedative”
were more pronounced than after the “stimulant” and that increases of certain states
like calm, relaxed for the “sedative” and alert, talkative for the “stimulant” were
more readily reported than decreases of states like feeling less anxious and tense
with the “stimulant” and less tired or drowsy for the “sedative” (Netter 1977).
Finally, information about possible side effects, explained to patients or participants
(nocebo effects), have been reported mostly in the predicted direction of the active
drug, mostly less frequently or as less intensive. Occasionally, when side effects are
assessed as open questions, e.g., in a study on effects of indomethacin on relief from
pain in rheumatoid arthritis, side effects of vomiting, diarrhea, and edemas were even
reported at a higher rate in the placebo than in the indomethacin group (Schindel
1967).
Neuropsychopharmacotherapy: Aspects of Placebo Effects 761

Factor “S” Effects

Placebo responses related to experimental or clinical setting (in or outpatient settings

group or isolated testing etc.) or behavior of the experimenter or clinician have been
studied in particular in early placebo research. A general conclusion is that the
placebo part of any drug effect is larger in everyday practice than in controlled
clinical trials (and may of course interact with the information about the placebo
drug (c) as well as with other factors of the environment (S)). The influence of the
personality or behavior of the physician on the course of a disease received the
special term “iatroplacebogenesis,” which could also be shown experimentally:
Physicians instructed to administer the placebo enthusiastically as a new antianxiety
drug induced larger symptom reduction rates than the physicians instructed to apply
the drug in a rational experimental way. This difference obtained in one hospital,
however, was reversed in a different hospital (interaction c  S) (Uhlenhuth et al.
1966).

Target Variables of Placebo Responses and Their Methods

of Assessment (Factors R and m)

Functions and Symptoms Responding to Placebo (Factor R)

With regard to target areas of response (factor R), emotional states like anxiety,
relaxation, or arousal as well as perception of pain are more susceptible to placebo
effects than physiological responses of the autonomic nervous system like heart rate,
blood pressure, or sweating and than psychomotor behavior and mental perfor-
mance. There are also reports of changes of the central nervous system (EEG
activity) indicating onset of slow wave sleep upon administration of placebo
sleeping pills. But these somatic changes, invisible to the individual, and consider-
ably less pronounced, are often accompanied by improvement of subjective well-
being. In all cases of somatic changes, the accompanying information is essential
and may exert very specific effects, as demonstrated by an experiment in which an
“antihypertensive” placebo distinctly lowered systolic blood pressure, but neither
diastolic blood pressure nor heart rate, heart rate variability, skin conductance, or
EEG activity were affected (Meissner and Ziep 2011).
In the clinical setting, symptoms of almost all diseases have been shown to
respond to placebos (Schedlowski et al. 2015). When ranking diseases according
to susceptibility to placebo effects, any disease related to pain perception like
headaches, migraine, rheumatism, gastrointestinal pain, dysmenorrhea, general
pains of limbs and back during flu, and fibromyalgia are ranging highest, followed
by psychiatric diseases (in particular anxiety and depression-related disorders and
addiction) which again are more “placebo-prone” than neurological diseases, like
motor disturbances as in Parkinson’s disease. These again are influenced to a greater
extent than allergies or infections and parameters of the endocrine, immunological,
or metabolic system. Yet, several studies demonstrate that not only responses of
762 P. Netter

heart rate or bowel activity, but also immune cell responses may be modified by
previous treatment or physician-induced expectations (Hadamitzky et al. 2018;
Schedlowski et al. 2015).

Methods of Assessment (Factor m)

As shown in a meta-analyses of placebo-controlled trials on antidepressants, method

of assessment makes a difference: the placebo effect obtained by observer ratings
was much higher than those obtained by self-ratings, and this also varies across years
of publication (Rief et al. 2009). A well-known experience of clinicians is the
discrepancy between patient self-reports and laboratory-based indicators of improve-
ment which also applies to placebo responses.
This also becomes evident in placebo effects on measures of pain: self-report pain
ratings usually show larger placebo effects than measurements of pain obtained by
objective methods, like by the signal detection method (SDT). This method also
allows within – assessment comparison between two parameters: sensitivity to
thermal pain measured by discrimination between two pain stimuli (d´ ¼ pain
threshold) did not show placebo responses, while the measure log ß indicating the
tendency to rate high stimulus intensities as lower was increased by “analgesic”
placebos (Rollman 1977). These effects become even more pronounced in interac-
tions with personal characteristics of the individual (see below).

Factors Associated with Patient/Participant Variables (Factors Pi

and Pj and Their Interactions)

There is a long tradition in placebo research attempting to identify attributes of a

healthy person or a patient which predict susceptibility to placebo effects. Since the
beginning of psycho-pharmacological research in the twentieth century, demo-
graphic variables, lifestyle, habits, drug history, and personality traits and states
were tested for their predictive power for placebo responsiveness (Jakšić et al. 2013).
It turned out that several traits, like extraversion, emotional stability, or optimism,
did yield differences in predicting placebo responses but only in interaction with
factors type c and/or S or in interaction between variables of type P, like age and
gender. For instance, optimists and extraverts were rather susceptible to positive
outcome information given with the drug and pessimists and neurotic persons rather
to negative ones like information about side effects. For instance, in a study in which
an inactive substance either declared as a substance that will make participants feel
unpleasant or declared as an inert substance, pessimists had a higher rate of reporting
unpleasant effects than optimists (Geers et al. 2005) (interactions between factors
Pi  c), and the predominance of responses to positive effects in optimists was only
obtained in a warm and empathetic therapeutic environment (factors Pi  S) (Kelley
et al. 2009). While in the beginning of placebo research interactions between gender
and age were, for instance, reported as predicting antidepressant placebo effects
Neuropsychopharmacotherapy: Aspects of Placebo Effects 763

(older men and younger women reporting better results (Interaction Pi  Pj) (Raskin
1974)), it could be concluded in a large meta-analysis of more than 500 placebo-
controlled clinical trials derived from 31 meta-analyses on placebo effects in psy-
chiatric disorders that age and gender could not be identified to be good general
predictors of placebo responsiveness, in spite of being relevant in drug- or disease-
specific studies (Weimer et al. 2015). Also drug taking history and attitudes toward
drugs were identified as predictors only in some clinical or experimental studies,
depending on the type of drug or disease. A certain universal finding correlated to
placebo responsiveness was low severity of symptoms at baseline (component B in
Fig. 1). This did not only refer to neuropsychiatric disorders but also to gastrointes-
tinal, cardiovascular, and allergic diseases (Weimer et al. 2015).
The modifying influences of individual differences (Pi, Pj) also depend on the
type of target symptoms or functions (Rk, Rl) and mode of assessment (m) which
again are differently affected by factors c and S as shown by an experiment which
tested the influences of different personality factors on the effects of a “stimulant
placebo” with respect to subjective and objective indicators of placebo-induced
changes in activation (Janke 1967, unpublished). The personality factor of neurot-
icism was positively correlated with an increase of activation rated on a checklist of
emotional states but negatively with speed of performance achieved in a psychomo-
tor test, while in extraverts this relationship was reversed.
Similar individual differences appeared when comparing respective patterns
following the information about a “sedative placebo” (c  P  R  m).
This means the expectation induced by the accompanying information affected
feelings and psychomotor performance differently depending on basic temperament
traits. Statistically speaking this means that with a given information provided along
with the placebo (type c variable), an interaction was observed between the person-
ality factors (Pi and Pj) and the dependent variable (Rk, Rl) and its mode of
assessment (mk ml).
Induction of expectations, which is a major factor in placebo effects, as demon-
strated above, is also a leading component in the trait of suggestibility (De Pascalis
et al. 2002; Netter 1989; Nitzan et al. 2015). It can be measured by a behavioral
device based on detection of nonverbal faked sensory stimuli (Gheorghiu et al. 1975;
Gheorghiu 1989) and has been shown to largely influence pain perception, for
instance, in patients suffering from headaches treated with metamizole or placebo,
respectively (Fig. 3).
It may be concluded that, as indicated also in several similar experiments, the
predictive power of the personality variable for placebo responsiveness (in this case
sensory suggestibility) depends on its similarity or closeness to the target variable
(sensory experience of pain reduction).
Defining “placebo responders” by special characteristics of the individual has
been tried for several decades in order to exclude placebo responders from controlled
clinical trials for increasing “true” drug effects. However, defining a placebo
responder as a general trait requires (a) consistence across time, that is, reproduc-
ibility of results upon consecutive trials (t1. . .tn) and (b) generalizability across
different drugs, drug informations, symptoms, or diseases assessed by different
764 P. Netter

15 Influence of personality
factor suggestibility

Ratings on scale of headaches

13

11

3
= low suggestible patients
= highly suggestible patients
1

Week post drug 0 1 2 3 4 5

Fig. 3 Decrease of headache ratings depending on sensory suggestibility in 30 headache out-

patients. Blue circle = low suggestible; red circle = highly suggestible patients. (Data from Classen
et al. 1983)

tools of measurement. That means: (a) will the placebo effect be detectable across
repeated trials? and (b) will a person responding, for instance, positively to reduction
of dental pain by an “analgesic” placebo also respond positively to a “sleeping pill”
placebo? Will this work in case he or she is participating in a controlled clinical trial
or being treated by a clinical practitioner? Will this depend on whether or not the
accompanying information was about positive effects or side effects?
It is obvious that this degree of generalizability cannot be achieved, so the
concept of a general placebo responder was already abandoned in the 1980s
(Brown 1988) and is still critically discussed (Kaptchuk et al. 2008). Not even
stability across time with the same drug, the same information, experimenter, and
clinical setting can be completely achieved in consecutive trials as shown by an old
experiment on frequent migraine attacks (Jellinek 1946). The reason is that in
particular in drug studies habituation occurs due to downregulation of receptors,
learning and adjusting expectations according to preceding experience. This is also
confirmed by declining placebo response rates during longitudinal observations
(Posternak and Zimmerman 2007).

Considerations on General Placebo Response Rates in Psychiatric

Drug Studies

A separate consideration on placebo response rates may be required in this context of

psychopharmacotherapy. Placebo response rates in clinical trials, particularly in
studies on psychiatric diseases, have been a matter of debate, because in some
meta-analyses of controlled clinical trials, it was concluded that there are no reliable
Neuropsychopharmacotherapy: Aspects of Placebo Effects 765

differences between response rates of antidepressants and placebos and that severity
of symptoms at baseline may be a source of bias artificially increasing active drug
response rates (Kirsch et al. 2008). However, authors of later meta-analyses and
consensus papers (Baghai et al. 2012; Möller et al. 2012; Melander et al. 2008) ruled
out the bias of differences in baseline severity of depression and criticized that
average differences in means of response rates between placebo and active treatment
are not the correct parameter for treatment success. Rather, a number of patients with
a critical reduction of symptom severity (usually defined by 2 or 3 points on accepted
depression rating scales) and numbers of patients needed to treat (NNT, Cook and
Sackett 1995) were considered as more relevant parameters (this is the inverted value
of the difference between percentages of patients showing responses in the active
treatment versus in the placebo group, i.e., the higher the value, the more patients are
needed to be treated in order to obtain one true response to the active drug). The
average placebo response rates vary with length of observation period, types of
antidepressants included, and homogeneity of samples, but summaries for differ-
ences between placebo and active drug response rates obtained in several meta-
analyses of controlled clinical trials have been reported to be between 13.5% and
19.5% (Baghai et al. 2012), and the average NNT values across different antide-
pressants range between 5 and 7 for acute treatment of depression and 4 for
maintenance treatment (Möller et al. 2012).
Since it was claimed that placebo response rates had been rising since the 1970s, a
critical meta-analysis by Furukawa et al. (2016) investigated the influence of pub-
lication year on placebo response rates in 252 placebo-controlled clinical trials on
more than 26,000 patients. Studies include first and second generation of antide-
pressants applied for acute treatment of major depression between 1978 and 2015.
Responses were defined by log transformed placebo responses based on 50% or
more reduction of depression severity assessed by valid depression scales. It became
evident that after 1991 the average placebo response rates have remained constant
between 35% and 40%.
However, these gross figures require detailed inspection of placebo response rates
separately analyzed according to their interactions with factors discussed above.

Mechanisms Operating in Placebo Responses

Major mechanisms operating in placebo response are expectation and learning as

predominant sources, but in addition, attribution, imagination, and desire for relief
and in particular respective biological mechanisms related to the opioid and dopa-
minergic system can be regarded as mediating mechanisms of placebo responses.

Cognitive Functions

Expectancy
It has long been known that expectation of success is correlated with drug-induced
increase of performance as well as with subjectively experienced improvement, as
766 P. Netter

shown by an old experiment testing effect of a nootropic drug on short-term memory

(Nash and Zimring 1969). Correlational analyses demonstrated that the positive
expectation mediated a positive correlation between the subjective and objective
drug effect on memory, while the two measures were uncorrelated in the non-drug
condition.
Also in experiments on ratings of experimental (thermal) pain with an “analgesic”
placebo, the degree of expectation of pain reduction was linearly correlated with the
degree of experienced reduction of pain (Price et al. 1999).

Learning
The second approach is based on learning theory. However, learning from previous
experience is supposed to be mediated by expectations (Price et al. 1999). A
previously taken active drug serves as the unconditioned stimulus; attributes of the
drug, accompanying information, and surrounding environment or behavior of the
physician as described above (factors c and S) serve as conditioned stimuli which
transfer the unconditioned response to the active drug (relief from symptoms) into
the corresponding conditioned response, when receiving the placebo.
This process of classical conditioning is supported by an experiment on pain
perception by Voudouris et al. (1985) in which pain intensity levels were experi-
mentally manipulated: in the first session, participants received two trials, one with
and one without an analgesic placebo with identical objective stimulus intensities of
5. In the second session, the stimulus intensity without the placebo was increased to
8 in one group and decreased to 2 in the second group, while in both groups the
stimulus intensity with the placebo was kept constant at 5. So the first group
experienced a positive placebo effect and the second group an increase of pain
(inefficiency of placebo or even a nocebo effect). After this conditioning procedure,
a third session, identical to the first, was applied to both groups, showing that group
one experienced a significant pain reduction with placebo compared to no drug,
while the second group judged pain intensity after the placebo as even stronger than
in the first trial (see Fig. 4).
There was a long fight between placebo researchers whether expectation or
learning is the dominating process. A possibility for decision was achieved by
adding experimental sessions in which (a) the deception in session 2 (experimental
manipulation of the pain stimulus) was disclosed to participants or not and
(b) extinction of the conditioned placebo responses was tested (Montgomery and
Kirsch 1997).
Conditioning theory was supported if (a) disclosure information had no effect and
(b) extinction of the conditioned placebo response upon repeated trials was possible,
while expectation theory was supported if disclosing the stimulus manipulation
(cognitive information processing) reduced the placebo response and (b) extinction
of the placebo response upon repeated trials was not possible (since the uncondi-
tioned stimulus keeps reinforcing expectations).
Classical conditioning of placebo effects also takes place in experiments not
related to pain but, for instance, in experimental induction of anxiety: in an exper-
iment in which aversiveness ratings of threatening pictures (from the standardized
Neuropsychopharmacotherapy: Aspects of Placebo Effects 767

Experiment supporting theory of conditioning

of placebo effects

3,0 Conditioning
difference between pain ratings in
the condition with minus without

2nd session:
2,5 stimulus
intensity =5
2,0 with and
intensity = 8
the placebo

without the
1,5 placebo
= positive
1,0 placebo effect
2nd session:
0,5 stimulus
intensity =5
with and
0,0
intensity = 3
1st session: stimulus 3rd session: ( after without the
placebo
intensity with and without conditioning) stimulus = negative
the placebo analgesic intensity with and withourt placebo effect
identical ( = 5) the placebo analgesic
identical (= 5)

Fig. 4 Experiment supporting classical conditioning theory of an “analgesic” placebo effect by

experimental manipulation of pain intensity. (After data from Voudouris et al. 1985)

International Affective Picture Series (IAPS)) were reduced by the benzodiazepine

midazolam serving as the unconditioned stimulus (UCS) for the conditioned
response to the “anxiolytic” placebo (Petrovic et al. 2005).
A step further in this debate was a series of sophisticated experiments performed
by Benedetti et al. (2003).
In experiment I tolerance to experimental pain induced by the tourniquet tech-
nique (pain resulting from blowing up a blood pressure cuff) was assessed, and
conditioning of an “analgesic” placebo effect (increased time of pain tolerance) was
achieved by using a nonsteroidal analgesic as the UCS. Expectations of hyper- or
hypo-analgesia by verbal instructions could also be shown to increase and decrease
pain tolerance, respectively. When the positive expectation (hypo-analgesia) was
induced after the conditioning, i.e., in addition to analgesic conditioning, the placebo
response was even increased above the level of the verbal suggestion alone. This
shows that conditioning and expectation processes work additively.
In experiment II improvement of motor velocity and performance in Parkinson
patients treated with deep brain stimulation electrodes inserted in their subthalamic
nuclei of the brain could be shown to follow the law of conditioning (achieved by
switching the stimulator off and on). Moreover, also the law of induction of
expectations by verbal suggestions could be demonstrated to improve motor perfor-
mance, that is, consciously controlled observable behaviors like perception of pain
(experiment I) and motor speed of hands (experiment II) are susceptible to effects of
conditioning and expectation and their combination.
768 P. Netter

Fig. 5 Model depicting

differential effects of Conditioning expectation conscious processes
conditioning and expectation (pain perception,motor processes)
on placebo responses no effect
according to Benedetti.
(Modified from Benedetti
et al. 2003)
Conditioning unconscious processes
(hormone seretion)

In experiment III, however, an experiment in which changes of hormones (cor-

tisol decrease and growth hormone increase induced by the serotonin 1d agonist
sumatriptan) were successfully placebo conditioned, the verbal suggestions of
increase or decrease of hormone release were ineffective.
Benedetti concluded that in these unconscious processes like changes of hor-
mones, conditioning of placebo effects is possible but that cognitive information
processing like verbal suggestions is ineffective, whereas in conscious processes
expectation may work directly or add on to a conditioning process (Fig. 5).

Additional Cognitive Mechanisms

Theories of attribution explain that patients attribute incidental changes or sponta-
neous remission to the medication or therapy they received. This would be covered
by the proportion of placebo response included in the total effect of an active drug or
therapy (parts ET + P in Fig. 1), even if the preceding drug or manipulation had no
active therapeutic component relevant to the symptom in question at all. This
attribution could also be defined as a process of expectancy.
Imagination has been claimed to be a separate mechanism for explaining placebo
effects similar to processes operating in cognitive techniques like concentration
exercises or autogenic training and relaxation techniques which induce true physi-
ological changes. This can be similarly achieved by the imagination of a pill actively
changing a state or symptom. This process is based on operant conditioning, in
which reward of symptom relief serves as reinforcement. However, unlike in placebo
effects, in this case the individual is aware that the stimulus does not exist, and
therefore this cannot be regarded as a true placebo mechanism.

Biological Mechanisms

Several reviews and meta-analyses on the biological mechanisms underlying pla-

cebo responses have been published in recent years (Benedetti and Amanzio 2013;
Colagiuri et al. 2015; Dodd et al. 2017; Zubieta and Stohler 2009). Pharmacological,
functional magnetic resonance imaging (fMRI) and positron emission tomography
(PET) studies contributed to knowledge about brain areas and neurochemical sys-
tems involved in placebo responses.
Neuropsychopharmacotherapy: Aspects of Placebo Effects 769

The Opioid System

It has been known for a long time that opioid receptors are involved in particular in
placebo responses to pain. This was first demonstrated by the observation that the
opioid receptor antagonist naloxone reversed placebo effects on pain reduction based
on previous experience with opioid analgetics (Levine et al. 1978). The selective μ
receptor antagonist naloxone acts on expectancy induced placebo analgesia in the
same way (though less pronounced) as when pain relief obtained by an active opioid
agonist is inhibited. Antagonism of placebo analgesia by naloxone can even partly
be achieved after conditioning to a non-opioid receptor-related analgetic drug like
the non-steroidal analgetic ketorolac. However, this only worked if expectation of
pain reduction was induced along with the ketorolac placebo, but not if the placebo
was explained to be a non-pain-related drug, for instance, an antibiotic (Amanzio
and Benedetti 1999). This shows that opioid receptor activation depends on expec-
tation of pain and that the placebo induced release of opioids is independent of the
type of the pharmacological action of the placebo associated drug, as long as the idea
of pain reduction is associated with the placebo.
Effects similar to naloxone can be observed with the peptide cholecystokinin,
which also acts as an opioid receptor antagonist and has been supposed to be
suppressing placebo-related opioid release when being excessively produced in the
brain. This has been supposed to possibly cause placebo non-response. It has also
been assumed to be released upon negative (nocebo) expectations (Benedetti et al.
2011b).
Also the endogenous cannabinoid system is involved in placebo responses. This
has been shown by applying a cannabinoid receptor CB1 antagonist rimonabant after
conditioning with the non-opioid analgetic ketorolac (see above), by which reversal
of the placebo effect had been shown to be only partially possible or completely
ineffective with naloxone, but in which placebo-induced analgesia was clearly
abolished by the CB1 antagonist (Benedetti et al. 2011a).
Furthermore, other peptides like vasopressin can increase pain-related placebo
effects (Colloca et al. 2016).
However, it can be shown that also non-pain-related placebo responses can be
pharmacologically antagonized, as shown in the experiment by Petrovic et al.
(2005), reported above with antianxiety placebo effects induced by midazolam
conditioning. The positive placebo effect of reduced aversiveness ratings of
the threatening IAPS pictures could be reversed by the GABA- antagonist
flumazenil.
Studies conducting fMRI measurement confirmed that certain brain regions like
the rostral anterior cortex of the cingulum (r ACC), the ventrolateral prefrontal
cortex (VLPFC), and the lateral orbitofrontal cortex (OFC), regions in which pain
perception, pain expectancy, and even pain sympathy have been found to be
represented, showed reduced activity during placebo-induced pain reduction
(Wager et al. 2004; Petrovic et al. 2005). Similarly, during nocebo-related hyper-
algesia, these regions showed increased activity (Colagiuri et al. 2015). FMRI
studies were validated by studies measuring release of endogenous opioids in
these specific regions by positron emission tomography (PET) during placebo
770 P. Netter

analgesia. It could be confirmed that the degree of mu receptor activation by opioid

release was proportional to the reduction of pain ratings.
These effects are not confined to studies on pain: in a study on patients suffering
from major depressive disorder (MDD) assessed in their medication-free period by a
placebo declared as a fast-acting powerful antidepressant or an inactive substance,
respectively, PET measurement using a mu receptor radiotracer revealed that opioid
release in the ACC, nucleus accumbens (NAC), thalamus, and hypothalamus was
clearly more pronounced during treatment with the “active” than with the “inactive”
placebo (Peciña et al. 2015).
Since these areas including the insula are also activated during aversive emotions,
which are also partly mediated by changes in opioid activity, it has been discussed if
also placebo-induced reduction of pain could be interpreted as reduction of anxiety
and negative affect. Therefore, induction of positive emotions and reduction of
anxiety and of negative emotions have been discussed as mediators of placebo
responses. In particular, opioid activity in the nucleus accumbens which is part of
the reward circuit has been shown to predict placebo responsiveness. The observa-
tion that placebo response intensity could be shown to be correlated with opioid
release may be seen as an objective indictor for discriminating placebo responders
from non-responders (see above), although perhaps restricted to specific conditions
and pain-related responses (type c, S, and R variables).

The Dopaminergic System

The involvement of the NAC in pain-related placebo response has led to the
assumption that also the dopaminergic system is involved in placebo responses
because of its role in reward and appetitive behavior (Berridge and Robinson
1998). Experiments in Parkinson patients demonstrated that significant dopamine
(DA) release in the ventral striatum (measured by PET) occurred, when patients were
informed that the probability of receiving active anti-Parkinson medication was high
(De la Fuente-Fernandez et al. 2006). It was suggested that this placebo-induced DA
activation of the reward circuity triggers the activation of the opioid system
(Lidstone et al. 2010). The involvement of the reward system in placebo responses
in Parkinson patients suggested that release of dopamine is also relevant in placebo
responses in other diseases. A PET study using a D2/D3 receptor radiotracer for
measuring dopamine activity found considerable dopamine transmission in the NAC
during placebo-induced expectation of relief from a continuous experimental pain
(Zubieta and Stohler 2009). The size of dopamine activation was positively corre-
lated with the size of expectation of analgesia and the size of subjectively rated
reduction of pain (change in pain intensity ratings over the 20 min study period).
Similar to the results with opioid activity reported above, also DA activation in the
NAC was positively correlated with the increase in ratings on positive affect during
placebo treatment. Since DA and opioid release were assessed in the same volun-
teers, it could also be shown that DA activity in the NAC correlated positively with
the magnitude of endogenous opioid release in the NAC, ventral putamen, amyg-
dala, and rACC. Similarly to the opioid system, NAC DA release was also larger in
placebo high than low responders, and, furthermore, deactivation of placebo-related
Neuropsychopharmacotherapy: Aspects of Placebo Effects 771

DA neurotransmission in the NAC was observed in nocebo responders indicating an

opposite effect to the positive association with the placebo effect.
However, blockade of dopamine receptors by haloperidol or application of the
dopamine precursor L-DOPA were ineffective in changing the analgetic placebo
response in patients suffering from neural pain after chest surgery (Skyt et al. 2018).
Also in healthy persons placebo responses to experimental heat pain were not
modulated by L-DOPA. This indicates that dopamine is not a prerequisite for
placebo-induced analgesia but rather supports the idea that dopamine release accom-
panies or even activates the release of opioids, in particular, when reward of pain
relief or any other desirable goal is implied. In fact it was supposed that any positive
affective states associated with placebo responses may be responsible for release of
dopamine (Zubieta and Stohler 2009).

Use of Placebos for Therapy and the Role of Nocebo in Clinical

Trials and Medical Practice

Placebo-controlled clinical trials have been accused to violate ethical aspects

because of (a) withholding an active therapy by application of placebos and
(b) deception of patients. Both arguments have been tried to be met by asking
informed consent, that is, explaining to patients that they might be receiving an
inactive substance or therapy. Withholding active treatment has been debated
because, according to § 233ff of the criminal code, it is conceived as “deliberate
somatic injury.” This would be particularly relevant in clinical trials testing drugs for
life-threatening diseases like cancer or myocardial infarction. Instead, when testing
drugs for psychiatric diseases, there are alternative drugs and non-drug therapies.
Obtaining informed consent is also problematic, since the selection of participants
for placebo-controlled clinical trials by this procedure distorts proportions of vari-
ables relevant for generalizability of results. In a small study on 200 patients,
suffering from chronic back pain or arthralgia, conducted partly in an outpatient
pain clinic, partly in an orthopedic clinic, they were asked if and why they would be
willing or unwilling to participate in a placebo-controlled trial testing a new anal-
gesic drug (Netter et al. 1986). Several additional questionnaires on personality traits
and habits applied in the study revealed that those responding they would give
consent as compared to those who would refuse were older, coming more often from
rural areas than from big cities, had a positive attitude toward drugs and positive
expectations about their present therapy; they did not believe in healthy food, were
less hostile, and had higher scores on experience and adventure seeking, whereas the
non-consenting ones had generally higher negative attitudes toward drugs and drug
studies, were more hostile, and, interestingly, had frequently applied for early
retirement. This shows that refusing participation may not be based on fear of an
inefficient therapy (placebo) but rather on a negative attitude against active drugs.
Asking consent (¼ excluding the refusing percentage of participants) may produce
more favorable results than to be expected in the total population of the disease
group.
772 P. Netter

In clinical practice ethical considerations on deceit and withholding therapy have

been less frequently discussed, because here placebo application is considered to
occur for the benefit of the patient. Although reliable figures on frequencies of
deliberate application of placebos for therapy by physicians are hard to obtain, in a
survey based on 22 publications from 11 countries, the use of placebos for therapy
was admitted between 17% and 80% of physicians and 50–100% of nurses (Fässler
et al. 2010). In one of the psychiatric hospitals, in which 6% of the female and 4% of
the male patients had received placebos for therapy, the major reasons given were
“preventing drug addiction,” “supposing nonorganic symptoms,” or “continuous
complaints of patients in spite of treatment.” Additional reasons given by 102 senior
nurses in another study were “avoiding detrimental side effects” or “last choice after
failure of everything else.” Furthermore, in another survey one third of the physi-
cians and two thirds of the nursing staff believed that treatment success by placebos
indicates that the complaints were simulated symptoms, and therefore one of the
reasons for administering placebos given was also “for diagnostic purposes.” Yet
these attitudes have changed since the second half of the twenty-first century after
knowledge about biological mechanisms of placebo effects has become more wide-
spread. Therapeutic use of placebos has become better accepted by physicians as
well as by patients, in particular, when doctors apply placebos as open label
(prescribing it with assent of the patient), frequently accompanied by explanations
about the somatic mechanisms and benefits operating in placebo responses similarly
as in active drugs (Evers et al. 2018). Therefore, a major effort of expert committees
is to elaborate recommendation to rather refrain from deceptive strategies in use of
placebos and to maximize placebo effects also in administration of active drugs by
accompanying remarks suitable to induce positive expectations in patients (Evers
et al. 2018).
This, however, is often not easily compatible with the obligation of physicians to
inform about side effects, in particular for obtaining informed consent in clinical
trials.

Nocebo Effects in Therapy

Not only investigators of clinical trials but also doctors in primary care or medical
specialists have to outline possible side effects of drugs and non-pharmacological
therapies to patients which can cause nocebo effects by inducing negative expecta-
tions in patients. The package inserts of pharmaceuticals even list frequency prob-
abilities of each type of side effect. This often leads to discontinuation of drug use in
patients and to denial of participation or dropout in drug studies. Nocebo effects not
only occur by intentionally provided information about therapeutic devices (see
“Examples of Factors “c” with Placebo Effects”) but also by the way a doctor
phrases accompanying comments before or during therapy, for instance, by giving
too much reassurance, by emphasizing the low rate of detrimental effects of the
therapy, by advising strictly to adhere to the therapeutic regimen, by asking if
patients feel nausea or headaches after therapy, or by using technical terms for
Neuropsychopharmacotherapy: Aspects of Placebo Effects 773

explanations which are incomprehensible for patients. A list of common nocebo

phrases which may unintentionally cause fear and cast doubt about effectiveness of
therapy is given by Häuser et al. (2012). Advisory boards of medicine nowadays
consider nocebo effects in their recommendations for therapy.
Experiments reporting effects of nocebo information accompanying therapeutic
procedure with the results of hyperalgesia or less pain relief are numerous (see
“Placebo”), and also publications of clinical studies confirming longer periods of
recovery, higher rates of side effects, or lower symptom reduction after unfavorable
verbal information or unintended behavioral nocebo effects of nursing staff are
increasing (Häuser et al. 2012).
Since drug companies are forced by law to publish even rare side effects with the
consequence of even withdrawing respective drugs from the market, nocebo phe-
nomena in the population can be increased. This has been demonstrated during the
pandemic in our days by the high number of persons refusing to be vaccinated by a
certain vaccine of which a certain extremely rare side effect had been published. The
reason for this effect in the population is that even highly educated persons are rarely
able to interpret probability rates of events correctly and to make use of risk
comparisons for their personal decisions (Reyna et al. 2009).

Cross-References

▶ Randomized Controlled Trials and the Efficacy of Psychotropic Medications

References
Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-
activated opioid systems versus conditioning-activated specific subsystems. J Neurosci.
1999;19(1):484–94.
Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: a role for
non-specific activation of endogenous opioids. Pain. 2001;90(3):205–15.
Baghai TC, Blier P, Baldwin DS, Bauer M, Goodwin GM, Fountoulakis KN, . . . Möller
HJ. Executive summary of the report by the WPA section on pharmacopsychiatry on general
and comparative efficacy and effectiveness of antidepressants in the acute treatment of depres-
sive disorders. Eur Arch Psychiatry Clin Neurosci. 2012;262(1):13–22.
Benedetti F. Placebo effects. 3rd ed. Oxford: Oxford University Press; 2020.
Benedetti F, Amanzio M. Mechanisms of the placebo response. Pulm Pharmacol Ther. 2013;26(5):
520–3.
Benedetti F, Maggi G, Lopiano L, Lanotte M, Rainero I, Vighetti S, Pollo A. Open versus hidden
medical treatments: the patient’s knowledge about a therapy affects the therapy outcome. Prev
Treat. 2003;6(1):1–18.
Benedetti F, Amanzio M, Rosato R, Blanchard C. Non-opioid placebo analgesia is mediated by
CB1 cannabinoid receptors. Nat Med. 2011a;17(10):1228–30.
Benedetti F, Amanzio M, Thoen W. Disruption of opioid-induced placebo responses by activation
of cholecystokinin type-2 receptors. Psychopharmacology. 2011b;213(4):791–7.
Berridge KC, Robinson TE. What is the role of dopamine in reward: hedonic impact, reward
learning, or incentive salience? Brain Res Rev. 1998;28(3):309–36.
774 P. Netter

Brown WA. Predictors of placebo response in depression. Psychopharmacol Bull. 1988;24(1):14–7.

Buckalew LW, Ross S. Relationship of perceptual characteristics to efficacy of placebos. Psychol
Rep. 1981;49(3):955–61.
Classen W, Feingold E, Netter P. Influence of sensory suggestibility on treatment outcome in
headache patients. Neuropsychobiology. 1983;10(1):44–7.
Colagiuri B, Schenk LA, Kessler MD, Dorsey SG, Colloca L. The placebo effect: from concepts to
genes. Neuroscience. 2015;307:171–90.
Colloca L. Neurobiology of the placebo effect part II. Washington DC: Academic; 2018.
Colloca L, Lopiano L, Lanotte M, Benedetti F. Overt versus covert treatment for pain, anxiety, and
Parkinson’s disease. Lancet Neurol. 2004;3(11):679–86.
Colloca L, Pine DS, Ernst M, Miller FG, Grillon C. Vasopressin boosts placebo analgesic effects in
women: a randomized trial. Biol Psychiatry. 2016;79(10):794–802.
Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect.
BMJ. 1995;310(6977):452–4.
De Craen AJ, Kaptchuk TJ, Tijssen JG, Kleijnen J. Placebos and placebo effects in medicine:
historical overview. J R Soc Med. 1999;92(10):511–5.
De la Fuente-Fernandez R, Lidstone S, Stoessl AJ. Placebo effect and dopamine release. In:
Parkinson’s disease and related disorders. Vienna: Springer; 2006. p. 415–41.
De Pascalis V, Chiaradia C, Carotenuto E. The contribution of suggestibility and expectation to
placebo analgesia phenomenon in an experimental setting. Pain. 2002;96(3):393–402.
Dodd S, Dean OM, Vian J, Berk M. A review of the theoretical and biological understanding of the
nocebo and placebo phenomena. Clin Ther. 2017;39(3):469–76.
Evers AW, Colloca L, Blease C, Annoni M, Atlas LY, Benedetti F, . . . Kelley JM. Implications of
placebo and nocebo effects for clinical practice: expert consensus. Psychother Psychosom.
2018;87(4):204–10.
Fässler M, Meissner K, Schneider A, Linde K. Frequency and circumstances of placebo use in
clinical practice-a systematic review of empirical studies. BMC Med. 2010;8(1):1–10.
Finniss DG. Placebo effects: historical and modern evaluation. Int Rev Neurobiol. 2018;139:1–27.
Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of
placebo effects. Lancet. 2010;375(9715):686–95.
Furukawa TA, Cipriani A, Atkinson LZ, Leucht S, Ogawa Y, Takeshima N, . . . Salanti G. Placebo
response rates in antidepressant trials: a systematic review of published and unpublished double-
blind randomised controlled studies. Lancet Psychiatry. 2016;3(11):1059–66.
Geers AL, Helfer SG, Kosbab K, Weiland PE, Landry SJ. Reconsidering the role of personality in
placebo effects: dispositional optimism, situational expectations, and the placebo response. J
Psychosom Res. 2005;58(2):121–7.
Gheorghiu VA. The development of research on suggestibility: critical considerations. In: Sugges-
tion and suggestibility. Berlin/Heidelberg: Springer; 1989. p. 3–55.
Gheorghiu VA, Hodapp V, Ludwig CM. Attempt to construct a scale for the measurement of the
effect of suggestion on perception. Educ Psychol Meas. 1975;35(2):341–52.
Hadamitzky M, Sondermann W, Benson S, Schedlowski M. Placebo effects in the immune system.
In: International review of neurobiology, vol. 138. Washinton DC: Academic; 2018. p. 39–59.
Häuser W, Hansen E, Enck P. Nocebo phenomena in medicine: their relevance in everyday clinical
practice. Dtsch Arztebl Int. 2012;109(26):459.
Jakšić N, Aukst-Margetić B, Jakovljević M. Does personality play a relevant role in the placebo
effect? Psychiatr Danub. 2013;25(1):0–23.
Janke W. Experimentelle untersuchungen zur ewirkung von placebo. Habnilitation treatease at the
science faculty of the University of Giessen. 1967;unpublished.
Jellinek EM. Clinical tests on comparative effectiveness of analgesic drugs. Biom Bull. 1946;2(5):
87–91.
Kaptchuk TJ, Miller FG. Placebo effects in medicine. N Engl J Med. 2015;373(1):8.
Kaptchuk TJ, Kelley JM, Deykin A, Wayne PM, Lasagna LC, Epstein IO, . . . Wechsler ME. Do
“placebo responders” exist? Contemp Clin Trials. 2008;29(4):587–59Kap5.
Neuropsychopharmacotherapy: Aspects of Placebo Effects 775

Kelley JM, Lembo AJ, Ablon JS, Villanueva JJ, Conboy LA, Levy R, . . . Kaptchuk TJ. Patient and
practitioner influences on the placebo effect in irritable bowel syndrome. Psychosom Med.
2009;71(7):789. definition 18(4), 318–322.
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and
antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration.
PLoS Med. 2008;5(2):e45. https://doi.org/10.1371/journal.pmed.0050045
Klebelsberg D. On the psychology of the placebo effect. Psychol Beitrage. 1974;16(2):168–87.
Krogsbøll LT, Hróbjartsson A, Gøtzsche PC. Spontaneous improvement in randomised clinical
trials: meta-analysis of three-armed trials comparing no treatment, placebo and active interven-
tion. BMC Med Res Methodol. 2009;9(1):1–10.
Lasagna L, Laties VG, Dohan JL. Further studies on the “pharmacology” of placebo administration.
J Clin Invest. 1958;37(4):533–7.
Levine JD, Gordon NC, Jones RT, Fields HL. The narcotic antagonist naloxone enhances clinical
pain. Nature. 1978;272(5656):826–7.
Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, . . . Stoessl AJ. Effects of expectation
on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry. 2010;67(8):
857–65.
Lienert GA. Die Bedeutung der Suggestion in pharmakopsychologischen Untersuchungen. Z Exp
Angew Psychol. 1956;3:418–38.
Meissner K, Ziep D. Organ-specificity of placebo effects on blood pressure. Auton Neurosci.
2011;164(1–2):62–6.
Melander H, Salmonson T, Abadie E, van Zwieten-Boot B. A regulatory Apologia – a review of
placebo-controlled studies in regulatory submissions of new-generation antidepressants. Eur
Neuropsychopharmacol. 2008;18(9):623–7.
Möller HJ, Bitter I, Bobes J, Fountoulakis K, Höschl C, Kasper S. Position statement of the
European Psychiatric Association (EPA) on the value of antidepressants in the treatment of
unipolar depression. Eur Psychiatry. 2012;27(2):114–28.
Montgomery GH, Kirsch I. Classical conditioning and the placebo effect. Pain. 1997;72(1–2):107–13.
Nash MM, Zimring FM. Prediction of reaction to placebo. J Abnorm Psychol. 1969;74(5):568.
Netter P. The placebo effect (author’s transl). MMW Munch Med Wochenschr. 1977;119(7):203–8.
Netter P. Sensory suggestibility: measurement, individual differences, and relation to placebo
and drug effects. In: Suggestion and suggestibility. Berlin/Heidelberg: Springer; 1989.
p. 123–33.
Netter P, Heck S, Müller H. What selection of patients is achieved by requesting informed consent
in placebo controlled drug trials? Pharmacopsychiatry. 1986;19:336–7.
Nitzan U, Chalamish Y, Krieger I, Erez HB, Braw Y, Lichtenberg P. Suggestibility as a predictor of
response to antidepressants: a preliminary prospective trial. J Affect Disord. 2015;185:8–11.
Peciña M, Bohnert AS, Sikora M, Avery ET, Langenecker SA, Mickey BJ, Zubieta JK. Association
between placebo-activated neural systems and antidepressant responses: neurochemistry of
placebo effects in major depression. JAMA Psychiat. 2015;72(11):1087–94.
Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M. Placebo in emotional
processing – induced expectations of anxiety relief activate a generalized modulatory network.
Neuron. 2005;46(6):957–69.
Posternak MA, Zimmerman M. Therapeutic effect of follow-up assessments on antidepressant and
placebo response rates in antidepressant efficacy trials: meta-analysis. Br J Psychiatry. 2007;190
(4):287–92.
Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS. An analysis of factors that
contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain. 1999;83(2):
147–56.
Raskin A. Age-sex differences in response to antidepressant drugs. J Nerv Ment Dis. 1974;159:
120–30.
Reyna VF, Nelson WL, Han PK, Dieckmann NF. How numeracy influences risk comprehension
and medical decision making. Psychol Bull. 2009;135(6):94.
776 P. Netter

Rief W, Nestoriuc Y, Weiss S, Welzel E, Barsky AJ, Hofmann SG. Meta-analysis of the placebo
response in antidepressant trials. J Affect Disord. 2009;118(1–3):1–8.
Rollman GB. Signal detection theory measurement of pain: a review and critique. Pain. 1977;3(3):
187–211.
Schedlowski M, Enck P, Rief W, Bingel U. Neuro-bio-behavioral mechanisms of placebo and
nocebo responses: implications for clinical trials and clinical practice. Pharmacol Rev. 2015;67
(3):697–730.
Schindel L. Placebo und Placeboeffekte in Klinik und Forschung, [Placebos and placebo effects in
clinical practice and research]. Arzneim Forsch. 1967;17:892–917.
Shapiro AK. Placebo effects in medicine, psychotherapy, and psychoanalysis. In: Handbook of
psychotherapy and behavior change: empirical analysis. Wiley Hoboken, NJ; 1971. p. 439–73.
Skyt I, Moslemi K, Baastrup C, Grosen K, Benedetti F, Petersen GL, . . . Vase L. Dopaminergic tone
does not influence pain levels during placebo interventions in patients with chronic neuropathic
pain. Pain. 2018;159(2):261–72.
Uhlenhuth EH, Rickels K, Fisher S, Park LC, Lipman RS, Mock J. Drug, doctor’s verbal attitude
and clinic setting in the symptomatic response to pharmacotherapy. Psychopharmacologia.
1966;9(5):392–418.
Voudouris NJ, Peck CL, Coleman G. Conditioned placebo responses. J Pers Soc Psychol. 1985;48
(1):47.
Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, . . . Cohen JD. Placebo-
induced changes in FMRI in the anticipation and experience of pain. Science. 2004;303(5661):
1162–7.
Weimer K, Colloca L, Enck P. Placebo effects in psychiatry: mediators and moderators. Lancet
Psychiatry. 2015;2(3):246.
Zubieta JK, Stohler CS. Neurobiological mechanisms of placebo responses. Ann N Y Acad Sci.
2009;1156:198.
Neuropsychopharmacotherapy:
International Regulations and Regulating
Laws in Japan

Akira Ishii and Yujin Natori

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
Single Convention on Narcotic Drugs, 1961 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
Convention on Psychotropic Substances, 1971 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988 . . . 781
The Laws Regulating Drug Control in Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Some Specific Topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787

Abstract
Psychopharmaceuticals contain various drugs of which chemical structures and
pharmacological effects are different. Each substance varies in usefulness for
medication purposes as well as risk of abuse. Various substance abuse counter-
measures have thus been implemented internationally and within each country. In
this chapter, the three main International Conventions for controlling and regu-
lating narcotics and psychotropics are outlined: the Single Convention on Nar-
cotic Drugs of 1961, the Convention on Psychotropic Drugs of 1971, and the
Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances
of 1988. The history on the abuse of narcotics and psychotropics in Japan is
explained, and their countermeasures including the four main domestic laws are
then presented: the Stimulants Control Act, the Narcotics and Psychotropic Drugs
Control Act, the Cannabis Control Act, and the Opium Control Act. Finally,
specific topics including the issues on benzodiazepines including etizolam and on
synthetic cannabinoids in Japan are described.

A. Ishii (*) · Y. Natori

Department of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine,
Nagoya, Japan
e-mail: akishii@med.nagoya-u.ac.jp

© Springer Nature Switzerland AG 2022 777

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_386
778 A. Ishii and Y. Natori

Introduction

Psychopharmaceuticals used for various neurological or psychiatric disorders have

diverse effects to the central nervous system (CNS). Some of them are not only
clinically applied but also abused. On the other hand, some abused drugs which are
not applied for neuropsychopharmacotherapy, and some psychopharmaceuticals,
have similar effects to the CNS. For comprehensively categorizing these substances,
as a more general term, “psychoactive substances” are usually used; according to the
WHO, psychoactive substances are defined as substances that, when taken in or
administered into one’s system, affect mental processes. Likewise, “psychotropic
drug” is another term that is also used for the general/neutral description of these
kinds of substances. Given the above conditions, various laws and guidelines are
settled for appropriately regulating these psychoactive substances. In this chapter,
the International Conventions for controlling these substances are summarized.
Then, the laws and regulations of the substances, including the history of abuse
and countermeasures in Japan, are also reviewed.

Single Convention on Narcotic Drugs, 1961

The first international regulation on psychoactive drugs was the 1912 Hague Interna-
tional Opium Convention, which consisted of 6 chapters and 25 articles. In addition to
opium and morphine, which were already under extensive international discussion, the
Hague Convention also included two new substances: cocaine and heroin [United
Nations Office of Drugs and Crime (UNODC) 2020]. Although loopholes existed
within the Hague Convention, it contained many elements of a comprehensive drug
control treaty. The 1925 International Opium Convention in Geneva was intended to
impose global control over a wider range of drugs, including, for the first time,
cannabis, which was referred to as “Indian hemp” (marijuana) in Article 11 of the
Convention (The Senate Special Committee on Illegal Drugs, Canada 2002). Several
treaties were signed thereafter. In 1961, the previous Conventions were integrated and
signed as the Single Convention on Narcotic Drugs and came into force in 1964. As of
July 2020, the Single Convention has 186 state Parties.
The preamble of the Single Convention on Narcotic Drugs, 1961, describes the
treaty as follows: “Recognizing that the medical use of narcotic drugs continues to be
indispensable for the relief of pain and suffering and that adequate provision must be
made to ensure the availability of narcotic drugs for such purposes, and recognizing
that addiction to narcotic drugs constitutes a serious evil for the individual and is
fraught with social and economic danger to mankind,” and based on “the compe-
tence of the United Nations in the field of narcotics control and desirous that the
international organs concerned should be within the framework of that Organiza-
tion,” “a generally acceptable international convention replacing existing treaties on
narcotic drugs, limiting such drugs to medical and scientific use, and providing for
continuous international co-operation and control for the achievement of such aims
and objectives” (UNODC 2013).
Neuropsychopharmacotherapy: International Regulations and Regulating Laws. . . 779

In Article 2, substances under legal control are categorized into four groups as
follows, from most restrictive to least restrictive: Schedule IV, Schedule I, Schedule
II, and Schedule III. Schedule I lists 124 substances including cannabis, carfentanyl,
heroin, morphine, and opium. Schedule II designates ten substances including
codeine and its derivatives. In Schedule III, lighter subsets of substances already
categorized in Substance II are listed, for when they are included as a minor
constituent of another medication. Schedule IV lists 20 drugs which are already
listed under Schedule I, but are particularly liable to abuse and produce adverse
effects: acetylfentanyl, cannabis, carfentanyl, and heroin [International Narcotics
Control Board (INCB) 2019a].
The main contents of the Single Convention are summarized as follows. Because
the medical use of these controlled substances is important, Articles 1, 2, 4, 9, 12, 19,
and 49 contain specifications for medical and scientific use of the drugs. Article
33 prohibits the possession of drugs except under legal authority. Article 36 stipulates
penal provisions; it requests that Parties adopt measures against “cultivation, pro-
duction, manufacture, extraction, preparation, possession, offering, offering for sale,
distribution, purchase, sale, delivery on any terms whatsoever, brokerage, dispatch,
dispatch in transit, transport, importation and exportation of drugs contrary to the
provisions of this Convention,” and “intentional participation in, conspiracy to
commit and attempts to commit, any of such offences, and preparatory acts and
financial operations in connexion with the offences referred to in this article”
(UNODC 2013). Article 38 stipulates measures against the abuse of drugs, including
treatment, after-care, rehabilitation, and social integration of drug addicts (UNODC
2013). Article 39 requests Parties to adopt measures of control “more strict or
severe” than those provided by the Convention.

Convention on Psychotropic Substances, 1971

Since the Single Convention on Narcotic Drugs of 1961, new psychopharma-

ceuticals or psychotropic drugs emerged and needed to be appropriately regulated.
During the 1960s, medications such as barbiturates and benzodiazepines, as well as
drugs-of-abuse such as amphetamine-like stimulants and psychedelics, became
widely circulated and posed serious concerns to the public health and welfare. For
example, benzodiazepines, which were prescribed for ameliorating anxiety and/or
insomnia, became abused among young persons. In order to control these psycho-
tropic drugs, the Convention on Psychotropic Substances, 1971, was adopted on
February 21, 1971. As of July 2020, the Convention has 184 state Parties.
The Preamble of the Convention states:“The Parties, Being concerned with the
health and welfare of mankind, Noting with concern the public health and social
problems resulting from the abuse of certain psychotropic substances,Determined to
prevent and combat abuse of such substances and the illicit traffic to which it gives
rise, Considering that rigorous measures are necessary to restrict the use of such
substances to legitimate purposes, Recognizing that the use of psychotropic sub-
stances for medical and scientific purposes is indispensable and that their availability
780 A. Ishii and Y. Natori

for such purposes should not be unduly restricted, Believing that effective measures
against abuse of such substances require co-ordination and universal action,
Acknowledging the competence of the United Nations in the field of control of
psychotropic substances and desirous that the international organs concerned should
be within the framework of that Organization, Recognizing that an international
convention is necessary to achieve these purposes,” agree to the articles outlined in
the Convention (UNODC 2013).
Article 1 defines the terms used in the Convention. Article 2 restricts the sub-
stances that should be controlled under the Convention and need to fulfill the
following items: (a) That the substances have the capacity to produce (i) (1) a state
of dependence and (2) CNS stimulation or depression, resulting in hallucinations or
disturbances in motor function or thinking or behavior or perception or mood or
(ii) similar abuse and similar ill effects as a substance in Schedule I, II, III, or IV, and
(b) that there is sufficient evidence that the substance is being or is likely to be
abused so as to constitute a public health and social problem warranting the placing
of the substance under international control (UNODC 2013). In 2019, 78 substances
including lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine
(MDMA), and the isomers of tetrahydrocannabinol, posing serious risk to the public
health while not having therapeutic value, were designated in Schedule I; 46 sub-
stances including amphetamine, gamma-hydroxyl butylic acid (GHB), methamphet-
amine, phencyclidine, secobarbital, and some synthetic cannabinoids were
designated in Schedule II, as having serious risk but also having some therapeutic
value; 9 substances including amobarbital, buprenorphine, flunitrazepam, and pen-
tobarbital having moderate risk and average therapeutic value were designated in
Schedule III; 62 substances including alprazolam, barbital, diazepam, mazindol,
phenobaribital, triazolam, and zolpidem having high therapeutic value and some
possibility of abuse were designated in Schedule IV (INCB 2019b).
The main contents of the Convention are summarized as follows. The usage of the
designated drugs is limited to medical and scientific purposes. Licensing or other
similar control measure is required for the manufacture of, trade in, and distribution
of the substances listed in Schedules II, III, and IV. The substances in Schedules II,
III, and IV need to be supplied or dispensed for use by individuals pursuant to
medical prescription only. Article 11 lists the guidelines for all Parties with regard to
recordkeeping of the substances in respective Schedules, such as the details of the
manufactured quantity, acquisition and disposal, and supplier–recipient information.
Article 13 provides descriptions regarding prohibition of and restriction on export/
import of the substances. Article 15 stipulates an inspection system of manufacturers
and all other bodies that use the substances for medical and scientific purposes. In
Article 16, the Parties are instructed to furnish their reports, such as annual reports
and any incident of illicit traffic, to the Secretary-General of the UN. Article
20 specifies measures against the abuse of psychotropic substances, including
preventative measures, personnel training, and assistance for the general public to
gain widespread understanding on the abuse of psychotropic substances (Kato
1999).
Neuropsychopharmacotherapy: International Regulations and Regulating Laws. . . 781

Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic

Substances, 1988

Since the Convention on Psychotropic Substances was ratified, the abuse of nar-
cotics or psychotropic drugs was rising in developed countries. In 1984, the General
Assembly of the UN requested the Commission on Narcotic Drugs to initiate
preparation of a draft convention against illicit traffic in narcotic drugs; the Conven-
tion against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988, was
then adopted on December 20, 1988. The purpose of this Convention is to promote
co-operation among the Parties for dealing with illicit trafficking in narcotic drugs
and psychotropic substances. As of July 2020, the Convention has 191 Parties.
Some of the statements in the permeable include the following:“(r)ecognizing
also that illicit traffic is an international criminal activity, the suppression of which
demands urgent attention and the highest priority,” “(d)etermined to deprive persons
engaged in illicit traffic of the proceeds of their criminal activities and thereby
eliminate their main incentive for so doing,” “(r)ecognizing the need to reinforce
and supplement the measures provided in the Single Convention on Narcotic Drugs,
1961, that Convention as amended by the 1972 Protocol Amending the Single
Convention on Narcotic Drugs, 1961, and the 1971 Convention on Psychotropic
Substances, in order to counter the magnitude and extent of illicit traffic and its grave
consequences,”and claim the necessity of “a comprehensive, effective and operative
international convention that is directed specifically against illicit traffic and that
considers the various aspects of the problem as a whole, in particular those aspects
not envisaged in the existing treaties in the field of narcotic drugs and psychotropic
substances” (UNODC 2013).
Article 3 stipulates the offenses to which countermeasures should be taken and
the sanctions for the offenses. Article 5 requires that the proceeds from drug offenses
as well as the drugs and any other equipment intended for the offenses be confis-
cated. Article 11 stipulates that controlled delivery be made by the Parties at the
international level, taking necessary measures and arranging mutual agreements in
view of identifying the persons involved in the drug offenses. Article 12 provides the
substances frequently used in the illicit market and manufacturers of narcotic drugs
and psychotropic substances; the International Narcotics Control Board designates
18 compounds including acetic anhydride, ephedrine, lysergic acid, norephedrine,
and pseudoephedrine in Table I, and 8 compounds including acetone, ethyl ether,
piperidine, and toluene in Table II, as controlled drug precursors (INCB 2018).

The Laws Regulating Drug Control in Japan

Control of Stimulant Drugs

Before 1945, Japan had not suffered much of drug addiction issues; there were some
cases of opium and cocaine sniffing (Nagahama 1968). Japan had a law for regulat-
ing opium and its smoking. Since 1945, massive amounts of not only narcotics but
782 A. Ishii and Y. Natori

also methamphetamine, which were used for performance enhancement of soldiers

and workers in the Allies and the Axis powers, became widely circulated among the
Japanese society. In the late 1940s, stimulants were designated as “powerful drugs”
and became regulated under the Pharmaceutical Act at first.1,2 The regulation
unfortunately failed to control the drugs; the number of arrested persons rose from
17,518 in 1951 to 38,263 in 1953 (Nagahama 1968). For combatting the substances
abuse, the Stimulants Control Act was newly enacted in 1951. Still, the number of
arrested persons increased, and crimes related to stimulants became threatening to
the society. The Stimulants Control Act was thus amended in 1954: more rigorous
penalties for stimulant offenses were introduced, with terms of imprisonment of up
to 5 years for a first-time offense and 7 years for re-offenders and traffickers
(Edström 2015). In January 1955, General Headquarters for Promotion of Policy
Against Stimulants was established to strengthen the countermeasures for stimulants
abuse; local headquarters were also established in 36 of 47 prefectures of Japan. It
initiated a vast campaign for abolishing methamphetamine abuse. Combination of
the above countermeasures improved the nationwide drug abuse situation; the
number of offenses drastically decreased from 53,211 in 1954 to 5014 in 1956
(Nagahama 1968). The low numbers of offenses sustained until the late 1970s (see
Fig. 1).
Article 1 stipulates the purpose of the Act to implement necessary control of
import, export, possession, manufacturing, assignment, acquisition, and use of
Stimulants and Stimulants’ Raw Materials, so as to prevent health and sanitation
hazards caused by abuse of stimulants (Ministry of Justice 2016). Article 2 restricts
the use of stimulants to only medical and scientific purposes. Articles 2 and 3 stip-
ulate that only entitled manufacturers, facilities, and researchers can manufacture
and/or possess stimulants. Article 13 prohibits the import or export of any stimu-
lants. Article 14 forbids the possession of stimulants except under proper licenses
and valid reasons. Article 19 prohibits the use of stimulants except by those specified
as stimulants manufacturer, physician, stimulants researcher, or recipients of stimu-
lants ordered by a physician – all whom are legitimately engaged with manufactur-
ing, dispensing, or researching of stimulants. Article 20 stipulates restriction on
dispensing stimulants. Articles 41–44 stipulate Penal Provisions.

Control of Narcotics and Other Psychotropics

As mentioned above, narcotics were controlled before 1945, although opium had
been used for medicinal purposes since the eighteenth century in Japan (Nagahama
1968). During the Edo Era, death penalty was introduced for opium peddling, and

1
Note: Many of the translated terms used in this manuscript are mainly taken from the “Japanese
Law Translation” Website of the Ministry of Justice, Japan (http://www.japaneselawtranslation.go.
jp/); however, these terms are not officially authorized. Researchers used different translation terms:
“Stimulant Control Act” or “Stimulant Control Law.” In this chapter, we basically adopted the
translation terms which are currently effective based on “Japanese Law Translation.”
2
In 2015, the Pharmaceutical Act was abolished, and the Act on Securing Quality, Efficacy and
Safety of Products Including Pharmaceuticals and Medical Devices newly came into effect.
Neuropsychopharmacotherapy: International Regulations and Regulating Laws. . . 783

60,000
Stimulants Control Act
50,000

40,000

30,000

20,000

10,000

-
1951
1954
1957
1960
1963
1966
1969

1976
1979
1982
1985
1988

1994
1997
2000
2003
2006
2009
2012
2015
2018
1972

1991
Fig. 1 The number of arrests for violation of the Stimulants Control Law. Based on the data of
White Paper on Crime 1997 and 2019 (Ministry of Justice 1997, 2019a, b)

cultivation and possession of opium were prohibited in 1840, under the influence of
the Opium War in 1940 (Nagahama 1968). In the Meiji Era, Japan continued to
control opium and participated in the International Opium Convention signed at The
Hague in 1912 and the International Opium Convention signed at Geneva in 1925;
the government promulgated the Narcotics Control Regulations in 1930. After
World War II, crimes related to narcotics increased; the number of offenses reached
to approximately 2000 in 1960 (Nagahama 1968, Ministry of Justice 1982). Heroin
abuse especially exploded in urban areas (the miserable situation of heroin abusers in
the Yokohama District was vividly depicted in Akira Kurosawa’s movie, High and
Low). Although the Narcotics Control Act had already been enacted in 1953 and was
amended several times, the laws did not curb the narcotics-abuse-related offenses. In
1962, the government amended the Narcotics Control Act, which consisted of three
pillars. First, penalties against offenders were strengthened: maximum penalty was
extended from 7 years to life imprisonment for heroin, and the maximum fine was
raised from 500,000 yen to 5,000,000 yen (equivalent to USD 1390–13,900 in
1962). Second, a compulsory hospitalization system was established. Third, licenses
for narcotics uses became restricted to only medical and academic purposes. The
number of offenders plummeted from 2571 in 1963 to 792 in 1964; the offenders
decreased to less than 500 in the late 1960s.
From the early 1960s, abuse of “sleeping drugs” and tranquilizers became
apparent among juvenile delinquents; the Ministry of Health and Welfare designated
those drugs as “habit-forming drugs” under the Pharmaceutical Affairs Law in 1961
(Nagahama 1968; Ministry of Justice 1964). The “habit-forming drugs” include
bromovalerylurea, propofol, flunitrazepam, triazolam, and pentazocine. Some of
widely abused “sleeping drugs,” such as methaqualone, were available over the
counter. These drugs were then designated as “deleterious drugs” under the Phar-
maceutical Act in 1963; the abuse cases of those drugs dropped after the amendment
784 A. Ishii and Y. Natori

of the Law (Ministry of Justice 1980). The offenders of the Narcotics Control Act
were kept in the range of 100 and 450 in the 1970s. In 1990, Japan adopted the
Convention on Psychotropic Substances, 1971; the new Narcotics and Psychotropics
Control Act, which encompassed not only narcotic drugs but also psychotropics, was
endorsed in the same year. It took 19 years for Japan to ratify the Convention on
Psychotropic Substances, 1971; it took 9 years in the US, 10 years in Italy, and
15 years in the UK to do the same. The long delay until ratification in many countries
has been assumed to be due to difficulties in regulating Schedule III and Schedule IV
drugs (Kato 1999). Offenses under the Narcotics Control Act (and the Narcotics and
Psychotropic Drugs Control Act) have been relatively regulated (see Fig. 2); how-
ever, in the mid-2010s, emergence of new psychoactive substances (NPSs) including
synthetic cannabinoids became a new problematic phenomenon in Japan. The
problems of these newly synthesized psychotropic drugs are discussed later.
Article 1 of the Narcotics and Psychotropic Drugs Control Act provides its
purpose: “to prevent the health and sanitation hazards caused by the abuse of
narcotics and psychotropics and to thereby promote the public welfare, by setting
in place the necessary controls on the import, export, manufacture, formulation of
pharmaceutical preparations, transfer, and other handling of narcotics and psycho-
tropics, as well as by taking action with regard to narcotics addicts such as
establishing measures to provide them with the necessary medical treatment” (Min-
istry of Justice 2016). Article 3 provides licensing for appropriate narcotics handlers;
a person not licensed cannot handle narcotics and psychotropics. Articles 12–29
stipulate prohibition and restrictions for narcotics. Article 50 provides licensing and
registration for appropriate psychotropic handlers. Articles 58–2 to 58–19 describe

3500

3000
Narcotics and Psychotropics
Cannabis
2500

2000

1500

1000
Opium
500

0
1951
1954
1957
1960
1963
1966
1969
1972
1976

1982
1985
1988
1991
1994
1997
2000
2003
2006
2009
2012
2015
1979

2018

Fig. 2 The number of arrests for violation of the Narcotics and Psychotropic Drugs Control Act
(dotted line with circles), the Cannabis Control Act (solid line), and the Opium Control Act (dotted
line with rectangles). Based on the data of White Paper on Crime 1997 and 2019 (Ministry of Justice
1997, 2019a, b)
Neuropsychopharmacotherapy: International Regulations and Regulating Laws. . . 785

Table 1 The international conventions and corresponding domestic Acts of Japan

Categorization (corresponding Act
The international conventions Substances of Japan)
Single Convention on Narcotic Opioids Cocaine Narcotics (The Narcotics and
drugs, 1961 Synthetic narcotics Psychotropics Control Act)
Opium and opium Opium (The Opium Control Act)
poppy
Cannabis including Cannabis (The Cannabis Control
resin Act)
Convention on Schedule LSD, MDMA, Narcotics (The Narcotics and
psychotropic I Psylocibine Psychotropics Control Act)
substances, 1971 Schedule PCP, Δ9-THC,
II 2C-B, GHB
Methamphetamine Stimulants (The Stimulants
Amphetamine Control Act)
Methaqualone Type I Psychotropics (The
Narcotics and Psychotropics
Control Act)
Schedule Pentazocine Type II Psychotropics (The
III Narcotics and Psychotropics
Control Act)
Schedule Triazolam Type III Psychotropics (The
iV Narcotics and Psychotropics
Control Act)
NSPs not regulated Narcotics (The Narcotics and
in the conventions Psychotropics Control Act)
Designated Drugs (The
Pharmaceutical and Medical
Device Acta)
a
The act on securing quality, efficacy and safety of products including pharmaceuticals and medical
devices

the measures for narcotics addicts, including reporting by appropriate personnel,

medical examinations, and hospitalization of addicts. Appended Table 1 provides the
list of narcotics. Psychotropics are categorized into Type I, Type II, and Type III; the
three types of psychotropics are shown in order for enforcement of the Narcotics and
Psychotropics Control Act (Ministry of Health, Labour and Welfare 2018).

Other Regulations for the Control of Cannabis and Opium

The Cannabis Control Act was enacted in 1948. Article 1 of the Act defines the term
“cannabis” to be the cannabis plant (Cannabis Sativa L.) and its products including
resin. The grown stalk and the seed, along with their products (excluding resin), are
excluded. Article 3 prohibits anyone who is not a cannabis handler from possession,
cultivation, receiving, or transfer of cannabis, or make research use of it (Ministry of
Justice 2015).
The Opium Control Act was enacted in 1954; this Act controls the supply of
opium for medical and research purposes and regulates the cultivation of the
786 A. Ishii and Y. Natori

Papaver somniferum L, Papaver setigerum, and other poppies designated by Min-

ister of Health, Labour and Welfare, and appropriate handlings of opium and opium
poppy. The Stimulants Control Act, the Narcotics and Psychotropic Drugs Control
Act, the Cannabis Control Act, and the Opium Control Act are the main four Acts to
properly control and regulate narcotics and psychotropics. The relationship between
the International Conventions and the domestic Acts presented above are shown in
Table 1 (Ministry of Health, Labour and Welfare 2018).

Some Specific Topics

Abuse of Etizolam
Etizolam, a thienotriazolobenzodiazepine derivative originally developed in Japan,
became commercially available in 1984; it has marketing authorization only in India,
Italy, and Japan [World Health Organization (WHO) 2019]. Etizolam has highly
anxiolytic potency and was not designated as any “psychotropic”; not only psychi-
atrists but also general physicians have thus prescribed etizolam for insomnia or
other psychosomatic symptoms. Although the risk of benzodiazepine abuse has been
acknowledged since the 1980s, benzodiazepine prescription cases were 6–20 times
higher in Japan compared to those prescribed in European countries from 1998 to
1999 (Murasaki 2001). The number of patients who were prescribed benzodiaze-
pines that developed abuse and dependence symptoms is not small; Matsumoto
pointed out that flunitrazepam, triazolam, etizolam, zolpidem, and brotizolam were
most abused in Japan (Matsumoto 2012). The Ministry of Health, Labour and
Welfare finally designated etizolam as a Type III psychotropic in 2016. Today,
etizolam is under national control in Denmark, Germany, Japan, Switzerland,
Poland, the United Arab Emirates, and the United Kingdom (WHO 2019).

Regulation of Synthetic Cannabinoids in Japan

In Japan, NPSs started being circulated around the late 1990s. These drugs contained
various compounds, including GHB, methylphenidate, alkyl nitrites, magic
mushrooms (psilocybin), and designer drugs such as 5-methoxy-N,N-
diisopropyltryptamine (5-MeO-DIPT); many of them were designated as narcotics
or psychotropics under the Narcotics and Psychotropics Control Act. However,
newly synthesized cannabinoids and synthetic cathinones became circulated in
Japan around 2008. Synthetic analogs of the already illegal substances intended to
mimic the pharmacological effects of the original drugs and to escape regulation
were already known as “designer drugs.” In the case of synthetic cannabinoids,
however, numerous numbers of newly synthesized analogs were disseminated so
quickly; legal control of those synthetic cannabinoids and their market circulation
were a long-lasting cat-and-mouse game (Uchiyama and Hanajiri-Kikura 2016). The
Narcotics and Psychotropics Control Act could not fully cope with the situation in
which newly emerged synthesized cannabinoids were circulating so rapidly; the
Ministry of Health, Labour and Welfare thus implemented a new blanket or generic
scheduling system for synthetic cannabinoids in 2013, which allowed the imposition
Neuropsychopharmacotherapy: International Regulations and Regulating Laws. . . 787

of the same designated drug scheduling on newer emerging synthetic cannabinoids

according to their classified structures. Despite such generic scheduling for synthetic
cannabinoids, new compounds such as 5-fluoro-ADB were still popular and fatal
intoxication cases were reported (Hasegawa et al. 2015, Kusano et al. 2018). The
generic scheduling system was enacted under the then Pharmaceutical Act; the
Ministry of Health, Labour and Welfare amended the Pharmaceutical Act to delegate
the official authority on the control of designated substances to a Narcotics Agent or
a Narcotics Control Official, and to ban the import, manufacture, selling, provision,
possession, receiving, and use of the designated substances in 2013 (Ministry of
Health, Labour and Welfare 2015). The Ministry inspected shops selling NPSs,
including synthetic cannabinoids, and ordered to halt their sales; the Ministry
requested internet providers to delete online stores that sold those drugs. The
combination of these countermeasures finally succeeded in nulling the shops dealing
with synthetic cannabinoids in 2015 (Ministry of Health, Labour and Welfare 2015,
Uchiyama and Hanajiri-Kikura 2016).

Cross-References

▶ Cognitive Enhancement and American Constitutional Law

▶ Ethical Issues in Neuropsychopharmacotherapy: US Perspective
▶ Ethics of Informed Consent: Coercive and Preventive Medication

References
Edström B. The forgotten success story: Japan and the methamphetamine problem. Japan Forum.
2015;27:519–43.
Hasegawa K, Wurita A, Minakata K, Gonmori K, Yamagishi I, Nozawa H, Watanabe K, Suzuki
O. Identification and quantitation of 5-fluoro-ADB, one of the most dangerous synthetic
cannabinoids, in the stomach contents and solid tissues of a human cadaver and in some herbal
products. Forensic Toxicology. 2015;33:112–21.
International Narcotics Control Board (INCB). List of precursors and chemicals frequently used in
the illicit manufacture of narcotic drugs and psychotropic substances under International
Control (Red List). 18th ed. 2018.
International Narcotics Control Board (INCB). List of narcotic drugs under international control
(Yellow List). 58th ed. 2019a.
International Narcotics Control Board (INCB). List of Psychotropic Substances under International
Control (Green List). 30th ed. 2019b.
Kato N. International conventions on psychotropics. (In Japanese). In: Matsushita M, Asai M,
Ushijima S, Kurachi M, Koyama T, Nakane H, Miyoshi Y, editors. Encyclopedia of clinical
psychiatry, Drugs and alcohol related disorders, vol. 8: Tokyo, Nakayama Shoten; 1999.
p. 109–23.
Kusano M, Zaitsu K, Taki K, Hisatsune K, Nakajima J, Moriyasu T, Asano T, Hayashi Y,
Tsuchihashi H, Ishii A. Fatal intoxication by 5F–ADB and diphenidine: detection, quantifica-
tion, and investigation of their main metabolic pathways in humans by LC/MS/MS and LC/Q-
TOFMS. Drug Test Anal. 2018;10:284–93.
788 A. Ishii and Y. Natori

Matsumoto T. Problems of psychiatric pharmacotherapy in view of clinical practices for drug

dependence: Findings from the “National Survey of Patients with Drug-related disorder in
Psychiatric Hospitals”. (in Japanese. Japanese Journal of Psychiatric Treatment. 2012;27:71–9.
Ministry of Health, Labour and Welfare. Main countermeasures to combat “Dangerous Drugs”
since 2013 (in Japanese). 2015. https://www.mhlw.go.jp/seisakunitsuite/bunya/kenkou_iryou/
iyakuhin/yakubuturanyou/oshirase/20150819-1-01.html. Accessed 25 July 2020.
Ministry of Health, Labour and Welfare. International Cooperation. Information on the prevention
of drug abuse (in Japanese). 2018. https://www.mhlw.go.jp/bunya/iyakuhin/yakubuturanyou/
gyousei-gaikyo/kokusai_kyoryoku.html. Accessed 25 July 2020.
Ministry of Justice, Cannabis Control Act, Japanese Law Translation. 2015. http://www.
japaneselawtranslation.go.jp/law/detail/?ft¼1&re¼2&dn¼1&x¼20&y¼15&co¼01&ia¼03&
ja¼04&ky¼%E5%A4%A7%E9%BA%BB&page¼15. Accessed 20 Dec 2020.
Ministry of Justice, Narcotics and Psychotropic Drugs Control Act, Japanese Law Translation.
2016. http://www.japaneselawtranslation.go.jp/law/detail/?ft¼1&re¼2&dn¼1&x¼65&
y¼11&co¼01&ia¼03&ja¼04&ky¼%E9%BA%BB%E8%96%AC%E5%90%91%E7%B2%
BE%E7%A5%9E%E8%96%AC&page 2. Accessed 20 Dec 2020.
Ministry of Justice, Stimulant Control Act, Japanese Law Translation. 2016. http://www.
japaneselawtranslation.go.jp/law/detail/?ft¼1&re¼2&dn¼1&x¼25&y¼14&co¼01&ia¼03&
ja¼04&ky¼%E8%A6%9A%E3%81%9B%E3%81%84%E5%89%A4%E5%8F%96%E7%
B7%A0%E6%B3%95&page¼9. Accessed 20 Dec 2020.
Ministry of Justice, White Paper on Crime, 1964. Abuse of sleeping drugs (in Japanese). 1964.
http://hakusyo1.moj.go.jp/jp/5/nfm/n_5_2_4_1_2_5.html. Accessed 25 July 2020.
Ministry of Justice, White Paper on Crime, 1980. Battle against white powder (Stimulants)
(in Japanese). 1980. https://www.npa.go.jp/hakusyo/s55/s550200.html. Accessed 25 July 2020.
Ministry of Justice, White Paper on Crime, 1982. Regulation of drug offenses in Japan
(in Japanese). 1982. http://hakusyo1.moj.go.jp/jp/23/nfm/n_23_2_4_1_2_1.html. Accessed
25 July 2020.
Ministry of Justice, White Paper on Crime, 1997. Drug related Crimes. (in Japanese). 1997. http://
hakusyo1.moj.go.jp/jp/38/nfm/n_38_2_1_4_3_1.html. Accessed 25 July 2020.
Ministry of Justice, White Paper on Crime, 2019. Violation of the cannabis control act and other acts
(in Japanese). 2019a. http://hakusyo1.moj.go.jp/jp/66/nfm/n66_2_4_2_1_2.html. Accessed on
25 July 2020.
Ministry of Justice, White Paper on Crime, 2019. Violation of the stimulants control act
(in Japanese). 2019b. http://hakusyo1.moj.go.jp/jp/66/nfm/n66_2_4_2_1_1.html. Accessed
25 July 2020.
Murasaki K. Present situation and new prospect of psychotropic drugs in Japan – toward the 21th
century (in Japanese) Japanese. J Clin Psychopharmacol. 2001;4:3–27.
Nagahama M. A review of drug abuse and counter measures in Japan since world war II. UN
Bulletin on Narcotics. 1968;20:19–24.
The Senate Special Committee on Illegal Drugs, Canada. Volume III Chapter 19. The international
legal environment. In: Cannabis: our position for a Canadian Public Policy Report of the Senate
Special Committee on Illegal Drugs; 2002. https://sencanada.ca/content/sen/committee/371/ille/
rep/repfinalvol3-e.htm. Accessed 30 July 2020.
Uchiyama N and Hanajiri-Kikura R. “Dangerous Drugs” and synthetic cannabinoids. (in Japanese)
Pharmacia 2016; 855–859.
United Nations Office of Drugs and Crime (UNODC). The international drug control conventions.
UNITED NATIONS, New York; 2013.
United Nations Office of Drugs and Crime (UNODC). The 1912 Hague International Opium
Convention. 2020. https://www.unodc.org/unodc/en/frontpage/the-1912-hague-international-
opium-convention.html. Accessed 26 Feb 2020.
World Health Organization. Critical review report: Etizolam. Expert committee on drug dependence
forty-second meeting. Geneva; 2019.
Health Economics for Neuropsychological
Diseases in China

Hai-lun Cui and Gang Wang

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
A Broad View of Health Economics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
General Classification of the Objects of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
The Association Between Health Economics and Neurology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
Economic Burden on Neurodegenerative Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803

Abstract
As an important economy branch dealing with the allocation of health-related
resource, health economics mainly covers studies concentrating on issues related
to multiple medical actions and disease researches concerning efficiency, effec-
tiveness, value, and behavior in the production and consumption of both health
and health care. The focus of this chapter is to give a brief introduction on the
notions and definitions of the modern health economies, as well as the general
containment of the works underlying this specific notion of study. Two commonly
seen neuropsychological or neurodegenerative diseases (Parkinson’s disease and
Alzheimer’s disease), both inconvertible and with relatively lengthy process, are
specifically described in order to illustrate the work of health economies in a well-
understood manner. The calculation of the economic burden and the process of
financial evaluation of the two examples would help demonstrate the importance
of economic planning of health problems.

H.-l. Cui · G. Wang (*)

Department of Neurology and Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao
Tong University School of Medicine, Shanghai, P.R. China
e-mail: cuihailun@sjtu.edu.cn; wg11424@rjh.com.cn

© Springer Nature Switzerland AG 2022 789

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_17
790 H.-l. Cui and G. Wang

Introduction

A Broad View of Health Economics

The focus of this chapter is on a rather doom-laden scope of subject that is not strictly
constrained within the field of pure medicine. In particular, it is the linkage between
economic analysis and the impact of means of medicine on which our life lifestyle
and life circumstances have exerted. As the discipline of economics concerned with
the efficient allocation of health-care resources, health economics is essentially
trying to maximize health benefits to society contingent upon available resources
generally. One may see the merits of the application of economic tools effortlessly,
since those proved general economic principles offer a theoretical foundation of
hygienic resource allocation dealing with an environment with a scarcity of
resources. Back to the early period of human society, medicine, as well as the act
of the medical treatment, seemed to be an intuition of moral salvation with a
mutually reciprocal effect on individuals; the advent of capitalistic era, however,
had brought with itself the private ownership and market economy, which redefined
the vocation of the medical workers previously thought to be unselfish saviors. For
the time being, medicine has gradually become an independent means of profession
and livelihood. At the meantime, along with the unprecedented promotion of world
socialization since the end of the World War II, the expenditures on personal medical
services, as well as the increasingly complex situation resulted from the ever-
increasing mobility of population and the restless urban development, have exerted
great pressure on global control and management of various diseases. From this
perspective, the derivation of economic section in medical field seems to be an
inevitable trend.
Economics rests on two basic hypotheses: that the economic entities are rationally
guided (i.e., the optimization of economic costs or interests) and that the economic
resources are relatively scarce but versatile. As a consequence, the efficient alloca-
tion of the limited medical resources turns out to be the fundamental researching
purpose. Meanwhile, economics renders two basic tools and a set of criteria in order
to analyze the issues of efficiency and distribution: the techniques of optimization
and the determination of equilibrium situations. Both tools could be used by
authorities in charge of health and other organizations to determine the most efficient
allocation of medical or nonmedical resources, as well as the total expenditures and
policies governing the redistribution of varied services, such as the national health
insurance.
Past decades have witnessed a more rapid growth of expenditures on personal
medical services than that of other goods or services in the economy on a global
respect (Fan and Savedoff 2014). Statistics of the United States showed a doubled
health’s proportion of GDP between 1980 and 2011, with the fastest increased
health-care expenditure (2.9%/year) compared to any other industries during the
2000–2010 period (Anderson and Chalkidou 2008). Part of this increase in total
medical care expenditures is the result of the enlarged aging population and pro-
longed life span (Durrani 2016). Other reasons, such as rising income, changes in the
Health Economics for Neuropsychological Diseases in China 791

financing and management of health care, as well as the availability of multiple

medical interventions and therapies that were not applicable before due to their high-
tech standards and technical requirements, should all be taken into account when
considering specific situations (Garibaldi et al. 2010). However, not all of the
increases on medical expenditures regarding medical technologies and changing
medical practices represent improvements in quantity and quality of available
services per capita (Sorenson et al. 2013). The price of medical care, as measured
by the Consumer Price Index, has been increasing annually at a rate relatively
commensurate with the national income growth. The circle of medical care is still
disputing over some basic principles such as “the nature of national health services,”
“the dominance over health industry by the government or the market,” as well as the
pricing mechanisms and insurance involvements of medical intervention (Fan and
Savedoff 2014). Governments are frequently faced with dilemmas of the necessity
of whether it is justifiable to spend an increasing share of its limited resources on
personal medical services when there are more urgent needs in the investment of
education and other public services. With problems concerned with almost every
aspect of health industry, the importance of the application of various solutions
posed by the study of health economics is much in evidence. It must be noted that,
while health can be viewed as the fundamental merchandise produced by consumers,
it is obvious that besides individual control over the level of health stock and its rate
of deprecation, personal health status is also affected by external forces underlay by
non-health-care policies (Hall and Jones 2007). At one extreme are the comprehen-
sive policies aiming at macroeconomy which could be a profound influential factor
on almost every aspect of the daily living. No matter how important the effect health
economic methods might have on the personal health control model, the economic
evaluation is essentially a microeconomic tool. Unfortunately, on this level a mere
evaluation of a relatively short term of intervention carried out by health economics
methods is insufficiently accurate at all. However, this is not a total repudiation of the
impacts of health economic tools against the backdrop of new rounds of economic
slump, but rather that the standard methods of economic evaluation need further
promotion and development in accordance with different situations.
Every country should mull over the scale that it intends to spend on medical
services and the best methods for its distribution. The problem of scarcity, eventu-
ally, is the foundation and starting point for the development and use of the
economist’s tools and principles. No matter how medical care is organized and
executed in a country, the skills deducted combining both medical features and
economic mechanics deserve to be the most rational and promising solution to
problems raising through the development of health career, as well as the develop-
ment course of human society.

General Classification of the Objects of Study

Health economics from its outset has been frequently misinterpreted to health-care
economics and has been used without specification on a wide range of topics. What
792 H.-l. Cui and G. Wang

exactly does this subject concentrate on, and to what extent this discipline of study
may apply to germane territory, is still under debate. Forerunners of this field have
tried to conceptualize this specific area more than once; and so far, the comprehen-
sively accepted encapsulation of this indistinctively delimited discipline was con-
cluded by Allan Williams in his schematic representation of the main elements in
health economics, which includes mainly 8 categories as follows: (A) What influ-
ences health (other than health care); (B) What is health, What is its value; (C)
Demand for health care; (D) Supply of health care; (E) Micro-economic evaluation
at treatment level; (F) Market equilibrium; (G) Evaluation at whole system level; (H)
Planning, budgeting and monitoring mechanisms (Williams 1987).
After a close look at the contents, we may notice that only two (A and B) of eight
categories are particularly related to health itself, while other domains are predom-
inantly occupied by factors such as health determinants and the evaluation, as well as
the operative features of health service organizations. However, since the aims for
health policies and researches are to improve the state of health of particular
individuals, of groups and of nations, it is essential that we combine analytical
insights with practical application to evaluate the real straits of the sick ones and
their caregivers.
Health services, like other goods, should be produced efficiently, and resources be
spread across various diseases so as to maximize benefits at the greatest extent; and
personal care should be given to reduce the burden of illness. Equity enters through-
out the health problem, across both its healing and care functions, but what is most
needed is a formulation of the problem in manageable form. The ethical and
philosophical issues, such as entitlement to equal health, the right to access proper
treatments, and the right to live or die, must also be faced at the end, and this is the
underlying core that health economics has pointed out. But the basics of measuring
health consumption, essential for the guidance of policy making, must be addressed
as primary task.

The Association Between Health Economics and Neurology

Neurodegenerative disease, as one of the most important part of neuropathology, is

an umbrella term for a range of conditions which primarily affect the neurons in the
human brain in a spontaneous manner. As the basic units that help forming the
nervous system which includes the brain and spinal cord, neurons normally don’t
reproduce or regenerate themselves, as a consequence no replacement could relieve
the impairment or death when irreversible damages happen. In practice, neurode-
generative diseases involve a large group of neurological disorders with hereditary
and sporadic conditions resulting in progressive dysfunction in specific subsets
of neurons of anatomic systems; they arise for obscure reasons and progress in
a relentless and chronic manner. The classification of this disease can be roughly
concluded with respect to its phenotypic effects (problems associated with neuropsy-
hological/mental function and/or movement function), even though many may
overlap with each other based on similar molecular pathways (Fan et al. 2017).
Health Economics for Neuropsychological Diseases in China 793

Since this malign neuronal injury is an inconvertible and relatively lengthy

process most probably caused by aging process, the neurodegenerative diseases
are incurable, and normally its dysfunction may lead to chronic symptoms both
debilitating and onerous for patients as well as their caregivers. Although the
mortality has been generally considered as the primary outcome measure when it
comes to the evaluation of the impact of a certain type of disease, the domestic
and social cost however is largely dependent on the disability they cause (Gooch
et al. 2017). Therefore, the nature of irreversibility and exacerbation have made this
type of neuropathological diseases the perfect research object to study the economic
burden and financial evaluation. In the coming decade, nations worldwide are facing
the same dilemma that we are getting older. Faced with this imperative trend of
worsening situation, we specify mainly on two commonly seen neuropsychological/
neurodegenerative disorders (Parkinson’s disease and Alzheimer’s disease) in this
chapter in order to estimate its economic impact on population based on the
investigation we have done in Shanghai China district (Wang et al. 2006, 2008).

Economic Burden on Neurodegenerative Diseases

Parkinson’s Disease

As one of the most common chronic neurodegenerative diseases, Parkinson’s disease

(PD) is associated with a significant cost burden to families and societies in many
countries. With the aging of global populations and the epidemiological transition
to chronic diseases late in life, the costs of health-care delivery related to PD are
predicted to continue to grow. The prevalence of PD in the United States is around
0.3% of the general population, which means 630,000 to 1,000,000 people affected,
and the figure is likely to be doubled by 2050 (Kowal et al. 2013). One study involv-
ing Beijing, Shanghai and Xi’an reported a prevalence of 1.7% in Chinese people
over 55 years old, while others estimated that the standardized prevalence of
PD could mainly be in the region of 79.5/100,000 to 193.3/100,000, which is
comparable to the results reported in Western countries (Rajput et al. 1984; von
Campenhausen et al. 2005; Muangpaisan et al. 2009; Zou et al. 2015). To provide
baseline data for future evaluations of health economic impacts of PD in China,
resource use and costs for treatment, social services, and productivity loss in patients
with PD were investigated and conducted by a “bottom-up” approach based on
a retrospective investigation for costs during 1 year.

Subjects and Methods

All patients with PD treated at the Department of Neurology at Ruijin Hospital
during the period from April to August 2005 were subjects of the study and were
identified with the International Classification of Disease, 9th edition (ICD-9)
diagnostic code for PD. All the patients at Ruijin Hospital were interviewed in
person. Patients were asked for information about PD-related cost and resource
use during the past year (April 2004 to March 2005) before the investigation, by
794 H.-l. Cui and G. Wang

using the questionnaire designed for this study. The questionnaire included two main
parts. Part I requested PD patient characteristics such as demographic details,
information on concurrent conditions, disease course, and disease stage according
to Hoehn & Yahr (H&Y). PD resource use and cost data for the 1-year period were
derived from Part II, which consisted of two sections: Part 2a assessed resource use
including drug treatment, number of outpatient visits and inpatient admissions,
means of transportation to the clinic, and special equipment; Part 2b directly
assessed the costs of inpatient care, outpatient visits, PD drugs (excluding drugs
for secondary symptoms such as constipation, sleep disorders, etc.), physical treat-
ment, purchase of equipment needed because of PD symptoms, medically related
travel expenses, professional home care, and productivity loss due to sick leave, and
early disability retirement. To ensure the accuracy of the recall information during
the interview, particularly for some patients with cognitive forfeit, PD patients were
asked to be accompanied by a caregiver and to bring their medical records, including
outpatient and inpatient records. The study was approved by the Research Ethics
Committee, the Medical School of Shanghai Jiaotong University, China. Voluntary
completion of the questionnaires was interpreted as consent to participate.

Calculation of Costs
The cost per patient was determined for each of the five H&Y stages of disease
progression. Unit costs were derived from the Shanghai public health administra-
tions tariff for 2004 (annual listing of all licensed drugs in Shanghai and their prices),
local taxi and public transportation published fares, Shanghai city guidelines for
mileage reimbursement, and the local fees for home care and home help service
provided by the local authority. Indirect costs were estimated using the human
capital approach. Evaluations of productivity loss due to long-term sick leave and
early retirement were based on the Shanghai city average annual income according
to the 2004 annual statistics almanac of Shanghai. For health-care cost and produc-
tion loss, only PD-related resource use was recorded. Monetary values were reported
as 2004 Chinese yuan, renminbi (RMB). For reference, the exchange rate was
USD 1 = RMB 8.3 or EUR 1 = RMB 10.5 in 2004.
To provide a measure of dosage change in dopaminergic drug use, the daily
L-dopa equivalent dose (LED) was calculated on the basis of the following equiv-
alences: 100 mg of standard L-dopa = 140 mg of controlled release L-dopa = 10 mg
of bromocriptine = 1 mg of pergolide = 5 mg of ropinirole = 1 mg of
pramipexole = 10 mg of selegiline.

Results

Characteristics of Patients
We interviewed 201 patients with PD, and all participants were permanent residents
in Shanghai. Valid data were collected from 190 patients, giving a response rate of
94.5%. There were 116 men and 74 women with an overall mean age of 67.9 years
(range, 36–85 years) a mean disease duration of 6.0 years (range, 1–23 years). With
regard to H&Y classification, there were 88 patients in Stage I, 80 in Stage II, 18 in
Health Economics for Neuropsychological Diseases in China 795

Stage III, 4 in Stage IV, and none in Stage V. Of these, 87 patients had at least one
additional chronic disease such as hypertension or diabetes. The mean annual
income per patient was RMB 13,462 (range, RMB 2,400–150,000).

Neurological Care
The average number of outpatient contacts with the Department of Neurology was
13.8 per patient per year. Visiting the PD clinic was the single most frequent form of
contacts, accounting for 99% of all contacts. There was a trend toward increasing
outpatient care across H&Y stages. During the year in question, 16 patients were
admitted for neurological care on a total of 16 occasions (0.1 per patient in total).
Except for one patient who received electrode implantation for deep brain stimula-
tion (DBS), the other 15 patients were hospitalized for treatment of severe symptoms
such as motor fluctuations and freezing of gait.

Drugs Used and LED

All patients but 2 (each in H&Y Stage I and II) received anti-Parkinsonism drugs.
The average number of drugs used per patient was 2.9 for the whole series, ranging
from 2.8 for those in H&Y Stage I to 4.3 in Stage IV (P = 0.225). The single most
frequently used drug was L-dopa (used by 90.5% of the patients). Dopamine receptor
agonists were also commonly used; 30% of patients took pergolide, 13.2% bromo-
criptine, 12.1% piribedil, and 11.6% α-dihydroergocriptine. Additional drugs were
used, including selegiline by 30%, anticholinergics by 25.8%, amantadine by 37.9%,
entacapone by 0.5%, and traditional Chinese medicine, mainly “Zhichan Tang
(tremor-inhibitory soup)” by 3.2% of the patients. The overall mean LED was
318.7 mg/day. There was a significant increase in the dosages of dopaminergic
agents with disease progression, as the mean LED from 267.9 mg/day in Stage I
to 468.9 mg/day in Stage IV (P = 0.001).

Transportation and Non-neurological Care

All but 25 patients took a transportation service to reach the neurological clinic.
Public transportation and taxis were used by 73.2% and 11.6% of patients, respec-
tively, whereas private cars or bicycles were used by only 1.1% and 0.5%, respec-
tively. One patient gave no response to this question. Most patients, 54.7%, visited
the neurology clinic without a companion. Beyond the health care provided by the
Department of Neurology, some patients also sought alternative traditional Chinese
health care, including acupuncture (5.8%), massage (1.6%), and cupping (1.1%)
provided by general practitioners and physiotherapists.

Home Care
In addition to getting help from family members, mainly from spouses and/or
children, 23.2% of patients also required a private nursemaid. To improve their
medical treatment, 25.8% of patients bought preventive health-care foods by
themselves. Special equipments, including wheel chairs and walking sticks, were
needed by 7.4% and 9.5% of patients, respectively.
796 H.-l. Cui and G. Wang

Loss of Production
There were 33 patients of working age, that is, under the age of 60 in China. Many
patients did not work full time before developing PD symptoms due to other factors,
including having other illnesses. Three people were on sick leave occasionally, and
one patient had retired early.

Costs
The mean costs per patient for 1 year were summarized in Table 1. Direct medical
care costs averaged approximately RMB 4,305 per year per patient, of which drugs
accounted for the major costly component. Annual drug costs averaged RMB 2,677
per patient and increased with disease progression (P = 0.018). Nonmedical direct
costs were much less than direct health-care costs, averaging approximately RMB
3,301. Costs due to loss of productivity averaged approximately RMB 73 per patient
per year. Taken together, the overall mean annual cost for PD in our series was
approximately RMB 7,679. The number of clinic visits and the patient’s H&Y stage
were found to be the factors significantly associated with the total cost. Meanwhile,
LED and the number of drugs taken were found to be associated with the drug cost in
the multivariable regression analysis (Table 2). A majority of the patients (86.8%)
had some kind of medical insurance, which covered a part of or the entire medical
cost. No significant difference of the total cost between the patients with medical
insurance and those without was found.

Alzheimer’s Disease

As one of the most common neurodegenerative diseases, Alzheimer’s disease (AD)

is characterized by a progressive impairment of cognitive, behavioral, and functional
abilities. With the aging of the global population and the increase of chronic diseases
late in life in the world, various epidemiological studies have shown the significant
growth of the absolute numbers of AD and other types of dementia cases (Langa
et al. 2017). Recently, it has been estimated that approximately 47 million people are
demented, with nearly half of the demented people in the world with dementia live in
Asia, including China (Zhang et al. 2017). Previous studies from China also show
that the incidence of senile dementia for the population aged 65 years and older was
~6%, with AD being the most common type of cognitive impairment (Liu et al.
2011; Zhang et al. 2012; Jia et al. 2014). As around 10% of the total population in
China age 60 or older, the costs of health-care delivery related to AD are significant
for health-care systems and predicted to continue to grow. Individuals, families and
communities are substantially affected by the medical, social, psychological, and
financial burdens. Previous studies revealed that the costs for patients with AD fell
to a large extent outside the health-care sector and especially focused on the informal
care provided by caregivers (Wu et al. 2016; Zhu et al. 2006; Zencir et al. 2005;
Allegri et al. 2007). In China, a high proportion of elderly people with dementia live
in the community and rely heavily on their relatives for care, while formal care
accounted for the majority of the dementia care in many Western industrialized
Health Economics for Neuropsychological Diseases in China 797

Table 1 Mean annual PD-related costs (RMB)/(USD) per patient for 1 year (the exchange rate was
USD 1 = RMB 8.3 in 2004)
H&Y I H&Y II H&Y III H&Y IV H&Y V
Costs (n = 88) (n = 80) (n = 18) (n = 4) (n = 190)
Direct medical 4,862/586 3,757/453 3,822/460 5,179/624 4,305/519
costs
Outpatient 159/19 181/22 158/19 192/23 169/20
costs
Impatient 2,291/276 446/55 444/53 0/0 1,329/160
costs
Western drug 2,202/265 2,812/339 3,041/366 4,986/601 2,597/313
costs
Physical 94/11 271/33 95/11 0/0 167/20
treatment
TCM drug 114/14 45/5 83/10 0/0 80/10
costs
Direct 2,146/259 3,342/403 7,871/948 7,196/867 3,301/398
nonmedical costs
Transportation 116/14 109/13 159/19 6/0.7 115/14
Home care 940/113 1,264/152 3,836/462 6,690/806 1,473/177
Preventive 1,089/131 1,908/230 3,500/422 0/0 1,640/198
care foods
Special 1/0 61/7 376/45 500/60 73/9
equipment
Indirect costs 42/5 101/12 115/14 0/0 73/9
Sick leave 42/5 79/10 115/14 0/0 64/8
Early 0/0 21/3 0/0 0/0 9/1
retirement
Overall mean 7,050/849 7,200/867 11,809/1423 12,375/ 7,679/925
total cost 1491
PD, Parkinson’s disease; RMB, renminbi; USD, United States dollar; TCM, traditional Chinese
medicine

countries (Prince 2004; Wong and Leung 2012; Wang et al. 2014). To better
understand the status of the economic impact of patients with dementia, and provide
baseline data for future evaluations of health economic impacts of AD in China, we
investigated the consumption of resource and analyzed total, direct, and indirect
costs and its variations associated with the disease severity in patients with AD in
Shanghai, China.

Subjects and Methods

Sixty-seven patients with AD and their primary caregivers (spouse or offspring to
the patient in most cases) were enrolled in an observational study. Subjects were
recruited among patients attending regular visits to the AD clinic at the Department
of Neurology, Ruijin Hospital, and were identified with the Diagnostic and Statistical
Manual of Mental Disorders, 4th Edition (DSM-IV-TR), for AD. Patients were
required to have at least one primary caregiver for inclusion into the study. The
798 H.-l. Cui and G. Wang

Table 2 AD-related costsa (RMB)/(USD) per patient for 1 year (mean  SD) (the exchange rate
was USD 1 = RMB 8.0 in 2006)
Disease severity according to MMSE
Moderate
Costs Mild (n = 13) (n = 37) Severe (n = 16) Total (n = 66)
Direct medical 5,333  4,650/ 5,510  5,311/ 6,191  4,524/ 5,640  4,944/
costs 667  581 688  664 774  566 705  618
Outpatient 229  148/ 183  79/23  10 252  150/ 208  117/
costs 29  19 32  19 26  15
Inpatient costs 192  693/ 0  0/0  0 625  2,500/ 189  1,264/
24  87 78  313 24  158
Medications 4,911  4,710/ 5,291  5,216/ 5,230  4,599/ 5,202  4,906/
costs 614  589 661  652 654  575 650  613
Physical 0  0/0  0 70  286/9  36 123  245/ 69  247/9  31
therapy 15  31
Direct 2,829  3,471/ 2,667  1,750/ 3,050  1,965/ 2,792  2,199/
nonmedical 354  434 333  219 381  246 349  275
costs
Transportation 155  163/ 205  134/ 229  158/ 201  146/
19  20 26  17 29  20 25  18
Formal care 1,866  1,958/ 2,462  1,615/ 2,758  1,898/ 2,416  1,753/
233  245 308  202 345  237 302  219
Special 807  2,765/ 0  0/0  0 62  170/8  21 174  1,232/
equipments 101  346 22  154
Indirect costs 4,653  2,672/ 9,329  7,281/ 18,238  7,891/ 10,568  8,209/
582  334 1,166  910 2,280  986 1,321  1,026
Caregiver 4,653  2,672/ 9,329  7,281/ 18,238  7,891/ 10,568  8,209/
unpaid cost 582  334 1,166  910 2,280  986 1,321  1,026
Overall 12,816  4,843/ 17,507  10,922/ 27,480  10,365/ 19,001  11,037/
average cost 1,602  605 2,188  1,365 3,435  1,296 2,375  1,380
a
Mean annual costs per patient in 2006 RMB

study was approved by the Research Ethics Committee, Ruijin Hospital, affiliated to
Shanghai Jiaotong University School of Medicine, Shanghai, China. Voluntary
completion of the questionnaires was interpreted as consent to participate.

Data Collection Procedure

We interviewed all consecutive patients with AD and their caregivers at Ruijin
Hospital in person during the study period. We used the prevalence approach to
estimate the costs of the disease during a 1-year period (Rajput et al. 1984; Zou et al.
2015). The caregivers and patients were asked for information about AD-related cost
and resource use during the past year (from October 2005 to September 2006) before
the investigation, by using a questionnaire designed for this study. The questionnaire
included two main parts. Part I requested AD patient characteristics such as demo-
graphic details, information on concurrent conditions, disease course, and disease
severity, which were classified into three levels of impairment: mild (scores of
21–26), moderate (11–20), and severe (0–10) according to the Mini-Mental State
Health Economics for Neuropsychological Diseases in China 799

Examination (MMSE). AD resource use and cost data for the 1-year period were
derived from Part II which consisted of two sections: Part 2a assessed resource use
including drug treatment (including the drugs only for direct treatment of cognitive
deficit and not including drugs for secondary symptoms like constipation, sleep
disorders, etc.), number of outpatient visits and inpatient admissions, and means of
transportation to the clinic and assistive devices; Part 2b directly assessed the costs
of inpatient care, outpatient visits, mediations, assistive devices, medical-related
travel expenses, formal or professional care, and unpaid caregiving for the patients.
The caregivers and patients were also asked to provide investigators with their
medical records and inpatient and/or outpatient invoices.
We used the MMSE, activity of daily living (ADL)/instrumental activity of daily
living (IADL) scales, and neuropsychiatric inventory (NPI) to examine the patients’
cognitive function, functional capacity, psychotic symptoms, and behavioral prob-
lems as well as the Zarit Burden Interview (ZBI) to assess the informal care burden
of caregivers. The assessment tools were employed for patients in the present study:
(1) MMSE was used to assess patients’ cognitive functions. Three levels of cognitive
impairment were classified according to the MMSE score: mild (21–26), moderate
(11–20), and severe (0–10); (2) ADL and IADL were employed to estimate the
functional capacity of patients; and (3) NPI was applied to evaluate psychopathology
in dementia patients. It covers 12 neuropsychiatric disturbances common in
dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability,
euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances,
and appetite and eating abnormalities. The severity and frequency of each neuro-
psychiatric symptom were rated on the basis of scripted questions administered
to the patient’s caregiver. A total NPI score that ranges from 0 to 144 was calculated,
in addition to the scores for the individual symptom domains ranging from 0 to 12.
The assessment tools were applied for caregivers: The ZBI comprised 22 items.
Caregivers were required to indicate the level of distress caused by each item,
ranging from “never” to “nearly always” distressing, on a scale of 0–4 and summed
with a total score ranging from 0 to 88, and a high score correlated with a high level
of burden.

Calculation of Costs
The cost per patient was determined for each of the three levels of the disease
severity. (1) Unit costs were derived from the Shanghai public health administra-
tion’s tariff for 2006 (annual listing of all licensed drugs in Shanghai and their
prices), local taxi and public transportation published fares, Shanghai city guidelines
for mileage reimbursement, and the local fees for home care and home help service
provided by the local authority. (2) Indirect costs were estimated using the replace-
ment wage approach (Guerriere et al. 2008; Harrow et al. 2004). Hours of unpaid
care provided per day for total caregiving task according to the tasks of ADL and
IADL were asked in the following categories: 0, 1–2 h, 3–5 h, 6–8 h, 9–11 h, and
12 h or more. We transformed the categories into continuous values using the mean
of each category as the estimated hours of care provided. For subjects who reported
12 h or more per day for a particular type of task, we top-coded the value as 12 h.
800 H.-l. Cui and G. Wang

Evaluations of informal caregiving cost were based on the minimum hourly earnings
from Shanghai Municipal Labor and Social Security Bureau as the hourly wage rate
to estimate unpaid care-giving cost. (3) For health-care cost, only AD-related
resource use was recorded. (4) Monetary values were reported as 2006 Chinese
Yuan, Renminbi (RMB). For reference, the exchange rate was 1 USD = 7.97 RMB
or 1 EUR = 10.01 RMB in 2006.

Results

Characteristics of Patients
We interviewed 67 patients with AD and their caregivers. All participants
were community-dwelling patients in Shanghai. Valid data were collected from 66
patients, giving a response rate of 98.5%. There were 23 men and 43 women with the
overall mean age of 74.0 years (range: 53–90 years) and the mean disease duration
was 2.7 years (range: 1–12 years). With regard to MMSE classification, there were
13 patients in mild stage (score: 21–26), 37 moderate (11–20), and 16 severe (0–10).
Of these, 36 patients had at least 1 additional chronic disease such as hypertension or
diabetes.
Resources use was summarized as follows:

1. Neurological care: The average number of outpatient visits to and contacts with
an AD clinic was 14.9 per patient per year. During the year in question, two
patients were hospitalized to get treatment for pneumonia and diabetes,
respectively.
2. Medications: 51 of 66 patients received anti-dementia drugs for therapy. The most
frequently used drug was acetylcholinesterase inhibitors (62.1% of patients took
huperzine A, 28.8% donepezil, and 4.5% rivastigmine), 6.1% of patients took
memantine, 13.6% Ginkgo biloba extract (EGB), and 4.5% traditional Chinese
medicine (TCM).
3. Transportation and non-neurological care: All but 12 patients took a transporta-
tion service to reach the AD clinic. Public transportation and taxi were used by 39
(59.1%) and 7 (10.6%) patients, while use of personal car was 8 (12.1%) patients.
Fifty-eight (87.8%) patients visited the AD clinic usually with a companion and
8 (12.1%) patients had 2 or more companions who usually were spouse or
offspring of patients. Beyond the health care provided by neurologists, few
patients sought alternative traditional Chinese health care, and only one received
massage (1.5%) provided by physiotherapists.
4. Formal care: In addition to getting help from family members, mainly from
spouses and/or offspring, 9.0% of patients also required a private nursemaid.
To improve their condition, 12.1% of patients took preventive health-care foods
from their relatives.
Special equipments including wheelchairs were needed by 6.0% of patients.
5. Informal care: There were 33 men and 33 women with the overall mean age of
64.8 years among the primary caregivers. 68.2% of caregivers were patients’
spouses, 30.3% offspring, and 1.5% other relatives. The average time spent (h/
Health Economics for Neuropsychological Diseases in China 801

day) was 4.45 (1.5–12) for each patient with AD. The mean costs per patient for
1 year are summarized in Table 2.

Direct medical care costs averaged approximately RMB 5,640 per year per
patient, of which drugs accounted for the major costly component. Annual drug
costs averaged RMB 5,202 per patient. Nonmedical direct costs were much less than
direct health-care costs, averaging approximately RMB 2,792. Caregiver cost aver-
aged approximately RMB 10,568 per patient per year and was the most significant
item in the overall cost. Taken together, the overall mean annual cost for AD in our
series was approximately RMB 19,001.

Discussion

As the Chinese population is rapidly aging and the prevalence of neurodegenerative

diseases increase with age, it is likely that the incidence of AD, as well as PD in the
general population will rise in the coming years, thus imposing an increased strain on
health care and community resource in China. We believe that as a main branch of
disease in neuropathy with a generally longer course, neurodegenerative diseases
(represented by AD and PD) serve as the most suitable researching object to evaluate
the economic burden the diseases have exerted on individuals and the whole society.
For this reason, a clear understanding of the current patterns of resources use and
cost of this area is required for health policies planning.
As one of the biggest cities in China, Shanghai was considered to be the first city
coming into the aging era in China. At the same time, as one of the largest PD and
AD clinics locally, the residences of our patients were distributed throughout all the
districts in Shanghai. Patients usually choose one from a few large hospitals with
a Department of Neurology and then regularly visit there for their medical treatment,
and neurologists in private practice in Shanghai have not become the choice of
priority dealing with this branch of diseases. Besides the costs for overall patients,
we also estimated the costs for patients with different severities of the disease.
Therefore, the results might be a more accurate representation of the burden of PD
and AD in every disease stage. We believe that the result of these two investigations
could reflect the complete and realistic cost situation of the target population in
general. The main strength of the studies lies in the bottom-up approach, which is
more suitable for obtaining a detailed understanding of the direct and indirect costs
for neurodegenerative diseases (Bragaglia and O’Brien 2007; Dodel et al. 2004).
In general, costs of illness are divided into direct and indirect costs. Direct costs
include multiple dimensions of medical care costs and nonmedical care costs.
Indirect costs refer to those resources for loss due to the illness, including premature
deaths, patient and caregiver lost productivity, and unpaid caregiving time. Although
the coverage of the costs related to the diseases is large enough to involve almost all
the aspects of the health consumption, there are several limitations that could not be
shunned. First, the results of our study were based on a cross-sectional investigation,
rather than a longitudinal study. Although our study involved some important
802 H.-l. Cui and G. Wang

clinical features associated with the costs, the associations found in the study should
be cautiously interpreted. Second, although the indirect cost for AD and PD was
estimated to be substantial, it should be noted that we underestimated the actual
indirect cost by only including the cost of caregivers’ time spent on caregiving. For
example, indirect cost may also include those related to caregivers’ lost productivity
and reduced hours of work and income. In our study of AD, the majority (68.2%) of
the primary caregivers were spouses of patients and old retired persons; therefore
costs from reduced work hours were relatively minor. At the same time, reductions
in work hours due to caregiving and hours spent on caregiving may overlap and lead
to possible double counting of caregivers’ cost. Third, the study is limited by a
relatively small sample size. These limitations were compensated by the general
representative and refinement of diagnosis and richness of clinical variables in
our study. Still, it is believed that our results will be referred to as a baseline for
large-scale investigations in the future.
As the disease progresses, there is a loss of cognitive and physical functions
which ultimately leads to complete dependency, as is believed to be applicable for all
types of neurodegenerative diseases. For example, previous studies have revealed
a significant relationship between total costs of care and the level of dementia
severity in AD (Jonsson et al. 2006; Park et al. 2015). The association of the cost
and the severity of dementia were assessed by the level of cognitive impairment
(e.g., MMSE), the occurrence of behavioral disorders (e.g., NPI), and the physical
abilities (e.g., ADL and IADL) of our patients. As cognitive and physical functions
are highly correlated, reduced cognitive function is likely responsible for the impor-
tant share of the physical dependency. By contrast, our studies revealed that the
caregivers’ burden was not a significant factor associated with the total cost. This
result possibly indicated that the caregiver burden is not always paralleled with the
severity of disease and may be explained by our negligence in calculations of the
intangible time cost which related to pain and suffering endured by the caregivers.
Based on these, the total cost increased with the disease severity should be under-
standable. The mean total cost for patients in the severe stage was almost double or
threefold of that for patients in the mild stage, which was consistent with the results
from previous studies. In addition, because we used the city minimum hourly
earnings for all private industries as the hourly wage rate to estimate unpaid
caregiving costs, the cost of caregiver’s time which increased with the disease
severity was also easily understandable. Compared with the situation of economic
burden of PD, there are different component features of total cost. For PD and some
other types of neuropathy, previous studies indicated that the indirect cost is only a
minority of the total cost (Wang et al. 2006). However, the indirect cost rather than
the direct cost is the majority of the total cost in AD cases. These characteristics
possibly reflect different roles of caregivers’ care and lost productivity in the cost of
care determined by the features of disease itself. In addition, AD-related direct health
costs were compared between our study and that from developed countries such as
the United States, the United Kingdom, and developing areas like Latin America and
Turkey (Yang et al. 2013; Morris et al. 2015; Manes 2016). Although the absolute
values reported in our study are far lower than that from developed countries and
Health Economics for Neuropsychological Diseases in China 803

close to that from developing countries, the differences can be partly explained by
the substantial differences in hourly wage rates and actual income between western
countries and China. Differences in income level between countries might be able to
explain the difficulty to compare the actual economic burden for patients around the
world.
The findings of this study indicate that the economic burden for Chinese patients
with neurodegenerative diseases is heavy and increases dramatically with the disease
severity. The cost estimates provided by this study can be useful in future economic
evaluations of interventions aimed at reducing the progression of AD and PD in
China.

References
Allegri RF, Butman J, Arizaga RL, Machnicki G, Serrano C, Taragano FE, Sarasola D, Lon L.
Economic impact of dementia in developing countries: an evaluation of costs of Alzheimer-type
dementia in Argentina. Int Psychogeriatr. 2007;19(4):705–18.
Anderson GF, Chalkidou K. Spending on medical care: more is better? JAMA. 2008;299(20):
2444–5.
Bragaglia P, O’Brien L. Chronic disease management: the primary care perspective. Healthc Pap.
2007;7(4):26–8; discussion 68–70.
Dodel RC, Haacke C, Zamzow K, Paweilik S, Spottke A, Rethfeldt M, Siebert U, Oertel WH,
Schoffski O, Back T. Resource utilization and costs of stroke unit care in Germany. Value
Health. 2004;7(2):144–52.
Durrani H. Healthcare and healthcare systems: inspiring progress and future prospects. mHealth.
2016;2:3.
Fan VY, Savedoff WD. The health financing transition: a conceptual framework and empirical
evidence. Soc Sci Med. 2014;105:112–21.
Fan J, Dawson TM, Dawson VL. Cell death mechanisms of neurodegeneration. Adv Neurobiol.
2017;15:403–25.
Garibaldi P, Martins JO, van Ours J. Ageing, health, and productivity: the economics of increased
life expectancy. Oxford: Oxford University Press; 2010.
Gooch CL, Pracht E, Borenstein AR. The burden of neurological disease in the United States:
a summary report and call to action. Ann Neurol. 2017;81(4):479–84.
Guerriere DN, Tranmer JE, Ungar WJ, Manoharan V, Coyte PC. Valuing care recipient and family
caregiver time: A comparison of methods. International Journal of Technology Assessment in
Health Care. 2008;24(01):52–9.
Hall RE, Jones CI. The value of life and the rise in health spending. Q J Econ. 2007;122(1):39–72.
Harrow BS, Mahoney DF, Mendelsohn AB, Ory MG, Coon DW, Belle SH, Nichols LO. Variation
in cost of informal caregiving and formal-service use for people with Alzheimer’s desease.
American Journal of Alzheimer’s Disease & Other Dementias. 2004;19(5):299–308.
Jia J, Zhou A, Wei C, Jia X, Wang F, Li F, Wu X, Mok V, Gauthier S, Tang M, Chu L, Zhou Y, Zhou
C, Cui Y, Wang Q, Wang W, Yin P, Hu N, Zuo X, Song H, Qin W, Wu L, Li D, Jia L, Song J,
Han Y, Xing Y, Yang P, Li Y, Qiao Y, Tang Y, Lv J, Dong X. The prevalence of mild cognitive
impairment and its etiological subtypes in elderly Chinese. Alzheimers Dement. 2014;10
(4):439–47.
Jonsson L, Eriksdotter Jonhagen M, Kilander L, Soininen H, Hallikainen M, Waldemar G, Nygaard
H, Andreasen N, Winblad B, Wimo A. Determinants of costs of care for patients with
Alzheimer’s disease. Int J Geriatr Psychiatry. 2006;21(5):449–59.
Kowal SL, Dall TM, Chakrabarti R, Storm MV, Jain A. The current and projected economic burden
of Parkinson’s disease in the United States. Mov Disord. 2013;28(3):311–8.
804 H.-l. Cui and G. Wang

Langa KM, Larson EB, Crimmins EM, Faul JD, Levine DA, Kabeto MU, Weir DR. A comparison
of the prevalence of dementia in the United States in 2000 and 2012. JAMA Intern Med.
2017;177(1):51–8.
Liu N, Zhang J, Guo L. Alzheimer’s disease epidemiological situation. J Liaoning Univ Tradit Chin
Med. 2011;1:35–6.
Manes F. The huge burden of dementia in Latin America. Lancet Neurol. 2016;15(1):29.
Morris S, Patel N, Baio G, Kelly L, Lewis-Holmes E, Omar RZ, Katona C, Cooper C, Livingston G.
Monetary costs of agitation in older adults with Alzheimer’s disease in the UK: prospective
cohort study. BMJ Open. 2015;5(3):e007382.
Muangpaisan W, Hori H, Brayne C. Systematic review of the prevalence and incidence of
Parkinson’s disease in Asia. J Epidemiol. 2009;19(6):281–93.
Park M, Sung M, Kim SK, Kim S, Lee DY. Multidimensional determinants of family caregiver
burden in Alzheimer’s disease. Int Psychogeriatr. 2015;27(8):1355–64.
Prince M. Care arrangements for people with dementia in developing countries. Int J Geriatr
Psychiatry. 2004;19(2):170–7.
Rajput AH, Offord KP, Beard CM, Kurland LT. Epidemiology of parkinsonism: incidence,
classification, and mortality. Ann Neurol. 1984;16(3):278–82.
Sorenson C, Drummond M, Bhuiyan Khan B. Medical technology as a key driver of rising health
expenditure: disentangling the relationship. Clinicoecon Outcomes Res. 2013;5:223–34.
von Campenhausen S, Bornschein B, Wick R, Botzel K, Sampaio C, Poewe W, Oertel W, Siebert U,
Berger K, Dodel R. Prevalence and incidence of Parkinson’s disease in Europe. Eur
Neuropsychopharmacol. 2005;15(4):473–90.
Wang G, Cheng Q, Zheng R, Tan YY, Sun XK, Zhou HY, Ye XL, Wang Y, Wang Z, Sun BM,
Chen SD. Economic burden of Parkinson’s disease in a developing country: a retrospective cost
analysis in Shanghai, China. Mov Disord. 2006;21(9):1439–43.
Wang G, Cheng Q, Zhang S, Bai L, Zeng J, Cui PJ, Zhang T, Sun ZK, Ren RJ, Deng YL, Xu W,
Wang Y, Chen SD. Economic Impact of Dementia in Developing Countries: An Evaluation of
Alzheimer-Type Dementia in Shanghai, China. Journal of Alzheimer’s Disease. 2008;15
(1):109–15.
Wang J, Xiao LD, He GP, De Bellis A. Family caregiver challenges in dementia care in a country
with undeveloped dementia services. J Adv Nurs. 2014;70(6):1369–80.
Williams A. Health and Economics. Palgrave Macmillan, London. 1987.
Wong YC, Leung J. Long-term care in China: issues and prospects. J Gerontol Soc Work. 2012;
55(7):570–86.
Wu C, Gao L, Chen S, Dong H. Care services for elderly people with dementia in rural China: a case
study. Bull World Health Organ. 2016;94(3):167–73.
Yang Z, Lin PJ, Levey A. Monetary costs of dementia in the United States. N Engl J Med. 2013;
369(5):489.
Zencir M, Kuzu N, Beser NG, Ergin A, Catak B, Sahiner T. Cost of Alzheimer’s disease in
a developing country setting. Int J Geriatr Psychiatry. 2005;20(7):616–22.
Zhang Y, Xu Y, Nie H, Lei T, Wu Y, Zhang L, Zhang M. Prevalence of dementia and major
dementia subtypes in the Chinese populations: a meta-analysis of dementia prevalence surveys,
1980–2010. J Clin Neurosci. 2012;19(10):1333–7.
Zhang H, Loi SM, Zhou S, Zhao M, Lv X, Wang J, Wang X, Lautenschlager N, Yu X, Wang H.
Dementia literacy among community-dwelling older adults in urban China: a cross-sectional
study. Front Public Health. 2017;5:124.
Zhu CW, Scarmeas N, Torgan R, Albert M, Brandt J, Blacker D, Sano M, Stern Y. Clinical features
associated with costs in early AD: baseline data from the Predictors Study. Neurology. 2006;
66(7):1021–8.
Zou YM, Liu J, Tian ZY, Lu D, Zhou YY. Systematic review of the prevalence and incidence
of Parkinson’s disease in the People’s Republic of China. Neuropsychiatr Dis Treat.
2015;11:1467–72.
Causal Inference Methods in
Pharmacoepidemiology

Laura Pazzagli and Xiaojuan Li

Contents
Pharmacoepidemiology and Causal Inference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 806
Common Study Designs in Pharmacoepidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
Cohort Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
New-User Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
Active Comparator Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Case-Control Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Within-Subjects Designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
Exposures in Pharmacoepidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
Confounding in Pharmacoepidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 812
Confounding Adjustment Methods in Pharmacoepidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . . 814
Potential Outcomes Framework and Causal Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814
Methods for Time-Fixed Confounding Adjustment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
Methods for Complex Time-Varying Confounding Adjustment . . . . . . . . . . . . . . . . . . . . . . . . . . . 816
Applications in Neuro-Psycho-Pharmacoepidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817
Applicability of Causal Inference Methods in Pharmacoepidemiology . . . . . . . . . . . . . . . . . . . . . . . . 818
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820

Abstract
This chapter provides an introduction to pharmacoepidemiology, with a special
focus on some of the key concepts related to the application of causal inference
methods in pharmacoepidemiology, particularly in the time-varying setting. The
chapter first describes frequently used study designs in pharmacoepidemiologic
studies of treatment effects. The chapter then follows with drug exposures and
L. Pazzagli (*)
Centre for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Stockholm,
Sweden
e-mail: laura.pazzagli@ki.se
X. Li
Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care
Institute, Boston, MA, USA
e-mail: Xiaojuan_Li@HarvardPilgrim.org

© Springer Nature Switzerland AG 2022 805

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_14
806 L. Pazzagli and X. Li

confounding in time-fixed and time-varying settings. The chapter continues with

a range of causal inference methods developed to evaluate treatment effects while
appropriately accounting for time-fixed and time-varying confounding, which is
followed by select examples of published studies that have applied these methods
to evaluate effects of drug treatments in the field of Neuro-Psycho-Pharmacoepi-
demiology. Finally, the chapter concludes with a discussion on the considerations
needed in the applications of these causal inference methods in studies with
observational data.

Pharmacoepidemiology and Causal Inference

Pharmacoepidemiology is a branch of science that incorporates principles from both

clinical pharmacology and epidemiology (Pharmacoepidemiology 2019a, b, c). A
special focus in pharmacoepidemiology is given to the investigation of the effects of
drug treatments measured in terms of beneficial (effectiveness) and adverse (safety)
events in large populations exposed to a drug compared to populations unexposed or
exposed to some comparator drug(s). Evidence of drug treatment effects can be
generated through randomized clinical trials (RCTs) or analysis of prospectively or
retrospectively collected observational data. While the RCTs have been traditionally
accepted as the standard for generating evidence, the use of observational studies for
evidence generation is gaining interest. Observational studies provide a great oppor-
tunity to evaluate real-world effectiveness and safety of drug treatments, especially
for long-term drug effects when longitudinal follow-up data are available.
RTCs, by definition, are conducted in the experimental setting where the expo-
sure to the treatment of interest is randomized. Based on clinical knowledge,
researchers decide beforehand the information to be collected on exposures to the
treatment, the health outcome events, and important factors influencing the
exposure-outcome association, such as age, sex, and comorbidities. Individuals in
the study population are randomized to the drug of interest or the comparator
treatment and followed for relevant health outcomes for a prespecified period of
time. The randomization of trial participants into the treatment groups controls for
measured and unmeasured confounding at baseline. Together with the possibility of
having access to all the important factors related to the association between the drug
and the health outcomes, a well-conducted RCT allows researchers to draw causal
conclusions and provide unbiased measures of the efficacy and safety of the drug
under study. Therefore, RCTs have been long considered the “gold standard” to
answer questions related to drug exposures.
Generally, the study populations included in the RCTs are small, likely selected,
and only followed for a short period of time due to time or resource constraints. The
presence of drop out or lack of adherence to the assigned treatment during the
follow-up can adversely affect the validity and generalizability of results in a trial
(Pearl et al. 2016). Moreover, due to ethical reasons or resource constraints, some-
times RCTs are not feasible for some research questions. Appropriate analyses of
observational data provide a valuable alternative to generate evidence. In recent
Causal Inference Methods in Pharmacoepidemiology 807

years, important efforts have been made to integrate evidence coming from both
experimental and observational settings and to enhance the use of retrospectively
collected observational data in pharmacoepidemiology (ElZarrad and Corrigan-
Curay 2019; Franklin et al. 2019; Schneeweiss et al. 2016). This has led to increased
use of observational studies to assess the effectiveness and safety of a drug after
regulatory approval, particularly when RCTs are unfeasible or cannot be done in a
timely manner.
Use of routinely collected observational data for evidence generation has many
advantages. Using readily available data, a research question can be answered in a
timely manner and at lower cost with an observational study relative to using an
RCT. The use of large heterogeneous populations, combined with appropriate
analyses, has the potential of wider generalizability of the estimated treatment
effects. However, challenges exist to provide valid evidence with observational
data. Because the treatment is not randomized in the observational setting,
researchers need to rely on the information collected in the data source to adjust
for potential confounding. However, because the data are routinely collected for
administrative or clinical reasons rather than for a specific research question, it is
possible that information is unmeasured on potentially important factors for the
exposure-outcome relationship of interest, leading to potentially biased estimates of
treatment effects. Moreover, when investigating time-varying treatment effects, the
presence of complex time-varying confounding, which may be affected by prior
treatments, necessitates the use of proper adjustment methods other than conven-
tional regression approaches. These challenges warrant the use of robust and flexible
causal inference methods in studies using observational data.
Causal inference is a set of graphical and mathematical tools developed to answer
causal questions using observational data. These methods allow to link causal
structures between the variables involved in a research question to the observed
data via causal assumptions and modeling needed to draw statistical inference.
Specifically, the potential outcomes framework (Rubin 1974) allows the estimation
of causal effects of treatments by comparing the potential outcomes that would have
been observed if all individuals in the study population were exposed to each
treatment of interest. Under this framework, several methods have been proposed
and used to assess drug effectiveness and safety in pharmacoepidemiology and will
be explored in the rest of this chapter.

Common Study Designs in Pharmacoepidemiologic Studies

Pharmacoepidemiologic studies use epidemiologic methods and study designs to

answer clinical and epidemiologic questions of interest related to the use of phar-
macological treatments. This section introduces some common study designs fre-
quently used in observational pharmacoepidemiologic studies, specifically for the
assessment of treatment effects in comparative effectiveness and safety research.
Each study design has its characteristics as well as strengths and limitations. It is
808 L. Pazzagli and X. Li

important to consider all potential study design options before choosing the most
appropriate one for any given research question.

Cohort Study Design

In general, epidemiologic studies are defined by how study participants are sampled.
In cohort studies, individuals are sampled based on their treatment (i.e., exposure) status
at a certain point in time and followed over time for the occurrence of outcome(s).
Cohort entry is often defined by a meaningful event such as initiation of a medication
treatment, as is the case for the new-user design discussed below (Ray 2003). A group
of individuals who have not been exposed to the medication under study or exposed to
a comparator drug are also included in the cohort to use as a comparison group. The
probabilities of developing the outcome of interest in the two groups are then compared
to estimate the treatment-outcome association.
A major advantage of the cohort study design is that it measures exposure and
outcome, and exposure and potential confounders in temporal sequence, making it
possible to elucidate causal relationships. Cohort studies also allow for investigation
into multiple outcomes from given treatments in one study. Compared to the design
and conduct of an RCT, cohort studies, especially with retrospective collection of
data from existing electronic health databases or registries, are also timelier and more
competitive in terms of economic resources.
The cohort study design becomes costly and less timely when study participants
need to be recruited first and followed over time such as in prospective cohort
studies. It can also be inconvenient for studies of rare outcomes (e.g., cancer) that
require a long follow up. The common challenges that affect all observational studies
also apply to the cohort study design, which include the inability to control for all
confounders that distort the treatment-outcome relationship under interest as well as
the potential for selection bias due to the way participants are selected into the cohort
and differential loss to follow up between the comparison groups due to migration,
death, or drop-out of the study.

New-User Design

Within cohort studies for investigating pharmacological treatment effects, the con-
ventional prevalent-user design includes both prevalent and new users of a drug.
However, prevalent users who have been taking a medication for some time are
likely to be more tolerant to the drug, perceive some therapeutic benefits, have better
health in general, or experience long-term adverse effects due to the accumulation of
the treatment over time (Glynn et al. 2001). Consequently, the prevalent-user design
is subject to selection bias and confounding bias. In addition, covariates selected for
confounding adjustment in prevalent-user studies may have been affected by prior
treatment. Necessary adjustment for these covariates to remove confounding will,
however, remove some treatment effect under study.
Causal Inference Methods in Pharmacoepidemiology 809

The new-user design (Ray 2003) provides a solution to remove the confounding
and selection bias associated with the prevalent-user design by restricting study
cohorts to all individuals in a defined population who initiate a course of treatment
with the study medication. This design ensures the appropriate temporal ordering of
baseline confounders, exposures, and outcomes and anchors the timescale for
analyses at time since treatment initiation for all individuals in the study, conse-
quently avoiding selection bias and adjustment for intermediate variables that may
be on the causal pathway between exposure and outcome. The new-user design is
widely used in pharmacoepidemiologic studies.

Active Comparator Design

In cohort studies, another important design aspect to consider is the choice of the
comparator group. When comparing treated individuals with untreated individuals,
the study is prone to confounding by indication (Epidemiology 1996) and
confounding by frailty, which are difficult to control for. The active-comparator
design (Lund et al. 2015) (Schneeweiss et al. 2007) uses a group of individuals
initiating on a different therapeutic alternative for the same indication to help
mitigate biases from both types of confounding. When coupled with the new-user
design, this design can also reduce the potential for immortal-time bias (Suissa
2003). The active-comparator, new-user study design is considered to be the stan-
dard for comparative effectiveness research in pharmacoepidemiology (Johnson
et al. 2013). Researchers can use current treatment guidelines for the condition of
interest to select active comparator treatments.

Case-Control Study Design

In contrast to the cohort study design, the case-control study design (Martinez et al.
2010) samples individuals into a study based on their outcome status. With this
design, individuals who have developed the outcome of interest are first identified
(i.e., cases). Their treatment exposure history is then compared with that of individ-
uals without the outcome of interest (i.e., controls) to estimate the odds ratio, the key
measure of treatment-outcome association in case-control studies. Due to the lack of
denominators for the two treatment groups, case-control studies cannot directly
estimate incidence or incidence rates of the outcome in the two groups, thus cannot
directly estimate the relative risk, unless additional information from the underlying
cohort is available. However, when the outcome under study is a rare condition, the
estimated odds ratio in case-control studies approximates the relative risk.
With the case-control study design, it is possible to examine multiple treatment
exposures in one single study. By oversampling of individuals with the outcome,
case control studies are efficient compared to traditional cohort studies in that they
generate the same adequate information using a smaller sample size, reducing the
cost and burden of prospective data collection. This efficiency gain, however, is
810 L. Pazzagli and X. Li

significantly reduced in the contemporary era of pharmacoepidemiology where large

electronic healthcare databases and registries become the main sources of data for
studies. Essentially all the relevant information can be derived from existing data,
largely reducing the cost of data collection for a full cohort study. The efficiency
benefits of the case-control study design can still be of importance when additional
data (e.g., validation data) needs to be collected for a given study.
The main challenges with the case-control study design include the appropriate
selection of controls, which otherwise could lead to selection bias. Additionally,
case-control studies are prone to recall bias, especially when the information on
treatment or confounders needs to be obtained retrospectively via interviews or
surveys. Individuals experiencing the outcome event are more likely to remember
certain antecedents compared to controls. Study participants may exaggerate or
minimize what they consider to be risk factors due to social desirability bias.
In the contemporary era of pharmacoepidemiology, increasingly available elec-
tronic healthcare databases, registries, and recent advances in computational sci-
ences make the advantages that previously made case-control studies attractive less
relevant. Some researches argue that these designs should no longer be applied when
using secondary data sources where information are already available and suitable
for a cohort design (Schuemie et al. 2019). However, this study design is still
commonly used for initial, inexpensive evaluation of risk factors. It is also particu-
larly useful when additional information is needed to be collected for a large study.

Within-Subjects Designs

Cohort study and case-control study designs assess effects of pharmacological

treatments by comparing two groups. When suitable comparison groups or controls
are difficult to identify, within-subject designs that use self-controls offer a good
alternative. These designs include case-cohort design (Prentice 1986), case-
crossover design (Maclure 1991), case-time controlled design (Suissa 1995), and
self-controlled case-series design (Farrington 2004; Whitaker et al. 2006). In addi-
tion to not requiring a separate comparison group, these designs also have the
advantages that all time-fixed confounders, measured or unmeasured, are well
controlled for by design since the comparisons are made within subjects. Many
studies have utilized these designs in pharmacoepidemiologic assessments.

Exposures in Pharmacoepidemiologic Studies

In most pharmacoepidemiologic studies, especially comparative effectiveness

research, the aim is to provide evidence regarding the benefits and harms of a
pharmacological treatment or intervention to inform clinical decision-marking. In
other words, often the interest is on the valid causal effect of some treatment/
exposure A on an outcome of interest Y as shown in the simplified directed acyclic
graph (DAG) in Fig. 1 by a direct arrow from A to Y. A detailed introduction to
Causal Inference Methods in Pharmacoepidemiology 811

DAGs is included in the next section on “Confounding in Pharmacoepidemiologic

Studies.” Briefly, DAGs are useful tools to draw causal diagrams and provide a
structured way to present an overview of the causal research question and its context
(Pearl 1995). Serving as a visual representation of causal relationships and making
underlying assumptions explicit, DAGs can help researchers identify the presence of
confounding and inform ways to address it.
Although there is a conceptual difference, for practical reasons, the terms treat-
ment and exposure are used interchangeably herein, indicating the exposure in this
instance is a pharmacological treatment. An exposure is considered to be fixed if an
individual’s baseline exposure level determines their exposure level at all later times.
Drug treatments can be time-fixed if they only occur at the start of follow-up,
sometimes referred to as point exposures. Examples of point exposures include
one-dose flu shot, or initiation of benzodiazepines. Drug treatment can also be
time-fixed if they do not change over time, or they change over time in a determin-
istic way. Nonpharmacological exposures that do not change over time include
genetic variants that contribute to variability in drug response in a pharmacogenomic
study. Examples of exposure that evolves deterministically include time since
treatment initiation of benzodiazepines.
An exposure that is not fixed is considered to be time-varying. With time-varying
treatments, the exposure to a pharmacological treatment changes over time (Fig. 2).
In fact, many exposures in pharmacoepidemiologic and comparative effectiveness
research studies are time-varying, especially when studies concern chronic condi-
tions such as hypertension, diabetes, depression, and other chronic mental disorders.
In many cases, effective long-term care of patients with these chronic conditions
requires ongoing medical interventions following the chronic care model
(Bodenheimer et al. 2002a; Bodenheimer et al. 2002b). Compared to the acute
care model, the chronic care model provides a framework for patient-centered care
and emphasizes personalized care according to patient needs, and optimization of
patient outcomes, through a series of interventions, and health services based on
evidence rather than expert opinion only. Under this model, treatment doses and/or
types are frequently adjusted based on a patient’s evolving clinical response. Several

Fig. 1 A simplified directed acyclic graph for the relationship between a treatment A and an
outcome Y

Fig. 2 A simplified directed acyclic graph for the relationship between a time-varying treatment
A and an outcome Y
812 L. Pazzagli and X. Li

neuropsychiatric programs have adopted the chronic care model to provide care,
such as treatments for depression care in elderly patients (Mcevoy and Barnes 2007).
Other examples of time-varying treatments include intermittent therapies such as
selective serotonin reuptake inhibitors (SSRIs) for the treatment of premenstrual
symptoms.
In this context, dynamic treatment strategies offer a way to operationalize the
sequential decision-making process involved in adaptive clinical practice. A
dynamic treatment strategy is a sequence of decision rules, one per each stage of
treatment/intervention depending on the clinical progress of the patient (Hernan et al.
2009). Each decision rule considers a patient’s individual characteristics and treat-
ment history observed up to a given stage and offers a recommended treatment at
that stage (recommendations can include treatment type, dosage, and timing).
Conceptually, a dynamic treatment strategy can be viewed as a decision support
system, which is one of the six elements of the chronic care model. By allowing
providers to adjust treatment due to side effects or lack of effectiveness, dynamic
treatment strategies are more realistic compared to static strategies or recommenda-
tions that require the same treatment over time regardless. Accordingly, more and
more clinical guidelines provide treatment recommendations in the format of
dynamic treatment strategies.

Confounding in Pharmacoepidemiologic Studies

The relationship between a drug treatment and a health outcome may be confounded
by factors which affect both the treatment and the outcome. In the presence of
confounding, the true effects of the treatment under study on the outcome of interest
are mixed with effects of factors other than the drug treatment itself (Greenland et al.
1999b). Without appropriately accounting for the presence of confounding, the
estimated treatment-outcome associations will be confounded. Special attention is
needed on the analytical methods to estimate unbiased causal effects in the presence
of confounding factors.
To identify confounding, a useful tool is provided and formalized in the theory of
DAGs (Greenland et al. 1999a; Pearl 1995). DAGs are directed in that the direction
of the arrowhead indicates the directions of the hypothesized relationships between
the variables. Because a variable cannot be caused by itself, and the future cannot
affect the past, DAGs are acyclic. The use of these diagrams allows one to visualize
causal links between variables in an intuitive way and, together with background
clinical knowledge, helps to identify potential confounders for the treatment-
outcome association under study. The presence of confounding, which exists if
the drug treatment remains associated with the outcome also after removing all the
arrows representing treatment effects, is intuitively represented in DAGs by the
presence of a common cause for the drug treatment and the health outcome (Fig. 3).
Background knowledge is often needed to draw the DAG for a research question.
In the example of a pharmacoepidemiologic study that concerns the effect of a drug
treatment on the health outcome of interest, background knowledge or assumptions
Causal Inference Methods in Pharmacoepidemiology 813

Fig. 3 A directed acyclic

graph for the relationships
between a treatment A, an
outcome Y, and a
confounder C

Fig. 4 A directed acyclic

graph for the relationships
between a time-varying
treatment A, an outcome Y,
and a time-varying
confounder C

are needed with respect to the mechanism of action. These assumptions are qualita-
tive rather than quantitative because causal links represented in causal diagrams do
not contain information about the functional form that connects variables.
The simplified DAG in Fig. 3 represents the scenario where confounding is
present for the relationship between a time-fixed drug treatment A and an outcome
Y. In order to estimate the true causal effect of the treatment A on Y, appropriate
adjustment for the confounder C is necessary.
When investigating long-term treatment effects using observational data, effect
modification may be introduced by time-varying covariates, and incorrect identifi-
cation of the causal pathways may occur (Newsome et al. 2018). Moreover, the DAG
gets more complex in the setting of time-varying treatments, especially in the
presence of time-varying confounding; the levels of the variables at different time
points affect the levels of the other variables involved in the study (Fig. 4). There-
fore, to identify drug treatment effects, analyses need to account for changes in
treatments and confounders across time.
In the setting of dynamic strategies with treatments changing over time, the
scenario becomes even more complex because some confounding variables may
also be affected by previous treatment. Thus, these time-varying confounders
become intermediates on the causal pathway between the treatment and the outcome,
introducing a treatment-confounder feedback (as shown by the direct arrow between
A0 and C1 in Fig. 5).
An example of a time-varying confounder that also acts as causal intermediate is a
drug adverse effect caused by the previous treatment received. Patients experiencing
adverse effects may be advised to stop or change the therapy (influencing the
814 L. Pazzagli and X. Li

Fig. 5 A directed acyclic

graph for the relationships
between a time-varying
treatment A, an outcome Y,
and a time-varying
confounder C in presence of
treatment-confounder
feedback

treatment at a later time t1) with consequences for the health outcome of interest.
This complex time-varying confounding deems traditional regression methods inva-
lid. Fortunately, causal inference methods are available to deal with this specific
problem and offer a great opportunity to estimate causal effects of time-varying
treatments in the presence of time-varying confounders and treatment-confounder
feedback (Robins and Hernán 2009).

Confounding Adjustment Methods in Pharmacoepidemiologic

Studies

Potential Outcomes Framework and Causal Assumptions

In causal inference, the potential outcomes framework, also known as the Neyman-
Rubin Potential Outcomes, or the Rubin causal model, provides an approach to
assess causality in nonrandomized studies (Rubin 1974, 1977, 1978). A potential
outcome is the outcome for an individual under a potential treatment or treatment
strategy. The causal effect of a treatment is the difference between the potential
outcome under the treatment and the potential outcome under no treatment (or the
comparator treatment). However, in reality, all potential outcomes for an individual
cannot be observed. Instead, only one outcome can be observed for any individual,
the outcome under the treatment actually received, making it impossible to estimate
individual causal effects. The missingness of potential outcomes under all possible
drug treatment strategies for individuals in a study is the fundamental problem of
causal inference, which relates causal inference from observational data to a problem
of missing data. Even though the estimation of individual causal effects is not
possible with the observed data, other contrasts of interest, such as the population
average treatment effect, can be estimated using observational data under the
potential outcomes framework.
The potential outcomes framework needs several assumptions to draw causal
inference using observational data. The stable-unit treatment value assumption
(SUTVA) (Rubin 1986) requires that the outcome of an individual is independent
from the treatments assigned to the other individuals in the study. This assumption is
often referred to as two parts: no interference and no multiple versions of a treatment
Causal Inference Methods in Pharmacoepidemiology 815

level. A second important assumption is no unmeasured confounders, also known as

ignorability of the mechanism for the treatment assignment or conditional exchange-
ability (Rosenbaum and Rubin 1983). This important assumption implies that, to be
able to draw causal conclusions, researchers must have access to all potential
confounders for the relationship between the drug treatment and the outcome
under study. Another assumption is referred to as positivity or overlap, which
implies that each individual in the study population is a potential receiver of all
possible drug treatment levels or strategies. When both no unmeasured confounders
and positivity assumptions hold, the strongly ignorable treatment assignment
assumption is reached (Rosenbaum and Rubin 1983). A fourth assumption referred
to as consistency is related to the potential outcomes used to define causal effects in
that it implies that the potential outcomes for each individual in the study correspond
to the actual outcomes under all the possible treatment strategies considered
(VanderWeele 2009). Lastly, to obtain valid estimates of causal treatment effects, it
is crucial that the models used in the estimation are correctly specified, as in any
statistical estimation questions.

Methods for Time-Fixed Confounding Adjustment

Given the lack of treatment randomization, observational studies are confounded by

definition. Appropriate methods are needed to adjust for time-fixed and time-varying
confounding to elucidate the true treatment effect. In the causal inference literature,
several methods have been developed to adjust for confounding and have been
applied for effect estimation in a number of pharmacoepidemiologic studies
(Palmsten et al. 2013; Sun et al. 2021; Wang et al. 2005). In general, the choice of
the confounding adjustment method depends strongly on the type of confounding
present in a specific study. Before introducing specific approaches to deal with each
type of confounding, a review of the general confounding adjustment methods is
presented.
Regression adjustment is a commonly used approach for confounding adjustment
by including the identified confounders as covariates in the outcome regression
model. The approach is straightforward, especially for time-fixed confounding, but
can incur estimation problems when the number of confounders to be controlled for
in the model is large, especially when the outcome under study is rare (Jackson et al.
2017). Confounding adjustment approaches such as matching (to match exposed
individuals to the comparators) and stratification (to stratify exposed individuals and
comparators based on specified characteristics) can be applied using the values of the
identified potential confounders. Another method to estimate drug treatment causal
effect is standardization, which allows identification of potential outcomes via
standardized means of the observed outcomes (Hernán 2020).
In settings with a large number of confounders, summary scores such as a
propensity score or disease risk score provide an alternative approach. The propen-
sity score is the probability of receiving the drug treatment conditional on a set of
baseline characteristics. An important property of the propensity score is the ability
816 L. Pazzagli and X. Li

to balance exposure groups with respect to the set of covariates used to estimate the
score (Rosenbaum et al. 2005). After estimation of the propensity score using a
regression model for the treatment, different confounding adjustment approaches
including matching, weighting, or stratification can then be used (Desai et al. 2017;
Glymour et al. 2019; Park et al. 2018). One can also adjust for confounding by
including the propensity score in the outcome regression model; however, this
approach requires the specification of the outcome model in relation to the propen-
sity score and that the relationship must be correctly specified. Moreover, the method
estimates a conditional treatment effect rather than a marginal treatment effect as
estimated via other propensity score-based methods. With propensity score
matching, individuals treated with the drug of interest are matched with individuals
from the comparison group on the estimated propensity scores, resulting in a group
of individuals with different treatment status balanced with respect to the covariates
used to estimate the propensity score. The treatment effect can then be estimated
using the matched groups in the outcome analysis. With propensity score stratifica-
tion, individuals in a study are grouped into strata based on their propensity score
values before effect estimation (Desai et al. 2017). With propensity score weighting,
the study population is weighed based on an inverse function of their estimated
propensity scores to create a pseudo-population in which the distributions of
covariates used in the propensity score estimation are balanced (which is similar to
standardization). The suite of propensity score-based approaches model the con-
founders in the model for the treatment rather than for the outcome, making them
particularly advantageous in the context of rare outcomes (Jackson et al. 2017).
Originally proposed for binary treatment, the propensity score methods have been
extended to the case of comparisons of multiple drug treatments where a generalized
propensity score can be used (Imai and Van Dyk 2004).
In studies involving time-fixed drug treatments, all these aforementioned
approaches can be used to estimate causal treatment effects. The choice of approach
depends on the research question and targeted treatment effect (e.g., average treat-
ment effect in the treated, or average treatment effect in the entire population). In
longitudinal studies with time-varying drug treatment and confounders, the methods
are still suitable, but regression models need to account for treatment and con-
founders as time-varying covariates. However, in situations where time-varying
confounders are affected by prior treatment, special problems arise and more
advanced approaches are needed.

Methods for Complex Time-Varying Confounding Adjustment

In longitudinal studies where chronic treatments are used, it is common to have

complex time-varying confounding where time-varying confounders are affected by
previous drug treatments, resulting in treatment-confounder feedback (Hernán
2020). Special caution is required when estimating causal drug treatment effects.
In this setting, a drug treatment strategy affects the subsequent value of a confounder
variable used to decide treatment strategies, and the modified confounder in turn
Causal Inference Methods in Pharmacoepidemiology 817

affects the decision on the next drug treatment level. This type of complex
time-varying confounding is very common in dynamic drug treatment strategies.
For example, in a study of effectiveness of continuous antidepressant treatments, the
severity of other comorbidities associated with the response to the treatments may be
affected by the antidepressants received earlier on and may affect the decision on the
future use of antidepressants. In the presence of complex time-varying confounding,
traditional regression methods that adjust for the severity of comorbidities (used as a
covariate in the model) would fail to estimate the part of the effect of antidepressants
use on the outcome of interest mediated by comorbidities severity.
The complexity introduced by the treatment-confounder feedback requires spe-
cific methods for confounding adjustment. Robins’ g-methods are a special class of
methods meant to deal with this type of time-varying confounding. They include
inverse probability weighting estimation of marginal structural models, the paramet-
ric g formula, and g-estimation of structural nested models. Marginal structural
models can be estimated via weighted regression models. Each individual in the
study will receive a weight, which is a function of the probability of receiving the
treatment conditional on the history of the time-varying treatments and confounders.
The weighting process allows simulation of the potential outcomes for the individ-
uals under all treatment strategies. This in turn allows for estimation of the marginal
effect of exposure to the treatment on the outcome without directly adjusting in the
regression model for time-varying confounders that have resulted in treatment-
confounder feedback. The parametric g formula uses parametric models for the
distribution of the outcomes conditional on treatment and confounders and the
joint distributions of the confounders to simulate the potential outcomes under
different treatment strategies (Robins 1986). G-estimation of structural nested
models allows to calculate the potential outcomes for each individual under all
possible treatment strategies using the observed data. The effect of the exposure to
the treatment on the outcome is estimated from the observed data independently at
each time point adjusting for the history of the time-varying treatments and con-
founders. The estimated effects can be used to calculate all the potential outcomes
and the difference between the potential outcomes that would be observed if
individuals were always exposed and the potential outcomes if individuals were
never exposed (or exposed to another treatment strategy) correspond to a causal
effect (Robins 1994). The g-methods differ in implementation and computational
intensity, but they all aim to simulate the potential outcomes that would have been
observed under all the potential dynamic treatment strategies (Daniel et al. 2013; Li
et al. 2017; Naimi et al. 2017; Pazzagli et al. 2018).

Applications in Neuro-Psycho-Pharmacoepidemiology

Applications of these causal inference methods have increased in the field of neuro-
psycho-pharmacoepidemiology over recent years. For example, an investigation of
the risk of suicide attempts and suicide in adults in relation to antidepressant agents
used a propensity score adjusted analysis (Schneeweiss et al. 2010). Another
818 L. Pazzagli and X. Li

example studied the risk of death in elderly users of conventional versus atypical
antipsychotic medications using traditional multivariate Cox models, propensity-
score adjustments, and an instrumental-variable analysis (Wang et al. 2005). The use
of antidepressants during pregnancy in relation to the risk of cardiac defects was
examined using a propensity score stratification approach (Huybrechts et al. 2014).
Propensity score stratification and high-dimensional propensity score have been
used to assess the risk of antidepressant use during late pregnancy and persistent
pulmonary hypertension in the newborn (Huybrechts et al. 2015). Anti-convulsant
use and the risk of attempted suicide, suicide, and violent death has been investigated
using Cox proportional hazards models and propensity score–matched analyses
(Patorno et al. 2010). The adjuvant use of gabapentinoids with opioids and the
association with the risk of opioid-related adverse events in patients undergoing
surgery has been studied using propensity score stratification (Bykov et al. 2020).
These studies are examples of a more extensive literature on causal inference
applications in Neuro-Psycho-Pharmacoepidemiology studies using observational
data.

Applicability of Causal Inference Methods

in Pharmacoepidemiology

This chapter gives an introduction to pharmacoepidemiology and highlights the

potential to use observational data to generate evidence on effectiveness and safety
of drug treatments, using appropriate study design combined with causal inference
methods. The increasing need to provide evidence regarding effectiveness and safety
of drug treatments in a timely manner draws unprecedented attention to observa-
tional studies using existing large databases and registries. Despite an appealing
alternative when randomized trials cannot be conducted, causal estimation of drug
treatment effect in observational studies is complicated by many challenges arising
from the use of observational data.
Among these challenges is the presence of confounding due to the lack of
treatment randomization in observational studies. The type of confounding, its
complexity, and the type of methods required to appropriately account for
confounding vary depending on the research question and the availability of data.
When the research interest is on the effect of a time-fixed treatment, researchers need
to account for confounders which are measured at one point in time and can choose
from a suite of methods such as traditional regression models, stratification, and
standardization as well as propensity score-based methods which are particularly
useful in the setting of high-dimensional confounding. When the research question is
concerned with the effect of time-varying treatments, some of these methods such as
regression models adjusting for time-varying confounders may still be used in the
absence of treatment-confounder feedback. However, when treatment-confounder
feedback is present, the complexity of the confounding involved requires the use of
more advanced methods. G-methods including inverse probability weighting esti-
mation of marginal structural models, the parametric g formula, and g-estimation of
Causal Inference Methods in Pharmacoepidemiology 819

structural nested models should be considered. The complexity of these advanced

methods and the lack of detailed data previously hindered their applications in
pharmacoepidemiologic studies. Fortunately, increasingly available rich data,
advances in software developments, and tutorial papers on the use of the methods
have been facilitating a wider use of these methods.
It is important to consider the assumptions required by these causal inference
methods when using them to tackle a pharmacoepidemiologic question of interest.
The assumptions such as SUTVA, no unmeasured confounders, positivity, consis-
tency, and correct model specifications must be evaluated and tested when possible.
Moreover, the use and validity of causal inference methods also strongly depends on
data availability. Without appropriate rich data with a great level of granularity, it is
challenging to adjust for the complex confounding structure and draw valid infer-
ence even with these advanced methods when assessing the effect of dynamic
treatment strategies (Li et al. 2017).
To conduct a pharmacoepidemiologic study, it is recommended to start with the
formulation of a specific research question, followed by a thorough evaluation of the
data, careful considerations of suitable study designs, and finally an appropriate
choice of graphical and analytical methods to minimize different sources of bias
surrounding observational data. The causal inference framework for observational
studies also highlights the importance of the target trial when conducting research
with the use of observational data (Cochran 1972; Dawid 2000; Dorn 1953;
Feinstein 1971; Robins 1986; Rubin 1974). Recently the concept has been proposed
again, and the emulation of the target trial has been formalized, providing
researchers with a set of decision rules to apply when studying treatment effective-
ness and safety using large observational data.
The target trial emulation framework recommends to start with a study protocol
which explicitly describes the emulation of key aspects of a target trial including the
inclusion/exclusion eligibility criteria, the treatment comparison groups, the treat-
ment assignment procedures, the follow-up period, the outcome of interest, the
causal contrast(s) of interest, and the analysis plan (Hernán and Robins 2016). An
explicit formulation of the protocol, thorough discussion of the feasibility, and
careful implementation of the protocol allow researchers to design studies to gener-
ate evidence that reflects evidence coming from a hypothetical target trial while
minimizing the impact of many potential biases.
A few studies have applied this framework to examine drug treatment effects
using observational data. Examples include the effect of postmenopausal hormone
therapy on coronary heart disease (Hernán et al. 2008), antiretroviral therapy regi-
mens and risk of adverse birth outcomes (Caniglia et al. 2018), statin use and
colorectal cancer (Dickerman et al. 2020), and statin use and risk of dementia
(Caniglia et al. 2020). In particular, a study from 2017 provided guidelines on how
to emulate a hypothetical target trial to improve accuracy of evidence generated from
observational studies investigating the risk of seizures among elderly epileptic
patients treated with a new-generation versus old-generation of antiepileptic drugs
(Moura et al. 2017). With the formal causal inference framework and methods
becoming more accessible, more high-quality evidence from observational data is
820 L. Pazzagli and X. Li

expected to increasingly become available. Together with evidence form RCTs, they
shall inform clinical decisions on appropriate treatment use in the field of neuro-
psycho-pharmacoepidemiology.

References
What is Pharmacoepidemiology? Pharmacoepidemiology. 2019a:1–26.
Basic principles of clinical pharmacology relevant to Pharmacoepidemiologic studies. Pharmacoe-
pidemiology. 2019b:27–43.
Basic principles of clinical epidemiology relevant to Pharmacoepidemiologic studies. Pharmacoe-
pidemiology. 2019c:44–59.
AM W. confounding by indication. Epidemiology. 1996;7(4):335–6.
Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic
illness. JAMA. 2002a;288(14):1775–9.
Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic
illness: the chronic care model, part 2. JAMA. 2002b;288(15):1909–14.
Bykov K, Bateman BT, Franklin JM, Vine SM, Patorno E. Association of Gabapentinoids with the
risk of opioid-related adverse events in surgical patients in the United States. JAMA Netw Open.
2020;3(12):e2031647-e.
Caniglia EC, Rebecca Z, Jacobson DL, Diseko M, Mayondi G, Lockman S, et al. Emulating a target
trial of antiretroviral therapy regimens started before conception and risk of adverse birth
outcomes. AIDS (London, England). 2018;32(1):113.
Caniglia EC, Rojas-Saunero LP, Hilal S, Licher S, Logan R, Stricker B, et al. Emulating a target trial
of statin use and risk of dementia using cohort data. Neurology. 2020;95(10):e1322–e32.
Cochran WG. Observational studies. Ames Iowa State University Press; 1972.
Daniel RM, Cousens SN, De Stavola BL, Kenward MG, Sterne JA. Methods for dealing with time-
dependent confounding. Stat Med. 2013;32(9):1584–618.
Dawid AP. Causal inference without counterfactuals. J Am Stat Assoc. 2000;95(450):407–24.
Desai RJ, Rothman KJ, Bateman BT, Hernandez-Diaz S, Huybrechts KF. A propensity score based
fine stratification approach for confounding adjustment when exposure is infrequent. Epidemi-
ology. 2017;28(2):249.
Dickerman BA, García-Albéniz X, Logan RW, Denaxas S, Hernán MA. Emulating a target trial in
case-control designs: an application to statins and colorectal cancer. Int J Epidemiol. 2020;49(5):
1637–46.
Dorn HF. Philosophy of inferences from retrospective studies. Am J Public Health Nations Health.
1953;43(6_Pt_1):677–83.
ElZarrad MK, Corrigan-Curay J. The US Food and Drug Administration’s real-world evidence
framework: a commitment for engagement and transparency on real-world evidence. Clin
Pharmacol Ther. 2019;106(1):33–5.
Farrington C. Control without separate controls: evaluation of vaccine safety using case-only
methods. Vaccine. 2004;22(15–16):2064–70.
Feinstein AR. XI. Sources of ‘chronology bias’ in cohort statistics. Clin Pharmacol Ther. 1971;12
(5):864–79.
Franklin JM, Glynn RJ, Martin D, Schneeweiss S. Evaluating the use of nonrandomized real-world
data analyses for regulatory decision making. Clin Pharmacol Ther. 2019;105(4):867–77.
Glymour MM, Gibbons LE, Gilsanz P, Gross AL, Mez J, Brewster PW, et al. Initiation of
antidepressant medication and risk of incident stroke: using the adult changes in thought cohort
to address time-varying confounding. Ann Epidemiol. 2019;35:42-7. e1.
Glynn RJ, Knight EL, Levin R, Avorn J. Paradoxical relations of drug treatment with mortality in
older persons. Epidemiology. 2001:682–9.
Causal Inference Methods in Pharmacoepidemiology 821

Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research. Epidemiology.
1999a:37–48.
Greenland S, Robins JM, Pearl J. Confounding and collapsibility in causal inference. Stat Sci.
1999b;14(1):29–46.
Hernán MA, Alonso A, Logan R, Grodstein F, Michels KB, Stampfer MJ, et al. Observational
studies analyzed like randomized experiments: an application to postmenopausal hormone
therapy and coronary heart disease. Epidemiology. 2008;19(6):766.
Hernan MA, McAdams M, McGrath N, Lanoy E, Costagliola D. Observation plans in longitudinal
studies with time-varying treatments. Stat Methods Med Res. 2009;18(1):27–52.
Hernán MARJ. Causal inference: what if. Boca Raton: Chapman & Hall/CRC; 2020.
Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not
available. Am J Epidemiol. 2016;183(8):758–64.
Huybrechts KF, Bateman BT, Palmsten K, Desai RJ, Patorno E, Gopalakrishnan C, et al. Antide-
pressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn.
JAMA. 2015;313(21):2142–51.
Huybrechts KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, et al. Antidepressant use
in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397–407.
Imai K, Van Dyk DA. Causal inference with general treatment regimes: generalizing the propensity
score. J Am Stat Assoc. 2004;99(467):854–66.
Jackson JW, Schmid I, Stuart EA. Propensity scores in pharmacoepidemiology: beyond the horizon.
Curr Epidemiol Rep. 2017;4(4):271–80.
Johnson ES, Bartman BA, Briesacher BA, Fleming NS, Gerhard T, Kornegay CJ, et al. The incident
user design in comparative effectiveness research. Pharmacoepidemiol Drug Saf. 2013;22(1):1–6.
Li X, Young JG, Toh S. Estimating effects of dynamic treatment strategies in Pharmacoepidemiologic
studies with time-varying confounding: a primer. Curr Epidemiol Rep. 2017;4(4):288–97.
Lund JL, Richardson DB, Stürmer T. The active comparator, new user study design in pharmacoe-
pidemiology: historical foundations and contemporary application. Curr Epidemiol Rep. 2015;2
(4):221–8.
Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute
events. Am J Epidemiol. 1991;133(2):144–53.
Martinez C, Assimes TL, Mines D, Dell’aniello S, Suissa S. Use of venlafaxine compared with
other antidepressants and the risk of sudden cardiac death or near death: a nested case-control
study. BMJ. 2010;340:c249.
Mcevoy P, Barnes P. Using the chronic care model to tackle depression among older adults who
have long-term physical conditions. J Psychiatr Ment Health Nurs. 2007;14(3):233–8.
Moura LM, Westover MB, Kwasnik D, Cole AJ, Hsu J. Causal inference as an emerging statistical
approach in neurology: an example for epilepsy in the elderly. Clin Epidemiol. 2017;9:9.
Naimi AI, Cole SR, Kennedy EH. An introduction to g methods. Int J Epidemiol. 2017;46(2):756–62.
Newsome SJ, Keogh RH, Daniel RM. Estimating long-term treatment effects in observational data:
a comparison of the performance of different methods under real-world uncertainty. Stat Med.
2018;37(15):2367–90.
Palmsten K, Hernández-Díaz S, Huybrechts KF, Williams PL, Michels KB, Achtyes ED, et al. Use
of antidepressants near delivery and risk of postpartum hemorrhage: cohort study of low income
women in the United States. BMJ. 2013;347
Park Y, Bateman BT, Kim DH, Hernandez-Diaz S, Patorno E, Glynn RJ, et al. Use of haloperidol
versus atypical antipsychotics and risk of in-hospital death in patients with acute myocardial
infarction: cohort study. BMJ. 2018;360
Patorno E, Bohn RL, Wahl PM, Avorn J, Patrick AR, Liu J, et al. Anticonvulsant medications and
the risk of suicide, attempted suicide, or violent death. JAMA. 2010;303(14):1401–9.
Pazzagli L, Linder M, Zhang M, Vago E, Stang P, Myers D, et al. Methods for time-varying
exposure related problems in pharmacoepidemiology: an overview. Pharmacoepidemiol Drug
Saf. 2018;27(2):148–60.
Pearl J. Causal diagrams for empirical research. Biometrika. 1995;82(4):669–88.
822 L. Pazzagli and X. Li

Pearl J, Glymour M, Jewell NP. Causal inference in statistics: a primer. John Wiley & Sons; 2016.
Prentice RL. A case-cohort design for epidemiologic cohort studies and disease prevention trials.
Biometrika. 1986;73(1):1–11.
Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J
Epidemiol. 2003;158(9):915–20.
Robins J. A new approach to causal inference in mortality studies with a sustained exposure
period—application to control of the healthy worker survivor effect. Math Model. 1986;7
(9–12):1393–512.
Robins JM. Correcting for non-compliance in randomized trials using structural nested mean
models. Commun Stat Theory Methods. 1994;23(8):2379–412.
Robins JM, Hernán MA. Estimation of the causal effects of time-varying exposures. Longitudinal
Data Anal. 2009;553:599.
Rosenbaum P, Armitage P, Colton T. Encyclopedia of biostatistics. 2005.
Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for
causal effects. Biometrika. 1983;70(1):41–55.
Rubin DB. Comment: which ifs have causal answers. J Am Stat Assoc. 1986;81(396):961–2.
Rubin DB. Bayesian inference for causal effects: the role of randomization. Ann Stat. 1978:34–58.
Rubin DB. Assignment to treatment group on the basis of a covariate. J Educ Stat. 1977;2(1):1–26.
Rubin DB. Estimating causal effects of treatments in randomized and nonrandomized studies.
J Educ Psychol. 1974;66(5):688–701.
Schneeweiss S, Eichler HG, Garcia-Altes A, Chinn C, Eggimann AV, Garner S, et al. Real world
data in adaptive biomedical innovation: a framework for generating evidence fit for decision-
making. Clin Pharmacol Ther. 2016;100(6):633–46.
Schneeweiss S, Patrick AR, Solomon DH, Mehta J, Dormuth C, Miller M, et al. Variation in the risk
of suicide attempts and completed suicides by antidepressant agent in adults: a propensity score–
adjusted analysis of 9 years’ data. Arch Gen Psychiatry. 2010;67(5):497–506.
Schneeweiss S, Patrick AR, Sturmer T, Brookhart MA, Avorn J, Maclure M, et al. Increasing levels
of restriction in pharmacoepidemiologic database studies of elderly and comparison with
randomized trial results. Med Care. 2007;45(10 Supl 2):S131–42.
Schuemie MJ, Ryan PB, Man KK, Wong IC, Suchard MA, Hripcsak G. A plea to stop using the
case-control design in retrospective database studies. Stat Med. 2019;38(22):4199–208.
Suissa S. Effectiveness of inhaled corticosteroids in chronic obstructive pulmonary disease: immor-
tal time bias in observational studies. Am J Respir Crit Care Med. 2003;168(1):49–53.
Suissa S. The case-time-control design. Epidemiology. 1995:248–53.
Sun JW, Hernández-Díaz S, Haneuse S, Bourgeois FT, Vine SM, Olfson M, et al. Association of
Selective Serotonin Reuptake Inhibitors with the risk of type 2 diabetes in children and
adolescents. JAMA Psychiat. 2021;78(1):91–100.
VanderWeele TJ. Concerning the consistency assumption in causal inference. Epidemiology.
2009;20(6):880–3.
Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, et al. Risk of death in
elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005;353
(22):2335–41.
Whitaker HJ, Paddy Farrington C, Spiessens B, Musonda P. Tutorial in biostatistics: the self-
controlled case series method. Stat Med. 2006;25(10):1768–97.
Neuropsychopharmacotherapy: Guidelines

Jelena Vrublevska and Lubova Renemane

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
Guideline Developing Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
Existing Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
Potential Benefits from Clinical Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
Limitations of Clinical Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
Review of the Important Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
Guidelines for the Treatment of Schizophrenia (Displayed in Table 1) . . . . . . . . . . . . . . . . . . . . 827
Guidelines for the Treatment of Major Depression (Displayed in Table 2) . . . . . . . . . . . . . . . . 832
Guidelines for the Treatment of Bipolar Disorder (Displayed in Tables 3, 4, and 5) . . . . . . 840
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849

Abstract
Practicing evidence-based medicine (EBM) requires the ability to evaluate rele-
vant evidence for the purpose of making an evidence-based treatment decision.
The need to standardize different therapeutic approaches has encouraged the
development of guidelines to advice on the treatment, management, and assess-
ment of psychiatric conditions. Treatment guidelines serve the purpose of gath-
ering and evaluating research data and transform them into comprehensive
treatment algorithm. Based on the current status of evidence, algorithms have
been combined to form a unified guideline for management. Clinical practice
guidelines form the basis of standard clinical practice for all disciplines of
medicine, including psychiatry. However, a significant challenge for psychiatry
is the incorporation of this new knowledge into the daily work of clinicians.
Moreover, there are several potential risks related with use of algorithms and

J. Vrublevska (*) · L. Renemane

Department of Psychiatry and Narcology, Riga Stradins University, Riga, Latvia
e-mail: vrublevskaja@inbox.lv; hlebnikdr@yahoo.com

© Springer Nature Switzerland AG 2022 823

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_16
824 J. Vrublevska and L. Renemane

guidelines. The evidence might be insufficient and the consensus panels might
express biased opinions. They are often not read or followed because of poor
quality or because of barriers to implementation due to either lack of agreement or
ambiguity. We briefly review practice guidelines for the treatment of schizophre-
nia, major depression, and bipolar disorder.

Introduction

During the past 150 years, two significant factors have shaped the modern health
system: first, the growth of scientific knowledge, and, second, the growth of public
acceptance of disease control. Throughout the years, much has been learned from
efficacy and effectiveness of various treatments – biologic, psychotherapeutic, and
social (Hanlon 2012).
Guidelines have existed for centuries, and recommendations about appropriate
care can be found even in ancient writings. However, until recent, they had no
provided evidence-based recommendations for the assessment and treatment of
psychiatric disorders. Moreover, the process used in their review was not
documented, and there were no process of revision (McIntyre 2002).
Only over the past few decades, the role of guidelines was described variously. As
defined by the Institute of Medicine (Amsterdam et al. 1996) report, practice
guidelines are “systematically developed statements to assist practitioner and patient
decisions about appropriate health care for specific clinical circumstances” (Field
et al. 1992). The IOM reported two objectives: first, to encourage constructive
expectations from guidelines, and, second, to promote the care and rigor for their
development, application, evaluation, and revision. To accept criteria for validity of
guidelines, the essential elements defined by the IOM were set out first. These
recommended attributes included validity, reliability, clinical applicability, clinical
flexibility, clarity, multidisciplinary process, scheduled review, and documentation
(Field and Lohr 1990).
Another definition of clinical practice guidelines (CPGs) states “CPGs are able to
enhance clinician and patient decision making by clearly describing and appraising
the scientific evidence and reasoning (the likely benefits and harms) behind clinical
recommendations, making them relevant to the individual patient encounter” (Field
and Lohr 1990). Modern guidelines are developed by professional organizations,
government, even insurance companies, and third parties, as well by providers of
care. Part of these guidelines are evidence-based, part of them based on expert
opinions or based on opinions or one more authors (Woolf 1992; Woolf et al. 1999).
In 1988, the American Medical Association organized a Practice Guideline
Partnership comprised of 14 specialty organizations including the American
Psychiatric Association (APA). This partnership also defined “good” guidelines
and identified five criteria. They: (a) are developed by physicians in active clinical
practice; (b) integrate relevant research and clinical expertise; (c) describe specific
treatment approaches, including indicators, efficacy, safety, and alternative treatment
strategies; (d) are reviewed and revised at regular intervals not longer than 5 years;
Neuropsychopharmacotherapy: Guidelines 825

and (e) after approval, are widely disseminated. They set the standard of care and
training for health professionals and they also identify priority areas for further
research, since they are based primarily on the available evidence, but also in
areas where evidence is not available, on expert opinion. Clinicians, policymakers,
and payers see guidelines as a tool for making care more consistent and efficient and
for closing the gap between what clinicians do and what scientific evidence supports
(Woolf et al. 1999).
A major challenge for psychiatry is to implement evidence-based knowledge
into the daily work and practice of clinicians (McIntyre 2002). A good guideline
should be able to identify the key decisions (e.g., diagnosis, assessment strategy, and
treatment choice), review the relevant, valid evidence on the benefits, risks, and costs
of alternative decisions, and present recommendations in a concise, updated format
(Woolf 1992; McIntyre 2002; Hasan et al. 2019).

Guideline Developing Process

Guidelines based on a consensus of expert opinion or on unsystematic literature

surveys have been criticized as not reflecting current medical knowledge and being
liable to bias (Brouwers et al. 2010; Mulrow 1994). Systematic review is defined as
“an efficient scientific technique to identify and summaries evidence on the effec-
tiveness of interventions and to allow the generalizability and consistency of
research findings to be assessed and data inconsistencies to be explored” (Woolf
1992). The literature search must focus on the best evidence available to address
each key question. Certain steps have to be followed for the development of the
treatment algorithm which includes: (a) defining the sources of data and choosing
which to use, (b) development of a grading method, (c) search of the literature, (d)
grading of the data, (e) defining the clinical parameters to take into consideration, (f)
development of a precise treatment algorithm, and (g) development of the clinical
guideline The sources for the data serve systematic reviews (including meta-ana-
lyses), randomized controlled trials, observational studies, diagnostic studies, and
economic studies (McIntyre 2002; Fountoulakis 2015; Kamens et al. 2019).

Existing Guidelines

Psychiatry, as a discipline, is relatively new in the field of evidence-based medicine;

yet, there exist several clinical guidelines designed to provide guidance of good
clinical practice. Some of the most well-known and widely accepted guidelines are
the APA guidelines by the American Psychiatric Association (APA), the CANMAT
Canadian Treatment Guidelines by the Canadian Psychiatric Association and the
Canadian Network for Mood and Anxiety Disorders (Yatham et al. 2013), the NICE
Guidelines by the National Institute of Health and Care Excellence (NICE 2014), the
Maudsley Prescribing Guidelines in Psychiatry (Taylor et al. 2018), the International
Colleague of Neuropsychopharmacology Guidelines (CINP), the World Federation
826 J. Vrublevska and L. Renemane

of Societies of Biological Psychiatry Treatment Guidelines and Consensus Paper

(WFSBP), the RANZCP Guidelines by the Royal Australian and New Zealand
Colleague of Psychiatrists (Galletly et al. 2016), and others.

Potential Benefits from Clinical Guidelines

The principal benefit from guidelines is to improve the quality of care received by
patients. For patients, the greatest benefit that could be achieved by guidelines is to
improve health outcomes. Guidelines can also improve the consistency of care;
studies around the world show that the frequency with which procedures are
performed varies dramatically among doctors, specialties, and even geographical
regions. Clinical guidelines can help patients by influencing public policy.
Moreover, they call attention to under-recognized health problems, clinical services,
and preventive interventions and to neglected patient populations and high-risk
groups. Guidelines aim to assist to clinicians and also policymakers (Woolf et al.
1999; Kredo et al. 2016).
Clinical guidelines can improve the quality of clinical decisions. They offer
explicit recommendations for clinicians who are uncertain about how to proceed,
improve the consistency of care, and provide authoritative recommendations
that reassure practitioners about the appropriateness of their treatment policies.
Guidelines based on a critical appraisal of scientific evidence clarify which inter-
ventions are of proved benefit and document the quality of the supporting data
(McIntyre 2002; Stasevic et al. 2019).
Health care systems that provide services, government bodies and private insurers
that pay for them, have found that clinical guidelines may be effective in improving
efficiency (Carnett 1999; Woolf et al. 1999).

Limitations of Clinical Guidelines

A major limitation that can affect the guidelines development is complexity of

psychiatric disorders – majority of patients present comorbid psychiatric conditions
and experience them in long term. This factor takes time for properly addressing the
tool for the evaluation and care. Moreover, barriers to the implementation of
guidelines could be classified into three major categories: (a) organizational
resources, (b) health care professionals’ individual characteristics, and (c) perception
of guidelines and implementation strategies (Forsner et al. 2010).
Methodological issues in clinical trials may result in trials which do not show a
difference between the effects of a drug and placebo despite one existing. This is
probably a common reason for evidence not being available despite the fact that
there is a general clinical impression that certain medications are effective for
particular conditions. Clinical trials of psychotherapies also have potential biases
including lack of blinding and expectation effects among both therapists and
patients. Psychotherapies are complex, multicomponent interventions, and contrary
Neuropsychopharmacotherapy: Guidelines 827

to the logic of the randomized controlled trial (RCT), patients’ experience of and
active participation in psychotherapy systematically influence the content of the
intervention they receive. It has therefore been argued that RCTs are not optimal
methodologies for validating psychotherapies, and instead process evaluation is
required (Moore et al. 2015). Therefore while RCTs carry significant weight, it
must be remembered that they and their meta-analyses are of variable quality and
validity. The scientific literature on psychological therapies is also influenced by
publication bias that positive outcome studies will be published (Driessen et al.
2013, 2015) and researcher allegiance effects (Munder et al. 2013).
Until the present time, it does not appear that the use of practice guidelines has
increased medical liability. Practice guidelines might have the potential to reduce the
number of malpractice cases and the costs of settling them. However, for practice
guidelines to exert any influence, they must be assumed to be developed for
conditions or procedures that frequently lead to events for which negligence claims
are filed; widely accepted in the medical profession; fully integrated into clinical
practice; and straightforward and readily interpreted in a litigation setting. Because
the validity of each of these assumptions can be questioned, the idea that inserting
practice guidelines into the existing litigation process will generate large savings is
overoptimistic. Another issue is that the recommendations of a guideline cannot be
followed because of a lack of adequate resources (Garnick et al. 1991; McIntyre
2002).
Finally, the guidelines are made with a methodology that takes little account of
the opinions of experts in daily practice; they refer to ideally selected patients in ideal
care settings; they do not take into account the complex patients with comorbid
psychiatric conditions in daily practice; they can be influenced by economic prior-
ities; they are different in the indications between them; often they change their
principles over time; they can be used for a defensive psychiatry that does not
privilege the patient’s benefit (Nivoli et al. 2017).

Review of the Important Guidelines

Guidelines for the Treatment of Schizophrenia (Displayed in Table 1)

The APA Practical Guideline for the Treatment of Patients with

Schizophrenia
The APA guideline is based on a comprehensive literature review; it is developed by
psychiatrists who are in active clinical practice, contributors, and academic
endeavors. Originally, the guideline was published in 2004 for the first time and
updated in 2010 (Lehman et al. 2004). The work group classified the guidelines
into three categories of endorsement, reflecting the support of clinical data: (I)
recommended with substantial clinical confidence, (II) recommended with moderate
clinical confidence, and (III) may be recommended on the basis of individual
circumstances.
Table 1 Treatment for schizophrenia across practice guidelines
828

Acute treatment of first Acute Stabilization

Guideline episode phase phase Stable phase/maintenance treatment Psychosocial management
APA SGAs, FGAs 6–12 weeks Up to 1–1.5 years; up to 5–10 years in case of Acute, stabilization phase:
2010 6 month 2 or more episodes, indefinite for psychoeducation of patient and family
multiple prior episodes or more than 2 Stable phase: family intervention,
episodes in 5 years supported employment, assertive
community treatment, skills training,
and cognitive behaviorally oriented
psychotherapy
CANMAT SGAs, FGAs 4–6 weeks – 18 months after the first episode –
2017 2–5 years or longer after relapse
NICE SGAs, FGAs – – 2 years in the first episode Acute episode: family intervention
2014 3 years if the person has not made a (psychoeducation), CBT, supported
stable recovery employment, arts therapy
RANZCP Amisulpride, – – 2–5 years in the first episode Family interventions:
2016 aripiprazole, quetiapine, Long-term, if incomplete remission or psychoeducation and group therapy;
risperidone treatment resistance individual placement; support
vocational recovery services; lifestyle
interventions; CBT
WFSPB SGAs, FGAs. – – 1 year after the first-episode and for –
2012, Amisulpride, 2–5 years in case of a recurring course
2013, olanzapine, quetiapine,
2015 risperidone
CINP SGAs, FGAs – – 6 years for multiple episode patients –
2013 and at least 1 year for first-episode
patients
BAP SGAs, FGAs 4 weeks – – –
2011
APA, American Psychiatric Association; CANMAT, Canadian Network for Mood and Anxiety Treatments; NICE, National Institute for Health and Care Excellence;
RANZCP, Royal Australian and New Zealand College of Psychiatrists; WFSPB, World Federation of Societies of Biological Psychiatry; BAP, British association of
J. Vrublevska and L. Renemane

psychopharmacology; CINP, The International College of Neuropsychopharmacology. SGAs, second-generation antipsychotics; FGAs: first-generation antipsychotics
Neuropsychopharmacotherapy: Guidelines 829

For the treatment of the acute phase of schizophrenia, the guideline recommends
to select the first-generation or the second-generation antipsychotic medication, and
the selection of medication should be guided by the patient’s previous experience
with antipsychotics, including the degree of symptom response, past experience of
side effects, and preferred route of administration. In addition, the psychoeducation
of the patient and the family members is advised during the acute phase of the
treatment. The treatment duration of the acute phase is determined as 4–6 weeks.
During the stabilization phase, the guideline recommends to continue the same dose
of the antipsychotics and to provide psychoeducation of the patient and the family
members up to 6 months with a goal to reduce stress on the patient and provide
support to minimize the likelihood of relapse.
There is a clear suggestion that antipsychotics and psychosocial therapies
should be used in the stable phase up to 1–1.5 years after a first episode, up to
5–10 years in case of two or more episodes, and indefinite for multiple prior
episodes or more than two episodes in 5 years; this should ensure that symptom
remission or control is sustained. The psychosocial treatments that have demon-
strated effectiveness during the stable phase include family intervention,
supported employment, assertive community treatment, skills training, and
cognitive behaviorally oriented psychotherapy.

Royal Australian and New Zealand College of Psychiatrists Clinical

Practice Guidelines for the Management of Schizophrenia and Related
Disorders (RAZNP)
The RANZCP provides recommendations for the clinical management of schizo-
phrenia and related disorders for health professionals. The workgroup consists of
experts with extensive research and clinical experience in the field of schizophrenia.
This guideline includes the management of ultra-high risk syndromes, first-episode
psychoses, and prolonged psychoses, including psychoses associated with substance
use. To reflect new evidence, the last revision of the guideline was carried out in
2016 (Galletly et al. 2016); it was an update of the previous RANZCP guideline that
was published in 2005 (McGorry et al. 2005).
The guideline uses a clinical staging model as a framework for recommendations
regarding assessment, treatment, and ongoing care. Evidence-based recommenda-
tions are categorized into four levels of evidence. They are assigned according to the
levels of evidence provided by Australia’ National Health and Medical Research
Council (NHMRC) (Coleman et al. 2009).
The guideline underlines that management of a first episode requires a systematic
approach which involves a comprehensive range of pharmacological and psychoso-
cial interventions. For the acute pharmacological treatment of first episode of
psychotic disorder, the second-generation antipsychotic agents are recommended
in preference to first-generation antipsychotic agents due to their better tolerability
and extrapyramidal side-effect profile. The RANZCP guidelines suggest to
use amisulpride, aripiprazole, quetiapine, and risperidone as first-choice agents.
Comprehensive treatment should be provided continuously for 2–5 years after a
first episode. If the patient has incomplete remission or is treatment resistant, a long-
830 J. Vrublevska and L. Renemane

term treatment is recommended. Concerning a long-term full recovery, the guide-

lines advise to provide psychosocial interventions.
After first psychotic episode, the guidelines recommend to provide family inter-
ventions (psychoeducation and group therapy), individual placement, vocational
recovery services, and lifestyle interventions to prevent weight gain and cognitive
behavioral psychotherapy (CBT).

NICE Guideline Concerning Psychosis and Schizophrenia in Adults:

Prevention and Management
In 2014, the NICE issued a clinical guideline for prevention and management of
psychosis and schizophrenia in adults (NICE 2014). The guideline is addressed to
health care professionals and people with psychosis or schizophrenia and their
families and carers. This guideline discusses early recognition and treatment, and
focuses on long-term recovery. It also recommends checking for coexisting health
problems and providing support for family members and carers.
For people with a first episode of psychosis, the NICE guideline offers oral
antipsychotic medication in conjunction with psychological interventions (family
intervention and individual CBT). It is recommended to choose second- or first-
generation of antipsychotic medications, taking into account the benefits and possi-
ble side effects of each drug. After a first psychotic episode, the guideline suggests to
continue the treatment for the next 2 years and, if the person has not made a stable
recovery, it recommends to continue the treatment for 3 years.

The World Federation of Societies of Biological Psychiatry (WFSBP)

Guidelines for Biological Treatment of Schizophrenia
The first edition of the WFSBP guidelines for biological treatment of schizophrenia
published in the years 2005 and 2006 and the last revision was done (Hasan et al.
2012, 2013, 2015). They are intended to be used physicians diagnosing and treating
patients with schizophrenia. The guidelines focus on biological treatments and not
include recommendations for psychotherapeutic interventions and psychosocial care.
These guidelines provide evidence-based practice recommendations which are clini-
cally and scientifically relevant and consist of three parts. The literature was evaluated
with respect to the strength of evidence for its efficacy and subsequently categorized
into six levels of evidence (A–F) and five levels of recommendation (1–5).
The guidelines suggest that the decision for one specific drug should follow a
strict risk-benefit-evaluation. In first-episode patients, SGAs (e.g., amisulpride,
olanzapine, quetiapine, risperidone) should be preferred to high-potency FGAs
(e.g., haloperidol, perphenazine) as first-line treatment. In patients with a relapsing
disease course, the choice should be guided by the patient’s preferences, previous
experience of response and tolerability, intended route of administration, as well as
potential interactions with other drugs. A combination of antipsychotic treatment
and psychosocial interventions must be offered to every patient with schizophrenia.
Based on expert opinion, the WFSBP guidelines recommend a continuous antipsy-
chotic maintenance treatment for at least 1 year after the first episode and for
2–5 years in case of a recurring course.
Neuropsychopharmacotherapy: Guidelines 831

The International College of Neuropsychopharmacology Schizophrenia

Guideline
The CINP schizophrenia guideline has been commissioned by the College of
Neuropsychopharmacology and focused on pharmacological treatment of schizo-
phrenia. The workgroup consisted of experts with extensive research and clinical
experience in the field of schizophrenia (Leucht et al. 2013). The recommendation
was based on three levels of evidence and graded as A, B, and C. For the treatment of
an acute episode of schizophrenia, the criteria for choice of antipsychotics depends
on evidence of prior response to the same drug, side-effects experienced with a drug
in the past, planned mode of administration, side-effect profiles, small differences in
antipsychotic efficacy, patient’s preference for a specific drug determined by shared-
decision making, and cost.
The guidelines suggest that duration of antipsychotic relapse prevention treatment
should be sustained at least 6 years for multiple episode patients and at least 1 year
for first-episode patients. The severity of episodes, current psychopathology, and
suicidal acts of aggression during acute episodes should also be considered in
duration of the treatment.

Canadian Network for Mood and Anxiety Treatments Clinical Guidelines

for the Management of Patients with Schizophrenia (CANMAT)
The CANMAT guideline for the Pharmacotherapy of Schizophrenia in Adults was
first published in 2017 and addressed for health professionals (Remington et al.
2017). Guidelines were developed using the ADAPTE process (ADAPTE 2009),
which takes advantage of existing guidelines, and recommendations were made
based on the available evidence and was divided into four levels of evidence and
for levels of recommendations.
For patients with first-episode psychosis, the guideline recommended antipsy-
chotic medication. Choice of antipsychotic medication should be made by the patient
and physician together, taking into account views of a carer and based on benefits
and side effects of each drug. The expert group suggested that an adequate acute
first-psychotic episode should be treated between 4 and 6 weeks, and after resolution
of positive symptoms, the duration of maintenance treatment with antipsychotics
should be at least 18 months.

British Association of Psychopharmacology

The BAP evidence-based guidelines for the pharmacological treatment of schizo-
phrenia was published in 2011 (Barnes 2011). The expert group based their recom-
mendations on available evidence from randomized controlled trials but also from a
broad range of other published research and the clinical experience. They used four
levels of evidence and five levels of recommendations (A–D, S).
For the treatment of the first episode of schizophrenia, the BAP guideline
suggests that choice of a first-line antipsychotic drug should be based on the
evidence for relative liability for side effects, particularly considering common and
serious effects such as extrapyramidal motor syndromes and metabolic problems,
risk factors for side effects, and relevant medical history.
832 J. Vrublevska and L. Renemane

For the majority of first-episode patients treated with an antipsychotic response to

antipsychotic medication within 4 weeks, and the guidelines recommended to
continue prescription of an antipsychotic are to prevent relapse, maintain long-
term control of symptoms and behavior and improve quality of life, with minimal
adverse effects. However, the duration of maintenance treatment was not mentioned
in the recommendations.

Guidelines for the Treatment of Major Depression (Displayed in

Table 2)

The guidelines for the treatment of patients with major depressive disorder (MDD)
are based on the criteria provided in the Diagnostic and Statistical Manual of Mental
Disorders of the American Psychiatric Association, 4th or 5th Edition (DSM–IV or
V) (APA 1994, 2013). All guidelines consider MDD, though some consider persis-
tent depressive disorder or dysthymia. They use a severity-based model of depres-
sion (e.g., subthreshold, mild, moderate, and severe). The approach to modelling of
the MDD varies in parameters of depressive subtype (e.g., melancholic, catatonic,
psychotic, atypical, seasonal, anxious), chronicity (e.g., chronic or recurrent MDD,
dysthymia, PDD), complexity (e.g., “uncomplicated,” “complex,” treatment-resis-
tant depression), and comorbidity (e.g., psychiatric or medical). Some guidelines
consider multiple domains concurrently. The guidelines will be analyzed in depth
taking into account their specific recommendations with a focus on the pharmaco-
logical treatment of MDD.

NICE Guidelines for the Management of Depression in Adults

The National Institute for Health and Clinical Excellence (NICE) published for the
first time the clinical guidelines “Depression in Adults: Recognition and Manage-
ment” in 2009 (NICE 2009). These guidelines were subsequently revised and the
latest update was issued in 2018. The guidelines focus on the identification, treat-
ment, and management of depression in adults aged 18 years and older, in primary
and secondary care. The guidelines reflect the opinion of the National Collaborating
Centre for Mental Health (a collaboration of the professional organizations involved
in the field of mental health, national patient and carer organizations, and a number
of academic institutions and NICE) on the available up-to-date evidence and the
systematic provision of treatment recommendations applicable to the majority of
people with depression. However, the strength of the evidence for the suggested
recommendations is not clearly defined in the guidelines.
The 2019 NICE guidelines used the criteria of DSM–IV (APA 1994) rather than
the ones of International Classification of Mental and Behavioural Disorders 10th
edition (ICD-10) (WHO 1992) that were reflected in the previous version of the
guidelines.
The 2019 NICE guidelines provide a four stepped-care model targeting patients
with depression. The first step focuses on patients with all known and suspected
presentations of depression. The nature of the intervention for this group includes
Table 2 Treatment for major depression across practice guidelines
Pharmacological treatment Severity of major depressive disorder
Moderate to
severe without
First-line Second-line Third-line Mild to psychotic Severe with Duration of
Guideline medication medication medication moderate features Severe psychotic features treatment
APA SSRIs, TCAs, – Psychosocial – ADs and ADs and Acute phase:
2010 SNRIs, nonselective and psychological antipsychotics or till remission.
mirtazapine, MAOIs psychological treatments or ADs and Continuation
bupropion treatments or ECT antipsychotics and phase: 4–
ADs or psychological 9 months.
psychological treatments or ECT Maintenance
treatments and phase: if 3 or
ADs or ECT more
Neuropsychopharmacotherapy: Guidelines

depressive
episodes
CANMAT SSRIs, TCAs, MAOIs, Psychosocial Medication – ADs and Acute phase:
2016 SNRIs, quetiapine, reboxetine and and antipsychotics or 6–12 weeks
agomelatine, trazodone, psychological psychological ECT Maintenance
bupropion, moclobemide, treatments or treatments With catatonic phase:
mirtazapine, selegiline, medication features: 6–9 month. If
vortioxetine levomilnacipran Benzodiazepines risk factors for
vilazodone recurrence,
extend
treatment to 2
or more years
NICE SSRIs – – Psychosocial ADs and ADs and ADs and Acute phase:
2018 and psychological psychological antipsychotics and till remission
psychological treatments treatments or psychological Continuation
treatments or ECT treatments or ECT phase:
ADs 6 months after
remission
833

(continued)
 834

Table 2 (continued)
Pharmacological treatment Severity of major depressive disorder
Moderate to
severe without
First-line Second-line Third-line Mild to psychotic Severe with Duration of
Guideline medication medication medication moderate features Severe psychotic features treatment
Maintenance
phase: 2 years
if they are at
risk of relapse
RANZCP SSRIs, SNRIs, TCAs, MAOIs, Psychosocial ADs and ADs and ADs and Acute phase:
2015 NARIs serotonin reversible and psychological psychological antipsychotics 6–12 weeks.
(reboxetine), modulator MAOIs psychological treatments treatments ADs, ECT Maintenance
NaSSAs, (vortioxetine) (Moclobemide), treatments or phase:
NDRIs SARIs ADs 6 months and
(Bupropion), Trazadone up to 1 year
agomelatine
WFSPB No single – – SSRIs and ADs (as for – TCAs, SSRIs, Acute phase:
2013, class of ADs other “newer mild) or SNRIs, MAOIs, 8–10 weeks
2015 has proven to ADs” (except psychosocial complex Continuation
be more reboxetine) or and psychotherapeutic phase: 6–
effective psychosocial psychological treatment, 9 months
and treatments and combination Maintenance
psychological ADs treatments or ECT phase: from
3 years to
J. Vrublevska and L. Renemane
 treatments and lifetime, if
ADs residual
symptoms or
psychotic
features;
5–10 years,
if greater risk
of relapse
BAP SSRIs TCAs, MAOIs – Psychosocial ADs and – ADs and Acute phase:
2015 and psychological antipsychotics, 6–8 weeks.
psychological treatments psychological Maintenance
treatments or treatments or ECT phase after full
ADs remission:
6–9 months, if
Neuropsychopharmacotherapy: Guidelines

low risk of
relapse, 1 year
if any
increased risk
of relapse,
2 years in
higher-risk
patients
APA, American Psychiatric Association; CANMAT, Canadian Network for Mood and Anxiety Treatments; NICE, National Institute for Health and Care
Excellence; RANZCP, Royal Australian and New Zealand College of Psychiatrists; WFSPB, World Federation of Societies of Biological Psychiatry; BAP,
British Association of Psychopharmacology; SSRIs: selective serotonin reuptake inhibitors; NARIs: noradrenaline reuptake inhibitors; NaSSAs: noradrenaline
and specific serotonergic antidepressants; NDRIs: noradrenaline dopamine reuptake inhibitors; SNRIs: serotonin and noradrenaline reuptake inhibitors; TCAs:
tricyclic antidepressants; MAOIs, monoamine oxidase inhibitors; SARIs, serotonin antagonist and reuptake inhibitors; ADs, antidepressants; ECT, electrocon-
vulsive therapy
835
836 J. Vrublevska and L. Renemane

assessment, support, psychoeducation, active monitoring, and referral for further risk
assessment, monitoring, and interventions. The second step focuses on persons with
recognized depression characterized by persistent subthreshold depressive symp-
toms or mild to moderate depression. Low-intensity psychosocial interventions,
psychological interventions, medication, and referral for further assessment and
interventions are recommended for the second step. The guidelines offer low-
intensity psychosocial interventions such as individual guided self-help based on
the principles of cognitive behavioral therapy (CBT), computerized cognitive behav-
ioral therapy (CCBT), and a structured group physical activity program. Drug
treatment is recommended for people either with a history of moderate or severe
depression or initial presentation of subthreshold depressive symptoms that have
been present at least for 2 years, or subthreshold depressive symptoms or mild
depression that persist(s) after other interventions. St John’s wort may be of benefit
in mild or moderate depression. The third step provides recommendations for
patients with persistent subthreshold depressive symptoms or mild to moderate
depression with inadequate response to initial interventions and moderate and severe
depression. The treatment options include antidepressants (SSRI), high-intensity
psychological interventions, combined treatments, collaborative care, and referral
for further assessment and interventions. Step four focuses on patients with severe
and complex depression, who are at significant risk of self-harm and have psychotic
symptoms. For this severity level of depressed patients, the guideline recommends
medication, high-intensity psychological interventions, electroconvulsive therapy
(ECT), crisis service, combined treatments, and multiprofessional and inpatient
care. For the people who have depression with psychotic symptoms, it is
recommended to augment the current treatment plan with antipsychotic medication.
The NICE guidelines specify a need to continue antidepressant treatment for at
least 6 months after remission taking into account episodes of depression. For those
who are at risk of relapse, it is advised to continue medical treatment for at least
2 years keeping the level of medication at which acute treatment was effective.

The APA Practical Guideline for the Treatment of Patients with Major
Depressive Disorder
The APA Practice Guideline for the Treatment of Patients with MDD, 3rd Edition,
was originally published in October 2010 (APA 2010). This guideline provides
evidence-based recommendations for the assessment and treatment of MDD and is
intended to assist in clinical decision-making by presenting systematically devel-
oped patient care strategies in a standardized format.
In the APA guideline that was produced in 2010, there are three categories of
endorsement identified for each recommendation. These categories represent vary-
ing levels of clinical confidence. The first level address recommendations with
substantial clinical confidence, the second level is attributed to recommendations
with moderate clinical confidence, and the third one – recommendations made on the
basis of individual circumstances.
The guideline suggests that acute phase treatment may include pharmacotherapy,
depression-focused psychotherapy, the combination of medications and psychotherapy,
Neuropsychopharmacotherapy: Guidelines 837

or other somatic therapies such as ECT, transcranial magnetic stimulation (TMS), or

light therapy.
For the treatment of the acute phase of MDD, selective serotonin reuptake inhib-
itors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), mirtazapine, or
bupropion are ranked as the first-choice agents, whereas tricyclic antidepressants and
nonselective monoamine oxidase inhibitors (MAOIs) are recommended as the second-
choice agents.
An antidepressant is recommended as an initial treatment choice for patients with
mild to moderate MDD. Depression-focused psychotherapies alone or in combina-
tion with antidepressants could be used to treat this severity of depression. ECT is
recommended for certain patients. For severe level of depression without psychotic
features, antidepressants or pharmacotherapy in combination with depression-
focused psychotherapy or ECT are recommended. The treatment strategy of the
APA guideline for severe depression with psychotic features suggests both antide-
pressant and antipsychotic medications alone or in combination with depression-
focused psychotherapy or ECT.
Treatment in the acute phase should be aimed at inducing remission of the major
depressive episode and achieving a full return to the patients’ baseline level of
functioning. During this phase of treatment, patients who have been treated success-
fully with antidepressant medications in the acute phase should continue treatment
with the same dose of these agents for 4–9 months to reduce the risk of relapse. In
order to reduce the risk of a recurrent depressive episode, patients who have had
three or more prior major depressive episodes or who have chronic MDD should
proceed to the maintenance phase of treatment. During the maintenance phase, an
antidepressant medication that produced symptom remission during the acute and
the continuation phase should be continued at a full therapeutic dose.

The Canadian Network for Mood and Anxiety Treatments (CANMAT)

Clinical Guidelines for Management of Adults with Major Depressive
Disorder
In 2016, the most recent revisions of the CANMAT evidence-based clinical guide-
lines for the treatment of depression were published. The scope of the 2016 guide-
lines remains the management of MDD in adults, with a target audience of
psychiatrists and other mental health professionals. These guidelines consist of six
sections and expand on burden and principles of care (Lam et al. 2016), psycholog-
ical treatments (Parikh et al. 2016), pharmacological treatments (Kennedy et al.
2016), neurostimulation treatments (Milev et al. 2016), complementary and alterna-
tive medicine treatments (Ravindran et al. 2016), and treatment approach in special
populations (MacQueen et al. 2016).
The CANMAT guidelines are based on an extensive review of the literature, reviews,
and individual and network meta-analyses. Each recommendation includes the level of
evidence for each graded line of treatment. The level of evidence varies from meta-
analysis with narrow confidence intervals and/or two or more RCTs with adequate
sample size, preferably placebo controlled (Level 1) till expert opinion (Level 4).
Eventually, every intervention is categorized into the first, the second or the third lines.
838 J. Vrublevska and L. Renemane

The 2016 CANMAT guidelines, to treat the acute phase of MDD, suggest
following first-line recommendations: SSRIs, SNRIs, agomelatine, bupropion,
mirtazapine, or vortioxetine. Second line includes TCAs, quetiapine, trazodone,
moclobemide, selegiline, levomilnacipran, and vilazodone; the third line of pharma-
cological treatment includes MAOIs and reboxetine.
Regarding the severity-based model of depression, they recommend to choose
between psychosocial and psychological treatments and medication for the mild to
moderate level of depression. For moderate to severe depression, a combination of
pharmacotherapy and psychological treatments is advised. The guidelines suggest
using a combination of antidepressants and antipsychotics or ECT for the treatment
of severe depression with psychotic features. For depression with catatonic features,
they recommend benzodiazepines. These guidelines define specific types of the
psychological interventions for acute and maintenance phases. The psychological
interventions are categorized in three lines and are shown in Table.
In terms of the duration of treatment, the guidelines recommend to provide the
treatment for 6–12 weeks in the acute phase and to continue it from 6 up to 9 months
in the maintenance phase. If the patient has risk factors for recurrence of disease, the
guidelines advise to extend the treatment up to 2 or more years.

Royal Australian and New Zealand College of Psychiatrists Clinical

Practice Guidelines for Mood Disorders
The Royal Australian and New Zealand College of Psychiatrists (RANZCP) published
a clinical practice guideline for mood disorders in 2015 (Malhi et al. 2015). The
guideline is based on scientific evidence-based knowledge supplemented by expert
clinical consensus; it formulates recommendations for the clinical management of
depressive and bipolar disorders, and advises specifically on diagnosis and treatment
strategies. The guideline focuses primarily on adults and is directed at psychiatrists,
psychologists, and physicians with a particular interest in mental health issues.
This guideline makes two types of recommendations: evidence-based recommen-
dations (EBR) and consensus-based recommendation. For each EBR, strength of
evidence was rated using the Australian National Health and Medical Research
Council levels of evidence for intervention studies according to the NHMRC
(Coleman et al. 2009) and is graded accordingly in the recommendation box (e.g.,
EBR I, II, III, or IV). Consensus-based recommendation was formulated when the
existing intervention evidence base was absent or the committee reached consensus
on the clinical utility of the recommendations.
For the acute phase pharmacological treatment of MDD, the first-line recommen-
dation includes SSRIs, NARIs (reboxetine), NaSSAs, NDRIs (bupropion), and
melatonin agonist (agomelatine). The second line includes SNRIs, TCAs, and
serotonin modulator (vortioxetine). The third-line pharmacological treatment
includes MAOIs, reversible MAOIs (moclobemide), and SARIs (trazodone).
The RANZCP guideline advises to start the treatment of mild to moderate severe
depression with psychosocial and psychological treatments alone or to prescribe
antidepressants. For the treatment of moderate to severe MDD, a combination
treatment of antidepressants and psychological treatments is recommended.
Neuropsychopharmacotherapy: Guidelines 839

For the severe cases of MDD with psychotic features, the guideline recommends to
combine antidepressants with antipsychotics or indicate ECT approach.
This guideline specifies the duration of acute phase treatment from 6 up to
12 weeks and recommends continuation treatment in the maintenance phase for
6 months and up to 1 year, to prevent the relapse.

The World Federation of Societies of Biological Psychiatry (WFSBP)

Guidelines for the Biological Treatment of Unipolar Depressive
Disorders
The WFSBP is a nonprofit, international organization composed of over 60 national
societies of biological psychiatry. The latest update of the practice guidelines for the
biological treatment of unipolar depressive disorders on the acute and continuation
treatment of unipolar depressive disorders was done in 2013 (Bauer et al. 2013) and
on the maintenance treatment – in 2015 (Bauer et al. 2015). These guidelines were
developed by an international Task Force of the WFSBP and provided an update of
contemporary knowledge and evidence-based recommendations for the treatment of
patients with MDD.
The identified literature was evaluated with respect to the strength of evidence for
its efficacy and was then categorized into six levels of evidence (A–F) and five levels
of recommendation grades labelled from 1 to 5, taking into account safety, tolera-
bility, and interaction potential of antidepressants.
For the treatment of the acute phase of MDD, the WFSPB guidelines suggest that
no single class of antidepressants has proven to be more effective. However, for mild
to moderate severe depression, they recommended SSRIs and other “newer antide-
pressants” (apart from reboxetine) or advise to combine psychosocial and psycho-
logical treatments with antidepressant. The same treatment approaches were
recommended for the moderate to severe level of depression.
The work group also clearly stated that psychological treatment should be used
only in combination with antidepressants, such as TCAs, SSRIs, SNRIs, and
MAOIs, for the treatment of severe depression with psychotic symptoms. ECT
also recommended for this severity level of depression.
The guideline suggests treating the acute phase for 8–10 weeks and recommends
continuing of the chosen treatment for 6–9 months after remission of the acute
depressive episode. The experts underline that the duration of maintenance therapy
may vary from 3 years to lifetime and commonly appropriate for recurrent patients,
particularly when an episode prior to the present one has occurred in the last 5 years
or when remission has been difficult to achieve. Maintenance treatment for
5–10 years or even indefinitely is recommended for those patients at greater risk,
particularly when two or three attempts to withdraw medication have been followed
by another episode within a year.

British Association of Psychopharmacology

BAP consensus evidence-based guideline for treating depressive disorders with
antidepressants was published in 2015 as a revision of the 2008 British Association
for Psychopharmacology guidelines (Cleare et al. 2015).
840 J. Vrublevska and L. Renemane

The quality of evidence was graded from category I to category IV, and strength
of recommendation was graded from A–D levels and S level was based on standard
of good practice.
This guideline cover the nature and detection of depressive disorders, acute
treatment with antidepressant drugs, choice of drug versus alternative treatment,
practical issues in prescribing and management, next-step treatment, relapse preven-
tion, treatment of relapse, and stopping treatment. The first-line antidepressant
treatment includes SSRIs. As second line, TCAs and MAOIs were recommended.
The guideline recommended antidepressants as a first-line treatment option for
moderate and severe MDD in adults irrespective of environmental factors and depres-
sion symptom profile, and for depression of any severity that has persisted for 2 years
or more. The guideline suggested antidepressants as a treatment option in short-
duration mild MDD and should be considered if there is a prior history of moderate
to severe recurrent depression or the depression persists for more than 2–3 months.
In terms of duration of treatment, they considered to continue the treatment at
least 6–9 months after full remission in patients at lower risk of relapse (e.g., first-
episode patients without other risk factors), duration in other cases should be tailored
to the individual relapse risk. They also note that a duration of at least 1 year after full
remission should to be provided in patients with any increased risk of relapse. In
higher-risk patients (e.g., more than five lifetime episodes and/or two episodes in the
last few years), the duration of treatment at least 2 years should be advised and
for most long-term treatment should be considered.

Guidelines for the Treatment of Bipolar Disorder (Displayed in

Tables 3, 4, and 5)

British Association of Psychopharmacology

The BAP introduced guidelines for treatment of bipolar disorder (BD) for the first
time in 2003 (Goodwin and Young 2003); the second version was issued in 2009
(Goodwin 2009). The second paper was a substantial revision of the original
document and was based on a consensus meeting, involving experts in bipolar
disorder and its treatment, reviewed key areas, and considered the strength of
evidence and clinical implications. Third version was issued in 2016 (Goodwin
et al. 2016). This guideline should be read alongside NICE 2014 Bipolar Disorder:
Assessment and Management (NICE 2014) (https://www.nice.org.uk/guidance/
cg185). The recommendations are presented together with a more detailed review
of the corresponding evidence. The evidence is categorized, ranging from Category I
(the most powerful evidence) to Category IV (the weakest). The BAP 2016 also
provides assessment and treatment in a broad way and basic information to patients
and caregivers about diagnosis and treatment.
For acute mania, the guidelines recommend dopamine antagonists or valproate as
an alternative treatment. Carbamazepine and lithium are also options.
For acute bipolar depression, if long-term treatment for bipolar disorder is not taken,
they recommend lamotrigine, lithium, and SSRI (fluoxetine) with a drug for mania. It is
Neuropsychopharmacotherapy: Guidelines 841

Table 3 Treatment for acute mania across practice guidelines

Acute treatment Maintenance treatment
First-line Second-line First-line Second-line
Guidelines treatment treatment treatment treatment
CANMAT Li Olanzapine Li Olanzapine
2018 Quetiapine Carbamazepine Quetiapine Carbamazepine
Divalproex Ziprasidone Divalproex Li/DVP
Asenapine Haloperidol Quetiapine +
Aripiprazole Li + DVP Li/DVP
Paliperidone Olanzapine +
Cariprazine Li/DVP
Quetiapine + ECT
Li/DVP
Aripiprazole
+ Li/DVP
Asenapine +
Li/DVP
NICE Without MS: Adding li or Val Same as during Same as during
2014 Haloperidol Alternative AP acute phase acute phase
Olanzapine
Quetiapine
Risperidone
With Li or
Val:
Optimization
Adding
Haloperidol
Olanzapine
Quetiapine
Risperidone
RANZCP Aripiprazole Li/Val + SGAP Li Olanzapine
2015 Asenapine (non-clozapine) Olanzapine (adjunct or
Haloperidol Paliperidone Quetiapine monotherapy)
Li Carbamazepine Lurasidone
Olanzapine ECT Polypharmacy:
Quetiapine Li/Val
Risperidone Adjunctive
Val Lamotrigine
Ziprasidone Quetiapine
Aripiprazole
WFSPB Aripiprazole Asenapine Aripiprazole Olanzapine
2009 Risperidone Haloperidol Lithium Risperidone
Ziprasidone Olanzapine Quetiapine
Quetiapine
carbamazepine
Lithium
CINP-BD Aripiprazole Olanzapine Li Li Carbamazepine +
2017 Asenapine Carbamazepine Aripiprazole Li
Cariprazine Haloperidol Olanzapine Quetiapine + Li
Paliperidone Ziprasidone Paliperidone (Val)
Quetiapine Asenapine + Li/Val Quetiapine,
(continued)
842 J. Vrublevska and L. Renemane

Table 3 (continued)
Acute treatment Maintenance treatment
First-line Second-line First-line Second-line
Guidelines treatment treatment treatment treatment
risperidone Aripiprazole + Risperidone Olanzapine (or
Valproate Li/Val (including RLAI) aripiprazole) + MS
Haloperidol + Li/
Val Olanzapine +
Li/Val
Allopurinol + Li
Val + TAP
Val + celecoxib
BAP Not taking Li/Val + dopamine Li Combination
2016 long-term antagonist/ therapy ADs
treatment: Aripiprazole Clozapine
Haloperidol Maintenance ECT
Olanzapine
Risperidone
Aripiprazole
Quetiapine
Val Li
Taking long-
term
treatment:
optimization
Haloperidol
Olanzapine
Risperidone
Quetiapine
BAP, The British Association of Psychopharmacology; CANMAT, Canadian Network for Mood
and Anxiety Treatments Clinical Guidelines for the Management of Patients with Bipolar Disorder;
CINP-BD The International College of Neuropsychopharmacology Treatment Guidelines for
Bipolar Disorder; NICE, National Institute for Health and Clinical Excellence Clinical Guideline
for Bipolar Disorder; WFSPB, The World Federation of Societies of Biological Psychiatry
(WFSBP) Guidelines for the Biological Treatment of BD; RANZCP, Royal Australian and New
Zealand College of Psychiatrists clinical practice guidelines for mood disorders; Ads, antidepres-
sants, Li, lithium; Val, valproate; ECT, electroconvulsive therapy; DVP, divalproex; TAP, typical
antipsychotics; RLAI, risperidone long-acting injection; MS, mood stabilizers

also recommended to consider ECT for patients with high suicidal risk, treatment
resistance psychosis, severe depression during pregnancy, or life-threatening inanition.
For the maintenance phase, these guidelines recommend the choice of treatment based
on predominant polarity. Maintenance treatment is recommended with lithium,
aripiprazole, quetiapine, valproate, olanzapine if the predominant polarity is mania,
and lamotrigine or quetiapine if predominant polarity is depression.

Canadian Network for Mood and Anxiety Treatments Guidelines for the
Management of Patients with Bipolar Disorder (CANMAT)
The CANMAT previously published guidelines for the first time in 1997
(Kusumakar et al. 1997). These guidelines were revised in 2005, along with
Neuropsychopharmacotherapy: Guidelines 843

Table 4 Treatment for acute depression (BD) across practice guidelines

Pharmacological treatment Maintenance treatment
First-line Second-line First-line Second-line
Guidelines treatment medication treatment medication
CANMAT Quetiapine Divalproex Quetiapine DVP
2018 Lurasidone + SSRIs/bupropion Li
Li/DVP (adj.) Lamotrigine
Lithium Cariprazine Lurasidone + Li/DVP
Lamotrigine Olanzapine +
Lurasidone FLX
Lamotrigine
(adj.)
NICE Without MS: Lamotrigine Same as during acute Same as during
2014 Olanzapine phase acute phase
Olanzapine +
FLX
Quetiapine
Lamotrigine
With MS:
Optimization,
Adjunctive
Olanzapine
+FLX,
Adjunctive
quetiapine
Olanzapine
(adj.)
Lamotrigine
(adj.)
RANZCP Quetiapine Quetiapine + Lamotrigine Olanzapine
2015 Lurasidone Li/Val/ quetiapine (adjunct or
Olanzapine Lamotrigine + Polypharmacy: monotherapy)
Li AD Li
Valproate Lurasidone + Val
Lamotrigine Li/Val + AD Adjunctive:
Olanzapine + Lamotrigine
Fluoxetine Quetiapine
Li + Lamotrigine/ Aripiprazole
Val + AD Olanzapine +
Val + Li + AD Fluoxetine
Lamotrigine + Li
WFSPB Quetiapine Fluoxetine Aripiprazole Olanzapine
2010 Olanzapine Lamotrigine Risperidone
Lamotrigine Li
Valproate Quetiapine
OFC
Modafinil +
ongoing
treatment
N-acetylcysteine
+ Li/Val
(continued)
844 J. Vrublevska and L. Renemane

Table 4 (continued)
Pharmacological treatment Maintenance treatment
First-line Second-line First-line Second-line
Guidelines treatment medication treatment medication
FEWP +
carbamazepine
CINP-BP Quetiapine Val Predominant polarity Add FLX or Li
2017 Lurasidone Li Li Carbamazepine
OFC Lurasidone+MS Aripiprazole + Li
Consider add Modafinil + MS Olanzapine Quetiapine +
on CBT Pramipexole + Paliperidone Li/ Val
MS Quetiapine Olanzapine or
Pioglitazone + Li Risperidone aripiprazole +
Carbamazepine (including RLAI) MS
plus FEWP
Add escitalopram
or FLX
BAP 2016 Not taking Add antimanic Li Lamotrigine
long-term agent Quetiapine
treatment: ECT Lurasidone
Quetiapine
Olanzapine
Olanzapine +
FLX
Lurasidone
Lamotrigine as
combination
BAP, The British Association of Psychopharmacology; CANMAT, Canadian Network for Mood
and Anxiety Treatments Clinical Guidelines for the Management of Patients with Bipolar Disorder;
CINP-BD The International College of Neuropsychopharmacology Treatment Guidelines for
Bipolar Disorder; NICE, National Institute for Health and Clinical Excellence Clinical Guideline
for Bipolar Disorder; WFSPB, The World Federation of Societies of Biological Psychiatry
(WFSBP) Guidelines for the Biological Treatment of BD; RANZCP, Royal Australian and New
Zealand College of Psychiatrists clinical practice guidelines for mood disorders; AD, antidepres-
sant, Li, lithium; Val, valproate; DVP, divalproex; TAP, typical antipsychotics; RLAI, risperidone
long-acting injection; MS, mood stabilizers; FLX, fluoxetine; Adj., adjunctive; FEWP, herbal
remedy “Free and easy wanderer plus”; OFC, olanzapine-fluoxetine combination

international commentaries and subsequent updates in 2007, 2009, and 2013

(Yatham et al. 2005, 2006; 2009, 2013). Previous two updates were appeared as a
collaboration of CANMAT and the International Society on Bipolar Disorders
(ISBD) (Yatham et al. 2013). These 2018 CANMAT (Yatham et al. 2018) and
ISBD Bipolar Treatment Guidelines represent the significant advances in the field
since the last full edition was published in 2005, including updates to diagnosis and
management as well as new research into pharmacological and psychological
treatments, and are based on the extensive review of the literature and data from
clinical trials. The evidence of efficacy, safety/tolerability, and risk of treatment-
Neuropsychopharmacotherapy: Guidelines 845

Table 5 Treatment for mixed episodes (BD) across practice guidelines

Pharmacological treatment Maintenance treatment
First-line Second-line First-line
Guidelines treatment medication treatment Second-line Treatment
CANMAT No – – –
2018 recommendations
NICE Same as for Same as for Same as for Same as for mania
2014 mania mania mania
RANZCP Predominant ECT Val No specific
2015 depression: recommendations
Olanzapine
Quetiapine
Val
Olanzapine + Val
Quetiapine or
Val + AD
Manic with
depression:
Asenapine
Olanzapine
Aripiprazole
Ziprasidone
Risperidone +
MS
WFSPB Olanzapine Aripiprazole Quetiapine Valproate
2018 Paliperidone (combination) (monotherapy) or manic
(MM, or mixed index episode
monotherapy) Quetiapine to prevent a
Quetiapine new episode after MxIE
MM (monotherapy)
(combination Olanzapine to prevent a
DS) new episode after MxIE
Risperidone (monotherapy)
for MM Lithium to prevent a
(monotherapy) new manic and any type
Ziprasidone episode after MxIE
DM (monotherapy)
(combination)
CINP-BP Olanzapine + Li/ Olanzapine Predominant Add FLX or Li
2017 Val Aripiprazole polarity Carbamazepine + Li
Olanzapine Li Quetiapine + Li/ Val
Aripiprazole Olanzapine or
Olanzapine aripiprazole + MS
Paliperidone
Quetiapine
Risperidone
(RLAI)
(continued)
846 J. Vrublevska and L. Renemane

Table 5 (continued)
Pharmacological treatment Maintenance treatment
First-line Second-line First-line
Guidelines treatment medication treatment Second-line Treatment
BAP 2016 Same as for Same as for Same as for Same as for mania
mania mania mania
BAP, The British Association of Psychopharmacology; CANMAT, Canadian Network for Mood
and Anxiety Treatments Clinical Guidelines for the Management of Patients with Bipolar Disorder;
CINP-BD The International College of Neuropsychopharmacology Treatment Guidelines for
Bipolar Disorder; NICE, National Institute for Health and Clinical Excellence Clinical Guideline
for Bipolar Disorder; WFSPB, The World Federation of Societies of Biological Psychiatry
(WFSBP) Guidelines for the Biological Treatment of BD; RANZP, Royal Australian and New
Zealand College of Psychiatrists clinical practice guidelines for mood disorders; AD, antidepres-
sant, Li, lithium; Val, valproate; DVP, divalproex; TAP, typical antipsychotics; RLAI, risperidone
long-acting injection; MS, mood stabilizers; FLX, fluoxetine; Adj., adjunctive; OFC, olanzapine-
fluoxetine combination; MM, manic mixed; DM, depressed mixed; MxIE, mixed index episode

emergent switch with pharmacological agents were categorized, ranging from Level
1 (the most powerful evidence) to Level 4 (the weakest, uncontrolled trial, anecdotal
reports, or expert opinion). Treatment recommendations were categorized into four
levels based on the strength of supporting evidence. These guidelines recommend
monotherapy of quetiapine, asenapine, paliperidone, risperidone, and cariprazine,
and adjunctive quetiapine or aripiprazole or risperidone or asenapine with lithium or
divalproex as first-line treatment strategies for treating mania. As second-line treat-
ment, they recommend olanzapine, carbamazepine, ziprasidone, haloperidol, and
combination of olanzapine and lithium/divalproex and combination of lithium and
divalproex. As the first-line treatment of bipolar depression, the CANMAT recom-
mends monotherapy of quetiapine, lithium, lamotrigine, lurasidone, and combina-
tion of lurasidone and lithium/divalproex. As second-line treatment, they
recommend divalproex, cariprazine, olanzapine-fluoxetine, adjunctive SSRI or
bupropion, and ECT.

The International College of Neuropsychopharmacology Treatment

Guidelines for Bipolar Disorder in Adults (CINP-BD)
The International College of Neuropsychopharmacology published guidelines for
BD for the first time in 2016 (Fountoulakis et al. 2016a, b, c, 2017). The guidelines
were based on a systematic search of the literature and a detailed presentation of the
results concerning placebo-controlled randomized trials for all the phases and
aspects of BD. It also includes the grading of treatment options in terms of efficacy
and tolerability/safety as well as a precise algorithm that still has to prove its
feasibility in everyday clinical practice. Efficacy data were graded on the basis of
a method developed by the authors and described in the first paper of the CINP
guidelines for BD (Fountoulakis et al. 2016c). Grading on the basis of efficacy
ranged from Level 1 (good research evidence) to Level 5 (negative data). Grading on
the basis of safety and tolerability ranged from Level 1 (very good tolerability) to
Level 3 (poor tolerability). Based on levels of efficacy and safety/tolerability, they
Neuropsychopharmacotherapy: Guidelines 847

offered five levels of recommendations for treatment. For the treatment of acute
mania, the CINP-BD guidelines suggest aripiprazole, asenapine, cariprazine,
paliperidone, quetiapine, risperidone, or valproate monotherapy. If the treatment
during the first step fails, CINP suggests olanzapine, lithium, carbamazepine, halo-
peridol, or ziprasidone monotherapy or combinations of lithium or valproate plus
asenapine, aripiprazole, haloperidol, olanzapine or lithium plus allopurinol,
valproate plus a first-generation antipsychotic, valproate plus celecoxib. For the
treatment of acute bipolar depression, the CINP-BD recommends quetiapine or
lurasidone or consider CBT as add-on to medication. For the second step of the
treatment of acute depression, they suggest monotherapy with olanzapine or OFC,
combination of a mood stabilizer with lurasidone, modafinil, or pramipexole, lithium
plus lamotrigine or pioglitazone, or add escitalopram or fluoxetine to ongoing
therapy. In the maintenance phase, the CINP suggests to take into account predom-
inant polarity and start with lithium, aripiprazole, olanzapine, paliperidone,
quetiapine, or risperidone, including risperidone long-acting injectable, mono-
therapy depending on predominant polarity (Fountoulakis et al. 2016a).

National Institute for Health and Clinical Excellence Clinical Guideline

for Bipolar Disorder
The first version of guidelines for the treatment of BD was introduced in 2006 and
revised version was published in 2014 (NICE 2014). The guidelines were provided
for professionals working in various fields of psychiatry, patients and their families,
and caregivers. For the treatment of acute mania, the NICE suggests haloperidol,
olanzapine, quetiapine, and risperidone. If the first antipsychotic is poorly tolerated
at any dose, the guidelines recommend to change to another antipsychotic based on
previous response to treatment, physical comorbidity, and side effects. If the person
is already taking lithium, the recommendation is to increase the dosage and the
suggestion is to add haloperidol, olanzapine, quetiapine, or risperidone have to be
considered. If the person is already taking valproate or another mood stabilizer as
prophylactic treatment, they recommend to consider increasing the dose, up to the
maximum level. If there is no improvement, the recommendation is to add haloper-
idol, olanzapine, quetiapine, or risperidone, depending on the person’s preference
and previous response to treatment. If a person develops bipolar depression and is
not taking a drug to treat their bipolar disorder, the NICE recommends fluoxetine
combined with olanzapine or olanzapine, quetiapine, lamotrigine monotherapy. If
there is no response to fluoxetine combined with olanzapine, or quetiapine,
the recommendation is lamotrigine on its own. During the maintenance phase, the
NICE guidelines recommend the treatment that the patient received during the acute
phase.

The World Federation of Societies of Biological Psychiatry (WFSBP)

Guidelines for the Biological Treatment of Bipolar Disorders
This practice guideline for the biological, mainly pharmacological, treatment for
bipolar depression was published in 2002 (Grunze et al. 2002), mania in 2003 (Grunze
et al. 2003), and maintenance treatment in 2004 (Grunze et al. 2004). Revisions were
848 J. Vrublevska and L. Renemane

published in 2009 for mania (Grunze et al. 2009), in 2010 for acute depression
(Grunze et al. 2010), for maintenance treatment in 2013 (Grunze et al. 2013), and
for the acute and long-term treatment of mixed states in 2018 (Grunze et al. 2018).
Their scientific rigor was categorized into six levels of evidence (A–F). The
scientific evidence was finally assigned different grades of recommendation to
ensure practicability.
For the treatment of acute mania based on the category of evidence and recom-
mendation grade as first-choice agents, the WFSBP recommends aripiprazole,
risperidone, valproate, and ziprasidone. As second choice, asenapine, haloperidol,
olanzapine, quetiapine, carbamazepine, and lithium were suggested.
For the treatment of acute depression, the WFSB guidelines as first-choice
treatment recommend only quetiapine, as second-choice agents fluoxetine,
olanzapine, lamotrigine, valproate as monotherapy. As combination and augmenta-
tion treatments, they suggest lamotrigine plus lithium, olanzapine fluoxetine
combination, modafinil plus ongoing treatment, N-acetylcysteine plus lithium or
valproate, FEWP + carbamazepine.
During the maintenance phase, they recommend aripiprazole, lithium, lamotrigine,
quetiapine but not all of them prevent episodes of both depression and mania.
For the treatment of manic symptoms in bipolar mixed states appeared responsive
to treatment with several atypical antipsychotics, the best evidence had olanzapine.
For depressive symptoms, addition of ziprasidone to treatment as usual may be
beneficial; however, the evidence base is much more limited than for the treatment of
manic symptoms. Valproate and lithium should also be considered for recurrence
prevention.

Royal Australian and New Zealand College of Psychiatrists Clinical

Practice Guidelines for Mood Disorders
The Mood Disorders Clinical Practice Guideline (Mood Disorders CPG) has been
developed by the Royal Australian and New Zealand College of Psychiatrists
(RANZCP) to guide the clinical management of real-world depressive and bipolar
disorders and to advise specifically on diagnosis and treatment strategies. This
guideline was developed as part of the RANZCP CPG Project 2013–2015, funded
solely by the College. A revised version of the guideline was released (June–July
2015) for public consultation Australia and New Zealand. The guideline is primarily
directed at psychiatrists, psychologists, and physicians, and primarily focuses on
adults and briefly addresses other specific populations (Malhi et al. 2015).
For the treatment of acute mania in the guidelines as the first option is
recommended aripiprazole, asenapine, quetiapine, risperidone, valproate, and
ziprasidone. If the first step is ineffective or not tolerated, they recommend two-
drug combination of lithium and valproate, lithium or valproate in combination with
second-generation antipsychotics, paliperidone, carbamazepine, and electroconvul-
sive therapy. For the treatment of bipolar depression, the RANZP recommends
quetiapine, lurasidone, olanzapine, lithium, valproate, lamotrigine monotherapy. If
the treatment during the first step fails, they suggest combinations of second-
generation antipsychotics, mood stabilizing agents, and antidepressants.
Neuropsychopharmacotherapy: Guidelines 849

During the maintenance phase, they recommended taking into consideration

dominant polarity.

Conclusions

The guidelines that were discussed in the chapter provide the evidence-based
recommendations that grow up from systematic process of gathering and critical
evaluation of the research data regarding a particular treatment. Randomized control
studies, cohort studies, observational case studies, and retrospective studies
were analyzed and categorized in the guidelines to prepare the levels of evidence.
However, a different level of agreement in recommendations for managing psychi-
atric disorders was found across the guidelines. Therefore, the clinician should also
recognize that there is no perfect treatment practice guideline that applies to all
patients. There is a need for internationally acceptable recommendations to be
developed and then set the framework for further development on a national basis.
International organizations such as the WPA or WHO may help formulate a unified
guideline, which may then be modified to meet the needs. This need, however, must
not underestimate the limits of the guidelines and must lead the specialist to a critical
acceptance of them in everyday clinical practice.

References
American Psychiatric Association (APA). Practice guideline for the treatment of patients with major
depressive disorder. 3rd ed. Washington, DC: APA; 2010.
Amsterdam JD, Fava M, Maislin G, Rosenbaum J, Hornig-Rohan M. TRH stimulation test as a
predictor of acute and long-term antidepressant response in major depression. J Affect Disord.
1996;38(2–3):165–72.
APA. Diagnostic and statistical manual of mental disorders. 4th ed. Washington: American
Psychiatric Association; 1994.
APA. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychi-
atric Association; 2013.
APA. American Psychiatric Association Practice Guidelines. https://psychiatryonline.org/
guidelines
Barnes TR. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recom-
mendations from the British Association for Psychopharmacology. J Psychopharmacol (Oxford,
England). 2011;25(5):567–620.
Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Moller HJ. World Federation of Societies of
Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive
disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive
disorders. World J Biol Psychiatry. 2013;14(5):334–85.
Bauer M, Severus E, Kohler S, Whybrow PC, Angst J, Moller HJ. World Federation of Societies of
Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive
disorders. Part 2: maintenance treatment of major depressive disorder-update 2015. World J
Biol Psychiatry. 2015;16(2):76–95.
Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing
guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839–42.
850 J. Vrublevska and L. Renemane

Carnett WG. Clinical practice guidelines: a tool to improve care. Qual Manag Health Care.
1999;8(1):13–21.
CINP. The International College of Neuropsychopharmacology. Guidelines. https://cinp.org/Guide
lines. Accessed April 2020.
Cleare A, Pariante CM, Young AH, Anderson IM, Christmas D, Cowen PJ, et al. Evidence-based
guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British
Association for Psychopharmacology guidelines. J Psychopharmacol (Oxford, England).
2015;29(5):459–525.
Coleman K, Norris S, Weston A, Grimmer-Somers K, Hilier S, Merlin T, et al. NHMRC additional
levels of evidence and grades for recommendations for developers of guidelines. Evidence
Translation Section, and supported by National Institute of Clinical Studies Officers of the
NHMRC. Australia; 2009. https://www.mja.com.au/sites/default/files/NHMRC.levels.of.evi
dence.2008-09.pdf. Accesed April 2020.
Driessen E, Van HL, Don FJ, Peen J, Kool S, Westra D, et al. The efficacy of cognitive-behavioral
therapy and psychodynamic therapy in the outpatient treatment of major depression: a random-
ized clinical trial. Am J Psychiatry. 2013;170(9):1041–50.
Driessen E, Hollon SD, Bockting CLH, Cuijpers P, Turner EH. Does publication bias inflate the
apparent efficacy of psychological treatment for major depressive disorder? A systematic review
and meta-analysis of US National Institutes of Health-Funded Trials. Plos One. 2015;10(9):
e0137864.
Field MJ, Lohr KN. Clinical practice guidelines: directions for a new program. Washington, DC:
National Academies Press 1990.
Field MJ, Lohr KN, Institute of Medicine. Guidelines for clinical practice : from development to
use. Washington, DC: National Academies Press; 1992.
Forsner T, Hansson J, Brommels M, Wistedt AA, Forsell Y. Implementing clinical guidelines in
psychiatry: a qualitative study of perceived facilitators and barriers. BMC Psychiatry.
2010;10:8.
Fountoulakis KN. Treatment guidelines bipolar disorder: an evidence based guide to manic
depression. 2015.
Fountoulakis KN, Grunze H, Vieta E, Young A, Yatham L, Blier P, et al. The International College
of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults
(CINP-BD-2017), part 3: the clinical guidelines. Int J Neuropsychopharmacol.
2016a;20(2):180–95.
Fountoulakis KN, Yatham L, Grunze H, Vieta E, Young A, Blier P, et al. The International College
of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults
(CINP-BD-2017), part 2: review, grading of the evidence, and a precise algorithm. Int J
Neuropsychopharmacol. 2016b;20(2):121–79.
Fountoulakis KN, Young A, Yatham L, Grunze H, Vieta E, Blier P, et al. The International
College of Neuropsychopharmacology (CINP) treatment guidelines for bipolar disorder in
adults (CINP-BD-2017), part 1: background and methods of the development of guidelines.
Int J Neuropsychopharmacol. 2016c;20(2):98–120.
Fountoulakis KN, Vieta E, Young A, Yatham L, Grunze H, Blier P, et al. The International
College of Neuropsychopharmacology (CINP) treatment guidelines for bipolar disorder in
adults (CINP-BD-2017), part 4: unmet needs in the treatment of bipolar disorder and recom-
mendations for future research. Int J Neuropsychopharmacol. 2017;20(2):196–205.
Galletly C, Castle D, Dark F, Humberstone V, Jablensky A, Killackey E, et al. Royal Australian and
New Zealand College of Psychiatrists clinical practice guidelines for the management of
schizophrenia and related disorders. Aust N Z J Psychiatry. 2016;50(5):410–72.
Garnick DW, Hendricks AM, Brennan TA. Can practice guidelines reduce the number and costs of
malpractice claims? JAMA. 1991;266(20):2856–60.
Goodwin GM. Evidence-based guidelines for treating bipolar disorder: revised second edition –
recommendations from the British Association for Psychopharmacology. J Psychopharmacol
(Oxford, England). 2009;23(4):346–88.
Neuropsychopharmacotherapy: Guidelines 851

Goodwin GM, Young AH. The British Association for Psychopharmacology guidelines for treat-
ment of bipolar disorder: a summary. J Psychopharmacol (Oxford, England). 2003;17(4
Suppl):3–6.
Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, et al. Evidence-based
guidelines for treating bipolar disorder: Revised third edition recommendations from the
British Association for Psychopharmacology. J Psychopharmacol (Oxford, England).
2016;30(6):495–553.
Grunze H, Kasper S, Goodwin G, Bowden C, Baldwin D, Licht R, et al. World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of bipolar
disorders. Part I: treatment of bipolar depression. World J Biol Psychiatry. 2002;3(3):115–24.
Grunze H, Kasper S, Goodwin G, Bowden C, Baldwin D, Licht RW, et al. The World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar
disorders, part II: treatment of mania. World J Biol Psychiatry. 2003;4(1):5–13.
Grunze H, Kasper S, Goodwin G, Bowden C, Moller HJ. The World Federation of Societies of
Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders, part
III: maintenance treatment. World J Biol Psychiatry. 2004;5(3):120–35.
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, et al. The World Federation
of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of
bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry.
2009;10(2):85–116.
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, et al. The World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar
disorders: update 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry.
2010;11(2):81–109.
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, et al. The World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar
disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry.
2013;14(3):154–219.
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Azorin JM, et al. The World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar
disorders: acute and long-term treatment of mixed states in bipolar disorder. World J Biol
Psychiatry. 2018;19(1):2–58.
Hanlon P. The future public health. Maidenhead: McGraw-Hill Education; 2012.
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophre-
nia, part 1: update 2012 on the acute treatment of schizophrenia and the management of
treatment resistance. World J Biol Psychiatry. 2012;13(5):318–78.
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophre-
nia, part 2: update 2012 on the long-term treatment of schizophrenia and management of
antipsychotic-induced side effects. World J Biol Psychiatry. 2013;14(1):2–44.
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthøj B, Gattaz WF, et al. World Federation of
Societies of biological psychiatry (WFSBP) guidelines for biological treatment of schizophre-
nia. Part 3: update 2015 management of special circumstances: depression, suicidality, sub-
stance use disorders and pregnancy and lactation. World J Biol Psychiatry. 2015;16(3):142–70.
Hasan A, Bandelow B, Yatham LN, Berk M, Falkai P, Möller H-J, et al. WFSBP guidelines on how
to grade treatment evidence for clinical guideline development. World J Biol Psychiatry.
2019;20(1):2–16.
Kamens SR, Cosgrove L, Peters SM, Jones N, Flanagan E, Longden E, et al. Standards and
guidelines for the development of diagnostic nomenclatures and alternatives in mental health
research and practice. J Humanist Psychol. 2019;59(3):401–27.
Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for
Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of
852 J. Vrublevska and L. Renemane

adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry.
2016;61(9):540–60.
Kredo T, Bernhardsson S, Machingaidze S, Young T, Louw Q, Ochodo E, et al. Guide to clinical
practice guidelines: the current state of play. Int J Qual Health Care. 2016;28(1):122–8.
Kusumakar V, Yatham LN, Haslam DR, Parikh SV, Matte R, Silverstone PH, et al. Treatment
of mania, mixed state, and rapid cycling. Can J Psychiatr Rev can psychiatr. 1997;42(Suppl
2):79s–86s.
Lam RW, McIntosh D, Wang J, Enns MW, Kolivakis T, Michalak EE, et al. Canadian Network for
Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of
adults with major depressive disorder: section 1. Disease burden and principles of care. Can J
Psychiatry. 2016;61(9):510–23.
Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice
guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry.
2004;161(2 Suppl):1–56.
Leucht S, Arango C, Fleischhacker WW, Kapur S, Stroup S, van Os J, et al. CINP SCHIZOPHRE-
NIA GUIDELINE. 2013. The International College of Neuropsychopharmacology (CINP)
https://www.cinp.org/resources/Documents/CINP-schizophrenia-guideline-24.5.2013-A-C-
method.pdf. Accessed April 2020.
MacQueen GM, Frey BN, Ismail Z, Jaworska N, Steiner M, Lieshout RJ, et al. Canadian Network
for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of
adults with major depressive disorder: section 6. Special populations: youth, women, and the
elderly. Can J Psychiatry. 2016;61(9):588–603.
Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, et al. Royal Australian and New
Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J
Psychiatry. 2015;49(12):1087–206.
McGorry P, Killackey E, Lambert T. Royal Australian and New Zealand College of Psychiatrists
clinical practice guidelines for the treatment of schizophrenia and related disorders. Aust N Z J
Psychiatry. 2005;39:1–30.
McIntyre JS. Usefulness and limitations of treatment guidelines in psychiatry. World Psychiatry.
2002;1(3):186–9.
Milev RV, Giacobbe P, Kennedy SH, Blumberger DM, Daskalakis ZJ, Downar J, et al. Canadian
Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the
management of adults with major depressive disorder: section 4. Neurostimulation treatments.
Can J Psychiatry. 2016;61(9):561–75.
Mulrow CD. Rationale for systematic reviews. BMJ. 1994;309(6954):597–9.
Munder T, Brütsch O, Leonhart R, Gerger H, Barth J. Researcher allegiance in psychotherapy
outcome research: an overview of reviews. Clin Psychol Rev. 2013;33(4):501–11.
NICE. National Institute for Health and Care Excellence. Depression in adults: recognition and
management (Clinical guideline 90). www.nice.org.uk/guidance/cg90. 2009.
NICE. Bipolar disorder: assessment and management clinical guideline. www.nice.org.uk/guid
ance/cg185. 2014
Nivoli G, Lorettu L, Carpiniello B, Milia P, Pinna F, Lepretti A, et al. [Charges and convictions of
psychiatrists for the violent behavior of the patient: psychiatric-forensic remarks]. Riv Psichiatr.
2017;52(3):101–8.
Parikh SV, Quilty LC, Ravitz P, Rosenbluth M, Pavlova B, Grigoriadis S, et al. Canadian Network
for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of
adults with major depressive disorder: section 2. Psychological treatments. Can J Psychiatry.
2016;61(9):524–39.
Ravindran AV, Balneaves LG, Faulkner G, Ortiz A, McIntosh D, Morehouse RL, et al. Canadian
Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the
management of adults with major depressive disorder: section 5. Complementary and alternative
medicine treatments. Can J Psychiatry. 2016;61(9):576–87.
Neuropsychopharmacotherapy: Guidelines 853

Remington G, Addington D, Honer W, Ismail Z, Raedler T, Teehan M. Guidelines for the

pharmacotherapy of schizophrenia in adults. Can J Psychiatry. 2017;62(9):604–16.
Stasevic M, Karlicic IS, Divac N, Grgurevic A, Grbic I. Factors associated with adherence to
guidelines of good clinical practice during hospital treatment of patients with the first episode of
schizophrenia spectrum disorders. Vojnosanit Pregl. 2019;76(10):998–1006.
Taylor DM, Barnes TRE, Young AH. The Maudsley prescribing guidelines in psychiatry. 13th ed.
India: Wiley-Blackwell; 2018.
The ADAPTE process: resource toolkit for guideline adaptation. Version 2.0. http://www.g-i-n.net
[Internet]. 2009.
Woolf SH. Practice guidelines, a new reality in medicine. II. Methods of developing guidelines.
Arch Intern Med. 1992;152(5):946–52.
Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential benefits,
limitations, and harms of clinical guidelines. BMJ. 1999;318(7182):527–30.
World Federation of Societies of Biological Psychiatry (WFSBP). Treatment guidelines and
consensus papers. https://www.wfsbp.org/educational-activities/wfsbp-treatment-guidelines-
and-consensus-papers/
World Health Organisation (WHO). The ICD-10 classification of mental and behavioural disorders.
Geneva: WHO; 1992.
Yatham LN, Kennedy SH, O’Donovan C, Parikh S, MacQueen G, McIntyre R, et al. Canadian
Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management
of patients with bipolar disorder: consensus and controversies. Bipolar Disord. 2005;7(Suppl
3):5–69.
Yatham LN, Kennedy SH, O’Donovan C, Parikh SV, MacQueen G, McIntyre RS, et al. Canadian
Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of
patients with bipolar disorder: update 2007. Bipolar Disord. 2006;8(6):721–39.
Yatham LN, Kennedy SH, Schaffer A, Parikh SV, Beaulieu S, O’Donovan C, et al. Canadian
Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar
Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients
with bipolar disorder: update 2009. Bipolar Disord. 2009;11(3):225–55.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, et al. Canadian Network for
Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders
(ISBD) collaborative update of CANMAT guidelines for the management of patients with
bipolar disorder: update 2013. Bipolar Disord. 2013;15(1):1–44.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al. Canadian Network for
Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders
(ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord.
2018;20(2):97–170.
Neuropsychopharmacotherapy: Differential
Dose Regimes in China

Jie Li and Shen Li

Contents
Prescription Patterns of Neuropsychopharmacotherapy in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
Brief Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
Antipsychotic Polypharmacy in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
Clozapine in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
Brief History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
Prevalence of Clozapine Use in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
Product Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
Pattern of Utilization of Clozapine in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863

Abstract
Prescription habits are affected by a variety of factors, including the healthcare
system, financing schemes, medical traditions, consumers’ choices, and the
overall sociocultural background of the respective countries. In the treatment of
psychosis, many Western countries have published national guidelines or con-
sensus statements that refer to the prescribing of neuropsychopharmacotherapy.
All advise against the use of high dosage other than in exceptional circumstances.
However, there are discrepancies between these guidelines or algorithms and
prescription patterns and that practice varies substantially according to patient,
prescriber, and institution.

J. Li (*)
Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China
e-mail: jieli@tjmhc.com
S. Li
Department of Psychiatry, Tianjin Medical University, Tianjin, China
e-mail: lishen@tmu.edu.cn

© Springer Nature Switzerland AG 2022 855

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_22
856 J. Li and S. Li

The present chapter aimed to assess the prescription patterns of psychotropic

drugs for patients with psychosis in China and to determine factors affecting their
prescriptions, especially the situation of antipsychotic polypharmacy in China.
Clozapine remains one of the most commonly used antipsychotic medications
in China. As China has the largest population internationally on clozapine
treatment, its experience and research findings are of keen interest to Western
psychiatrists. Here, it was systematically introduced clozapine use in China,
including brief history, prevalence of clozapine use, product Information, and
pattern of utilization of clozapine.

Prescription Patterns of Neuropsychopharmacotherapy in China

Brief Introduction

Cross-sectional surveys of prescription patterns for psychiatric patients are an

inexpensive, efficient, and fast way of obtaining a global picture of the appropriate-
ness of pharmacotherapy in a given setting (Ungvari et al. 1997). To date, little is
known about how clinicians use psychotropic drugs in China, where the character-
istics of the mental health system are fundamentally different from those of Western
countries. Prescription patterns are fundamentally different across countries and
even regions due to variations in factors including healthcare policies, availability
and cost of drugs, psychiatric training, and preferred treatment modalities (Chong
et al. 2004; Percudani et al. 2005).
Significant differences would be found in the prescription patterns of antipsy-
chotic drugs (AP), anticholinergics, mood stabilizers, and antidepressants between
the mainland of China and Western countries. For this reason, we assume that the
diversity of prescription practices might be due to the following non-clinical factors.
(1) Insurance coverage. Currently in mainland China, comprehensive health insur-
ance only covers employed patients in urban regions. Therefore, people who fall ill
at an early age before obtaining a job, and all residents in rural regions, are rarely
covered by health insurance (Phillips et al. 1997). (2) Less stringent drug regulations
in China allow for a more liberal prescription of benzodiazepines. (3) Less stringent
regulations in Western countries allow for a more liberal prescription of psychotropic
polypharmacy. It has been reported that public health policies, the cost of medica-
tion, and prescription tradition all affect prescription practices (Sim et al. 2004).

Antipsychotic Polypharmacy in China

Antipsychotic polypharmacy (APP) refers to the concurrent use of more than

one antipsychotic medication. Although antipsychotic monotherapy is consistently
recommended as the preferred treatment for schizophrenia in numerous treatment
guidelines (Buchanan et al. 2010; Moore et al. 2007), APP is common practice in
modern psychiatry worldwide. APP is used clinically in patients with severe
Neuropsychopharmacotherapy: Differential Dose Regimes in China 857

schizophrenia, particularly those with mania or with violent or aggressive behaviors,

or to avoid side effects resulting from high doses of a single drug (Jeon and Kim
2017). APP may also be used in treatment-resistant schizophrenia as a combination
of clozapine with an atypical antipsychotic or as a combination of atypical antipsy-
chotics in patients with clozapine resistance, although strong evidence supporting
the effectiveness of these regimens is currently lacking (Galling et al. 2017).
Studies performed in multiple countries in various settings illustrate inconsistent
patterns of APP over the past decades. Several database studies utilizing health
claims data in the USA reported APP prevalence rates from 4.6% to 23% (Ganguly
et al. 2004; Morrato et al. 2007). APP prevalence rates reported from Asia were often
higher, ranging from 17.8% to 51.7% (Hou et al. 2016; Kochi et al. 2017). Most
studies conducted in Asia were patient surveys or chart reviews. Only one study was
conducted using community-based pharmacy data and reported the APP rate as
17.8% in Japan (Kochi et al. 2017). However, patient diagnoses were lacking in that
database, making the rate nonspecific for schizophrenia treatment. Systematic
reviews of APP across multiple geographic regions between 1970 and 2009 showed
a global median prevalence rate of 19.6% of patients receiving APP, with the highest
rate in Asia (32%), where the rate of APP with three or more antipsychotics was also
highest, followed by Europe (23%), while the lowest was in North America (16%)
and Oceania (16.4%). This pattern has been consistent for the last four decades.
A large-scale cross-sectional survey in East Asia showed variations in APP across
countries, with the highest rate in Singapore (74%), followed by Japan (51.3%),
Korea (40.6%), and mainland China (36.8%) (Ito et al. 2012). In a recent study, the
observed rates of antipsychotic polypharmacy ranged from 12.7% in China to 19.9%
in Japan. Switching from monotherapy to antipsychotic polypharmacy was most
likely to occur in younger patients with schizophrenia (Qiu et al. 2018). A study
highlighted a relatively low APP rate in Hong Kong when compared to other
countries in East Asia (Lung et al. 2018). Substantial variations in psychotropic
medication treatment patterns for patients with schizophrenia living in community
were found between rural and urban areas in China. Common use of antipsychotic
polypharmacy, clozapine, and benzodiazepines in urban area, and anticholinergics
in rural area are the more prominent problems (Hou et al. 2019).
According to the survey carried out in 2012, the five most commonly mono-
prescribed SGAs in China was risperidone (38.7%), clozapine (14.3%), olanzapine
(13.5%), aripiprazole (9.6%), and quetiapine (7.8%) (Li et al. 2015a).
A network meta-analysis aimed to create hierarchies of the efficacy, acceptability,
and tolerability of eight atypical antipsychotics in the treatment of Chinese patients
with acute schizophrenia. Sixty high-quality RCTs with 6418 participants were
included. A pattern of superiority from olanzapine, paliperidone, and amisulpride
was seen in the primary outcome. Only paliperidone was found better than
aripiprazole (odds ratio, 0.49 [95% credible intervals, 0.25–0.99]), ziprasidone
(0.42 [0.21–0.85]), and quetiapine (0.36 [0.13–0.93]) in terms of all-cause discon-
tinuation. The best and worst drugs in terms of weight gain, EPS, and somnolence
were aripiprazole and olanzapine, clozapine and amisulpride, aripiprazole and clo-
zapine, respectively (Bai et al. 2017).
858 J. Li and S. Li

Most of the publications to date reported cross-sectional approaches in which the

design could not distinguish cross-tapering of different antipsychotics from actual
combination therapy or patient interviews which might have been influenced by
observational or recall biases. None of these longitudinal studies were conducted
in Asia. Longitudinal studies using large healthcare databases are becoming increas-
ingly important in describing treatment patterns for many diseases, including
schizophrenia.

Clozapine in China

Brief History

In 1959, the molecule clozapine was identified by the pharmaceutical company

Wander Laboratories; however, clozapine was not introduced into the market until
the first part of the 1970s (Hippius 1999). Clozapine which was the first atypical
antipsychotic has shown to be more robustly and consistently superior to other
antipsychotics (Leucht et al. 2013), particularly in patients with treatment-resistant
schizophrenia (TRS) (Essali et al. 2009), and has a low propensity to cause extra-
pyramidal side effects (EPS). In 1975, clozapine was withdrawn as a result of eight
fatal cases of clozapine-induced agranulocytosis in Finland, an adverse effect not
observed in the initial studies (Amsler et al. 1977). Despite clozapine only being
available for a short period of time, it improved the symptoms of many patients
based on clinical observation, which ultimately led to its reintroduction (Hippius
1999). This in turn provoked the development of mandatory hematological moni-
toring, which has almost eliminated the risk of fatal agranulocytosis (Honigfeld et al.
1998). Clozapine was not introduced in the USA until 1990, after the pivotal study
by Kane et al. proved that it was significantly superior to chlorpromazine in patients
with schizophrenia resistant to retrospective antipsychotic treatment and one pro-
spective antipsychotic trial (Kane et al. 1988).
The superiority of clozapine for treatment-resistant schizophrenia has been
documented in several clinical trials (Kane et al. 1988; Conley et al. 2003). Despite
non-response to other antipsychotic drugs, the chance of responding to clozapine is
more than 60% (Schulte 2003). In addition to the effects in treatment-resistant
schizophrenia, clozapine has also shown benefits in a wide variety of serious
psychiatric conditions. It shows antisuicidal (Meltzer et al. 2003) and anti-aggressive
(Krakowski et al. 2006) properties in patients with schizophrenia and seems to
reduce hospitalizations and bed days as well as intentional self-harm in bipolar
patients (Nielsen et al. 2012a; Ifteni et al. 2014). Additionally, clozapine has
shown benefits for tardive dyskinesia (Ye et al. 2014) and psychosis in patients
with Parkinson’s disease (Fernandez et al. 2004). A recent study showed long-term
clozapine treatment may protect low bone mineral density compared to prolactin-
raising and non-clozapine prolactin-sparing antipsychotics among patients with
schizophrenia (Lin et al. 2019). In contrast, in addition to agranulocytosis, clozapine
can cause low blood pressure, sedation, serious constipation, and increase the risk of
Neuropsychopharmacotherapy: Differential Dose Regimes in China 859

metabolic syndrome, lowering treatment adherence (Iqbal et al. 2003). It was found
that many patients discontinue clozapine in clinical practice because of its adverse
effects (Mustafa et al. 2015). Nowadays, the prevalence of clozapine-associated
agranulocytosis is low, and agranulocytosis-related death appears rare (Li et al.
2019). Thirty years of both ignorance and clinical experience suggest that clozapine
intoxication during co-occurring infections and inflammation may have higher
morbidity and mortality than is currently believed (Ruan and De Leon 2019).
Serious infections or inflammations have been associated with serum clozapine
concentration increases and sometimes with clozapine toxicity (Ruan et al. 2018).
Clozapine is frequently and increasingly prescribed for schizophrenia in Asia,
with large variation across countries and territories (Xu et al. 2019). Unlike most
countries around the world in which clozapine is considered a second-line medica-
tion reserved for use in treatment-resistant schizophrenia, China embraced clozapine
as a first-line treatment for schizophrenia and other psychotic disorders for many
years from the early 1980s (Tang et al. 2008; Potter et al. 1989). For a time, clozapine
was even the first choice for acute schizophrenia (Tang et al. 2008; Mao et al. 2007).
The major reason for the initial interest in clozapine was the widespread belief of
clinicians that its use was associated with a reduced risk of tardive dyskinesia.
Furthermore, the profound efficacy of clozapine in the treatment of schizophrenia
(Lieberman et al. 1989) and its minimal cost further contributed to its popularity
among clinicians (Mao et al. 2007; Tang 2000). The use of clozapine is cost efficient
because of the reduction in hospitalizations (Nielsen et al. 2012b; Aitchison and
Kerwin 1997). Increasingly, however, Chinese clinicians have become more aware
of the potentially severe side effects associated with clozapine and now tend to use it
mostly for treatment-resistant patients, particularly since a wide variety of new
second-generation antipsychotics (SGAs) has become available (Mao et al. 2007).
As China has the largest international population on clozapine treatment, its
experience and research findings with this compound are of keen interest to Western
psychiatrists. However, there is a substantial lack of scientific communication
between the Chinese and Western psychiatric communities. In particular, most
of the reports on clozapine have been published only in the Chinese language,
with very few papers published in international journals. To our knowledge, the
first report on the Chinese experience in English (Potter et al. 1989) was published
nearly 30 years ago, while another brief letter on the use of clozapine in China was
published in French in 1996 (Stip et al. 1996).

Prevalence of Clozapine Use in China

Long-term observational, pharmacoepidemiological surveys, such as the

Schizophrenia Outpatient Health Outcomes (SOHO) Study (Haro and Salvador-
Carulla 2006) and the Research on Asian Psychotropic Prescription Patterns
(REAP) project (Xiang et al. 2012), are important to describe the real-world use
patterns and correlates of antipsychotic treatment in schizophrenia. The use of
clozapine in patients with schizophrenia varies substantially worldwide, with rates
860 J. Li and S. Li

as high as 60% in some parts of China to as low as 2–3% in some parts of the USA
(Nielsen et al. 2016).
A national, cross-sectional pharmacoepidemiological survey project on pre-
scription trends for psychotropic drugs in schizophrenia was initiated by the
Chinese Society of Psychiatry in 2002 (Si et al. 2004). Approximately one-third
of Chinese schizophrenia patients received clozapine in the pooled sample with a
steadily decreasing prescription trend from 2002 to 2012 of 13.3%, representing a
relative drop by 33.5% (Li et al. 2015b). The figures found in this study are also
higher than those reported in the Western literature. For example, the frequency of
clozapine prescription was 8% in Afro-American and 15% in Caucasian patients
in the USA (Kuno and Rothbard 2002). Also clozapine was prescribed to less than
10% of schizophrenia patients in the USA between 1991 and 1996 (Rothbard et al.
2003).
Similar to the findings in the REAP surveys (Xiang et al. 2011), clozapine
prescriptions gradually, but steadily decreased in China (39.7% in 2002, 32.5% in
2006 and 26.4% in 2012), which could be due to the introduction of strict guidelines
for clozapine use, starting with the Chinese Psychiatric Association guidelines in
2003, and the introduction of other SGAs (Xiang et al. 2013). In addition, while
in the rest of the world clozapine underutilization is a large concern, clozapine was
probably overused in China (Xiang et al. 2011, 2013). The influence of recent
publications and presentations at academic conferences may have enhanced Chinese
clinicians’ awareness of rational prescription practices resulting in reduced and,
possibly, more appropriate clozapine prescriptions.
Clozapine prescription was associated with a number of demographic and clinical
variables. Clozapine is mainly used for treating TRS, which could explain the
association of frequent clozapine use with inpatient status, family history of psychi-
atric disorders, CGI-based severity of psychopathology, earlier age of onset, and
longer duration of illness, features characteristic of TRS (Yang et al. 2005). Unlike
positive symptoms, negative symptoms are far more difficult to treat, and they tend
to occur more frequently in TRS, increasing the likelihood of clozapine use
(Buchanan et al. 2010; Iqbal et al. 2003; Xiang et al. 2007). In this study, patients
receiving clozapine presented with less severe delusions and hallucinations, yet, they
had higher global illness scores on the CGI. The reason for this apparent discrepancy
is that the CGI reflects patients’ global functioning determined by the patients’
personal and psychiatric history, psychosocial circumstances, psychiatric symptoms,
and the impact of symptoms on patients’ functioning. Thus, the CGI is a more
comprehensive measure than the severity of delusions or hallucinations (Busner and
Targum 2007). Therefore, although the severity of delusions and hallucinations may
be lower, patients with treatment-resistant schizophrenia are rated as having a more
severe illness and as being more impaired overall, which is consistent with the
families’ lower satisfaction with treatment.
In conclusion, approximately one-third of Chinese schizophrenia patients
received clozapine in this study during the decade of 2002–2012. Considering
the increased likelihood of drug-induced side effects related to clozapine and
families’ dissatisfaction with psychiatric treatment in general and possibly
Neuropsychopharmacotherapy: Differential Dose Regimes in China 861

clozapine in particular, further examination of the rationale, target groups, efficacy,

and tolerability of clozapine use in Chinese patients with schizophrenia is
warranted.

Product Information

Orally disintegrating tablets are only available in the USA and China, but the oral
suspension form is available in China, Denmark, Ireland, The Netherlands,
New Zealand, the UK, and the USA. Injectable clozapine is only available in The
Netherlands as an unlicensed medicinal product at a hospital pharmacy (clozapine
injection 125 mg = 5 ml; supplier Brocacef Ziekenhuisfarmacie). The maximum
licensed dosage is 900 mg/day in all countries, with the exception of Japan and
Romania, where it is only 600 mg (Nielsen et al. 2016).
According to the summaries of product characteristics, clozapine is licensed
in all countries for treatment-resistant schizophrenia, the criteria which vary
among the included countries. In the USA, treatment-resistant schizophrenia is
defined as “only severely ill patients not responding to standard antipsychotic
treatment,” whereas in most other countries, it is defined as inadequate response
to at least two antipsychotics, with at least one of them being a second-
generation antipsychotic (SGA). Minimum duration of treatment or dose is not
otherwise specified.
Clozapine is licensed for treatment of psychosis in Parkinson’s disease patients in
most countries, with the exception of China, Japan, the USA, and New Zealand,
whereas it is only licensed for suicidal behaviors in patients with schizophrenia in the
USA and Romania.
The Chinese Medical Association also recommends clozapine, in addition to the
abovementioned indication, for patients with schizoaffective disorder, treatment-
resistant mania or severe treatment-resistant psychotic depression, and for other
treatment-resistant psychiatric disorders, i.e., patients with pervasive developmental
disorder, autism, or obsessive-compulsive disorder.
Although it is poorly investigated, Asian patients may have a slower metabolism
and may warrant lower doses (Ng et al. 2005). In general, psychiatrists are reluctant
to use clozapine above 600 mg/day (Nielsen et al. 2010). Clozapine provokes large
interindividual variation in pharmacokinetic properties, and although response
occurs across the whole range of plasma levels, the chance of response is twice as
high above a clozapine plasma level of approximately 400 ng/ml (Schulte 2003).
Therefore, some patients may even warrant higher doses than 900 mg because of
ultrahigh activity in the cytochrome P450 (CYP) 1A2 enzyme (Maccall et al. 2009).
Therapeutic drug monitoring (TDM) is not mandatory in any country, although it
may be of important value in the optimization of clozapine treatment (Nielsen et al.
2011). It is worth noting that a large number of patients respond at much lower
concentrations than suggested above, and clozapine should always be used at the
lowest effective dose in order to minimize the burden of adverse effects (Nielsen
et al. 2011).
862 J. Li and S. Li

Pattern of Utilization of Clozapine in China

In China, the national guidelines for the prevention and treatment of psychiatric
disorders in 2003 stipulated that (1) clozapine should be considered only after
FGAs or other SGAs have been deemed ineffective following 6–8 weeks of
treatment and (2) blood monitoring for patients on clozapine weekly or biweekly
during the first 6 months and biweekly or monthly afterwards is mandatory
(Chinese Medical Association 2003). As the most effective antipsychotic for
TRS, clozapine is often the last resort in clinical practice, at least in countries
other than China (Esposito et al. 2005; Malalagama et al. 2011; Schulte 2003).
Approximately 15–25% of schizophrenia patients can be characterized as TRS
(Conley and Buchanan 1997), all of whom are potential candidates for clozapine
(Howes et al. 2012). The common prescription of clozapine in China could be
accounted for by the following reasons: clozapine has continuously been used
since its introduction in 1976 in China, yielding extensive clinical experience
(Xiang et al. 2007) and making it one of the most frequently used antipsychotics
in China, even as the first-line treatment in some areas (Liu and Li 2003). In
addition, clozapine is one of the cheapest antipsychotics in China, costing only
US$0.08 for 300 mg. Moreover, clozapine and risperidone were the only SGAs
covered by public health insurance in China before 2005.
In China, a study showed the mean clozapine daily dose was 206.1 mg/day
(Li et al. 2015b), which was lower than the recommended doses for Western
patients (Barnes and Schizophrenia Consensus Group of British Association for
Psychopharmacology 2011; Buchanan et al. 2010). Ethnic differences may account
for the dose difference between Chinese and Western patients (Wang et al. 2010).
In addition, in most Western countries clozapine is only prescribed for treatment-
resistant schizophrenia, while in China clozapine is more widely used and even
prescribed as a first-line treatment (Liu and Li 2003), which may also contribute to
the lower doses of clozapine in China.
With the exception of China, Denmark, Romania, and The Netherlands, all the
included countries have a database for hematological monitoring that is run by the
manufacturer.
Male patients were more likely to receive clozapine, which could be related to
males being overrepresented in this study with poorer treatment response (Carbon
and Correll 2014) and/or males having more severe negative symptoms compared
to females (Abel et al. 2010).
Prior surveys also found that adjunctive FGAs were less frequently co-prescribed
with clozapine, which is consistent with the current treatment recommendation
(Chinese Medical Association 2003) based on the lack of compelling evidence of
the superiority of this combination (Remington et al. 2005), and the greater possi-
bility of tardive dyskinesia with FGAs (Correll et al. 2004) APP, particularly the
combination of clozapine with risperidone or sulpiride, may provide some additional
clinical benefit in TRS (Josiassen et al. 2005; Shiloh et al. 1997), although the
findings are equivocal (Correll et al. 2009; Honer et al. 2006; Miyamoto et al. 2014,
2015). A further problem with APP is that it could increase the risk of side effects
Neuropsychopharmacotherapy: Differential Dose Regimes in China 863

and also make it difficult to gauge which medication really works (Gallego et al.
2012; Henderson and Goff 1996; Kapur et al. 2001).
Patients without health insurance in China are usually treated in Level-II hospitals
because of the relatively low treatment expenses. Clozapine is one of the cheapest
antipsychotics in China, thus it is more frequently used in uninsured patients.
Clozapine was associated with more frequent and severe side effects in this study,
which could be one of the reasons for the increasing likelihood of lower antipsy-
chotic doses in the clozapine group.
Clozapine use was associated with families’ poor satisfaction with treatment,
which may be attributed to the greater likelihood of clozapine use in TRS patients
whose continued illness severity albeit reduced by clozapine with regard to halluci-
nations and delusions remains a source of frustration and creates ongoing family
stress and burden, resulting in dissatisfaction with the overall effectiveness of the
treatment.
In summary, some important aspects of clinical practice with clozapine in China
are also different from those occurring in Western settings. For example, the dosing
schedule of clozapine by Chinese psychiatrists is more aggressive. Furthermore,
there is evidence supporting the benefit of clozapine in both mania- and treatment-
resistant depression. Overall, the authors believe that clozapine is still an important
antipsychotic agent for Chinese patients and psychiatrists. However, due to its
potentially severe side effects, we also strongly recommend that Chinese psychia-
trists need to pay more attention to this safety issue and should primarily consider
clozapine only for treatment-resistant patients with schizophrenia or chronic patients
with a low risk for diabetes.

References
Abel KM, Drake R, Goldstein JM. Sex differences in schizophrenia. Int Rev Psychiatry.
2010;22:417–28.
Aitchison KJ, Kerwin RW. Cost-effectiveness of clozapine. A UK clinic-based study. Br J
Psychiatry. 1997;171:125–30.
Amsler HA, Teerenhovi L, Barth E, Harjula K, Vuopio P. Agranulocytosis in patients treated with
clozapine. A study of the Finnish epidemic. Acta Psychiatr Scand. 1977;56:241–8.
Bai Z, Wang G, Cai S, Ding X, Liu W, Huang D, Shen W, Zhang J, Chen K, Yang Y, Zhang L,
Zhao X, Ouyang Q, Zhao J, Lu H, Hao W. Efficacy, acceptability and tolerability of 8 atypical
antipsychotics in Chinese patients with acute schizophrenia: a network meta-analysis. Schizophr
Res. 2017;185:73–9.
Barnes TR, Schizophrenia Consensus Group of British Association for Psychopharmacology.
Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommenda-
tions from the British Association for Psychopharmacology. J Psychopharmacol. 2011;25:
567–620.
Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B,
Peterson E, Aquino PR, Keller W, Schizophrenia Patient Outcomes Research Team. The 2009
schizophrenia PORT psychopharmacological treatment recommendations and summary state-
ments. Schizophr Bull. 2010;36:71–93.
Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical
practice. Psychiatry (Edgmont). 2007;4:28–37.
864 J. Li and S. Li

Carbon M, Correll CU. Clinical predictors of therapeutic response to antipsychotics in schizophre-

nia. Dialogues Clin Neurosci. 2014;16:505–24.
Chinese Medical Association. Guideline for the prevention and treatment of psychiatric disorders
in China. Beijing: Chinese Medical Association; 2003.
Chong MY, Tan CH, Fujii S, Yang SY, Ungvari GS, Si T, Chung EK, Sim K, Tsang HY, Shinfuku N.
Antipsychotic drug prescription for schizophrenia in East Asia: rationale for change. Psychiatry
Clin Neurosci. 2004;58:61–7.
Conley RR, Buchanan RW. Evaluation of treatment-resistant schizophrenia. Schizophr Bull.
1997;23:663–74.
Conley RR, Kelly DL, Richardson CM, Tamminga CA, Carpenter WT Jr. The efficacy of high-dose
olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind crossover
study. J Clin Psychopharmacol. 2003;23:668–71.
Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-
generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;
161:414–25.
Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S. Antipsychotic combinations vs
monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull.
2009;35:443–57.
Esposito D, Rouillon F, Limosin F. Continuing clozapine treatment despite neutropenia. Eur J Clin
Pharmacol. 2005;60:759–64.
Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for
schizophrenia. Cochrane Database Syst Rev. 2009;1:CD000059.
Fernandez HH, Donnelly EM, Friedman JH. Long-term outcome of clozapine use for psychosis
in parkinsonian patients. Mov Disord. 2004;19:831–3.
Gallego JA, Nielsen J, De Hert M, Kane JM, Correll CU. Safety and tolerability of antipsychotic
polypharmacy. Expert Opin Drug Saf. 2012;11:527–42.
Galling B, Roldan A, Hagi K, Rietschel L, Walyzada F, Zheng W, Cao XL, Xiang YT, Zink M,
Kane JM, Nielsen J, Leucht S, Correll CU. Antipsychotic augmentation vs. monotherapy
in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World
Psychiatry. 2017;16:77–89.
Ganguly R, Kotzan JA, Miller LS, Kennedy K, Martin BC. Prevalence, trends, and factors
associated with antipsychotic polypharmacy among Medicaid-eligible schizophrenia patients,
1998–2000. J Clin Psychiatry. 2004;65:1377–88.
Haro JM, Salvador-Carulla L. The SOHO (Schizophrenia Outpatient Health Outcome) study:
implications for the treatment of schizophrenia. CNS Drugs. 2006;20:293–301.
Henderson DC, Goff DC. Risperidone as an adjunct to clozapine therapy in chronic schizophrenics.
J Clin Psychiatry. 1996;57:395–7.
Hippius H. A historical perspective of clozapine. J Clin Psychiatry. 1999;60(Suppl 12):22–3.
Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, Falkai P, Pomarol-Clotet E,
Mckenna PJ, Stip E, Williams R, Macewan GW, Wasan K, Procyshyn R, Clozapine and
Risperidone Enhancement Study Group. Clozapine alone versus clozapine and risperidone
with refractory schizophrenia. N Engl J Med. 2006;354:472–82.
Honigfeld G, Arellano F, Sethi J, Bianchini A, Schein J. Reducing clozapine-related morbidity and
mortality: 5 years of experience with the Clozaril National Registry. J Clin Psychiatry. 1998;
59(Suppl 3):3–7.
Hou CL, Ma XR, Zang Y, Jia FJ, Lin YQ, Chiu HF, Ungvari GS, Ng CH, Zhong BL, Cao XL, Li Y,
Cai MY, Xiang YT. Antipsychotic polypharmacy and quality of life in patients with
schizophrenia treated in primary care in China. Int J Clin Pharmacol Ther. 2016;54:36–42.
Hou CL, Wang SB, Wang F, Xu MZ, Chen MY, Cai MY, Xiao YN, Jia FJ. Psychotropic medication
treatment patterns in community-dwelling schizophrenia in China: comparisons between rural
and urban areas. BMC Psychiatry. 2019;19:242.
Howes OD, Vergunst F, Gee S, Mcguire P, Kapur S, Taylor D. Adherence to treatment guidelines in
clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J Psychiatry.
2012;201:481–5.
Neuropsychopharmacotherapy: Differential Dose Regimes in China 865

Ifteni P, Correll CU, Nielsen J, Burtea V, Kane JM, Manu P. Rapid clozapine titration in treatment-
refractory bipolar disorder. J Affect Disord. 2014;166:168–72.
Iqbal MM, Rahman A, Husain Z, Mahmud SZ, Ryan WG, Feldman JM. Clozapine: a clinical
review of adverse effects and management. Ann Clin Psychiatry. 2003;15:33–48.
Ito H, Okumura Y, Higuchi T, et al. International variation in antipsychotic prescribing
for schizophrenia: pooled results from the research on East Asia psychotropic prescription
(REAP) studies. Open J Psychiatry. 2012;2:340–6.
Jeon SW, Kim YK. Unresolved issues for utilization of atypical antipsychotics in schizophrenia:
antipsychotic polypharmacy and metabolic syndrome. Int J Mol Sci. 2017;18:2174.
Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, Shaughnessy RA.
Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized,
double-blind, placebo-controlled trial. Am J Psychiatry. 2005;162:130–6.
Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic.
A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–96.
Kapur S, Roy P, Daskalakis J, Remington G, Zipursky R. Increased dopamine d(2) receptor
occupancy and elevated prolactin level associated with addition of haloperidol to clozapine.
Am J Psychiatry. 2001;158:311–4.
Kochi K, Sato I, Nishiyama C, Tanaka-Mizuno S, Doi Y, Arai M, Fujii Y, Matsunaga T, Ogawa Y,
Furukawa TA, Kawakami K. Trends in antipsychotic prescriptions for Japanese outpatients
during 2006–2012: a descriptive epidemiological study. Pharmacoepidemiol Drug Saf.
2017;26:642–56.
Krakowski MI, Czobor P, Citrome L, Bark N, Cooper TB. Atypical antipsychotic agents in
the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen
Psychiatry. 2006;63:622–9.
Kuno E, Rothbard AB. Racial disparities in antipsychotic prescription patterns for patients with
schizophrenia. Am J Psychiatry. 2002;159:567–72.
Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR,
Geddes JR, Kissling W, Stapf MP, Lassig B, Salanti G, Davis JM. Comparative efficacy and
tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.
Lancet. 2013;382:951–62.
Li Q, Xiang YT, Su YA, Shu L, Yu X, Chiu HF, Correll CU, Ungvari GS, Lai KY, Ma C, Wang GH,
Bai PS, Li T, Sun LZ, Shi JG, Chen XS, Mei QY, Li KQ, Si TM. Antipsychotic polypharmacy
in schizophrenia patients in China and its association with treatment satisfaction and quality
of life: findings of the third national survey on use of psychotropic medications in China. Aust
N Z J Psychiatry. 2015a;49:129–36.
Li Q, Xiang YT, Su YA, Shu L, Yu X, Correll CU, Ungvari GS, Chiu HF, Ma C, Wang GH, Bai PS,
Li T, Sun LZ, Shi JG, Chen XS, Mei QY, Li KQ, Si TM, Kane JM. Clozapine in schizophrenia and
its association with treatment satisfaction and quality of life: findings of the three national surveys
on use of psychotropic medications in China (2002–2012). Schizophr Res. 2015b;168:523–9.
Li XH, Zhong XM, Lu L, Zheng W, Wang SB, Rao WW, Wang S, Ng CH, Ungvari GS, Wang G,
Xiang YT. The prevalence of agranulocytosis and related death in clozapine-treated patients:
a comprehensive meta-analysis of observational studies. Psychol Med. 2019;12:1–12.
Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical management. J Clin
Psychiatry. 1989;50:329–38.
Lin CH, Lin CY, Wang HS, Lane HY. Long-term use of clozapine is protective for bone density in
patients with schizophrenia. Sci Rep. 2019;9:3895.
Liu TL, Li CY. The comparison of use of antipsychotics in first-episode patients with schizophrenia
(in Chinese). Med J Chin People Health. 2003;15:289–90.
Lung SLM, Lee HME, Chen YHE, Chan KWS, Chang WC, Hui LMC. Prevalence and correlates of
antipsychotic polypharmacy in Hong Kong. Asian J Psychiatr. 2018;33:113–20.
Maccall C, Billcliff N, Igbrude W, Natynczuk S, Spencer EP, Flanagan RJ. Clozapine: more than
900 mg/day may be needed. J Psychopharmacol. 2009;23:206–10.
Malalagama G, Bastiampillai T, Dhillon R. Clozapine prescription patterns in Australia over the last
10 years. Aust N Z J Psychiatry. 2011;45:498–9.
866 J. Li and S. Li

Mao PX, Tang YL, Wang ZM, Jiang F, Gillespie CF, Cai ZJ. Antipsychotic drug use in 503 Chinese
inpatients with schizophrenia. Int J Psychiatry Clin Pract. 2007;11:29–35.
Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G,
Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S, International Suicide Prevention
Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide
Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60:82–91.
Miyamoto S, Jarskog LF, Fleischhacker WW. New therapeutic approaches for treatment-resistant
schizophrenia: a look to the future. J Psychiatr Res. 2014;58:1–6.
Miyamoto S, Jarskog LF, Fleischhacker WW. Schizophrenia: when clozapine fails. Curr Opin
Psychiatry. 2015;28:243–8.
Moore TA, Buchanan RW, Buckley PF, Chiles JA, Conley RR, Crismon ML, Essock SM,
Finnerty M, Marder SR, Miller DD, Mcevoy JP, Robinson DG, Schooler NR, Shon SP,
Stroup TS, Miller AL. The Texas Medication Algorithm Project antipsychotic algorithm for
schizophrenia: 2006 update. J Clin Psychiatry. 2007;68:1751–62.
Morrato EH, Dodd S, Oderda G, Haxby DG, Allen R, Valuck RJ. Prevalence, utilization patterns,
and predictors of antipsychotic polypharmacy: experience in a multistate Medicaid population,
1998–2003. Clin Ther. 2007;29:183–95.
Mustafa FA, Burke JG, Abukmeil SS, Scanlon JJ, Cox M. “Schizophrenia past clozapine”:
reasons for clozapine discontinuation, mortality, and alternative antipsychotic prescribing.
Pharmacopsychiatry. 2015;48:11–4.
Ng CH, Chong SA, Lambert T, Fan A, Hackett LP, Mahendran R, Subramaniam M, Schweitzer I.
An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels. Int
Clin Psychopharmacol. 2005;20:163–8.
Nielsen J, Dahm M, Lublin H, Taylor D. Psychiatrists’ attitude towards and knowledge of clozapine
treatment. J Psychopharmacol. 2010;24:965–71.
Nielsen J, Damkier P, Lublin H, Taylor D. Optimizing clozapine treatment. Acta Psychiatr Scand.
2011;123:411–22.
Nielsen J, Kane JM, Correll CU. Real-world effectiveness of clozapine in patients with bipolar
disorder: results from a 2-year mirror-image study. Bipolar Disord. 2012a;14:863–9.
Nielsen J, Nielsen RE, Correll CU. Predictors of clozapine response in patients with treatment-
refractory schizophrenia: results from a Danish Register Study. J Clin Psychopharmacol.
2012b;32:678–83.
Nielsen J, Young C, Ifteni P, Kishimoto T, Xiang YT, Schulte PF, Correll CU, Taylor D. Worldwide
differences in regulations of clozapine use. CNS Drugs. 2016;30:149–61.
Percudani M, Barbui C, Fortino I, Petrovich L. Epidemiology of first- and second-generation
antipsychotic agents in Lombardy, Italy. Pharmacopsychiatry. 2005;38:128–31.
Phillips MR, Lu SH, Wang RW. Economic reforms and the acute inpatient care of patients with
schizophrenia: the Chinese experience. Am J Psychiatry. 1997;154:1228–34.
Potter WZ, Ko GN, Zhang LD, Yan WW. Clozapine in China: a review and preview of US/PRC
collaboration. Psychopharmacology (Berl). 1989;99(Suppl):S87–91.
Qiu H, He Y, Zhang Y, He M, Liu J, Chi R, Si T, Wang H, Dong W. Antipsychotic polypharmacy in
the treatment of schizophrenia in China and Japan. Aust N Z J Psychiatry. 2018. https://doi.org/
10.1177/0004867418805559.
Remington G, Saha A, Chong SA, Shammi C. Augmentation strategies in clozapine-resistant
schizophrenia. CNS Drugs. 2005;19:843–72.
Rothbard AB, Kuno E, Foley K. Trends in the rate and type of antipsychotic medications prescribed
to persons with schizophrenia. Schizophr Bull. 2003;29:531–40.
Ruan CJ, De Leon J. Thirty years of both ignorance and clinical experience suggest that clozapine
intoxication during co-occurring infections and inflammation may have higher morbidity and
mortality than is currently believed. Psychosomatics. 2019;60:221–2.
Ruan CJ, Zhang XL, Guo W, Li WB, Zhuang HY, Li YQ, Wang CY, Tang YL, Zhou FC, De Leon J.
Two cases of high serum clozapine concentrations occurring during inflammation in Chinese
patients. Int J Psychiatry Med. 2018;53:292–305.
Neuropsychopharmacotherapy: Differential Dose Regimes in China 867

Schulte P. What is an adequate trial with clozapine?: therapeutic drug monitoring and time to
response in treatment-refractory schizophrenia. Clin Pharmacokinet. 2003;42:607–18.
Shiloh R, Zemishlany Z, Aizenberg D, Radwan M, Schwartz B, Dorfman-Etrog P, Modai I,
Khaikin M, Weizman A. Sulpiride augmentation in people with schizophrenia partially respon-
sive to clozapine. A double-blind, placebo-controlled study. Br J Psychiatry. 1997;171:569–73.
Si TM, Shu L, Yu X, Ma C, Wang GH, Pai PS, Liu XH, Ji LP, Shi JG, Chen XS, Mei QY, Li KQ,
Zhang HY, Ma H. Antipsychotic drug patterns of schizophrenia in China: a cross-sectional study
(in Chinese). Chin J Psychiatry. 2004;37:152–5.
Sim K, Su A, Chan YH, Shinfuku N, Kua EH, Tan CH. Clinical correlates of antipsychotic
polytherapy in patients with schizophrenia in Singapore. Psychiatry Clin Neurosci. 2004;
58:324–9.
Stip E, Yan H, Lee P. Clozapine in a Chinese population. J Psychiatry Neurosci Bull. 1996;
21:283–4.
Tang YL. Pharmacotherapy of schizophrenia. In: Cai ZJ, Weng YZ, Tang YL, editors.
Schizophrenia: from biology to treatments (Chinese). 1st ed. Beijing: The Science Press;
2000. p. 214–27.
Tang YL, Mao PX, Jiang F, Chen Q, Wang CY, Cai ZJ, Mitchell PB. Clozapine in China.
Pharmacopsychiatry. 2008;41:1–9.
Ungvari GS, Chow LY, Chiu HF, Ng FS, Leung T. Modifying psychotropic drug prescription
patterns: a follow-up survey. Psychiatry Clin Neurosci. 1997;51:309–14.
Wang CY, Xiang YT, Cai ZJ, Weng YZ, Bo QJ, Zhao JP, Liu TQ, Wang GH, Weng SM, Zhang HY,
Chen DF, Tang WK, Ungvari GS, Risperidone Maintenance Treatment in Schizophrenia
Investigators. Risperidone maintenance treatment in schizophrenia: a randomized, controlled
trial. Am J Psychiatry. 2010;167:676–85.
Xiang YT, Weng YZ, Leung CM, Tang WK, Ungvari GS. Clinical correlates of clozapine
prescription for schizophrenia in China. Hum Psychopharmacol. 2007;22:17–25.
Xiang YT, Wang CY, Si TM, Lee EH, He YL, Ungvari GS, Chiu HF, Shinfuku N, Yang SY,
Chong MY, Kua EH, Fujii S, Sim K, Yong MK, Trivedi JK, Chung EK, Udomratn P, Chee KY,
Sartorius N, Dixon LB, Kreyenbuhl JA, Tan CH. Clozapine use in schizophrenia: findings
of the Research on Asia Psychotropic Prescription (REAP) studies from 2001 to 2009. Aust
N Z J Psychiatry. 2011;45:968–75.
Xiang YT, Wang CY, Si TM, Lee EH, He YL, Ungvari GS, Chiu HF, Yang SY, Chong MY, Tan CH,
Kua EH, Fujii S, Sim K, Yong KH, Trivedi JK, Chung EK, Udomratn P, Chee KY, Sartorius N,
Shinfuku N. Antipsychotic polypharmacy in inpatients with schizophrenia in Asia (2001–2009).
Pharmacopsychiatry. 2012;45:7–12.
Xiang YT, Buchanan RW, Ungvari GS, Chiu HF, Lai KY, Li YH, Si TM, Wang CY, Lee EH,
He YL, Yang SY, Chong MY, Kua EH, Fujii S, Sim K, Yong MK, Trivedi JK, Chung EK,
Udomratn P, Chee KY, Sartorius N, Tan CH, Shinfuku N. Use of clozapine in older Asian
patients with schizophrenia between 2001 and 2009. PLoS One. 2013;8:e66154.
Xu SW, Dong M, Zhang Q, Yang SY, Chen LY, Sim K, He YL, Chiu HF, Sartorius N, Tan CH,
Chong MY, Shinfuku N, Lin SK, Ng CH, Ungvari GS, Najoan E, Kallivayalil RA,
Jamaluddin R, Javed A, Iida H, Swe T, Zhang B, Xiang YT. Clozapine prescription pattern in
patients with schizophrenia in Asia: the REAP survey (2016). Psychiatry Res. 2019.
Yang HC, Yang KJ, Liu TB, Gao H, Lu YW. The clinical characteristics of patients with treatment-
resistant schizophrenia. Med J Chin People’s Health. 2005;17:257–9.
Ye M, Tang W, Liu L, Zhang F, Liu J, Chen Y, Chen DC, Tan YL, Yang FD, Hong Xiu M, Hui L,
Lv MH, Soares JC, Zhang XY. Prevalence of tardive dyskinesia in chronic male inpatients with
schizophrenia on long-term clozapine versus typical antipsychotics. Int Clin Psychopharmacol.
2014;29:318–21.
Nutrition in Brain Aging: Its Relevance
to Age-Associated Neurodegeneration

Wakako Maruyama, Masayo Shamoto Nagai, and Makoto Naoi

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870
The Molecular Mechanism of Brain Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871
Oxidative Stress and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871
Impaired Proteolysis Systems for Abnormal Proteins in Aging and PD . . . . . . . . . . . . . . . . . . . 875
Mitochondrial Dysfunction in Aging and PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 876
How to Intervene the Brain Aging and Age-Associated Neurodegeneration? . . . . . . . . . . . . . . . . . 877
Calorie Restriction (CR) and Small Natural Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
Can Dietary Habits Prevent Aging and Age-Associated Neurodegeneration? . . . . . . . . . . . . . 883
Gut-Brain Axis in Aging and Neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 888
Discussion and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 888
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889

Abstract
In the modern society, the number of the aged population having dementia and
disablement is rapidly increasing, which induces medical, social, and financial
problems in the developed country. The prevalence of Alzheimer and Parkinson
diseases increases according to aging, indicating that brain aging is the most potent
risk factor of these neurodegeneration. The molecular mechanism of aging is still an
enigma. Heterogeneous and complexed factors such as accumulated oxidative stress,
impaired proteolysis system, mitochondrial dysfunction, and gene mutation have
been proposed. Calorie restriction (CR) can prolong the lifespan of various animals,
suggesting that nutrient sensing pathways regulate the aging process. Several natural
compounds called CR mimics, like metformin, rapamycin, and plant food–derived
phytochemicals, were found to target the multiple intracellular signal transduction
systems and delay the aging phenotypes in the animal and cellular models. However,

W. Maruyama (*) · M. Shamoto Nagai · M. Naoi

Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin
University, Nisshin, Aichi, Japan
e-mail: maruyama@dpc.agu.ac.jp; nagaim@dpc.agu.ac.jp; mnaoi@dpc.agu.ac.jp

© Springer Nature Switzerland AG 2022 869

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_20
870 W. Maruyama et al.

at present clinical intervention trials have failed to show their effectiveness. Recent
epidemiological studies and clinical trials suggest that lifestyle including diet,
exercise, and sleep affects the risk or progression of brain aging. Especially,
Mediterranean diet and low-carbohydrate diet have shown to ameliorate cognitive
decline and reduce the incidence of age-associated neurodegenerative diseases. This
review presents the vital role of oxidative stress, possible clinical markers, and
beneficial dietary habits in aging and age-related neurodegeneration. Future strategy
to intervene the brain aging by nutrition in human is discussed.

Introduction

Aging is an irreversibly progressive deleterious process and the most potent risk
factor for neurodegenerative diseases, such as Parkinson and Alzheimer diseases
(PD and AD). Aging is caused by accumulation of diverse damages, resulting in the
failure to maintain tissue homeostasis. Gene expression pattern regulates lifespan by
the modulation of several factors in the inter- and intracellular signal pathways. On
the other hand, environmental factors, including diet, exercise, sleep, and exposure
to toxic factors, affect the aging process. Harman proposed “Free radical theory of
ageing” based on that oxidative stress increases the susceptibility to diseases and
death by regulating aging process (Harman 1956). Twin studies presented that the
heredity of the human lifespan is 20–30% (Ekmekciouglu 2020) and that the ratio of
genetic contribution increases with age (vB Hjelmborg et al. 2006). Cellular aging
has been considered to be due to the continuous free radical reactions, leading to
oxidative stress, mitochondrial dysfunction, impaired proteolysis systems, such as
the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway
(ALP), and deficit energy synthesis (Wyss-Coray 2016).
The strategy to slow down the brain aging by dietary manipulations has been
proposed. Caloric restriction (CR) has been shown to prolong the lifespan in exper-
imental models from yeast to the higher animals (Fontana et al. 2010), suggesting that
various molecular effectors regulate nutrient sensing pathways and longevity. In
human, Mediterranean diet (MedDiet) was found to reduce not only the risk of general
geriatric disorders, but also cognitive decline in aging and incidence of AD (van den
Brink et al. 2019). A population-based cohort study in Sweden presented association
of adherence to MedDiet with lower risk for PD (Yin et al. 2021). However, most of
such human intervention trials have not shown sufficient evidence for neuroprotection,
because the nutritional intervention contains complex issues to be solved, such as the
dietary habits regulated by the religions and the histories (Vauzour et al. 2017).
Nutraceuticals are defined as concentrated bioactive compounds from food and used
for enhancing health or medical benefits, as well as prevention and treatment of
diseases, including lipids, vitamins, proteins, glycosides, phenolic compounds, phy-
tochemicals, and others. The role of nutraceuticals in antiaging therapy has been
repeatedly discussed, but the results are still controversial. At present, only a few
nutraceuticals, such as coenzyme Q10 (CoQ1) and n-3 fatty acids, have shown
beneficial effects against various neurodegenerative disorders in clinical trials.
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 871

In this chapter the recent basic and clinical topics of brain aging are reviewed. The
novel strategy to develop the diet and nutrients to ameliorate the human brain aging
is discussed.

The Molecular Mechanism of Brain Aging

Oxidative Stress and Aging

“Free radical theory of ageing” proposed by Harman postulates aging and

age-associated disorders as the consequence of cellular and tissue damages by free
radicals (Harman 1981; Muller et al. 2007). Free radicals, reactive oxygen and
nitrogen species (ROS and RNS), are produced in normal physiological cellular
process, including mitochondrial complexes I and III in the electron transport chain
(ETC) and xanthine, NADPH, monoamine, and cytochrome P450 oxidases. Oxida-
tive stress is caused by excessive production beyond cellular clearance capacity of
ROS/RNS and damages cellular constituents. Oxidatively modified biomolecules,
such as proteins, lipids, DNA/RNA, and bioactive amines, increase in the human
brain according to aging. Neuronal cells are selectively vulnerable to oxidative
stress, because of its enriched unsaturated fatty acids in the membrane, high con-
sumption of oxygen, presence of redox active transition metals, oxidation of mono-
amine neurotransmitters, and modest antioxidant defense system in the brain. In
addition, the reproduction capacity is limited for postmitotic neuronal cells, resulting
in accumulation of aging-dependent oxidative damages.
Oxidatively modified proteins are the biological markers of brain aging and their
impaired functions associated with aging phenotypes, like dementia. Radicals,
superoxide (O2•
), hydroxyl radical, (OH•)•, nitric oxide (NO), carbonyl (CO3•
),
peroxynitrite (ONOO
), and secondary products (aldehydes, quinones, and
dehydroalanine) modify distinct amino acid residues in protein; some are stable
and detected in serum, urine, and cerebrospinal fluid (CSF) and are proposed as
surrogate marker candidates of oxidative stress in human (Hawkins and Davies
2019).

Oxidative Modification of Amino Acids and Proteins

Proteins and amino acids are the target of free radical and their oxidative modifica-
tions change the structure and function of enzymes, hormones, and receptors, and
contribute to age-related pathophysiologies. Aromatic amino acids, tryptophan and
tyrosine, are prone to be oxidized. Tyrosine is modified to form 3-nitro-L-tyrosine
(3NT), 3,4-dihydroxyphenylalanine, and 3,30 -dityrosine. Nitration targets a rela-
tively limited number of amino acids and only one or a few specific tyrosine residues
are nitrated, suggesting modulation of the distinct function. L-tyrosine plays an
essential role in 3D conformation and is the molecular recognition site of the protein.
Nitration of 3-hydroxy group in phenolic ring inhibits tyrosine phosphorylation
relating to growth factors, neurotrophic factors, cytokines, and hormone. 3NT is a
reactive product of free and protein-bound L-tyrosine with peroxynitrite, a
872 W. Maruyama et al.

condensation product of nitric oxide and superoxide. 3NT and dityrosine were found
in aging-related lipofuscin, composed of lipids, metals, and aggregated proteins in
the neurons (Kato et al. 1998). 3NT significantly increases in the CSF during aging
and patients with AD and amyotrophic lateral sclerosis (ALS) (Tohgi et al. 1999).
3NT is detected in plasma and urine of human, and increases in inflammatory
diseases, suggesting 3NT as a biomarker for systemic nitro-oxidative stress and
inflammation like diabetes mellitus (Feeney and Schöneich 2012). 3NT is identified
in α-synuclein (αSyn), the main composition of Lewy bodies (He et al. 2021) and
mitochondrial complex I (NADH dehydrogenase-ubiqutin oxidoreductase) in the
PD brain (Chinta and Andersen 2011). Decreased complex I activity and accumu-
lation of toxic abnormal αSyn are considered as the causative factors for
idiopathic PD.
Cross-linkage of the amino acids in the proteins destroys its higher structure.
Covalent ortho-ortho coupling of two tyrosine residues forms dityrosine in the
presence of copper, which was detected in the CSF of AD (Ahmed et al. 2005).
Dityrosine cross-linking stabilizes amyloid β (Aβ) oligomer (Al-Hilaly et al. 2013)
and promotes αSyn assemblies and deposition in Lewy bodies of PD brain
(Al-Hilaly et al. 2016). Cysteine residues are also oxidized and nitrated, but the
oxidation is mostly reversible. In the brain of aged humans, S-nitrated cysteine
residues increased in the hippocampus, substantia nigra, and frontal cortex (Finelli
2020). S-Sulfonylation and disulfide bonds were detected in antioxidant enzymes,
SOD and peroxiredoxins (PRDXs).

Proteins Modified by Lipid Radicals

Neuronal membrane is highly enriched with polyunsaturated fatty acids (PUFAs),
such as n-6 arachidonic acid (ARA) and n-3 docosahexaenoic acid (DHA) (Fig. 1).
Lipid peroxidation is a process of oxidation of lipids, such as PUFAs, containing
carbon-carbon double bonds by lipid peroxyl radicals and hydroperoxides. Lipid
peroxidation of PUFA-containing lipids produces bioactive α,β-unsaturated alde-
hydes, including acrolein (ACR, CH2 ¼ CHCHO), malondialdehyde (MDA,
β-hydroxyacrolein), propanol, hexanol, and trans-4-hydroxy-2-nonenal (HNE).
Peripheral MDA is derived from nonenzymatic oxidative degradation of unsatu-
rated lipids and is reacted with thiobarbituric acid (TBA) to form MDA-TBA adduct.
HNE, MDA, and ACR covalently modify proteins and form peptide adduct with
thiols and amino acids, in order cysteine >> histidine > lysine  arginine residues
(Ayala et al. 2014). The lipophilic properties of HNE increase its affinity to
biomembrane and HNE can easily react with membranous proteins and lipids.
HNE in the CSF and plasma significantly increased in PD patients (Selley 1998).
Lipid peroxidation biomarkers and TBA-reactive substances, free MDA, HNE, and
ACR, increased in blood and peripheral tissues from patients with AD, PD, and
MCI, but the results are conflicting (Mangialasche et al. 2009). Covalently modified
macromolecules are bioactive and induce long-lasting biological consequences,
impair the ETC, increase ROS production in mitochondria, and finally cause cell
death. HNE stimulates phosphorylation of MAPK and regulates several transcription
factors, such as nuclear factor erythroid 2-related factor 2 (Nrf2), activating protein-1
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 873

O
COOH O O

4-Oxo-2-nonenal (4ONE) Malondialdehyde

n-3 fatty acid : docosahexaenoic acid derived from n-6 fatty acid

OH
COOH
O
O

4-Hydroxy-2-nonenal (4HNE)
n-6 fatty acid : arachidonic acid derived from n-6 fatty acid Acrolein

・OH (radical species) decomposition

+ O2
R1 ・ R2
O
H
N
Lipid radical
HOO O NH
R1 R2
Propanoylation
Propanoylation
Lipid hydroperoxide derived from
derived n-3PUFA
from fatty acid peroxide
peroxide
Acylation to O
lysine residue HOOC
H
N

O NH

Succinylation
Succinylation
derived from
derived n-3 PUFA
from fatty acid peroxide
peroxide

Fig. 1 Oxidative decomposition of n-3 and n-6 polyunsaturated fatty acids (PUFAs). PUFAs rich
in neural membrane are the target of oxyradicals, and hydroxyl radical (.OH) produces intermediate
lipid radicals to form lipid hydroperoxide. Lipid hydroperoxide produces reactive lipid aldehyde,
such as 4-oxo-2-nonenal (4ONE), 4-hydroxy-2-nonenal (4HNE), malon-dialdehyde and acrolein as
shown in the figure. In addition, lipid hydroperoxide and lipid radicals make adducts with the
specific amino acids in proteins

(Ap-1), NF-κB, and peroxisome-proliferator-activated receptor (PPAR). ACR is

derived from metal-catalyzed oxidation of PUFAs and preferentially reacts with
lysine residues in tau protein, and the ACR adducts were identified in neurofibrillary
tangles.
Lipid hydroperoxides are nonradical intermediates of lipid peroxidation and
perturb membrane structure and function (Girotti 1998). Lipid peroxidation produces
hydroperoxides in prior to aldehyde and forms amide-type adducts. Nε-(Hexanoyl)
lysine was formed from peroxidation adduct of n-6 fatty acids with lysine, whereas
Nε-(propanonyl)lysine from that of n-3 fatty acids (Kato and Osawa 2010).

Oxidative Modified α-Synuclein (αSyn) in PD

Neurodegenerative disorders, such as PD, AD, and ALS, and Huntington disease
(HD) are characterized by loss of disease-specific types of neurons with accumula-
tion of disease-distinct toxic proteins. Oxidative modified proteins are resistant to
degradation by the UPS and ALP and accumulated in the cytoplasm and mitochon-
dria, which perturbs cellular function and deregulates mitochondrial dynamics
(fission and fusion) and degradation by autophagy (mitophagy). PD is the second
874 W. Maruyama et al.

common neurodegenerative disorder in the aged, and its prevalence increases

according to aging. The pathological hallmarks of PD are the degeneration of
dopaminergic neurons in the substantia nigra (SN) and the occurrence of Lewy
bodies composed of abnormal αSyn aggregates. Dopaminergic neurons are selec-
tively vulnerable to ROS produced from dopamine oxidation enzymatically or
nonenzymatically (autoxidation). Lipid peroxidation, oxidation of mitochondrial
DNA, and cytoplasmic RNA are increased in dopaminergic neurons of parkinsonian
brain.
Oxidatively modified αSyn is proposed as a pathogenic factor for syn-
ucleinopathies, including PD and dementia with Lewy bodies (Schildknecht et al.
2013). Under physiological condition, αSyn is abundant in presynaptic compartments,
associated with vesicles, binds to membrane phospholipids, and exists in the cyto-
plasm as unfolded monomer or tetramer. αSyn is involved in neuronal plasticity,
presynaptic signals, vesicle trafficking, and membrane dynamics (Bendor et al.
2013). Under physiological conditions monomeric αSyn interacts with ATP synthase
α subunit and increases brain ATP synthase activity (Ludtmann et al. 2016). Oligo-
merization and fibrillation of αSyn are essential steps for the neurotoxicity. Oligomeric
αSyn is accumulated within the inner mitochondrial membrane, inhibits complex I and
dysregulates mitochondrial function, induces selective oxidation of ATP synthase β
subunit, opens the mitochondrial permeability transition pore (mPTP), and induces
cell death in inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA
triplication (Ludtmann et al. 2018). In PD, products of duplicated, triplicated, point-
mutated SNCA, and posttranslationally modified αSyn are misfolded, polymerized,
and aggregated, and the conformation and configuration are closely associated with
αSyn toxicity (He et al. 2021). The N-terminal domain of αSyn has amphipathic
helices containing seven KAKEGVVAAAE repeats as the membrane-contacting
motif, and the binding to membrane makes αSyn highly enriched in α-helical structure.
About 15% of αSyn molecules are bound to membrane in vivo, and after released in
the cytosol, membrane-bound αSyn tends to be oligomerized and seeds the aggrega-
tion (Lee et al. 2002) (Fig. 2). Incubation of αSyn with DHA induced the oligomer-
ization and amyloidogenesis in vitro (Shamoto-Nagai et al. 2018), whereas with
saturated fatty acid, like stearic acid, did not. Recently, αSyn was found to form
covalent adduct with DHA at His50 and reduce the early peroxidation products,
suggesting its role in neuroprotection in vitro (De Franceschi et al. 2017). αSyn may
behave as a natural scavenger of lipid radicals derived from membrane PUFA, but lipid
radical–modified αSyn may produce the toxic oligomer.
Proteins modified by oxidized lipid aldehydes, 4HNE and ACR, were accumu-
lated in the nigral neurons in the parkinsonian brains (Shamoto-Nagai et al. 2007).
Modification of αSyn by HNE enhanced αSyn oligomerization and cell-to-cell
transfer in cultured neurons (Zhang et al. 2018). Postmortem study of the parkinso-
nian brain presents that intracellular transmission of toxic, abnormal αSyn is the key
in spreading PD pathology from the brain stem to throughout the brain (Braak and
Del Tredici 2017). They claim that the origin of prion-like αSyn seed may be nasal or
gastric tract, and oxidative modification of αSyn in peripheral tissue, especially naso-
oral cavity and gastrointestinal tract, should be further investigated.
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 875

Intracellular
transmission of toxic
oligomers
exosome

Aggregated
Production of modified proteins
membrane-derived Lipid radical-modified proteins
lipid radicals
Toxic oligomer

Autophagosome Autolysosome
Proteolysis by Digestion
ubiquitin-proteosome
Lysosome

Fig. 2 Production and detoxification of toxic oxidized lipid radical–modified proteins in the
neurons. αSyn is stabilized by binding to PUFAs in membrane phospholipids. Oxidation of
membrane PUFA and modification of αSyn by lipid radicals accelerate modified αSyn release to
the cytosol. αSyn modification by lipid aldehyde enhances αSyn oligomerization and aggregation,
and the cell-to-cell transfer in cultured neurons. Toxic αSyn oligomer is degraded by the UPS and
the ALP, or secreted by the exosome

Impaired Proteolysis Systems for Abnormal Proteins in Aging and PD

Increasing number of evidence suggests that disruption of protein quality control

system and accumulation of toxic abnormal proteins play the central role in brain
aging and neurodegeneration. Recent studies revealed that proteolysis systems, the
UPS and ALP, and extracellular secretion by exosome clear the neurotoxic proteins
(Fig. 2). The UPS is composed of multiple subunits and regulates rapid protein
turnover in the cells. Aggregated αSyn, but not the monomeric or membrane-bound
αSyn, inhibited proteasome activity (Snyder et al. 2003). The activity of 26S
proteasome is dependent on ATP, and mitochondrial dysfunction decreases its
activity. We found a mitochondrial complex I inhibitor, rotenone, that decreased
the activity of 26S proteasome in situ using proteasome sensor vector via oxidative
modification of proteasome with ACR (Shamoto-Nagai et al. 2007).
The ALP is another major proteolysis system, and autophagy is classified into
macroautophagy (generally referred as autophagy), chaperone-mediated autophagy
(CMA), and microautophagy. Autophagy is regulated by nutrient levels through
complex network of proteins and signaling pathways. Nutrient-sensing pathways,
such as AMP-activated kinase (AMPK) and mammalian target of rapamycin
876 W. Maruyama et al.

(mTOR), modulate autophagy. Autophagy plays a major role in maintaining cellular

homeostasis and influencing lifespan and longevity. Aging downregulates the
expression of autophagy-related genes (Atgs) and related sirtuin1 (SIRT1) and
autophagic activity, especially CMA, causing inefficient stress responses and accu-
mulation of damaged protein (Kaushik and Cuervo 2018).
αSyn contains a CMA recognition motif and is translocated into lysosome
and degraded. αSyn mutants, A53T and A30P, inhibit the uptake into lysosome
and reduce the degradation by CMA (Cuervo et al. 2004). In SH-SY5Y cells, mutant
and wild-type αSyn impair CMA activity and activate macroautophagy (Xilouri
et al. 2009). CMA requires precise peptide sequence (VKKDQ) in the substrate
proteins, indicating that misfolded or modified αSyn may not be recognized. Macro-
autophagy is a degradation system for nonspecific bulk intracytoplasmic proteins
through vesicular trafficking. Atg7 is essential for macroautophagy in the central
nervous system of mice, and its loss caused massive neuronal loss in the cerebral and
cerebellar neurons with polyubiquitinated protein accumulation (Komatsu et al.
2007), indicating macroautophagy is the final degrading system for proteolysis-
resistant proteins, like abnormal αSyn in PD.

Mitochondrial Dysfunction in Aging and PD

Mitochondria have diverse functions, such as ATP synthesis, ROS/RNS production,

and contribute cellular stress responses, which determines cellular life and death
signaling pathways. In the mitochondrial ETC, 1–2% of oxygen consumed during
physiological respiration produces superoxide (O2•
), which is synergistically
increased by mitochondrial damage. Oxidative stress damages mitochondrial DNA
(mtDNA), which encodes 13 polypeptides, 21 transfer RNAs (tRNAs), and 2 ribo-
somal RNAs (rRNAs) in the ETC, and initiates a vicious cycle of oxidative stress
and bioenergetic failure. Iron-sulfur (Fe-S) proteins, such as aconitases, are prefer-
entially oxidized and inactivated, resulting in Fe2+ and H2O2 release, which is
converted to potent toxic hydroxyl radical by Haber-Weiss and Fenton reactions.
ROS stimulates lipid peroxidation in mitochondrial membrane, and lipid peroxides
damage mitochondrial oxidative phosphorylation, induces mitochondrial membrane
potential decline, impairs Ca2+ buffering capacity, opens the mPTP, and activates
apoptosis cascade.
Mitochondria are dynamic organelle, whose quantity is continuously controlled
by the synthesis (mitogenesis), dynamics (fission and fusion), and autophagy
(mitophagy). Age-related mtDNA depletion may inhibit the mitogenesis to destroy
mitochondrial quality control. Mitochondrial dynamics seem to protect cells against
damages caused by oxidative stress and mutated mtDNA. In aged animals synapto-
somal mitochondria are shifted to a profusion state, age-associated alteration in the
expression of fusion/fission proteins, such as fission-promoting dynamin-related
protein (Drp1) and fusion-promoting mitofusin (Mfn)1/2 and optic atrophy
1 (Opa1) (Grimm and Eckert 2017). Functional mitochondrial dynamics may be
associated to longevity of AL-32 rats. Mitophagy removes damaged mitochondria
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 877

from the cells and declines by aging in human skin fibroblasts. Age-related Drp-1
deficit suppressed fission and mitophagy and was proposed to be associated with
some age-related cognitive decline and hippocampal atrophy (Oettinghaus et al.
2016).
Mitochondrial dysfunctions have been proposed to cause neurodegenerative and
metabolic disorders. After the discovery of 1-methy-4-phenyl-1,2,3,6-teterahydro-
pyridine (MPTP), a synthesized neurotoxin which causes parkinsonism in humans
by inhibiting mitochondrial complex I, numerous papers reported the role of mito-
chondrial dysfunction in PD (Trinh et al. 2021). Complex I activity decreased in the
SN and frontal cortex of PD patients and complex I and IV activities decreased in
platelets and skeletal muscle of patients with sporadic PD (Benecke et al. 1993);
however, the results are not fully reproducible.
In familial (genetic) PD, mitochondrial dysfunction is caused by autosomal dom-
inant mutations of SNCA and leucine-rich repeat kinase 2 (LRRK2), and autosomal
recessive mutations of Parkin, PTEN-induced putative kinase (PINK1) and P5-type
ATPase 13a2 (ATP13a2). PINK1 is a mitochondria-targeted serine/threonine kinase
and phosphorylates Parkin, a cytosolic E3 ubiquitin ligase, which ubiquitinates target
proteins, Mfns (Pickrell and Youle 2015). Parkin is incorporated into mitochondria,
activates peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and
mitogenesis, promotes fission/fusion and mitophagy, and maintains mitochondrial
homeostasis (Poole et al. 2008). Mutated Parkin and PINK1 in autosomal PD
dysregulate mitophagy and mitochondrial dynamics. Damaged mitochondria are
ubiquitinated by activated Parkin and degraded by the UPS. PINK1 or Parkin mutation
causes the accumulation of damaged mitochondria in axons in parkinsonian patients
(Liu et al. 2012).
In conclusion, oxidative stress, impaired proteolysis system, and mitochondrial
dysfunction make a vicious cycle for brain aging and age-associated neurodegeneration,
like PD.

How to Intervene the Brain Aging and Age-Associated

Neurodegeneration?

Calorie Restriction (CR) and Small Natural Components

To intervene aging and age-associated neurodegenerative diseases, two strategies

have been proposed based on animal experiments, CR and natural bioactive com-
ponents. CR consists of chronic reduction of the total calorie intake without malnu-
trition. CR has been shown to prolong the lifespan in yeast, fish, rats, hamsters, and
dogs, and also rhesus monkeys. At present, it remains unclear if CR can be effective
in human health, as discussed below (Smith Jr et al. 2010). Several dietary compo-
nents have been reported to exert antioxidant and anti-inflammatory functions and to
increase neurotrophic factors, such as brain- and glial cell line–derived neurotrophic
factor (BDNF and GDNF), and to inhibit insulin signal. In this section the natural
compounds, which are proposed to extend the life expectancy, are reviewed.
878 W. Maruyama et al.

CR for Prolonged Healthy Lifespan

CR affects energy and oxygen radical metabolism and cellular stress response
system, by modulating lifespan-regulating signal pathways such as SIRTs, insulin/
IGF-1 signaling, AMPK, mTOR, Forkhead box O (FOXO), and PPARγ (Canto and
Auwerx 2009). SIRTs are NAD+-dependent histone deacetylases and play the
essential role in aging and autophagy. In order to achieve beneficial effects of CR
without reduction of actual food intake, natural CR mimetics (CRMs), such as
metformin, rapamycin, and other mTOR regulators, resveratrol and related poly-
phenols, have been proposed (Roth and Ingram 2016).
In rhesus monkeys (Macaca mulatta), two active randomized studies of long-
term CR were reported. CR study at the Wisconsin University at Madison showed
reduction of age-related mortality and disease in CR-treated monkeys (Colman et al.
2009). CR reduced the incidence of diabetes, cancer, cardiovascular disease (CVD),
and brain atrophy. Another study at the National Institute on Aging (NIA) could not
prolong the lifespan by CR when it initiated at older age, but improved metabolic
profile and reduced oxidative stress, whereas CR initiated at younger monkeys
showed a trend to delay in age-associated disease onset (Mattison et al. 2012).
These controversial results still suggest that CR can significantly reduce incidence
of age-related diseases, cancer, glucoregulatory impairment, and CVD in monkeys.
In MPTP-treated PD model of adult male rhesus monkeys, CR (30% calorie
restriction) improved locomotor activity, increasing survival of dopaminergic neu-
rons in the SN, which may be due to significant increase in GDNF levels in the
caudate (Maswood et al. 2004).
In healthy human adults, 24 months of continuous CR (15–25% reduction) was
found to be safe and improve mood, quality of life and sleep, and reduce 10–13% body
weight (Martin et al. 2016). CR significantly improved cardiovascular and metabolic
health and reduced inflammation, especially in obese humans, but the beneficial effect
of CR on longevity has not been proved. An NIA-funded randomized clinical research
study was reported to assess the effects of CR (~25% for 2 years) in nonobese, healthy
individuals as the CALERIE study (Comprehensive Assessment of Long-Term Effects
of Reducing Intake of Energy) (Rochon et al. 2011). The trial presented the effects of
CR, including reduced body weight and insulin, increased mitogenesis in muscle, and
improved lipid profiles, suggesting reduction of the incidence of age-related diseases
by CR (Das et al. 2017). In addition, in Okinawa, an island in the south part of Japan,
longer lifespan was confirmed in both the gender, which was ascribed to low calorie
contents of Okinawa traditional foods (17% less calories than the rest of Japan)
(Willcox and Willcox 2014). However, recent rapid change of dietary habits to
westernized ones increased cardio-metabolic risks and reduced lifespan in Okinawa
even to shorter than in Japanese main island.

Small Natural Molecules Modulate Metabolism and Life Span Like CR

CR aimed to reduce the total calorie intake to be 60% of ad lib for a lifelong may be
not practical, in order to prolong the lifespan and reduce the incidence of geriatric
disorders. Several kinds of CR mimetic candidates of natural compounds and
polyphenols may be more practically applicable for human.
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 879

Metformin
Metformin (N,N-dimethylimidodicarbonimidic diamide) is a guanidine derivative
present in French lilac, used as a traditional herb since the seventeenth century in
Europe. Metformin was synthesized for the first time in 1922 and is the first-line
agent for treatment of type 2 diabetes mellitus. It increases the effects of insulin and
suppresses endogenous gluconeogenesis from L-lactate by liver. Metformin is
multifunctional, inhibits mitochondrial complex I activity (Owen et al. 2000),
activates AMPK, and inhibits glucagon-induced elevation of cAMP and mitochon-
drial glycerophosphate dehydrogenase. Recent reports suggest that metformin
reduces human body weight by increasing nonoxidative glucose disposal into
skeletal muscle and gut Escherichia species, which is associated with glycogen-
like peptide-1 (GLP-1) and releasing blood glucose to the intestine (Morita et al.
2020) (Fig. 3).
Recently metformin is proposed as an antiaging drug and a geroprotector
(Piskovatska et al. 2019) from preclinical investigations and beneficial effects for
type 2 diabetics and CVDs (Glossmann and Lutz 2019). Metformin prolongs the
lifespan of lower animals (yeast, fly, and worm) and mammals (mice and dog)
(Martin-Montalvo et al. 2013). Metformin activated mTOR-dependent protein phos-
phatase 2A (PP2A), dephosphorylated tau at Ser202, Ser262, and Ser356, and αSyn
at Ser129, and downregulated their neurotoxicity (Perez-Revuelta et al. 2014). In

Appetite loss

Change of enteric
microbiota
Metformin

Body weight loss

mGPDH Complex I

Inhibition of glycerophosphate shuttle Inhibition of respiratory chain

Reduction of NAD+ Increased [AMP/ATP]

Reduced production of pyruvate Activation of AMPK Inhibition of adenylate cyclase

from lactate
Inhibition of glycogen action
Reduced gluconeogenic gene expression

Reduced gluconeogenesis
Fig. 3 The multiple functions of metformin. Metformin reduces gluconeogenesis, ameliorates
insulin resistance, and reduces body weight through several target molecules. Metformin prolongs
the lifespan of lower animals and mammals, but the effectiveness in human has not been proved
880 W. Maruyama et al.

APPswe/PSS1De9 mice (a familial AD model), chronic metformin treatment

enhanced microglia autophagy, and reduced amyloid β (Aβ) deposits and tau
pathology in neurites (Chen et al. 2021).
In a clinical trial, called TAME (Targeting Aging by Metformin), aging-targeting
effects of metformin was investigated using blood-based biomarkers for aging: IL-6,
TNF-α-receptor I or II, CRP, CDF15, insulin, IGF1, cystatin, and hemoglobin A1c
(Justice et al. 2018). At present the lifespan-extending effects of metformin have
been not fully proved in humans.

Rapamycin
Rapamycin is a macrolide compound, an antibiotic and an inhibitor of mTOR, a
nutrient-sensing signaling. Rapamycin was isolated for the first time in 1972 from
samples of Streptomyces hygroscopicus found on Easter Island. Rapamycin has
immune-suppressant and antiproliferative functions and is proposed to prolong the
lifespan in animals. Rapamycin prolongs the lifespan in yeast, Caenorhabditis
elegans, Drosophila, and mice, improves age-associated decline of physiological
functions in rodents, dogs, and nonhuman primates, and may suppress aging and
age-related diseases, such as cancer, obesity, atherosclerosis, and neurodegeneration
in humans (Blagosklonny 2019). Rapamycin extended the median and maximal
lifespan of old mice (Harrison et al. 2009), suggesting that the pathway for the
longevity effect by rapamycin may be independent of CR response, which needs
early start.
The mTOR pathway is phosphatidylinositol-3-kinase (PI3K)-related serine/thre-
onine kinase, interacts with IGF and AMPK signaling pathways, and regulates
transcription, metabolism, and cytoarchitecture. mTOR drives cellular growth and
functions early in life, and later in life converses quiescence to senescence
(geroconversion); it induces cellular hyperfunction and promotes age-related pathol-
ogies. mTOR signaling pathway regulates autophagy (Kim and Guan 2015). In
postmortem tissue from the inferior parietal lobule of early stage of AD patients,
alteration of mTOR signaling, reduction of autophagy, and hyperactivity of PI3K/
Akt/mTOR pathway were detected (Tramutola et al. 2015). Rapamycin inhibits
mTORC1 (mTOR complex 1) by binding to FKBP12, activates autophagy, degrades
abnormal toxic proteins, and exerts neuroprotection in in vivo models of AD (Singh
et al. 2017).
Rapamycin reduced amyloid plaque deposition and microtubule-associated pro-
tein tau (MAPT/tau) aggregation and improved cognition in transgenic mouse model
of AD (Carosi and Sargeant 2019). In MPTP-induced mouse model of PD,
rapamycin attenuated impaired protein degradation by the UPS and ALP and
protected dopaminergic neurons (Dehay et al. 2010). Rapamycin inhibited
ubiquitination and increased IL-6 with reduced inflammatory cytokines by mTOR/
Akt/NF-κB signal pathway, preserved expression of glutamate transporter in astro-
cytes, and exerted neuroprotection (Zhang et al. 2017). However, the potency of
rapamycin as an immunosuppressant prevents its clinical application as an antiaging
drug in human.
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 881

Polyphenols: Resveratrol and Flavonoids

Epidemiological studies have shown the health-promoting, antiaging, and
neuroprotective effects of polyphenol-rich food, such as fruits, vegetables, coffee,
tea, and wine (Maccariello and D’Angelo 2021). Polyphenols are major phytochem-
icals, the second metabolites from plant diet. Polyphenols improve antioxidant
activity, mitochondrial homeostasis, and autophagy, exert anti-apoptosis and anti-
inflammatory effects, and induce pro-survival gene expression in in vitro experi-
ments (Naoi et al. 2017, 2019). The major bioactive small molecules in MedDiet and
Okinawa diet are flavonoids, curcumin (diferulonylmethane), astaxanthin, resvera-
trol, and hydroxytyrosol, oleuropein, and spermidine and they play a main role to
downregulate aging-related risk factors and disease occurrence. Resveratrol is asso-
ciated with red wine in MedDiet and present in Japanese knotweed, herbal medicine.
Astaxanthin (3,30 -dihydrox-β,β-carotene-4,40 -dione), a potent antioxidant, is found
in seafood (salmon, shrimp, and red seabream) as red color, and oleuropein and
hydroxytyrosol (3,4-dihydroxyphnylethanol) are phenolic compounds rich in virgin
olive oil, and spermidine, a polyamine, is found in red wine, soybean, and fresh fruits
and vegetables.
Bioactive food compounds, like polyphenol, may enhance mitochondrial synthe-
sis, maintain the dynamics and quality control, and prevent mitochondrial dysfunc-
tion. Resveratrol, epigallocatechin gallate (EGCG), and curcumin inhibit cAMP
phosphodiesterases and increase cAMP and NAD, activate PKCε and AMPK/
Sirt1/PGC-1α pathway, and stimulate mitochondrial functions, biogenesis and
dynamics (Higashida et al. 2013). Flavones, isoflavones curcumin, hydroxytyrosol,
and oleuropein increased the expression of mtDNA, mitochondrial transcription
factor A (TFAM), PGC-1α, and complex II and IV, regulated mitochondrial func-
tions, mitogenesis and dynamics, through Mfn1 and DRP1 in vivo. Epicatechin-rich
cocoa increased SIRT1, PGC-1α, TFAM, and complex I and V, and enhanced
mitogenesis in biopsied skeletal muscle from patients with type 2 diabetes and
heart failure, and dark chocolate significantly increased AMPA and PGC-1α and
enhanced mitogenesis in normal sedentary subjects (Taub et al. 2016).
The French paradox means the low incidence of CVDs among red wine drinkers in
France despite high intake of dietary saturated fat (Renaud and de Lorgeril 1992).
Regular consumption of red wine in older adults might reduce the risk for develop-
ment of dementia, AD, and macular degeneration (Orgogozo et al. 1997). Resveratrol
is a polyphenol found abundantly in red wine and skin of red grapes, mulberries, red
cherries, and grape. Resveratrol is the “prima donna” in “the French Paradox.”
Resveratrol, often called as a “CR-mimic,” is the first polyphenol reported to prolong
the lifespan in yeast, Caenorhabditis elegans, Drosophila melanogaster, and zebrafish
((Baur et al. 2006). Resveratrol has a wide range of pharmacological properties:
neuroprotective, antioxidative, anti-inflammatory, and immune-modulating effects.
Resveratrol enhances expression of SIRT1, PGC-1α, and TFAM, promotes
mitogenesis and mitophagy in vivo and in vitro, and mitigates pathologies caused
by mitochondrial dysfunction (Varghese et al. 2020). Resveratrol exerted
neuroprotective effects in animal and cell models prepared by several kinds of
neurotoxins, nitric oxide, and Aβ peptide (Han et al. 2004). The mechanisms of
882 W. Maruyama et al.

neuroprotection by resveratrol include antioxidant and anti-inflammatory activity,

suppressing expression of cyclooxygenase (COX)-1 and -2, TNFα, attenuating
activation of NF-κB, and induction of heme oxygenase 1 (HO-1) (Bastianetto et al.
2015). In addition to resveratrol, other polyphenols, such as quercetin, fisetin
(3,30 ,40 ,7-tetrahydroxy-flavone), berberine (an isoquinoline alkaloid), and curcumin,
activate SIRT1-mediated signaling pathways, and several clinical trials have been
reported (Iside et al. 2020).
In patients with moderate AD, resveratrol treatment (1 g twice day orally) for
52 weeks markedly decreased macrophage-derived chemokines (MDC) and Aβ42 in
the CSF, increased plasma metalloproteinases (MMPs), decreased IL-12P40 and
IL12P40, and ameliorated decline in mini-mental status examination (MMSE)
scores and activities of daily living (ADL) score (Turner et al. 2015). Resveratrol
administration (200 mg/day for 26 weeks) in healthy aged increased memory
performance (memory retention score) and functional connectivity of the hippocam-
pus by magnetic resonance imaging (MRI) and decreased glycated hemoglobulin
(HbA1c) level (Witte et al. 2014). However, the concentration required for resver-
atrol to activate SIRT1 in vivo is extremely higher than the actual concentration
derived from diet. To increase the stability and bioavailability, trials of several
chemical modification and delivery systems, such as lipid nanocarriers and lipo-
somes of resveratrol, are under way (Chimento et al. 2019).

Vitamins and Other Small Compounds in Aging

Deficiency of vitamins may deregulate neuronal metabolism and function, resulting
in neurodegeneration. Vitamin-based trials for neuroprotection have been proposed
for aging and related disorders (Rai et al. 2021). Fat-soluble (vitamins A, D, E, and
K) and water-soluble vitamins (8 vitamins B and vitamin C) are expected to slow
down the brain aging through antioxidant and anti-inflammatory capacity, or mito-
chondrial maintenance, autophagy regulation, and neurogenesis promotion by
induction of pro-survival genes. However, food frequency questionaries in large
number of PD patients could not present the association of vitamins A, E, and C with
the risk of PD (Rai et al. 2021).
Antioxidative vitamins, especially fat-soluble ones, are of importance to reduce the
age-relating brain injury by lipid peroxidation. α-Lipoic acid is an organosulfer
compound with antioxidant activity. Oral administration of 600 mg of α-lipoic acid
stabilized cognitive function in relatively small scale of dementia patients (Hager et al.
2001). Coenzyme Q10 (CoQ10) is an electron acceptor and a potent antioxidant
playing a vital role in ATP synthesis in the electron transport chain. RCT study showed
large dose (1200–2400 mg/d) of CoQ10 combined with vitamin E could not present
beneficial effect to PD symptom (Parkinson Study Group QE3 Investigators et al.
2014). However, another study presented reduced form of CoQ10 improved UPDRS
score of patients with PD (Yoritaka et al. 2015). Vitamin A deficiency may occur in
normal aging, and a few studies presented correlation between vitamin A intake and
cognition, but vitamin A supplement to cognitively healthy people could not improve
the cognition (Rutjes et al. 2018). Vitamin E and its congener, α-tocopherol, are natural
antioxidants and regulators of signal transduction and gene expression, redox sensor,
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 883

and modular of distinct cell functions (Joshi and Pratico 2012). In clinical studies in
patients with AD or MCI, vitamin E (2000 IU/day) supplement exerted benefit against
cognitive impairment and progression to AD, but the results are inconsistent (Browne
et al. 2019). The neuroprotective effect of α-tocopherol to early PD patients was
examined but could not show effectiveness (Shoulson 1998). In addition, vitamin E
treatment has potential risk to increase the incidence of malignancy (Nicastro and
Dunn 2013). The effect of fat-soluble antioxidative vitamins may be double edged, as
anti- and pro-oxidants.
Essential water-soluble vitamins are vitamin B1 (thiamine), B2 (riboflavin), B3
(niacin, nicotinic acid), B5 (pantothenic acid), B6 (pyridoxine derivatives), B7
(biotin, vitamin H), B9 (folic acid), B12 (cobalamin), and vitamin C. Declines in
pyridoxine, folic acid, and cobalamin have been reported to be associated with
cognition, depression, and idiopathic fatigue syndrome. These vitamin Bs are
cofactors for neurotransmitter and myelin synthesis, and the deficit increases levels
of homocysteine, a neurotoxic sulfur-containing metabolite of methionine, which is
found to increase in PD and AD. A randomized trial for patients with MCI presented
that vitamin B group (folic acid and vitamins B6 and B12) treatment combined with
n-3 fatty acids decreased plasma homocysteine levels and slowed decline in cogni-
tion by aging (Oulhaj et al. 2016). Vitamin C (ascorbic acid, AA) is a potent water-
soluble antioxidant. The AA concentration in neurons was quite higher (~10 mM)
than in the CSF (~120 μM) and plasma (~40 μM), suggesting the requirement of
constant supplement from diet into neurons. Aging-dependent loss of the BBB
integrity is considered to reduce the ability to retain AA in the brain. However,
epidemiological studies could not confirm the reduced AD risk by high AA intake.
High AA combined with vitamin E intake may reduce incidence of vascular demen-
tia (Masaki et al. 2000), but the effect is not consistent.
The neuroprotective effects of vitamins cannot be denied, but the results are
fluctuated by the dose, duration, and the heterogenity of patients. RCT with more
rational designs and surrogate markers are required considering the cellular mech-
anism of brain aging in future.

Can Dietary Habits Prevent Aging and Age-Associated

Neurodegeneration?

Epidemiological observation presents that lifestyle, especially dietary habit and

exercise, can lower the risk of age-related disorders and various preclinical studies
of diets and nutrients proved to delay or prevent the aging and age-related disorders.
However, only limited number of intervention trials with distinct diet have shown
their beneficial effect in human. The discrepancy between the experimental results
and clinical studies might be due to the fact that dietary habits, but not intake of
single food or nutrient, can prevent brain aging and neurodegeneration.
Low-carbohydrate diet and MedDiet are most promising candidates to prevent
aging and age-associate disorders (Madeo et al. 2019) and recently increasing
number of human studies have proved their beneficial effects.
884 W. Maruyama et al.

The Low-Carbohydrate or Ketogenic Diet

Ketogenic diets containing high fat (80–90% fat-derived calorie in the total con-
sumed calorie) and low carbohydrates have been clinically used as the symptomatic
effective therapy for drug-resistant child epilepsy (Sampaio 2016). Classic ketogenic
diet is composed of a macronutrient ratio of 4:1 (4 g fat for every 1 g of protein and
carbohydrate combined), but now the ketogenic diet with ratio 1:1 to 2:1 is com-
monly used. Ketogenic diet is effective to treat common epilepsy and catastrophic
epilepsy syndromes of infancy, such as West syndrome, Lennox-Gastaut syndrome,
and Dravert syndrome. In ketogenic diet, the intake of carbohydrate is limited to less
than 10% of consumed energy, and ketone bodies derived from fatty acids are the
major source of energy production in the brain and peripheral tissues. Plasma levels
of ketone bodies, such as acetoacetate and β-hydroxybutyrate, increased three- to
fourfold from the basal levels. Recently ketogenic diets have been proposed for
treatments of AD and PD, and reported to provide not only symptomatic, but also
neuroprotective effect.
Ketone bodies increased by ketogenic diet have multiple biological functions.
Ketones can modulate neurotransmitter synthesis and release, and in the human CSF
and brain tissue ketogenic diet increased GABA, taurine, serine, and glycine levels
(Dahlin et al. 2005). Neuroprotection by ketogenic diet is ascribed to reduced ROS
production, antioxidative effects, activation of AMPAK, and decrease in mTOR
activity, as shown in kainate-treated rat model of epilepsy (McDaniel et al. 2011).
Mitochondria from animals fed with a ketogenic diet increased mitogenesis and
function, and downregulated ROS production. Ketone bodies increased the threshold
of calcium-induced mPTP opening and prevented apoptosis in isolated brain mito-
chondria (Kim et al. 2015). In a transgenic mouse model of AD prepared with London
mutation (APP/V7171), ketogenic diet reduced Aβ40 and Aβ42 content in brain
homogenates but did not affect cognitive functions (Van der Auwera et al. 2005).
Ketone body suppressed Aβ42 entry into mitochondria, ameliorated complex I impair-
ment, reduced oxidative stress, and improved learning and memory ability in another
mouse model of AD (Yin et al. 2016). β-Hydroxybutyrate (4 mM) protected cultured
hippocampal neurons from toxicity of Aβ(1–42) and cultured mesencephalic neurons
treated with MPP+ by modulating mitochondrial function (Kashiwaya et al. 2000).
Exogenous administration of β-hydroxybutyrate or acetoacetate reduced neuronal loss
and improved function in animal models of hypoxia, hypoglycemia, and focal
ischemia.
In the brains of AD patients, glucose hypometabolism is detected before the
onset of cognitive decline, whereas brain ketone uptake remains normal. In
patients with MCI, cognitive ability was improved in correlation to improvement
of brain energy status by ketones (Krikorian et al. 2012). Cognitive benefit of
ketogenic therapies was most significant in patients without apolipoprotein E
(APOE) ε4 allele (Henderson et al. 2009). To increase the levels of ketones in
blood and brain, a ketogenic medium chain triglyceride drink was tried for MCI
and AD patients in a randomized controlled BENEFIC (Brain Energy, Functional
Imaging, and Cognition) trial. β-Hydroxybutyrate was found to be the better
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 885

efficient energy source than glucose in the brain, and elevated β-hydroxybutyrate
produced from medium-chain triglycerides was considered to improve memory
function. Now several RCTs of ketogenic diet are ongoing in individuals with
subjective memory impairment, mild AD, or healthy control (McDonald and
Cervenka 2018). Also in PD, ketogenic diet exerted moderate to very good
improvement in symptom, a mean of 43% reduction assessed as UPDRS (United
Parkinson’s disease Rating Scale) scores (Vanitallie et al. 2005). In a randomized,
placebo-controlled, crossover study for PD patients, a ketone ester drink enhanced
endurance exercise performance with increased serum β-hydroxybutyrate levels
(Norwitz et al. 2020). However, there are often adverse effects of ketogenic diet
among adult treated for epilepsy and other neurological disorders: weight loss,
gastrointestinal effects, and increase of cholesterol and low-density lipoprotein
(LDL) in serum. In addition, high-fat and low-carbohydrate diet is not tasty and
hard to be digested, which means it may worsen the malnutrition in the aged. Long-
term strategy of ketogenic diet in human has not been established.

The Mediterranean Diet (MedDiet)

MedDiet is the traditional diet pattern among the people of the Mediterranean basin,
mainly in Crete, other sites of Greece, and Southern Italy in the early 1960s. It is
characterized by high consumption of olive oil, plant foods (vegetables, fruits,
cereals, and legumes), moderate intakes of red wine, moderate consumption of
fish, seafood, yogurt and cheese, and low consumption of red and processed meat.
Epidemiological studies found that low content of saturated lipids in MedDiet
contributes low incident of coronary heart disease in Mediterranean counties (Tri-
chopoulou et al. 2014). MedDiet has been confirmed to reduce incidence of CVDs,
thrombotic stroke, cancer, diabetes mellitus, and age-related decline of cognition in
AD and PD (Dinu et al. 2018). Health-promoting effects of MedDiet have been
intensively investigated in a large-scale trial, PREDIMED (Prevencion con Dieta
Mediterranea) (Ros et al. 2014). This trial is designed to prove whether MedDiet can
reduce chronic disease burden and mortality. MedDiet is now considered not only
food patterns but also a cultured model for selection, production, procession, and
distribution of food, and was acknowledged by UNESCO as an Intangible Cultural
Heritage of Humanity in 2010 (Bach-Faig et al. 2011).
The basic concept of MedDiet and expectation of corresponding nutritional
effects are summarized as follows.

1. Increase the intake of fish and seafoods to enhance the contents of PUFA
2. Increase the intake of extra virgin (cold-pressed) olive oil, nuts, and legumes to
enhance the content of monounsaturated fatty acid (MUFA)
3. Increase the intake of leafy green vegetables, fruits, and cereals (whole grain) to
enhance the content of dietary fiber and antioxidative polyphenols
4. Increase the intake of poultry and egg to enhance the content of protein with low
content of saturated fatty acid (SFA)
5. Reduce the intake of red meats and dairy foods to lower the content of SFA
886 W. Maruyama et al.

6. Reduce the intake of sweets to lower the excessive intake of carbohydrate

7. Moderate red wine to increase the content of polyphenols

The mechanisms underlying health-promoting effects of MedDiet are multifactorial

(Schwingshackl et al. 2020). High intake of whole grains, vegetables, fruits, seeds, and
nuts modulates lipid metabolism, lowering LDL-C, cholesterol, increased synthesis of
short-chain fatty acids, and decrease of triglyceride synthesis from SFA. Polyphenols
present in olive oil, oleuropein and hydroxytyrosol, activate AMPK signal transduc-
tion pathway to reduce lipid biosynthesis. MedDiet and especially extra virgin olive oil
and red wine are rich in antioxidants, antioxidant vitamins, phytochemicals, folate, and
carotenoids (Price et al. 2012). Hydroxytyrosol and resveratrol activate SIRT1 and
increase expression of antioxidative enzymes (catalase and glutathione). n-3 fatty acids
and some phytochemicals (ferulic acid, apigenin, and lignans) activate PPAR-γ,
increase production of anti-inflammatory cytokines, and prevent activation of pro-
inflammatory NF-κB and increase in inflammatory cytokines (TNF-a, IL-1, and IL-6).
MedDiet ingredients were reported to modulate insulin signaling, but the results of
intervention studies remain inconclusive (Fig. 4).
Epidemiologic studies have reported that MedDiet prevents age-depending
decline of brain function, especially of cognition (Gardener and Caunca 2018).

Low carbohydrate diet Mediterranean diet

Carbohydrate/Lipid Unsaturated/saturated fatty acids
Polyphenol and antioxidants
β-oxidation
Dietary fibers

Reduced synthesis of toxic lipid

Increased blood ketones radical-modified proteins

Altered gene expression

Change of enteric microbiota

Neuroprotection ?
Fig. 4 The mechanism of possible neuroprotective effects by low-carbohydrate diet and MedDiet.
Ketone bodies increased by low-carbohydrate diet have multiple biological functions, including
neuroprotection. MedDiet has been confirmed to reduce incidence of metabolic disease, geriatric
disorders, age-related decline in cognition, AD, and PD. Neuroprotection by MedDiet is proposed
to be due to reduced synthesis of lipid radicals, altered gene expression, and change of enteric
microbiota
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 887

MedDiet supplemented with extra virgin oil (1 L/week) or mixed nuts (30 g/day)
improved cognitive composites (memory, attention, and execution and global) in
447 healthy volunteers after average 4.1-year intervention (Valls-Pedret et al. 2015).
Higher adherence to MedDiet and DASH (Dietary Approaches to Stop Hyperten-
sion) diet decreased cognitive decline and incidence of AD (Dominguez and
Barbagallo 2018). MedDiet and DASH accordance score were computed from
food and nutrient components. DASH diet specifies low consumption of saturated
fat, commercial pastries and sweets, and higher consumption of dairy than MedDiet.
In a large-scale prospective, population-based study, the both the MedDiet and
DASH dietary patterns containing high levels of whole grains, nuts, and legumes
were well associated with higher levels of cognitive functions in elderly men and
women over an 11-year period (Wengreen et al. 2013). The effect of dietary habit on
the incidence and progression of AD and PD was investigated in a clinical study
called MIND (Mediterranean DASH Intervention for Neurodegenerative Delay) for
older adults by comparison with the MedDiet. MIND diet slowed cognitive decline
with aging over average 4.7 years among 960 participants and reduced incidence of
AD more remarkedly than MedDiet and DASH (Morris et al. 2015a, b). In a three-
year brain imaging study of 70 cognitively normal participants, high adherence to
MedDiet modulated changes in AD biomarkers, increased 11C-Pittsburg compound
B-PET for brain β-amyloid load, declined 18F-fluorodeoxy-glucose PET for
neurodegeneration, and provided 1.5–3.5 years of protection against AD (Berti
et al. 2018). Higher MIND diet scores were associated with a decreased risk of PD
and a slower rate of the PD progression and MedDiet with a reduced progression,
whereas DASH diet was not associated with either outcome (Agarwal et al. 2018).
MIND diet adherence was strongly associated with later onset of PD in female
subgroup (Metcalfe-Roach et al. 2021) and lower probability of prodromal PD (2%
decrease) in older people (Maraki et al. 2019). In a population-based cohort of
Swedish women (>47,000), higher adherence to MedDiet at the middle age was
associated with lower risk (by a 29%) for PD (Yin et al. 2021). In the European
subject NU-AGE (new dietary strategies addressing the specific needs of elderly
population for a healthy aging in Europe), MedDiet demonstrated beneficial effects
on global cognition and episodic memory (Marseglia et al. 2018). After one-year
adherence to NU-AGE diet–given individually tailored dietary advice, cognition
function showed significant improvement in subjects with higher adherence com-
pared to those with lower adherence.
Recently, the mechanisms behind modulation of aging-related pathology by
MedDiet ingredients have been intensively studied. MedDiet ingredients, such as
oleuropein, oleocanthal, hydroxytyrosol, and resveratrol, activate autophagy pro-
cesses though AMPK, SIRT1/mTOR signaling pathways in in vivo and in vitro
models of AD (Cordero et al. 2018), and modulate aging process, prevent cognition
decline, and promote healthy aging (de Pablos et al. 2019). MedDiet ingredients
have epigenomic effects (DNA methylation and histone modification microRNAs
[miRNAs]) and transcriptomic effects, and modulate pathways including inflamma-
tion, oxidative stress, lipid metabolism, and carcinogenesis, and has potential impact
on human health. In the PREDIMED study, adherence to MedDiet and consumption
888 W. Maruyama et al.

of extra virgin olive oil were correlated with DNA methylation levels of inflamma-
tion- and intermediate metabolism–related genes (Arpon et al. 2016).
The definition of MedDiet is variable according to the studies, e.g., general
descriptive definition, diet pyramids/number of servings of key foods, grams of
key foods/food groups, and nutrient and flavonoid contents. In addition, each
MedDiet receipt depends on the local dietary pattern and food products (Davis
et al. 2015). Global, clinically available scoring to evaluate MedDiet is needed. In
addition, to compare the effect of dietary habit quantitively in individual human,
universal surrogate marker is essential.

Gut-Brain Axis in Aging and Neurodegeneration

Recent research in the gut-brain axis highlights new aspects on the neuroprotective
function of diets and nutraceuticals. Inside the gastrointestinal tract, the gut micro-
biota is composed of more than 100 trillion of microorganisms of numerous species.
Environment of gastrointestinal tract may affect the function of central nervous
system through the neural network and humoral factors. Gut microbiota is associated
with the absorption and metabolism of nutrients, production of short-chain fatty
acids (SCFAs), protection against pathogens, and regulation of host immunity. In
PD, gut microbiota composition changes to Bacrioides enriched from Prevotella-
and Firmicutes-enriched flora. Altered microbiota composition enhances gut inflam-
mation, increases intestinal permeability, and elevates stool inflammatory cytokines,
leading to damages in the gastrointestinal system, which has been proposed to be one
of risk factors of prodromal PD (Heinzel et al. 2020). Dietary habits modulate gut
microbial profiles and exert the disease-modifying effect in PD (Quigley 2020).
Aging affects gut microbial ecology and reduces biodiversity of microbiota in
elderly people, which may change the homeostasis between gut microbiota and
host and cause “immunosenescence.” Decrease of SCFA-producing Eubacterium
rectale and Roseburia reduces the metabolites in gut, then affects various human
physiology. Increased relative population of Bacteroidetes, Streptococcus, and
Blautia was associated with markers of cognitive and nutritional deficiencies
(Claesson et al. 2012). Dietary intervention has been reported to alter microbiota
composition in PD. High MedDiet adherence exerted beneficial effects on micro-
biota profile, smaller presence of E. coli, and increase of Bifidobacteria, thus the
higher levels of SCFAs, suggesting that typical health benefits by MedDiet might be
attributed to specific microbiota composition (Tosti et al. 2018).

Discussion and Conclusion

Epidemiological studies and clinical intervention trials of dietary habit, especially

MedDiet, suggest that overall dietary quality is more practical to promote human
health than diet quantity (such as CR). Dietary habits depend on the country, culture,
race, ethnicity, sex, season, and economic state and the effects of diet on aging and
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 889

age-associated neurological disorders are very hard to be quantitatively estimated. In

addition, most of the intervention studies of dietary and nutraceutical factors on
cognition and dementia might start too late and miss the critical periods.
How can we evaluate the scientific bases for dietary habit on aging? To find most
potent ingredients in diet, various preclinical studies of isolated single compounds
have shown beneficial effects in cellular and animal models, but the effects have
been not confirmed in human studies. Bioactivity and bioavailability of food are
regulated by absorption, metabolism, transport, and permeability across membrane
and the blood-brain-barrier. Development of effective nutraceuticals from complex
diet requires further sophisticated designs based on more detailed information of
pharmacological and metabolic processes of individual components.
Quantitative, comparable analysis of brain aging should be established. Analyses
of cognitive, motor, and sensory activities, clinical symptoms, daily life activity, and
imaging studies of the brain should be quantified. In addition, age-related peripheral
markers are required. As discussed above, oxidative stress–related markers, like
oxidatively modified proteins, might be applicable for surrogate markers.
Neurological disease is the second leading cause of death (GBD 2015 Neurolog-
ical Disorders Collaborator Group 2017) and the number of suffering patients is
increasing in the modern country. Nutritional intervention is one of the most
promising ways to prevent or delay the neurological disability in future. Further,
intensive and both the basic and clinical investigation is needed.

Cross-References

▶ Neuropsychopharmacotherapy: Complementary Treatments

▶ Psychopharmacotherapy in Aged Patients

Conflict of Interest The authors declare that there are no conflicting financial interests in relation
to the work described.

Source of Funding This work was supported by JSPS KAKENHI Grant Number 18 K07430
(W.M).

References
Agarwal P, Wang Y, Buchman AS, Holland TM, Bennett DA, Morris MC. MIND diet associated
with reduced incidence and delayed progression of Parkinsonism in old age. J Nutr Health
Aging. 2018;22(10):1211–5. https://doi.org/10.1007/s12603-018-1094-5.
Ahmed N, Ahmed U, Thornalley PJ, Hager K, Fleischer G, Münch G. Protein glycation, oxidation
and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer’s disease and
link to cognitive impairment. J Neurochem. 2005;92(2):255–63. https://doi.org/10.1111/j.1471-
4159.2004.02864.x.
AL-Hilaly YK, Williams TL, Stewart-Parker M, et al. A central role for dityrosine crosslinking of
amyloid-β in Alzheimer’s disease. Acta Neuropathol Commun. 2013;1:83. https://doi.org/10.
1186/2051-5960-1-83.
890 W. Maruyama et al.

Al-Hilaly Y, Biasetti L, Blakeman BJ, Pollack SJ, Zibaee S, Abdul-Sada A, Thorpe JR, Xue WF,
Seppell LC. The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in
Lewy bodies in Parkinson’s disease. Sci Rep. 2016;16(6):39171. https://doi.org/10.1038/srep39171.
Arpon A, Riezu-Boj JI, Milagro FI, et al. Adherence to Mediterranean diet is associated with
methylation changes in inflammation-related genes in peripheral blood cells. J Physiol Biochem.
2016;73(3):445–55. https://doi.org/10.1007/s13105-017-0552-6.
Ayala A, Munoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling
mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Med Cell Longev.
2014;2014:360438. https://doi.org/10.1155/2014/360438.
Bach-Faig A, Berry EM, Lairon D, et al. Mediterranean diet pyramid today. Science and cultural
updates. Public Health Nutr. 2011;14(12A):2274–84. https://doi.org/10.1017/
S1368980011002515.
Bastianetto S, Menard C, Quirion R. Neuroprotective action of resveratrol. Biochim Biophys Acta.
2015;1852(6):1195–201. https://doi.org/10.1016/j.bbadis.2014.09.011.
Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-
calorie diet. Nature. 2006;444(7117):337–42. https://doi.org/10.1038/nature05354.
Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79(6):1044–66.
https://doi.org/10.1016/j.neuron.2013.09.004.
Benecke R, Strumper P, Weiss H. Electron transfer complexes I and IV of platelets are abnormal in
Parkinson’s disease but normal in Parkinson-plus syndromes. Brain. 1993;116(6):1451–63.
https://doi.org/10.1093/brain/116.6.1451.
Berti V, Walters M, Sterling J, et al. Mediterranean diet and 3-year Alzheimer brain biomarker
changes in middle-aged adults. Neurology. 2018;90(20):e1789–98. https://doi.org/10.1212/
WNL.0000000000005527.
Blagosklonny MV. Rapamycin for longevity: opinion article. Aging. 2019;11(19):8048–67. https://
doi.org/10.18632/aging.102355.
Braak H, Del Tredici K. Neuropathological staging of brain pathology in sporadic Parkinson’s
disease: separating the wheat from the chaff. Parkinsons Dis. 2017;7(s1):S71–85. https://doi.
org/10.3233/JPD-179001.
Browne D, McGuinness B, Woodside JV, McKay GJ. Vitamin E and Alzheimer’s disease: what do
we know so far? Clin Invt Aging. 2019;14:1303–17. https://doi.org/10.2147/CIA.S186760.
Canto C, Auwerx J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab.
2009;20(7):325–31. https://doi.org/10.1016/j.tem.2009.03.008.
Carosi JM, Sargeant TJ. Rapamycin and Alzheimer disease: a double-edged sword? Autophagy.
2019;15(8):1460–2. https://doi.org/10.1080/15548627.2019.1615823.
Chen Y, Zhao S, Fan Z, et al. Metformin attenuates plaque-associated tau pathology and reduced
amyloid-β burden in APP/PS1 mice. Alzheimers Res Ther. 2021;13(1):40. https://doi.org/10.
1186/s13195-020-00761-9.
Chimento A, De Amicis F, Sirianni R, Sinicropi MS, Fuoci F, Casaburi I, Saturnino C, Pezzi
V. Progress to improve oral bioavailability and beneficial effects of resveratrol. Int J Mol Sci.
2019;20(6):1381. https://doi.org/10.3390/ijms20061381.
Chinta SJ, Andersen JK. Nitrosylation and nitration of mitochondrial complex I in Parkinson’s
disease. Free Radic Res. 2011;45(1):53–8. https://doi.org/10.3109/10715762.2010.509398.
Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health
in the elderly. Nature. 2012;488(7410):178–84. https://doi.org/10.1038/nature11319.
Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality
in rhesus monkeys. Science. 2009;325(5937):201–4. https://doi.org/10.1126/science.1173635.
Cordero JG, Garcia-Escudero R, Avila J, Gargini R, Garcia-Escudero V. Benefit of oleuropein
aglycone for Alzheimer’s disease by promoting autophagy. Oxidative Med Cell Longev.
2018;2018:5010741. https://doi.org/10.1155/2018/5010741.
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant
α-synuclein by chaperone-mediated autophagy. Science. 2004;305(5688):1292–5. https://doi.
org/10.1126/science.1101738.
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 891

Dahlin M, Elfving A, Ungerstedt U, Amark P. The ketogenic diet influences the levels of excitatory
and inhibitory amino acids in the CSF in children with refractory epilepsy. Epilepsy Res.
2005;64(3):115–25. https://doi.org/10.1016/j.eplepsyres.2005.03.008.
Das SK, Roberts SB, Bhapkar MV, et al. Body-composition changes in the comprehensive
assessment of long-term effects of reducing intake of energy (CALERIE)-2 study: a 2-y
randomized controlled trials of calorie restriction in nonobese humans. Am J Clin Nutr.
2017;105(4):913–27. https://doi.org/10.3945/ajcn.116.137232.
Davis C, Bryan J, Hodgson J, Murphy K. Definition of the Mediterranean diet; a literature review.
Nutrients. 2015;7(11):9139–53. https://doi.org/10.3390/nu7115459.
De Franceschi G, Fecchio C, Sharon R, Schapira AHV, Proukakis C, Bellotti V, de Laureto
PP. α-Synuclein structural features inhibit harmful polyunsaturated fatty acid oxidation,
suggesting roles in neuroprotection. J Biol Chem. 2017;292(17):6927–37. https://doi.org/10.
1074/jbc.M116.765149.
de Pablos R, Espinosa-Oliva AM, Hornedo-Ortega R, Cano M, Arguelles S. Hydroxytyrosol
protects from aging process via AMPK and autophagy; a review of its effects on cancer,
metabolic syndromes, osteoporosis, immune-mediated and neurodegenerative diseases.
Pharmacol Res. 2019;143:58–72. https://doi.org/10.1016/j.phrs.2019.03.005.
Dehay B, Bove J, Rodriguez-Muela N, Perier C, Recasens A, Boya P, Vila M. Pathogenic lysosomal
depletion in Parkinson’s disease. J Neurosci. 2010;30(37):12535–44. https://doi.org/10.1523/
JNEUROSCI.1920-10.2010.
Dinu M, Pagliai G, Casini A, Sofi F. Mediterranean diet and multiple health outcomes: an umbrella
review of meta-analyses of observational studies and randomized trials. Eur J Clin Nutr.
2018;72(1):30–43. https://doi.org/10.1038/ejcn.2017.58.
Dominguez L, Barbagallo M. Nutritional prevention of cognitive decline and dementia. Acta
Biomed. 2018;89(2):276–90. https://doi.org/10.23750/abm.v89i2.7401.
Ekmekciouglu C. Nutrition and longevity-from mechanisms to uncertainties. Crit Rev Food Sci
Nutr. 2020;60(18):3063–82. https://doi.org/10.1080/10408398.2019.1676698.
Feeney MB, Schöneich C. Tyrosine modifications in aging. Antioxid Redox Signal. 2012;17(11):
1571–9. https://doi.org/10.1089/ars.2012.4595.
Finelli MJ. Redox post-translational modifications of protein thiols in brain aging and neurodegen-
erative conditions – focus on S-nitration. Front Aging Neurosci. 2020;12:254. https://doi.org/
10.3389/fnagi.2020.00254.
Fontana L, Partridge L, Longo VD. Dietary restriction, growth factors and aging: from yeast to
humans. Science. 2010;328(5976):321–6. https://doi.org/10.1126/science.1172539.
Gardener H, Caunca MR. Mediterranean diet in preventing neurodegenerative diseases. Curr Nutr
Rep. 2018;7(1):10–20. https://doi.org/10.1007/s13668-018-0222-5.
GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of
neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease
Study 2015. Lancet Neurol. 2017;16:877–97. https://doi.org/10.1016/S1474-4422(17)30299-5.
Girotti AW. Lipid hydroperoxide generation, turnover, and effector action in biological systems.
J Lipid Res. 1998;39(8):1529–42.
Glossmann HH, Lutz OMD. Metformin and aging: a review. Gerontology. 2019;65(6):581–90.
https://doi.org/10.1159/000502257.
Grimm A, Eckert A. Brain aging and neurodegeneration: from a mitochondrial point of view.
J Neurochem. 2017;143(4):418–31. https://doi.org/10.1111/jnc.14037.
Hager K, Marahrens A, Kenklies M, Riederer P, Münch G. Alpha-lipoic acid as a new treatment
option for Alzheimer type dementia. Arch Gerontol Geriatr. 2001;32(3):275–82. https://doi.org/
10.1016/s0167-4943(01)00104-2.
Han YS, Zheng WH, Bastianetto S, Chabot JG, Quirion R. Neuroprotective effects of resveratrol
against β-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein
kinase C. Br J Pharmacol. 2004;141(6):997–1005. https://doi.org/10.1038/sj.bjp.0705688.
Harman D. Aging: a theory based on free radical and radiation. J Gerontol. 1956;11(3):298–300.
https://doi.org/10.1093/geronj/11.3.298.
892 W. Maruyama et al.

Harman D. The aging process. Proc Natl Acad Sci U S A. 1981;78(11):7124–8. https://doi.org/10.
1073/pnas.78.11.7124.
Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically
heterogeneous mice. Nature. 2009;460(7253):392–5. https://doi.org/10.1038/nature08221.
Hawkins CL, Davies MJ. Detection, identification, and quantification of oxidative protein modifi-
cations. J Biol Chem. 2019;194(51):19683–708. https://doi.org/10.1074/jbc.REV119.006217.
He S, Wang F, Yung KKL, Zhang S, Qu S. Effects of α-synuclein-associated post-translational
modifications in Parkinson’s disease. ACS Chem Neurosci. 2021;12(7):1061–71. https://doi.
org/10.1021/acschemneuro.1c00028.
Heinzel S, Aho VTE, Suenkel U, et al. Gut microbiome signatures of risk and prodromal markers of
Parkinson disease. Ann Neurol. 2020;88(2):320–31. https://doi.org/10.1002/ana.25788.
Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent
AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled,
multicenter trial. Nutr Metab (London). 2009;6:31. https://doi.org/10.1186/1743-7075-6-31.
Higashida K, Kim SH, Jung SR, Asaka M, Holloszy JO, Han DH. Effects of resveratrol and Sirt1 on
PGC-1α activity and mitochondrial biogenesis: a reevaluation. PLoS Biol. 2013;11(7):
e1001603. https://doi.org/10.1371/journal.pbio.1001603.
Iside C, Scafuro M, Nebbioso A, Altucci L. SIRT1 activation by natural phytochemicals: and
overview. Front Pharmacol. 2020;11:1225. https://doi.org/10.3389/fphar.2020.01225.
Joshi YB, Pratico D. Vitamin E in aging, dementia, and Alzheimer’s disease. Biofactors.
2012;38(2):90–7. https://doi.org/10.1002/biof.195.
Justice JN, Ferrucci L, Newman AB, et al. A framework for selection of blood-based biomarkers for
geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup. Genoscience.
2018;40(5–6):419–36. https://doi.org/10.1007/s11357-018-0042-y.
Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-β-hydroxybutyrate
protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci U S
A. 2000;97(19):5440–4. https://doi.org/10.1073/pnas.97.10.5440.
Kato Y, Osawa T. Detection of lipid-lysine amide-type adduct as a marker of PUFA oxidation and
its application. Arch Biochem Biophys. 2010;501(2):182–7. https://doi.org/10.1016/j.abb.2010.
06.010.
Kato Y, Maruyama W, Naoi M, Hashizume Y, Osawa T. Immunohistochemical detection of
dityrosine in lipofuscin pigments in the aged human brain. FEBS Lett. 1998;439(3):231–4.
https://doi.org/10.1016/s0014-5793(98)01372-6.
Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell
Biol. 2018;19(6):365–81. https://doi.org/10.1038/s41580-018-0001-6.
Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest.
2015;125(1):25–32. https://doi.org/10.1172/JCI73939.
Kim DY, Simeone KA, Simeone TA, et al. Ketone bodies mediate antiseizure effects through
mitochondrial permeability transition. Ann Neurol. 2015;78(1):77–87. https://doi.org/10.1002/
ana.24424.
Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, Chait BT, Tanaka K,
Yue Z. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and
the prevention of axonal degeneration. Proc Natl Acad Sci U S A. 2007;104(36):14489–94.
https://doi.org/10.1073/pnas.0701311104.
Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, Clegg DJ. Dietary ketosis enhances
memory in mild cognitive impairment. Neurobiol Aging. 2012;33(2):425.e19–27. https://doi.
org/10.1016/j.neurobiolaging.2010.10.006.
Lee HJ, Choi C, Lee SJ. Membrane-bound α-synuclein has a high aggregation propensity and the
ability to seed the aggregation of the cytosolic form. J Biol Chem. 2002;277(1):671–8. https://
doi.org/10.1074/jbc.M107045200.
Liu S, Sawada T, Lee S, et al. Parkinson’s disease-associated kinase PINK1 regulates Miro protein
level and axonal transport of mitochondria. PLoS Genet. 2012;8(3):e1002537. https://doi.org/
10.1371/journal.pgen.1002537.
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 893

Ludtmann MHR, Angelova PR, Ninkina NN, Gandhi S, Buchman VL, Abramov AY. Monomeric
α-synuclein exerts a physiological role on brain ATP synthase. J Neurosci. 2016;36(41):
10510–21. https://doi.org/10.1523/JNEUROSCI.1659-16.2016.
Ludtmann MHR, Angelova PR, Horrocks MH, et al. α-Synuclein oligomers interact with ATP
synthase and open the permeability transition pore in Parkinson’s disease. Nat Commun.
2018;9(1):2293. https://doi.org/10.1038/s41467-018-04422-2.
Maccariello R, D’Angelo S. Impact of polyphenolic-food on longevity: an elixir of life. An
overview. Antioxidants. 2021;10(4):507. https://doi.org/10.3390/antiox10040507.
Madeo F, Carmona-Gutierrez D, Hofer SJ, Kroemer G. Caloric restriction mimetics against
age-associated disease: targets, mechanisms, and therapeutic potential. Cell Metab.
2019;29(3):592–610. https://doi.org/10.1016/j.cmet.2019.01.018.
Mangialasche F, Polidori MC, Monastero R, Ercolani S, Camarda C, Cecchetti R, Mecocci
P. Biomarkers of oxidative and nitrosative damage in Alzheimer and mild cognitive impairment.
Ageing Res Rev. 2009;8(4):285–305. https://doi.org/10.1016/j.arr.2009.04.002.
Maraki MI, Yannakoulia M, Stamelou M, et al. Mediterranean diet adherence is related to reduced
probability of prodromal Parkinson’s disease. Mov Disord. 2019;34(1):48–57. https://doi.org/
10.1002/mds.27489.
Marseglia A, Xu W, Fratiglioni L, et al. Effect of the NU-AGE diet on cognitive functioning in older
adults: a randomized controlled trial. Front Physiol. 2018;9:349. https://doi.org/10.3389/fphys.
2018.00349.
Martin CK, Bhapkar M, Pittas AG, et al. Effect of caloric restriction on mood, quality of life, sleep
and sexual function in healthy nonobese adults: the CALERIE 2 randomized clinical trial.
JAMA Intern Med. 2016;176(6):743–52. https://doi.org/10.1001/jamainternmed.2016.1189.
Martin-Montalvo A, Mercken EM, Mitchel SJ, et al. Metformin improves healthspan and lifespan
in mice. Nat Commun. 2013;4:2192. https://doi.org/10.1038/ncomms3192.
Masaki KH, Losonczy KG, Izmirlian G, Foley DJ, Ross GW, Petrovitch H, Havlik R, White
LR. Association of vitamin E and C supplement use with cognitive function and dementia in
elderly men. Neurology. 2000;54(6):1265–72. https://doi.org/10.1212/wnl.54.6.1265.
Maswood N, Young J, Tilmont E, et al. Caloric restriction increases neurotrophic factor and
attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease.
Proc Natl Acad Sci U S A. 2004;101(52):18171–6. https://doi.org/10.1073/pnas.0405831102.
Mattison JA, Roth GS, Beasley TM, et al. Impact of caloric restriction on health and survival in
rhesus monkeys from the NIA study. Nature. 2012;489(7415):318–21. https://doi.org/10.1038/
nature11432.
McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M. The ketogenic diet inhibits the
mammalian target of rapamycin (mTOR) pathway. Epilepsia. 2011;52(3):e7–e11. https://doi.
org/10.1111/j.1528-1167.2011.02981.x.
McDonald TJ, Cervenka MC. Ketogenic diets for adult neurological disorders. Neurotherapeutics.
2018;15(4):1018–31. https://doi.org/10.1007/s13311-018-0666-8.
Metcalfe-Roach A, Yu AC, Golz E, et al. MIND and Mediterranean diets associated with later onset
of Parkinson’s disease. Mov Disord. 2021;36(4):977–84. https://doi.org/10.1002/mds.28464.
Morita Y, Nogami M, Sakaguchi K, Okada Y, Hirota Y, Sugawara K, Tamori Y, Zeng F,
Murakami T, Ogawa W. Enhanced release of glucose into the intraluminal space of the intestine
Associated with metformin treatment as revealed by [18F]Fluorodeoxyglucose PET-MRI. Dia-
betes Care. 2020;43(8):1796–802. https://doi.org/10.2337/dc20-0093.
Morris MC, Tangney CC, Wang Y, Sacks FM, Benett DA, Aggarwal NT. MIND diet associated
with reduced incidence of Alzheimer’s disease. Alzheimers Dement. 2015a;11(9):1007–14.
https://doi.org/10.1016/j.jalz.2014.11.009.
Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL, Bennett DA, Aggarwal NT. MIND diet
slow cognitive decline with aging. Alzheimers Dement. 2015b;11(9):1015–22. https://doi.org/
10.1016/j.jalz.2015.04.011.
Muller F, Lustgarten M, Jang Y, Richardson A, Van Remmen H. Trends in oxidative aging theories.
Free Radic Biol Med. 2007;43(4):477–503. https://doi.org/10.1016/j.freeradbiomed.2007.03.034.
894 W. Maruyama et al.

Naoi M, Inaba-Hasegawa K, Shamoto-Nagai M, Maruyama W. Neurotrophic function of phyto-

chemicals for neuroprotection in aging and neurodegenerative disorders: modulation of intra-
cellular signaling and gene expression. J Neural Transm. 2017;124(12):1515–27. https://doi.
org/10.1007/s00702-017-1797-5.
Naoi M, Wu Y, Shamoto-Nagai M, Maruyama W. Mitochondria in neuroprotection by phytochem-
icals: bioactive polyphenols modulate mitochondrial apoptosis system, function and structure.
Int J Mol Sci. 2019;20(10):2451. https://doi.org/10.3390/ijms20102451.
Nicastro HL, Dunn BK. Selenium and prostate cancer prevention: insights from the selenium and
vitamin E cancer prevention trial (SELECT). Nutrients. 2013;5(4):1122–48. https://doi.org/10.
3390/nu5041122.
Norwitz NG, Dearlove DJ, Lu M, Clarke K, Dawes H, Hu MT. A ketone ester drink enhances
endurance exercise performance in Parkinson’s disease. Front Neurosci. 2020;14:584130.
https://doi.org/10.3389/fnins.2020.584130.
Oettinghaus B, Schulz JM, Restelli LM, et al. Synaptic dysfunction, memory deficits and hippo-
campal atrophy due to ablation of mitochondrial fission in adult forebrain neurons. Cell Death
Differ. 2016;23(1):18–25. https://doi.org/10.1038/cdd.2015.39.
Orgogozo JM, Dartigues JF, Lafont S, Letenneur L, Commenges D, Salamon R, Renaud S, Breteler
MB. Wine consumption and dementia in the elderly: a prospective study in the Bordeaux area.
Rev Neurol (Paris). 1997;153(3):185–92.
Oulhaj A, Jerneren F, Refsum H, Smith AD, de Jager CA. Omega-3 fatty acid status enhances the
prevention of cognitive decline by B vitamins in mild cognitive impairment. J Alzheimers Dis.
2016;50(2):547–57. https://doi.org/10.3233/JAD-150777.
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects
through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem
J. 2000;348(3):607–14.
Parkinson Study Group QE3 Investigators, Beal MF, Oarkes D, et al. A randomized clinical trial of
high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol.
2014;71(5):543–52. https://doi.org/10.1001/jamaneurol.2014.131.
Perez-Revuelta BI, Hettich MM, Ciociaro A, Rotermund C, Kahle PJ, Krauss S, Di More
DA. Metformin lowers Ser-129 phosphorylated α-synuclein levels via mTOR-dependent pro-
tein phosphatase 2A activation. Cell Death Dis. 2014;5(5):e1209. https://doi.org/10.1038/cddis.
2014.175.
Pickrell AM, Youle RJ. The role of PINK1, parkin, and mitochondrial fidelity in Parkinson’s
disease. Neuron. 2015;85(2):257–73. https://doi.org/10.1016/j.neuron.2014.12.007.
Piskovatska V, Stefanyshyn N, Storey KB, Vaiserman AM, Lushchak O. Metformin as a
geroprotector: experimental and clinical evidence. Biogerontology. 2019;20(1):33–48. https://
doi.org/10.1007/s10522-018-9773-5.
Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ. The PINK1/
Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A. 2008;105(5):
1638–43. https://doi.org/10.1073/pnas.0709336105.
Price RK, Wallace JM, Hamill LL, Keaveney EM, Strain JJ, Parker MJ, Welch RW. Evaluation of
the effect of wheat aleurone-rich foods on markers of antioxidant status, inflammation and
endothelial function in apparently healthy men and women. Br J Nutr. 2012;108(9):1644–451.
https://doi.org/10.1017/S0007114511007070.
Quigley EMM. Nutraceuticals as modulators of gut microbiota: role in therapy. Br J Pharmacol.
2020;177(6):1351–62. https://doi.org/10.1111/bph.14902.
Rai SN, Singh P, Steinbusch HWM, Vamanu E, Ashraf G, Sigh MP. The role of vitamins in
neurodegenerative disease: an update. Biomedicine. 2021;9(10):1284. https://doi.org/10.3390/
biomedicines9101284.
Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart
disease. Lancet. 1992;339(8808):1523–6. https://doi.org/10.1016/0140-6736(92)91277-f.
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 895

Rochon J, Bales CW, Ravussin E, et al. Design and conduct of the CALERIE study: comprehensive
assessment of long-term effects of reducing intake of energy. J Gerontol A Biol Sci Med Sci.
2011;66A(1):97–108. https://doi.org/10.1093/gerona/glq168.
Ros E, Martinez-Gonzalez MA, Estruch R, Salas-Salvado J, Fito M, Martinez JA, Corella
D. Mediterranean diet and cardiovascular health: teachings of the PREDIMEZ study. Adv
Nutr. 2014;5(3):330S–6S. https://doi.org/10.3945/an.113.005389.
Roth GS, Ingram DK. Manipulation of health span and function by dietary caloric restriction
mimetics. Ann N Y Acad Sci. 2016;1363:5–10. https://doi.org/10.1111/nyas.12834.
Rutjes AW, Denton DA, Di Nisio M, et al. Vitamin and mineral supplement for maintaining
cognitive function in cognitively healthy people in mild and late life. Cochrane Database Syst
Rev. 2018;12(12):CD-11906. https://doi.org/10.1002/14651858.CD011906.pub2.
Sampaio LP. Ketogenic diet for epilepsy treatment. Arq Neuropsiquiatr. 2016;74(10):842–8. https://
doi.org/10.1590/0004-282X20160116.
Schildknecht S, Gerding HR, Karreman C, Drescher M, Lashuel HA, Quteiro TF, Di Monte DA,
Leist M. Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: implica-
tions for disease mechanisms and interventions in synucleinopathies. J Neurochem.
2013;125(4):491–511. https://doi.org/10.1111/jnc.12226.
Schwingshackl L, Morze J, Hoffmann G. Mediterranean diet and health status: active ingredients
and pharmacological mechanisms. Br J Pharmacol. 2020;177(6):1241–57. https://doi.org/10.
1111/bph.14778.
Selley ML. (E)-4-Hydroxy-2-nonenal may be involved in the pathogenesis of Parkinson’s disease.
Free Radic Biol Med. 1998;25(2):169–74. https://doi.org/10.1016/s0891-5849(98)00021-5.
Shamoto-Nagai M, Maruyama W, Hashizume Y, Yoshida M, Osawa T, Riederer P, Naoi M. In
parkinsonian substantia nigra, α-synuclein is modified by acrolein, a lipid peroxidation product,
and accumulates in the dopamine neurons with proteasome activity. J Neural Transm.
2007;114(12):1559–67. https://doi.org/10.1007/s00702-007-0789-2.
Shamoto-Nagai M, Hisaka S, Naoi M, Maruyama W. Modification of α-synuclein by lipid perox-
idation products derived from polyunsaturated fatty acids promotes toxic oligomerization: its
relevance to Parkinson disease. J Clin Biochem Nutr. 2018;62(3):207–12. https://doi.org/10.
3164/jcbn.18-25.
Shoulson I. DATATOP: a decade of neuroprotective inquiry. Parkinson Study Group. Deprenyl and
tocopherol antioxidative therapy of Parkinsonism. Ann Neurol. 1998;44(3 Suppl 1):S160–6.
Singh AK, Kashyap MP, Tripathi VK, Singh S, Garg G, Rizvi SI. Neuroprotection through rapamycin-
induced activation of autophagy and PI3K/Akt1/mTOR/ CREB signaling against amyloid-β-induced
oxidative stress, synaptic/ neurotransmission dysfunction, and neurodegeneration in adult rats. Mol
Neurobiol. 2017;54(8):5815–28. https://doi.org/10.1007/s12035-016-0129-3.
Smith DL Jr, Nagy TR, Allison DB. Calorie restriction: what recent results suggest for the future of
ageing research. Eur J Clin Investig. 2010;40(5):440–50. https://doi.org/10.1111/j.1365-2362.
2010.02276.x.
Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin BJ. Aggregated and monomeric
α-synuclein bind to the S6’ proteasomal protein and inhibit proteasomal function. J Biol Chem.
2003;278(14):11753–9. https://doi.org/10.1074/jbc.M208641200.
Taub PR, Ramirez-Sanchez I, Patel M, et al. Beneficial effects of dark chocolate on exercise
capacity in sedentary subjects: underlying mechanisms. A double blind, randomized, placebo
controlled trial. Food Funct. 2016;7(9):3686–93. https://doi.org/10.1039/c6fo00611f.
Tohgi H, Abe T, Yamazaki K, Murata T, Ishizaki E, Isobe C. Alterations of 3-nitrotyroeine
concentration in the cerebrospinal fluid during aging and in patients with Alzheimer’s disease.
Neurosci Lett. 1999;269(1):52–4. https://doi.org/10.1016/s0304-3940(99)00406-1.
Tosti V, Bertozzi B, Fontana L. Health benefits of the Mediterranean diet: metabolic and molecular
mechanisms. J Gerontol A Biol Sci Med Sci. 2018;73(3):318–26. https://doi.org/10.1093/gerona/
glx227.
896 W. Maruyama et al.

Tramutola A, Triplett JC, Di Domenico F, Niedowicz DM, Murphy MP, Coccia R, Perluigi M,
Butterfield DA. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease
(AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and
late-stage AD. J Neurochem. 2015;133(5):739–49. https://doi.org/10.1111/jnc.13037.
Trichopoulou A, Martinez-Gonzalez MA, Tong TY, Forouhi NG, Khandelwal S, Prabhakaran D,
Mozaffarian D, de Lorgeril M. Definitions and potential health benefits of the Mediterranean
diet: views from experts around the world. BMC Med. 2014;12:112. https://doi.org/10.1186/
1741-7015-12-112.
Trinh D, Israw A, Ararhoon LR, Gleave JA, Nash JE. The multi-faced role of mitochondrial in the
pathology of Parkinson’s disease. J Neurochem. 2021;156(6):715–52. https://doi.org/10.1111/
jnc.15154.
Turner RS, Thomas RG, Craft S, et al. A randomized, double-blind, placebo-controlled trial of
resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383–91. https://doi.org/10.1212/
WNL.0000000000002035.
Valls-Pedret C, Sala-Vila A, Sarra-Mir M, et al. Mediterranean diet and age-related cognitive
decline. A randomized clinical trial. JAMA Intern Med. 2015;175(7):1094–103. https://doi.
org/10.1001/jamainternmed.2015.1668.
van den Brink AC, Brouwer-Brolsma EM, Berendsen AAM, van de Rest O. The Mediterranean,
dietary approaches to stop hypertension (DASH), and Mediterranean-DASH intervention for
neurodegenerative delay (MIND) diets are associated with less cognitive decline and a lower
risk of Alzheimer’s disease – a review. Adv Nutr. 2019;10(6):1040–65. https://doi.org/10.1093/
advances/nmz054.
Van der Auwera I, Wera S, Van Leuven F, Henderson ST. A ketogenic diet reduces amyloid beta
40 and 42 in a mouse model of Alzheimer’s disease. Nutr Metab (Lond). 2005;2:28. https://doi.
org/10.1186/1743-7075-2-28.
Vanitallie TB, Nonas C, Di Rocco A, Boyar K, Hyams K, Heymsfield SB. Treatment of Parkinson
disease with diet-induced hyperketonemia: a feasibility study. Neurology. 2005;64(4):728–30.
https://doi.org/10.1212/01.WNL.0000152046.11390.45.
Varghese N, Werner S, Grimm A, Eckert A. Dietary mitophagy enhancer: a strategy for healthy
brain aging? Antioxidants. 2020;9(10):932. https://doi.org/10.3390/antiox9100932.
Vauzour D, Camprubi-Robles M, Miquel-Kergoat S, et al. Nutrition for the ageing brain: towards
evidence for an optimal diet. Ageing Res Rev. 2017;35:222–40. https://doi.org/10.1016/j.arr.
2016.09.010.
vB Hjelmborg J, Iachine I, Skytthe A, et al. Genetic influence on human lifespan and longevity.
Hum Genet. 2006;119(3):312–21. https://doi.org/10.1007/s00439-006-0144-y.
Wengreen H, Munger RG, Cutler A, et al. Prospective study of dietary approaches to stop
hypertension- and Mediterranean-style dietary patterns and age-related cognitive change: the
Cache Country study on memory, health and aging. Am J Clin Nutr. 2013;98(5):1263–71.
https://doi.org/10.3945/ajcn.112.051276.
Willcox BJ, Willcox DC. Caloric restriction, CR mimetics, and healthy aging in Okinawa: contro-
versies and clinical implications. Curr Opin Clin Nutr Metab Care. 2014;17(1):51–8. https://doi.
org/10.1097/MCO.0000000000000019.
Witte AV, Kerti L, Margulies DS, Flöel A. Effects of resveratrol on memory performance,
hippocampal functional connectivity, and glucose metabolism in healthy older adult.
J Neurosci. 2014;34(23):7862–70. https://doi.org/10.1523/JNEUROSCI.0385-14.2014.
Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature. 2016;539(7628):180–6.
https://doi.org/10.1038/nature20411.
Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L. Abberant α-synuclein confers toxicity to
neurons in part through inhibition of chaperone-mediated autophagy. PLoS One. 2009;4(5):
e5515. https://doi.org/10.1371/journal.pone.0005515.
Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration 897

Yin JX, Maalouf M, Han P, et al. Ketones block amyloid entry and improve cognition in an
Alzheimer’s model. Neurobiol Aging. 2016;39:25–37. https://doi.org/10.1016/j.
neurobiolaging.2015.11.018.
Yin W, Löf M, Pedersen NL, Sandin S, Fang F. Mediterranean dietary pattern at middle age and risk
of Parkinson’s disease: a Swedish cohort study. Mov Disord. 2021;36(1):255–60. https://doi.
org/10.1002/mds.28314.
Yoritaka A, Kawajiri S, Yamamoto Y, Nakahara T, Ando M, Hashimoto K, Nagase M, Saito Y,
Hattori N. Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10
for Parkinson’s disease. Parkinsonism Relat Disord. 2015;21(8):911–9. https://doi.org/10.1016/
j.parkreldis.2015.05.022.
Zhang Y, He X, Wu X, et al. Rapamycin upregulates glutamate transporter and IL-6 expression in
astrocytes in a mouse model of Parkinson’s disease. Cell Death Dis. 2017;8(2):e2611. https://
doi.org/10.1038/cddis.2016.491.
Zhang S, Eitan E, Wu TY, Mattson MP. Intercellular transfer of pathogenic α-synuclein by
extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal. Neurobiol
Aging. 2018;61:52–65. https://doi.org/10.1016/j.neurobiolaging.2017.09.016.
Ethnopharmacology and the Development
of Psychoactive Drug: A Critical Overview

Elaine Elisabetsky

Contents
Natural Products, Ethnopharmacology, and Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
Ethnopharmacology in the Context of Psychopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901
Lost in Translation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
Like It or Not, You Do Want to See and Know How Homemade Medicines Are Made . . . 903
The Magic Bullet Fairytale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
Too Little About Too Many . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 905
Putting the Cart Before the Horse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
Perspectives for a Translational Ethnopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909

Abstract
The purpose of this chapter is to provide a critical overview of ethnopharmacology
as a research strategy in the search of psychoactive drugs. Despite the prominent role
of natural products, alkaloids specially, in the development of psychopharmacology,
new plant-derived psychoactive drugs are lacking. Advantages of natural products
over synthetic compounds for interacting with biological systems of therapeutic
interest have been repeatedly documented. Advantages of ethnopharmacology-
driven plant collections over the biodiversity or chemotaxonomy-oriented ones
have also been reported. The main focus of this review is to discuss the advantages
to incorporate ethnopharmacology data into the research design in order to optimize
the identification of innovative drugs for neurological and mental illnesses. For that
matter, traditional medical systems need to be regarded and studied as such, instead
of just the plant species used to prepare the traditional formulas. Studies are used to
illustrate relevant methodological aspects for a proper evaluation of traditional
remedies used for treating the mentally ill, including the collection of clinical data

E. Elisabetsky (*)
Departamento de Bioquímica, Instituto de Ciência Básicas da Saúde, Universidade Federal do Rio
Grande do Sul, Porto Alegre, RS, Brazil

© Springer Nature Switzerland AG 2022 899

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_459
900 E. Elisabetsky

in the field, the phytochemical and pharmacological approaches, the insufficient

reproducibility and translational value, and the scarcity of accumulated knowledge
on promising species. The adoption of joint efforts and improved methodological
approaches will foster the discovery of innovative psychoactive drugs from natural
origin.

Natural Products, Ethnopharmacology, and Drug Development

The advantages of screening natural products over synthetic molecules for drug
discovery have been advocated over decades and recently reviewed (Harvey et al.
2015). A pragmatic gauge is that 34% of the new medicines approved by the US Food
and Drug Administration (FDA) between 1981 and 2010 were based on natural
products and/or their direct derivatives. From a chemical point of view, the advantages
of natural products include (Harvey et al. 2015; Skirycz et al. 2016) (a) having a wide
range and high degree of stereochemistry pharmacophores, resulting in not only
bioactivity but likelihood to reach the site of action; (b) they characteristically fit the
molecular chemical descriptors adequate for bioactivity; (c) they probe a different,
wider, and more drug-like chemical space than the scaffolds present among commer-
cial drugs; (d) they cover parts of chemical characteristics of bioactivity targets that
medicinal chemistry compounds do not; and (e) the vast majority of all drugs have a
close match natural product (Harvey et al. 2015). Overcoming snags that marked the
field in the past are the advances in chemical methods for identifying active com-
pounds, better thought off libraries (such as “natural product-derived” and “natural
product-inspired”), improved nuclear magnetic resonance (NMR) techniques to solve
compound structures with minute (microgram range) samples, and new approaches
such as genomics, metabolomics, interactomics, and chemoinformatic (Harvey et al.
2015; Skirycz et al. 2016).
In view of such favorable evidence, it is somewhat surprising that the interest in
natural products as the basis for drug development has been coming in waves at least
since the 1980s. It has been estimated that only 5–15% of higher plants have been
systematically examined as sources of compounds with medicinal properties
(McChesney et al. 2007) nor had been scrutinized the 200,000 plant metabolites
already identified, not to mention the tens of thousands of plant-based homemade
remedies used daily for therapeutic purposes by the majority of mankind. The
explanation may combine the low yield and complex structure of compounds
(Skirycz et al. 2016) and the political nature of drug development, ruled by several
factors other than the medicine qualities/flaws. Specifically for bioprospection
initiatives, the sociopolitical issues, intellectual property rights (IPR), and benefit
sharing issues established by the 1992 Biological Convention are viewed as upfront
hurdles driving pharma interest away (Elisabetsky 1991).
In 1984 Professor Norman Farnsworth (University of Illinois at Chicago) posed
the question, “How can the well be dry when it is filled with water?” (Farnsworth
1984). As considered above, in the nearly four decades since this question was
posed, advances in phytochemistry and synthesis methods can largely overcome the
Ethnopharmacology and the Development of Psychoactive Drug: A Critical Overview 901

complications faced at that time to identify and characterize active compounds in

plant extracts and formulas. Still, FDA-approved psychoactive drugs from natural
products are scarce (Heinrich and Lee Teoh 2004; Newman and Cragg 2020). The
purpose of this chapter is to contemplate how well are we tapping the well.

Ethnopharmacology in the Context of Psychopharmacology

Despite well-known examples of plant-derived drugs, such as morphine from a

poppy or vincristine and vinblastine from the Madagascar periwinkle, only about
200 of the 10,000–15,000 higher plants with reported medicinal properties are taken
advantage of in Western medicine (Birari and Bhutani 2007; McChesney et al.
2007). While the herbal market is established as such, newly approved botanical
drugs are rare (Wu et al. 2020). Though ethnopharmacology has been found to be
more effective than chemotaxonomy or random collection strategies in the search for
active extracts/compounds (Gyllenhaal et al. 2012), it is often considered as second-
class scientific approach.
Ethnopharmacology, a multidisciplinary subject that includes domains from
social and biomedical sciences, is an approach to understand various aspects of
traditional systems of medicine. Ethnopharmacology data can be used for several
purposes such as to document history, subsidize health policies, inform traditional
communities in a culturally sensitive manner, and produce improved (or branded)
herbals, among others (Anderson et al. 2003; Etkin and Elisabetsky 2005). The focus
here in on its use for the discovery and development of psychoactive drugs. The
seemly simple idea to use traditional medical systems as sources of information for
drug development contrasts with the difficulties in translating traditional medical
practices, inextricably linked in culture (regardless of which medical system one
looks at), to the now dominant evidence based on the Western biomedical paradigm.
Ethnopharmacology has received numerous definitions over time (Heinrich
2015). As an old version of the “bed to bench strategy,” ethnopharmacology records
the biological effects reported by users as the basis to articulate a working hypothesis
to drive subsequent chemical/pharmacological investigation of homemade remedies.
One definition of interest to this discussion is Daniel Moerman’s: “Essentially
ethnopharmacology is the examination of non-Western (not mine) medicinal plant
use in terms of Western (mine) plant use” (Heinrich 2015) (p. 4). In confirmation
with this definition, studies in this field often conclude on the “validation” (or lack
of) of a traditional remedy; a positive validation is reached when the in vivo or
in vitro effect observed for the extract/fraction/compound under study was to be
expected, or made sense, in relation to the original therapeutic claim (Verpoorte
2012). Though Moerman’s definition is perfectly accurate to describe most of the
published papers in journals of this field, I argue that this understanding can be
counterproductive to identify drugs with truly innovative mechanisms of action.
Traditional (indigenous) and modern (Western biomedical) medical systems
evolved from distinct sociohistorical contexts, relate to singular belief systems, and,
accordingly, are based on different models of disease causality and treatment. In spite
902 E. Elisabetsky

of such profound differences, peoples worldwide make use of concepts and practices
from various medical systems in order to maintain or reestablish health (Ceuterick and
Vandebroek 2017; Crandon 1986; Freymann et al. 2006). An informed multi-
disciplinary research team can extract from the description of signs, symptomatology,
and disease course reported by healers and/or users key information to formulate a
sound working hypothesis to foster the necessary hypothesis-driven laboratory exam-
ination (Elisabetsky 2007). Nevertheless, as I hope to illustrate with the following
examples, if ethnopharmacology data is worth using to increase the chances of success
in drug discovery, methods must be optimized. Considering the high rate of dropouts
when translationing preclinical data to successful clinical outcome, the report of a
specific therapeutic outcome (and adverse reactions) from plant-based formulas
ingested orally by men and women is an advantage for drug development that cannot
be underestimated (Mullane et al. 2014).

Lost in Translation

Traditional medical systems are organized as cultural systems (Etkin et al. 1990;
Moerman 2002) and may greatly differ in the meanings of health, disease, disease
etiologies, and cure (Wang 2012), resulting in medicinal practices not easily accom-
modated into the biomechanical paradigm of contemporary Western medicine. On top
of the expected differences in the understanding/beliefs of what causes the condition,
the very description of psychiatric symptomatology varies in different cultures (Gadit
2003; Shepard 1998; Weisman et al. 2000). Nonetheless, the common ground that can
be most effectively used to define the correspondence of emic and Western nosology is
the descriptions of symptomatology and the natural course of the disease. In the same
line, precious information can be obtained about the clinical outcome of therapies, as
when and how amelioration and/or resolution is perceived, adverse effects, etc.
Unfortunately, though, a significant (if not major) part of ethnopharmacology is
based on secondhand information and/or field data collected (and interpreted) by
personnel with no biomedical training. As a result, literature searches and cultural-
driven libraries end up built upon misleading information. Despite cultural beliefs,
informed clinical data collected in the field is highly instrumental for a sound working
hypothesis behind laboratory and/or to designed clinical studies (Graz 2013). Obser-
vational studies have been proposed as an initial step to optimize the choice of species
to be studied, the format of the research design, and to develop improved herbals
(Akubue and Mittal 1982; Graz 2013; Willcox et al. 2011).
Within the context of drug development the interest in traditional medical systems
resides on the assumption that plants processed as traditional medicines have a higher
probability to contain bioactive compounds. Nevertheless, the research designs rarely
(if ever, in industrial settings) consider basic pharmacological hallmarks, such as the
formulation and posology of traditional remedies. Disregarding information on how
any drug is formulated, how much, how often, and for how long it is used is against
basic principles widely admitted as key for a good outcome with any modern drug. As
no investigation on a synthetic drug would disregard the crucial issue of posology, it is
Ethnopharmacology and the Development of Psychoactive Drug: A Critical Overview 903

the lack of respect for traditional knowledge that results in the transformation of a
remedy into an extract or sample, ultimately limiting the quality of the evaluation and
the chances to identify new drugs. As Etkin put it, “ethnopharmacologists of all
backgrounds can enhance their work by projecting pharmacologic data against a
backdrop of medical ethnography” (Etkin 2001).

Like It or Not, You Do Want to See and Know How Homemade

Medicines Are Made

Traditional pharmacotechniques reflect the best way to extract compounds of interest

with the available resources. As not all compounds present in a plant species will also
be present in the remedy, a phytochemical analysis of the traditional remedy as
originally used is of interest given that whatever the active compound(s) is(are) it
ought to be ingested by the patient. A customized analysis is certainly not feasible for
screening large libraries of extracts, but even at academic settings, this practice is often
overlooked. Since traditional modes of preparation do exclude compounds from the
plant (while concentrating others), it is counterproductive to initiate preclinical exper-
iments with extracts bearing little resemblance to the original formulation.
Traditional pharmacotechniques also bring insights on the best choice for extraction
and isolation procedures, by narrowing the possibilities and thus decreasing the
workload. For instance, one can expect components of essential oils to be the active
compounds in aromatic teas (where the plant is added to hot water for a few minutes),
while thermally sensitive compounds can be excluded from nonaromatic teas (where
the plant is added to cold water and then boiled). In the case of drugs active at the
central nervous system (CNS), one must be attentive to the presence of alkaloids
(as free bases, glycosides, salts of primary, secondary, tertiary amines, or quaternary
ammonium salts) and explore 9:1 or 1:1 water/ethanol extracts for remedies prepared
as bottles in wine or distilled spirit (Nunes 1996). The analysis of a traditional formula
used for epilepsy in the Brazilian Amazon illustrates the point. The remedy is prepared
from mashing the fresh leaves of three species (two of which are aromatic) together
with sesame seeds, the mixture filtered through a clean cloth, and ingested orally.
Whereas this exact formula just delayed pentylenetetrazol-induced convulsions in
mice, linalool (the major component of Aeollanthus suaveolens essential oil) was
found to possess a clear and broad anti-convulsant profile (Elisabetsky and Brum
2003). Linalool acts by inhibiting glutamate release with no apparent direct interaction
with GABAA receptors (Elisabetsky et al. 1999; Silva Brum et al. 2001). The sesame
seeds are likely to facilitate the extraction of the essential oils and the marked aroma of
the traditional formula hinted to the relevance of studying the essential oils from
A. suaveolens. It is not improbable that a standard fractionation/isolation protocol
could have defatted the sample (losing or modifying the active component) or would
had led to a more convoluted and lengthier path to identify linalool as an important
active component.
As allopathic drugs, traditional remedies are used following specific instructions
and for varying periods of time. In pharmacodynamic terms, it is expected that
904 E. Elisabetsky

long-term use may have effects significantly different than acute (single administra-
tion) or sub-chronic (few administrations) challenge in any given molecular target.
Nevertheless, for planning screening or drug development programs, the traditional
posology is rarely taken into consideration. Understandably, the correspondence
between traditional use and its laboratory investigation collides with practical matters,
such as the need for higher amounts of compounds/extracts/fraction for in vivo, orally
administered, and/or repeated administration. Be as it may, the answer to the research
hypothesis of a given biological activity based on users’ claims cannot be conclusive
before a fair assessment is accomplished. Needless to say that for CNS drugs, this issue
is of upmost importance since it has been established that the long-term effects on
initial targets are often required to achieve a new functional state (Hyman and Nestler
1996). Importantly, in vitro methodologies are, unfortunately, more often than not
inadequate for these purposes (Houghton et al. 2007). The use of experimental models
with good predictability validity, usually practical requiring one single dose, is suitable
to initiate the investigation; if these initial results are positive, especially if showing
dose-dependent and sizable effects, a more elaborate phase using models with trans-
lational value and attention for the original posology can be launched.
Even when acute experiments are the only starting possibility (e.g., due to limited
test samples), a realistic notion of the traditional formulation and posology can be
informative. For instance, a hypothesis of antipsychotic properties was raised for
plant-based medicine used by Dr. Chidi, a Nigerian traditional psychiatrist. The
study led to the identification of the active compound, the indole alkaloid alstonine
showing a clear antipsychotic profile (positive, negative, and cognitive symptoms
mice models) and unique mechanism of action (Linck et al. 2015). Alstonine proved
to be active in mice models at 0.5–2.0 mg/kg dose range, far lower than the usual
20–200 mg/kg used in most studies, but compatible with the amount of the alkaloid
expected to be in the traditional preparation as recorded in field work (Costa-Campos
et al. 1998); had we concluded that alstonine had no antipsychotic effect based on the
negative results with 20 mg/kg or higher doses, the entire line of research would
have been abandoned.

The Magic Bullet Fairytale

Frequently the use of traditional remedies involves mixture of plants, and a single
plant-based remedy may already contain tens of compounds. Nevertheless, the
majority of the studies aim to identify “the” active component, which may be just
a part of what is of interest. For instance, caboclos from the state of Pará in the
Brazilian Amazon use the species Psychotria colorata to prepare a remedy to treat
earache: a handful of cut-up fresh flowers are mushed in milk (preferably “mother’s
milk”), packed in banana leaves, and left for a few minutes over warm ashes; the
resulting mixture is filtered through a piece of cloth and drops applied into the ear; it
is said that abdominal pain also responds to the species, but for that purpose roots
and fruits are mixed with water, left to boil, and the decoction taken orally
(Elisabetsky and Castilhos 1990). Extracts of P. colorata flowers showed marked
Ethnopharmacology and the Development of Psychoactive Drug: A Critical Overview 905

analgesic activity at various pain mice models (Elisabetsky et al. 1995), and
pyrrolidinoindoline alkaloids were identified as the major components in the flower
extract (but absent in the leaves). Several alkaloids with analgesic activity were
isolated and identified: hodgkinsine has a dual mechanism of action acting as opioid
agonist (Amador et al. 2000) and glutamate N-methyl-D-aspartate receptor
(NMDAR) antagonist; psychotridine acts as glutamate NMDAR antagonist
(Amador et al. 2001). It is the combined effects of the alkaloids, equivalent to use
morphine and dizocilpine, that result in the remedy’s potent analgesic effects. Dual
mechanism of action and/or various active components were also identified for
Sceletium tortuosum, where selective serotonin reuptake inhibitor (SSIR) was char-
acterized for mesembrine and mesembrone, whereas mesembrone also acts as
specific phosphodiesterase 4 inhibitor (Harvey et al. 2011). Examples such as
these call attention to the advantage of starting with in vivo analysis, given that
active compounds and/or mechanisms of action could have been lost if a target-
driven screening was the research approach.
Well-documented examples of biological activity resulting from various active
compounds (and lost or diminished when any one in separately assessed) include
plants of relevance in the herb market such as gingko (Liu et al. 2018; Tian et al.
2017), ginseng (Murthy et al. 2018), and kava (Celentano et al. 2019). The same
holds true for the synergic interactions of different active ingredients at complex
formulas, such as in the Ayahuasca beverage, the Japanese Kampö (Satoh 2013), and
traditional Chinese medicine (TCM) (Hong et al. 2017). Unfortunately though, even
with the changes in mainstream pharmacology with regard to multiple mechanisms
of action and network pharmacology (Hopkins 2007, 2008), a significant part of
medicinal plant research still pursue the active compound.

Too Little About Too Many

The fields of natural products pharmacology and ethnopharmacology are marked by

a pattern of limited data about species and/or compounds, easily confirmed at
meetings, poster sessions, or journal volumes. In contrast, different aspects of
known or newer synthetic drugs are extensively investigated.
Let us take the essential oils, for instance, which represent another example of
complex mixtures of compounds extensively used in traditional systems of medicines.
A Web of Science survey revealed 785 reference abstracts with the keyword “essential
oil” and hypnotic/anxiolytic/anti-convulsant/antidepressant and/or neuroprotector
properties. The effects of essential oil inhalation in anxiety and depression has been
documented in clinical settings (Aponso et al. 2020; Malcolm and Tallian 2017) and
often interact with more than one CNS target (Wang and Heinbockel 2018). As
essential oils are characterized for their very complex compositions (a core aspect of
their uniqueness) and marked variability among samples, experiments performed with
essential oils as such are difficult to reproduce. For that reason, the revision focused
only on compounds isolated from essential oils with the aim to understand psychoac-
tive profiles and underlying mechanism of actions (Elisabetsky and Nunes, 2020).
906 E. Elisabetsky

The sample was eventually reduced to 300 studies selected on the basis of the
scientific quality of the reports, from which 61 compounds were identified as being
active at the CNS. The Web of Science survey was repeated using the compound name
and the same CNS activities as keywords. After dismissing reports with scientifically
frail data, the sample was reduced to 34 compounds subjected to thorough revision in
the relevant scientific literature. Of these, 25 compounds were reported to have
anxiolytic activity, 9 with hypnotic properties, 18 as anti-convulsants, 9 as antidepres-
sants, and 10 showed a neuroprotective profile, based on at least one behavior and/or
in vivo electrophysiology assay. Since anxiolytics, hypnotics, and anti-convulsants are
sedatives (psycholetics), with known drugs often sharing the same mechanism of
action and effects (at different doses and efficacy), it was somewhat expected that
the same compounds were active in these three domains. Nevertheless, only six
(phytol, α-asarone, γ-decanolactone, safranal, dehydrofukinone, and oleamide) show
all three properties. Of the 34 reviewed compounds only for linalool, α-asarone, and
thymoquinone a substantial body of data is available, studies were replicated by
different research groups, therefore showing a reliable psychoactive profile
(as antiepileptic/anti-convulsant). Thymol is active in the three most common antide-
pressant experimental models (two with predictive and one with face validity) and
shows mechanisms of action relevant to depression (affecting noradrenaline, serotonin,
and neuroinflammation). Among the compounds claimed to act as neuroprotectors,
data is scattered over compounds and models, except for antioxidant activity assessed
in all but one compound. Several compounds had only one study reported or have been
studied by one group only, which limits the data reliability (Ioannidis 2018). More
often than not, only one experimental model is used, whereas a battery of models
would yield in more reliable picture and rule out false positives. Another potential
limitation is that the mechanism of action is often inferred from the antagonist effect
performed with single-dose experiments, a limitation also noted by Zhu and colleagues
(Zhu et al. 2014) in their review of anti-convulsant compounds isolated from medicinal
plants. Though acceptable in exploratory research (Kenakin et al. 2014), these studies
are unlikely to be selected for drug development before a far more rigorous analysis is
in place (Kimmelman et al. 2014).
Unfortunately, the pattern of a small set of experiments on a wide range of species
is dominant (obviously excluding the best known and/or important commercialized
species). Perhaps the idea of original research is translated into studying a species for
which most data is lacking. Be what may, the lack of accumulated data, including a
battery of in vivo and in vitro tests, phytochemistry, and toxicology, certainly does
not help to make a compelling case for drug development.

Putting the Cart Before the Horse

The history of pharmacology in general, and psychopharmacology in particular, is

full of examples of drugs introduced to clinic long before the mechanism of action
was properly clarified. A plant-based product example is Saint John’s wort (Hyper-
icum perforatum) widely used for decades as antidepressant in various continents
Ethnopharmacology and the Development of Psychoactive Drug: A Critical Overview 907

(Linde et al. 2008; Ng et al. 2017), though the definition of its active compounds and
mechanisms of action are still unclear (Barnes et al. 2001). The research design often
employed to “validate” traditional uses of medicinal plants by starting with in vitro
tests may gear the search away from truly innovative drugs.
For instance, 34 medicinal species (75 extracts) associated which ethnophar-
macology information interpreted as possible emic description of depressive states
were screened for serotonin transporter affinity. From the five positive hits, two
species were discarded for having compounds deemed inappropriate for long-term
use (tropane alkaloids and cardiac glycosides); the three remaining species were
examined for activity at the forced swimming and tail suspension tests showing
varying positive effects. Bio-guided fractionation led to the identification of
buphanamine-type alkaloids (such as lycorine) and the monoterpene lactone (-)-
loliolide (Jäger 2015). Were the traditional remedies used for long periods? Could
the ones ruled out be fast-acting antidepressants? Did the traditional formulation
contain significant amounts of the potentially toxic alkaloids found in the extracts?
Does the in vitro affinity translate to sizable effect in relevant CNS areas? Do
lycorine and (-)- loliolide administered for a long enough time result in the same
serotoninergic neurotransmitter changes observed with known SSRI? These are
questions that need to be addressed if the data is to be used as incentive for drug
development (trustworthy herbal or new chemical entity). Likewise, a wide range of
species were found to possess MAO-A inhibition properties (Viña et al. 2012), often
due to the presence of quercetin (Chimenti et al. 2006).
The failure to incorporate detailed traditional use (e.g., posology, observed
effects, and side effects) in the research design, the choice of workflow (e.g.,
in vitro before in vivo), and the limited use of experimental models with good
translational value often leads to a somewhat misapplied investment in time and
resources in the study of plant species used for medical purposes. If acceptable for
the varied academic purposes, this modus operandi adds little to the discovery of
innovative CNS drugs. It also may well be part of the reasons to explain the pathetic
yield (and cost/benefit) of high-throughput screenings that were once the hype and
hope in the search for drugs from natural origin (Fox et al. 2006).

Perspectives for a Translational Ethnopharmacology

Drug development is not an academic purpose nor its responsibility. Nevertheless,

academics working with medicinal plants, or its isolated compounds, do wish their
studies to contribute to the discovery of new drugs, to the development of high-
quality herbals, or at least for a better-informed use of these healthcare resources.
Of relevance is the argument that the financial resources that fund academic research,
often public, require at least an inherent intent to provide a tangible benefit to society
(Horrobin 2003). Alternatively, if the justifiable goal of the studies is just unveiling
aspects of traditional remedies, concluding remarks on the relevance of the study for
drug development should be avoided.
908 E. Elisabetsky

Starting the evaluation of medicinal plants with methodologies that gauge the
effect on experimental models with translational value, rather than checking if it
matches a predetermined mechanism of action, may be especially relevant in the
field of mental disorders for which the pathological basis are still elusive (Ledford
2014). A fair assessment requires hypothesis-driven and customized research
designs that consider modes of preparation (types and dose range of components)
and posology (single x fractionated doses) of traditional medicines. As in biomedical
sciences in general, a more rigorous standard is required to afford credibility and
reproducibility to ethnopharmacology studies (Ioannidis 2005), in which the null
hypothesis is often accepted or rejected even when plant part, type of extract, dose
range, and the experimental model might have been inadequate or bear little corre-
spondence to the traditional use.
It is a consensus that the pharmaceutical potential of natural products has yet to be
explored (Cragg and Newman 2013). The preference of combinatorial over natural
product libraries may have contributed to the small number of new chemical entities,
fueling the pharma productivity crisis (Ogbourne and Parsons 2014). Yet, only 5%
out of 2000 studies including ethnopharmacology in the title or keywords include
CNS activities (Heinrich 2015). Collaborative efforts in drug development have
been put in place where consortiums are formed with specific goals such as defining
biomarkers or sharing specific data (Patridge et al. 2016; Wehling 2009). Collabo-
rative efforts, perhaps steered by scientific organizations devoted to specific neuronal
and mental disorders, could collate different academic skills and resources to attain a
substantial enough body of knowledge on promising compounds/species to attract
industrial research.
The extended interpretation of cause-effect relationships in physics calls for the
substitution of “cause” to “determining conditions,” where all the conditions of a
process or state are equally important. For complex diseases such as mental disor-
ders, where genetic, developmental, and ontogenetic factors are increasingly recog-
nized, the concept of determination fits better than causality (Vineis and Porta 1996).
When diseases are understood as processes, where an interplay of multiple factors
has to be considered, it becomes attractive to study complex plant formulas that may
simultaneously modulate more than one target (Rasoanaivo et al. 2011; Roth et al.
2004). In order to truly profit from studying traditional medical systems as such,
rather than medicinal plants as sources of bioactive molecules, ethnopharma-
cologists, pharmacologists, and phytochemists need to be unprejudiced and open-
minded, allowing an unbiased appreciation of potentially new drug paradigms. The
somewhat new paradigm of network pharmacology (Hopkins 2008) bears more
likeness to traditional remedies (more than one active compound, various mecha-
nisms of action) than the now outdated single bullet – yet phytomedicine is often
seen as messy and untrustworthy. Ethnopharmacology combined with a rigorous
hypothesis-driven laboratory scrutiny, by operating a comprehensive understanding
of traditional medical concepts and practices, can be a fruitful strategy to innovative
psychoactive drug development.
Ethnopharmacology and the Development of Psychoactive Drug: A Critical Overview 909

Cross-References

▶ Cannabinoid Drugs in Mental Health Disorders

▶ Hallucinogens as Therapeutic Agents: Past, Present, and Future
▶ Psychopharmacology: A Brief Overview of Its History
▶ TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus
on Depression

Acknowledgments I wish to express my appreciation to Prof. Peter Riederer for including

ethnopharmacology as a relevant topic in this reference series. I am grateful to Dan Moerman,
Domingos Nunes, Roberto Regensteiner, and David Oren for useful discussions and/or proofread-
ing of this manuscript.

References
Akubue PI, Mittal GC. Clinical evaluation of a traditional herbal practice in Nigeria: a preliminary
report. J Ethnopharmacol. 1982;6:355–9. https://doi.org/10.1016/0378-8741(82)90056-3.
Amador TA, Verotta L, Nunes DS, Elisabetsky E. Antinociceptive profile of Hodgkinsine. Planta
Med. 2000;66:770–2. https://doi.org/10.1055/s-2000-9604.
Amador TA, Verotta L, Nunes DS, Elisabetsky E. Involvement of nmda receptors in the analgesic
properties of psychotridine. Phytomedicine. 2001;8:202–6. https://doi.org/10.1078/0944-7113-
00025.
Anderson LM, Scrimshaw SC, Fullilove MT, Fielding JE, Normand J. Culturally competent
healthcare systems: a systematic review. Am J Prev Med. 2003;24:68–79. https://doi.org/10.
1016/S0749-3797(02)00657-8.
Aponso M, Patti A, Bennett LE. Dose-related effects of inhaled essential oils on behavioural
measures of anxiety and depression and biomarkers of oxidative stress. J Ethnopharmacol.
2020;250:112469. https://doi.org/10.1016/j.jep.2019.112469.
Barnes J, Anderson LA, Phillipson JD. St John’s wort (Hypericum perforatum L.): a review of its
chemistry, pharmacology and clinical properties. J Pharm Pharmacol. 2001;53:583–600. https://
doi.org/10.1211/0022357011775910.
Birari RB, Bhutani KK. Pancreatic lipase inhibitors from natural sources: unexplored potential.
Drug Discov Today. 2007;12:879–89. https://doi.org/10.1016/j.drudis.2007.07.024.
Celentano A, Tran A, Testa C, Thayanantha K, Tan-Orders W, Tan S, Syamal M, McCullough MJ,
Yap T. The protective effects of Kava (Piper Methysticum) constituents in cancers: a systematic
review. J Oral Pathol Med. 2019;48:510–29. https://doi.org/10.1111/jop.12900.
Ceuterick M, Vandebroek I. Identity in a medicine cabinet: discursive positions of Andean migrants
towards their use of herbal remedies in the United Kingdom. Soc Sci Med. 2017;177:43–51.
https://doi.org/10.1016/j.socscimed.2017.01.026.
Chimenti F, Cottiglia F, Bonsignore L, Casu L, Casu M, Floris C, Secci D, Bolasco A, Chimenti P,
Granese A, Befani O, Turini P, Alcaro S, Ortuso F, Trombetta G, Loizzo A, Guarino I. Quercetin
as the active principle of Hypericum hircinum exerts a selective inhibitory activity against
MAO-A: extraction, biological analysis, and computational study. J Nat Prod. 2006;69:945–9.
https://doi.org/10.1021/np060015w.
Costa-Campos L, Lara DR, Nunes DS, Elisabetsky E. Antipsychotic-like profile of alstonine.
Pharmacol Biochem Behav. 1998;60:133–41. https://doi.org/10.1016/s0091-3057(97)00594-7.
Cragg GM, Newman DJ. Natural products: a continuing source of novel drug leads. Biochim
Biophys Acta. 2013;1830:3670–95. https://doi.org/10.1016/j.bbagen.2013.02.008.
910 E. Elisabetsky

Crandon L. medical dialogue and the political economy of medical pluralism: a case from rural
highland Bolivia. Am Ethnol. 1986;13:463–76. https://doi.org/10.1525/ae.1986.13.3.
02a00040.
Elisabetsky E. Sociopolitical, economical and ethical issues in medicinal plant research. J
Ethnopharmacol. 1991;32:235–9. https://doi.org/10.1016/0378-8741(91)90124-V.
Elisabetsky E. Phytotherapy and the new paradigm of drugs mode of action. Scientia et Technica.
2007;33:459–64.
Elisabetsky E, Brum L. Linalool as active component of traditional remedies: anticonvulsant
properties and mechanisms of action. Curare. 2003;26:45–52.
Elisabetsky E, Castilhos ZC. Plants used as analgesics by Amazonian Caboclos as a basis for
selecting plants for investigation. Int J Crude Drug Res. 1990;28:309–20. https://doi.org/10.
3109/13880209009082838.
Elisabetsky E, Amador TA, Albuquerque RR, Nunes DS, do Carvalho Ana CT. Analgesic activity
of Psychotria colorata (Willd. ex R. & S.) Muell. Arg. alkaloids. J Ethnopharmacol. 1995;48:
77–83. https://doi.org/10.1016/0378-8741(95)01287-N.
Elisabetsky E, Brum LF, Souza DO. Anticonvulsant properties of linalool in glutamate-related
seizure models. Phytomed Int J Phytother Phytopharm. 1999;6:107–13. https://doi.org/10.1016/
s0944-7113(99)80044-0.
Elisabetsky, E. Nunes, Domingos S. Central Nervous System Effects of Essential Oil Compounds.
In: K. Husnu Can Baser, Gerhard Buchbauer. (Org.). Handbook of Essential Oils, 3rd edition.
London: Taylor and Francis Group, 2020, v. 1, p. 304–344.
Etkin NL. Perspectives in ethnopharmacology: forging a closer link between bioscience and
traditional empirical knowledge. J Ethnopharmacol. 2001;76:177–82. https://doi.org/10.1016/
s0378-8741(01)00232-x.
Etkin NL, Elisabetsky E. Seeking a transdisciplinary and culturally germane science: the future of
ethnopharmacology. J Ethnopharmacol. 2005;100:23–6. https://doi.org/10.1016/j.jep.2005.05.
025.
Etkin NL, Ross PJ, Muazzamu I. The indigenization of pharmaceuticals: therapeutic transitions in
rural Hausaland. Soc Sci Med. 1990;30:919–28. https://doi.org/10.1016/0277-9536(90)90220-M.
Farnsworth NR. How can the well be dry when it is filled with water? Econ Bot. 1984;38:4–13.
https://doi.org/10.1007/BF02904411.
Fox S, Farr-Jones S, Sopchak L, Boggs A, Nicely HW, Khoury R, Biros M. High-throughput
screening: update on practices and success. J Biomol Screen. 2006;11:864–9. https://doi.org/10.
1177/1087057106292473.
Freymann H, Rennie T, Bates I, Nebel S, Heinrich M. Knowledge and use of complementary and
alternative medicine among British undergraduate pharmacy students. Pharm World Sci.
2006;28:13–8. https://doi.org/10.1007/s11096-005-2221-z.
Gadit AA. Ethnopsychiatry – a review. JPMA. 2003;53:1–6.
Graz B. What is “clinical data”? Why and how can they be collected during field surveys on
medicinal plants? J Ethnopharmacol. 2013;150:775–9. https://doi.org/10.1016/j.jep.2013.08.
036.
Gyllenhaal C, Kadushin MR, Southavong B, Sydara K, Bouamanivong S, Xaiveu M, Xuan LT, Hiep
NT, Hung NV, Loc PK, Dac LX, Bich TQ, Cuong NM, Ly HM, Zhang HJ, Franzblau SG, Xie H,
Riley MC, Elkington BG, Nguyen HT, Waller DP, Ma CY, Tamez P, Tan GT, Pezzuto JM, Soejarto
DD. Ethnobotanical approach versus random approach in the search for new bioactive com-
pounds: support of a hypothesis. Pharm Biol. 2012;50:30–41. https://doi.org/10.3109/13880209.
2011.634424.
Harvey AL, Young LC, Viljoen AM, Gericke NP. Pharmacological actions of the South African
medicinal and functional food plant Sceletium tortuosum and its principal alkaloids. J
Ethnopharmacol. 2011;137:1124–9. https://doi.org/10.1016/j.jep.2011.07.035.
Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in
the genomics era. Nat Rev Drug Discov. 2015;14:111–29. https://doi.org/10.1038/nrd4510.
Ethnopharmacology and the Development of Psychoactive Drug: A Critical Overview 911

Heinrich M. Ethnopharmacology: a short history of a multidisciplinary field of research. In:

Ethnopharmacology. London: Wiley Blackwell; 2015. p. 1–9.
Heinrich M, Lee Teoh H. Galanthamine from snowdrop – the development of a modern drug
against Alzheimer’s disease from local Caucasian knowledge. J Ethnopharmacol. 2004;92:147–
62. https://doi.org/10.1016/j.jep.2004.02.012.
Hong C, Schüffler A, Kauhl U, Cao J, Wu C-F, Opatz T, Thines E, Efferth T. Identification of
NF-κB as determinant of posttraumatic stress disorder and its inhibition by the Chinese herbal
remedy free and easy wanderer. Front Pharmacol. 2017;8 https://doi.org/10.3389/fphar.2017.
00181.
Hopkins AL. Network pharmacology. Nat Biotechnol. 2007;25:1110–1. https://doi.org/10.1038/
nbt1007-1110.
Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4:
682–90. https://doi.org/10.1038/nchembio.118.
Horrobin DF. Modern biomedical research: an internally self-consistent universe with little contact
with medical reality? Nat Rev Drug Discov. 2003;2:151–4. https://doi.org/10.1038/nrd1012.
Houghton PJ, Howes M-J, Lee CC, Steventon G. Uses and abuses of in vitro tests in ethnophar-
macology: visualizing an elephant. J Ethnopharmacol. 2007;110:391–400. https://doi.org/10.
1016/j.jep.2007.01.032.
Hyman SE, Nestler EJ. Initiation and adaptation: a paradigm for understanding psychotropic drug
action. Am J Psychiatry. 1996;153:151–62. https://doi.org/10.1176/ajp.153.2.151.
Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2:e124. https://
doi.org/10.1371/journal.pmed.0020124.
Ioannidis JPA. Meta-research: why research on research matters. PLoS Biol. 2018;16:e2005468.
https://doi.org/10.1371/journal.pbio.2005468.
Jäger. Medicinal plant research: a reflection on translational tasks. In: Ethnopharmacology; 2015.
p. 11–6.
Kenakin T, Bylund DB, Toews ML, Mullane K, Winquist RJ, Williams M. Replicated, replicable
and relevant–target engagement and pharmacological experimentation in the 21st century.
Biochem Pharmacol. 2014;87:64–77. https://doi.org/10.1016/j.bcp.2013.10.024.
Kimmelman J, Mogil JS, Dirnagl U. Distinguishing between exploratory and confirmatory preclin-
ical research will improve translation. PLoS Biol. 2014;12:e1001863. https://doi.org/10.1371/
journal.pbio.1001863.
Ledford H. Medical research: if depression were cancer. Nature. 2014;515:182–4. https://doi.org/
10.1038/515182a.
Linck VM, Ganzella M, Herrmann AP, Okunji CO, Souza DO, Antonelli MC, Elisabetsky
E. Original mechanisms of antipsychotic action by the indole alkaloid alstonine (Picralima
nitida). Phytomed Int J Phytother Phytopharm. 2015;22:52–5. https://doi.org/10.1016/j.
phymed.2014.10.010.
Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev.
2008:CD000448. https://doi.org/10.1002/14651858.CD000448.pub3.
Liu H, Tan L, Huang X, Liao Y, Zhang W, Li P, Wang Y, Peng W, Wu Z, Su W, Yao
H. Chromatogram-bioactivity correlation-based discovery and identification of three bioactive
compounds affecting endothelial function in Ginkgo biloba extract. Molecules. 2018;23:1071.
https://doi.org/10.3390/molecules23051071.
Malcolm BJ, Tallian K. Essential oil of lavender in anxiety disorders: ready for prime time? Ment
Health Clin. 2017;7:147–55. https://doi.org/10.9740/mhc.2017.07.147.
McChesney JD, Venkataraman SK, Henri JT. Plant natural products: back to the future or into
extinction? Phytochemistry. 2007;68:2015–22. https://doi.org/10.1016/j.phytochem.2007.04.032.
Moerman DE. Meaning, medicine, and the “placebo effect,” Cambridge studies in medical anthro-
pology. Cambridge/New York: Cambridge University Press; 2002.
Mullane K, Winquist RJ, Williams M. Translational paradigms in pharmacology and drug discov-
ery. Biochem Pharmacol. 2014;87:189–210. https://doi.org/10.1016/j.bcp.2013.10.019.
912 E. Elisabetsky

Murthy HN, Dandin VS, Park S-Y, Paek K-Y. Quality, safety and efficacy profiling of ginseng
adventitious roots produced in vitro. Appl Microbiol Biotechnol. 2018;102:7309–17. https://
doi.org/10.1007/s00253-018-9188-x.
Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades
from 01/1981 to 09/2019. J Nat Prod. 2020;83:770–803. https://doi.org/10.1021/acs.jnatprod.
9b01285.
Ng QX, Venkatanarayanan N, Ho CYX. Clinical use of Hypericum perforatum (St John’s wort) in
depression: a meta-analysis. J Affect Disord. 2017;210:211–21. https://doi.org/10.1016/j.jad.
2016.12.048.
Nunes DS. Chemical approaches to the study of ethnomedicines. In: Medical resources of the
tropical forest. Columbia University Press; 1996. p. 41–7.
Ogbourne SM, Parsons PG. The value of nature’s natural product library for the discovery of New
Chemical Entities: the discovery of ingenol mebutate. Fitoterapia. 2014;98:36–44. https://doi.
org/10.1016/j.fitote.2014.07.002.
Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs: natural products
and their derivatives. Drug Discov Today. 2016;21:204–7. https://doi.org/10.1016/j.drudis.
2015.01.009.
Rasoanaivo P, Wright CW, Willcox ML, Gilbert B. Whole plant extracts versus single compounds
for the treatment of malaria: synergy and positive interactions. Malar J. 2011;10(Suppl 1):S4.
https://doi.org/10.1186/1475-2875-10-S1-S4.
Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective
drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004;3:353–9. https://doi.
org/10.1038/nrd1346.
Satoh H. Pharmacological characteristics of Kampo medicine as a mixture of constituents and
ingredients. J Integr Med. 2013;11:11–6. https://doi.org/10.3736/jintegrmed2013003.
Shepard GH. Psychoactive plants and ethnopsychiatric medicines of the Matsigenka. J Psychoac-
tive Drugs. 1998;30:321–32. https://doi.org/10.1080/02791072.1998.10399708.
Silva Brum LF, Emanuelli T, Souza DO, Elisabetsky E. Effects of linalool on glutamate release and
uptake in mouse cortical synaptosomes. Neurochem Res. 2001;26:191–4. https://doi.org/10.
1023/a:1010904214482.
Skirycz A, Kierszniowska S, Méret M, Willmitzer L, Tzotzos G. Medicinal bioprospecting of the
Amazon Rainforest: a modern Eldorado? Trends Biotechnol. 2016;34:781–90. https://doi.org/
10.1016/j.tibtech.2016.03.006.
Tian J, Liu Y, Chen K. Ginkgo biloba extract in vascular protection: molecular mechanisms and
clinical applications. Curr Vasc Pharmacol. 2017;15 https://doi.org/10.2174/
1570161115666170713095545.
Verpoorte R. Good practices: the basis for evidence-based medicines. J Ethnopharmacol. 2012;140:
455–7. https://doi.org/10.1016/j.jep.2012.02.033.
Viña D, Serra S, Lamela M, Delogu G. Herbal natural products as a source of monoamine oxidase
inhibitors: a review. Curr Top Med Chem. 2012;12:2131–44. https://doi.org/10.2174/
156802612805219996.
Vineis P, Porta M. Causal thinking, biomarkers, and mechanisms of carcinogenesis. J Clin
Epidemiol. 1996;49:951–6. https://doi.org/10.1016/0895-4356(96)00118-7.
Wang Q. Individualized medicine, health medicine, and constitutional theory in Chinese medicine.
Front Med. 2012;6:1–7. https://doi.org/10.1007/s11684-012-0173-y.
Wang Z-J, Heinbockel T. Essential oils and their constituents targeting the GABAergic system and
sodium channels as treatment of neurological diseases. Mol Basel Switz. 2018;23 https://doi.
org/10.3390/molecules23051061.
Wehling M. Assessing the translatability of drug projects: what needs to be scored to predict
success? Nat Rev Drug Discov. 2009;8:541–6. https://doi.org/10.1038/nrd2898.
Ethnopharmacology and the Development of Psychoactive Drug: A Critical Overview 913

Weisman AG, López SR, Ventura J, Nuechterlein KH, Goldstein MJ, Hwang S. A comparison of
psychiatric symptoms between Anglo-Americans and Mexican-Americans with Schizophrenia.
Schizophr Bull. 2000;26:817–24. https://doi.org/10.1093/oxfordjournals.schbul.a033496.
Willcox ML, Graz B, Falquet J, Diakite C, Giani S, Diallo D. A “reverse pharmacology” approach
for developing an anti-malarial phytomedicine. Malar J. 2011;10(Suppl 1):S8. https://doi.org/
10.1186/1475-2875-10-S1-S8.
Wu C, Lee S-L, Taylor C, Li J, Chan Y-M, Agarwal R, Temple R, Throckmorton D, Tyner
K. Scientific and regulatory approach to botanical drug development: A U.S. FDA perspective.
J Nat Prod. 2020;83:552–62. https://doi.org/10.1021/acs.jnatprod.9b00949.
Zhu H-L, Wan J-B, Wang Y-T, Li B-C, Xiang C, He J, Li P. Medicinal compounds with
antiepileptic/anticonvulsant activities. Epilepsia. 2014;55:3–16. https://doi.org/10.1111/epi.
12463.
Antidepressants: Molecular Aspects of
SSRIs

Adeline Etievant, Nasser Haddjeri, and Thorsten Lau

Contents
Citalopram Versus S-Citalopram: Molecular Insights into Antidepressant Treatment . . . . . . . . 916
SSRI’s Mode of Action: Targeting the Serotonin Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917
Citalopram Binding Properties Underlying the Antidepressant Response . . . . . . . . . . . . . . . . . 919
Citalopram-SERT Interaction at the Cellular Level: Regulation of SERT Cell
Surface Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
Modulation of SERT Binding Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
Effect of 5-HT on Citalopram Modulation of SERT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925
Kinase’s Modulation of SERT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 926
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928

A. Etievant
Integrative and Clinical Neurosciences EA481, University of Bourgogne Franche-Comté,
Besançon, France
e-mail: adeline.etievant@univ-fcomte.fr; adeline.etievant@gmail.com
N. Haddjeri
Stem Cell and Brain Research Institute, INSERM, U1208, Bron, France
Université de Lyon, Université Lyon 1, Lyon, France
e-mail: nasser.haddjeri@inserm.fr
T. Lau (*)
Central Institute of Mental Health, Department of Translational Brain Research, Medical Faculty
Mannheim; Heidelberg University, Hector Institute for Translational Brain Research, Mannheim,
Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
e-mail: thorsten.lau@zi-mannheim.de

© Springer Nature Switzerland AG 2022 915

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_369
916 A. Etievant et al.

Abstract
Major depressive disorders are among the most common psychiatric diseases
featuring an insufficient serotonin signaling as the most prominent core patho-
mechanism. Therefore, selective serotonin re-uptake inhibitors are firstly
employed to restore serotonin neurotransmission in depressed patients. One
member of this class of antidepressants, which selectively targets the serotonin
transporter, is citalopram. Citalopram was first synthesized in 1972 and consists
of equal molecular amounts of the isomers R-citalopram and S-citalopram,
generally referred to as escitalopram, which exerts the antidepressant effect.
Underlying citalopram’s mode of action is an allosteric mechanism, by which
citalopram modulates its own binding to the primary binding site at the serotonin
transporter. The following chapter will provide an overview of recent findings on
the molecular binding characteristics determining citalopram’s docking to the
serotonin transporter and the allosteric modulation of the citalopram-induced
antidepressant response. Here, the focus will be on the acute citalopram-induced
effects, which result in dose-dependent internalization of serotonin transporter
molecules and diminished neuronal activity of serotonergic neurons.

Citalopram Versus S-Citalopram: Molecular Insights into

Antidepressant Treatment

Major depressive disorder is one of the most common mental disorders, and according
to a report made by the World Health Organization, in 2015 about 300 million people
suffered from this disease worldwide. Suffering from depression may become a
serious health threat, especially when depression symptoms persist and turn into
long-term burden with moderate or even severe intensities. A more threatening
situation is caused by the lethal outcome of depression: roughly a million people of
patients diagnosed with depression commit suicide each year, which actually is the
second leading cause of death in people aged 15–30 years (World Health Organization
2017). Furthermore, based on the projections of a steadily increasing numbers of
patients, MDD will be the most common disease by the year 2030 (Mathers and
Loncar 2006). Although various treatment options in terms of pharmacological inter-
vention are available, two major problems still remain: (1) there is a significant number
of patients, which does not respond to antidepressant pharmacotherapy and suffer from
chronic and refractory form of depression, and (2) there is a delayed onset of beneficial
antidepressant response in patients that may last up to 2 months (Berton and Nestler
2006; Stahl et al. 2013; Gibbons et al. 2012; Akil et al. 2018).
Up to date, the pathophysiology of depression is poorly understood, and the
interaction of the relation of identified core patho-mechanisms is not well-known.
The most postulated hypotheses focus on dysfunctions of the hypothalamic-pitui-
tary-adrenal axis, immunological disturbances, or altered monoaminergic neuronal
systems. With regard to impaired monoaminergic neurotransmission, diminished
and insufficient serotonin (5-hydroxytryptamine, 5-HT) signaling was identified to
Antidepressants: Molecular Aspects of SSRIs 917

be a main feature of depression (Boku et al. 2018; Dell’Osso et al. 2016; Kraus et al.
2017; Nestler et al. 2002; Robson et al. 2017; Yu et al. 2008). 5-HT signaling is
maintained by serotonergic neurons, which are located in the raphe nuclei.
From here, these neurons give rise to an extensive axonal network, building
projections into different brain regions, such as prefrontal cortex or hippocam-
pus, and providing a constant 5-HT tonus inside the innervated brain regions
(Törk 1990; Hornung 2003; Puig and Gulledge 2011; Quentin et al. 2018; Vizi
2000). One major approach in antidepressant pharmacotherapy is to restore 5-
HT signaling by employing selective serotonin re-uptake inhibitors (SSRI).
These molecules primarily target and functionally inhibit the serotonin trans-
porter (SERT), which plays a key role in serotonergic neurotransmission: its
uptake activity terminates 5-HT signaling and thereby determines duration of
strength of 5-HT receptor activation (Chen et al. 2004, 2005). Upon binding to
their targets, SSRI prevent SERT-dependent 5-HT re-uptake into serotonergic neu-
rons. An acute functional consequence of re-uptake inhibition is the increase of
extracellular 5-HT, which is now able to prolong the activation of 5-HT receptors
and thereby enhance 5-HT signaling (Haenisch and Bonisch 2011; Morrissette and
Stahl 2014). Over the past decades, a number of SSRI were developed as a first
choice antidepressant therapy, including fluoxetine, sertraline, and citalopram, which
was first synthesized by Klaus Bogeso in 1972 (Bogeso and Sánchez 2012; Bigler et
al. 1977). The following chapter will start with a brief overview of SSRI’s
molecular impact on 5-HT signaling and then focus on citalopram-SERT interac-
tion on the cellular level, addressing citalopram-induced SERT internalization and
the allosteric modulation of SERT function.

SSRI’s Mode of Action: Targeting the Serotonin Transporter

Like other monoamine transporters in their respective signaling pathways,

SERT plays a central role in serotonergic neurotransmission and represents a
highly potential molecular target for clinically effective antidepressants, includ-
ing SSRI (Blakely and Bauman 2000; Canli and Lesch 2007; Murphy and Lesch
2008; Rudnick 2006). The first and initial step in SSRI’s mode of action is the
binding to SERT molecules, which are localized at the cell surface of serotonergic
neurons (Fig. 1). Thereby, SSRI inhibit SERT-dependent re-uptake of 5-HT back
into serotonergic neurons and prolong 5-HT signaling (Nemeroff 1998; Coyle and
Duman 2003; Schloss and Henn 2004). SSRI-dependent inhibition of SERT is
assumed to elevate 5-HT signaling via enhanced activation of postsynaptic 5-HT
receptors. The second phase of SSRI activity is the delayed and adaptive processes,
which include (1) the downregulation of available functional SERT molecules at the
cell surface of serotonergic neurons (Benmansour et al. 2002; Kittler et al. 2010;
Matthäus et al. 2016), (2) the desensitization of 5-HT receptors (Mnie-Filali et al.
2007; Morrissette and Stahl 2014; Stahl 1998), and (3) beneficial effects on the
impaired or damaged neuronal plasticity during the progression of major depressive
disorder (Duric and Duman 2013; Morrissette and Stahl 2014). The SSRI-induced
918 A. Etievant et al.

Fig. 1 Effect of acute citalopram treatment on neuronal activity and SERT availability in 5-
HT neurons. Acute application of citalopram (C) results in binding to and inhibition of SERT
molecules located at the cell surface of serotonergic neurons, thereby elevating extracellular
bioactive 5-HT concentrations (S). 5-HT is now able to enhance stimulation of 5-HT autoreceptors
(R) expressed on serotonergic neurons, which are postulated to differentially modulate 5-HT
neuronal activity. Here, 5-HT 1A autoreceptors (1A) play a central role, as their activation leads
to subsequent inhibition of 5-HT release. Regarding the availability of SERT molecules, citalopram-
SERT interaction triggers the internalization of SERT molecules (+), shifting the kinase-regulated
shuttling of SERT to and from the cell surface toward retrograde trafficking. Extra: extracellular;
intra: intracellular

retrograde SERT trafficking that occurs during the second phase seems to be a time-
and concentration-dependent event. Overall, the redistribution of SERT to internal
compartments during acute SSRI treatment reduces the amount of SERT molecules
that takes up 5-HT after release and thereby further enhances 5-HT signaling
(Benmansour et al. 2002; Kittler et al. 2010; Matthäus et al. 2016). The increased
5-HT levels also act on 5-HT autoreceptors, namely, 5-HT receptor 1A (5-HTR1A)
and putatively 5-HT receptor 2B (5-HTR2B), which are key molecules of the
autoregulatory feedback loop of serotonergic neuronal activity (Blier et al. 1998).
In general, activation of 5-HTR1A autoreceptors inhibits neuronal 5-HT firing
activity inside the dorsal raphe nuclei; indeed, acute antidepressant treatment was
shown to cause a shutdown of 5-HT release (Aghajanian et al. 1970; Piñeyro and
Blier 1999; Courtney and Ford 2016; Mnie-Filali et al. 2016; El Mansari et al. 2005).
Similarly, acute administration of citalopram, as well as its isomer S-citalopram,
suppresses the neuronal activity of serotonergic neurons via activation of 5-HTR1A.
Furthermore, prolonged administration of both substances diminished the spontane-
ous neuronal firing activity of serotonergic neuron. The diminished activity recov-
ered after desensitization of somatodendritic 5-HTR1A, which took 2 weeks in case
of S-citalopram treatment, yet needed one additional week to fully recover in case of
using the racemate citalopram for antidepressant treatment (El Mansari et al. 2005).
In contrast to 5-HTR1A autoreceptors, evidence for a positive modulation of 5-HT
signaling by 5-HTR2B autoreceptors was recently provided in mice (Belmer et al.
2018) but apparently not in rat (Cathala et al. 2019), leaving the question
Antidepressants: Molecular Aspects of SSRIs 919

unanswered whether 5-HT2B autoreceptors may interfere with 5-HTR1A’s potential

to diminish 5-HT release. In summary, the SSRI-dependent inhibition of SERT
function, increasing extracellular 5-HT concentrations, not only enhances signaling
received by postsynaptic neurons but also affects the activity of autoreceptors and
thereby neuronal activity of serotonergic neurons itself. These mechanisms provide
the cornerstone for the hypothesis of autoreceptor-dependent delay of clinical
efficacy shown by established antidepressant pharmacotherapy. As for all SSRI
available, citalopram treatment may enhance the activation of 5-HTR1A auto-
receptors, which in turn results in a diminished 5-HT release and thereby negatively
affects an efficient antidepressant response (Blier and de Montigny 1994; Celada et
al. 2013; Richardson-Jones et al. 2010).

Citalopram Binding Properties Underlying the Antidepressant

Response

Citalopram is an antidepressant of the SSRI class, composed by equal molecular

amounts of the isomers S-citalopram, generally referred as escitalopram, and R-
citalopram. The ligand binding characteristics of citalopram’s isomers produce
differential effects on SERT function and thereby molecular mechanism underlying
antidepressant responses. Of both isomers, S-citalopram exhibits a higher efficacy
and faster onset of antidepressant responses triggered by inhibition of SERT-depen-
dent 5-HT uptake, whereas R-citalopram rather diminishes escitalopram’s antide-
pressant potential. Indeed, compared to R-citalopram, S-citalopram displays a 50-
fold higher affinity to SERT (Chen et al. 2005; Sánchez and Kreilgaard 2004;
Sanchez 2006; Zhong et al. 2009). Noteworthy, R-citalopram was shown to present
a slower clearance than escitalopram, explaining in part the observed superiority of
escitalopram versus citalopram in clinic (Kasper et al. 2009; Montgomery et al.
2011).

Modulation of SERT Binding Sites

Studies investigating the molecular properties of citalopram’s binding to and disso-
ciation from SERT identified two different binding sites which can mutually influ-
ence citalopram’s mode of action when both binding sites are occupied (Fig. 2).
Moreover, this mutually dependent influence varies in strength and manner
depending on the SSRI used (Cipriani et al. 2009). The characterization of
citalopram-SERT interaction revealed the existence of a high-affinity primary (ortho-
steric) binding site, called S1 binding site, and a low-affinity secondary (allosteric)
binding site, called S2 binding site (Sanchez 2006), which was recently confirmed
by X-ray structure crystallography analysis of citalopram docking to human SERT at
the primary and allosteric binding sites (Coleman et al. 2016; Topiol et al. 2017). In
the recent years, a number of studies provided valuable insights in uncovering the
molecular basis of SSRI binding to SERT and identifying the localization of binding
pockets and participating amino acid residues. With the help of X-ray crystallogra-
phy analysis of citalopram-bound SERT, the primary binding site was located
920 A. Etievant et al.

Fig. 2 Schematic representation of the mechanism of action of S-citalopram (S-cit) on the 5-

HT transporter. (a) Basal condition: illustration of the allosteric (S2) and the orthosteric (primary
S1) binding sites and of the molecules of 5-HT in both intra- and extracellular compartments of the
5-HT neuron. (b) When the two enantiomers are present, S-cit binds primarily to the S1 site, while
R-citalopram (R-cit) binds only to S2. The activity of inhibition of re-uptake of 5-HT is comparable
to other SSRIs. (c) When only the S-cit is present, the two carrier binding sites are occupied by this
ligand. S-cit binds with high affinity to the S2 and positively modulates his own binding to the S1,
resulting in a stronger inhibition of re-uptake of the 5-HT. (d) R-cit, in double concentration, is able
to counteract the effect of S-cit on SERT. (Modified from Mnie-Filali et al. 2007)

between the transmembrane helices 1, 3, 6, 8, and 10 (Coleman et al. 2016). Four of

these domains, transmembrane domains 1, 3, 6, and 8, are essential for the formation
of the 5-HT binding pocket, with the amino acids Tyr95, Asn177, and Thr439
implied to directly interact with the substrate (Penmatsa et al. 2013; Adkins et al.
2001; Celik et al. 2008; Koldso et al. 2010). An analysis of the molecular docking
characteristics inside the 5-HT-SERT complex showed that ionic interaction of
ligand and amino acid residues at transmembrane helices 6 and 8 as well as with
those of the intracellular loop 1 may be of high relevance for 5-HT translocation
through SERT (Gabrielsen et al. 2012).
According to the X-ray crystallography study performed by Coleman and col-
leagues, citalopram’s binding to the S1 site by SSRI directly inhibits the binding of
5-HT to SERT, blocking the neurotransmitter’s re-uptake (Coleman et al. 2016).
Regarding the relevance for citalopram binding inside this important region, the
Antidepressants: Molecular Aspects of SSRIs 921

amino acid residues Asp98, Ile172, and Ser438 were identified for citalopram-SERT
interaction and additionally implied Asn177 to be important for escitalopram-medi-
ated SERT inhibition (Barker et al. 1999, 1998; Henry et al. 2006; Andersen et al.
2009). Regarding its binding to SERT, a study suggested that citalopram adjusts its
docking position with an orientation of the cyano group locating inside the trans-
porter protein to most likely interact with Val343, while the fluorine group is
spatially orientated toward Ile172, Ala173, and Asn177 (Andersen et al. 2010).
Another study addressing the ligand binding characteristics of citalopram-SERT
interaction revealed that the fluorine atom of S-citalopram is located in the proximity
of the amino acid residues Ala173 and Thr439, while the cyano group is proximally
orientated toward the residue of Phe341. For R-citalopram binding to SERT, the
orientation of these groups was found to be in the reversed orientation (Koldso et al.
2010). The recent study by Coleman and colleagues, which analyzed molecular
binding characteristics with the help of X-ray crystallography of human SERT,
identified three subsites regarding the S1 binding site for S-citalopram binding
(Coleman et al. 2016). The residues of Tyr95, Asp98, Tyr176, Ile172, and Phe341
were identified to establish the S1 subsite A, with the latter three residues most likely
providing interaction partners for the hydrophobic groups of S-citalopram and other
antidepressants. The S1 subsite B, a hydrophobic cavity built by the residues of
Ala169, Ala173, Ser439, and Leu443, was identified to be of high importance for S-
citalopram’s high-affinity binding, and to be a signature structure of human SERT,
which is not found in other monoamine transporters. Finally, the residues Phe335,
Thr497, and Val501 form S1 subsite C, which provides a nonpolar/polar region for
interaction of S-citalopram’s fluoro and cyano groups. Compared to the findings
reported using two different docking models based on the leucine transporter
(Andersen et al. 2010), Coleman and colleagues did not identify the residues
Asn177 and Val 343 to be involved in S-citalopram binding to human SERT. Yet
both approaches identified an overlapping set of amino residues to be important
determinants of citalopram docking to SERT. Interestingly, in transgenic mice
carrying a single isoleucine to methionine substitution (I172M), an amino acid
exchange directly affecting the biochemical characteristics of the S1 binding site,
an extremely diminished inhibitory efficacy of multiple antidepressant agents was
observed, including citalopram (Thompson et al. 2011; Henry et al. 2006).

The Allosteric Binding Site

The allosteric site was localized to the periphery of the extracellular vestibule
surrounded by the extracellular loops 4 and 6 as well as the transmembrane helices
1, 6, 10, and 11. Two studies employing humanized SERT transgenic animals have
featured a deletion of the allosteric binding site. The amino acid residues identified
and modified in these studies in order to abolish the allosteric binding site were
A505V, L506F, I507L, S574T, and I575T (Jacobsen et al. 2014; Murray et al. 2016).
In addition to the detailed analysis of the primary S1 binding site, the X-ray-based
crystallography analysis of S-citalopram-SERT interaction also comprised the
molecular localization of the allosteric S2 binding site (Coleman et al. 2016).
Here, the allosteric binding site was located to the extracellular loops 4 and 6 and
922 A. Etievant et al.

the transmembrane domains 1, 6, 10, and 11, regions identical to those carrying the
amino acid exchanges for the transgene allosteric site-missing animal models.
However, the binding studies have revealed different interacting residues for S-
citalopram docking to the allosteric site. The residues of Ala331, Gln332, and
Phe556 most likely establish a groove and interaction domains for S-citalopram’s
fluoro group, while the extracellularly located amino acids Arg104, Asp308, and
Glu494 provide interaction partners for the cyano group. Although the amino acid
exchanges in the animal models affect different amino acid residues, the exchanges
may most likely alter the biochemical surroundings for efficient citalopram-SERT
interaction at the allosteric S2 binding site. Interestingly, Anderson and colleagues
were not able to detect robust docking kinetics of S-citalopram to the allosteric
binding site in both kinetic models applied in their study (Andersen et al. 2010).
Recently, Zhu and colleagues employed atomic force microscopy to gain further
insight on citalopram’s binding characteristics on the molecular level. In their study,
two SERT binding sites for citalopram were identified, providing physical evidence
for the existence of the S1 and S2 binding sites (Zhu et al. 2018).
The binding of citalopram to the allosteric site is thought to affect citalopram’s
affinity for binding to the primary S1 site (Fig. 2; Zhong et al. 2012a, b). The
structural-conformational analysis of citalopram binding to the allosteric S2 site
revealed that occupation of the allosteric site results in a spatial barrier that prevents
ligands to dissociate from the primary S1 site. The interaction with both binding sites
is thought to cause the superior antidepressant effect of S-citalopram compared to
racemic citalopram. For the racemic citalopram, R-citalopram’s binding to the
allosteric binding site of SERT is thought to antagonize S-citalopram binding to
the primary binding site SERT (Coleman et al. 2016; Sanchez 2006; Zhong et al.
2009). There are a number of studies that provide evidence for the hypothesis that R-
citalopram negatively influencing S-citalopram-SERT binding efficacy by an allo-
steric mechanism (Zhong et al. 2012a). On the molecular level, R-citalopram’s
antagonistic effect is assumed to depend on the binding to the low-affinity allosteric
S2 site which affects escitalopram binding to the high-affinity orthosteric S1 site. In
the absence of R-citalopram, escitalopram binds to the allosteric binding site and
thereby enhances its own binding to the orthosteric binding site. The latter would
result in a stronger inhibition of 5-HT uptake and enhanced 5-HT signaling, while R-
citalopram interference via S2 binding would diminish S-citalopram binding to S1
and thereby resulting in an incomplete block of the 5-HT binding pocket (Plenge et
al. 2007; Sanchez 2006; Zhong et al. 2012a). Experimental animal studies success-
fully demonstrated that R-citalopram is able to antagonize escitalopram’s antide-
pressant action using chronic mild stress paradigms (Sánchez et al. 2003), to abolish
escitalopram-enhanced 5-HT signaling (Mansari et al. 2007; Mork et al. 2003), and
to suppress acute escitalopram-mediated neuronal firing of dorsal raphe serotonergic
neurons (El Mansari et al. 2005; Mansari et al. 2007; Mnie-Filali et al. 2007). In
addition, tomography studies demonstrated R-citalopram’s ability to bind human
SERT (Klein et al. 2006; Lundberg et al. 2007), most likely also contributing to
initial 5-HT re-uptake inhibition, and that R-citalopram’s antagonizing effect is most
likely caused by chronic treatment with the racemate citalopram (Klein et al. 2007).
Antidepressants: Molecular Aspects of SSRIs 923

Modulation of Allosteric Binding Site

While on the molecular level, the phenomenon of R-citalopram interference with S-
citalopram binding to SERT is rather an allosteric modulation of S-citalopram binding
than direct competing for S1 binding, on the cellular level, there is evidence that
protein kinases are involved in the allosteric modulation of SERT function. For
example, the inhibition of protein kinase C activity annihilates R-citalopram’s
counteracting effect on S-citalopram-induced suppression of 5-HT neuronal firing
and SERT internalization (Mnie-Filali et al. 2016). However, observations made in
transgenic models featuring dysfunctional allosteric S2 sites, including disabled allo-
steric S2-sites in human SERT, are differing to these observations. Although both
models employ a different set of amino acid exchanges to provide a loss of S2 binding
characteristics required for efficient docking, the respective transgenic animals
exhibited a normal 5-HT physiology. Neither the lack of the allosteric S2 site nor R-
citalopram treatment did affect extracellular 5-HT concentrations. Furthermore, rela-
tively minor behavioral effects were observed using clinically relevant S-citalopram
treatment, which seemed to be enhanced by additional R-citalopram treatment
(Jacobsen et al. 2014; Murray et al. 2016). Conversely, these studies failed to provide
evidence for R-citalopram’s antagonizing effects on S-citalopram’s action, which was
proposed by experimental data found in in vitro studies (Zhong et al. 2009).

Effect of 5-HT on Citalopram Modulation of SERT

Actually, the administration of SSRI is shown to reduce the neuronal firing rate of
serotonergic neurons in the dorsal raphe nuclei, consequently resulting in diminished
extracellular 5-HT concentrations (Mansari et al. 2007; El Mansari et al. 2005;
Matthäus et al. 2016). S-citalopram as well as the racemate citalopram significantly
diminished the firing activity of serotonergic neurons in the dorsal raphe nuclei, and
both effects were countered by application of R-citalopram (El Mansari et al. 2005).
In transgenic mice carrying a heterozygous SERT knockout, 48 h of escitalopram
treatment resulted in 60% decrease of serotonin neuronal firing rate in the dorsal
raphe nuclei compared to 70% reduction of neuronal activity observed in wild-type
animals. In this study, prolonged S-citalopram exposure for 21 days resulted in a
recovery of neuronal firing rates exclusively in wild-type animals (Guiard et al.
2012). Furthermore, using the transgenic S2 site-deficient human SERT mouse
model of Jacobsen and colleagues, compared to wild-type human SERT expressing
mice, a significant slower reduction of neuronal firing activity was demonstrated in
the dorsal raphe nuclei of mutated mice. This differential effect on neuronal firing
was not observed using either paroxetine or sertraline to inhibit SERT (Matthäus et
al. 2016). These observations not only provide evidence for S-citalopram affecting
its own binding to the orthosteric binding site but also for the importance of SERT
availability at the cell surface regarding establishing 5-HT signaling during the
antidepressant response. In case of the allosteric modulation, the presence of a
functional S2 site seems to enhance an S-citalopram-mediated increase of extracel-
lular 5-HT levels. This in turn enhances 5-HTR1A activation and thereby diminishes
5-HT release. This would be in line with the hypothesis of S-citalopram’s enhance-
ment of its own binding efficacy to the primary S1 site by occupation of the S2 site
924 A. Etievant et al.

(Sanchez 2006; Zhong et al. 2009). Similarly, diminished SERT availability may
also result in enhanced 5-HTR1A activity and subsequent reduced 5-HT release.
In conclusion, the discrepant results observed in rodent models may be based on
species-specific differential functional regulation of rodent and human SERT.
Research approaches may overcome this obstacle by employing humanized rodent
models, for example, as in the studies by Jacobsen or Matthäus and colleagues
(Jacobsen et al. 2014; Matthäus et al. 2016), which provides the cornerstone for
pharmacological analysis of human SERT by means of experimental approaches
normally restricted to animal models. Furthermore, such experimental approaches
may be supported by complementary murine or human stem cell-derived serotonergic
neurons that contribute to understand citalopram’s mode of action on a cellular level.

Citalopram-SERT Interaction at the Cellular Level: Regulation of

SERT Cell Surface Exposure

Modulation of SERT Binding Sites

Upon binding to SERT and inhibition of 5-HT re-uptake, citalopram subsequently

induces internalization of transporter molecules to intracellular compartments
(Thompson et al. 2011; Lau et al. 2009; Matthäus et al. 2016; Oz et al. 2010). The
analysis of SERT cell surface localization in in vitro-generated stem cell-derived
serotonergic neurons showed that S-citalopram more strongly induced SERT redis-
tribution away from the cell surface compared to the racemate citalopram (Matthäus
et al. 2016). Interestingly, R-citalopram, although characterized by a lower affinity to
the S1 binding site (Sanchez 2006; Zhong et al. 2009), leads to a reduction of SERT
molecules on the neuronal cell surface when applied at high doses, yet not as
efficient as observed after application of S-citalopram or the racemate citalopram.
In line with previous reports showing that R-citalopram negatively affects the
association of S-citalopram to SERT and thereby enhances its dissociation from
the transporter (Mansari et al. 2007; Zhong et al. 2009), R-citalopram was shown to
interfere with the efficient S-citalopram-induced SERT internalization (Matthäus et
al. 2016). In transgenic models featuring an ablation of the S2 binding site in human
SERT, different observations were found. Here, R-citalopram failed to affect S-
citalopram-enhanced 5-HT concentrations in transgenic mice (Jacobsen et al.
2014). On the cellular level, in the absence of a functional S2 binding site, R-
citalopram on its own was capable to induce SERT redistribution from the cell
surface of stem cell-derived serotonergic neurons with a similar efficacy as observed
with S-citalopram (Matthäus et al. 2016). The differential citalopram-dependent
effects on SERT internalization in vitro are reflected by earlier findings of SERT
availability in vivo. A PET study used equimolar doses of S-citalopram and a
racemic mixture of R- and S-citalopram to compare the effect on SERT occupancy
by radioligand binding in the human brain (Lundberg et al. 2007). Here, compared to
the combination of R- and S-citalopram, S-citalopram application on its own resulted
in less SERT availability in various brain regions. The inhibition constant for
Antidepressants: Molecular Aspects of SSRIs 925

radioligand binding to SERT was significantly stronger in case of the S-citalopram

application, and SERT occupancy numerically reduced depending on the brain
region observed. In accordance with other findings, this study shows that SERT is
differentially regulated by the citalopram racemate, with S-citalopram on its own
having a most likely stronger effect on SERT inhibition and cell surface exposure as
compared to the combination of R- and S-citalopram. Interestingly, analyzing
citalopram’s allosteric regulation of SERT in vivo, the elimination of the allosteric
S2 binding site, albeit a distinct allosteric-null mutant from the group of Jacobsen et
al. (2014), did not result in alterations of hippocampal extracellular 5-HT concen-
trations in S-citalopram-treated transgenic animals and only revealed modest effects
in behavioral experiments in case of using ten times higher S-citalopram concentra-
tions compared to wild-type mice (Murray et al. 2016). Accordingly, the authors
concluded that clinically relevant concentrations for S-citalopram, and used for the
behavioral and metabolic analysis in their study, may be too low to trigger significant
allosteric effects observed in vitro.

Effect of 5-HT on Citalopram Modulation of SERT

In the neuronal surroundings, where citalopram-SERT interaction takes place, SERT’s

natural ligand 5-HT itself is present. Consequently, one may be interested in finding
out how 5-HT may affect citalopram-SERT interaction. To understand both 5-HT and
citalopram binding characteristics, molecular docking studies are of high importance.
Comparison’s study of 5-HT and S-citalopram binding to SERT revealed that 5-HT
and citalopram share the ability to lock onto SERT’s S1 as well as S2 binding domain
by 5-HT/S-citalopram hybrid binding (Topiol et al. 2016). Moreover, several in vitro
studies demonstrate that 5-HT itself caused a reversible dose- and time-dependent
reduction of SERT activity and its localization at the cell surface (Iceta et al. 2008;
Kittler et al. 2010; Jørgensen et al. 2014). In combination with citalopram or fluoxe-
tine, 5-HT application proved to be additive to SSRI-dependent SERT inhibition, yet
this effect was only observed at low concentrations of both SSRI. Conversely, applied
in the presence of higher concentrations, 5-HT showed no enhancement on diminished
SERT activity (Iceta et al. 2008). However, the detailed information on the interacting
mechanisms of 5-HT, citalopram’s isomers, most of all the antidepressant-effective S-
citalopram, and SERT still remain elusive. Recently, a study employing fast-scan
cyclic voltammetry to measure 5-HT release and re-uptake in vivo showed that
acute treatment with different doses of S-citalopram resulted in a rapid increase of 5-
HT release in serotonergic projection areas. The voltammetric recordings also showed
that during acute S-citalopram administration, 5-HT re-uptake was gradually raised
(Wood and Hashemi 2013). Of note, citalopram’s metabolite, desmethylcitalopram,
was shown to retain its selectivity for SERT binding and being still able to inhibit
SERT-dependent 5-HT re-uptake. Even more, desmethylcitalopram accumulated in
the brain (Krout et al. 2017) and thereby may contribute on one side to the antide-
pressant response and on the other side to increasing concentrations of SERT antag-
onists in chronic citalopram treatment.
926 A. Etievant et al.

Kinase’s Modulation of SERT

Overall, the experimental data on initial inhibition and subsequent internalization of

SERT molecules indicate that citalopram’s antidepressant response is limited to a
specific dose- and time-dependent optimum. Most likely, falling short to meet the
optimal window of the antidepressant response results in less beneficial or even
potentially non-antidepressant effects. In order to further characterize citalopram-
SERT interaction and subsequently triggered cellular responses, it is also important
to understand SERT’s physiological regulation. SERT localization and function at the
cell surface is controlled by kinase activity-dependent anterograde and retrograde
trafficking. Cell surface-located proteins, including neurotransmitter transporters and
receptors, are regulated by various kinase signaling pathways with p38 mitogen-
activated protein kinase (MAPK) and protein kinase C (PKC) being at the helm. For
SERT, activation of PKC activity rapidly reduces SERT cell surface localization,
which is reflected by a decreased 5-HT uptake (Qian et al. 1997; Ramamoorthy et
al. 1998; Haase et al. 2001; Jayanthi et al. 2005; Carneiro and Blakely 2006). In
accordance to these observations, inhibition of p38 MAPK resulted in diminished
SERT cell surface exposure and consequently reduced 5-HT uptake, while activation
of p38 MAPK yielded enhanced 5-HT uptake levels (Samuvel et al. 2005; Prasad et al.
2005). Recently, a live cell imaging study using a fluorescent ligand for SERT showed
that acute or prolonged citalopram exposure decreased SERT-dependent uptake of the
fluorescent substrate in a similar way as observed for PKC activation, both observa-
tions in line with citalopram-dependent inhibition and subsequent SERT internaliza-
tion. As observed before in studies on kinase-regulated SERT cell surface localization,
p38 MAPK activation lead to an increase in fluorescence ligand uptake (Oz et al.
2010). Hence, a study focused on the involvement of protein kinases in the allosteric
modulation of SERT in vivo and provided a first insight into potential kinase activity
underlying allosteric modulation of SERT function. Using a rodent model, it was
shown that acute R-citalopram administration interfered with S-citalopram-induced
inhibition of 5-HT neuronal activity (Mnie-Filali et al. 2016). In addition, the behav-
ioral analysis showed that acute R-citalopram treatment also prevented an increase in
head twitches caused by L-5-hydroxytryptophan injections, a rodent behavior which
results from an enhanced monoaminergic neurotransmission (Kim et al. 1998). The
systemic application of the nonselective protein kinase inhibitor staurosporine negated
the effects on 5-HT neuronal activity as well as on head twitching caused by acute
R-citalopram application. Furthermore, the study demonstrated that activation of
protein kinase C signaling by phorbol-12-myristate-13-acetate (PMA) directly
abolished the preventive effect of staurosporine on 5-HT neuronal activity. On the
cellular level, this study compared the effect of the kinase inhibitor staurosporine on
R- and S-citalopram-induced SERT internalization in vitro, with R-citalopram show-
ing slight internalization of SERT molecules and S-citalopram leading to a strong
removal of SERT molecules from the cell surface. In case of single treatments, as well
as for the combination of R- and S-citalopram, staurosporine altered all effects on
SERT internalization (Mnie-Filali et al. 2016). Interestingly, using fast-scan cyclic
Antidepressants: Molecular Aspects of SSRIs 927

voltammetry technic, it has been shown that acute citalopram treatment resulted in
frequency-dependent increases of evoked 5-HT release that required SERT expression
(Dankoski et al. 2016). Therefore, if protein kinase signaling is involved in citalopram-
SERT interaction by regulating SERT trafficking to and from the cell surface, one also
has to consider SERT expression levels, which represent the very beginning of SERT
availability. Indeed, a study using transgenic mice that feature either a heterozygous or
homozygous SERT deletion showed an age-dependent response to S-citalopram
treatment linked to SERT expression levels (Mitchell et al. 2016). SERT expression
changed during the age of the mice, steadily increasing from postnatal to adult stages.
However, the binding kinetics remained unchanged, indicating that SERT expressed in
postnatal and adolescent brain stages displays similar pharmacological characteristics
compared to SERT expressed in adult brain stages. Therefore, at constant S-citalopram
concentrations, the strongest antidepressant effect in wild-type and heterozygous
SERT mice was observed during early stages, up to 4 weeks after birth, while
SERT-depleted mice did not show antidepressant responses.

Summary

Citalopram’s binding kinetics to SERT depend on the interaction to the amino acid
residues establishing the orthosteric (primary) S1 binding site and the allosteric S2
binding site. The superior antidepressant efficacy of citalopram’s isomer S-
citalopram compared to the racemate itself is attributed to the lacking allosteric
modulation by the isomer R-citalopram. Upon acute exposure, citalopram and S-
citalopram both result in elevation of bioactive 5-HT concentrations. On one side,
this affects the neuronal activity of serotonergic neurons, suppressing 5-HT release
predominantly due to enhanced activation of 5-HT1A autoreceptors. On the other
side, protein kinase-dependent SERT shuttling to and from the cell surface is
shifted toward internalization of SERT molecules, enhancing SERT’s retrograde
trafficking. Both events present the first steps in citalopram-induced antidepressant
response, similar to molecular events triggered by acute exposure to other SSRI.
Especially, the interference with 5-HT neuronal activity is considered to add to the
already dysfunctional 5-HT signaling under disease conditions and provide the
cornerstone for the hypothesis of autoreceptor-dependent delay of clinical efficacy
shown by established antidepressant pharmacotherapy. Up to date, many interac-
tions driving 5-HT autoregulatory feedback loops maintained by 5-HT auto-
receptor and SERT activity are not well understood, particularly under complex
pathological conditions. In order to identify new and more efficient antidepres-
sants, a more detailed insight into SSRI’s potential to interfere with physiological
molecular and cellular processes is fundamental. Major depressive disorders were
too long to be considered as synaptopathies, addressing how 5-HT dysfunction
affects synaptic plasticity, while neglecting the putative role of 5-HT signaling, and
SSRI-dependent modulation of 5-HT signaling, in intrinsic, cellular, and circuit
changes.
928 A. Etievant et al.

Cross-References

▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and

Resistance to Therapy
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Neurobiological Principles: Neurotransmitters
▶ Pharmacokinetic and Pharmacodynamic Principles

References
Adkins EM, Barker EL, Blakely RD. Interactions of tryptamine derivatives with serotonin trans-
porter species variants implicate transmembrane domain I in substrate recognition. Mol
Pharmacol. 2001;59(3):514–23.
Aghajanian GK, Graham AW, Sheard MH. Serotonin-containing neurons in brain: depression of
firing by monoamine oxidase inhibitors. Science. 1970;169(3950):1100–2.
Akil H, Gordon J, Hen R, Javitch J, Mayberg H, McEwen B, Meaney MJ, Nestler EJ. Treatment
resistant depression: a multi-scale, systems biology approach. Neurosci Biobehav Rev.
2018;84:272–88.
Andersen J, Taboureau O, Hansen KB, Olsen L, Egebjerg J, Stromgaard K, Kristensen AS.
Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438
in recognition of citalopram and tricyclic antidepressants. J Biol Chem. 2009;284
(15):10276–84.
Andersen J, Olsen L, Hansen KB, Taboureau O, Jorgensen FS, Jorgensen AM, Bang-Andersen B,
Egebjerg J, Stromgaard K, Kristensen AS. Mutational mapping and modeling of the binding site
for (S)-citalopram in the human serotonin transporter. J Biol Chem. 2010;285(3):2051–63.
Barker EL, Perlman MA, Adkins EM, Houlihan WJ, Pristupa ZB, Niznik HB, Blakely RD. High
affinity recognition of serotonin transporter antagonists defined by species-scanning mutagen-
esis. An aromatic residue in transmembrane domain I dictates species-selective recognition of
citalopram and mazindol. J Biol Chem. 1998;273(31):19459–68.
Barker EL, Moore KR, Rakhshan F, Blakely RD. Transmembrane domain I contributes to the
permeation pathway for serotonin and ions in the serotonin transporter. J Neurosci. 1999;19
(12):4705–17.
Belmer A, Quentin E, Diaz SL, Guiard BP, Fernandez SP, Doly S, Banas SM, Pitychoutis PM,
Moutkine I, Muzerelle A, Tchenio A, Roumier A, Mameli M, Maroteaux L. Positive regulation
of raphe serotonin neurons by serotonin 2B receptors. Neuropsychopharmacology. 2018;43
(7):1623–32.
Benmansour S, Owens WA, Cecchi M, Morilak DA, Frazer A. Serotonin clearance in vivo is altered
to a greater extent by antidepressant-induced downregulation of the serotonin transporter than
by acute blockade of this transporter. J Neurosci. 2002;22(15):6766–72.
Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat
Rev Neurosci. 2006;7(2):137–51.
Bigler AJ, Bøgesø KP, Toft A, Hansen V. Quantitative structure–activity relationships in a series of
selective 5-HT uptake inhibitors. Eur J Med Chem. 1977;12:289–95.
Blakely RD, Bauman AL. Biogenic amine transporters: regulation in flux. Curr Opin Neurobiol.
2000;10:328–36.
Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends
Pharmacol Sci. 1994;15(7):220–6.
Blier P, Piñeyro G, el Mansari M, Bergeron R, de Montigny C. Role of somatodendritic 5-HT
autoreceptors in modulating 5-HT neurotransmission. Ann N Y Acad Sci. 1998;861:204–16.
Antidepressants: Molecular Aspects of SSRIs 929

Bogeso K, Sánchez C. The discovery of citalopram and its refinement to escitalopram. In: Fischer J,
Ganellin CR, Rotella DP, editors. Analogue-based drug design III. Weinheim: Wiley-VCH
Verlag GmbH & Co. KGaA; 2012.
Boku S, Nakagawa S, Toda H, Hishimoto A. Neural basis of major depressive disorder: beyond
monoamine hypothesis. Psychiatry Clin Neurosci. 2018;72(1):3–12.
Canli T, Lesch KP. Long story short: the serotonin transporter in emotion regulation and social
cognition. Nat Neurosci. 2007;10(9):1103–9.
Carneiro AM, Blakely RD. Serotonin-, protein kinase C-, and Hic-5-associated redistribution of the
platelet serotonin transporter. J Biol Chem. 2006;281(34):24769–80.
Cathala A, Devroye C, Drutel G, Revest JM, Artigas F, Spampinato U. Serotonin(2B) receptors in
the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin
neurons. Exp Neurol. 2019;311:57–66.
Celada P, Bortolozzi A, Artigas F. Serotonin 5-HT1A receptors as targets for agents to treat
psychiatric disorders: rationale and current status of research. CNS Drugs. 2013;27(9):703–16.
Celik L, Sinning S, Severinsen K, Hansen CG, Moller MS, Bols M, Wiborg O, Schiott B. Binding
of serotonin to the human serotonin transporter. Molecular modeling and experimental valida-
tion. J Am Chem Soc. 2008;130(12):3853–65.
Chen NH, Reith ME, Quick MW. Synaptic uptake and beyond: the sodium- and chloride-dependent
neurotransmitter transporter family SLC6. Pflugers Arch. 2004;447(5):519–31.
Chen F, Larsen MB, Sanchez C, Wiborg O. The S-enantiomer of R,S-citalopram, increases inhibitor
binding to the human serotonin transporter by an allosteric mechanism. Comparison with other
serotonin transporter inhibitors. Eur Neuropsychopharmacol. 2005;15:193–8.
Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa
A, Omori IM, McGuire H, Tansella M, Barbui C. Comparative efficacy and acceptability of 12
new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746–58.
Coleman JA, Green EM, Gouaux E. X-ray structures and mechanism of the human serotonin
transporter. Nature. 2016;532(7599):334–9.
Courtney NA, Ford CP. Mechanisms of 5-HT1A receptor-mediated transmission in dorsal raphe
serotonin neurons. J Physiol. 2016;594(4):953–65.
Coyle JT, Duman RS. Finding the intracellular signaling pathways affected by mood disorder
treatments. Neuron. 2003;38(2):157–60.
Dankoski EC, Carroll S, Wightman RM. Acute selective serotonin reuptake inhibitors regulate the
dorsal raphe nucleus causing amplification of terminal serotonin release. J Neurochem.
2016;136(6):1131–41.
Dell’Osso L, Carmassi C, Mucci F, Marazziti D. Depression, serotonin and tryptophan. Curr Pharm
Des. 2016;22(8):949–54.
Duric V, Duman RS. Depression and treatment response: dynamic interplay of signaling pathways
and altered neural processes. Cell Mol Life Sci. 2013;70(1):39–53.
El Mansari M, Sánchez C, Chouvet G, Renaud B, Haddjeri N. Effects of acute and long-term
administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo
electrophysiological study in rat brain. Neuropsychopharmacology. 2005;30(7):1269–77.
Gabrielsen M, Ravna AW, Kristiansen K, Sylte I. Substrate binding and translocation of the
serotonin transporter studied by docking and molecular dynamics simulations. J Mol Model.
2012;18(3):1073–85.
Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. Benefits from antidepressants: synthesis of 6-
week patient-level outcomes from double-blind placebo-controlled randomized trials of fluox-
etine and venlafaxine. Arch Gen Psychiatry. 2012;69:572–9.
Guiard BP, Mansari ME, Murphy DL, Blier P. Altered response to the selective serotonin reuptake
inhibitor escitalopram in mice heterozygous for the serotonin transporter: an electrophysiolog-
ical and neurochemical study. Int J Neuropsychopharmacol. 2012;15(3):349–61.
Haase J, Killian AM, Magnani F, Williams C. Regulation of the serotonin transporter by interacting
proteins. Biochem Soc Trans. 2001;29(Pt 6):722–8.
Haenisch B, Bonisch H. Depression and antidepressants: insights from knockout of dopamine,
serotonin or noradrenaline re-uptake transporters. Pharmacol Ther. 2011;129:352–68.
930 A. Etievant et al.

Henry LK, Field JR, Adkins EM, Parnas ML, Vaughan RA, Zou MF, Newman AH, Blakely RD.
Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact
to establish high affinity recognition of antidepressants. J Biol Chem. 2006;281(4):2012–23.
Hornung JP. The human raphe nuclei and the serotonergic system. J Chem Neuroanat. 2003;26
(4):331–43.
Iceta R, Aramayona JJ, Mesonero JE, Alcalde AI. Regulation of the human serotonin trans-
porter mediated by long-term action of serotonin in Caco-2 cells. Acta Physiol. 2008;193
(1):57–65.
Jacobsen JP, Plenge P, Sachs BD, Pehrson AL, Cajina M, Du Y, Roberts W, Rudder ML, Dalvi P,
Robinson TJ, O’Neill SP, Khoo KS, Morillo CS, Zhang X, Caron MG. The interaction of
escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse.
Psychopharmacology. 2014;231(23):4527–40.
Jayanthi LD, Samuvel DJ, Blakely RD, Ramamoorthy S. Evidence for biphasic effects of protein
kinase C on serotonin transporter function, endocytosis, and phosphorylation. Mol Pharmacol.
2005;67(6):2077–87.
Jørgensen TN, Christensen PM, Gether U. Serotonin-induced down-regulation of cell surface
serotonin transporter. Neurochem Int. 2014;73:107–12.
Kasper S, Sacher J, Klein N, Mossaheb N, Attarbaschi-Steiner T, Lanzenberger R, Spindelegger C,
Asenbaum S, Holik A, Dudczak R. Differences in the dynamics of serotonin reuptake trans-
porter occupancy may explain superior clinical efficacy of escitalopram versus citalopram. Int
Clin Psychopharmacol. 2009;24(3):119–25.
Kim HS, Park IS, Park WK. NMDA receptor antagonists enhance 5-HT2 receptor-mediated
behavior, head-twitch response, in mice. Life Sci. 1998;63:2305–11.
Kittler K, Lau T, Schloss P. Antagonists and substrates differentially regulate serotonin transporter
cell surface expression in serotonergic neurons. Eur J Pharmacol. 2010;629(1–3):63–7.
Klein N, Sacher J, Geiss-Granadia T, Attarbaschi T, Mossaheb N, Lanzenberger R, Potzi C, Holik
A, Spindelegger C, Asenbaum S, Dudczak R, Tauscher J, Kasper S. In vivo imaging of
serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects
administered different doses of escitalopram or citalopram. Psychopharmacology.
2006;188:263–72.
Klein N, Sacher J, Geiss-Granadia T, Mossaheb N, Attarbaschi T, Lanzenberger R, Spindelegger C,
Holik A, Asenbaum S, Dudczak R, Tauscher J, Kapser S. Higher serotonin transporter occu-
pancy after multiple dose administration of escitalopram compared to citalopram: an [123I]
ADAM SPECT study. Psychopharmacology. 2007;191:333–9.
Koldso H, Severinsen K, Tran TT, Celik L, Jensen HH, Wiborg O, Schiott B, Sinning S. The two
enantiomers of citalopram bind to the human serotonin transporter in reversed orientations. J
Am Chem Soc. 2010;132(4):1311–22.
Kraus C, Castrén E, Kasper S, Lanzenberger R. Serotonin and neuroplasticity – links between
molecular, functional and structural pathophysiology in depression. Neurosci Biobehav Rev.
2017;77:317–6.
Krout D, Rodriquez M, Brose SA, Golovko MY, Henry LK, Thompson BJ. Inhibition of the
serotonin transporter is altered by metabolites of selective serotonin and norepinephrine reup-
take inhibitors and represents a caution to acute or chronic treatment paradigms. ACS Chem
Neurosci. 2017;8(5):1011–8.
Lau T, Horschitz S, Bartsch D, Schloss P. Monitoring mouse serotonin transporter internalization in
stem cell-derived serotonergic neurons by confocal laser scanning microscopy. Neurochem Int.
2009;54(3–4):271–6.
Lundberg J, Christophersen JS, Petersen KB, Loft H, Halldin C, Farde L. PET measurement of
serotonin transporter occupancy: a comparison of escitalopram and citalopram. Int J Neuropsy-
chopharmacol. 2007;10:777–85.
Mansari ME, Wiborg O, Mnie-Filali O, Benturquia N, Sánchez C, Haddjeri N. Allosteric modula-
tion of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. Int J
Neuropsychopharmacol. 2007;10(1):31–40.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030.
PLoS Med. 2006;3(11):e442.
Antidepressants: Molecular Aspects of SSRIs 931

Matthäus F, Haddjeri N, Sánchez C, Martí Y, Bahri S, Rovera R, Schloss P, Lau T. The allosteric
citalopram binding site differentially interferes with neuronal firing rate and SERT trafficking in
serotonergic neurons. Eur Neuropsychopharmacol. 2016;26(11):1806–17.
Mitchell NC, Gould GG, Koek W, Daws LC. Ontogeny of SERT expression and antidepressant-like
response to escitalopram in wild-type and SERT mutant mice. J Pharmacol Exp Ther. 2016;358
(2):271–81.
Mnie-Filali O, Faure C, Mansari ME, Lambas-Senas L, Berod A, Zimmer L, Sanchez C, Haddjeri
N. R-citalopram prevents the neuronal adaptive changes induced by escitalopram. Neuroreport.
2007;18:1553–6.
Mnie-Filali O, Lau T, Matthaeus F, Abrial E, Delcourte S, El Mansari M, Pershon A, Schloss P,
Sánchez C, Haddjeri N. Protein kinases alter the allosteric modulation of the serotonin trans-
porter in vivo and in vitro. CNS Neurosci Ther. 2016;22(8):691–9.
Montgomery S, Hansen T, Kasper S. Efficacy of escitalopram compared to citalopram: a meta-
analysis. Int J Neuropsychopharmacol. 2011;14(2):261–8.
Mork A, Kreilgaard M, Sanchez C. The R-enantiomer of citalopram counteracts escitalopram-
induced increase in extracellular 5-HT in the frontal cortex of freely moving rats. Neurophar-
macology. 2003;45:167–73.
Morrissette DA, Stahl SM. Modulating the serotonin system in the treatment of major depressive
disorder. CNS Spectr. 2014;19(Suppl 1):57–67; quiz 54–7, 68
Murphy DL, Lesch KP. Targeting the murine serotonin transporter: insights into human neurobi-
ology. Nat Rev Neurosci. 2008;9(2):85–96.
Murray KE, Ressler KJ, Owens MJ. In vivo investigation of escitalopram’s allosteric site on the
serotonin transporter. Pharmacol Biochem Behav. 2016;141:50–7.
Nemeroff CB. Psychopharmacology of affective disorders in the 21st century. Biol Psychiatry.
1998;44(7):517–25.
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression.
Neuron. 2002;34(1):13–25.
Oz M, Libby T, Kivell B, Jaligam V, Ramamoorthy S, Shippenberg TS. Real-time, spatially
resolved analysis of serotonin transporter activity and regulation using the fluorescent substrate,
ASP+. J Neurochem. 2010;114(4):1019–29.
Penmatsa A, Wang KH, Gouaux E. X-ray structure of dopamine transporter elucidates antidepres-
sant mechanism. Nature. 2013;503(7474):85–90.
Piñeyro G, Blier P. Autoregulation of serotonin neurons: role in antidepressant drug action.
Pharmacol Rev. 1999;51(3):533–91.
Plenge P, Gether U, Rasmussen SG. Allosteric effects of R- and S-citalopram on the human 5-HT
transporter: evidence for distinct high- and low-affinity binding sites. Eur J Pharmacol.
2007;567:1–9.
Prasad HC, Zhu CB, McCauley JL, Samuvel DJ, Ramamoorthy S, Shelton RC, Hewlett WA,
Sutcliffe JS, Blakely RD. Human serotonin transporter variants display altered sensitivity to
protein kinase G and p38 mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 2005;102
(32):11545–50.
Puig MV, Gulledge AT. Serotonin and prefrontal cortex function: neurons, networks, and circuits.
Mol Neurobiol. 2011;44(3):449–64.
Qian Y, Galli A, Ramamoorthy S, Risso S, DeFelice LJ, Blakely RD. Protein kinase C activation
regulates human serotonin transporters in HEK-293 cells via altered cell surface expression. J
Neurosci. 1997;17(1):45–57.
Quentin E, Belmer A, Maroteaux L. Somato-dendritic regulation of raphe serotonin neurons; a key
to antidepressant action. Front Neurosci. 2018;12:982.
Ramamoorthy S, Giovanetti E, Qian Y, Blakely RD. Phosphorylation and regulation of antidepres-
sant-sensitive serotonin transporters. J Biol Chem. 1998;273(4):2458–66.
Richardson-Jones JW, Craige CP, Guiard BP, Stephen A, Metzger KL, Kung HF, Gardier AM,
Dranovsky A, David DJ, Beck SG, Hen R, Leonardo ED. 5-HT1A autoreceptor levels deter-
mine vulnerability to stress and response to antidepressants. Neuron. 2010;65(1):40–52.
Robson MJ, Quinlan MA, Blakely RD. Immune system activation and depression: roles of
serotonin in the central nervous system and periphery. ACS Chem Neurosci. 2017;8(5):932–42.
932 A. Etievant et al.

Rudnick G. Serotonin transporters – structure and function. J Membr Biol. 2006;213(2):101–10.

Samuvel DJ, Jayanthi LD, Bhat NR, Ramamoorthy S. A role for p38 mitogen-activated protein
kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms
involved in transporter surface expression. J Neurosci. 2005;25(1):29–41.
Sanchez C. The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the
effect of S-citalopram. Basic Clin Pharmacol Toxicol. 2006;99(2):91–5.
Sánchez C, Kreilgaard M. R-citalopram inhibits functional and 5-HTP-evoked behavioural
responses to the SSRI, escitalopram. Pharmacol Biochem Behav. 2004;77(2):391–8.
Sánchez C, Bergqvist PB, Brennum LT, Gupta S, Hogg S, Larsen A, Wiborg O. Escitalopram, the S-
(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in
animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology.
2003;167(4):353–62.
Schloss P, Henn FA. New insights into the mechanisms of antidepressant therapy. Pharmacol Ther.
2004;102(1):47–60.
Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and
pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51(3):215–35.
Stahl SM, Lee-Zimmerman C, Cartwright S, Morrissette DA. Serotonergic drugs for depression and
beyond. Curr Drug Targets. 2013;14(5):578–85.
Thompson BJ, Jessen T, Henry LK, Field JR, Gamble KL, Gresch PJ, Carneiro AM, Horton RE,
Chisnell PJ, Belova Y, McMahon DG, Daws LC, Blakely RD. Transgenic elimination of high-
affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter. Proc Natl
Acad Sci U S A. 2011;108:3785–90.
Topiol S, Bang-Andersen B, Sanchez C, Bøgesø KP. Exploration of insights, opportunities and
caveats provided by the X-ray structures of hSERT. Bioorg Med Chem Lett. 2016;26
(20):5058–64.
Topiol S, Bang-Andersen B, Sanchez C, Plenge P, Loland CJ, Juhl K, Larsen K, Bregnedal P,
Bøgesø KP. X-ray structure based evaluation of analogs of citalopram: compounds with
increased affinity and selectivity compared with R-citalopram for the allosteric site (S2) on
hSERT. Bioorg Med Chem Lett. 2017;27(3):470–8.
Törk I. Anatomy of the serotonergic system. Ann N Y Acad Sci. 1990;600:9–34; discussion 34–5
Vizi ES. Role of high-affinity receptors and membrane transporters in nonsynaptic communication
and drug action in the central nervous system. Pharmacol Rev. 2000;52(1):63–89.
Wood KM, Hashemi P. Fast-scan cyclic voltammetry analysis of dynamic serotonin responses to
acute escitalopram. ACS Chem Neurosci. 2013;4(5):715–20.
World Health Organization (WHO). Depression and other common mental disorders, fact sheet no.
369; WHO reference number: WHO/MSD/MER/2017.2. 2017.
Yu S, Holsboer F, Almeida OF. Neuronal actions of glucocorticoids: focus on depression. J Steroid
Biochem Mol Biol. 2008;108(3–5):300–9.
Zhong H, Hansen KB, Boyle NJ, Han K, Muske G, Huang X, Egebjerg J, Sánchez C. An allosteric
binding site at the human serotonin transporter mediates the inhibition of escitalopram by R-
citalopram: kinetic binding studies with the ALI/VFL-SI/TT mutant. Neurosci Lett. 2009;462
(3):207–12.
Zhong H, Haddjeri N, Sanchez C. Escitalopram, an antidepressant with an allosteric effect at the
serotonin transporter – a review of current understanding of its mechanism of action. Psycho-
pharmacology. 2012a;219(1):1–13.
Zhong H, Sanchez C, Caron MG. Consideration of allosterism and interacting proteins in the
physiological functions of the serotonin transporter. Biochem Pharmacol. 2012b;83(4):435–42.
Zhu R, Gruber HJ, Hinterdorfer P. Two ligand binding sites in serotonin transporter revealed by
nanopharmacological force sensing. Methods Mol Biol. 2018;1814:19–33.
Neurochemical Mobile: A Heuristic Tool
for Understanding Dynamic Complexity
and Treatment of Alcohol Withdrawal

Felix Tretter

Contents
Quest for Theoretical Modeling in Neuropsychiatry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
Empiricism, “Methodism,” and “Dataism”: How to Understand “Complexity”? . . . . . . . . . . 934
“Theoretical Neurobiology”: Ways to the Big Picture? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935
The Brain as a Systemic Symptom Generator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Systems Pathology of the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Systems Neurobiology and Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
The Basic Whole-Brain Macro-circuit Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938
The View of Neurochemistry of the Circuitry: The Cellular and Subcellular Level . . . . . . . 939
Clinical Foundations of a Systems Pathology of Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
Symptoms of Alcohol Withdrawal: Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
Quantification of Withdrawal Course: Assessment Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
Treatment of Alcohol Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
Neurobiological Theory and Modeling of Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
Alcohol Effects on the Main Neurotransmitter Systems (NTMS) . . . . . . . . . . . . . . . . . . . . . . . . . . 944
The Basic Neurochemical Systems Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
The “Neurochemical Matrix”: A Heuristic Structure Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
The “Neurochemical Mobile”: A Metaphorical Process Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
Alcohol and the Neurochemical Mobile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948
Conclusion and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952

Abstract
This chapter initially criticizes the lack of a “theoretical” (neuro)psychiatry that
helps to understand mental disorders and their pharmaceutical treatment. In the
chapter, the complex pathophysiology of alcohol withdrawal is used as an
example to demonstrate the utility of systemic modeling of the brain: pharma-
ceutical treatment of alcohol withdrawal syndrome is usually based on

F. Tretter (*)
Bertalanffy Center for the Study of Systems Science, Vienna, Austria
e-mail: felix.tretter@bcsss.org; felix.tretter@yahoo.com

© Springer Nature Switzerland AG 2022 933

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_448
934 F. Tretter

stage-dependent polypharmacy – anti-noradrenergic drugs (clonidine), GABA-

ergic drugs (benzodiazepines), anti-dopaminergic drugs (haloperidol), sometimes
cholinergic drugs (physostigmine), and also anti-glutamatergic drugs (ketamine)
are used. They should suppress specific symptoms such as sympathetic hyperac-
tivity, anxiety, restlessness, generalized tonic-clonic seizures, and delirious states
at different stages and forms of alcohol withdrawal. Benefit-risk evaluations for
treatment decisions regarding medications are still pragmatic, as appropriate
RCTs are not conducted for several reasons (organizational restrictions, question-
able validity of rating scales, etc.). Nevertheless, the general treatment strategy for
prevention of seizures and deliria favors benzodiazepines. They prevent seizures
and may reduce hyperactivity of the sympathetic nervous system.
The chapter briefly links to neurobiological data and current recommendations
for treatment of alcohol withdrawal, but focuses on the pathophysiological
dynamics of the interconnected imbalanced neurotransmitter systems. This
leads to the construction of a qualitative dynamic system model that is composed
of six relevant neurotransmitter systems. This model has already been tested in a
computerized version, and therefore, it is finally proposed that it could help to
understand other mental disorders in general psychiatry.

Quest for Theoretical Modeling in Neuropsychiatry

The “explanation” of mental disorders by neurobiological data has some basic short-
comings: these are the explanatory brain-mind gap, the choice of the appropriate level
of neural organization, knowledge integration of animal data and human data, under-
standing circular causality, conceptually coping with emergence, etc. (Craver 2006;
Kotchoubey et al. 2016). Moreover, neuropsychiatry has no elaborated field of
“theoretical psychiatry” (comp. Wang and Krystal 2014, Jakovljevic and Jakovljevic
2019). Instead of theoretical efforts, neuropsychiatry promotes further detailed exper-
imental research on neurobiological correlates.
In contrast, it is suggested here that a co-evolution of empirical research and
theoretical research should be practiced, as it can be seen in the history of physics,
which shows a balanced interplay between these two fields. The basic idea proposed
here is that a principle-oriented interpretation of different observations and data (e.g.,
self-organized re-balancing) could provide a heuristic framework that can “explain”
hypothetically and even “forecast” psychopharmaceutical strategies.

Empiricism, “Methodism,” and “Dataism”: How to Understand

“Complexity”?

The prevailing roadmap for biological psychiatry has been a top-down and structure-
oriented experimental approach aiming to identify the genes responsible for the
occurrence of mental disorders. After the “systemic turn” in molecular biology
around 2000 (Kitano 2002), management of data complexity by computational
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 935

science was prioritized, and the idea of reconstructing “the whole” (brain) from the
bottom-up through computational tools guided research strategies (Tretter et al.
2010a).
Because the National Institute of Mental Health was aware of the difficulties to
integrate the plenty of methodologically heterogeneous data gathered by biological
psychiatry, the Research Domain Criteria (RDoC) were established (Insel et al.
2010). RDoC essentially provides a matrix of five domains of functions specified
as basic regulatory functions, positive valence functions, negative valence functions,
cognitive functions, and social functions. These domains – for addiction, mainly the
valence systems – are described through various methodologies including genetics,
molecules, cells, circuitry, physiology, behavior, and even self-reports.
In a similar way, the Human Brain Project, funded by the EU as a flagship project,
intends to gather a broad range of basic biological knowledge about the brain (HBP
2021).
Lately, promising connectomics brain research emerged (Sporns 2013; Morgan
and Lichtman 2013). In this context, also modeling strategies based on system theory
are used, such as the coupled neuronal-neurotransmitter whole-brain model
(Kringelbach and Deco 2020). However, there are several severe problems to
understand structural and functional connectomics already on the ultramicro-level
of “synapses” which are the connecting devices in the nervous system. Functional
understanding of synapses still is insufficient, even in the context of “systems
biology of the brain” (Tretter et al. 2010b). This raises the fundamental question of
how to integrate the complexity of data within an appropriate conceptual framework.
Also Harvard brain researchers Joshua Morgan and Jeff Lichtman summarize
connectomics research: “Both cellular and systems neuroscience are making steady
progress, but the critical bridge between them that understands how many neurons
organize into functional networks is still unbuilt” (Morgan and Lichtman 2017). This
is also true for the brain-mind gap (Kotchoubey et al. 2016).

“Theoretical Neurobiology”: Ways to the Big Picture?

Since psychiatry relies heavily on neurobiology, the question arises as to how

“theoretical neurobiology” might contribute to a theoretical (neuro)psychiatry. One
of the first seminal book on theoretical neuroscience was published by Peter Dayan
and Laurence F. Abbott (2001). The subtitle of the book is “Computational and
Mathematical Modeling of Neural Systems,” indicating that in the context of
neuroscience “theoretical” is mainly understood as “computational.” It remains
questionable whether this approach is effective in helping people with mental
disorders because not much effort with regard to conceptual work for psychiatry
can be seen. Clearly, we still do not know enough details to propose sufficient
computational brain theories and to explain mental disorders. For this reason, it
seems useful to develop “hypothetical exploratory and explanatory models” that start
from the clinical level and aim to explain symptoms by neurobiological mechanisms
through a top-down function analysis. This approach could help to integrate different
936 F. Tretter

areas of psychiatric knowledge. In the following text, this theoretical strategy is

demonstrated through the concept of a “neurochemical mobile.”

The Brain as a Systemic Symptom Generator

The coincidence of neural activity with mental states and processes could be
explained by the high structural connectivity of the nervous system and the enor-
mous number of possible states of the brain. This is mainly due to the about
100 trillion synapses and their information transmitting sites for transmitter sub-
stances. Also each neuron has receptors for different transmitter substances, and
therefore, for example, benzodiazepines via GABA-A receptors can act in an
inhibitory way – so to say as a master molecule – on all cellular symptom generators:
inhibition of noradrenaline (norepinephrine) transmitting neurons results in a reduc-
tion of sympathetic activation, inhibition of glutamate-transmitting neurons reduces
cerebral excitation, etc. The effects on organs as final effectors vary in terms of
latency, intensity, and duration of responses, depending on the temporal pattern of
the activity of the neuron assemblies in different brain areas.

Systems Pathology of the Brain

The high degree of connectivity of brain cells and cells of other organs justifies to
propose a general systems pathology that is embedded into integrative systems
medicine (Tretter 2019). This approach understands syndromes (e.g., withdrawal
syndrome) as the emergence of a causally effective network of symptoms that are
based on physiological/psychological dysfunctions. Systems pathology is rooted in
concepts of general systems theory (GST) as outlined by Ludwig von Bertalanffy
(von Bertalanffy 1968). One central theme of GST is the assumption that diseases
can be understood basically as a persistent imbalance of opposing forces that, under
normal conditions, are in a fluctuating dynamic balance (Bertalanffy: “Fließgle-
ichgewicht”): stress syndromes can be understood by the persistent dominance of
ergotropic mechanisms over trophotropic mechanisms, several endocrine dysfunc-
tions are the result of disbalances of upregulating and downregulating organ and/or
tissue functions, and immune disorders in some cases are a result of dominance of
pro-inflammatory versus anti-inflammatory mechanisms and vice versa. According
to this general theoretical principle, every disease is conceptually framed by the basic
notion of dynamics in terms of spatio-temporal on-off patterns of symptom inten-
sity and symptom generators. This principle will be applied later to justify a
neurochemical systems model.
In this context, it has to be highlighted that building systemic models in medicine
should be based on an explicit systems methodology that is “transdisciplinary”
(researchers and clinicians). It starts with a list of components which are supposed
to constitute a system and that are combined to a comprehensive network model
depicting all possible bidirectional connections. In a next step, a circuit model with
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 937

A B

ENVIRONMENT COR
MIND, + +
BEHAVIOR

ORGANISM
STRIA
_ _
+
ORGANSYSTEM D1R D2R GPe

_
ORGAN
SN/
VTA
STN
Kortex

CIRCUITS Thalamus Putamen

_ _ +
Pallidum

+
TISSUE
GPi

CELL
2 in 3 in

GENES,
PROTEINES
THAL

Fig. 1 Multi-level view of systems neurobiology and selective modeling. (a) Top-down analysis to
molecular biology and bottom-up reconstruction of the whole by computational science. (b)
Qualitative central circuit model with imbalances accompanied with Parkinson syndrome or
schizophrenia. D2R-mediated indirect and D1R-mediated direct pathways that modulate the
thalamus-cortex interaction via 3 and 2 inhibitions that are exerted on the thalamus. Legend: Cor,
cortex; Stria, striatum; GPe, globus pallidus externus; SN, substantia nigra; VTA, ventral tegmental
area; STN, subthalamic nucleus; GPi, globus pallidus internus; Thal, thalamus; SN, substantia
nigra; VTA, ventral tegmental area; D1R, dopamine D1 receptors; D2R, dopamine D2 receptors; in,
inhibitory component; +, activating effect;
, inhibitory effect

semiquantitative qualitative relations semiquantitative qualitative models is to be

constructed and finally proceeding to an “exploratory” quantitative system model
that can be tested and optimized by computer simulations. Importantly, the level of
resolution of the model’s conceptual components depends on the aim of the model.
But a model cannot represent all details of the system. The utility of the model
depends on a smart selection of details. This is an important distinction from data-
driven “hyper-complex” models which are generated by computational big data
analysis, mainly based on graph theoretical and multivariate statistical analyses.
It is proposed here that concept-oriented modeling is a heuristically valuable
additional approach (Fig. 1).

Systems Neurobiology and Addiction

Neurobiology, in a multi-level system theoretical view, studies circuits at the macro-

level, local neuronal networks at a meso-level, cells at the micro-level, and molecules
at the ultramicro-level (Fig. 2a).
938 F. Tretter

Frequency/
intensity
ES (Glu) DT (DA, 5HT)

SHA
(NA)

0 5 10 15
Time (days)

Fig. 2 Schematic of clinical observations and study results of time course of symptoms of severe
alcohol withdrawal syndromes (and their neurochemical “drivers”). SHA ¼ sympathetic hyperac-
tivity (NA ¼ noradrenaline, norepinephrine). ES ¼ epileptic seizures (Glu ¼ glutamate). DT ¼
delirium tremens (DA ¼ dopamine, 5-HT ¼ serotonin)

The Basic Whole-Brain Macro-circuit Model

The basic macro-neuroanatomy of the whole brain shows the structure of long-
range circuits that exist between different brain areas such as cortex, striatum,
globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem/mid-
brain, and so on (compare Fig. 1b). The functions of macro-level circuits of
these components and the conditions of their local neural networks and their
synapse-based transmission systems, driven by glutamate (Glu), GABA, and
dopamine (DA), are relevant for neurology and psychiatry (Carlsson 1959).
They are called here simply as “Glu system,” etc. instead of “glutamatergic”
systems, etc. These systems were first discovered by pathology of neuroanatomy
and neurochemistry of motor system disorders such as Parkinson’s disease (PD;
Birkmayer and Hornykiewicz 1961) but also of schizophrenia (SZ; Carlsson
2006). The “standard circuit model” of this core system of the brain encompasses
the basal ganglia, consisting essentially of the striatum (Stria), globus pallidus pars
interna (GPi), globus pallidum pars externa (GPe), subthalamic nucleus (STN), and
substantia nigra (SN; see Fig. 2b). Although structurally well known (Albin et al.
1989; DeLong 1990; Sian et al. 1999; Foley and Riederer 2000), this system is still
not completely understood functionally, although even sophisticated systems ana-
lyses and computer simulations were conducted (Porenta and Riederer 1986;
Schroll and Hamker 2013; Berns and Sejnowski 2021). There is general agreement
however that – in the case of neuropathological conditions – two dynamic imbal-
ances, between the direct subsystem (accelerator) and the indirect subsystem
(brake) and in addition between the D1 and D2 receptor-based DA subsystem,
can result in distinct clinical syndromes (Fig. 2b):
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 939

– Normally, the activation of the signal flow from Cor to Stria and from there with
inhibitory effects to GPi that inhibits Thal corresponds to a so-called “direct”
system. With its double serial inhibitory function (i.e., activating function) on
Thal itself, it is activated by the dopamine system on the level of Stria via D1
receptors.
– The (long) “indirect” system starts also from Cor to Stria and from there runs over
GABA-based inhibitory connections to the GPe that inhibits the STN which
activates the GPi that inhibits Thal. Also this subsystem with triple serial inhibi-
tions on Thal causing an inhibition of Thal is modulated by DA, namely, by
inhibitory D2 receptors on the level of Stria.
– In addition a “short indirect pathway” has been identified, extending from Cor to
Stria to GPe and directly to GPi and Thal, and also a “hyperdirect pathway” from
Cor to STN and GPi was found.
– In the pathological case of a low-level dopamine function, PD occurs, where the
D1 receptors could dominate.
– In the pathological case with a high dopamine level, the D2 receptors could play a
strong role and psychotic states of SZ can emerge.
– Interestingly, in addicts, which are the focus of this chapter, a low level of D2
receptors is observed (Volkow et al. 2006).

Aiming to understand this system functionally, it is probably sufficient to make

simple computer simulations that are developed and discussed in the triangle
between neurobiologists, clinicians, and simulation experts. This kind of interdisci-
plinarity is called “transdisciplinarity” (Klein 2014).

The View of Neurochemistry of the Circuitry: The Cellular

and Subcellular Level

It must be added here to this brain-global model that the various cell types of the
different involved brain areas are not considered explicitly in this so-called standard
model of basal ganglia. Furthermore, at the level of opposing receptor types of the
DA system where pharmaceuticals can act upon, the “behavioral function” is still
highly hypothetical: maybe the D1 receptors are involved in a behavioral “prepare”
function, whereas the D2 receptors enable a behavioral “select” function (Keeler
et al. 2014). For a deeper functional understanding of this system, it must be seen that
on the meso-level of local networks (e.g., Stria), the peculiarity of the nervous
system, especially of the brain, to have multiply connected elements (neurons)
implies that, on average, feedback occurs after about three or four connections
(synapses) mixed with convergences, divergences, and feedforwards: striatal
GABA output neurons, in addition to dopaminergic input, receive glutamatergic
corticofugal input and inhibitory input from local cholinergic interneurons which
already constitute a complicated system, as these components of the system also
have several interactions. Looking at the local networks in the cortex, mainly
940 F. Tretter

neurons are present that operate via excitatory Glu transmission (e.g., pyramidal
cells) and via inhibitory GABA transmission (e.g., basket cells). Through their
interaction with excitation and inhibitory returns, they could work like a
two-component oscillator, where the relative strength of inhibitory GABA deter-
mines the intensity and frequency of the oscillations as is known by simulation
studies (Buzsáki 2006; Liljenström 2010).
At the micro-level of the cells, in addition to the synapses at the cell body,
dendritic synapses as input sites and synaptic sites at axon terminals as output
structures are of particular interest.
Studies at the ultramicro-level of the intracellular molecular world are concerned
with omics studies of the genome, epigenome, transcriptome, proteome, meta-
bolome, etc. and with the analysis of various signal transduction pathways (Nestler
and Lüscher 2019).
All these areas of neurobiology provide information about the mechanisms of
addiction. However, we still lack heuristically valuable models. Here a sketch of
such a model will be presented, of course ignoring much of the data of neurobiology,
but with a high ecological validity in relation to clinical issues. Also a lot of data is
missing at constituting the model, but this was already mentioned in the section on
“theory.” As a next step and as a concrete example, some of the clinical knowledge
of alcoholism is mentioned here.

Clinical Foundations of a Systems Pathology of Addiction

Although alcoholism is a common disorder, alcohol research is sparse because it is

not emphasized very much by pharmaceutical companies. For this reason, there is a
plurality of treatment protocols and a wide range of psychopharmaceuticals in use.
Also in this chapter, for many arguments, the extensive clinical experience of the
author must be added as evidence because representative and controlled studies are
very often lacking.

Symptoms of Alcohol Withdrawal: Clinical Aspects

With regard to addiction as a form of alcohol use disorders (AUD), it is assumed here
that the global time course of this disorder can be divided – with overlaps – into an
acute phase, a chronic phase, a withdrawal phase, a restitutional phase, and a
relapse phase (Tretter 2000). The clinically relevant symptoms for the diagnosis
are listed according to DSM 5 with dimensional categories (APA 2021). For basic
function analytic considerations, a reduction of these features to symptoms that are
significant for the disease dynamics to neurobiological correlates seems to be
helpful.
Interestingly, the main knowledge about the pathophysiology of alcohol with-
drawal is known from “cold withdrawal” without medication in the context of prison
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 941

and classical psychiatric institutions as already documented by Karl Bonhoeffer at

the end of the nineteenth century (Bonhoeffer 1901).
From a clinical point of view, and by reconstructing medical records of cases with
severe alcohol withdrawal syndromes, the time course of the risky stages corre-
sponds also to hyper- and hypofunctions of several transmitter systems and the
respective treatment. A brief overview is given here:

1. Sympathetic hyperactivity: Patients in most cases during the typical withdrawal

initially show sweating, tremor, mydriasis, tachycardia, and hypertension. These
symptoms are correlated with a hyperactivity of the noradrenaline (norepineph-
rine) transmitter system (NA).
2. Generalized tonic-clonic seizures: Withdrawal seizures not often occur without
autonomous hyperactivation. Sometimes a seizure is immediately followed by a
delirium. Seizures are thought to be caused by an imbalance of dominant exciting
glutamate (Glu) and subdominant inhibiting gamma-aminobutyric acid (GABA).
This view is supported by the finding that medication with GABA-ergic
substance such as benzodiazepines reduces the risk of suffering from generalized
seizures during alcohol withdrawal.
3. Delirium tremens: This severe syndrome is characterized by disorientation,
suggestibility, visual hallucinations, anxiety, psychomotor restlessness, etc. It
occurs usually with a small delay after the onset of withdrawal. The leading
neurotransmission system for this psychosis-like state seems to be a hyperactive
DA system and also the 5-HT system, although hypoactive Glu could also
provoke a psychosis. However, in withdrawal a hyperactivity of Glu is to be
assumed which seems to be contradictory, but it can be resolved as the mobile
model illustrates (see Fig.7a at the end): hypothetically, hyperactive NA, DA, and
5-HT altogether could dominate hyperactive Glu. This relational neurochemical
explanation is supported by the fact that the most effective treatment is seen in
antipsychotic substances that suppress DA and 5-HT transmission, whereas Glu
antagonists might enhance delirium. This will be discussed more in detail later.

The sequence of these syndromes is not always in this way. In some cases an
initial phase of sympathetic hyperactivation is followed by a delirium, but very
seldom a delirium occurs without clinical precursors. In some cases withdrawal
seizures appear first, sometimes deliria follow seizures, etc. Interestingly, in terms of
biological rhythmicity, deliria very often occur in evening hours.

Quantification of Withdrawal Course: Assessment Scales

Several rating scales are used to quantify withdrawal syndromes, with at least daily
applications: the Clinical Institute Withdrawal Assessment for Alcohol (CIWA and
CIWA-Ar; Sullivan et al. 1989) or the Short Alcohol Withdrawal Scale (SAWS;
Gossop et al. 2002) are widely used scales for description of the course of the
severity of withdrawal symptoms and to control the efficacy of pharmaceutical
942 F. Tretter

treatment. Other scales have been designed to make predictions about the prospec-
tive time course of the withdrawal: the Prediction of Alcohol Withdrawal Severity
Scale (PAWSS; Maldonado et al. 2014) or the Luebeck Alcohol-Withdrawal Risk
Scale (LARS; Junghanns and Wetterling 2017). They use levels of blood alcohol
concentration at clinical admission, level of liver enzymes, electrolytes, blood
pressure, history of addiction and withdrawals, etc. as predictors.
Summarizing the frequently observed time courses, sympathetic arousal in most
cases is first, then a risk for probably glutamatergic seizures occurs, and a few hours
later a dopamine-based delirium can develop (Fig. 2).

Treatment of Alcohol Withdrawal

The most critical phase in the treatment of alcohol dependence is the withdrawal
phase. Depending on the degree of dependence, an in-patient treatment is
recommended and also because of uncertainties of predictive power of assessment
scales in individual cases.
The strategy of “cold withdrawal” was continued in general psychiatry until
the 1980s. The rationale was that an addicted person should not be given
medications that themselves have an addictive potential, such as what benzodi-
azepines are supposed to have. On the other hand, these withdrawal procedures
were accompanied with several severe complications, mainly due to generalized
seizures and severe courses of delirium tremens, even with fatal outcome. Today,
in withdrawal management mainly the reduction of risks for severe complica-
tions such as generalized withdrawal seizures and delirium tremens is aimed. In
consequence, the benefit-risk assessment to apply psychopharmaceuticals or not
eventually led to the low-threshold indication of benzodiazepines although it is
still observed that later on some of these patients substitute alcohol with benzo-
diazepines or take both substances together. From the practical standpoint,
individuals with AUD are recommended to reduce or to discontinue their daily
alcohol dose. In addition, benzodiazepines are used as an effective and safe
withdrawal suppressant, but also other medications could be applied, although
satisfying randomized controlled studies still are lacking to make strong
recommendations.

Benzodiazepines
These drugs act on the GABA receptor. They are effective and recommended:
“Benzodiazepines are first-line treatment because of their well-documented effec-
tiveness in reducing the signs and symptoms of withdrawal including the incidence
of seizure and delirium” (ASAM 2021, p. 7). Benzodiazepines can be antagonized
by anexate.

Clomethiazole
It operates on the GABA receptor, but there is no antidote known. Treatment with
this substance is very effective but the drug has several side effects.
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 943

Clonidine
Clonidine acts as an alpha-2 adrenergic receptor agonist that enhances the inhibitory
action of the presynaptic receptor: as a result, the release of noradrenaline (norepi-
nephrine) is reduced and the sympathetic symptoms are attenuated.

Physostigmine
The utility of physostigmine as an acetylcholine agonist in treatment of delirium
tremens in intensive care units is reappearing (Rasimas et al. 2018).

Phenobarbital
This substance acts agonistically on the GABA receptors and is widely used as an
alternative to benzodiazepines in anglophonic countries. In these countries, they are
also used as an adjunct to benzodiazepines to control resistant alcohol withdrawal
syndrome in settings with close monitoring. These drugs cannot be antagonized.

Propofol
Acting on the GABA receptor it may be used in patients in intensive care units
experiencing resistant alcohol withdrawal and who already require mechanical
ventilation (APA 2013).

Anti-convulsants
Valproate and carbamazepine supposedly act on voltage-gated sodium channels.
They are frequently used, especially for prevention of withdrawal seizures.

Antipsychotics
If the patient develops productive psychotic symptoms, haloperidol with anti-
dopaminergic effects is a widely used drug in different medical disciplines. How-
ever, risperidone and quetiapine with anti-serotonergic effects are preferred because
they comparably do not reduce the seizure threshold.
Summarizing this section, from a clinical point of view, the two main risks –
seizures and delirium – can be prevented and treated at best if benzodiazepines are
applied from the very beginning of the withdrawal. It is also useful if clonidine as an
anti-noradrenergic drug is applied early in treatment.

Neurobiological Theory and Modeling of Addiction

Focusing on the neurochemical level of the addicted brain is useful as the drug and
the medications act on the molecular sites of the neurons. But it should be minded
that only recently, George Koob, Michel Le Moal, and Nora Volkow have developed
what is currently the leading comprehensive neurobiological systems model of
addiction that also bridges some gaps that exist to psychotherapy (Koob and Le
Moal 2001; Koob and Volkow 2016). For instance, these authors designed a stage-
based concept that ranges from a brain center-oriented paradigm to a (“systemic”)
944 F. Tretter

neuro-network view. Moreover, they emphasize basically the concept of an opposing

functional organization of behavior consisting of the reward system (nucleus
accumbens) and the stress/punishment system (amygdala). This theoretical model
of addiction is an example that current progress in neurobiological knowledge
strongly drives theoretical understanding of some key mechanisms of addiction.

Alcohol Effects on the Main Neurotransmitter Systems (NTMS)

At first, it has to be considered that alcohol as a very small molecule acts at the
molecular level of cells, namely, at sites of synapses that provide intercellular
communication. These sites are mainly receptors, which enforce or inhibit signal
transmission through ligand-gated ion channels or by other gating mechanism and
have direct effects on intracellular signal transduction. Generally saying, the most
important neurotransmitter systems (NTMSs) for both, psychiatry and neurology,
are as follows (Birkmayer and Riederer 1989; Stahl 2013): noradrenaline (NA;
norepinephrine), dopamine (DA), serotonin (5-HT), acetylcholine (Ach), glutamate
(Glu), and gamma-aminobutyric acid (GABA). These TMSs have topographical
features. For instance, in the cortex Glu and GABA are predominant, whereas in
brain stem areas NA, DA, 5-HT, and Ach exhibit cellular clusters.
Theoretical modeling requires proper summarizing of empirical observations and
data. However, regarding alcohol effects many neurobiological studies are still
contradictory, and they also use different subjects (e.g., healthy individuals, animals
of different species, in vitro tissue studies), different substrates (genes, cell tissue),
and different methods (intracerebral concentration measures, spinal fluid concentra-
tions of metabolites, etc.). For these reasons, generalizations such as those made here
are not as consistent as they should be. Here, a selection of data of six basic
transmitter systems is made:
Glutamate (Glu): Alcohol inhibits N-methyl-D-aspartate (NMDA) receptor func-
tion and reduces calcium influx (Tabakoff and Hoffman 1993; Lovinger et al. 1989;
Lovinger et al. 1990). An upregulation of NMDA receptors is found with chronic use
(Hoffman and Tabakoff 1994). Alcohol withdrawal is associated with an increase in
glutamate in the striatum, the nucleus accumbens, and the hippocampus (Tsai and
Coyle 1998).
GABA: Low doses of alcohol increase tonic inhibition that is mediated by GABA-
A receptors, particularly those containing δ-subunits and located extrasynaptically
(Wei et al. 2004). At higher concentrations, it leads to acute intoxication by poten-
tiating the gamma-aminobutyric acid (GABA) effects. Under conditions of chronic
alcohol consumption, downregulation of GABA-A receptors occurs (Davies 2003).
Noradrenaline (NA): Interestingly, cross-species findings of suppressive effects
of alcohol on NA are by no means consistent, but chronic alcohol use suppresses
noradrenergic signaling, and there is a rebound of the system during acute with-
drawal, resulting in increased NA release (Fitzgerald 2013).
Dopamine (DA): Alcohol stimulates dopamine release in the nucleus accumbens
(Weiss et al. 1995) and is suppressed in chronic alcohol use (Di Chiara 1997) and in
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 945

early withdrawal, but can be normalized immediately by alcohol administration

(Weiss et al. 1996). It is likely that the opioid system is necessary for these effects.
Serotonin (5-HT): Increased serotonin release is observed after acute alcohol
exposure in various brain regions (McBride et al. 1993). Alcohol enhances also
5-HT3-based signaling (Lovinger and Zhou 1994).
Acetylcholine (ACh): Alcohol can increase extracellular acetylcholine levels in
the ventral tegmental area (Larsson et al. 2005).
Putting together these observations of the six main NTMSs by use of a multi-axial
interaction framework, most disturbed mental disorders can be understood on a
neurochemical basis (Tretter 2000).

The Basic Neurochemical Systems Model

The design of systems models in biology can be started from a list of described
elements, compiled in an interaction matrix to make an overview about the kind and
strength of effective interrelations. In addition to this structure model, a process model
can be constructed that depicts the imbalances and the process dynamics of the
components. If enough data are available, “exploratory” and even “explanatory”
computer simulations can be realized to test the model and to put some new empirical
questions for improving the data basis of the model (Tretter 2001; Qi et al. 2014).

The “Neurochemical Matrix”: A Heuristic Structure Model

Theories of health and disease can be reduced for heuristic reasons to the interaction
of opposing forces or by adaptive counter-actions: growth and apoptosis, activation
and inhibition of functions, etc. A balance concept also was successfully applied at
the level of transmitter systems (Birkmayer et al. 1972). This principle was already
used in addiction to explain drug effects and complementary withdrawal symptoms
within one conceptual framework proposed by Himmelsbach (Himmelsbach 1941).
Similarly, the allostasis concept by Solomon and Corbit has been a fruitful heuristic
(Solomon and Corbit 1974). This idea of a general opponent principle is extended in
this sketch of a neurochemical systems model of alcohol addiction.
In this view, summarizing roughly the effects of acute and chronic alcohol
consumption on the NTMSs mentioned in the section above, in a first step of
modeling, an effect table of alcohol on NTMSs can be constructed that shows
opposite effects of acute versus chronic alcohol application (Table 1). This table

Table 1 Effects of acute and chronic alcohol consumption. 5-HT ¼ serotonin, DA ¼ dopamine,
NA ¼ noradrenaline, ACh ¼ acetylcholine, Glu ¼ glutamate, GABA ¼ gamma-aminobutyric acid
5-HT DA NA ACh Glu GABA
Acute alcohol consumption " / (#) " # "/0? # "
Chronic alcohol consumption and withdrawal #? # " # " #
946 F. Tretter

needs further confirmation. However, it could be already extended with regard to the
opioid system, the cortisol system, etc. if it is important for further explanations.
Also brain-local peculiarities could be depicted, and of course the local/regional
presence of receptor subtypes is essential.
In the framework of the basic six-component model, it is assumed that the GABA
system and the DA system are enhanced during acute alcohol consumption, whereas
Glu and NA are inhibited. By chronic alcohol consumption, the GABA system and
DA are downregulated and Glu and NA are upregulated. In the situation of with-
drawal, this constellation characterizes the clinical syndrome: hyperexcitation, gen-
eralized withdrawal seizures, and delirious states can occur.
The NTMSs are highly connected neural networks in the brain stem. To under-
stand this dynamics, a heuristic network model can be derived from the tabular
description of the NTMSs and transformed into a network model for exploratory
purposes. Such a model that represents only six relevant transmission systems
already exerts a remarkable dynamics which indicates that more complex multi-
level models with hundreds or thousands of differential equations might not have
much more explanatory value (Fig. 3).
Spontaneous and circadian fluctuations of the activity of the brain interfere with
the on-off pattern of the activity of the various NTMSs during alcohol withdrawal as
it was mentioned above by the time course of significant symptoms (Fig. 1). Also
circadian oscillations are of importance with the dominance of the noradrenaline
system in the morning and the dominance of the acetylcholine system in the
afternoon and evening/night. This is probably relevant as heavy dreaming (REM
phases) is a predictor for delirious states. In consequence, the time structure of the
effects of the various NTMSs is of importance for an appropriate medication.
However, there is not enough known to draw a strong evidence-based picture of

NA ACh
ALCOHOL

DA Glu

ALCOHOL
5-HT GABA

Fig. 3 Hypothetical neurochemical network model. Hypothetical interactions and observed main
effects of acute alcohol consumption on DA, NA, GABA, and Glu. Legend: Lines with tran-
soms ¼ inhibitory action; for abbreviations see Table 1
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 947

Fig. 4 The hypothetical percent

simulated time course of 200
hypo- and hyperactivity of
GABA and glutamate as
important transmitter systems
in the case of acute alcohol 150
GABA Glutamate
consumption, chronic alcohol
consumption, and during
withdrawal. (Adapted from 62) 100
GABA
Glutamate
50

Exposure Adaptation Withdrawal

0
time

the situation. For this reason, only a preliminary schematic for the dynamics of
glutamate and GABA can be suggested. It could serve as a theoretical guide for
further empirical research. In spite of these flaws, the network model was explored
validly in our computer simulation of alcoholism (62; see Fig. 4).

The “Neurochemical Mobile”: A Metaphorical Process Model

The model proposed here is a heuristic and can be used for further developments of
hypotheses. The construction of the mobile relies on the view that each component
of the neurochemical mobile represents the “relative functional weight” of a neuro-
transmitter, a term which summarily captures its physiological or behavioral impor-
tance and will be discussed later. The functional weight determines how the
respective neurotransmitter system is balanced during health or is off balance if it
is perturbed by substance abuse and/or by addiction.
The mobile can be differentiated according to other subclasses of receptors
(Fig. 3b): alpha 1 (a1) and alpha 2 (a2) receptors in the noradrenaline system, D1
and D2 receptors of the dopamine system, 5-HT1 and 5-HT2 receptors in the
serotonin system, nicotinergic (nACh) and muscarinergic (mACh) receptors in the
acetylcholine system, GABA-A and GABA-B receptors of the GABA system,
NMDA or AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) recep-
tors, and metabotropic glutamate receptors (mGlu). By this diversification already
12 subsystems are depicted in the model and the formalized and numerical calcula-
tion becomes difficult. For such reasons of complexity reduction, a qualitative
(semiquantitative) modeling strategy with only six components is a heuristically
useful first step (Fig. 5).
948 F. Tretter

NORADRENALINE ACETYLCHOLINE

SEROTONIN DOPAMINE GLUTAMATE GABA

NA ACh

+ _ + _
a1 a2 nACh mACh

5-HT DA Glu GABA

_ _ _ + _
+ + +
5-HT2 5-HT1 D1 D2 AMPA mGlu GABA-B GABA-A

Fig. 5 The neurochemical mobile as a system of scales. (a) Basic model. (b) With paired subtypes
of receptors that have opposing effects. Abbreviations: see Table 1 and text

Alcohol and the Neurochemical Mobile

When acute alcohol is consumed, activation of the dopamine system and the
GABA system and inhibition of the noradrenaline system and the glutamate
system occur (Fig. 6). If the person consumes alcohol chronically, these
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 949

Acute
A alcohol

NORADRENALINE ACETYLCHOLINE

SEROTONIN

GLUTAMATE

GABA
DOPAMINE

B
Chronic
alcohol

ACETYLCHOLINE
NORADRENALINE

SEROTONIN DOPAMINE GABA

GLUTAMATE

Fig. 6 Constellation of the neurochemical mobile in acute alcohol consumption (a) and in chronic
alcohol consumption (b). (a) The activity of several neurochemical transmitter systems is altered, for
example, GABA is enforced and glutamate is inhibited. This correlates with the pleasant feeling of
alcoholization. (b) Adaptation with recovery of balance of the scales. There is dominance of noradren-
aline, serotonin, and glutamate, whereas mainly GABA is subdominating. GABA downregulates to a
lower level of function, whereas glutamate transmission exhibits enhancement of function
950 F. Tretter

systems counter-regulate with a strong glutamate system and noradrenaline

system and with a weak dopamine and GABA system, but other transmitter
systems also adapt. Subsequently, this constellation correlates with a high
blood concentration of alcohol, but with an unsuspicious behavior (Fig. 7a).
This constellation determines also the withdrawal situation (Fig. 7b). Because
of the network character of the transmitter systems, also the other systems are
disorganized and generate other clinical symptoms of alcohol withdrawal
syndrome.

Conclusion and Perspectives

The utility of the neurochemical mobile as an instrument to qualitatively study the

interactions of different neurochemical subsystems of the brain can capture neuro-
chemical pathology and enables exploratory predictions of the effects of different
medications. It has a consistent structure in terms of clinical observations, although
some inconsistencies exist with regard to experimental data which could be
discussed.
This model also enables the description of the neurochemical constella-
tion in depression as an important comorbidity in alcohol dependence and
also for schizophrenia, which as a syndrome has some similarities to the
delirium.
In depression, as a widespread comorbidity to alcoholism, weak noradrenergic,
dopaminergic, and serotonergic transmission and strong glutamatergic transmis-
sion are usually assumed, so that acute alcohol consumption can improve the
subjective experience by activating dopamine and inhibiting glutamate, but with
the risk of the development of alcohol addiction. In schizophrenia, a relative
hyperactivity of the dopamine and the serotonin system combined with a low
activity level of glutamate transmission is generally suggested, so that alcohol by
enforcing GABA may reduce at least the unpleasant experience of psychotic
symptoms.
Regarding these aspects, a wider application of this model might be useful for
exploring the neurochemistry and neuropsychopharmacology of other mental disor-
ders and their treatment options. Some more detailed aspects regarding the relational
activity level of the transmission systems must be clarified. This could be explored
by a standardized quantitative computer model, and it could also lead to the
development of more appropriate psychopharmaceuticals for major mental
disorders.
In consequence, this systems theory-based approach of theory building in neu-
ropsychiatry could be a fruitful supplement to the method- and data-driven main-
stream of neuropsychiatric research. Interestingly, the metaphorical mobile can also
be used in multidimensional treatment programs as one element of psycho-education
for the patients indicating complex dynamics of the brain chemistry that is disturbed
by chronic drug consumption.
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 951

A
Withdrawal

ACETYLCHOLINE

NORADRENALINE

GABA

DOPAMINE GLUTAMATE

SEROTONIN

B Withdrawal

Anti-noradrenergic
drugs

ACETYLCHOLINE

NORADRENALINE Cholinergic
drugs ?
Glutamate
Serotonin antagonists ?
antagonists ?

GABA

DOPAMINE GLUTAMATE

SEROTONIN
Benzodiazepines

Dopmain antagonists

Fig. 7 Constellation of the neurochemical mobile in alcohol withdrawal (a) and options for
treatment (b). Substances with question marks are possible candidates for pharmaceutical treatment
952 F. Tretter

Cross-References

▶ Pharmacotherapy of Alcohol Use Disorders

▶ Therapy of Withdrawal Syndromes, Addiction Disorders, and Substitution
Therapies

References
Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends
Neurosci. 1989;12:366–75. https://doi.org/10.1016/0166-2236(89)90074-X.
APA, American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th
ed. Arlington: American Psychiatric Publishing; 2013.
APA, American Psychiatric Association. Clinical practice guidelines. APA; 2021. https://www.
psychiatry.org/psychiatrists/practice/clinical-practice-guidelines
ASAM, American Society of Addiction Medicine. The Asam clinical practice guideline on alcohol.
ASAM 2021. https://www.Asam.Org/Docs/Default-Source/Quality-Science/The_Asam_Clini
cal_Practice_Guideline_On_Alcohol-1.pdf?sfvrsn¼ba255c2_2
Berns GS, Sejnowski TJ. A computational model of how the basal ganglia produce sequences. J
Cogn Neurosci. 2021;10:108–21. https://doi.org/10.1162/089892998563815.
Bertalanffy L. General system theory. New York: Braziller; 1968.
Birkmayer W, Hornykiewicz O. Der L-Dioxyphenylalanin (¼ L-Dopa)-Effekt bei der Parkinson-
Akinese. Wien Klien Wschr. 1961;73:787–78.
Birkmayer W, Riederer P, editors. Understanding the neurotransmitters: key to the workings of the
brain. Vienna, New York: Springer; 1989.
Birkmayer W, Danielczyk W, Neumayer E, et al. The balance of biogenic amines as condition for
normal behaviour. J Neural Transm. 1972;33:163–78. https://doi.org/10.1007/BF01260902.
Bonhoeffer K. Die akuten Geisteskrankheiten der Gewohnheitstrinker. Eine klinische Studie. Jena:
Fischer Verlag; 1901.
Buzsáki G. Rhythms of the brain. Oxford: Oxford University Press; 2006.
Carlsson A. The occurrence, distribution and physiological role of catecholamines in the nervous
system. Pharmacol Rev. 1959;11(2, Part 2):490–3. [PMID: 13667431]
Carlsson A. The neurochemical circuitry of schizophrenia. Pharmacopsychiatry. 2006;39(S1):10–4.
Craver C. Explaining the brain. Oxford: Oxford University Press; 2006.
Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous
system. J Psychiatry Neurosci. 2003;28:263–74.
Dayan P, Abbott L. Theoretical neuroscience. Computational and mathematical modeling of neural
systems. Cambridge: MIT Press; 2001.
DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci.
1990;13:281–5. https://doi.org/10.1016/0166-2236(90)90110-V.
Di Chiara G. Alcohol and dopamine. Alcohol Health Res World. 1997;21(2):108–14.
Fitzgerald PJ. Elevated norepinephrine may be a unifying etiological factor in the abuse of a broad
range of substances: alcohol, nicotine, marijuana, heroin, cocaine, and caffeine. Substance
Abuse Res Treat. 2013;7:171–83. https://doi.org/10.4137/SART.S13019.
Foley P, Riederer P. The motor circuit of the human basal ganglia reconsidered. In: Mizuno Y, Calne
DB, Horowski R, Poewe W, Riederer P, Youdim MBH, editors. Advances in research on
neurodegeneration. Vienna: Springer; 2000. https://doi.org/10.1007/978-3-7091-6284-2_8.
Gossop M, Keaney F, Stewart D, Marshall EJ, Strang J. A short alcohol withdrawal scale (SAWS):
development and psychometric properties. Addict Biol. 2002;7(1):37–43. https://doi.org/10.
1080/135562101200100571. PMID: 11900621
HBP, Human Brian Project. The human Brian project. 2021. https://www.humanbrainproject.eu/en/
about/project-structure/work-packages/work-package-1/
Neurochemical Mobile: A Heuristic Tool for Understanding Dynamic. . . 953

Himmelsbach CK. The morphine abstinence syndrome, its nature and treatment. Ann Intern Med.
1941;15:829–43.
Hoffman PL, Tabakoff B. The role of the NMDA receptor in ethanol withdrawal. EXS. 1994;71:
61–70. https://doi.org/10.1007/978-3-0348-7330-7_7. PMID: 8032173
Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P. Research
domain criteria (RDoC): toward a new classification framework for research on mental disor-
ders. Am J Psychiatry. 2010;167(7):748–51.
Jakovljevic M, Jakovljevic I. Theoretical psychiatry as a link between academic and clinical psychi-
atry. In: Kim YK, editor. Frontiers in psychiatry. Advances in experimental medicine and biology,
vol. 1192. Singapore: Springer; 2019. https://doi.org/10.1007/978-981-32-9721-0_19.
Junghanns K, Wetterling T. Der komplizierte Alkoholentzug: Grand-Mal-Anfälle, Delir und
Wernicke-Enzephalopathie [Alcohol withdrawal and its major complications]. Fortschr Neurol
Psychiatr. 2017;85(3):163–77. https://doi.org/10.1055/s-0043-103052. Epub 2017 Mar 20.
German. PMID: 28320026
Keeler JF, Pretsell DO, Robbins TW. Functional implications of dopamine D1 vs. D2 receptors: a
‘prepare and select’ model of the striatal direct vs. indirect pathways. Neuroscience. 2014;282:
156–75.
Kitano H. Systems biology: a brief overview. Science. 2002;295(5560):1662–4. https://doi.org/10.
1126/science.1069492. PMID: 11872829
Klein JT. Interdisciplinarity and transdisciplinarity: keyword meanings for collaboration science
and translational medicine. J Transl Med Epidemiol. 2014;2(2):1024.
Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychophar-
macology. 2001;24(2):97–129. https://doi.org/10.1016/S0893-133X(00)00195-0. PMID:
11120394
Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry.
2016;3(8):760–73. https://doi.org/10.1016/S2215-0366(16)00104-8.
Kotchoubey B, Tretter F, Braun HA, Buchheim T, Draguhn A, Fuchs T, Hasler F, Hastedt H,
Hinterberger T, Northoff G, Rentschler I, Schleim S, Sellmaier S, Tebartz van Elst L, Tschacher
W. Methodological problems on the way to integrative human neuroscience. Front Integr
Neurosci. 2016;10:41.
Kringelbach ML, Deco G. Brain states and transitions: insights from computational neuroscience.
Cell Rep. 2020;32(10):108128. https://doi.org/10.1016/j.celrep.2020.108128. PMID: 32905760
Larsson A, Edström L, Svensson L, Söderpalm B, Engel JAV. Voluntary ethanol intake increases
extracellular acetylcholine levels in the ventral tegmental area in the rat. Alcohol Alcohol.
2005;40(5):349–58. https://doi.org/10.1093/alcalc/agh180.
Liljenström H. Network effects of synaptic modifications. Pharmacopsychiatry. 2010;43(Suppl. 1):
S67–81.
Lovinger DM, Zhou Q. Alcohols potentiate ion current mediated by recombinant 5-HT3RA
receptors expressed in a mammalian cell line. Neuropharmacology. 1994;33:1567–72.
Lovinger DM, White G, Weight FF. Ethanol inhibits NMDA-activated ion current in hippocampal
neurons. Science. 1989;243:1721–4.
Lovinger DM, White G, Weight FF. NMDA receptor-mediated synaptic excitation selectively
inhibited by ethanol in hippocampal slice from adult rat. J Neurosci. 1990;10:1372–9.
Maldonado JR, Sher Y, Ashouri JF, Hills-Evans K, Swendsen H, Lolak S, Miller AC. The
“prediction of alcohol withdrawal severity scale” (PAWSS): systematic literature review and
pilot study of a new scale for the prediction of complicated alcohol withdrawal syndrome.
Alcohol. 2014;48(4):375–90. https://doi.org/10.1016/j.alcohol.2014.01.004. Epub 2014 Feb 19.
PMID: 24657098
McBride WJ, Murphy JM, Yoshimoto K, Lumeng L, Li T-K. Serotonin mechanisms in alcohol
drinking behavior. Drug Dev Res. 1993;30:170–7.
Morgan JL, Lichtman JW. Why not connectomics? Nat Methods. 2013;10(6):494–500. https://doi.
org/10.1038/nmeth.2480.
Morgan JL, Lichtman JW. Digital tissue and what it may reveal about the brain. BMC Biol.
2017;15:101. https://doi.org/10.1186/s12915-017-0436-9.
954 F. Tretter

Nestler EJ, Lüscher C. The molecular basis of drug addiction: linking epigenetic to synaptic and
circuit mechanisms. Neuron. 2019;102(1):48–59. https://doi.org/10.1016/j.neuron.2019.01.
016. PMID: 30946825; PMCID: PMC6587180
Porenta G, Riederer P. Some aspects of modeling neuronal interactions in the basal ganglia. In:
Trappl R, editor. Cybernetics and systems. Vienna: Austrian Research Institute for Artificial
Intelligence; 1986. p. 351–8.
Qi Z, Tretter F, Voit EO. A heuristic model of alcohol dependence. PLoS One. 2014;9(3):e92221.
https://doi.org/10.1371/journal.pone.0092221. Published online 2014 Mar 21
Rasimas JJ, Sachdeva KK, Donovan IW. Revival of an antidote: bedside experience with physo-
stigmine. Toxicol Commun. 2018;2(1):85–101. https://doi.org/10.1080/24734306.2018.
1535538.
Schroll H, Hamker FH. Computational models of basal-ganglia pathway functions: focus on
functional neuroanatomy. Front Syst Neurosci. 2013;7:122. https://doi.org/10.3389/fnsys.
2013.00122.
Sian J, Youdim MBH, Riederer P, et al. Biochemical anatomy of the basal ganglia and associated
neural systems. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic neurochemistry:
molecular, cellular and medical aspects. 6th ed. Philadelphia: Lippincott-Raven; 1999. Available
from: https://www.ncbi.nlm.nih.gov/books/NBK27905/.
Solomon RL, Corbit JD. An opponent-process theory of motivation: I. Temporal Dynam Affect
Psychol Rev. 1974;81:119–45.
Sporns O. The human connectome: origins and challenges. NeuroImage. 2013;80:53–61.
Stahl SM. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications.
Cambridge: Cambridge University Press; 2013.
Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal:
the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict.
1989;84(11):1353–7. https://doi.org/10.1111/j.1360-0443.1989.tb00737.x. PMID: 2597811
Tabakoff B, Hoffman PL. Ethanol, sedative hypnotics, and glutamate receptor function in brain and
cultured cells. Behav Genet. 1993;23:231–6. https://doi.org/10.1007/BF01067428.
Tretter F. Suchtmedizin. Stuttgart: Schattauer; 2000.
Tretter F. Systemisch-kybernetische Modellansätze der Psychologie der Sucht. In: Tretter F,
Müller A, editors. Psychologie der Sucht. Göttingen: Hogrefe; 2001. p. 165–99.
Tretter F. “Systems medicine” in the view of von Bertalanffy’s “organismic biology” and systems
theory. Res Behav Sci. 2019;36:346–62.
Tretter F, Winterer G, Gebicke-Haerter PJ, Mendoza ER, editors. Systems biology in psychiatric
research: from high-throughput data to mathematical modeling. Weinheim: Wiley-Blackwell;
2010a.
Tretter F, Rujescu D, Pogarell O, Mendoza E, editors. Systems biology of the synapse. Pharmacop-
sychiatry. 2010b;43:S1–S98.
Tsai G, Coyle JT. The role of glutamatergic neurotransmission in the pathophysiology of alcohol-
ism. Annu Rev Med. 1998;49:173–84.
Volkow ND, Wang G, Begleiter H, et al. High levels of dopamine D2 receptors in unaffected
members of alcoholic families: possible protective factors. Arch Gen Psychiatry. 2006;63(9):
999–1008. https://doi.org/10.1001/archpsyc.63.9.999.
Wang X-J, Krystal JH. Computational psychiatry. Neuron. 2014;84:638–54.
Wei W, Faria LC, Mody I. Low ethanol concentrations selectively augment the tonic inhibition
mediated by δ subunit- containing GABAA receptors in hippocampal neurons. J Neurosci.
2004;24:8379–82.
Weiss F, Lorang MT, Bloom FE, Koob GF. Oral alcohol self-administration stimulates dopamine
release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp
Ther. 1995;267:250–8.
Weiss F, Parsons LH, Schulteis G, Hyytia P, Lorang MT, et al. Ethanol self-administration restores
withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in
dependent rats. J Neurosci. 1996;16:3474–85.
Delusion and Dopamine: Neuronal Insights
in Psychotropic Drug Therapy

Markus Karl Huber, Josef Schwitzer, Erwin Kirchler, and

Peter Lepping

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956
Delusions and Predictions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958
The Role of Dopamine in Delusion Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
Moving Current Models Forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 961
Understanding Delusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963
Delusional Infestation: Interface Between Hallucination and Delusion . . . . . . . . . . . . . . . . . . . . . . . 964
Psychotropic Drug Therapy in Delusional Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 970
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 970

Abstract
Delusions are a central topic for neuropsychiatric research given their insidious
psychotic nature. According to the Bayesian brain hypothesis (predictive coding
theory), delusions are regarded as an aberrant inference process. It is believed that
an excess of dopamine contributes to abnormal salience attribution, which is
considered to be the basis of delusional formation. This is explained in detail by
the neuromodulatory effect of dopamine on the integration of prediction errors
and aberrant prediction errors respectively, into a person’s thinking. All currently

M. K. Huber (*) · E. Kirchler

Department of Psychiatry, General Hospital Bruneck, South Tyrol, Italy
e-mail: markuskarl.huber@sabes.it; erwin.kirchler@sabes.it
J. Schwitzer
Department of Psychiatry, General Hospital Brixen, South Tyrol, Italy
P. Lepping
Wrexham Academic Unit, Bangor University, Bangor, Wales, UK
Heddfan Psychiatric Unit, Betsi Cadwaladr University Health Board, Wrexham, Wales, UK
Mysore Medical College/Research Institute, Honorary Professor Bangor University, Mysore, India
e-mail: peter.lepping@wales.nhs.uk

© Springer Nature Switzerland AG 2022 955

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_411
956 M. K. Huber et al.

approved antipsychotics block dopamine receptors, usually by D2 dopamine

receptor antagonism. Available clinical data points toward a good response to
antipsychotic therapy in delusional disorders. A timely and adequate antipsy-
chotic treatment of patients with delusions, accompanied by a stable and trusting
doctor-patient relationship, is recommended.

Introduction

Delusions represent a central topic for neuropsychiatric research, given their insid-
ious psychotic nature (Corlett et al. 2010; Feeney et al. 2017). Delusions are key
symptoms of mental illness, and physicians have been trying for more than a
hundred years to understand deluded patients and offer them treatment. Nosologi-
cally, delusions are a nonspecific symptom, and delusions occur in a wide range of
mental, medical, neurological, and substance-induced disorders. For example, there
is a core feature of schizophrenia, occurring in around 70% of patients, most
commonly with concomitant hallucinations, and grouped as “positive symptoms”
(Andreasen and Olsen 1982; Fenton et al. 1997). Delusions present as a primary
form of mental disorder, when occurring as a purely delusional disorder (ICD-11
delusional disorder/DSM-5:297.1). As such, they are isolated as a circumscribed
monothematic disorder without identifiable psychological or physical triggers
(Huber et al. 2020). Secondary forms occur as a result of another medical, neuro-
logical, or psychiatric condition. The distinction between primary and secondary
forms of delusions is of great importance because it focuses the treatment on the
underlying cause whenever possible. The term “primary” does not exclude neuro-
biological backgrounds (Keshavan and Kaneko 2013), but the emphasis of treatment
will center around antipsychotic medication and specific psychotherapies, rather
than the treatment of an underlying illness.
A delusion is usually defined as a “fixed false belief out of keeping with the
patient’s cultural background,” but recently in clinical psychiatry the aspect of being
“false” is considered less important than the aspect of being “fixed” (Freudenmann
and Lepping 2009). According to Karl Jaspers (1883–1969), one of the founders of
modern psychiatry, delusions can be recognized by (i) an extraordinary conviction
and an incomparable, subjective certainty, (ii) which cannot be influenced by
experience or logical conclusions, although (iii) their content is impossible. Because
ultimately, it can be difficult to prove or disprove certain beliefs, psychiatrists
identify delusions not primarily by judging the reality or falsity of the content of
the belief, although this might seem the most obvious. According to Freudenmann
and Lepping, the “best practice in diagnosing delusions is to look at the form of
reasoning, not the content, because the third Jasperian criterion of delusions (impos-
sibility) can be a pitfall” (Freudenmann and Lepping 2009). They use the example of
a patient with schizophrenia who may believe him- or herself to be persecuted by the
Mafia (possible; it is difficult, if not impossible, to prove the contrary): Asked to
substantiate this belief, the patient refers to strikingly many black Italian cars in front
of his or her house (obviously insufficient explanation or proof). Unlike a
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 957

hallucination, a deluded person misreads (misinterprets) reality, while a hallucinat-

ing person perceives things that are not there. Freudenmann and Lepping call this an
“error of probabilistic reasoning” (Freudenmann and Lepping 2009).
The concept of a mono-symptomatic delusional disorder was introduced by Emil
Kraepelin around 1910 with his famous textbook of psychiatry (Die Verrücktheit),
and further validated empirically by Kenneth Kendler in the 1980s (simple delu-
sional disorder that differs from schizophrenia spectrum disorders) (Kendler and
Hays 1981). With the introduction of ICD-11 and DSM-5, the disease is classified as
a delusional disorder that cannot be attributed to schizophrenia or other primary
psychotic disorders. Notable examples of monothematic delusional disorders are
persecutory delusions, delusions of jealousy, and somatic delusions. The lives of
people with delusional disorders are usually impaired because the delusional content
is not shared by the person’s environment. Instead, it is often vehemently rejected or
even declared as “crazy.” In psychiatric hospitals, patients with delusional disorders
are relatively rare and do not account for more than 2–3% of patients. That is not
much, given a lifetime prevalence of around 0.18–0.3%, and an annual incidence
rate of 1–3 new cases per 100.000 inhabitants (Perälä et al. 2007). However, the
number of unrecorded cases may be significantly higher.
Delusional disorders as a group are little investigated in neuroscience and in
clinical trials because the patients usually fail to consent or adhere to any study
protocol (Lepping et al. 2010). As a patient group, they are a challenge for any
treating physician. This is unfortunate because delusional disorders would offer a
great opportunity to investigate underlying brain abnormalities in the absence of
other confounding symptoms (e.g., formal thought disorder, disorganization, nega-
tive symptoms, and hallucinations). Few neurobiological studies have addressed
delusion per se. Rather, they have investigated schizophrenia or other psychotic
disorders in all their heterogeneity. This is why all suggested neurobiological
hypotheses in connection with delusional syndromes must be read with the caveat
that they might relate more to psychosis in general than to delusions in particular.
However, the clinical effectiveness of antipsychotics in delusional syndromes,
regardless of their aetiology, supports the hypothesis of dopaminergic hyperactivity
in people with delusions (Skelton et al. 2015; Huber et al. 2020). In fact, first-
(FGAs) and second-generation antipsychotics (SGAs) have their dopamine antago-
nistic properties in common.
No aspect of the definition of delusions is set in stone, and every point is open to
challenge, including what a rationale health belief should be, and what makes beliefs
delusional. Delusions may not necessarily be pathological or clinically relevant,
false beliefs can also be accepted, tolerated, or even desired in a particular cultural
and social context. The intensity of the delusional belief can be variable and often
changes over time. Yet, despite the observed difficulties of definition, delusions
remain a cornerstone in the diagnosis of psychosis and severe mental illness.
More recently, studies on the inferential brain have raised the problem of
distinguishing between healthy and delusional beliefs at the neuronal level. Believ-
ing is a complex cortical process, and probably best explained by the hypothesis that
brains are prediction machines (Bayesian brains). Within the Bayesian brain
958 M. K. Huber et al.

hypothesis, the predictive coding theory sees delusions as an aberrant inference

process. The aberration could be due to a failure of sensory attenuation in the context
of an abnormal weighting of previous experiences (error of probabilistic reasoning).
The basis of this model goes back to Thomas Bayes. Bayes’ theorem, published
posthumously in 1763 (An essay toward solving a problem in the doctrine of
chance), describes the probability of an event based on prior knowledge of condi-
tions that might be related to the event. This theorem of conditional probabilities of
event A for a given event B offers a way to explain the function of information
processing of single neurons, to groups of neurons and systems up to associative
learning and beliefs.

Delusions and Predictions

Karl John Friston (born 1959) represents the doctrine that one of the main tasks of
our brain is to make predictions about our environment (Friston 2010; Friston et al.
2016). According to Friston and other scientists who have worked intensively on
models of delusions in recent years, our brain represents a “prediction organ” that
designs mental life as a constant stream of predictions and error corrections (predic-
tive-coding theory) (Corlett et al. 2010; Sterzer et al. 2018). With regard to delusions,
this means in a simplified form: Cogito, ergo praedico. I think, therefore I make
predictions; if these predictions are wrong, and yet I am uncorrectably convinced of
the opposite, then I have a delusion. The French philosopher Jean-Jacques Rousseau
(1712–1778) claimed that human foresight is the beginning of all madness (Les
Confessions). The Prussian philosopher Immanuel Kant (1724–1804) also saw
much adversity in the human foresight and describes the madman as the figure
who is used to confusing imagination and object (Versuch über die Krankheiten des
Kopfes). The British clergyman and mathematician Reverend Thomas Bayes (1701–
1761) is regarded as the mastermind of the “Bayesian statistics,” named after him,
which provides the mathematical (statistical) basis of the predictive-coding theory
(Fletcher and Frith 2009; Aitchison and Lengyel 2017). It is unlikely that the three
contemporaries (Rousseau, Kant, and Bayes) ever met, but their considerations
exemplify how early philosophers discussed the subject of delusions.
More recent hypotheses about the origins of delusions assert that humans and
animals undeniably have a brain that allows them to anticipate future situations by
pattern recognition. This enables survival by maximizing rewards and minimizing
punishments. The brain accomplishes this mathematically by making predictions
and minimizing prediction errors because of its functional-hierarchical organized
brain anatomy (neuronal networks). Predictions are communicated in a top-down
fashion from higher to lower cerebral layers. When predictions encounter bottom-up
sensory information that does not match the predictions, errors are generated (pre-
diction error), which are either accommodated (ignored) or assimilated (integrated
into future predictions). Such future predictions, named priors, provide the source of
top-down predictions (Friston and Kiebel 2009).
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 959

Perception and its cerebral processing is not a passive neurobiological represen-

tation of the outside world (bottom-up processing) but is constantly subject to the
active influence of higher neuronal structures (top-down processing) (Gordon et al.
2019). Top-down processing generates predictions using more sophisticated cogni-
tive functions such as expectations. This leads to a compromise (integration)
between sensory data (bottom-up) and internal concepts (top-down). Thus stream-
lined, the brain uses two sources to generate reality: sensory stimuli (bottom-up) and
predictions (top-down). The brain constantly draws conclusions (predictions) from
its experiences (priors) about what the future will bring. Avoiding prediction errors is
therefore considered the supreme cerebral principle, according to the rules of
conditional probability (Bayesian statistics). A prediction error occurs when the
perception (bottom-up) does not match the expectation (top-down). The discrepancy
is ignored or integrated. The neuronal integration of a prediction error therefore
corresponds to an appropriate learning effect, or it can become an error of probabi-
listic reasoning (Freudenmann and Lepping 2009). In that case, it becomes an
abnormal prediction error and occurs when the expectation overrides the perception.
The discrepancy can again be ignored or integrated. In case of integration, however,
the resulting learning effect will be inappropriate. Importantly, prediction errors are
identified as dopaminergic mediated neuronal signals, which encode the absence or
exceeding of the expected prediction (Corlett et al. 2007a; Dudley et al. 2016;
Feeney et al. 2017). Encoding in this context means a neuronal process by which
the new information, obtained from the prediction error, is transformed into a code
type (neuronal representation) that is accepted (integrated) and recognized by one’s
memory.
It is crucial in the development of delusions that cortical regions, especially the
prefrontal cortex, are responsible for the top-down structuring and control of incom-
ing sensory inputs, and that dopaminergic neurotransmission is involved in the
mediation between sensory input (bottom-up) and expectations (top-down) (Friston
et al. 2014). It is hypothesized that pathological overactivity of dopaminergic
neurotransmission leads to aberrant prediction errors (Kapur 2003; Corlett et al.
2010; Heinz et al. 2019). Aberrant prediction errors cause inappropriately high
attributions of significance to perceived (sensory) information (bottom-up)
(Winton-Brown et al. 2014; Corlett and Fletcher 2015). This abnormal neuronal
processing appears to be crucial for the formation of delusions. Exemplary of this is
an investigation by Hannes Rössler in healthy people (Rössler 2016). He showed
that the haplotype of Catechol-O-Methyl-Transferase (COMT) with the highest
resulting synaptic dopamine levels was associated with a higher tendency to
unfounded, delusional beliefs, as well as with a stronger influence on top-down
predictions. The COMT haplotype represents a genetically induced, increased dopa-
mine neurotransmission due to reduced dopamine degradation, caused by an altered
COMT. This can lead to an 11- to 25-fold increase in dopamine levels in the synaptic
cleft, depending on how severely the degradation activity of COMT is affected. The
transition from unfounded (false) beliefs in healthy people to their pathological form
in ill people as delusion probably represents a continuum. This is in keeping with
clinical observations that delusional intensity can be variable.
960 M. K. Huber et al.

When a conflict between expectations and perceptions arises inappropriately,

such as in the case of inappropriately increased dopamine exposure, false beliefs
(delusions) result (Corlett et al. 2007a, 2010; Corlett and Fletcher 2015). These
delusions might be manifestations of aberrant prediction errors (errors of probabi-
listic reasoning). The prediction error model (predictive-coding theory) has become
a key process in theoretical models of human causal learning and belief formation
(Dickinson 2001; Lavin et al. 2005). By minimizing prediction errors, our brain
creates the causal structure of our environment. If prediction errors occur when they
should not have, inappropriate associations can be formed and strengthened, culmi-
nating in delusional beliefs.

The Role of Dopamine in Delusion Formation

The dopamine system is undoubtedly involved in the pathogenesis of psychotic

disorders. More than a hundred years after Karl Jasper’s definition of delusion, we
now better understand the role of dopamine in encoding prediction errors. We make
no attempt in this chapter to incorporate psychoanalytical explanations of delusion
formation but focus on the neurobiological aspects. It is generally accepted that
excessive and inappropriate dopamine signaling makes casual events important
(salient). This is highlighted in Shitij Kapur’s salience theory of psychosis (schizo-
phrenia), which was further developed by Aaron Mishara and Paolo Fusar-Poli, and
stipulates that psychosis develops as a result of aberrant incentive salience, driven by
an excess of dopamine in the ventral striatum (Kapur 2003; Mishara and Fusar-Poli
2013). Directly or indirectly (e.g., via glutamatergic signaling), dopaminergic
dysregulation (dopamine excess) leads to inappropriate prediction error signaling
(Corlett et al. 2007a, b).
Deriving from formal learning theory, explaining the mechanisms of animal
conditioning, it was proven that prediction errors are signaled by dopamine and
glutamate activity (Rescorla and Wagner 1972). Following on from this, Manfred
Spitzer proposed a hypothesis that combines the aspect of a disturbed dopaminergic
neurotransmission in deluded patients with the concept of neuronal networking
derived from computer science, assuming that increased dopaminergic transmission
leads to an increased signal-to-noise difference (Spitzer 1995). Physiologically,
signal-to-noise differences are perceived as the signal that triggers the cascade of
mechanisms that would set in motion a search for and possibility of a prediction
error, namely the search for explanation and learning (Friston and Kiebel 2009;
Preuschoff et al. 2006). This is significant because inappropriate prediction error
signals have been considered to be the consequence of a change in signal-to-noise
characteristics secondary to inadequate dopamine signal transmission. Therefore, the
neurochemical dopamine is of greatest interest because of its effects on reward,
learning, and belief formation. The exact mechanisms of dopamine in each of these
processes are still a matter of debate at the end of 2020 when this chapter was
written, with a number of partially overlapping hypotheses (salience dysregulation,
default mode network, and predictive coding). However, there is increasing evidence
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 961

that in psychosis as well as delusional and hallucinatory syndromes, increased

release and unconnected triggering of dopamine occurs (Murray et al. 2008).
Dopamine is also involved in memory formation (coding, storage, and recall), and
it is physiologically increased when the system is confronted with a cue (sign
stimulus) (Puig et al. 2014). If this increased dopamine release happens indepen-
dently of a cue, supposedly neutral objects or pieces of information may assume a
special significance. Thereby, an aberrant phasic dopamine response inappropriately
labels external (environment) or internal (body’s own) events as surprising or with
unexplained significance (inappropriate salience) (Corlett et al. 2013). Thus, a
passing man may appear suspicious as a pursuer, or a memory can develop strange
meanings. Equally, sensations on one’s skin may be interpreted as parasitic rather
than a normal itch. In this hypothesis, delusions are explanations for abnormal
experiences, but they are similar in all essential aspects to those that occur in the
formation of healthy beliefs. For healthy beliefs, prediction errors lead to correct
thoughts, which consolidate the formation of causal explanatory beliefs (priors). For
false beliefs, aberrant prediction errors lead to delusional thoughts, which consoli-
date the formation of delusional explanatory beliefs (priors), influencing future
predictions which maintain the delusion. At the neuronal level, this processing
corresponds to an aberrant modulation of postsynaptic amplification, presumably
related to the function of the NMDA receptors (Friston 2010). This is consistent
with the role of dopamine in controlling signal-to-noise differences and the numer-
ous hypotheses that dopamine (at least in terms of its tonic discharge rates)
encodes uncertainty or violation of expectations (Fiorillo 2008; Preuschoff et al.
2006). The current view of dopamine has therefore expanded from a simple mediator
of the “reward prediction error” to a spreader of “unexpected significance” (Smith
et al. 2006).

Moving Current Models Forward

Belief modeling, in the above-mentioned context, moves the focus on a dopamine-

driven prediction system that links the firing of dopamine neurons with reward,
learning, and belief formation. This allows us to consider predictive coding for
psychoses, for which dopamine imbalance is considered typical. Within the formal
framework of the prediction error model, the distinction between the prediction error
itself and the precision (accuracy) of its neuronal registration (encoding) cannot be
stressed enough. It is assumed that delusions, respectively their neurotransmitter
basis (dopamine), represent a failure to properly encode the precision of predictions
and prediction errors. In other words, inappropriate dopamine excess leads to a
failure to optimize uncertainty about sensory information. The neuroscientific evi-
dence that implicates dopamine in both prediction error and uncertainty concurs with
formal learning theories, suggesting that a learned uncertainty about stimuli is
important for the allocation of attention. This may be mediated by an interaction
between phasic prediction error firing and increased tonic activity in dopamine
neurons (Fiorillo et al. 2005).
962 M. K. Huber et al.

Importantly, dopamine acts as a neuromodulator in the central nervous system by

modulating the encoding of environmental stimuli and the neuronal correlates of
emotions and memories of previous experiences (Kienast and Heinz 2006). Goal-
directed activities are only possible if relevant stimuli can be distinguished from
irrelevant stimuli. In particular, learning theories have shown that goal-directed,
respectively reality-conforming behavior fails if the gate to irrelevant stimuli is
opened, causing distractibility and uncertainty. Therefore, the relevant neuronal
mechanism to ensure this has to be the correct encoding of a prediction error, defined
as the discrepancy between anticipation and occurrence of an event. As we now
know, this encoding and its precision is dopamine-mediated, depending on an
appropriate dopamine firing of both phasic and tonic dopamine firing (Schultz et
al. 1997; Corlett et al. 2010). From behavioral psychology research, it can be
assumed that phasic dopamine firing is responsible for the formation, and tonic
dopamine firing for the subsequent utilization of the new information (Smith et al.
2006). Linking the predictive error model and firing of dopamine neurons with
classical models of associative learning is seen as an important step toward a better
understanding of the pharmacology and psychology of psychoses. Antipsychotics
(dopamine receptor antagonists), which currently block all dopamine, could protect
against the formation of unhelpful (aberrant) internal associations by attenuating the
effect of the phasic response, thus indirectly influencing existing associations by
attenuating the tonic response (Smith et al. 2006).
Any mismatch between expectancy and experience is transmitted up the cortical
hierarchy to the level above via differentiated glutamate (AMPA/NMDA) receptor
signaling (Friston 2005). Slower neuro-modulatory transmitters, such as dopamine,
acetylcholine, serotonin, and cannabinoids, are engaged, mediating the post-
prediction error response by encoding the precision or uncertainty associated with
a particular prediction error (Corlett et al. 2009). Such signals influence subsequent
neuronal processing, e.g., in working memory or the modulation of synaptic plas-
ticity according to the cerebral hierarchy from top to bottom, so that subsequent
responses can be tuned (Lavin et al. 2005; Herrero et al. 2008). This view coincides
with the Bayesian model on cortical processing by feedforward signaling of sensory
stimuli and feedback signaling of expectations and priors. On the one hand, dopa-
mine D2 receptor signaling, for example, is associated with an instability of pre-
frontal representations, providing mechanisms for rapid, surprising readjustment of
representations and new learning (Seamans and Yang 2004). On the other hand,
dopamine also acts via D1 receptors and their interactions with NMDA channels
reinforcing cell assemblies that represent expected salient events (O’Donnell 2003).
According to this hypothesis, excessive D2 signaling leads to disturbed D1 signaling
and depleted NMDA signaling in fronto-striatal cell assemblies. This leads to a poor
specification of previous expectations, thus creating false associations with the
consequence of psychotic states (Corlett et al. 2010).
An important role of the dopaminergic system is suggested by studies using
ketamine as a reliable inducer of delusions. Ketamine is able to provoke psychotic
symptoms due to its antiglutamatergic and dopaminergic effects (Kegeles et al.
2000; Kokkinou et al. 2018). Delusional beliefs occur parallel to a disturbed
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 963

encoding of the prediction error in frontal cortical regions under ketamine action
(Corlett et al. 2006). A functional MRI (fMRI) study with ketamine confirmed the
relationship between a disturbed encoding of a prediction error and the development
of delusions (the extent of the disturbance correlated with the tendency to form
delusions) (Corlett et al. 2007b). Importantly, these abnormal responses under
ketamine correlated with the severity of altered beliefs across all subjects. While
the primary action of ketamine is the blockade of the glutamatergic NMDA receptor,
ketamine has important direct and indirect actions on both glutamate and dopamine.
Indeed, it has been argued that the cognitive and behavioral effects of ketamine
might be attributable to stimulation of D2 receptors rather than to the blockade of
NMDA receptors (Kapur and Seeman 2001). It has been ascertained that acute
treatment with NMDA receptor antagonists increases dopamine release in the
striatum, nucleus accumbens, and prefrontal cortex of experimental animals and
enhances the firing rate of dopamine in the midbrain (Svensson et al. 1998; Sitges et
al. 2000). In human subjects, positron emission tomography (PET) imaging of 11C-
raclopride binding following ketamine administration revealed that ketamine
induces striatal dopamine release. The magnitude of this release correlated with
the intensity of the ketamine-induced psychosis (Smith et al. 1998; Vollenweider et
al. 2000). Lawrence Kegeles was the first to suggest that the psychotomimetic effects
of NMDA receptor antagonism may be due to a disruption in the glutamatergic
control of dopamine function (Kegeles et al. 2000). Ketamine-induced disruption of
fronto-striatal dopamine/glutamate function leads to characteristic psychopathology
by aberrant prediction error-based associative causal learning.

Understanding Delusions

This chapter does not aim to understand delusions as a psychotherapeutic or Gestalt

psychology-related process, but it is concerned with neurobiological aspects of
delusion formation. We specifically do not wish to negate other theories of delusion
formation but rather want to focus on its neuronal level. Understanding delusion and
dopamine needs a much more sophisticated view than merely as a process of simple
excess of dopamine leading to delusions. The formation of delusions requires an
increased availability of dopamine, independent of a cue (Howes et al. 2009, 2012).
In accordance with these findings, Anissa Abi-Dargham observed an association
between increased synaptic dopamine concentrations and the severity of positive
symptoms in psychosis, as measured by PET (Abi-Dargham et al. 2000). Further-
more, we need to be aware that the brain changes in delusions are not limited to one
brain area or region and are not due to one neurochemical, such as dopamine. Certain
neuronal connections (brain networks) are increasingly being recognized as signif-
icant for our higher-order thinking and delusion formation: The salience network, for
example, consists of the anterior cingulate cortex and the anterior insula and is
normally involved (activated) when our attention is needed (Winton-Brown et al.
2014). The default mode network, consisting of the posterior cingulate, ventromedial
prefrontal cortex, the inferior parietal cortex, and the angular gyrus, is active when
964 M. K. Huber et al.

we are not actively concentrating (e.g., during daydreaming) (Greicius et al. 2003).
The central executive network is involved in our decisions by recognizing what is
important. It can therefore take complex information into account, process it, and
react to it. The central executive network is involved in our decisions to understand
what is important in order to respond to diversity (environmental complexity)
(Talpos and Shoaib 2015). Individuals with psychosis have structural, functional,
and neurochemical changes within these networks and how they are activated. While
Karl Jaspers wrote about the phenomenology and subjective experiences of delu-
sional patients, there is now a wealth of information that allows us to see our
understanding of delusional beliefs more in the context of altered brain structures
and functions. However, it should be noted that these changes are not necessarily
specific to delusions and go beyond positive symptoms. But this is not a contradic-
tion, because the theory of predictive coding is comprehensive and provides a
unified brain theory. Prediction errors or abnormal prediction errors occur at different
hierarchical levels of the brain, with different consequences, whether as learning
disturbances, hallucinations, or delusions. One and the same neurotransmitter (e.g.,
dopamine) can have different modes of action at different hierarchical levels of the
brain, and thus cause different functional disorders. Hallucinations could also be due
to cue-independent dopamine activation and be experienced as heard, seen, or felt
(false perception), but at a lower level of the brain hierarchy as delusions (false
beliefs) (Upthegrove et al. 2016). The concepts of salience dysregulation, self-
reference (via the so-called default mode network), and the prediction error model
have made a fundamental contribution to the neurobiological understanding of the
formation of delusional beliefs (overactive dopaminergic neurotransmission, abnor-
mal prediction errors, and increased influence of cognitive predictions/top-down).

Delusional Infestation: Interface Between Hallucination and

Delusion

The need to understand delusions and hallucinations together is still of great psychi-
atric and neuroscientific interest. Since primary delusions are rarely recorded, the
current understanding of delusional beliefs is largely limited to persecutory beliefs,
secondary delusions (e.g., in substance abuse), and investigations within the frame-
work of schizophrenia research. Within the category of delusional disorders, delu-
sional infestation (previously known as delusional parasitosis or Ekbom syndrome) is
a unique subtype of somatic delusion (Delusional Disorder in ICD-11; DSM-5:297.1).
Individuals with delusional infestation are convinced that they are infested by small
animals (insects, mites, and bugs) or inanimate pathogens that effect the patient’s skin,
other organs, or immediate environment (Lepping et al. 2015). Usually, patients with
delusional infestation complain of itching and may have secondary skin damage
(scratching effects or other self-damage with, e.g., disinfectants). While they often
complain of multiple systemic symptoms, dermatological symptoms are typical. The
alleged pathogen can be felt (tactile hallucinations), and often seen (visual
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 965

hallucinations), although there is no dermatological or other medical evidence of an

infestation (Freudenmann and Lepping 2009).
The validity of including hallucinations in the diagnosis of delusional disorders
has long been debated (Kendler and Hays 1981). Similarly, there was a long
controversy over which tactile sensations constitute hallucinations or delusions
(Berrios 1982; Baker et al. 1995). Currently, in diagnostic classification manuals
(ICD-11/DSM-5/), hallucinations may occur in delusional disorders if they are
closely related to the delusional theme. In no other psychiatric disorder is the overlap
between hallucinations (false perceptions) and delusions (false beliefs) more evident
than in delusional infestation. The sensory phenomenon that is the cause of the
patient’s complaint (visuo-tactile hallucinations) is an integral part of the false belief
of being infested. Neuronally, following the prediction error model, a strict distinc-
tion between hallucinations and delusions is not necessary at all, since top-down and
bottom-up processing with all their interactions represents a common brain pro-
cessing type. Delusions of infestation may arise either from an erroneous bottom-up
processing (false perception) or alternatively from an inappropriate top-down expec-
tation (false belief), or better, from a faulty processing of both, often initially
triggered by an abnormal visual-tactile perception. Inappropriate top-down expec-
tations are particularly easy to understand where infestations are concerned because
of their closeness to primal human instincts.
Predictive coding postulates that expectations, of whatever kind, flow down
from higher association areas to lower level areas and vice versa. The power of
cognition in the production of cutaneous sensations is underlined by contagious
itch sensations, experienced when subjects are exposed to conversations and
images about insects on the skin. Sensations on the skin are possibly a result of
the same interaction between top-down and bottom-up mechanisms that have been
shown for visual perceptions. The classic example of this is the rubber hand
illusion (Tsakiris and Haggard 2005). Humans can experience fake body parts as
their own just by simple visuo-tactile synchronous stimulation. This body-illusion
(rubber-hand illusion) is accompanied by a spatial drift in the perception of the real
limb toward the fake limb, suggesting an update of body estimation resulting from
stimulation. Interestingly, individuals with delusional infestation are more suscep-
tible to the rubber hand illusion indicating a deficit in Bayesian multisensory
integration (Eccles et al. 2015). Thus, body inference can be seen as prediction
error minimization that unites predictive coding and causal inference, i.e., inte-
grating perception, even when we are subjected to intermodal sensory distur-
bances. It appears that the processes of multisensory integration involved in
judging ownership of a body part involve synaptic learning via associative
Hebbian mechanisms. This represents the confluence of seeing and feeling of a
stimulated hand. The Hebbian theory states that an increase in synaptic effective-
ness is caused by repeated and sustained stimulation of a postsynaptic cell by a
presynaptic cell (Keysers et al. 2004). Physiological noise in multisensory inte-
gration that confers bodily ownership may generate distorted prior expectations
about the body, which biases subsequent perception, resulting in somatic delusions
of body representations.
966 M. K. Huber et al.

We recently published the first structural magnetic resonance imaging (MRI)

studies, using univariate and multivariate statistical methods for structural data
analyses. The results support the hypothesis that the delusional belief to be infested
with pathogens is likely to be associated with disrupted prefrontal control over
somato-sensory representations (Wolf et al. 2013; Huber et al. 2018). Importantly,
in these studies, we provided clear evidence that patients with delusional infestation
differ from patients with other monothematic delusions and healthy controls by a
specific pattern of lower grey matter volumes in thalamic, striatal (putamen), insular,
and medial prefrontal brain regions. The findings of frontostriatal/subcortical abnor-
malities in delusional infestation support the hypothesis that delusions of infestation
may arise as a prefrontal lobe failure to optimize visuo-tactile uncertainty, leading to
a false belief (delusion) about visuo-tactile information, presumably originating from
a damaged putamen. The putamen, in addition to its role in the regulation of motor
activities, strongly influences visuo-tactile perception by encoding visuo-tactile
information (Graziano and Gross 1993). The putamen contains bimodal cells with
visual- and tactile-receptive fields, which help to encode the location of sensory
stimuli mainly near the face (Ladavas et al. 1998).
Interestingly, the cortical systems closely associated with delusional infestation
include the frontal brain and especially posterior regions of the so-called “peri-
personal space” (PPS), where visual and tactile signals converge (putamen, insular,
and parietal cortex) (Huber et al. 2018). The PPS-Network is thought to play a
fundamental role in the representation of the space in the immediate vicinity of the
body (10–20 cm). It permits the construction of a special cerebral encoding of the
space that lies in the boundary zone between objects near the body and the body
itself (Di Pellegrino and Ladavas 2015; Serino 2019). The putamen, a brain region
with bimodal visual-tactile neurons, plays a key role in PPS. An abnormal,
presumably hyperdopaminergic activity of these neurons seems to be causally
involved in delusional infestation (Huber et al. 2007). The cocaine and amphet-
amine-sensitive dopamine transporter (DAT), represented with high density in the
striatum, particularly in the putamen, is known as the main target of numerous
triggers of delusional infestation. Striatal lesions and dopamine agonists (e.g.,
psychostimulants) can all engender delusions of infestation. In human stroke
patients, delusions of infestation often occur following lesions of the right
temporoparietal cortex, thalamus, and putamen (Huber et al. 2008). On the other
hand, antipsychotics (dopamine antagonists) achieve the best results in the treat-
ment of delusional infestation (Lepping et al. 2007), suggesting hyper-
dopaminergic dysfunction in such patients (Huber et al. 2011). The findings of
impaired prefrontal control over somatosensory representations and disrupted
dopaminergic signaling in delusional infestation indicate deficits in multisensory
integration that lead to aberrant prediction errors (inappropriate visuo-tactile asso-
ciations). These associations between sensation and a particular spatial location
might be represented by bimodal cells in the striatum (putamen). The resulting
distorted priors form a top-down bias (prediction) of skin perception that contrib-
utes to the maintenance of the delusion (in this case, delusions of infestation). This
is supported by a novel proposal by Brian Colder for the role of the basal ganglia in
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 967

biasing perception by selecting the expected sensation and initiating the top-down
transmission of those expectations in predictive coding (Colder 2015).
The evidence of structural abnormalities in frontal and body perception-related
brain areas in delusional infestation is consistent with current concepts of delusion
formation. Frontal dysfunction explains the impaired judgment with resulting false
beliefs (delusions), while dysfunctional processing in the dorsal striato-subcortical
loop explains false (visuo-tactile) perceptions (hallucinations). Such a distinction
between perception and belief is consistent with Max Coltheart’s two-factor theory
of monothematic delusions, postulating that the perception is disturbed (factor 1),
and then linked to an irrational explanation, due to a nonconforming probabilistic
frontal reasoning (factor 2) (Coltheart 2010; Coltheart et al. 2018). Moreover, the
structural data are compatible with the current predictive coding model of delusions,
postulating that perception is mainly colored by prior expectations (Corlett 2020).
Subsequently, our findings support the notion that the delusional belief to be infested
with pathogens is likely to be associated with disrupted prefrontal control over
somato-sensory representations. This may indicate that delusions originate from a
neuronal network failure between top-down and bottom-up processing and represent
a mismatch between expectations and experience (aberrant prediction errors).

Psychotropic Drug Therapy in Delusional Disorder

On a neuronal level, the dopamine system has been explored as a main target in
which biological, psychological, and social stressors have their impact to induce
psychotic symptoms (McCutcheon et al. 2019). In particular, neuroimaging studies
(PET) revealed increased striatal dopamine in the synaptic cleft in people with
positive symptoms and delusions, respectively (Fusar-Poli and Meyer-Lindenberg
2012). Additional dopamine agonists trigger psychosis, of which paranoid delusions
are the most common symptom (Voce et al. 2019). It is believed that an excess of
dopamine contributes to abnormal salience attribution, which is considered to be the
basis of delusional formation. This is explained in detail by the neuromodulatory
effect of dopamine on the integration of prediction errors within the predictive-
coding theory (Bayesian brain) (Corlett et al. 2009; Sterzer et al. 2018; Corlett 2020).
It is presumed that altered hyperdopaminergic transmission leads to abnormal
weighting of perceptual prediction errors. Such abnormal weighting leads to aberrant
prediction errors, inappropriate learning, and consequently to misinterpretations
(delusions) in “higher thinking” brain structures. Chronically, overstimulated dopa-
mine receptors lose their ability to block out irrelevant signals (stimuli). Therefore,
inappropriate associations arise and delusions are formed.
Importantly, almost all currently approved antipsychotics (neuroleptics) block
dopamine receptors, traditionally by D2 dopamine receptor antagonism (Kapur and
Seeman 2001; Kapur 2003). In addition, stimulant drugs (e.g., methamphetamine),
which increase activity at mesolimbic D2 dopamine receptors, raise the risk of
psychosis and delusions (Voce et al. 2019). Furthermore, PET studies (in vivo)
have shown that for most antipsychotic drugs, a 65–70% occupancy of the D2-
968 M. K. Huber et al.

dopamine receptors is required to achieve an antipsychotic (therapeutic) benefit

(Tauscher et al. 2004). Even though D2 dopamine antagonism corresponds to the
primary therapeutic effect of antipsychotics, we know that there are different dopa-
mine receptors, subdivided into D2-class receptors (D2, and its variants, plus D3 and
D4) and D1-class receptor (D1 and D5). For both classes, it is assumed that they
regulate signal-to-noise differences of inhibitory and excitatory microcircuits of the
brain. Basic research and therapeutic practice suggest that not only the D2 dopamine
receptor, but also other dopamine receptors are involved in the therapeutic effect of
antipsychotics. The antipsychotic site of action is generally assumed to be the
mesolimbic pathway. Unfortunately, antipsychotics do not bind selectively and
also block D2-dopamine receptors in other dopaminergic pathways such as the
mesocortical, tuberoinfundibular, and nigrostriatal pathways.
In practical work, antipsychotics are usually used transdiagnostically, e.g., in
schizophrenia, schizoaffective disorder, bipolar affective disorder, psychotic
depression, secondary psychoses, and especially for the pharmacological treatment
of delusional disorders (Morrison et al. 2018; Huber et al. 2020). However, for the
typical delusional disorder, there is a lack of high-quality pharmaco-therapeutic
evidence regarding antipsychotic treatment. There has not been a single RCT-study
(double-blind, randomized control trial/evidence class A) on the treatment of
delusional disorder with antipsychotics (Skelton et al. 2015). Therefore, recom-
mendations for the antipsychotic therapy of delusional disorders are only based on
individual case studies (evidence class D), case series (evidence class C), and
corresponding retrospective review analyses. Nevertheless, based on clinical expe-
rience, antipsychotic treatment has been established as the mainstay of drug
treatment for delusional disorders (González-Rodríguez et al. 2018). As early as
1995, Munro and Mok reported high success rates in the treatment of delusional
disorders with antipsychotics (responder rates of 81% and full remission rates of
69%) and spoke of a good to very good prognosis if antipsychotic treatment is
given (i.e., long-term, for more than 1 year) (Munro and Mok 1995). They were the
first to show that delusional disorders are not resistant to antipsychotic treatment.
Recent studies fully support the optimistic approach of a primarily antipsychotic-
based therapy of delusional disorders, with high success rates, and support the
recommendation to use antipsychotics as first-line therapy for delusional disorders
(Muñoz-Negro and Cervilla 2016; Lepping et al. 2007). Especially, delusional
infestation responds well to antipsychotic (antidopaminergic) medication, with a
clear link between early treatment and better outcome (Romanov et al. 2018;
Lepping et al. 2020).
Clinical psychiatrists know that the treatment of delusional disorders is usually
not a problem as long as engagement in treatment and concordance with medication
can be achieved. However, this is often not the case because of the delusional nature
of the beliefs patients have and the associated lack of insight into their illness. The
success of treatment with antipsychotics is evident in the majority of cases, but it
always depends on the individual clinical picture, the duration of delusion, and the
patient’s engagement. Therefore, the doctor-patient relation and the involvement of
close family members or acquaintances play a crucial role in the pharmacotherapy of
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 969

delusional disorder. It is often a relative who encourages concordance with medica-

tion. Patients with delusional disorder rarely agree to intramuscular (i.m.) long-
acting formulations. Early treatment is important, as a shorter duration of untreated
psychosis (DUP) is specifically associated with better outcome (Gunduz-Bruce et al.
2005; Romanov et al. 2018; Lepping et al. 2020). This is clinically important
because the risk of symptom exacerbation and poor outcome despite medication
increases with more time spent without adequate treatment. From a clinical point of
view, the available data point toward a good response to antipsychotic therapy in
delusional disorders (Huber et al. 2020). However, no particular antipsychotic drug
has proven superiority in the pharmacotherapy of delusional disorder. FGAs and
SGAs are equally effective. The most common antipsychotics with full or partial
remission documented in the literature are risperidone and olanzapine. The historical
preference for pimozide in delusional infestation could not be confirmed, and
because of its unfavorable side effect profile, pimozide is no longer recommended
as first-line treatment (Lepping et al. 2015).
The knowledge about the pathogenesis of delusions will continue to improve,
including the hope of developing other, perhaps better, therapeutics than D2 dopa-
mine receptor antagonists. In the future, it may be possible to develop new thera-
peutic strategies that focus, for example, on intracellular and molecular targets,
rather than just D2 or 5-HT2A antagonism. Newer developments will target addi-
tional processes, such as glutamatergic, cholinergic, and cannabinoid receptor tar-
gets, and the emerging field of pharmacogenetics aims to tailor treatments to
individual patients in terms of efficacy and tolerability.

Conclusion

Delusions and dopamine belong together like Pythagoras and the right angle.
Prediction error signaling and stimulus-reward learning primarily implicate dopa-
mine as the major neurotransmitter in delusion formation. Similarly, the dopamine
hypothesis is the dominant pathophysiological model of psychosis and delusions.
This is also supported by the neurochemical actions of antipsychotics (dopamine
antagonism). Inappropriate prediction error signaling explains the formation of
delusions and provides the basis for inappropriate processing of stimuli, perception,
attention, associations, thoughts, and formation of beliefs. A chronically inappropri-
ate excess of dopamine leads to irrelevant associations and beliefs being imbued
with inappropriate significance. The brain’s attempt to integrate these inappropriate
experiences leads to inappropriate priors, the beginning, and the maintaining of
delusions. Such processes are driven by prediction error signals, i.e., discrepancies
between what an organism expects in a given environment and what actually
happens. These neuronal processes are mainly signaled by dopaminergic and
glutamatergic mechanisms. Disruption of these neurobiological systems may under-
lie delusional formation through aberrant prediction error firing. This leads to
attention being drawn to inappropriate stimuli resulting in inappropriate priors, the
source of predictions. On a practical clinical level, the long-standing clinical
970 M. K. Huber et al.

experience of the authors confirms the importance of a timely and adequate treatment
of patients with delusions with antipsychotics, accompanied by a stable and trusting
doctor-patient relationship.

Cross-References

▶ Definition and Classification of Parkinsonian Drugs

▶ Hallucinogens as Therapeutic Agents: Past, Present, and Future
▶ Ketamine in Psychiatric Disorders
▶ Side Effects, Contraindications, and Drug-Drug Interactions in the Use of
Antiparkinsonian Drugs

References
Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB,
Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2
receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA. 2000;97:8104–9.
Aitchison L, Lengyel M. With or without you: predictive coding and Bayesian inference in the
brain. Curr Opin Neurobiol. 2017;46:219–27.
Andreasen NC, Olsen S. Negative v positive schizophrenia. Definition and validation. Arch Gen
Psychiatry. 1982;39:789–94.
Baker PB, Cook BL, Winokur G. Delusional infestation: the interface of delusions and hallucina-
tions. Psychiatr Clin North Am. 1995;18:345–61.
Berrios GE. Tactile hallucinations: conceptual and historical aspects. J Neurol Neurosurg Psychi-
atry. 1982;45:285–93.
Colder B. The basal ganglia select the expected sensory input used for predictive coding. Front
Comput Neurosci. 2015;23(9):119.
Coltheart M. The neuropsychology of delusions. Ann N Y Acad Sci. 2010;1191:16–26.
Coltheart M, Cox R, Sowman P, Morgan H, Barnier A, Langdon R, Connaughton E, Teichmann L,
Williams N, Polito V. Belief, delusion, hypnosis, and the right dorsolateral prefrontal cortex: a
transcranial magnetic stimulation study. Cortex. 2018;101:234–48.
Corlett PR. Predicting to perceive and learning when to learn. Trends Cogn Sci. 2020;24(4):259–60.
Corlett PR, Fletcher PC. Delusions and prediction error: clarifying the roles of behavioural and
brain responses. Cogn Neuropsychiatry. 2015;20:95–105.
Corlett PR, Honey GD, Aitken MR, Dickinson A, Shanks DR, Absalom AR, Lee M, Pomarol-
Clotet E, Murray GK, McKenna PJ, Robbins TW, Bullmore ET, Fletcher PC. Frontal responses
during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition,
brain activity, and psychosis. Arch Gen Psychiatry. 2006;63:611–21.
Corlett PR, Murray GK, Honey GD, Aitken MRF, Shanks DR, Robbins TW, Bullmore ET,
Dickinson A, Fletcher PC. Disrupted prediction-error signal in psychosis: evidence for an
associative account of delusions. Brain. 2007a;130:2387–400.
Corlett PR, Honey GD, Fletcher PC. From prediction error to psychosis: ketamine as a pharmaco-
logical model of delusions. J Psychopharmacol. 2007b;21:238–52.
Corlett PR, Krystal JH, Taylor JR, Fletcher PC. Why do delusions persist? Front Hum Neurosci.
2009;3:12.
Corlett PR, Taylor JR, Wang XJ, Fletcher PC, Krystal JH. Toward a neurobiology of delusions. Prog
Neurobiol. 2010;92(3):345–69.
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 971

Corlett PR, Cambridge V, Gardner JM, Piggot JS, Turner DC, Everitt JC, Arana FS, Morgan HL,
Milton AL, Lee JL, Aitken MR, Dickinson A, Everitt BJ, Absalom AR, Adapa R, Subramanian
N, Taylor JR, Krystal JH, Fletcher PC. Ketamine effects on memory reconsolidation favor a
learning model of delusions. PLoS One. 2013;8(6):e65088.
Di Pellegrino G, Ladavas E. Peripersonal space in the brain. Neuropsychologia. 2015;66:126–33.
Dickinson A. The 28th Bartlett memorial lecture causal learning: an associative analysis. Q J Exp
Psychol. 2001;54(1):3–25.
Dudley R, Taylor P, Wickham S, Hutton P. Psychosis, delusions and the “Jumping to conclu-
sions” reasoning Bias: a systematic review and meta-analysis. Schizophr Bull. 2016;42
(3):652–65.
Eccles JA, Garfinkel SN, Harrison NA, Ward J, Taylor RE, Bewley A, Critchley HD. Sensations of
skin infestation linked to abnormal frontolimbic brain reactivity and differences in self-repre-
sentation. Neuropsychologia. 2015;77:90–6.
Feeney EJ, Groman SM, Taylor JR, Corlett PR. Explaining delusions: reducing uncertainty through
basic and computational neuroscience. Schizophr Bull. 2017;43(2):263–72.
Fenton WS, McGlashan TH, Victor BJ, Blyler CR. Symptoms, subtype, and suicidality in patients
with schizophrenia spectrum disorders. Am J Psychiatry. 1997;154(2):199–204.
Fiorillo CD. Towards a general theory of neural computation based on prediction by single neurons.
PLoS One. 2008;3:e3298.
Fiorillo CD, Tobler PN, Schultz W. Evidence that the delay-period activity of dopamine neurons
corresponds to reward uncertainty rather than backpropagating TD errors. Behav Brain Funct.
2005;1:7.
Fletcher PC, Frith CD. Perceiving is believing: a Bayesian approach to explaining the positive
symptoms of schizophrenia. Nat Rev Neurosci. 2009;10:48–58.
Freudenmann RW, Lepping P. Delusional infestation. Clin Microbiol Rev. 2009;22(4):690–732.
Friston K. A theory of cortical responses. Philos Trans R Soc Lond B Biol Sci. 2005;360:815–36.
Friston K. The free energy principle: a unified brain theory? Nat Rev Neurosci. 2010;11(2):127–38.
Friston K, Kiebel S. Predictive coding under the free-energy principle. Phil Trans R Soc B.
2009;364:1211–21.
Friston K, Schwartenbeck P, FitzGerald T, Moutoussis M, Behrens T, Dolan RJ. The anatomy of
choice: dopamine and decision-making. Philos Trans R Soc Lond Ser B Biol Sci. 2014;5:369.
Friston K, FitzGerald T, Rigoli F, Schwartenbeck P, Pezzulo G. Active inference. A process theory.
Neural Comput. 2016;21:1–49.
Fusar-Poli P, Meyer-Lindenberg A. Striatal presynaptic dopamine in schizophrenia, Part II: meta-
analysis of [18F/11C]-DOPA PET studies. Schizophr Bull. 2012;39(1):33–42.
González-Rodríguez A, Estrada F, Monreal JA, Palao D, Labad J. A systematic review of the
operational definitions for antipsychotic response in delusional disorder. Int Clin
Psychopharmacol. 2018;33(5):261–7.
Gordon N, Tsuchiya N, Koenig-Robert R, Hohwy J. Expectation and attention increase the
integration of top-down and bottom-up signals in perception through different pathways.
PLoS Biol. 2019;17(4):e3000233.
Graziano MS, Gross CG. A bimodal map of space: somatosensory receptive fields in the macaque
putamen with corresponding visual receptive fields. Exp Brain Res. 1993;97(1):96–109.
Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a
network analysis of the default mode hypothesis. Proc Natl Acad Sci USA. 2003;100
(1):253–8.
Gunduz-Bruce H, McMeniman M, Robinson DG, Woerner MG, Kane JM, Schooler NR,
Lieberman JA. Duration of untreated psychosis and time to treatment response for delusions
and hallucinations. Am J Psychiatry. 2005;162(10):1966–9.
Heinz A, Murray GK, Schlagenhauf F, Sterzer P, Grace AA, Waltz JA. Towards a unifying
cognitive, neurophysiological, and computational neuroscience account of schizophrenia.
Schizophr Bull. 2019;45(5):1092–100.
Herrero JL, Roberts MJ, Delicato LS, Gieselmann MA, Dayan P, Thiele A. Acetylcholine contrib-
utes through muscarinic receptors to attentional modulation in V1. Nature. 2008;454:1110–4.
972 M. K. Huber et al.

Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E,
Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM. Elevated striatal dopamine
function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66(1):13–20.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S. The nature of
dopamine dysfunction in schizophrenia and what this means for treatment: meta-analysis of
imaging studies. Arch Gen Psychiatry. 2012;69(8):776–86.
Huber M, Kirchler E, Karner M, Pycha R. Delusional parasitosis and the dopamine transporter. A
new insight of etiology? Med Hypotheses. 2007;68(6):1351–8.
Huber M, Karner M, Kirchler E, Lepping P, Freudenmann RW. Striatal lesions in delusional
parasitosis revealed by magnetic resonance imaging. Prog Neuro-Psychopharmacol Biol Psy-
chiatry. 2008;32(8):1967–71.
Huber M, Lepping P, Pycha R, Karner M, Schwitzer J, Freudenmann RW. Delusional infestation:
treatment outcome with antipsychotics in 17 consecutive patients (using standardized reporting
criteria). Gen Hosp Psychiatry. 2011;33(6):604–11.
Huber M, Wolf RC, Lepping P, Kirchler E, Karner M, Sambataro F, Herrnberger B, Corlett PR,
Freudenmann RW. Regional gray matter volume and structural network strength in somatic vs.
non-somatic delusional disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;82:115–22.
Huber M, Kirchler E, Wolf RC. Pharmakotherapie der wahnhaften Störung. NeuroTransmitter.
2020;31(6):46–53. (SpringerMedizin).
Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology,
and pharmacology in schizophrenia. Am J Psychiatry. 2003;160:13–23.
Kapur S, Seeman P. Ketamine has equal affinity for NMDA receptors and the high-affinity state of
the dopamine D2 receptor. Biol Psychiatry. 2001;49:954–7.
Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, Cooper
TB, Carlsson A, Laruelle M. Modulation of amphetamine-induced striatal dopamine release by
ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000;48(7):627–40.
Kendler KS, Hays P. Paranoid psychosis (delusional disorders) and schizophrenia. Arch Gen
Psychiatry. 1981;38:547–51.
Keshavan MS, Kaneko Y. Secondary psychoses: an update. World Psychiatry. 2013;12(1):4–15.
Keysers C, Wicker B, Gazzola V, Anton JL, Fogassi L, Gallese V. A touching sight: SII/PV
activation during the observation and experience of touch. Neuron. 2004;42(2):335–46.
Kienast T, Heinz A. Dopamine and the diseased brain. CNS Neurol Disord Drug Targets.
2006;5:109–31.
Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-
analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry.
2018;23:59–69.
Ladavas E, Zeloni G, Farne A. Visual peripersonal space centered on the face in humans. Brain.
1998;121(Pt12):2317–26.
Lavin A, Nogueira L, Lapish CC, Wightman RM, Phillips PE, Seamans JK. Mesocortical dopamine
neurons operate in distinct temporal domains using multimodal signaling. J Neurosci. 2005;25
(20):5013–23.
Lepping P, Russell I, Freudenmann RW. Antipsychotic treatment of delusional parasitosis–a
systematic review. Br J Psychiatry. 2007;191:198–205.
Lepping P, Baker C, Freudenmann RW. Delusional infestation in dermatology in the UK: preva-
lence, treatment strategies, and feasibility of a RCT. Clin Exp Dermatol. 2010;35(8):841–4.
Lepping P, Huber M, Freudenmann RW. How to approach delusional infestation. BMJ. 2015;350:
h1328.
Lepping P, Aboalkaz S, Squire SB, Romanov DV, Bewley A, Huber M, Noorthoorn EO. Later age
of onset and longer duration of untreated psychosis are associated with poorer outcome in
delusional infestation. Acta Derm Venereol Acta Ven. 2020. in print.
McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: from
biology to symptoms. Trends Neurosci. 2019;42:205–20.
Delusion and Dopamine: Neuronal Insights in Psychotropic Drug Therapy 973

Mishara A, Fusar-Poli P. The phenomenology and neurobiology of delusion formation during

psychosis onset: jaspers, Truman symptoms, and aberrant salience. Schizophr Bull. 2013;39
(2):278–86.
Morrison AP, Law H, Carter L, Sellers R, Emsley R, Pyle M, French P, Shiers D, Yung AR, Murphy
EK, Holden N, Steele A, Bowe SE, Palmier-Claus J, Brooks V, Byrne R, Davies L, Haddad PM.
Antipsychotic drugs versus cognitive behavioral therapy versus a combination of both in people
with psychosis: a randomized controlled pilot and feasibility study. Lancet Psychiatry. 2018;5
(5):411–23.
Muñoz-Negro JE, Cervilla JA. A systematic review on the pharmacological treatment of delusional
disorder. J Clin Psychopharmacol. 2016;36(6):684–90.
Munro A, Mok H. An overview of treatment in paranoia/delusional disorder. Can J Psychiatr.
1995;40(10):616–22.
Murray G, Corlett PR, Clark L, Pessiglione M, Blackwell A, Honey G, Fletcher P. How dopamine
dysregulation leads to psychotic symptoms? Abnormal mesolimbic and mesostriatal prediction
error signaling in psychosis. Mol Psychiatry. 2008;13(3):239.
O’Donnell P. Dopamine gating of forebrain neural ensembles. Eur J Neurosci. 2003;17:429–35.
Perälä J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsä E, Pirkola S, Partonen T, Tuulio-
Henriksson A, Hintikka J, Kieseppä T, Härkänen T, Koskinen S, Lönnqvist J. Lifetime preva-
lence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry.
2007;64:19–28.
Preuschoff K, Bossaerts P, Quartz SR. Neural differentiation of expected reward and risk in human
subcortical structures. Neuron. 2006;51:381–90.
Puig MV, Antzoulatos EG, Miller EK. Prefrontal dopamine in associative learning and memory.
Neuroscience. 2014;282:217–29.
Rescorla RA, Wagner AR. A theory of pavlovian conditioning: variations in the effectiveness of
reinforcement and nonreinforcement. In: Black AH, Prokasy WF, editors. Classical conditioning
II: current research and theory. New York: Appleton- Century-Crofts; 1972. p. 64–99.
Romanov DV, Lepping P, Bewley A, Huber M, Freudenmann RW, Lvov A, Squire SB,
Noorthoorn EO. Longer duration of untreated psychosis is associated with poorer outcomes
for patients with delusional infestation. Acta Derm Venereol. 2018;98(9):848–54.
Rössler H. Dissertationsschrift 9 Dezember 2016. Aus der Klinik für Psychiatrie und
Psychotherapie Campus Charité Mitte der Medizinischen Fakultät Charité Universitätsmedizin
Berlin: Neurobiologische Grundlagen des Einflusses von Vorhersagen auf die Wahrnehmung-
Implikationen für die Pathogenesemodelle von Schizophrenie und bipolarer Störung.
Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science.
1997;275:1593–9.
Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the
prefrontal cortex. Prog Neurobiol. 2004;74:1–58.
Serino A. Peripersonal space (PPS) as a multisensory interface between the individual and the
environment, defining the space of the self. Neurosci Biobehav Rev. 2019;99:138–59.
Sitges M, Nekrassov V, Guarneros A. Simultaneous action of MK-801 (dizclopine) on dopamine,
glutamate, aspartate and GABA release from striatum isolated nerve endings. Brain Res.
2000;854:48–56.
Skelton M, Khokhar WA, Thacker SP. Treatments für delusional disorder. Schizophr Bull. 2015;41
(5):1010–1012. Cochrane Database Syst Rev. 2015;5:CD009785.
Smith GS, Schloesser R, Brodie JD, Dewey SL, Logan J, Vitkun SA, Simkowitz P, Hurley A,
Cooper T, Volkow ND, Cancro R. Glutamate modulation of dopamine measured in vivo with
positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsy-
chopharmacology. 1998;18:18–25.
Smith A, Li M, Becker S, Kapur S. Dopamine, prediction error and associative learning: a model-
based account. Netw Comput Neural Syst. 2006;17:61–84.
Spitzer M. A neurocomputational approach to delusions. Compr Psychiatry. 1995;36:83–105.
974 M. K. Huber et al.

Sterzer P, Adams RA, Fletcher P, Frith C, Lawrie SM, Muckli L, Petrovic P, Uhlhaas P, Voss M,
Corlett PR. The predictive coding account of psychosis. Biol Psychiatry. 2018;84(9):634–43.
Svensson TH, Mathe JM, Nomikos GG, Schilstrom B. Role of excitatory amino acids in the ventral
tegmental area for central actions of non-competitive NMDA-receptor antagonists and nicotine.
Amino Acids. 1998;14:51–6.
Talpos J, Shoaib M. Executive function. Handb Exp Pharmacol. 2015;228:191–213.
Tauscher J, Hussain T, Agid O, Verhoeff NPLG, Wilson AA, Houle S, Remington G, Zipursky RB,
Kapur S. Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentia-
tion from other atypical antipsychotics. Am J Psychiatry. 2004;161:1620–5.
Tsakiris M, Haggard P. The rubber hand illusion revisited: visuotactile integration and self-attribu-
tion. J Exp Psychol Hum Percept Perform. 2005;31:80–91.
Upthegrove R, Ives J, Broome MR, Caldwell K, Wood SJ, Oyebode F. Auditory verbal hallucina-
tions in first-episode psychosis: a phenomenological investigation. Br J Psychiatr Open. 2016;2
(1):88–95.
Voce A, Calabria B, Burns R, Castle D, McKetin R. A systematic review of the symptom profile and
course of methamphetamine-associated psychosis substance use and misuse. Subst Use Misuse.
2019;54(4):549–59.
Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL. Effects of (S)-ketamine on striatal
dopamine: a [11C] raclopride PET study of a model psychosis in humans. J Psychiatr Res.
2000;34:35–43.
Winton-Brown TT, Fusar-Poli P, Ungless MA, Howes OD. Dopaminergic basis of salience
dysregulation in psychosis. Trends Neurosci. 2014;37:85–94.
Wolf RC, Huber M, Depping MS, Thomann PA, Karner M, Lepping P, Freudenmann RW.
Abnormal gray matter and white matter volume in delusional infestation. Prog Neuro-
Psychopharmacol Biol Psychiatry. 2013;46(1):19–24.
Hallucinogens as Therapeutic Agents: Past,
Present, and Future

Elena Vos, Stephen Snelders, and Toine Pieters

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
Chemistry and Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 978
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
Adverse Effects and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984

Abstract
Hallucinogens have a long history as therapeutic agents. After the synthesis of
lysergic acid diethylamide (LSD) in 1938 by Albert Hofmann, the popularity of
classical hallucinogens with psychedelic properties increased among scientists,
psychiatrists, neurologists, and psychotherapists. Research in the 1950s and
1960s showed great promise for the use of psychedelics in medical research
and treatment. Psychedelics are characterized by their mind revealing effects,
which are valuable in the treatment of major depressive disorder (MDD) and of
stress- and trauma-related mental disorders (PTSD). However, research into the
E. Vos
University of Amsterdam, Amsterdam, The Netherlands
e-mail: elena.vos@student.uva.nl
S. Snelders
Freudenthal Institute, Utrecht University, Utrecht, The Netherlands
e-mail: s.a.m.snelders@uu.nl
T. Pieters (*)
Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
e-mail: t.pieters@uu.nl

© Springer Nature Switzerland AG 2022 975

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_425
976 E. Vos et al.

therapeutic uses of psychedelics became restricted, in part due to their classifica-

tion as drugs with abuse potential in the mid-1960s. In the past decade, psyche-
delic research has been reestablished among several groups around the world
(Nutt, Erritzoe, and Carhart-Harris, Cell181 (1):24–28, 2020). There is growing
anticipation, awareness, and hope for the potential of these substances to become
medically approved as psychoactive treatments (Belouin and Henningfield, Neu-
ropharmacology 142:7–19, 2018). In this chapter, we offer a historical overview
of psychedelic drugs and their uses and a discussion of chemical and pharmaco-
logical properties, mechanisms of action, clinical studies, adverse effects, and
psychotherapeutic combination therapies with hallucinogens.

Introduction

For thousands of years, people have been using mind-altering drugs for religious and
healing purposes. The earliest evidence of the use of classical hallucinogens or
psychedelic substances dates back 5700 years to northeastern Mexico, where the
remains of peyote cacti and red beans containing mescaline were found in inhabited
caves (Rucker et al. 2018). The term “psychedelic” is a neologism derived from the
ancient Greek words “psychē” (“mind” or “soul”) and dēlein (“to reveal” or “to
open”). The mind-opening effects of the drugs make psychedelics valuable in
psychotherapy. This therapeutic value was widely researched in the 1950s and
1960s. Psychedelics showed great promise for medical use in combination with
psychotherapy and were considered breakthrough treatments for patients with major
depressive disorder (MDD), addiction, end-of-life anxiety, chronic pain, obsessive–
compulsive disorder, and anorexia (Nutt et al. 2020). Use was advocated by many
psychiatrists and psychotherapists from diverse cultural backgrounds (Snelders and
Kaplan 2002). Although the therapeutic effects seemed promising, research became
restricted after the 1960s because of the popularity of psychedelics for recreational
use (especially among young people), which led to most classical hallucinogens
being classified as drugs with abuse potential. In recent years, research on these
substances has been reestablished by different groups around the world (Snelders
and Pieters 2020).

History

Although there were experiments with therapy involving classical hallucinogens

such as peyote and mescaline before the Second World War, a decisive impetus
towards psychedelic research came with the discovery of lysergic acid
diethylamide (LSD), a hallucinogenic agent active in dosages of tens of micro-
grams. LSD was first synthesised in 1938 by the Swiss chemist Albert Hofmann.
Five years later, Hofmann discovered its psychoactive properties through self-
experimentation. Subsequently the Swiss pharmaceutical company Sandoz made
Hallucinogens as Therapeutic Agents: Past, Present, and Future 977

LSD available to qualified researchers in Europe and the USA under the brand
name Delysid (Geiger et al. 2018). The goal of this distribution was to gain insight
into the safety risks and potential clinical benefits of LSD (Belouin and
Henningfield 2018). The timing of this introduction turned out to be ideal when,
as part of a psychopharmacologic revolution, psychiatry changed during the
1950s. New stimulating, calming, and narcotic agents became available. LSD
and psilocybin were two such agents, fitting perfectly within this psychopharma-
cological revolution (Snelders and Pieters 2020). LSD research also played a
crucial role in the emerging field of modern neuropsychopharmacology. Scientists
noticed close similarities between the chemical structures of serotonin and LSD in
1954 (Woolley and Shaw 1954). In 1957, the influential American journal Life
published an article by Robert Gordon Wasson about the Mexican psilocybin
mushroom. One year later, Hofmann isolated the psychoactive compounds in the
mushroom: psilocybin and its most prominent active metabolite psilocin. Subse-
quently, Sandoz promoted the use of these psychedelic compounds for both basic
pharmaceutical and therapeutic clinical research (Geiger et al. 2018). The popu-
larity of psychedelics among scientists and psychiatrists increased. From the end
of the 1940s onwards, clinical studies of psychedelics were performed on patients
with psychoses, MDD, addiction, anxiety, or compulsive disorders (Rucker et al.
2018). Psychedelics share the remarkable ability of enhancing both perception of
meaning and suggestibility. Experiences of ego dissolution and spiritually mean-
ingful experiences are commonly mentioned responses, and are correlated with
the success of therapy (Breeksema et al. 2020). Between 1950 and 1965, over
1000 scientific papers on psychedelics were published and LSD alone was
prescribed as a treatment to over 40,000 patients. Unfortunately, most of these
studies were observational, uncontrolled, and with small number of participants.
When research continued, concern arose among scientists about the long-term
effects of psychedelics. The “dark side” of psychedelics (so-called “bad trips,”
psychoses, “flashbacks,” and suicides) became more visible (Snelders and Pieters
2020). In the sociopolitical context, psychedelics became associated with the
counterculture and political activism in the USA and Europe during the 1960s
and 1970s. These social developments led to psychedelics earning an unfavorable
reputation among many political and medical leaders. In 1966, hallucinogens
were placed in Schedule I of the UN Single Convention on Narcotic Drugs.
Manufacture, possession, and use of most psychedelics were regulated in national
legislations (Belouin and Henningfield 2018; Rucker et al. 2018). Thus, reduced
interest in psychedelics in medicine was related to a complex interplay of these
internal and external factors. It seemed that psychedelics, mainly LSD and
psilocybin, had followed the typical cyclic movement of psychotropic drugs:
from popularity to criticism to oblivion (Snelders et al. 2006). Still, psychoactive
substances have never completely disappeared and were always propagated by
psychedelic enthusiasts, both outside and inside of medicine (Snelders and Pieters
2020). Nowadays, there is growing anticipation, awareness, and hope for the
potential of psychedelic compounds to become medically approved as psychoac-
tive treatments (Belouin and Henningfield 2018).
978 E. Vos et al.

Chemistry and Mechanism of Action

Hallucinogens can be divided into classical, atypical, and dissociative compounds,

entactogens, and others. In Table1, the properties of these different hallucinogenic
substances are summarized. Psychedelics (or classical hallucinogens) are serotonergic
5-HT2A receptor agonists. 5-HT2A receptors are involved in signal transmission
across different locations in the brain and in a wide range of processes, such as
learning, memory, circadian rhythms, and processing pain stimuli. Serotonin 5-
HT2A receptors are strongly expressed in pyramidal neurons in layer V of the
neocortex. These neurons are involved in the regulation of attention and visual
perception. Through their serotonergic properties, hallucinogens mainly activate the
reticular nucleus. The reticular nucleus subsequently influences the thalamus via
GABA projection (van Elk 2020). The thalamus is a brain structure composed of
different nuclei, which filters information from inside (interoceptive signals) and
outside (exteroceptive signals) the body by means of feedback loops. In this way,
the cortex is being protected from an overload of intero- and exteroceptive signals.
This theory is called the cortico-striato-thalamo-cortical (CSTC) model. The GABA
projection of the reticular nucleus leads to inhibition of the thalamic filter mechanism.
This eventually causes an increase in signals entering the cortex, which comes together
with changed consciousness (Geyer and Vollenweider 2008). Besides 5-HT2A recep-
tors, classical psychedelics bind other receptor types, among which are dopamine
receptors and other serotonin subtypes. The trace amine-associated receptor (TAAR) is
also involved in the therapeutic effects of psychedelics. The TAAR1 receptor is
activated by psychedelics like N, N-dimethyltryptamine (DMT) and LSD, which
subsequently causes a decrease in dopaminergic activity (van Elk 2020; Carhart-Harris
2019). By changing sensitivity to stress and reward, these other receptor mechanisms
probably play a role in the therapeutic effects of psychedelics for mental disorders like
depression and addiction (Kyzar et al. 2017). However, there are currently more
questions than answers about the exact neurobiological mechanisms of classical
hallucinogens. These psychedelics have, at a sufficient dose, a mind opening effect
with changes in consciousness, perception, thinking, and feeling, and they often lead
to cosmic and/or mystic experiences (van den Brink et al. 2020a).
Atypical hallucinogens can also lead to psychedelic effects but differ in pharma-
cology and chemical structure from classical hallucinogens. Atypical hallucinogens
are kappa-opioid receptor antagonists which can lead to changes in perception
(hallucinations) and changes in the experience of time and place. There are also
dissociative substances with an antagonistic effect on the NMDA (glutamate) recep-
tor, such as, for example, ketamine, dextromethorphan, and nitrous oxide. In suffi-
ciently high doses, these substances lead to increased feelings of relaxation,
euphoria, and empathy, often accompanied by dissociation. Besides these, the
typical subjective effects of classical hallucinogens can also appear. Ibogaine is a
5-HT2A receptor agonist as well as a kappa-opioid receptor antagonist and addi-
tionally has a NMDA antagonist function. Lastly, there are empathogen or
entactogen substances (3,4-methylenedioxymethamphetamine, or MDMA) that
mainly act by increasing serotonin levels (van den Brink et al. 2020b).
Table 1 Properties of hallucinogens
Atypical Dissociative
Classical hallucinogens hallucinogens hallucinogens Entactogens Others
Mechanism 5-HT2A agonist (prim.) Kappa-opioid receptor NMDA-antagonist Increase release of 5-HT2Aagonist, kappa-
(van den Brink et al. antagonist (prim.) (van (prim.) (van den Brink serotonin (prim.) (van opioid receptor
2020b), increase synaptic den Brink et al. 2020b) et al. 2020b), increase den Brink et al. 2020b), antagonist, NMDA-
plasticity, reduce synaptic plasticity, increase fear extinction, antagonist (van den Brink
amygdala reactivity facilitate fear extinction, and reduce amygdala et al. 2020b)
during emotional and block memory activity (Gasser et al.
processing (Gasser et al. reconsolidation (Gasser 2014)
2014) et al. 2014)
Examples LSD, psilocybin, Salvia divinorum, S-ketamine, R-ketamine MDMA (ecstasy), MDA, Ibogaine (van den Brink
ayahuasca/DMT, Amanita muscaria (Nichols 2018), MDEA (van den Brink et al. 2020b)
mescaline/peyote, 2C-B (van den Brink et al. dextromethorphan, et al. 2020b)
(van den Brink et al. 2020b) nitrous oxide (van den
2020b) Brink et al. 2020b)
Effects Hallucinations, mind Hallucinations, Relaxation, euphoria, Energetic, euphoria, Intense perception,
manifesting, mystical changes in time and empathy, dissociation intense perception, changes in time and
experience, synesthesia space, dissociation (van den Brink et al. increased need for social space, mystical
Hallucinogens as Therapeutic Agents: Past, Present, and Future

(van den Brink et al. (van den Brink et al. 2020b) contact (van den Brink experience (van den Brink
2020b) 2020b) et al. 2020b) et al. 2020b)
Risks Psychosis (when Psychosis, HPPD (van Addiction, bladder Hyperthermia, liver Heart rhythm disturbance,
vulnerable), hallucinogen den Brink et al. 2020b) problems, HPPD (van den damage, serotonin psychosis (when
persisting perception Brink et al. 2020b) syndrome, HPPD (van vulnerable), HPPD (van
disorder (HPPD) (van den den Brink et al. 2020b), den Brink et al. 2020b)
Brink et al. 2020b) cardiac arrhythmias
(Ionescu et al. 2019)
Adapted from van den Brink et al. (2020b)
Prim. primarily
979
980 E. Vos et al.

Pharmacokinetics

In this paragraph, the pharmacokinetics of hallucinogens are summarized in Table 2

and the neurobiological mechanisms of action are elucidated.
The interaction of hallucinogens with other therapeutic substances is important to
take into consideration. Prior to the clinical use of hallucinogens, commonly pre-
scribed psychiatric medications should be withdrawn. For example, short-term
administration of selective serotonergic reuptake inhibitors (SSRIs), lithium, halo-
peridol, and some tricyclic antidepressants may increase sensitivity to hallucinogens.
Monoamine oxidase inhibitors and the chronic administration of SSRIs, in contrast,
appear to reduce sensitivity to psychedelics. Benzodiazepines and antagonists of the
5-HT2A receptor (most antipsychotic drugs) attenuate response to psychedelics,
particularly in short-term use (Rucker et al. 2018).

Clinical Studies

To give an indication of the present clinical studies into psychedelics, we have

chosen to show the most recent double-blind clinical studies in Table 3.

Table 2 Pharmacokinetics of hallucinogens used in psychedelic research

LSD Psilocybin MDMA Ketamine
Administration Oral (Gasser et Oral (Brown et al. Oral (Mithoefer Oral, IV, IN
al. 2014), IV 2017), IV (Carhart- et al. 2019) (Smith-
(Kaelen et al. Harris et al. 2012) Apeldoorn
2016) et al. 2020)
Mean dose 0.05–0.20 22–30 (Agin-Liebes 75.0–125 7.0–35 (Smith-
(mg) (Nichols 2018) et al. 2020) (Vermetten and Apeldoorn
Yehuda 2020) et al. 2020)
Metabolic NADH- UGT1A10 in the catechol-O- CYP2B6,
enzymes dependent small intestine and methyl CYP3A4,
microsomal UGT1A9 in the transferase CYP2A6,
liver enzymes liver (Geiger et al. (COMT) (De la CYP2B6
(Nichols 2018) 2018) Torre et al. (Zanos et al.
2004) 2018)
Half-life (h) 2.5–3.0 2.5–3.5 (Geiger 8.0–9.0 (De la 0.25–0.50
(Nichols 2018) et al. 2018) Torre et al. (Zanos et al.
2004) 2018)
Cmax (ng/mL) 1.3–3.1 1.1–2.3 (Brown 166–277 (De la 100–250
(Nichols 2018) et al. 2017) Torre et al. (Zanos et al.
2004) 2018)
Tmax (h) 1.4–1.5 1.3–3.0 (Brown 1.0–2.0 (De la 0.2–0.4 (World
(Nichols 2018) et al. 2017) Torre et al. Health
2004) Organization
2015)
IV intravenous, IN intranasal, Cmax peak plasma concentration, Tmax time to reach Cmax
Table 3 Clinical studies of hallucinogens
Study, N, patients
authors, country/ Predominant diagnosis, study arms, Results (scores, response/remission Dropout
year countries comparators, placebo rates) rates Relevant and severe side effects
RCT; N ¼ 12, Patients with life-threatening Significant reduction in state anxiety, N¼3 Emotional distress, anxiety, gait
Gasser et al. Switzerland disease, 20 or 200 μg LSD no significant reduction in trait disturbance
(2014) anxiety
RCT; N ¼ 51, US Patients with life-threatening Significant decrease in symptoms of N ¼ 10 Mild elevation of blood
Griffiths disease, 1 or 3 mg psilocybinand 22 depressed mood and anxiety, and pressure, nausea, physical/
et al. (2016) or 30 mg psilocybin increased quality of life psychological discomfort,
anxiety
RCT; Singh N ¼ 67, US Patients with treatment-resistant Significant effect on achieving rapid N ¼ 29 Headache, anxiety, transient
et al. (2016) depression, 0.5 mg/kg RS-ketamine onset and maintaining dissociation, nausea, and
or 0.9% sodium chloride placebo antidepressant efficacy dizziness
RCT; N ¼ 20, Patients with treatment-resistant Significant effect on self-rated N¼1 Transient anxiety, nausea,
Carhart- UK depression, 10 and 25 mg psilocybin mood, maximum at 5 weeks paranoia, and
Harris et al. uncommunicativeness
Hallucinogens as Therapeutic Agents: Past, Present, and Future

(2018)
RCT; N ¼ 26, US Patients with treatment-resistant No significant difference in N¼2 No adverse events described
Ionescu depression, 6  0.5 mg/kg ketamine depression severity between placebo
et al. (2019) or saline placebo and ketamine
RCT; N ¼ 26, US Patients with post-traumatic stress Active doses of MDMA with N¼2 Anxiety, headache, muscle
Mithoefer disorder (PTSD), 30, 75, or 125 mg adjunctive psychotherapy were tension, and fatigue
et al. (2018) MDMA effective and well tolerated in
reducing PTSD symptoms
981
982 E. Vos et al.

Indications

A brief overview is given in Table 4 of the clinical indications of hallucinogens used

for in trials since 2000.

Adverse Effects and Toxicology

In this paragraph, we will discuss frequently reported side effects of hallucinogens

when moderate clinical dosages are used in a controlled setting. Because of their low
toxicity and the absence of dependence liability, classical hallucinogens are physi-
ologically safe substances. Physical side effects that do occur, such as headache,
nausea, and increased blood pressure, are mild and transient in nature. Most reported
psychic side effects are negative emotions like fear, panic, paranoia, and dysphoria.
More serious adverse events include seizures and hallucinogen persisting perception
disorder (HPPD). HPPD is associated with overly intense or frequent psychedelic
experiences which may cause abrupt “flashbacks” to a psychedelic experience
(Breeksema et al. 2020; Nichols 2018; Geiger et al. 2018). Most of the reported
physical side effects of dissociative anaesthetics such as ketamine are headache,
dizziness, increased blood pressure, nausea, sleepiness, and increased heart rate.
Dissociation was the most reported psychological side effect followed by fear. Most
side effects were reported right after administration, linked to peak plasma concen-
tration, and were of short duration and transient. Potential risks of long-term use are
cognitive changes, ketamine dependence, toxicity of urinary tract and liver (Smith-
Apeldoorn et al. 2020), and HPPD (van den Brink et al. 2020a). The acute side
effects of entactogens, such as MDMA, vary from relatively mild and temporary
(loss of concentration, increased perspiration, and sleeplessness) to severe and

Table 4 Clinical indications of psychedelics

Substance Indication in trials
Classic
psychedelics
LSD + PT Treatment-resistant depression, anxiety associated with life-threatening
diseases
Treatment-resistant depression, anxiety associated with advanced-stage
Psilocybin + PT cancer, nicotine addiction, alcohol addiction, and obsessive–compulsive
disorder
Treatment-resistant depression
Ayahuasca + PT
Entactogens
MDMA + PT Treatment-resistant depression, PTSD
Dissociative
anesthetics
Ketamine + PT Treatment-resistant depression
Reprinted from van der Gronde et al. (2020)
Hallucinogens as Therapeutic Agents: Past, Present, and Future 983

sometimes permanent. Hyperthermia in particular is a frequently observed adverse

health effect. However, this is probably due to the use of the drug under unfavorable
circumstances instead of within a controlled research setting. At the moment, there is
little convincing evidence to suggest that entactogens cause brain damage, but
cognitive side effects cannot be ruled out (van Amsterdam and van den Brink
2020; Dunlap et al. 2018). Furthermore, individual risk profiles are important to
take into consideration. For example, in several studies individuals who scored high
in terms of personality traits such as emotional liability or rigidity were excluded on
the grounds that these traits have been associated with negative experiences during
hallucinogen administration. Thorough psychiatric screening is therefore necessary
for minimizing the risks of psychedelic use (Johnson et al. 2008).

Combination Therapy

Psychedelic-assisted therapy refers to a specific manner of psychedelic substance

use in which the psychological and subjective effects of the substance play an
important role in psychotherapeutic intervention. Psychedelic-assisted psycho-
therapy usually includes three parts. First, there are preparation sessions before
the psychedelic session during which psychoeducation is provided regarding the
psychedelic experience. Second, a psychedelic dosing session takes place, during
which support is provided to ensure safety and meet any immediate needs during
the experience. Finally, integration or “debriefing” sessions are held, during
which the participant’s experience is thoroughly reviewed. In some cases, thera-
peutic techniques are applied during integration sessions to reinforce specific
aspects of the experience and sustain beneficial patterns of behavior and thought.
Integration can thus be understood as a continuation of the therapeutic process
that began during preparation sessions and became intensified during the psyche-
delic experience (Sloshower et al. 2019). Present trials are always guided by two
experienced mental health professionals (Carhart-Harris et al. 2018). Psychedelics
share the remarkable ability to enhance the perception of meaning and suggest-
ibility. Commonly mentioned mediators of this response are experiences of ego
dissolution and spiritually meaningful experiences. The occurrence of these
mediators is correlated with the success of therapy (Hartogsohn 2018). The
therapeutic action of psychedelics seems to be fundamentally reliant on the
influence of “set” and “setting.” Set includes the personality structure or profile
of the user and the assumptions, expectations, and other preexisting psychological
factors (including psychopathology) one brings to an experience. Setting is
explained as the environmental context in which the experience occurs, including
cultural beliefs and social relationships (e.g., between therapist and patient).
During recent trials with psychedelics, special attention has been given to set
and setting by providing extensive psychological preparation (involving several
visits before and after the psychedelic session) and paying attention to the
therapeutic environment (aesthetic and living room-like with low lighting and
carefully selected music playlists) (Carhart-Harris et al. 2018).
984 E. Vos et al.

Conclusion

Research into classical hallucinogens or psychedelics has been reestablished in

recent years, after restrictions in the late twentieth century due to extenuating factors
in medicine, industry, science, and the public sphere. Present preliminary studies
with psychedelics have shown promise for using them as a potential treatment for
anxiety disorders, addiction, major depressive disorder (MDD), and post-traumatic
stress disorder (PTSD). The ability for psychedelics to enhance perceptions, repro-
gram meanings and evaluations of experiences, and increase suggestibility to ther-
apists’ interventions appears to make them an important possible addition to
psychotherapy. When moderate clinical dosages are used in a controlled setting,
psychedelics are physiologically safe substances with low toxicity and an absence of
dependence liability. However, thorough clinical screening is necessary in order to
minimize risk factors, and attention must be paid to set and setting in the therapeutic
sessions. The resurrection of research into the therapeutic application and neurosci-
ence of psychedelics is one of the most important innovations in psychiatry in recent
decades. In the future, psychedelics could be used as psychoactive therapy in
combination with psychotherapy.

Cross-References

▶ Ethical Issues in Neuropsychopharmacotherapy: US Perspective

▶ Ketamine in Psychiatric Disorders
▶ Psychopharmacology: A Brief Overview of Its History

References
Agin-Liebes GI, Malone T, Yalch MM, Mennenga SE, Ponté KL, Guss J, Bossis AP, Grigsby J,
Fischer S, Ross S. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric
and existential distress in patients with life-threatening cancer. J Psychopharmacol. 2020;34
(2):155–66.
Belouin SJ, Henningfield JE. Psychedelics: where we are now, why we got here, what we must do.
Neuropharmacology. 2018;142:7–19.
Breeksema JJ, van den Brink W, Veraart JKE, Smith-Apeldoorn SY, Vermetten E, Schoevers RA.
Psychedelica bij de behandeling van depressie, angst en obsessieve-compulsieve stoornis.
Tijdschr Psychiatr. 2020;62(8):618–28.
Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller D, Thomas CD, Hetzel SJ,
Henriquez KM, Ribaudo AS, Hutson PR. Pharmacokinetics of escalating doses of oral psilo-
cybin in healthy adults. Clin Pharmacokinet. 2017;56(12):1543–54.
Carhart-Harris RL. How do psychedelics work? Curr Opin Psychiatry. 2019;32(1):16–21.
Carhart-Harris RL, Leech R, Williams TM, Erritzoe D, Abbasi N, Bargiotas T, Hobden P, Sharp DJ,
Evans J, Feilding A, Wise RG, Nutt DJ. Implications for psychedelic-assisted psychotherapy:
functional magnetic resonance imaging study with psilocybin. Br J Psychiatry. 2012;200
(3):238–44.
Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, Kaelen M, Giribaldi
B, Bloomfield M, Pilling S, Rickard JA, Forbes B, Feilding A, Taylor D, Curran HV, Nutt DJ.
Hallucinogens as Therapeutic Agents: Past, Present, and Future 985

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.

Psychopharmacology. 2018;235(2):399–408.
De la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J. Human
pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit.
2004;26(2):137–44.
Dunlap LE, Andrews AM, Olson DE. Dark classics in chemical neuroscience: 3,4-methylenediox-
ymethamphetamine. ACS Chem Neurosci. 2018;9(10):2408–27.
Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B, Passie T, Brenneisen R. Safety and
efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-
threatening diseases. J Nerv Ment Dis. 2014;202(7):513–20.
Geiger HA, Wurst MG, Daniels RN. DARK classics in chemical neuroscience: psilocybin. ACS
Chem Neurosci. 2018;9(10):2438–47.
Geyer MA, Vollenweider FX. Serotonin research: contributions to understanding psychoses. Trends
Pharmacol Sci. 2008;29(9):445–53.
Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP,
Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and
anxiety in patients with life-threatening cancer: a randomized double-blind trial. J
Psychopharmacol. 2016;30(12):1181–97.
Hartogsohn I. The meaning-enhancing properties of psychedelics and their mediator role in
psychedelic therapy, spirituality, and creativity. Front Neurosci. 2018;12:129.
Ionescu DF, Bentley KH, Eikermann M, Taylor N, Akeju O, Swee MB, Pavone KJ, Petrie SR,
Dording C, Mischoulon D, Alpert JE, Brown EN, Baer L, Nock MK, Fava M, Cusin C. Repeat-
dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: a
randomized, double blind, placebo controlled trial. J Affect Disord. 2019;243:516–24.
Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J
Psychopharmacol. 2008;22(6):603–20.
Kaelen M, Roseman L, Kahan J, Santos-Ribeiro A, Orban C, Lorenz R, Barrett FS, Bolstridge M,
Williams T, Williams L, Wall MB, Feilding A, Muthukumaraswamy S, Nutt DJ, Carhart-Harris
R. LSD modulates music-induced imagery via changes in parahippocampal connectivity. Eur
Neuropsychopharmacol. 2016;26(7):1099–109.
Kyzar EJ, Nichols CD, Gainetdinov RR, Nichols DE, Kalueff AV. Psychedelic drugs in biomed-
icine. Trends Pharmacol Sci. 2017;38(11):992–1005.
Mithoefer MC, Mithoefer AT, Feduccia AA, Jerome L, Wagner M, Wymer J, Holland J, Hamilton
S, Yazar-Klosinski B, Emerson A, Doblin R. 3,4-Methylenedioxymethamphetamine (MDMA)-
assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and
police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psy-
chiatry. 2018;5(6):486–97.
Mithoefer MC, Feduccia AA, Jerome L, Mithoefer A, Wagner M, Walsh Z, Hamilton S, Yazar-
Klosinski B, Emerson A, Doblin R. MDMA-assisted psychotherapy for treatment of PTSD:
study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized
controlled trials. Psychopharmacology. 2019;236(9):2735–45.
Nichols DE. Dark classics in chemical neuroscience: lysergic acid diethylamide (LSD). ACS Chem
Neurosci. 2018;9(10):2331–43.
Nutt D, Erritzoe D, Carhart-Harris R. Psychedelic psychiatry’s brave new world. Cell. 2020;181
(1):24–8.
Rucker JJ, Iliff J, Nutt DJ. Psychiatry & the psychedelic drugs. Past, present & future. Neurophar-
macology. 2018;142:200–18.
Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, Pinter C, Murrough JW, Sanacora G,
Shelton RC, Kurian B, Winokur A, Fava M, Manji H, Drevets WC, Van Nueten L. A double-
blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in
patients with treatment-resistant depression. Am J Psychiatry. 2016;173(8):816–26.
Sloshower J, Guss J, Krause R, Wallace RM, Williams MT, Reed S, Skinta MD. Psilocybin-assisted
therapy of major depressive disorder using Acceptance and Commitment Therapy as a thera-
peutic frame. J Contextual Behav Sci. 2019;15:12–9.
986 E. Vos et al.

Smith-Apeldoorn SY, Veraart JKE, Kamphuis J, Breeksema JJ, van den Brink W, Aan Het Rot M,
Schoevers RA. Ketamine als anestheticum, analgeticum en als antidepressivum. Tijdschr
Psychiatr. 2020;62(8):629–39.
Snelders S, Kaplan C. LSD therapy in Dutch psychiatry: changing socio-political settings and
medical sets. Med Hist. 2002;46(2):221–40.
Snelders S, Pieters T. De opkomst, val en opkomst van LSD. Tijdschr Psychiatr. 2020;62(8):707–12.
Snelders S, Kaplan C, Pieters T. On cannabis, chloral hydrate, and career cycles of psychotropic
drugs in medicine. Bull Hist Med. 2006;80(1):95–114.
van Amsterdam J, van den Brink W. Recreatief ecstasygebruik in Nederland: gebruikskenmerken,
gezondheidsschade en criminaliteit. Tijdschr Psychiatr. 2020;62(8):693–701.
van den Brink W, Breeksema JJ, Vermetten E, Schoevers RA. Psychedelica bij de behandeling van
verslaving en psychose. Tijdschr Psychiatr. 2020a;62(8):650–8.
van den Brink W, Schoevers RA, Vermetten E, Van R, Breeksema JJ. Effectiviteit van psychedelica
bij de behandeling van psychiatrische aandoeningen: inleiding. Tijdschr Psychiatr. 2020b;62
(8):613–7.
van der Gronde T, Los L, Herremans A, Oosting R, Zorzanelli R, Pieters T. Toward a new model of
understanding, preventing, and treating adolescent depression focusing on exhaustion and
stress. Front Psychiatry. 2020;11:412.
van Elk M. Neurowetenschappelijke en psychologische verklaringen voor de therapeutische
effecten van psychedelica. Tijdschr Psychiatr. 2020;62(8):677–83.
Vermetten E, Yehuda R. MDMA-assisted psychotherapy for posttraumatic stress disorder: a
promising novel approach to treatment. Neuropsychopharmacology. 2020;45(1):231–2.
Woolley DW, Shaw E. A biochemical and pharmacological suggestion about certain mental
disorders. Proc Natl Acad Sci U S A. 1954;40(4):228–31.
World Health Organization. Ketamine (INN): update review report. Geneva: World Health Orga-
nization; 2015.
Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EFR, Albuquerque
EX, Thomas CJ, Zarate CA Jr, Gould TD. Ketamine and ketamine metabolite pharmacology:
insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621–60.
Lipid Metabolism Disturbances During
Antipsychotic Treatment for Schizophrenia

Shin Ono and Toshiyuki Someya

Contents
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
Lipid Metabolism and Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
The Risk of Hyperlipidemia and Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990
Antipsychotic Drugs and Lipid Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 992
Meta-analysis of Lipid Parameters Among Antipychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994
Effect of Smoking Status and Gender Differences on Lipid Parameters . . . . . . . . . . . . . . . . . . . . . . 994
Race/Ethnicity Differences in the Risk of Hyperlipidemia Among Schizophrenia . . . . . . . . . . . . 995
Hypotheses Regarding the Mechanisms for the Association Between Antipsychotics
and Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
Guidelines and Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999

Abstract
Patients with schizophrenia experience increased morbidity and mortality and have
an approximately 20% shorter lifespan. Patients with schizophrenia also have a
relatively increased prevalence of cardiometabolic risk factors, such as obesity, type
2 diabetes, hypertension, hyperglycemia, and dyslipidemia. The odds ratio (OR) for
metabolic syndrome in patients with chronic schizophrenia compared to the general
population was 2.35. Although the individual differences of these metabolic
disturbances have been observed, an understanding of the underlying mechanisms
is still uncertain. A meta-analysis demonstrated that approximately 40% of patients
with schizophrenia and related disorders have abnormalities in lipid metabolism.

S. Ono (*)
Department of Community Psychiatric Medicine, Niigata University Graduate School of Medical
and Dental Sciences, Niigata, Japan
e-mail: onoshin@med.niigata-u.ac.jp
T. Someya
Department of Psychiatry, Niigata University Graduates School of Medicine and Dental Science,
Niigata, Japan
e-mail: psy@med.niigata-u.ac.jp

© Springer Nature Switzerland AG 2022 987

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_402
988 S. Ono and T. Someya

This chapter reviews the association between antipsychotics and dyslipidemia in

patients with schizophrenia and the appropriate monitoring and interventions to
address metabolic disorders in this population. Olanzapine use was associated with
nearly a five-fold increase in the odds of developing hyperlipidemia compared with
no antipsychotic exposure in database studies. In meta-analyses, total cholesterol
level increased with quetiapine, olanzapine, and clozapine. Further prospective
studies are necessary on the association between schizophrenia and lipid metabo-
lism including various factors such as age, weight, gender, diet, exercise, and race
that may affect lipid metabolism. In addition, regular monitoring is important in
clinical settings.

Background

Patients with schizophrenia experience increased morbidity and mortality and have
an approximately 20% shorter life expectancy (Harris and Barraclough 1998),
manifesting as a premature mortality gap of 10–20 years compared with the
general population (Walker et al. 2015). Patients with schizophrenia also have a
relatively increased prevalence of cardiometabolic risk factors, such as obesity,
type 2 diabetes, hypertension, hyperglycemia, and dyslipidemia (Dixon et al. 2000;
McEvoy et al. 2005; Meyer and Stahl 2009). A retrospective cohort study of adult
patients with schizophrenia aged 20–64 years in the United States showed mortal-
ity rate was >3.5 times greater than that for general population adults for all-cause
standardized mortality ratios (3.7; 95% confidence interval [CI], 3.7–3.7) (Olfson
et al. 2015). In this cohort, schizophrenic patients with cardiovascular disease had
the highest mortality rate (403.2 per 100,000 person-years) and a standardized
mortality ratio of 3.6 (95% CI, 3.5%–3.6%) (Olfson et al. 2015). Furthermore,
meta-analysis revealed that 33% of people with schizophrenia have metabolic
syndrome, with a rate as high as 69% in schizophrenic patients with chronic illness
(Vancampfort et al. 2015). The odds ratio (OR) for metabolic syndrome in patients
with chronic schizophrenia compared to the general population was 2.35
(Vancampfort et al. 2013).
In the general population, lipid metabolism disorders have been associated
with an increased risk for cardiovascular events, such as myocardial infarction and
stroke (Kannel et al. 1971; Gordon et al. 1981; Castelli et al. 1986). A decreased
high-density lipoprotein (HDL) level, a cardiometabolic risk factor, is strongly and
inversely associated with the risk of coronary heart disease (Chirovsky et al. 2009).
Some studies in patients with schizophrenia attributed their metabolic disturbance
to poor lifestyle choices, such as a sedentary lifestyle, smoking, poor diet, and
prolonged stress, as well as use of antipsychotic drugs, and genetic susceptibility
(De Hert et al. 2009; Correll et al. 2011). In addition, significant elevations in
triglyceride and cholesterol levels were reported in association with second-
generation antipsychotic (SGA) treatment (Meyer 2002).
Although the individual differences of these metabolic disturbances have been
observed, an understanding of the underlying mechanisms is still uncertain (De Hert
Lipid Metabolism Disturbances During Antipsychotic Treatment for. . . 989

et al. 2012). A meta-analysis demonstrated that approximately 40% of patients with

schizophrenia and related disorders have abnormalities in lipid metabolism (Mitchell
et al. 2013). Although attention has been focused on antipsychotic-related lipid
metabolism, metabolic syndrome, and cardiovascular disease risk in schizophrenia,
these patients do not receive adequate monitoring of cardiovascular health (Baller
et al. 2015). Against this background, this chapter reviews the association between
antipsychotics and dyslipidemia in patients with schizophrenia and the appropriate
monitoring and interventions to address metabolic disorders in this population.

Lipid Metabolism and Schizophrenia

Metabolic risk factors are often present in patients with a first episode of psychosis or
drug-naive schizophrenia and are thought to be associated with sedentary lifestyle,
poor diet, smoking, and prolonged stress. Regarding sedentary lifestyle, the degree
of moderate and vigorous physical activity for the current population with schizo-
phrenia remains significantly less compared with healthy controls (Stubbs et al.
2016). Regarding HDL, levels were lower in both the drug-naive and drug-free
groups of patients with schizophrenia compared with healthy controls (Enez Darcin
et al. 2015). A case control study that compared differences in lipid metabolism
parameters between drug-free patients with a first episode of schizophrenia and
healthy individuals matched for age, race, and sex showed lower total cholesterol
and higher HDL levels for the schizophrenia patients (Wu et al. 2013). In contrast,
another study conducted in drug-free psychotic patients diagnosed with schizophre-
nia spectrum disorder after their first episode reported no significant difference in
lipid profile compared with healthy controls (Sengupta et al. 2008). Studies with
drug-naive patients with a first episode of schizophrenia found no significant differ-
ences in a range of metabolic measures, including blood glucose, lipids, insulin, and
measures of fat deposits (Arranz et al. 2004; Zhang et al. 2004). This no significant
metabolic difference from the healthy population has also been reported for drug-
naive participants in the European First Episode schizophrenia Trial (the EUFEST
study) (Fleischhacker et al. 2013). This range of findings illustrates the controversy
over the presence of dyslipidemia in unmedicated schizophrenia.
A meta-analysis investigated lipid metabolism in which fasting total cholesterol,
low-density lipoprotein (LDL), HDL, triglyceride, and adipocytokine parameters
were compared between individuals with a first episode of schizophrenia and no or
minimal antipsychotic drug exposure and healthy controls. The 20 case-control
studies that met inclusion criteria included 1167 patients and 1184 controls. Total
cholesterol and LDL levels were significantly decreased in schizophrenic patients
versus controls, corresponding to an absolute reduction of 0.26 mmol/L and
0.15 mmol/L, respectively. Triglyceride levels were also significantly increased in
the schizophrenia group, corresponding to an absolute increase of 0.08 mmol/L.
However, HDL and leptin levels were not altered in patients with schizophrenia
compared with controls (Pillinger et al. 2017).
990 S. Ono and T. Someya

Another meta-analysis and systematic review of patients with first-episode,

non-affective psychosis assessed 19 studies representing 1803 participants. Pooled
analysis revealed that these patients had significantly lower levels of total cholesterol
(effect size (ES),
0.16; 95% CI,
0.27% to
0.06%), LDL (ES,
0.13; 95% CI,

0.24 to
0.01), and HDL (ES,
0.27; 95% CI,
0.49% to
0.05%) as well as
significantly higher levels of triglyceride (ES, 0.22; 95% CI, 0.11%–0.32%) com-
pared with controls. After removing single studies in the sensitivity analysis, the ES
estimate for LDL levels was insignificant. Antipsychotic-naive patients with first-
episode non-affective psychosis presented subclinical dyslipidemia (Misiak et al.
2017). Although the extent of metabolic and lipid changes in first-episode or drug-
naive patients with schizophrenia remains unclear, schizophrenic patients appear to
have changes in lipid metabolism, such as in LDL, HDL, and triglyceride levels,
regardless of the effects of antipsychotics.

The Risk of Hyperlipidemia and Antipsychotics

It is well established that antipsychotic drug treatment can induce substantial weight
gain, with different drugs having greater or lesser effects and the greatest increases
occurring with SGA (Allison et al. 1999; Taylor and McAskill 2000). The mecha-
nisms underlying this antipsychotic drug-induced weight gain are likely multifacto-
rial. Antagonism of the serotonin receptor 5-HT2C, for which several antipsychotic
drugs – particularly olanzapine and clozapine – have high affinity, is a strong
candidate because the receptor is known to influence appetite and thereby weight
gain (Nonogaki et al. 1998). Association of a polymorphism of the 5-HT2C receptor
gene with antipsychotic drug-induced weight gain provides further evidence of the
importance of the receptor in this process (Reynolds et al. 2002). Dyslipidemia and
impaired glucose tolerance may be secondary to obesity and lifestyle habits or may
be caused by oral antipsychotics themselves.
Several database studies have estimated the relative risk of developing hyper-
lipidemia associated with SGAs. A nested case-control study of 1268 incident
cases of hyperlipidemia among 18,309 schizophrenia patients was conducted in
England and Wales (Koro et al. 2002). Olanzapine use was associated with nearly a
five-fold increase in the odds of developing hyperlipidemia compared with no
antipsychotic exposure, controlling for sex, age, and other medications and disease
conditions influencing lipid levels (OR, 4.65; 95% CI, 2.44%–8.85%). Risperi-
done was not associated with an increased OR for hyperlipidemia compared with
no antipsychotic exposure (1.12; 95% CI, 0.60%–2.11%), whereas the OR of
olanzapine versus first-generation antipsychotics (FGAs) was 1.4 (95% CI,
0.92%–2.22%).
In a study using a medical claims database in California and controlling for age,
ethnicity, type 2 diabetes, or hypothyroidism, the reported risk of developing
hyperlipidemia was increased for olanzapine (OR, 1.20; 95% CI, 1.08%–1.33%)
Lipid Metabolism Disturbances During Antipsychotic Treatment for. . . 991

compared with FGAs. Exposure to clozapine (OR, 1.16; 95% CI, 0.99%–1.37%),
risperidone (OR, 1.00; 95% CI, 0.90%–1.12%), and quetiapine (OR, 1.01; 95% CI,
0.78%–1.32%) was not associated with an increased risk during the 12-week
exposure window (Lambert et al. 2005).
A case-control analysis using pharmacy and claims in the United States compared
patients managed without antipsychotics to those who received antipsychotics
and showed that treatment was associated with a significant increase in risk of
incident hyperlipidemia with the following drugs: clozapine (OR, 1.82; 95% CI,
1.61%–2.05%), risperidone (OR, 1.53; 95% CI, 1.43%–1.64%), quetiapine (OR,
1.52; 95% CI, 1.40%–1.65%), olanzapine (OR, 1.56; 95% CI, 1.47%–1.67%),
ziprasidone (OR, 1.40; 95% CI, 1.19%–1.65%), and FGAs (OR, 1.26; 95% CI,
1.14%–1.39%). However, aripiprazole (OR, 1.19; 95% CI, 0.94%–1.52%) was not
associated with an increased risk (Olfson et al. 2006).
In Japan, a sequence symmetry analysis using health insurance claims data was
conducted to analyze the risks for hyperlipidemia associated with these drugs:
risperidone, paliperidone, perospirone hydrochloride hydrate, blonanserin, cloza-
pine, olanzapine, quetiapine fumarate, aripiprazole, and zotepine. Olanzapine was
significantly associated with increased hyperlipidemia (adjusted sequence ratio
[ASR], 1.56; 95% CI, 1.25%–1.95%). The ASRs obtained for risperidone (1.01;
95% CI, 0.80%–1.27%), perospirone (0.93; 95% CI, 0.63–1.39), blonanserin
(0.83; 95% CI, 0.52–1.33), quetiapine fumarate (0.93; 95% CI, 0.73%–1.18%),
and aripiprazole (1.02; 95% CI, 0.82%–1.26%) were all approximately 1.0. Unsta-
ble estimates, defined as wide CIs, were obtained for paliperidone and zotepine
because of the small sample size (Takeuchi et al. 2015). These database studies
show that exposure to olanzapine or clozapine results in a high OR for
hyperlipidemia.
SGAs are thought to be more commonly associated with dyslipidemia than
FGAs. Lund et al. investigated the risk of dyslipidemia in a comparison between
clozapine and FGAs in a retrospective cohort using medical and pharmacy claims
(Lund et al. 2001). They reported no significant differences in overall incidence
rates for hyperlipidemia between the two patient groups, adjusting for age, sex, and
duration of available follow-up. Among younger patients (age 20–34 years),
clozapine was associated with a significantly increased relative risk of hyperlipid-
emia (2.4 [95% CI, 1.1–5.2]). A systematic review and meta-analysis evaluated
SGAs and FGAs for the risk of dyslipidemia in patients with severe mental illness.
The analysis included a cross-sectional study, a cohort study, a case-control study,
and an intervention study that directly compared SGAs and FGAs in patients with
severe psychiatric disorders and evaluated dyslipidemia as the primary or second-
ary outcome. The reported associations between SGAs versus FGAs with
dyslipidemia were inconsistent, with high variability among studies, and ulti-
mately only a full qualitative synthesis was feasible. Determining the relative
risk of SGAs and FGAs in the effects of antipsychotics on dyslipidemia can be
difficult to clarify clinically because each drug can cause a variety of adverse
effects (Buhagiar and Jabbar 2019).
992 S. Ono and T. Someya

Antipsychotic Drugs and Lipid Disturbances

Several open-label studies, randomized controlled trials (RCT), and meta-analyses

have been conducted on the relationship between efficacy and tolerability of anti-
psychotics including lipid parameters. Among them, many reports show that
olanzapine and clozapine are related to lipid metabolism, as described in the
following text.
Serum triglyceride level elevations associated with clozapine treatment have been
prospectively reported at 12 weeks of treatment (Dursun et al. 1999), and retrospec-
tively reported at 6 months of treatment (Spivak et al. 1999). In a 5-year naturalistic
study of patients treated with clozapine, there was a nonsignificant increase in total
cholesterol and a significant increase in triglyceride levels (Henderson et al. 2000).
In a cross- sectional study of 210 patients, with schizophrenic or schizoaffective
disorder treated with clozapine, risperidone, olanzapine, or a FGA, patients treated
with clozapine and olanzapine had higher triglyceride levels than risperidone
patients (Smith et al. 2005).
A randomized double-blind 14-week trial measured cholesterol in treatment-
resistant schizophrenia patients, and participants in the trial received clozapine,
olanzapine, risperidone, or haloperidol. There was a significant increase in choles-
terol in the olanzapine, with a nonsignificant increase in cholesterol in risperidone
(Lindenmayer et al. 2003). In an 8-week double-blind randomized trial in patients
treated with risperidone or olanzapine, increases in mean total cholesterol (13.5 mg/
dl (SD 2.4)), LDL cholesterol (11.0 mg/dl (SD 2.2)), and triglyceride (14.8 mg/dl
(SD 7.6)) occurred in the olanzapine group, while significant changes in total
cholesterol (
3.9 mg/dl (SD 2.5)) and triglyceride (
32.8 mg/dl (SD 7.8)) were
noted in the risperidone group (Kelly et al. 2008). In a randomized 5-month study in
patients with chronic schizophrenia, there were no differential effects on total
cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride between olanzapine
and risperidone (Smith et al. 2010).
In a 28-week, randomized, double-blind study of olanzapine versus aripiprazole,
mean total cholesterol change was +4.09 mg/dL for olanzapine and
9.85 mg/dL for
aripiprazole. Mean LDL cholesterol change was +1.74 mg/dL for olanzapine and

6.72 mg/dL for aripiprazole. Mean HDL cholesterol change was
1.70 mg/dL for
olanzapine and +1.43 mg/dL for aripiprazole. Mean triglyceride change was
+25.66 mg/dL for olanzapine and
17.52 mg/dL for aripiprazole (Kane et al.
2009). Similarly, in a 26-week comparative study by McQuade RD et al., changes
of total cholesterol, HDL cholesterol, and triglyceride were significantly different
between olanzapine and aripiprazole, with worsening of the lipid profile among
patients treated with olanzapine (McQuade et al. 2004). In a 52-week comparison
study of olanzapine and aripiprazole, olanzapine was associated with significantly
greater weight gain than aripiprazole (Chrzanowski et al. 2006). The change in HDL
from baseline was significantly lower in the olanzapine group than in the
aripiprazole group at the 52-week endpoint at which the weight gain related to the
two drugs was highest. In a 1-year observation study on first-episode drug-naive
patients, significant differences were found in HDL decreases between groups of
Lipid Metabolism Disturbances During Antipsychotic Treatment for. . . 993

patients who gained >20% or <20% of their baseline body mass index, and no
significant differences in HDL levels between olanzapine- and risperidone-treated
patients were shown (Perez-Iglesias et al. 2009). In a randomized comparison study
of aripiprazole and olanzapine, no group differences were observed in the propor-
tions of patients with potentially clinically significant fasting HDL levels because the
weight gain at the study endpoint was significantly greater with olanzapine than with
aripiprazole (Fleischhacker et al. 2009).
In a 28-week RCT of olanzapine and ziprasidone, lipid parameters of
olanzapine versus ziprasidone were shown: increased total cholesterol (0.08 mmol/L
(SD 0.95) vs. mean,
0.33 mmol/L (SD 0.81)); increased LDL (0.02 mmol/L
(SD 0.77) vs. –0.27 mmol/L (SD 0.67)), and increased triglyceride (0.39 mmol/L
(SD 1.99) vs. –0.24 mmol/L (SD 1.09)). However, a significant decrease in HDL levels
was shown for the olanzapine (
0.06 mmol/L (SD 0.26)) versus ziprasidone
(0.02 mmol/L (SD 0.25)) (Breier et al. 2005).
In a 6-week RCT of paliperidone extended release (ER), mean changes from
baseline in LDL, HDL, total cholesterol, and triglyceride levels were not different
among the lower-dose, higher-dose paliperidone ER and placebo (Canuso et al.
2010). In another study, paliperidone ER at three doses (3 mg, 9 mg, and 15 mg) and
olanzapine were compared with placebo in a 6-week RCT. No significant changes
from baseline to endpoint in LDL, HDL, total cholesterol, or triglyceride levels were
found (Davidson et al. 2007).
In a 6-week RCT of brexpiprazole, slight increases occurred in total cholesterol
and HDL levels from baseline to the last visit with 2 mg (0.63 mg/dL (SD 31.74)
and 1.33 mg/dL (SD 9.11)) and 4 mg (4.24 mg/dL (SD 30.33) and 0.48 mg/dL
(SD 7.26)) for the brexpiprazole groups compared with slight decreases in the
placebo group; however, these changes were neither clinically relevant nor statis-
tically significant. Slight increases were also shown in LDL and triglyceride levels
in the 4-mg brexpiprazole group (2.57 mg/dL (SD 26.79) and 6.76 mg/dL
(SD 69.54)); however, these differences were also not clinically relevant (Correll
et al. 2015).
In a phase III trial of cariprazine, mean changes from baseline of total cholesterol
and LDL levels were significantly decreased in the cariprazine 6- mg/day group
(
4.5 md/dL (SD 32.4) and 3.5 md/dL (SD 30.7)) versus placebo. No other
differences among groups were shown for changes in total cholesterol, LDL,
HDL, and triglyceride levels (Durgam et al. 2015). Subsequent placebo-controlled
trials also reported similar results for parameters such as total cholesterol, LDL,
HDL, and triglyceride levels (Earley et al. 2017).
In a 6-week RCT of lurasidone, endpoint changes in levels of total cholesterol,
triglyceride, and LDL were comparable for both the lurasidone (40 mg/day and
120 mg/day) and placebo groups, whereas the olanzapine group showed a signif-
icant median increase compared with the placebo group in cholesterol levels,
LDL, and triglyceride (Meltzer et al. 2011). In another 6-week RCT in Asia, no
clinically meaningful differences were shown between lurasidone and placebo in
terms of the effect on total cholesterol, LDL, HDL, and triglyceride levels
(Higuchi et al. 2019).
994 S. Ono and T. Someya

Meta-analysis of Lipid Parameters Among Antipychotics

Some studies were conducted as meta-analyses to determine the association between

antipsychotics and lipid parameters. A recent systematic review and meta-analysis
of SGAs and metabolic changes searched for a blind, randomized controlled trial
comparing placebo with 18 antipsychotics for the acute treatment of schizophrenia:
amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, flupen-
thixol, fluphenazine, haloperidol, iloperidone, lurasidone, olanzapine, quetiapine,
risperidone, paliperidone, sertindole, ziprasidone, and zotepine. The median duration
of treatment was 6 weeks. For total cholesterol levels, compared with placebo, no
differences were observed with iloperidone, cariprazine, sertindole, ziprasidone,
lurasidone, brexpiprazole, aripiprazole, risperidone and paliperidone, haloperidol,
and amisulpride; in contrast, total cholesterol increased with quetiapine, olanzapine,
and clozapine. For LDL levels, compared with placebo, no strong evidence of change
was observed with ziprasidone, lurasidone, risperidone and paliperidone, aripiprazole,
and brexpiprazole; however, a decrease in LDL occurred with cariprazine and
increases in LDL occurred with quetiapine and olanzapine. For changes in HDL
levels, compared with placebo, no strong evidence was observed with amisulpride,
olanzapine, quetiapine, risperidone and paliperidone, lurasidone, cariprazine, or
ziprasidone; however, HDL levels increased with aripiprazole and brexpiprazole.
For changes in triglyceride levels, compared with placebo, no strong evidence was
shown for brexpiprazole, lurasidone, sertindole, cariprazine, ziprasidone, aripiprazole,
risperidone and paliperidone, amisulpride, haloperidol, and iloperidone; however,
triglyceride concentrations increased with quetiapine, olanzapine, zotepine, and clo-
zapine (Pillinger et al. 2020).
A systematic review and a meta-analysis of total cholesterol levels among
patients taking SGAs searched for randomized, blinded trials comparing orally
administered SGAs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine,
risperidone, sertindole, ziprasidone, zotepine) head-to-head in the treatment of
schizophrenia or related disorders (schizoaffective, schizophreniform, or delusional
disorder). Olanzapine produced statistically significantly more increase in total
cholesterol levels than aripiprazole, risperidone, and ziprasidone. Quetiapine pro-
duced significantly more increase in total cholesterol levels than risperidone and
ziprasidone. Risperidone produced significantly more increase in total cholesterol
levels compared with aripiprazole and ziprasidone. No statistically significant dif-
ferences in total cholesterol levels were observed between amisulpride and
olanzapine, clozapine and olanzapine, clozapine and risperidone, olanzapine and
quetiapine, and risperidone and sertindole (Rummel-Kluge et al. 2010).

Effect of Smoking Status and Gender Differences on Lipid

Parameters

A meta-analysis of studies worldwide reported a higher rate of smoking in

patients with schizophrenia than in the general population (de Leon and Diaz
2005); however, the reasons for this higher prevalence remain unclear. It is well-
Lipid Metabolism Disturbances During Antipsychotic Treatment for. . . 995

known that smoking alters lipid profiles, as characterized by increased total choles-
terol, triglyceride, and LDL levels, along with decreased HDL levels (Maeda et al.
2003); however, the mechanisms by which smoking changes lipid levels are still
unknown. A few studies have investigated the smoking versus nonsmoking and lipid
profiles in schizophrenia, and one such study showed no significant difference
in total cholesterol, triglyceride, HDL, and LDL levels between the smokers and
nonsmokers (Hui-Mei et al. 2016).
In the general population, cholesterol and triglyceride levels are known to be
affected by age and sex. It was suggested that women have a greater vulnerability to
develop psychotropic-drug–induced metabolic disturbances than men (Correll et al.
2015; Seeman 2009). The risk of developing hypercholesterolemia was significantly
greater for female versus male patients in a retrospective adolescent cohort
(McIntyre and Jerrell 2008). A study that investigated the sex differences in the
effects of antipsychotics on glucose and lipid metabolism in first-episode schizo-
phrenia randomized 112 patients with schizophrenia to receive clozapine,
olanzapine, risperidone, or sulpiride for 8 weeks. After treatment, the waist-to-hip
ratio, triglyceride levels, and insulin resistance index for men were higher than that
for women in the clozapine and olanzapine groups. In the sulpiride group, body mass
index and triglyceride levels, insulin levels, and insulin resistance index for women
was higher than that for men. No significant sex difference was shown for all
assessments in the risperidone group (Wu et al. 2007).
Body mass index and triglyceride levels are also positively correlated in the
general population. A study on the prevalence of obesity in chronic schizophrenia
reported an approximately two times rate higher for female versus male patients.
This study used a stepwise multiple regression to determine which factors contrib-
uted to obesity and found that type 2 diabetes and triglyceride levels were signifi-
cantly associated with obesity in female patients but that only triglyceride levels
were associated with obesity in male patients (Li et al. 2016). It is thought that lipid
metabolism is largely regulated by sex hormones. Indeed, in another study plasma
triglyceride concentrations during both fasting and fed conditions were reported to
be lower in premenopausal women than in age-matched men in the general popula-
tion (Wang et al. 2011).

Race/Ethnicity Differences in the Risk of Hyperlipidemia Among

Schizophrenia

For race/ethnicity differences in the risk of hyperlipidemia, the prevalence of hyper-

lipidemia differed by race/ethnicity, obesity, and insulin resistance in a contemporary,
multiethnic, cohort study in the United States. Compared with white patients, the
adjusted OR for hyperlipidemia was 0.48 in African Americans (95% CI, 0.30–0.75),
1.33 in Hispanics (95% CI, 0.93–1.91), and 1.06 in Asians (95% CI, 0.62–1.82)
(Paramsothy et al. 2009). Furthermore, an association was reported for race and the
risk of metabolic dysfunction in schizophrenia using a post hoc analysis of data from a
26-week, double-blind, randomized trial of aripiprazole and olanzapine in schizo-
phrenic patients. For the 167 white patients, olanzapine significantly worsened all
996 S. Ono and T. Someya

metabolic parameters except HDL and fasting glucose, which was significantly
different than aripiprazole for every outcome except fasting glucose. In the black/
Hispanic cohort of 137 patients, olanzapine resulted in adverse metabolic outcomes,
and these changes were significantly different from aripiprazole for adiposity, total
cholesterol, and non- HDL cholesterol. Aripiprazole decreased the odds of metabolic
syndrome at the study endpoint compared with olanzapine for all study participants
(OR, 0.33; 95% CI, 0.19–0.55), for the white cohort (OR, 0.20; 95% CI, 0.10–0.41),
and for the African American/Hispanic cohort (OR, 0.53; 95% CI, 0.25–1.12);
however, the results for the African American/Hispanic were not statistically signifi-
cant ( p ¼ 0.096). Within the aripiprazole group, white patients had significantly lower
risk for metabolic syndrome, whereas no significant difference in metabolic syndrome
was evident between white and African American/Hispanic patients exposed to
olanzapine. These findings suggest that race/ethnicity may be an important moderator
of metabolic risk during SGA therapy (Meyer et al. 2009).

Hypotheses Regarding the Mechanisms for the Association

Between Antipsychotics and Lipids

The use of antipsychotics is frequently associated with weight gain, hyper-

triglyceridemia, and other metabolic disturbances. Although the mechanisms
involved in antipsychotic-induced hypertriglyceridemia remain to be fully eluci-
dated, several studies have proposed that this adverse effect may be associated with
weight gain and obesity. Several hypotheses have been reported regarding the
mechanisms for the association between antipsychotics and lipids. On study reported
a direct effect on triglyceride metabolism either by stimulation of hepatic triglyceride
production and insulin or by inhibition of lipoprotein lipase-mediated triglyceride
polypeptides and an indirect mechanism associated with obesity and insulin resis-
tance (Yan et al. 2013). Another study reported the mechanism of neurotransmitters
on metabolic regulation. Antipsychotic drugs seem to interfere with feeding behav-
iors and energy balance, processes that control metabolic regulation. Reward and
energy balance centers in central nervous system constitute the central level of
metabolic regulation. The peripheral level consists of skeletal muscles, the liver,
the pancreas, the adipose tissue, and neuroendocrine connections. Neurotransmitter
receptors have crucial roles in metabolic regulation, and they are also targets of
antipsychotic drugs. Interaction of antipsychotics with neurotransmitters could have
both protective and harmful effects on metabolism (Siafis et al. 2018). Further
preclinical and clinical research is needed to test these hypotheses.

Guidelines and Interventions

Antipsychotic-induced metabolic derangements are often difficult to manage. The

prevention of both metabolic syndrome and cardiovascular disease is an important
aspect of care for patients with schizophrenia, and physicians should give careful
Lipid Metabolism Disturbances During Antipsychotic Treatment for. . . 997

consideration to the potential cardiovascular and metabolic consequences before

prescribing an antipsychotic medication. One study investigated the content of the
guidelines for cardiovascular risk in patients with schizophrenia published between
2000 and 2010 and determined 18 guidelines published worldwide are sufficient for
clinical use (De Hert et al. 2011). Most of the guidelines stated that the frequency of
monitoring is dependent on the presence of risk factors (including being overweight
and obesity) and on the time since starting the antipsychotic medication. In the most
of the guidelines, monitoring after a baseline assessment was recommended for the
following measurements: fasting glucose, body mass index, fasting triglyceride,
fasting cholesterol, waist, HDL, LDL, blood pressure, and the symptoms of diabetes.
In terms of nonpharmacologic interventions, most guidelines recommended that the
patient receive advice on physical activity, advice on diet, psychoeducation (for both
the patient and family), treatment of lipid abnormalities, treatment of diabetes,
referral for advice and treatment, and advice on smoking cessation. Some clinicians
have proposed monitoring metabolic parameters during treatment in patients receiv-
ing antipsychotics known to induce metabolic disturbances, including close moni-
toring during the first 3 months of treatment (Manu et al. 2015; Cooper et al. 2016).
The importance of early changes in lipid levels to predict a worsening lipid profile
and development of dyslipidemia in long-term treatment with psychotropic drugs
(antipsychotics or mood stabilizers) has been demonstrated. Patients whose lipid
levels increased by 5% during the first month of psychotropic treatment were more
prone to have a considerable worsening of their lipid profiles after 3 months of
treatment and to develop dyslipidemia compared with other patients (Delacretaz
et al. 2018). These authors also conducted a 1-year longitudinal study in adolescents
taking psychotropic drugs. They reported that almost half (49%) of the study patients
had an early increase of total cholesterol levels by 5% during the first month of
treatment, and 33% developed new-onset hypercholesterolemia during the first year
of treatment (Delacretaz et al. 2019). These results suggest the importance of careful
monitoring of metabolic parameters before and after administration of
antipsychotics.
The Framingham Score, published in 1998, scores age, sex, total cholesterol
levels, HDL levels, systolic blood pressure, diabetes, and smoking. It is known that
the total score can predict the onset of ischemic heart disease within 10 years (Peter
et al. 1998). The Framingham scores of 689 patients who participated in the CATIE
trial was compared at baseline with age-, race-, and sex-matched controls. For
patients with schizophrenia compared with controls, the score was significantly
elevated in male (9.4% vs. 7.0%, respectively) and female (6.3% vs. 4.2%, respec-
tively) patients. The Framingham score remained significantly elevated in schizo-
phrenia patients after controlling for body mass index (Goff et al. 2005). Another
study compared the Framingham score for the 10-year coronary heart disease risk
among antipsychotic treatment groups in 1125 patients followed to the end of phase
1 in the CATIE Trial. The covariate-adjusted mean change in 10-year coronary heart
disease risk differed significantly between treatments. Olanzapine was associated
with a 0.5% (SE 0.3) increase and quetiapine was associated with a 0.3% (SE 0.3)
increase, whereas the risk decreased for patients treated with perphenazine (
0.5%;
998 S. Ono and T. Someya

SE 0.3), risperidone (
0.6%; SE 0.3), and ziprasidone (
0.6%; SE 0.4) (Daumit

et al. 2008). The change in Framingham risk score has also been investigated in a
6-week trial of double-blind treatment with ziprasidone or olanzapine. Men who
received olanzapine demonstrated a mean increase in their total cholesterol levels
(+18.5 mg/dL) and LDL levels (+13.0 mg/dL), whereas men who received
ziprasidone demonstrated a mean decrease in their total cholesterol levels
(
8.5 mg/dL) and LDL levels (
7.2 mg/dL). In addition, men who received
olanzapine showed an increase in their baseline Framingham risk score (+7.69%),
whereas men who received ziprasidone showed a decrease in the baseline score
(
11.06%). In women, treatment differences in the Framingham risk score numer-
ically favored ziprasidone but were not statistically significant. The authors reported
that olanzapine was associated with an increase in the Framingham risk score versus
ziprasidone (Del Valle et al. 2006). It is important to note that the tools to measure
cardiovascular risk such as Framingham risk score that have been validated for
general population may not apply to patients with schizophrenia. Thus, although the
monitoring of just recommended subjects is important, indicators for assessing the
risk of such cardiovascular disease may also be useful.
It may also lead to improvement of lipid parameter due to switching of antipsy-
chotics. However, switching of antipsychotics has the benefit of improving weight
gain and dyslipidemia, but on the other hand, there is also the risk of acute exacerba-
tion of psychiatric symptoms, treatment interruption, and hospitalization. It is neces-
sary to balance the risks and benefits in each individual case in clinical setting (Weiden
and Buckley 2007). Stroup et al. examined whether switching to aripiprazole would
result in an improvement in metabolic measures. The subjects were schizophrenia with
body-mass index 27 and a non- HDL cholesterol 130 mg/dl taking olanzapine,
quetiapine, and risperidone, and were randomly divided into the switch group and the
stay group for 24 weeks. All participants were also enrolled in a behavioral program.
In non- HDL cholesterol, the least squares means decreased more for the switch than
the stay groups (
20.2 vs.
10.8 mg/dl), with a difference of
9.4 mg/dl (95% CI

2.2,
16.5). Triglyceride decreased for the switch group and increased for the stay
group (
25.7 vs. +7.0 mg/dl). There were no differences between the treatment groups
in changes in HDL or LDL cholesterol (Stroup et al. 2011). Switching from
olanzapine, quetiapine, or risperidone to aripiprazole, which has less effect on lipids,
was effective in helping metabolic patients to improve their lipid profiles and lose
weight. Stroup et al. also evaluated changes in Framingham Risk Score among the
same sample. Least squares mean estimates of 10-year coronary heart disease (CHD)
risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from
7.4% to 6.4%); thus the 10-year risk reduction was 25% for switchers compared to
13.5% for stayers (Stroup et al. 2013).
Using concomitant medications to counteract these adverse outcomes may be a
rational option. Metformin is the most studied agent to combat antipsychotic-
associated weight gain and lipid disturbance. Metformin is an antihyperglycemic
that inhibits hepatic gluconeogenesis and improves skeletal muscle insulin sensitiv-
ity through increases in adenosine monophosphate kinase (Zhou et al. 2018).
Metformin produces substantial improvement in glycemia, triglyceride, and LDL
Lipid Metabolism Disturbances During Antipsychotic Treatment for. . . 999

in patients with type 2 diabetes (Wulffele et al. 2004). In a meta-analysis of add-on

medications to counteract antipsychotic-induced metabolic disturbance in patients
with schizophrenia, significant effects of metformin to improve triglyceride were
observed (mean,
16.42 mg/dL; 95% CI,
29.40% to
3.44%), whereas
aripiprazole trials resulted in significant mean differences for total cholesterol
(mean,
12.81; 95% CI,
19.35 to
6.27) and LDL (mean,
11.69; 95% CI,

19.12 to
4.26]) (Mizuno et al. 2014).
A systematic review and meta-analyses were conducted to compare the pharma-
cologic and nonpharmacologic interventions that have been investigated for improv-
ing physical health outcomes in patients with schizophrenia (Vancampfort et al.
2019). For the nonpharmacologic interventions, multidisciplinary lifestyle/behav-
ioral interventions had a small benefit for both total cholesterol and LDL. No
significant effects on HDL elevations were found with lifestyle or dietary interven-
tions. Regarding total triglyceride, multidisciplinary lifestyle/behavioral interven-
tions had a small effect compared with care as usual. Dietary interventions did not
outperform care as usual. For the pharmacologic interventions investigated for on
triglyceride compared with control conditions, the effect was medium for topiramate,
small for metformin, and negligible for aripiprazole augmentation. Regarding total
cholesterol, metformin demonstrated a medium effect, whereas aripiprazole aug-
mentation had a small effect. No significant reduction compared with control
conditions was observed for topiramate. Regarding LDL, topiramate outperformed
the control conditions, although this effect was negligible. No significant reductions
compared with control conditions were found for aripiprazole augmentation.
Regarding HDL, only metformin had a small effect, whereas aripiprazole augmen-
tation and topiramate did not differ from the control condition. If nonpharmacologic
interventions to antipsychotic-induced metabolic disturbance are insufficient, and
switching antipsychotics is not difficult for reasons such as efficacy, using concom-
itant medications to counteract these adversities may be a rational option.
The association between antipsychotics and dyslipidemia in schizophrenia was
reviewed in this section. However, the effects on lipid metabolism by antipsychotics
are complex, and the mechanism of that remains unclear. Further prospective studies
on the association of schizophrenia and lipid metabolism including various factors
such as age, weight, gender, diet, exercise, and race that may affect lipid metabolism,
as well as the effects of antipsychotics, including the presence of clinically mean-
ingful dyslipidemia is necessary. In addition, regular monitoring is important in
clinical settings.

References
Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive
research synthesis. Am J Psychiatr. 1999;156:1686–96.
Arranz B, Rosel P, Ramírez N, Dueñas R, Fernández P, Sanchez JM, Navarro MA,
San L. Insulin resistance and increased leptin concentrations in noncompliant schizophrenia
patients but not in antipsychotic-naive first-episode schizophrenia patients. J Clin Psychiatry.
2004;65(10):1335–42.
1000 S. Ono and T. Someya

Baller JB, McGinty EE, Azrin ST, Juliano-Bult D, Daumit GL. Screening for car- diovascular
risk factors in adults with serious mental illness: a review of the evidence. BMC Psychiatry.
2015;15:55.
Breier A, Berg PH, Thakore JH, Naber D, Gattaz WF, Cavazzoni P, Walker DJ, Roychowdhury SM,
Kane JM. Olanzapine versus ziprasidone: results of a 28-week double-blind study in patients
with schizophrenia. Am J Psychiatry. 2005;162(10):1879–87.
Buhagiar K, Jabbar F. Association of first- vs. second-generation antipsychotics with lipid
abnormalities in individuals with severe mental illness: a systematic review and meta-analysis.
Clin Drug Investig. 2019;39(3):253–73.
Canuso CM, Lindenmayer JP, Kosik-Gonzalez C, Turkoz I, Carothers J, Bossie CA,
Schooler NR. A randomized, double-blind, placebo-controlled study of 2 dose ranges of
paliperidone extended-release in the treatment of subjects with schizoaffective disorder. J Clin
Psychiatry. 2010;71(5):587–98.
Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of
coronary heart disease and lipoprotein cholesterol levels: the Framingham study. JAMA.
1986;256:2835–8.
Chirovsky DR, Fedirko V, Cui Y, Sazonov V, Barter P. Prospective studies on the relationship
between high-density lipoprotein cholesterol and cardiovascular risk: a systematic review. Eur
J Cardiovasc Prev Rehabil. 2009;16:404–23.
Chrzanowski WK, Marcus RN, Torbeyns A, Nyilas M, McQuade RD. Effectiveness of long-term
aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a
52-week, open-label comparison with olanzapine. Psychopharmacology. 2006;189:259–66.
Cooper SJ, Reynolds GP, Barnes T, With expert co-authors (in alphabetical order), et al.
BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular
risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol.
2016;30(8):717–48.
Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med. 2011;17(2):
97–107.
Correll CU, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, Nyilas M, Carson WH,
Sanchez R, Eriksson H. Efficacy and safety of brexpiprazole for the treatment of acute
schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry.
2015;172(9):870–80.
Daumit GL, Goff DC, Meyer JM, Davis VG, Nasrallah HA, McEvoy JP, Rosenheck R, Davis SM,
Hsiao JK, Stroup TS, Lieberman JA. Antipsychotic effects on estimated 10-year coronary heart
disease risk in the CATIE schizophrenia study. Schizophr Res. 2008;105(1–3):175–87.
Davidson M, Emsley R, Kramer M, Ford L, Pan G, Lim P, Eerdekens M. Efficacy, safety and early
response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week,
randomized, placebo-controlled study. Schizophr Res. 2007;93(1–3):117–30.
De Hert M, Schreurs V, Vancampfort D, VAN Winkel R. Metabolic syndrome in people with
schizophrenia: a review. World Psychiatry. 2009;8:15–22.
De Hert M, Vancampfort D, Correll CU, Mercken V, Peuskens J, Sweers K, van Winkel R,
Mitchell AJ. Guidelines for screening and monitoring of cardiometabolic risk in schizophrenia:
systematic evaluation. Br J Psychiatry. 2011;199(2):99–105.
De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse
effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2012;8(2):114–26.
de Leon J, Diaz F. A meta-analysis of worldwide studies demonstrates an association between
schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005;7(6):135–57.
Del Valle MC, Loebel AD, Murray S, Yang R, Harrison DJ, Cuffel BJ. Change in framingham risk
score in patients with schizophrenia: a post hoc analysis of a randomized, double-blind, 6-week
trial of ziprasidone and olanzapine. Prim Care Companion J Clin Psychiatry. 2006;8(6):329–33.
Delacretaz A, Vandenberghe F, Gholam-Rezaee M, et al. Early changes of blood lipid levels during
psychotropic drug treatment as predictors of long-term lipid changes and of new onset
dyslipidemia. J Clin Lipidol. 2018;12(1):219–29.
Lipid Metabolism Disturbances During Antipsychotic Treatment for. . . 1001

Delacretaz A, Vandenberghe F, Glatard A, Dubath C, Levier A, Gholam-Rezaee M, Holzer L,

Ambresin AE, Conus P, Eap CB. Lipid disturbances in adolescents treated with second-
generationantipsychotics: clinical determinants of plasma lipid worsening and new-onset hyper-
cholesterolemia. J Clin Psychiatry. 2019;80(3):18m12414.
Dixon L, Weiden P, Delahanty J, Goldberg R, Postrado L, Lucksted A, et al. Prevalence and
correlates of diabetes in national schizophrenia samples. Schizophr Bull. 2000;26:903–12.
Durgam S, Cutler AJ, Lu K, Migliore R, Ruth A, Laszlovszky I, Németh G, Meltzer HY.
Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized,
double-blind, placebo- and active-controlled trial. J Clin Psychiatry. 2015;76(12):e1574–82.
Dursun SM, Szemis A, Andrews H, Reveley MA. The effects of clozapine on levels of total
cholesterol and related lipids in serum of patients with schizophrenia: a prospective study.
J Psychiatry Neurosci. 1999;24:453–5.
Earley W, Durgam S, Lu K, Laszlovszky I, Debelle M, Kane JM. Safety and tolerability of
cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four
phase II/III randomized, double-blind, placebo-controlled studies. Int Clin Psychopharmacol.
2017;32(6):319–28.
Enez Darcin A, Yalcin Cavus S, Dilbaz N, Kaya H, Dogan E. Metabolic syndrome in
drug-naïve and drug-free patients with schizophreniaand in their siblings. Schizophr Res.
2015;166(1–3):201–6.
Fleischhacker WW, McQuade RD, Marcus RN, Archibald D, Swanink R, Carson WH. A double-
blind, randomized comparative study of aripiprazole and olanzapine in patients with schizo-
phrenia. Biol Psychiatry. 2009;65:510–7.
Fleischhacker WW, Siu CO, Bodén R, Pappadopulos E, Karayal ON, Kahn RS, EUFEST study
group. Metabolic risk factors in first-episode schizophrenia: baseline prevalence and course
analysed from the European First-Episode Schizophrenia Trial. Int J Neuropsychopharmacol.
2013;16(5):987–95.
Goff DC, Sullivan LM, McEvoy JP, Meyer JM, Nasrallah HA, Daumit GL, Lamberti S,
D’Agostino RB, Stroup TS, Davis S, Lieberman JA. A comparison of ten-year cardiac risk
estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res.
2005;80(1):45–53.
Gordon T, Kannel WB, Castelli WP, Dawber TR. Lipoproteins, cardiovascular disease, and death:
the Framingham study. Arch Intern Med. 1981;141:1128–31.
Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;1(73):11–53.
Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA,
Goff DC. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year
naturalistic study. Am J Psychiatry. 2000;157:975–81.
Higuchi T, Ishigooka J, Iyo M, Yeh CB, Ebenezer EG, Liang KY, Lee JS, Lee SY, Lin SK, Yoon BH,
Nakamura M, Hagi K, Sato T. Lurasidone in the treatment of schizophrenia: results of a double-
blind, placebo-controlled trial in Asian patients. Asia Pac Psychiatry. 2019;11(2):e12352.
Hui-Mei A, Tan YL, Tan SP, Shi J, Wang ZR, Yang FD, Huang XF, Soars JC, Kosten TR,
Zhang XY. Smoking and serum lipid profiles in schizophrenia. Neurosci Bull. 2016;32(4):
383–8.
Kane JM, Osuntokun O, Kryzhanovskaya LA, Xu W, Stauffer VL, Watson SB, Breier A. A
28-week, randomized, double-blind study of olanzapine versus aripiprazole in the treatment
of schizophrenia. J Clin Psychiatry. 2009;70(4):572–81.
Kannel WB, Castelli WP, Gordon T, McNamara PM. Serum cholesterol, lipoproteins, and the risk
of coronary heart disease: the Framingham study. Ann Intern Med. 1971;74:1–12.
Kelly DL, Conley RR, Love RC, Morrison JA, McMahon RP. Metabolic risk with second-
generation antipsychotic treatment: a double-blind randomized 8-week trial of risperidone and
olanzapine. Ann Clin Psychiatry. 2008;20(2):71–8.
Koro CE, Fedder DO, L’Italien GJ, Weiss S, Magder LS, Kreyenbuhl J, et al. An assessment of
the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in
schizophrenic patients. Arch Gen Psychiatry. 2002;59:1021–6.
1002 S. Ono and T. Someya

Lambert BL, et al. Association between antipsychotic treatment and hyperlipidemia among
California Medicaid patients with schizophrenia. J Clin Psychopharmacol. 2005;25(1):12–8.
Li Q, Chen D, Liu T, et al. Sex differences in body mass index and obesity in chinese patients with
chronic schizophrenia. J Clin Psychopharmacol. 2016;36:643–8.
Lindenmayer JP, Czobor P, Volavka J, Citrome L, Sheitman B, McEvoy JP, Cooper TB, Chakos M,
Lieberman JA. Changes in glucose and cholesterol levels in patients with schizophrenia treated
with typical or atypical antipsychotics. Am J Psychiatry. 2003;160(2):290–6.
Lund BC, Perry PJ, Brooks JM, et al. Clozapine use in patients with schizophrenia and the risk of
diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch Gen Psychiatry.
2001;58:1172–6.
Maeda K, Noguchi Y, Fukui T. The effects of cessation from cigarette smoking on the lipid and
lipoprotein profiles: a meta-analysis. Prev Med. 2003;37:283–90.
Manu P, Dima L, Shulman M, et al. Weight gain and obesity in schizophrenia: epidemiology,
pathobiology, and management. Acta Psychiatr Scand. 2015;132(2):97–108.
McEvoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L, et al. Prevalence of
the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical
Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial and comparison
with national estimates from NHANES III. Schizophr Res. 2005;80:19–32.
McIntyre RS, Jerrell JM. Metabolic and cardiovascular adverse events associated with antipsy-
chotic treatment in children and adolescents. Arch Pediatr Adolesc Med. 2008;162(10):929–35.
McQuade RD, Stock E, Marcus R, Jody D, Gharbia NA, Vanveggel S, Archibald D,
Carson WH. A comparison of weight change during treatment with olanzapine or aripiprazole:
results from a randomized, double-blind study. J Clin Psychiatry. 2004;65(Suppl 18):47–56.
Meltzer HY, Cucchiaro J, Silva R, Ogasa M, Phillips D, Xu J, Kalali AH, Schweizer E, Pikalov A,
Loebel A. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo-
and olanzapine-controlled study. Am J Psychiatry. 2011;168(9):957–67.
Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone-
and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry.
2002;63(5):425–33.
Meyer JM, Stahl SM. The metabolic syndrome and schizophrenia. Acta Psychiatr Scand. 2009;119:
4–14.
Meyer JM, Rosenblatt LC, Kim E, Baker RA, Whitehead R. The moderating impact of ethnicity
on metabolic outcomes during treatment with olanzapine and aripiprazole in patients with
schizophrenia. J Clin Psychiatry. 2009;70(3):318–25.
Misiak B, Stanczykiewicz B, Laczmanski L, Frydecka D. Lipid profile disturbances in
antipsychotic-naive patients with first-episode non-affective psychosis: a systematic review
and meta-analysis. Schizophr Res. 2017;190:18–27.
Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M. Prevalence of metabolic
syndrome and metabolic abnormalities in schizophrenia and related disorders – a systematic
review and meta-analysis. Schizophr Bull. 2013;39:306–18.
Mizuno Y, Suzuki T, Nakagawa A, Yoshida K, Mimura M, Fleischhacker WW,
Uchida H. Pharmacological strategies to counteract antipsychotic-induced weight gain and
metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr
Bull. 2014;40(6):1385–403.
Nonogaki K, Strack AM, Dallman MF, et al. Leptin-independent hyperphagia and type 2 diabetes in
mice with a mutated serotonin 5-HT2C receptor gene. Nat Med. 1998;4:1152–6.
Olfson M, Marcus SC, Corey-Lisle P, et al. Hyperlipidemia following treatment with antipsychotic
medications. Am J Psychiatry. 2006;163:1821–5.
Olfson M, Gerhard T, Huang C, Crystal S, Stroup TS. Premature mortality among adults with
schizophrenia in the United States. JAMA Psychiat. 2015;72(12):1172–81.
Paramsothy P, Knopp R, Bertoni AG, Tsai MY, Rue T, Heckbert SR. Combined hyperlipidemia
in relation to race/ethnicity, obesity, and insulin resistance in the Multi-Ethnic Study of
Atherosclerosis. Metabolism. 2009;58:212–9.
Lipid Metabolism Disturbances During Antipsychotic Treatment for. . . 1003

Perez-Iglesias R, Mata I, Pelayo-Teran JM, Amado JA, Garcia-Unzueta MT, Berja A, et al. Glucose
and lipid disturbances after 1 year of antipsychotic treatment in a drug-naïve population.
Schizophr Res. 2009;107:115–21.
Peter WFW, Ralph BD’A, Daniel L, et al. Prediction of coronary heart disease using risk factor
categories. Circulation. 1998;97:1837–1847. https://www.ahajournals.org/doi/full/10.1161/01.
CIR.97.18.1837.
Pillinger T, Beck K, Stubbs B, Howes OD. Cholesterol and triglyceride levels in first-episode
psychosis: systematicreview and meta-analysis. Br J Psychiatry. 2017;211(6):339–49.
Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, Beck K, Natesan S,
Efthimiou O, Cipriani A, Howes OD. Comparative effects of 18 antipsychotics on metabolic
function in patients with schizophrenia, predictors of metabolic dysregulation, and association
with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry.
2020;7(1):64–77.
Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a
polymorphism of the promoter region of the 5-HT2C receptor gene. Lancet. 2002;359:2086–7.
Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, Kissling W, Davis JM,
Leucht S. Head-to-head comparisons of metabolic side effects of second generation antipsy-
chotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res.
2010;123(2–3):225–33.
Seeman MV. Secondary effects of antipsychotics: women at greater risk than men. Schizophr Bull.
2009;35(5):937–48.
Sengupta S, Parrilla-Escobar MA, Klink R, Fathalli F, Ying KN, Stip E, Baptista T, Malla A,
Joober R. Are metabolic indices different between drug-naive first-episode psychosis patients
and healthy controls? Schizophr Res. 2008;102(1–3):329–36.
Siafis S, Tzachanis D, Samara M, Papazisis G. Antipsychotic drugs: from receptor-binding profiles
to metabolic side effects. Curr Neuropharmacol. 2018;16(8):1210–23.
Smith RC, Lindenmayer JP, Bark N, Warner-Cohen J, Vaidhyanathaswamy S,
Khandat A. Clozapine, risperidone, olanzapine, and conventional antipsychotic drug effects
on glucose, lipids, and leptin in schizophrenic patients. Int J Neuropsychopharmacol. 2005;8(2):
183–94.
Smith RC, Lindenmayer JP, Hu Q, Kelly E, Viviano TF, Cornwell J, Vaidhyanathaswamy S,
Marcovina S, Davis JM. Effects of olanzapine and risperidone on lipid metabolism in chronic
schizophrenic patients with long-term antipsychotic treatment: a randomized five month study.
Schizophr Res. 2010;120(1–3):204–9.
Spivak B, Lamschtein C, Talmon Y, Guy N, Mester R, Feinberg I, Kotler M,
Weizman A. The impact of clozapine treatment on serum lipids in chronic schizophrenic
patients. Clin Neuropharmacol. 1999;22:98–101.
Stroup TS, McEvoy JP, Ring KD, Hamer RH, LaVange LM, Swartz MS, Rosenheck RA,
Perkins DO, Nussbaum AM, Lieberman JA, Schizophrenia Trials Network. A randomized
trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to
aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems
(CAMP). Am J Psychiatry. 2011;168(9):947–56.
Stroup TS, Byerly MJ, Nasrallah HA, Ray N, Khan AY, Lamberti JS, Glick ID, Steinbook RM,
McEvoy JP, Hamer RM. Effects of switching from olanzapine, quetiapine, and risperidone to
aripiprazole on 10-year coronary heart disease risk and metabolic syndrome status: results from
a randomized controlled trial. Schizophr Res. 2013;146(1–3):190–5.
Stubbs B, Firth J, Berry A, Schuch FB, Rosenbaum S, Gaughran F, et al. How much physical
activity do people with schizophrenia engage in? A systematic review, comparative meta-
analysis and meta-regression. Schizophr Res. 2016;176:431–40.
Takeuchi Y, Kajiyama K, Ishiguro C, Uyama Y. Atypical antipsychotics and the risk of hyperlip-
idemia: a sequence symmetry analysis. Drug Saf. 2015;38(7):641–50.
Taylor DM, McAskill R. Atypical antipsychotics and weight gain – a systematic review. Acta
Psychiatr Scand. 2000;101:416–32.
1004 S. Ono and T. Someya

Vancampfort D, Wampers M, Mitchell AJ, Correll CU, De Herdt A, Probst M, et al. A meta-analysis
of cardio-metabolic abnormalities in drug naive, first-episode and multi-episode patients with
schizophrenia versus general population controls. World Psychiatry. 2013;12:240–50.
Vancampfort D, Stubbs B, Mitchell AJ, De Hert M, Wampers M, Ward PB, et al. Risk of metabolic
syndrome and its components in people with schizophrenia and related psychotic disorders,
bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World
Psychiatry. 2015;14:339–47.
Vancampfort D, Firth J, Correll CU. The impact of pharmacological and non-pharmacological
interventions to improve physical health outcomes in people with schizophrenia: a meta-review
of meta-analyses of randomized controlled trials. World Psychiatry. 2019;18(1):53–66.
Walker ER, McGee RE, Druss BG. Druss. Mortality in mental disorders and global disease burden
implications: a systematic review and meta-analysis. JAMA Psychiat. 2015;72(4):334–41.
Wang X, Magkos F, Mittendorfer B. Sex differences in lipid and lipoprotein metabolism: it’s not
just about sex hormones. J Clin Endocrinol Metab. 2011;96:885–93.
Weiden PJ, Buckley PF. Reducing the burden of side effects during long-term antipsychotic
therapy: the role of “switching” medications. J Clin Psychiatry. 2007;68(Suppl 6):14–23.
Wilson PW, D’Agostino RB, Levy D, Balanger AM, Silbershatz H, Kannel WB. Prediction of
coronary heart disease using risk factor categories. Circulation. 1998;97:1837–47.
Wu RR, Zhao JP, Zhai JG, Guo XF, Guo WB. Sex difference in effects of typical and atypical
antipsychotics on glucose-insulin homeostasis and lipid metabolism in first-episode schizophre-
nia. J Clin Psychopharmacol. 2007;27(4):374–9.
Wu X, Huang Z, Wu R, Zhong Z, Wei Q, Wang H, Diao F, Wang J, Zheng L, Zhao J,
Zhang J. The comparison of glycometabolism parameters and lipid profiles between drug-
naïve, first-episode schizophrenia patients and healthy controls. Schizophr Res. 2013;150(1):
157–62.
Wulffele MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT. The effect of metformin on
blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic
review. J Intern Med. 2004;256(1):1–14.
Yan H, Chen JD, Zheng XY. Potential mechanisms of atypical antipsychotic-induced hyper-
triglyceridemia. Psychopharmacology. 2013;229(1):1–7.
Zhang ZJ, Yao ZJ, Liu W, Fang Q, Reynolds GP. Effects of antipsychotics on fat deposition and
changes in leptin and insulin levels. Magnetic resonance imaging study of previously untreated
people with schizophrenia. Br J Psychiatry. 2004;184:58–62.
Zhou T, Xu X, Du M, Zhao T, Wang J. A preclinical overview of metformin for the treatment of type
2 diabetes. Biomed Pharmacother. 2018;106:1227–35.
Cannabinoid Drugs in Mental Health
Disorders

Stefan Kloiber, Justin Matheson, Helena K. Kim, and Bernard Le Foll

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006
Search Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
Cannabinoids in Treatment of Mental Health Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
Anxiety Disorders / OCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
Post-Traumatic Stress Disorder (PTSD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
Psychotic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
Tourette Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
Other Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
Cannabinoids in Treatment of Substance Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
Cannabis Use Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
Nicotine Dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
Opioid Use Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1028
Alcohol Use Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029

S. Kloiber (*)
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health
(CAMH), Department of Psychiatry, University of Toronto, Toronto, ON, Canada
e-mail: Stefan.Kloiber@camh.ca
J. Matheson
Translational Addiction Research Laboratory, CAMH, Toronto, ON, Canada
e-mail: Justin.Matheson@camh.ca
H. K. Kim
Department of Psychiatry, University of Toronto, Toronto, ON, Canada
e-mail: helena.kim@camh.ca
B. Le Foll
Translational Addiction Research Laboratory, Acute Care Program, and Campbell Family Mental
Health Research Institute, CAMH, Departments of Family and Community Medicine,
Pharmacology and Toxicology, Psychiatry, and Institute of Medical Science, University of Toronto,
Toronto, ON, Canada
e-mail: Bernard.LeFoll@camh.ca

© Springer Nature Switzerland AG 2022 1005

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_465
1006 S. Kloiber et al.

Discussion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029

Mental Health Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029
Substance Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032

Abstract
Endocannabinoid signalling plays an important role in affect, anxiety, and
reward, and thus targeting this system could potentially be used to treat mental
health and substance use disorders. This chapter discusses the current state of the
clinical evidence evaluating the potential of various cannabinoid drugs as mental
health and addiction pharmacotherapy, with a focus on randomized controlled
trials. A few small clinical trials have found preliminary evidence for different
cannabinoids in mental health disorders, including cannabidiol (CBD) for anxiety
disorders, and Δ9-tetrahydrocannabinol (THC) for post-traumatic stress disorder
(PTSD) and Tourette syndrome. The evidence for cannabinoids in other mental
health conditions (e.g., psychotic disorders) is mixed. The clinical evidence also
suggests that a combination of CBD and THC may be useful in reducing cannabis
craving and/or withdrawal in patients with cannabis use disorder (CUD), with
possible longer-term effects on reducing cannabis use and promoting abstinence.
CBD alone may have the potential to reduce cannabis use, promote tobacco
smoking cessation, and attenuate opioid craving, though these findings need
replication. Finally, the cannabinoid type-1 (CB1) receptor antagonist rimonabant
showed promise as a smoking cessation pharmacotherapy, yet this drug was
withdrawn from the market due to serious psychiatric adverse effects. The current
evidence demonstrates the potential for cannabinoid drugs in the treatment of
mental health and substance use disorders, yet this evidence is clearly in its early
stages. Future directions for the field are discussed.

Introduction

The endocannabinoid system (ECS) is an evolutionarily conserved lipid signalling

system that has been found in nearly all vertebrate animals and many invertebrates
(Elphick and Egertova 2005) and is composed of two primary receptors, two primary
endogenous transmitters, and the enzymes responsible for the synthesis and degra-
dation of the transmitters. The two canonical cannabinoid receptors, cannabinoid
receptor type-1 (CB1) and type-2 (CB2) , are 7-transmembrane domain G-protein
coupled receptors (GPCRs), and CB1 receptors are regarded as the most abundant
GPCRs in the mammalian brain (Howlett et al. 2002). The endogenous transmitters
(the endocannabinoids) are phospholipid derivatives containing a polyunsaturated
fatty acid moiety (arachidonate) and a polar head group, either ethanolamine in the
case of anandamide (AEA) or glycerol in the case of 2-arachidonoylglycerol (2-AG)
(Pamplona and Takahashi 2012). AEA is a high-affinity partial agonist for CB1 with
Cannabinoid Drugs in Mental Health Disorders 1007

very little activity at CB2, while 2-AG is a low-affinity, high-efficacy agonist for both
receptors (Lu and Mackie 2016). Many enzymes are involved in the synthesis and
degradation of AEA and 2-AG, including fatty acid amide hydrolase (FAAH), which
is responsible for the majority of AEA metabolism, and monoacylglycerol lipase
(MAGL), which is often responsible for the degradation of 2-AG (Pamplona and
Takahashi 2012).
The wide expression of CB1 receptors in the brain, especially in the frontal cortex,
basal ganglia, and medial temporal lobes (Hu and Mackie 2015), positions the ECS
as an important mediator of cognitive and affective processes. Research has consis-
tently shown an important role of the ECS in symptoms and models of anxiety,
depression, and psychosis in both animals and humans (Ibarra-Lecue et al. 2018;
Connor et al. 2021). In humans, there is a strong link between the use of cannabis/
cannabinoids and mood and anxiety disorders (Botsford et al. 2020; Lev-Ran et al.
2012; Mammen et al. 2018), and alleviation of mood/anxiety symptoms is a com-
mon motivation for using cannabis (Wycoff et al. 2018). Similarly, there is a wealth
of evidence demonstrating the role of the ECS in drug reward and addiction (Parsons
and Hurd 2015). For example, CB1 receptor signalling plays a role in nicotine,
cannabis, alcohol, and opioid behaviours in animals and humans (Sloan et al. 2017;
Le Foll and Goldberg 2005).
To date, several different ECS-targeting drugs have been evaluated for their
potential to treat mental health disorders and substance use disorders (SUDs).
These include Δ9-tetrahydrocannabinol (THC), the primary psychoactive compound
in the cannabis plant, and its encapsulated oral formulation dronabinol (Marinol ®);
cannabidiol (CBD), a non-intoxicating cannabinoid; nabiximols (Sativex ®), an
oromucosal spray containing both THC and CBD (2.7 mg THC and 2.5 mg CBD
per spray); nabilone (Cesamet ®), a synthetic analogue of THC; and various CB1
receptor antagonists/inverse agonists, most notably rimonabant, among other drugs
targeting the ECS.
The goal of this chapter is to provide an overview of the existing clinical
evidence, with a focus on controlled clinical trials evaluating the feasibility and/or
efficacy of ECS-targeting drugs as treatment for mental health and addictive disor-
ders. Preclinical and human laboratory evidence will be discussed to support the
clinical evidence where relevant.

Search Strategy

PubMed was searched in February 2021 with the following terms: cannabinoid or
THC or CBD or “FAAH inhibitor” or “MAGL inhibitor” and addiction or “use
disorder” or “mental health” or psychiatry or depression or anxiety or schizophrenia
or “mood disorder” or GAD or OCD or “social phobia” or SAD or PTSD), and the
“Clinical Trial” filter was applied. This resulted in a total of 424 articles. Eligible
studies were clinical trials or case series in humans, involved the administration of a
drug targeting the ECS, and included a primary endpoint related to mental health or
substance use. Studies were excluded if they recruited only healthy participants.
1008 S. Kloiber et al.

Fig. 1 Clinical trials assessing the effects of cannabinoid drugs on mental health symptoms and
psychiatric disorders

Using Covidence systematic review software (Veritas Health Innovation, Mel-

bourne, Australia; available at www.covidence.org), two reviewers screened articles
by title/abstract and identified 66 studies for full-text review. Of these studies,
22 were excluded, leaving 44 studies to be included (see Fig. 1). Three additional
studies (Masataka 2019; Lintzeris et al. 2019, 2020) were added that were not
captured by the search strategy.

Cannabinoids in Treatment of Mental Health Conditions

Non-medical cannabis use is elevated in individuals with mental health disorders,

including depression, anxiety, post-traumatic disorder (PTSD), and psychotic
disorders, suggesting a potential therapeutic benefit of cannabinoids or a vulnera-
bility for cannabis use (Bonn-Miller et al. 2014; Sarvet et al. 2018). An increasing
number of preclinical and clinical studies have reported anxiolytic, antidepressant,
antipsychotic, and cognitive effects of cannabinoids (Hill et al. 2012; Mandolini
et al. 2018; Noel 2017; Bonaccorso et al. 2019). However, negative effects of
Cannabinoid Drugs in Mental Health Disorders 1009

cannabinoids, primarily THC, on mental health are also well studied, where
cannabinoids were associated with early age of onset and severity of bipolar
disorder, risk for schizophrenia and worsening of psychotic symptoms, and neg-
ative effects on anxiety and mood (reviewed in Suryadevara et al. 2017). Canna-
binoids examined for their potential effects in mental health disorders to date
include CBD, THC, nabiximols, dronabinol, rimonabant, and nabilone (Black
et al. 2019; Bonaccorso et al. 2019). The following sections will discuss the
potential effect of these compounds in anxiety disorders and OCD, PTSD,
psychotic disorders, Tourette syndrome, psychiatric symptoms of dementia,
non-motor symptoms of Parkinson’s disease, depression, and other conditions.
See Table 1 for an overview of controlled clinical studies that met our eligibility
criteria.

Anxiety Disorders / OCD

Cannabis and anxiety have a complex relationship, as acute administration of

cannabis and cannabinoids to humans can elicit transient episodes of anxiety
(including panic attacks), especially among infrequent users or drug-naïve subjects,
while the use of cannabis to alleviate anxiety is a common motive endorsed by
regular cannabis users (Crippa et al. 2009). While cannabis users tend to have
elevated risk of anxiety disorders (Crippa et al. 2009), it is unclear whether this
relationship is causal or not (Shalit and Lev-Ran 2020). Preclinical studies have
explored the role of cannabinoids in anxiety disorders, where CBD administration
was shown to exert its anxiolytic effects during chronic stress in mice by increasing
hippocampal proliferation (Campos et al. 2013). Preclinical studies have demon-
strated a broad range of relevant actions of CBD, including anxiolytic, panicolytic,
and anti-compulsive actions, suggesting a role of CBD in multiple different anxiety
disorders (Blessing et al. 2015).
Five clinical trials (Bergamaschi et al. 2011; Crippa et al. 2011; Fabre and
McLendon 1981; Kayser et al. 2020; Masataka 2019) have been completed to date
on anxiety and related disorders, with three being on social anxiety disorder
(Bergamaschi et al. 2011; Crippa et al. 2011; Masataka 2019), one on psychoneurotic
anxiety (Fabre and McLendon 1981), and one on obsessive-compulsive disorder
(Kayser et al. 2020). All five studies were placebo-controlled and randomized but
had small sample sizes, ranging from 10 to 37 participants. Two studies examining
social anxiety disorder reported on the effect of a single oral dose of CBD at 400 or
600 mg (Bergamaschi et al. 2011; Crippa et al. 2011), which significantly decreased
anxiety and cognitive impairment. In one study, 300 mg CBD was administered daily
over 4 weeks to individuals with social anxiety disorder and avoidant personality
disorder, and an effect of CBD on anxiety was found compared to placebo (Masataka
2019). Psychoneurotic anxiety, which is a non-DSM diagnosis, was significantly
improved with nabilone 1 mg, three times a day, administered for 28 days (Fabre
and McLendon 1981). On the other hand, in patients with obsessive-compulsive
disorder, THC and CBD were found to have no effect (Kayser et al. 2020).
1010 S. Kloiber et al.

Table 1 Clinical trials assessing the effects of cannabinoid drugs on mental health symptoms in
patients
Reference Sample Study design Intervention Relevant findings
Anxiety disorders / OCD
Bergamaschi 24 treatment- Double-blind, CBD 600 mg, CBD significantly
et al. (2011) naïve adult placebo- single dose reduced anxiety,
patients with controlled, cognitive
social anxiety randomized impairment, and
disorder study discomfort during a
(simulated public simulated public
speaking test) speaking test as
measured by the
Visual Analogue
Mood Scale
compared to placebo
Crippa et al. 10 male adult Double-blind, CBD 400 mg, CBD significantly
(2011) patients with placebo- single dose decreased subjective
social anxiety controlled, anxiety measured by
disorder cross-over the Visual Analogue
study Mood Scale
compared to placebo
Fabre and 20 adult patients Double-blind, Nabilone 1 mg Nabilone
McLendon with placebo- three times a day significantly
(1981) psychoneurotic controlled for 28 days decreased anxiety
anxiety study as measured by the
Hamilton
Anxiety Rating
Scale compared to
placebo
Kayser et al. 12 adult patients Placebo- Single dose, 50% Both THC and
(2020) with obsessive- controlled, of 800 mg CBD did not change
compulsive randomized mixture OCD symptoms as
disorder study administered in measured by the
cigarette form of Yale-Brown
THC and CBD Obsessive-
combined, Compulsive Scale
ranging from 7% and the Obsessive-
to 0% THC and Compulsive Visual
10.4% to 0% Analog Scale
CBD. compared to
placebo
Masataka 37 teenage Double-blind, CBD oil 300 mg CBD significantly
(2019) patients with placebo- daily for 4 weeks lowered symptoms
social anxiety controlled of social anxiety
disorder and study disorder as
avoidant measured by the
personality Fear of Negative
disorder Evaluation
Questionnaire and
the Liebowitz
Social Anxiety
Scale compared to
placebo
(continued)
Cannabinoid Drugs in Mental Health Disorders 1011

Table 1 (continued)
Reference Sample Study design Intervention Relevant findings
Post-traumatic stress disorder
Jetly et al. 10 Canadian Double-blind, Nabilone Nabilone produced a
(2015) male military placebo- 0.5–3 mg for significant decrease
personnel with controlled, 7 weeks in nightmares as
PTSD randomized, measured by the
cross-over Clinician-
study Administered PTSD
Scale, Recurring and
Distressing Dream
Scale, and increased
general well-being
measured by the
General Well Being
Questionnaire
compared to placebo
Rabinak et al. 19 adult patients Randomized, Dronabinol Response time to
(2020) with PTSD and double-blind, 7.5 mg single threatening faces
27 trauma- and placebo- dose was used as a
exposed adults controlled marker of fear
without PTSD study response in patients
combined with PTSD, where
slower response
time would indicate
greater fear and
anxiety. THC
resulted in faster
response time to
threatening faces
compared to
placebo treatment
Psychotic disorders
Boggs et al. 17 adult patients Double-blind, Adjunctive Rimonabant did not
(2012) with placebo- rimonabant produce
schizophrenia or controlled, 20 mg daily for improvement in the
schizoaffective randomized 16 weeks Repeatable Battery
disorder being study for the
treated with Assessment of
second- Neuropsychological
generation Status total score
antipsychotics compared to placebo
Boggs et al. 41 adult patients Double- Adjunctive CBD CBD augmentation
(2018) with blinded, 600 mg daily for was not associated
schizophrenia randomized, 6 weeks with improvement in
treated with placebo- Positive And
antipsychotics controlled Negative Syndrome
study Scale (PANSS)
scores or MATRICS
Consensus
Cognitive Battery
scores compared to
placebo
(continued)
1012 S. Kloiber et al.

Table 1 (continued)
Reference Sample Study design Intervention Relevant findings
Kelly et al. 15 adult patients Double-blind, Adjunctive Rimonabant
(2011) with placebo- rimonabant significantly
schizophrenia or controlled 20 mg daily for decreased Brief
schizoaffective study 16 weeks Psychiatric Rating
disorder taking Scale (BPRS)
second- scores compared to
generation placebo
antipsychotics
Leweke et al. 39 adult patients Double-blind, Cannabidiol Cannabidiol
(2012) with acute placebo- 600–800 mg produced clinical
paranoid controlled, daily for 28 days improvement as
schizophrenia and measured by the
randomized Positive And
study Negative Syndrome
Scale (PANSS)
compared to placebo
McGuire 88 adult patients Double-blind, Adjunct CBD CBD lowered
et al. (2018) with randomized, 1000 mg/day for positive symptoms
schizophrenia placebo- 6 weeks as measured
treated with controlled Positive And
antipsychotics study Negative Syndrome
Scale (PANSS),
produced
significant global
improvement as
measured by the
Clinical Global
Impression
scale (CGI), but did
not produce
significant changes
in overall
functioning or
cognitive
performance
compared to
placebo
Meltzer et al. 72 adult patients Double-blind, SR141716 (CB1 SR141716 did not
(2004) with randomized, antagonist) for change any
schizophrenia or placebo- 6 weeks outcomes compared
schizoaffective controlled to placebo as
disorder study measured by the
Positive and
Negative Syndrome
Scale (PANSS),
Brief Psychiatric
Rating
Scale (BPRS), and
Clinical Global
Impression Scale
(CGI)
(continued)
Cannabinoid Drugs in Mental Health Disorders 1013

Table 1 (continued)
Reference Sample Study design Intervention Relevant findings
Schwarcz 6 adult patients Clinical case Dronabinol Four out of 6
et al. (2009) with severe series up-titrated from patients improved
chronic 2.5 mg twice a with dronabinol as
schizophrenia day to 10 mg measured by the
treated with twice a day in Clinical Global
antipsychotics 3 weeks, then Impression Scale
maintained at (CGI) and Brief
10 mg for up to Psychiatric Rating
5 more weeks. Scale (BPRS)
compared to
baseline.
Zuardi et al. 3 male inpatients Cross-over CBD up to One out of 3 patients
(2006) with treatment- design, 1280 mg daily showed mild
resistant placebo- for 29 days improvement as
schizophrenia controlled measured by the
Brief Psychiatric
Rating Scale
(BPRS) and Positive
and Negative
Syndrome Scale
(PANSS)
Tourette syndrome
Muller-Vahl 12 adult patients Double-blind, THC 5–10 mg THC significantly
et al. (2002) with Tourette placebo- per day for improved tics and
syndrome controlled, 2 days obsessive-
randomized- compulsive
cross-over behaviour, motor
design tics, but not vocal
tics as measured by
the Tourette’s
Syndrome Symptom
List, Yale Global Tic
Severity Scale,
Shapiro Tourette’s
Syndrome Severity
Scale, and Tourette’s
Syndrome Global
Scale compared to
placebo
Muller-Vahl 24 adult patients Double-blind, THC 10 mg daily THC decreased
et al. (2003) with Tourette placebo- for 6 weeks symptoms as
syndrome controlled, measured by the
randomized Tourette Syndrome
study Clinical Global
Impression Scale,
Tourette-Syndrome
Severity Scale, Yale
Global Tic Severity
Scale, and Video
Rating Scale
compared to placebo
(continued)
1014 S. Kloiber et al.

Table 1 (continued)
Reference Sample Study design Intervention Relevant findings
Dementia (psychiatric symptoms)
de Faria et al. 24 patients with Double-blind, CBD 300 mg, CBD significantly
(2020) Parkinson’s placebo- single dose decreased simulated
disease controlled, public speaking test-
(simulated public randomized, induced anxiety as
speaking test) cross-over measured by the
study Visual Analog
Mood Scale
compared to placebo
Herrmann 39 adult patients Double-blind, Nabilone 1–2 mg Nabilone decreased
et al. (2019) with Alzheimer’s randomized, daily for 6 weeks agitation as
disease and placebo- measured by the
agitation controlled, Coben Mansfield
cross-over agitation inventory,
design Neuropsychiatric
Inventory – Nursing
home total score and
caregiver distress
score, and improved
standardized Mini-
Mental State
Examination scores
compared to placebo
Peball et al. 47 patients with Placebo- Nabilone 0.25 Nabilone
(2020) Parkinson’s controlled, once daily to significantly
disease with double-blind, 1 mg twice daily decreased
disturbing randomized treatment for symptoms
non-motor study 4 weeks compared to
symptoms, placebo as
including measured by the
sensory changes, Movement Disorder
sleep Society – Unified
disturbances, and PD Rating Scale – I
autonomic
dysfunction
van den 24 patients Randomized, THC 1.5 mg Neuropsychiatric
Elsen et al. diagnosed with double-blind, 3 times daily for symptoms as
(2015a) Alzheimer’s placebo- 3 weeks measured by the
disease/vascular controlled Neuropsychiatric
dementia/mixed study Inventory did not
dementia significantly change
with THC compared
to placebo
van den 22 adult patients Randomized, THC 0.75 mg THC did not reduce
Elsen et al. with dementia double-blind, twice daily for neuropsychiatric
(2015b) with placebo- 6 weeks symptoms as
neuropsychiatric controlled, measured by the
symptoms cross over Neuropsychiatric
design Inventory compared
to placebo
(continued)
Cannabinoid Drugs in Mental Health Disorders 1015

Table 1 (continued)
Reference Sample Study design Intervention Relevant findings
Volicer et al. 11 hospitalized Randomized, Dronabinol Dronabinol
(1997) patients in the placebo- 2.5 mg for significantly
dementia Study controlled, 6 weeks decreased severity
unit with cross over of disturbed
Alzheimer’s design behaviour as
disease who measured by Cohen-
were Mansfield Agitation
refusing food. Inventory compared
to placebo
Walther et al. 6 patients with Open-label, Dronabinol Dronabinol caused
(2006) late-stage not placebo- 2.5 mg treatment a significant
dementia controlled for 2 weeks reduction in
(Alzheimer’s or nocturnal motor
vascular) activity compared
suffering from to placebo as
circadian and measured by
behavioural actigraphy and
disturbances improvement in
Neuropsychiatric
Inventory total
score and agitation,
aberrant motor, and
night-time
behaviour subscales
Depression
Kotin et al. 8 adult inpatients Double-blind, THC at 0.3 mg/ THC did not show
(1973) with moderate to placebo- kg twice a day an antidepressant
severe controlled for 7 days effect measured
depression study using a 15-point
nurse-rated scale
compared to placebo
Other conditions
Cooper et al. 30 adult patients Double-blind, Sativex (1:1 Sativex spray did
(2017) with ADHD randomized, THC and CBD; not produce a
placebo- 2.7 mg and significant change in
controlled 2.5 mg per cognitive
study 100 microlitres, performance and
respectively) activity level
oromucosal measured using the
spray up to QbTest compared to
14 sprays per day placebo;
Sativex did produce
a significant
improvement in
hyperactivity/
impulsivity
measured with the
Conners’ Adult
ADHD rating scale
compared to placebo
(continued)
1016 S. Kloiber et al.

Table 1 (continued)
Reference Sample Study design Intervention Relevant findings
Grant et al. 14 female adult Open-label Dronabinol 2.5 – Dronabinol
(2011) patients with study, no 15 mg daily for significantly
trichotillomania control group 12 weeks decreased hair
pulling as
measured by the
Massachusetts
General Hospital
Hair Pulling Scale
compared to
baseline
Heussler 20 children and Open-label ZYN002 ZYN002
et al. (2019) adolescents clinical trial, (transdermal significantly
(6–17 yo) with no control CBD gel) decreased Anxiety,
fragile X group 50–250 mg twice Depression, and
syndrome daily for Mood Scale
12 weeks score, Aberrant
Behavior
Checklist –
Community for
FXS score,
Pediatric Quality of
Life Inventory
score, and Pediatric
Anxiety Rating
Scale score
compared to
baseline scores
a
Abbreviations: CBD (cannabinol), THC (Δ9 – tetrahydrocannabinol)

Post-Traumatic Stress Disorder (PTSD)

An emerging body of studies has also evaluated a potential role for cannabinoids in
the treatment of intrusive and arousal symptoms of PTSD (Walsh et al. 2017). Two
randomized, double-blind, and placebo-controlled clinical trials have examined the
effect of cannabinoids in PTSD (Jetly et al. 2015; Rabinak et al. 2020). The sample
sizes were small, with one study having 10 participants (Jetly et al. 2015) and the
other 19 (Rabinak et al. 2020). Both studies reported a significant effect of
cannabinoids, where nabilone ranging from 0.5 to 3 mg administered over
7 weeks (Jetly et al. 2015) was found to decrease PTSD symptoms and a single
dose of dronabinol 7.5 mg (Rabinak et al. 2020) using a behavioural/fMRI
paradigm resulted in the attenuation of amygdala activation and increase of medial
prefrontal cortex and adjacent rostral anterior cingulate cortex activation and
corticolimbic functional connectivity to threat compared to placebo, as well as
reduction of slowing of response to threatening vs. non-threatening cues. This
finding may reflect a normalization of behavioural responses to the threat that
accompanies the observed THC-related modulation of underlying corticolimbic
circuitry.
Cannabinoid Drugs in Mental Health Disorders 1017

Psychotic Disorders

Acute administration of cannabis can induce transient psychotomimetic symptoms

in healthy individuals (D’Souza et al. 2004) and in individuals at clinical high risk
for psychosis (Vadhan et al. 2017), which prompted interest in CB1 receptor antag-
onism as a potential treatment for psychotic disorders (Zamberletti et al. 2012).
Cannabidiol has been shown to attenuate some effects of THC (Freeman et al. 2019)
and has also been studied for its potential antipsychotic properties since the 1970s
(Karniol et al. 1974). Preclinical studies have suggested that the anti-inflammatory
and neuroprotective effects of CBD may contribute to its hypothesized antipsychotic
properties (Gomes et al. 2015; Hahn 2018). Other hypothesized pathways include
modulation of dopamine D2 receptor activity (Seeman 2016) and endocannabinoid
signalling pathways (Leweke et al. 2012). Furthermore, CBD was shown to decrease
pre-pulse inhibition impairment produced by amphetamine, which can induce psy-
chotic symptoms (Pedrazzi et al. 2015).
We identified eight clinical studies examining patients with psychotic disorders,
where six studies were double-blind and placebo-controlled clinical trials (Boggs et al.
2012, 2018; Kelly et al. 2011; Leweke et al. 2012; McGuire et al. 2018; Meltzer et al.
2004), and two studies were a case series with three or six patients (Schwarcz et al.
2009; Zuardi et al. 2006). All studies examined patients with schizophrenia and/or
schizoaffective disorder. Sample sizes varied widely, ranging from 6 to 88 participants.
Cannabinoids examined included rimonabant, CBD, dronabinol, and a CB1 antago-
nist, SR141716. Rimonabant 20 mg administered over 16 weeks (Boggs et al. 2012)
and CBD 600 mg administered for 6 weeks (Boggs et al. 2018) did not improve
symptoms. Administration of a CB1 antagonist for 6 weeks also did not produce any
improvement (Meltzer et al. 2004). However, another study examining rimonabant
20 mg administered for 16 weeks showed a significant decrease in symptoms (Kelly
et al. 2011). Furthermore, two studies examining treatment with CBD 600–800 mg for
28 days (Leweke et al. 2012) and CBD 1000 mg for 6 weeks (McGuire et al. 2018)
showed a significant improvement in symptoms. Interestingly, the two-case series that
examined the effect of CBD and dronabinol reported partial improvement of symp-
toms in some of the patients (Zuardi et al. 2006; Schwarcz et al. 2009).

Tourette Syndrome

Two small double-blind, placebo-controlled, and randomized clinical trials published

by the same group examined the effect of oral THC 5–10 mg administered over
6 weeks on tics and obsessive-compulsive behaviour (Muller-Vahl et al. 2002, 2003).
Both studies concluded that THC was effective in improving these symptoms.

Dementia

Anti-inflammatory and neuroprotective effects of cannabinoids produced a signifi-

cant amount of interest in using cannabinoids for the treatment of neurodegenerative
1018 S. Kloiber et al.

disorders (Bonaccorso et al. 2019; Aso et al. 2013; Iuvone et al. 2009). Synthetic
agonists at both CB1 and CB2 receptors have been demonstrated to reduce the
harmful effects of beta-amyloid peptide action in preclinical studies and prevent
memory deficits in beta-amyloid treated rodents (Aso and Ferrer 2014). Further-
more, CBD was reported to reduce tau protein hyperphosphorylation in a mouse
model of Alzheimer’s dementia and decrease the production of nitric oxide and
cytokines (Aso et al. 2013, 2016; Casarejos et al. 2013; Iuvone et al. 2009).
Our search identified seven clinical studies examining the effect of cannabinoids
on psychiatric symptoms in patients with dementia, including Alzheimer’s dementia,
vascular dementia, and Parkinson’s disease, where six studies were blinded, placebo-
controlled, and randomized (de Faria et al. 2020; Herrmann et al. 2019; Peball et al.
2020; van den Elsen et al. 2015a, b; Volicer et al. 1997) and one was an open-label
study (Walther et al. 2006). Sample sizes were small, ranging from 6 to 47 partici-
pants. Five studies reported positive findings, where nabilone 1–2 mg for 6 weeks
was found to decrease agitation (Herrmann et al. 2019), nabilone 0.25–1 mg for
4 weeks improved non-motor symptoms of Parkinson’s disease (Peball et al. 2020),
dronabinol 2.5 mg for 6 weeks or 2 weeks decreased severity of disturbed behaviour
and nocturnal motor activity, respectively (Volicer et al. 1997; Walther et al. 2006),
and CBD 300 mg decreased anxiety (de Faria et al. 2020). However, 2 studies
reported no effect of THC 1.5 or 4.5 mg for 3 or 6 weeks, respectively, in patients
with dementia (van den Elsen et al. 2015a, b).

Depression

Epidemiological studies have shown a significant relationship between cannabis use

and depressive symptoms, and the current evidence suggests that depression signif-
icantly increased the likelihood of initiating or escalating cannabis use (Feingold and
Weinstein 2021). Given that dysregulation of the ECS has been suggested to occur to
depression, an increasing number of studies have evaluated the potential role of
cannabinoids in the treatment of depression (Walsh et al. 2017; Black et al. 2019). A
series of preclinical studies have examined the role of endocannabinoids in mood
regulation, where depressive symptoms were found in CB1 knockout mice and
treatment with CB1 receptor antagonist, rimonabant (Martin et al. 2002; Moreira
and Crippa 2009; Gueye et al. 2016). Several preclinical studies suggest that the
antidepressant effect of cannabinoids may occur, at least in part, through the
serotonin pathway, including facilitation of 5HT1A receptor activity (Sartim et al.
2016; Zanelati et al. 2010) and elevation of tryptophan levels, which is a precursor of
serotonin (Jenny et al. 2010).
One small double-blind and placebo-controlled trial in patients with depression
failed to show an effect of THC (Kotin et al. 1973). Most of the studies published to
date examined depression secondary to another medical condition (Black et al.
2019), making it difficult to draw conclusions regarding the effect of cannabinoids
in primary depressive disorders. While not specifically covered in this chapter, a
recent meta-analysis that included studies examining depressive symptoms
Cannabinoid Drugs in Mental Health Disorders 1019

occurring secondary to a medical condition concluded that pharmaceutical cannabi-

noids did not produce significant changes (Black et al. 2019). Of note, as discussed
elsewhere in this chapter, the CB1 receptor antagonist/inverse agonist rimonabant
was withdrawn due to serious psychiatric adverse effects including depression, and
suicidality occurred in a limited number of participants in rimonabant trials (Moreira
and Crippa 2009). Thus, CB1 antagonism is unlikely to be a safe or effective strategy
for depression.

Other Conditions

The effect of cannabinoids was also examined in adult patients with ADHD in a
double-blind placebo-controlled study, where nabiximols was not found to be
effective in decreasing symptoms of ADHD (Cooper et al. 2017). One study
examined the effect of dronabinol 2.5–15 mg administered over 12 weeks in patients
with trichotillomania, where it was found to be effective in decreasing hair pulling
(Grant et al. 2011). Lastly, one open-label clinical trial examined the effect of a
transdermal CBD gel (ZYN002) administered daily for 12 weeks on children and
adolescents with fragile X syndrome, where ZYN002 was found to significantly
improve mood and anxiety (Heussler et al. 2019).

Cannabinoids in Treatment of Substance Use Disorders

Given the important role of the ECS in mediating reward and learning, there has been
considerable interest in investigating cannabinoids as potential treatments for SUDs
(Chye et al. 2019; Sloan et al. 2017). It is important to note that pharmacotherapeutic
strategies for treating SUDs with ECS-targeting drugs are likely to be substance-
specific. For example, CB1 receptor agonists may be useful as a substitution strategy
to treat cannabis use disorder (CUD), while CB1 receptor antagonists may be useful
to mitigate some of the reinforcing effects of other psychoactive drugs (Sloan et al.
2017; Le Foll and Goldberg 2005). The following section will review the clinical
evidence for the role of cannabinoid drugs in reducing symptoms of SUDs, including
CUD, nicotine dependence, opioid use disorder (OUD), and alcohol use disorder
(AUD). All studies administered either CBD or THC (alone, or in combination, i.e.,
nabiximols), nabilone (the synthetic analogue of THC), or a CB1 receptor antagonist/
inverse agonist (rimonabant, taranabant, or surinabant). See Table 2 for an overview
of included clinical studies that met our eligibility criteria.

Cannabis Use Disorder

Agonist substitution/replacement has been an effective approach for treating opioid

and nicotine dependence and thus has been proposed as a potential treatment for
CUD (Allsop et al. 2015; Trigo et al. 2016a, b, 2018). In support of this approach,
1020 S. Kloiber et al.

Table 2 Clinical trials assessing the effects of cannabinoid drugs on substance-related outcomes in
patients with substance use disorders
Reference Sample Study design Intervention Relevant findings
Cannabis
Allsop 51 participants Two-site Six-day Nabiximols significantly
et al. (2014) with DSM-IV parallel- treatment with reduced cannabis
cannabis groups, nabiximols withdrawal scores
dependence double-blind, (maximum compared to placebo
randomized, daily dose No significant difference
inpatient trial 86.4 mg in reductions in cannabis
THC/80 mg use at follow-up
CBD) (n ¼ 27)
or placebo
(n ¼ 24) with
standardized
psychosocial
intervention
Freeman 82 participants Phase 2a, Four weeks of In the first treatment
et al. (2020) with DSM-5 randomised, treatment in phase, CBD 200 mg was
cannabis use double-blind, two phases: eliminated as an
disorder placebo (I) placebo ineffective dose
(at least controlled, (n ¼ 12), oral At the final analysis, both
moderate parallel-group CBD 200 mg/ CBD 400 mg and 800 mg
severity) trial day (n ¼ 12), exceeded primary
CBD 400 mg endpoint criteria (i.e. had
(n ¼ 12), CBD a probability of greater
800 mg than 0.9 of being superior
(n ¼ 12); to placebo) for both
(II) placebo urinary THC-COOH-
(n ¼ 11), CBD creatinine ratio and days
400 mg of abstinence from
(n ¼ 12), CBD cannabis
800 mg
(n ¼ 11) with
motivational
interviewing
Hill et al. 12 participants Parallel- Ten weeks of No difference between
(2017) with DSM-IV groups, treatment with nabilone and placebo in
cannabis double-blind, oral nabilone cannabis-related
dependence randomized (maximum outcomes (as measured
trial 2 mg/day) by Timeline Follow Back
(n ¼ 6) or and daily diaries)
placebo
(n ¼ 6) with
medical
management
behavioural
intervention
Levin et al. 156 participants Randomized, Twelve weeks No difference between
(2011) with DSM-IV- double-blind, of treatment dronabinol and placebo in
with oral 2-week continuous
(continued)
Cannabinoid Drugs in Mental Health Disorders 1021

Table 2 (continued)
Reference Sample Study design Intervention Relevant findings
TR cannabis parallel-group dronabinol abstinence from cannabis.
dependence trial (maximum Greater reduction in
40 mg/day) withdrawal symptoms in
(n ¼ 79) or dronabinol
placebo group vs. placebo
(n ¼ 77) with
psychosocial
intervention
(coping skills
plus
motivational
enhancement
therapy)
Levin et al. 122 participants Randomized, Eleven weeks No difference between
(2016) with DSM-IV- double-blind, of treatment dronabinol-lofexidine
TR cannabis parallel-group with oral and placebo in achieving
dependence trial dronabinol abstinence from cannabis
(maximum No group difference in
60 mg/day) withdrawal symptoms
and lofexidine
(maximum
1.8 mg/day)
(n ¼ 61) or
placebo
(n ¼ 61) plus
motivational
enhancement
and cognitive
behavioural/
relapse
prevention
therapy
Lintzeris 128 participants Phase Twelve weeks Outcomes during
et al. (2019), with ICD-10 3, multisite, of treatment treatment (Lintzeris et al.
Lintzeris cannabis outpatient with 2019): nabiximols group
et al. (2020) dependence randomized, nabiximols reported significantly
double-blind, (maximum fewer days of cannabis
Parallel-design daily dose use over the course of the
trial 86.4 mg 12 weeks of treatment
THC/80 mg compared to the placebo
CBD) (n ¼ 61) group
or placebo Three-month follow up
(n ¼ 67) plus (Lintzeris et al. 2020): the
CBT nabiximols groups
psychosocial reported significantly
intervention fewer days of cannabis
and had a higher
proportion of abstinent
participants in the 28 days
prior to the 3-month
(continued)
1022 S. Kloiber et al.

Table 2 (continued)
Reference Sample Study design Intervention Relevant findings
follow up, as compared to
placebo
Lundahl and 14 participants Placebo- Three single- Both doses of dronabinol
Greenwald with DSM-IV controlled, dose (10 mg and
(2015) cannabis within- experimental 20 mg vs. placebo)
dependence subjects, sessions: attenuated cannabis-
crossover trial Placebo, 10 mg induced increases in
oral craving and anxiety
dronabinol,
20 mg
dronabinol
Trigo et al. 4 participants Open-label Twelve weeks Decrease in cannabis use
(2016b) with DSM-IV pilot trial of treatment over the course of
cannabis with treatment, with
dependence nabiximols accompanying decrease
(maximum in craving and
daily dose withdrawal
113.4 mg
THC/105 mg
CBD) plus
motivational
enhancement
therapy and
cognitive
behavioural
therapy
Trigo et al. 9 participants Double-blind, Five days of Nabiximols (compared to
(2016a) with current placebo- treatment with placebo) significantly
DSM-IV controlled, self-titration of reduced withdrawal, but
cannabis crossover trial placebo, fixed not craving, during
dependence (ABACADAE dose of abstinence
study design, placebo, self-
where B-E are titration of
abstinence nabiximols
phases with (up to
medication maximum
intervention 108 mg
and A is THC/100 mg
smoking as CBD), or fixed
usual phase) dose of
nabiximols
(108 mg
THC/100 mg
CBD) or
placebo
(medication
phases B-D),
each followed
by smoking as
usual period
(A)
(continued)
Cannabinoid Drugs in Mental Health Disorders 1023

Table 2 (continued)
Reference Sample Study design Intervention Relevant findings
Trigo et al. 27 participants Double-blind, Twelve weeks No significant difference
(2018) with current placebo- of treatment in abstinence rates
DSM-IV controlled, with between nabiximols and
cannabis parallel-group nabiximols placebo groups
dependence randomized (maximum Significant group by time
trial daily dose interaction for craving
113.4 mg (greater reduction in
THC/105 mg craving in nabiximols
CBD) (n ¼ 13) group vs. placebo at week
or placebo 7), but no effect on
(n ¼ 14) with withdrawal
motivational
enhancement
therapy and
cognitive
behavioural
therapy
Nicotine
Morgan et al. 24 daily Double-blind, One week of Significant reduction in
(2013) tobacco placebo- treatment with the number of cigarettes
smokers controlled, a CBD inhaler smoked in the CBD
intending to parallel-group (participants group, but not in the
quit randomized instructed to placebo group
trial use the inhaler No effect of CBD on
when they had nicotine craving
an urge to
smoke;
estimated
400μg CBD
per use)
(n ¼ 12) or
placebo
(n ¼ 12)
Morrison 317 daily Multicentre Eight weeks of No significant difference
et al. (2010) tobacco (11-site), treatment with (taranabant vs. placebo)
smokers who double-blind, oral taranabant in continuous abstinence
had at least randomized, (CB1 receptor
three previous placebo- inverse
quit attempts controlled, agonist;
outpatient trial maximum
daily dose
8 mg)
(n ¼ 159) or
placebo
(n ¼ 158) with
brief,
individualized
counselling
intervention
(continued)
1024 S. Kloiber et al.

Table 2 (continued)
Reference Sample Study design Intervention Relevant findings
Rigotti 735 daily Multicentre Rimonabant Significantly greater odds
et al. (2009) tobacco (15-site) (20 mg daily, of achieving smoking
smokers with randomized, oral) given cessation in the nicotine
intent to quit double-blind, open-label for patch + rimonabant
placebo- 9 weeks; compared to placebo
controlled participants patch + rimonabant
parallel-group randomized to
trial nicotine patch
(n ¼ 369) or
placebo patch
(n ¼ 366) plus
weekly
cognitive-
behavioural
smoking
counselling
Robinson 2097 daily Pooled Ten weeks of Continuous abstinence
et al. (2018) tobacco analysis of treatment with rates were significantly
smokers with three oral greater in the 20 mg (but
intent to quit multicentre, rimonabant not 5 mg) rimonabant
randomized, (5 mg group vs. placebo (when
double-blind, (n ¼ 518) or assessed at end of
placebo- 20 mg treatment, and at 48-week
controlled (n ¼ 790) follow-up)
trials daily) or
placebo
(n ¼ 789) plus
behavioural
counselling
Tonstad and 810 daily Randomized, Eight weeks of No difference in
Aubin (2012) tobacco multicentre treatment with continuous abstinence
smokers (35 site), oral surinabant rates between surinabant
motivated to double-blind, (CB1 receptor (at any dose tested) and
quit 4-arm parallel- antagonist) at placebo
group placebo- 2.5 mg/day
controlled trial (n ¼ 199),
5 mg/day
(n ¼ 204),
10 mg/day
(n ¼ 205), or
placebo
(n ¼ 202) plus
brief smoking
cessation
counselling
Opioids
Bisaga et al. 60 treatment- Randomized, Treatment with Dronabinol (vs. placebo)
(2015) seeking double-blind, oral dronabinol reduced withdrawal
participants placebo- (maximum during the initial acute
with current controlled daily dose inpatient phase, prior to
30 mg) naltrexone induction
(continued)
Cannabinoid Drugs in Mental Health Disorders 1025

Table 2 (continued)
Reference Sample Study design Intervention Relevant findings
DSM-IV opioid parallel-group (n ¼ 40) or No difference between
dependence trial placebo dronabinol and placebo
(n ¼ 20) groups in withdrawal
during symptoms during the
inpatient outpatient phase or
detoxification proportion of patients
and naltrexone inducted onto and
induction maintained on injection
(8 days total) naltrexone
and then
subsequent
5 weeks of
outpatient care
Hurd et al. 42 participants Double-blind, Three days of Both doses of CBD
(2019) with current placebo- treatment with reduced heroin
DSM-IV opioid controlled, oral CBD at cue-induced craving and
dependence, randomized, 400 mg anxiety compared to
recently parallel-group (n ¼ 14) and placebo, both when
abstinent from trial 800 mg assessed acutely (i.e.,
heroin (n ¼ 13) or after the first dose of
placebo CBD/placebo during the
(n ¼ 15) first experimental
session) and when
assessed 1 week after the
final CBD exposure
Alcohol
Soyka et al. 258 participants Phase 2a Twelve weeks No significant difference
(2008) with current (proof-of- of treatment (rimonabant vs. placebo)
DSM-IV concept), with oral in time to first drink or
alcohol double-blind, rimonabant heavy drinking
dependence placebo- (20 mg/day)
who had controlled (n ¼ 131) or
recently parallel-group placebo
detoxified from trial (n ¼ 127)
alcohol
a
Abbreviations: CBD (cannabinol), THC (Δ9 – tetrahydrocannabinol)

human laboratory studies have found that oral THC or its synthetic analogue
nabilone reduce cannabis withdrawal when compared to placebo (Panlilio et al.
2016). CBD has also shown promise in reducing cannabis-related outcomes (e.g.,
self-administration, withdrawal) in animal models and in humans (Chye et al. 2019).
Combining THC and CBD (e.g., nabiximols) has received particular attention given
the extant evidence from human studies that CBD can at least partly attenuate the
acute effects of THC (Freeman et al. 2019).
Eleven studies that met our eligibility criteria assessed the impact of cannabinoid
drugs on cannabis-related outcomes. All included studies administered either oral
1026 S. Kloiber et al.

CBD alone (Freeman et al. 2020), oral THC (i.e., dronabinol) alone (Levin et al.
2011, 2016; Lundahl and Greenwald 2015), nabiximols (Allsop et al. 2014; Trigo
et al. 2016a, b, 2018; Lintzeris et al. 2019, 2020), or oral nabilone (Hill et al. 2017).
Freeman et al. (2020) conducted a phase 2a, double-blind, placebo-controlled
trial that randomized 82 participants with DSM-5 CUD (at least moderate severity)
to receive 4 weeks of treatment with oral CBD (200, 400, or 800 mg/day) or placebo
in two phases. In the first phase, CBD 200 mg was eliminated as an ineffective dose.
In the second phase, at the final analysis, both CBD 400 mg and 800 mg exceeded
primary endpoint criteria (i.e., had a probability greater than 0.9 of being superior to
placebo) for both urinary cannabinoid concentrations and days of abstinence from
cannabis (Freeman et al. 2020).
Levin and colleagues conducted two RCTs evaluating the efficacy of dronabinol
in promoting abstinence from cannabis use. In the first trial, 156 participants with
DSM-IV-TR cannabis dependence were randomized to 12 weeks of treatment with
oral dronabinol (maximum 40 mg/day, n ¼ 79) or placebo (n ¼ 77). There was no
difference between dronabinol and placebo in 2-week continuous abstinence from
cannabis, but there was a greater effect of dronabinol on withdrawal symptoms when
compared to placebo (Levin et al. 2011). In a follow-up trial, 122 participants with
DSM-IV-TR cannabis dependence were randomized to 11 weeks of treatment with
combined oral dronabinol (maximum 60 mg/day) and lofexidine (an α2A adrenergic
receptor agonist; maximum 1.8 mg/day) (n ¼ 61) or placebo (n ¼ 61). There was no
difference in continuous abstinence or withdrawal symptoms between treatment
groups; however, dronabinol was not administered alone (only in combination
with lofexidine) (Levin et al. 2016). Lundahl and Greenwald (2015) conducted a
single-dose crossover trial with 14 participants meeting DSM-IV criteria for canna-
bis dependence. Dronabinol (at 10 mg and 20 mg) significantly attenuated cannabis-
induced increases in craving and anxiety (compared to placebo) (Lundahl and
Greenwald 2015).
Six clinical studies have found evidence that nabiximols may be an effective
treatment for cannabis dependence. Allsop et al. (2014) randomized 51 participants
with DSM-IV cannabis dependence to receive 6 days of treatment with nabiximols
(maximum daily dose 86.4 mg THC/80 mg CBD, n ¼ 27) or placebo (n ¼ 24) and
found that nabiximols significantly reduced cannabis withdrawal compared to pla-
cebo, though there was no difference in cannabis use at 28-day follow up. Trigo and
colleagues provided additional clinical evidence suggesting nabiximols as an effec-
tive therapy for CUD. In an open-label pilot study, they found that 12 weeks of
treatment with nabiximols (maximum daily dose 113.4 mg THC/105 mg CBD) led
to a significant decrease in cannabis use, craving, and withdrawal (Trigo et al.
2016b). Trigo and colleagues also conducted a crossover trial in nine participants
with current DSM-IV cannabis dependence, who underwent 5 days of treatment with
self-titration of a placebo, self-titration of nabiximols, fixed dose of placebo, and
fixed dose of nabiximols (108 mg THC/100 mg CBD) during a period of abstinence,
each followed by smoking as usual period. This study found that nabiximols
significantly reduced craving but not withdrawal, as compared to placebo (Trigo
et al. 2016a). Finally, the authors conducted a double-blind, placebo-controlled trial
Cannabinoid Drugs in Mental Health Disorders 1027

where participants with current DSM-IV cannabis dependence were randomized to

12 weeks of treatment with nabiximols (maximum daily dose 113.4 mg THC/105 mg
CBD, n ¼ 13) or placebo (n ¼ 14) (Trigo et al. 2018). In this study, there was no
difference in abstinence rates in the nabiximols or placebo groups and no effect of
nabiximols on withdrawal, but nabiximols did reduce craving more than placebo
(Trigo et al. 2018). Most recently, Lintzeris et al. (2019) conducted a phase 3, multi-
site, outpatient RCT that randomized participants with ICD-10 cannabis dependence
to receive 12 weeks of treatment with nabiximols (n ¼ 61; maximum daily dose
86.4 mg THC/80 mg CBD) or placebo (n ¼ 67). The nabiximols-treated group
reported significantly fewer days of cannabis use over the course of treatment
compared to the placebo group (Lintzeris et al. 2019). Importantly, in a separate
publication, the authors reported that the nabiximols-treated group continued to have
favourable cannabis-related outcomes 3 months after the end of treatment, with
significantly fewer days of cannabis use and a greater proportion of abstinent
participants in the past 28 days, as compared to the placebo group (Lintzeris et al.
2020).
Hill et al. (2017) recruited 12 participants with DSM-IV cannabis dependence,
who were randomized to receive 10 weeks of treatment with oral nabilone (maxi-
mum 2 mg/day, n ¼ 6) or placebo (n ¼ 6). There was no significant difference
between nabilone and placebo in the primary cannabis-related outcomes, as assessed
by the Timeline Follow Back and by daily diaries (Hill et al. 2017).

Nicotine Dependence

Converging lines of evidence from preclinical and human studies have strongly
implicated a role of the CB1 receptor in nicotine reward and reinforcement (Gamaleddin
et al. 2015). In animal models, rimonabant (a CB1 receptor antagonist/inverse agonist)
has been shown to decrease nicotine self-administration, block the development of
nicotine-induced conditioned place preference, and block reinstatement of previously
extinguished nicotine-seeking behaviour (Gamaleddin et al. 2015; Le Foll and Gold-
berg 2004). Rimonabant emerged as a promising candidate for smoking cessation
pharmacotherapy based on converging evidence from animal models and human trials,
yet significant psychiatric adverse effects ultimately led to rimonabant being withdrawn
from the market (Sloan et al. 2017). Similarly, the development of two other CB1
receptor antagonists (surinabant and taranabant) was halted due to the risk of serious
adverse effects. CBD has been another promising candidate for a smoking cessation
drug, in large part due to its non-competitive antagonism of CB1 receptor signalling,
likely through negative allosteric modulation, which would mean it lacks the adverse
effects caused by inverse agonists such as rimonabant (Sloan et al. 2017; Chye et al.
2019). Human laboratory evidence has suggested that CBD can reduce attentional bias
to tobacco cues (e.g., Hindocha et al. 2018).
Five studies that met our eligibility criteria assessed the impact of cannabinoid
drugs on nicotine-related outcomes. One study administered inhaled CBD (Morgan
et al. 2013), while the remaining four administered one of three different CB1 receptor
1028 S. Kloiber et al.

antagonists/inverse agonists (rimonabant, taranabant, or surinabant) (Morrison et al.

2010; Tonstad and Aubin 2012; Rigotti et al. 2009; Robinson et al. 2018).
A single double-blind, placebo-controlled trial assessed the efficacy of 1 week of
ad hoc use of a CBD inhaler (compared to placebo) on smoking cessation in a sample
of 24 daily tobacco smokers intent on quitting who were otherwise healthy (Morgan
et al. 2013). The study found a significant reduction in the number of cigarettes
smoked in the CBD group, but not the placebo group, though there was no effect of
CBD on nicotine craving (Morgan et al. 2013).
One pooled analysis of three multicentre, double-blind, placebo-controlled trials
assessed the efficacy of 10 weeks of treatment with oral rimonabant (5 mg/day or
20 mg/day compared to placebo) on smoking cessation in a sample of 2,097 daily
smokers intent on quitting (Robinson et al. 2018). There was a statistically significant
effect of treatment arm: participants receiving rimonabant at 20 mg/day (but not 5 mg/
day) were more likely to achieve continuous abstinence than those in the placebo arm
(Robinson et al. 2018). An earlier study found that adding the nicotine patch to 20 mg/
day rimonabant nearly doubled the odds of achieving smoking cessation compared to
20 mg/day rimonabant alone after 9 weeks of treatment, but the study was unable to
test the direct efficacy of rimonabant given there was no placebo comparator (Rigotti
et al. 2009). Two other trials found no additional evidence of an effect of CB1 receptor
antagonism/inverse agonism on smoking cessation. Morrison et al. (2010) found no
significant difference in smoking cessation in groups treated with taranabant (max
8 mg/day; n ¼ 159) or placebo (n ¼ 158) for 8 weeks in a sample of 317 daily smokers
who had at least three previous quit attempts. Similarly, Tonstad and Aubin (2012)
found no significant effect of surinabant (2.5 mg/day, n ¼ 199; 5 mg/day, n ¼ 204;
10 mg/day, n ¼ 205; or placebo, n ¼ 202) on smoking cessation in a sample of
810 daily tobacco smokers motivated to quit.

Opioid Use Disorder

Decades of preclinical studies have demonstrated that cannabinoids can reduce

morphine withdrawal in rodent models (Hurd et al. 2015; Chye et al. 2019). CBD
in particular has been demonstrated to reduce opioid-related outcomes, e.g., inhibi-
tion of cue-induced heroin seeking and reduction of morphine withdrawal, in animal
models (Hurd et al. 2015). Further evidence comes from observational studies
suggesting that patients with an OUD who use cannabis have better treatment
retention outcomes during naltrexone treatment than patients who do not use can-
nabis (Raby et al. 2009; Socías et al. 2018).
Two studies that met our eligibility criteria assessed the impact of cannabinoid
drugs on opioid-related outcomes. One study administered dronabinol (Bisaga et al.
2015) and the other administered oral CBD (Hurd et al. 2019). Bisaga et al. (2015)
examined the effect of treatment with oral dronabinol (max 30 mg/day, n ¼ 40; or
placebo, n ¼ 20) in patients with current DSM-IV opioid dependence undergoing
inpatient detoxification. The study found that dronabinol reduced withdrawal symp-
toms compared to placebo during the initial acute inpatient phase, prior to naltrexone
Cannabinoid Drugs in Mental Health Disorders 1029

induction, but did not have sustained effects during the subsequent 5 weeks of
outpatient care (Bisaga et al. 2015). Hurd et al. (2019) recruited 42 participants
with current DSM-IV opioid dependence who were recently abstinent from heroin
and randomized them to receive three consecutive days of treatment with oral CBD
400 mg (n ¼ 14), CBD 800 mg (n ¼ 13), or placebo (n ¼ 15). The authors found that
both doses of CBD effectively reduced cue-induced craving and anxiety compared
to placebo, both when measured after the first dose of CBD/placebo and when
assessed 1 week after the final day of CBD/placebo treatment (Hurd et al. 2019).

Alcohol Use Disorder

The bidirectional relationship between alcohol exposure and the ECS has been
extensively characterized in animal models, with studies showing that alcohol intake
leads to changes in CB1 receptors and endocannabinoid levels and that infusion of
CB1 receptor agonists can enhance alcohol self-administration (Basavarajappa et al.
2019). Preclinical evidence has also suggested that CB1 receptor antagonism can
reduce alcohol self-administration (Sloan et al. 2017). Only one relevant clinical trial
was identified for the present review. A single phase 2a (proof-of-concept) trial
found no significant evidence of an effect of rimonabant (20 mg daily for 12 weeks)
compared to placebo on time to first drink or time to first heavy drinking in a sample
of 258 participants with DSM-IV alcohol dependence who had recently undergone
detoxification from alcohol (Soyka et al. 2008). Emerging evidence has also
supported the role of CBD in reducing alcohol-related outcomes (Nona et al.
2019), though no published clinical trials were identified for inclusion in this chapter.

Discussion and Future Directions

Mental Health Conditions

While the role of cannabinoids for some disorders, such as chemotherapy-induced

nausea, spasticity in multiple sclerosis, or specific forms of childhood epilepsy, has
been extensively studied, examination of the effects of cannabinoids in the treatment
of mental health conditions is still in its very early stages (Black et al. 2019; Walsh
et al. 2017). In agreement with previously published systematic reviews examining the
effect of cannabinoids in mental disorders, studies reviewed here suggest that canna-
binoids may have therapeutic effects in the treatment of some psychiatric disorders
such as anxiety disorders, PTSD, or Tourette syndrome (Black et al. 2019, Whiting
et al. 2015, 2017). More specifically, some preliminary results have indicated potential
effects of CBD in social anxiety disorder, nabilone in PTSD, and THC in Tourette’s
syndrome (see Table 1 for detailed information). While the antipsychotic properties of
cannabinoids have been extensively explored in preclinical studies, findings from
clinical trials in patients with schizophrenia or schizoaffective disorder are mixed,
and more studies are required to determine the potential use of cannabinoids in the
1030 S. Kloiber et al.

treatment of psychotic disorders. Similar to psychotic disorders, while several preclin-

ical studies have examined the potential effects of cannabinoids in depression, we only
identified one clinical trial examining the effect of cannabinoids in primary depression
(Kotin et al. 1973). More studies are required to elucidate the effect of cannabinoids in
depressive disorders that occur independently of medical conditions (Black et al.
2019). The majority of the studies examining patients with dementia showed effects
of cannabinoids in improving psychiatric symptoms associated with dementia (de Faria
et al. 2020; Herrmann et al. 2019; Peball et al. 2020; van den Elsen et al. 2015a, b;
Volicer et al. 1997; Walther et al. 2006), suggesting that this may be a promising area
for further exploration.
While an emerging body of small studies show promising initial results indicating
a possible future role of cannabinoids in the treatment of mental disorders, more and
larger placebo-controlled and randomized clinical trials are required to ascertain their
efficacy. This was also pointed out by previously published systematic reviews and
meta-analyses (Walsh et al. 2017; Bonaccorso et al. 2019). Together, despite some
promising preliminary findings, current evidence does not support the use of can-
nabinoids in the treatment of mental health conditions and further research including
larger controlled trials are warranted to evaluate efficacy and safety (Stanciu et al.
2021; Sarris et al. 2020). Published studies also vary widely in dosages and length of
treatment, even within the same mental health condition, making it additionally
challenging to draw conclusions based on existing studies at this time. Future studies
examining optimal dosage ranges and treatment duration are thus required. It would
also be important to compare the efficacy of cannabinoids to first-line pharmacolog-
ical treatments that are used for the psychiatric condition being examined. Lastly,
examining long-term cognitive effects of cannabinoid use, particularly in children
and older adults, as well as potential risks of developing substance use disorders, are
important areas for further exploration.

Substance Use Disorders

The evidence reviewed supports the role of cannabinoid drugs in treating SUDs,
though most findings have yet to be replicated in large trials. The included clinical
studies seem to support a role for CBD in reducing cannabis use (Freeman et al. 2020),
promoting tobacco smoking cessation (Morgan et al. 2013), and attenuating opioid
craving (Hurd et al. 2019). Cannabinoid substitution therapy (with dronabinol or
nabiximols) shows promise as a strategy to reduce cannabis craving and/or withdrawal
in patients with CUD (Allsop et al. 2014; Levin et al. 2011, 2016; Trigo et al. 2016a,
2018), and the most recent evidence suggests that nabiximols has potential to reduce
cannabis use and promote abstinence (Lintzeris et al. 2019, 2020). Preliminary
evidence suggests that dronabinol may also be useful for reducing opioid withdrawal
(Bisaga et al. 2015), though this finding also needs replication in a larger RCT.
A pooled analysis of over 2000 participants of smoking cessation trials found
compelling evidence that rimonabant is effective in promoting abstinence from
tobacco smoking (Robinson et al. 2018), yet rimonabant has been withdrawn due
to its serious psychiatric adverse effects, including depressive symptoms and
Cannabinoid Drugs in Mental Health Disorders 1031

suicidality (Sloan et al. 2017). So far, the use of other CB1 receptor antagonists – i.e.,
surinabant (Tonstad and Aubin 2012) and taranabant (Morrison et al. 2010) – have
not shown efficacy in promoting smoking cessation in clinical trials, and develop-
ment of these drugs ceased after the withdrawal of rimonabant. Given the success of
rimonabant, there has been interest in developing alternative strategies for antago-
nizing the CB1 receptor without the serious psychiatric adverse effects. Such strat-
egies include peripherally restricted CB1 antagonists (e.g., JD5037), neutral CB1
receptor antagonists that lack the inverse agonism of rimonabant (e.g., AM4113),
and negative allosteric modulators of CB1 receptors (e.g., Pepcan-12) (Galaj and Xi
2019). So far, only the neutral CB1 receptor antagonist AM4113 has demonstrated
the potential to reduce nicotine self-administration, yet all three types of CB1
receptor-targeting compounds have demonstrated the potential to reduce alcohol
intake, suggesting that these alternative CB1 receptor antagonism strategies may
have the potential for AUD (Galaj and Xi 2019).
Another strategy for modulating the ECS to treat SUDs and mental health conditions
that has received increasing attention is the use of enzyme inhibitors such as FAAH or
MAGL inhibitors (Galaj and Xi 2019; Sloan et al. 2017). Inhibiting FAAH increases
levels of AEA, which has shown promise in preclinical studies to modulate nicotine and
alcohol intake and in preliminary human studies to reduce cannabis use and withdrawal
in CUD (Galaj and Xi 2019). Similarly, the inhibition of MAGL leads to increased
levels of 2-AG, though currently, there is less evidence suggesting that MAGL
inhibitors can reduce drug-related behaviours (Galaj and Xi 2019). For example, in
rodents, FAAH inhibition was shown to attenuate cue-induced reinstatement of
nicotine-seeking (Forget et al. 2016), while MAGL inhibition actually enhanced
cue-induced reinstatement (Trigo and Le Foll 2016), so more work is clearly needed
to delineate the effect of MAGL inhibition. Interestingly, dual inhibition of FAAH and
MAGL with the compound SA-57 has been shown to reduce heroin self-administration
in rodents (Wilkerson et al. 2017). More work is clearly needed to evaluate the potential
of FAAH and MAGL inhibitors to reduce drug self-administration and reinforcement,
but this remains a promising avenue for future human trials. Preclinical studies of
FAAH or MAGL inhibitors using stress paradigms indicated potential effects on
depression- and anxiety-like behaviours, as well as social behaviours, potentially
mediated through the restoration of AEA and brain-derived neurotrophic factor
(BDNF) (Alteba et al. 2020; Dong et al. 2020; Carnevali et al. 2020). A recently
published clinical trial of an FAAH inhibitor in social anxiety disorder (Schmidt et al.
2021) showed a negative result of the primary outcome, though the authors indicated a
small to modest anxiolytic effect in severe social anxiety disorder and that measured
FAAH and drug levels may warrant exploration of higher doses.

Conclusion

A growing body of evidence has indicated the potential of different cannabinoids to

treat symptoms of mental health disorders and SUDs, which is in line with the
important role of the ECS in affect, anxiety, reward, and cognition. However, most of
the evidence so far is preclinical, and only a few randomized controlled trials have
1032 S. Kloiber et al.

been conducted to explore the effects of cannabinoids in the treatment of these

conditions. It is of note that the majority of the clinical trials reviewed in this chapter
were pilot or proof-of-concept trials with small sample sizes. In addition, there is
significant heterogeneity in previous clinical studies investigating cannabinoids in
mental health and substance use conditions with a large variety of cannabinoids,
dosages, duration of interventions, and outcome measures.
Although the legalization of cannabis and/or medical cannabis programs are
expected in additional countries, increasing the availability of cannabis and use of
cannabinoids in the treatment of mental health conditions and SUDs, the current
scientific evidence does not support the use of cannabinoids as treatment of SUDs or
psychiatric conditions. Thus, additional research and definite clinical trials are
urgently needed to address this knowledge gap as well as challenges of patients,
care providers, and society associated with the large controversy and uncertainty
about potential risks or beneficial effects of cannabinoids, in particular for poten-
tially vulnerable individuals with mental health conditions or SUDs.

Cross-References

▶ The Endocannabinoid System in the Central Nervous System: Emphasis on the

Role of the Mitochondrial Cannabinoid Receptor 1 (mtCB1R)

References
Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, Rivas GR, Holland RM,
Muhleisen P, Norberg MM, Booth J, McGregor IS. Nabiximols as an agonist replacement
therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiat. 2014;71:281–
91.
Allsop DJ, Lintzeris N, Copeland J, Dunlop A, McGregor IS. Cannabinoid replacement therapy
(CRT): Nabiximols (Sativex) as a novel treatment for cannabis withdrawal. Clin Pharmacol
Ther. 2015;97:571–4.
Alteba S, Mizrachi Zer-Aviv T, Tenenhaus A, Ben David G, Adelman J, Hillard CJ, Doron R,
Akirav I. Antidepressant-like effects of URB597 and JZL184 in male and female rats exposed to
early life stress. Eur Neuropsychopharmacol. 2020;39:70–86.
Aso E, Ferrer I. Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Front
Pharmacol. 2014;5:37.
Aso E, Juves S, Maldonado R, Ferrer I. CB2 cannabinoid receptor agonist ameliorates Alzheimer-
like phenotype in AbetaPP/PS1 mice. J Alzheimers Dis. 2013;35:847–58.
Aso E, Andres-Benito P, Ferrer I. Delineating the efficacy of a Cannabis-based medicine at
advanced stages of dementia in a murine model. J Alzheimers Dis. 2016;54:903–12.
Basavarajappa BS, Joshi V, Shivakumar M, Subbanna S. Distinct functions of endogenous canna-
binoid system in alcohol abuse disorders. Br J Pharmacol. 2019;176:3085–109.
Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F,
Quevedo J, Roesler R, Schroder N, Nardi AE, Martin-Santos R, Hallak JE, Zuardi AW, Crippa
JA. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive
social phobia patients. Neuropsychopharmacology. 2011;36:1219–26.
Cannabinoid Drugs in Mental Health Disorders 1033

Bisaga A, Sullivan MA, Glass A, Mishlen K, Pavlicova M, Haney M, Raby WN, Levin FR, Carpenter
KM, Mariani JJ, Nunes EV. The effects of dronabinol during detoxification and the initiation of
treatment with extended release naltrexone. Drug Alcohol Depend. 2015;154:38–45.
Black N, Stockings E, Campbell G, Tran LT, Zagic D, Hall WD, Farrell M, Degenhardt
L. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a
systematic review and meta-analysis. Lancet Psychiatry. 2019;6:995–1010.
Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for
anxiety disorders. Neurotherapeutics. 2015;12:825–36.
Boggs DL, Kelly DL, McMahon RP, Gold JM, Gorelick DA, Linthicum J, Conley RR, Liu F,
Waltz J, Huestis MA, Buchanan RW. Rimonabant for neurocognition in schizophrenia: a
16-week double blind randomized placebo controlled trial. Schizophr Res. 2012;134:207–10.
Boggs DL, Surti T, Gupta A, Gupta S, Niciu M, Pittman B, Schnakenberg Martin AM,
Thurnauer H, Davies A, D’Souza DC, Ranganathan M. The effects of cannabidiol (CBD) on
cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo
controlled trial. Psychopharmacology. 2018;235:1923–32.
Bonaccorso S, Ricciardi A, Zangani C, Chiappini S, Schifano F. Cannabidiol (CBD) use in
psychiatric disorders: a systematic review. Neurotoxicology. 2019;74:282–98.
Bonn-Miller MO, Boden MT, Bucossi MM, Babson KA. Self-reported cannabis use characteristics,
patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Abuse. 2014;40:
23–30.
Botsford SL, Yang S, George TP. Cannabis and cannabinoids in mood and anxiety disorders: impact
on illness onset and course, and assessment of therapeutic potential. Am J Addict. 2020;29:9–26.
Campos AC, Ortega Z, Palazuelos J, Fogaca MV, Aguiar DC, Diaz-Alonso J, Ortega-Gutierrez S,
Vazquez-Villa H, Moreira FA, Guzman M, Galve-Roperh I, Guimaraes FS. The anxiolytic effect
of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement
of the endocannabinoid system. Int J Neuropsychopharmacol. 2013;16:1407–19.
Carnevali L, Statello R, Vacondio F, Ferlenghi F, Spadoni G, Rivara S, Mor M, Sgoifo
A. Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially
isolated female rats. Eur Neuropsychopharmacol. 2020;32:77–87.
Casarejos MJ, Perucho J, Gomez A, Munoz MP, Fernandez-Estevez M, Sagredo O, Fernandez
Ruiz J, Guzman M, de Yebenes JG, Mena MA. Natural cannabinoids improve dopamine
neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J Alzheimers
Dis. 2013;35:525–39.
Chye Y, Christensen E, Solowij N, Yücel M. The endocannabinoid system and Cannabidiol’s
promise for the treatment of substance use disorder. Front Psych. 2019;10:63.
Connor JP, Stjepanović D, Le Foll B, Hoch E, Budney AJ, Hall WD. Cannabis use and cannabis use
disorder. Nat Rev Dis Primers. 2021;7:16.
Cooper RE, Williams E, Seegobin S, Tye C, Kuntsi J, Asherson P. Cannabinoids in attention-deficit/
hyperactivity disorder: a randomised-controlled trial. Eur Neuropsychopharmacol. 2017;27:
795–808.
Crippa JA, Zuardi AW, Martín-Santos R, Bhattacharyya S, Atakan Z, McGuire P, Fusar-Poli
P. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009;24:
515–23.
Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, Simoes MV,
Bhattacharyya S, Fusar-Poli P, Atakan Z, Santos Filho A, Freitas-Ferrari MC, McGuire PK,
Zuardi AW, Busatto GF, Hallak JE. Neural basis of anxiolytic effects of cannabidiol (CBD) in
generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25:121–30.
D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT, Braley G, Gueorguieva R,
Krystal JH. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy
individuals: implications for psychosis. Neuropsychopharmacology. 2004;29:1558–72.
de Faria SM, de Morais Fabricio D, Tumas V, Castro PC, Ponti MA, Hallak JE, Zuardi AW, Crippa
JAS, Chagas MHN. Effects of acute cannabidiol administration on anxiety and tremors induced
by a simulated public speaking test in patients with Parkinson’s disease. J Psychopharmacol.
2020;34:189–96.
1034 S. Kloiber et al.

Dong B, Shilpa BM, Shah R, Goyal A, Xie S, Bakalian MJ, Suckow RF, Cooper TB, Mann JJ,
Arango V, Vinod KY. Dual pharmacological inhibitor of endocannabinoid degrading enzymes
reduces depressive-like behavior in female rats. J Psychiatr Res. 2020;120:103–12.
Elphick MR, Egertova M. The phylogenetic distribution and evolutionary origins of endo-
cannabinoid signalling. Handb Exp Pharmacol. 2005;168:283–97.
Fabre LF, McLendon D. The efficacy and safety of nabilone (a synthetic cannabinoid) in the
treatment of anxiety. J Clin Pharmacol. 1981;21:377S–82S.
Feingold D, Weinstein A. Cannabis and depression. Adv Exp Med Biol. 2021;1264:67–80.
Forget B, Guranda M, Gamaleddin I, Goldberg SR, Le Foll B. Attenuation of cue-induced
reinstatement of nicotine seeking by URB597 through cannabinoid CB1 receptor in rats.
Psychopharmacology. 2016;233:1823–8.
Freeman AM, Petrilli K, Lees R, Hindocha C, Mokrysz C, Curran HV, Saunders R, Freeman
TP. How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol
(THC) in humans? A systematic review. Neurosci Biobehav Rev. 2019;107:696–712.
Freeman TP, Hindocha C, Baio G, Shaban NDC, Thomas EM, Astbury D, Freeman AM, Lees R,
Craft S, Morrison PD, Bloomfield MAP, O’Ryan D, Kinghorn J, Morgan CJA, Mofeez A,
Curran HV. Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind,
placebo-controlled, randomised, adaptive Bayesian trial. Lancet Psychiatry. 2020;7:865–74.
Galaj E, Xi ZX. Potential of cannabinoid receptor ligands as treatment for substance use disorders.
CNS Drugs. 2019;33:1001–30.
Gamaleddin IH, Trigo JM, Gueye AB, Zvonok A, Makriyannis A, Goldberg SR, Le Foll B. Role of
the endogenous cannabinoid system in nicotine addiction: novel insights. Front Psych.
2015;6:41.
Gomes FV, Llorente R, Del Bel EA, Viveros MP, Lopez-Gallardo M, Guimaraes FS. Decreased
glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr Res.
2015;164:155–63.
Grant JE, Odlaug BL, Chamberlain SR, Kim SW. Dronabinol, a cannabinoid agonist, reduces hair
pulling in trichotillomania: a pilot study. Psychopharmacology. 2011;218:493–502.
Gueye AB, Pryslawsky Y, Trigo JM, Poulia N, Delis F, Antoniou K, Loureiro M, Laviolette SR,
Vemuri K, Makriyannis A, Le Foll B. The CB1 neutral antagonist AM4113 retains the
therapeutic efficacy of the inverse agonist Rimonabant for nicotine dependence and weight
loss with better psychiatric tolerability. Int J Neuropsychopharmacol. 2016;19
Hahn B. The potential of Cannabidiol treatment for Cannabis users with recent-onset psychosis.
Schizophr Bull. 2018;44:46–53.
Herrmann N, Ruthirakuhan M, Gallagher D, Verhoeff N, Kiss A, Black SE, Lanctot
KL. Randomized placebo-controlled trial of Nabilone for agitation in Alzheimer’s disease.
Am J Geriatr Psychiatry. 2019;27:1161–73.
Heussler H, Cohen J, Silove N, Tich N, Bonn-Miller MO, Du W, O’Neill C, Sebree T. A phase 1/2,
open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol
(ZYN002) for the treatment of pediatric fragile X syndrome. J Neurodev Disord. 2019;11:16.
Hill AJ, Williams CM, Whalley BJ, Stephens GJ. Phytocannabinoids as novel therapeutic agents in
CNS disorders. Pharmacol Ther. 2012;133:79–97.
Hill KP, Palastro MD, Gruber SA, Fitzmaurice GM, Greenfield SF, Lukas SE, Weiss RD. Nabilone
pharmacotherapy for cannabis dependence: a randomized, controlled pilot study. Am J Addict.
2017;26:795–801.
Hindocha C, Freeman TP, Grabski M, Stroud JB, Crudgington H, Davies AC, Das RK, Lawn W,
Morgan CJA, Curran HV. Cannabidiol reverses attentional bias to cigarette cues in a human
experimental model of tobacco withdrawal. Addiction. 2018;113:1696–705.
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M,
Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology.
XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161–202.
Hu SS-J, Mackie K. Distribution of the endocannabinoid system in the central nervous system. In:
Pertwee RG, editor. Endocannabinoids. Cham: Springer International Publishing; 2015.
Cannabinoid Drugs in Mental Health Disorders 1035

Hurd YL, Yoon M, Manini AF, Hernandez S, Olmedo R, Ostman M, Jutras-Aswad D. Early phase
in the development of Cannabidiol as a treatment for addiction: opioid relapse takes initial center
stage. Neurotherapeutics. 2015;12:807–15.
Hurd YL, Spriggs S, Alishayev J, Winkel G, Gurgov K, Kudrich C, Oprescu AM, Salsitz
E. Cannabidiol for the reduction of Cue-induced craving and anxiety in drug-abstinent individ-
uals with heroin use disorder: a double-blind randomized placebo-controlled trial. Am J
Psychiatry. 2019;176:911–22.
Ibarra-Lecue I, Pilar-Cuéllar F, Muguruza C, Florensa-Zanuy E, Díaz Á, Urigüen L, Castro E,
Pazos A, Callado LF. The endocannabinoid system in mental disorders: evidence from human
brain studies. Biochem Pharmacol. 2018;157:97–107.
Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L. Cannabidiol: a promising drug for
neurodegenerative disorders? CNS Neurosci Ther. 2009;15:65–75.
Jenny M, Schrocksnadel S, Uberall F, Fuchs D. The potential role of cannabinoids in modulating
serotonergic signaling by their influence on tryptophan metabolism. Pharmaceuticals (Basel).
2010;3:2647–60.
Jetly R, Heber A, Fraser G, Boisvert D. The efficacy of nabilone, a synthetic cannabinoid, in the
treatment of PTSD-associated nightmares: a preliminary randomized, double-blind, placebo-
controlled cross-over design study. Psychoneuroendocrinology. 2015;51:585–8.
Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the
effects of delta 9 - tetrahydrocannabinol in man. Eur J Pharmacol. 1974;28:172–7.
Kayser RR, Haney M, Raskin M, Arout C, Simpson HB. Acute effects of cannabinoids on
symptoms of obsessive-compulsive disorder: a human laboratory study. Depress Anxiety.
2020;37:801–11.
Kelly DL, Gorelick DA, Conley RR, Boggs DL, Linthicum J, Liu F, Feldman S, Ball MP, Wehring HJ,
McMahon RP, Huestis MA, Heishman SJ, Warren KR, Buchanan RW. Effects of the cannabinoid-
1 receptor antagonist rimonabant on psychiatric symptoms in overweight people with schizophre-
nia: a randomized, double-blind, pilot study. J Clin Psychopharmacol. 2011;31:86–91.
Kotin J, Post RM, Goodwin FK. 9 -tetrahydrocannabinol in depressed patients. Arch Gen Psychi-
atry. 1973;28:345–8.
Le Foll B, Goldberg SR. Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place
preferences. Neuroreport. 2004;15:2139–43.
Le Foll B, Goldberg SR. Cannabinoid CB1 receptor antagonists as promising new medications for
drug dependence. J Pharmacol Exp Ther. 2005;312:875–83.
Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV. Dronabinol for the treatment
of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol
Depend. 2011;116:142–50.
Levin FR, Mariani JJ, Pavlicova M, Brooks D, Glass A, Mahony A, Nunes EV, Bisaga A,
Dakwar E, Carpenter KM, Sullivan MA, Choi JC. Dronabinol and lofexidine for cannabis use
disorder: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend.
2016;159:53–60.
Lev-Ran S, Le Foll B, McKenzie K, Rehm J. Cannabis use and mental health-related quality of life
among individuals with anxiety disorders. J Anxiety Disord. 2012;26:799–810.
Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkotter J, Hellmich M,
Koethe D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of
schizophrenia. Transl Psychiatry. 2012;2:e94.
Lintzeris N, Bhardwaj A, Mills L, Dunlop A, Copeland J, McGregor I, Bruno R, Gugusheff J,
Phung N, Montebello M, Chan T, Kirby A, Hall M, Jefferies M, Luksza J, Shanahan M,
Kevin R, Allsop D. Nabiximols for the treatment of Cannabis dependence: a randomized
clinical trial. JAMA Intern Med. 2019;179:1242–53.
Lintzeris N, Mills L, Dunlop A, Copeland J, McGregor I, Bruno R, Kirby A, Montebello M, Hall M,
Jefferies M, Kevin R, Bhardwaj A. Cannabis use in patients 3 months after ceasing nabiximols
for the treatment of cannabis dependence: results from a placebo-controlled randomised trial.
Drug Alcohol Depend. 2020;215:108220.
1036 S. Kloiber et al.

Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry.

2016;79:516–25.
Lundahl LH, Greenwald MK. Effect of oral THC pretreatment on marijuana cue-induced responses
in cannabis dependent volunteers. Drug Alcohol Depend. 2015;149:187–93.
Mammen G, Rueda S, Roerecke M, Bonato S, Lev-Ran S, Rehm J. Association of Cannabis with
long-term clinical symptoms in anxiety and mood disorders: a systematic review of prospective
studies. J Clin Psychiatry. 2018;79
Mandolini GM, Lazzaretti M, Pigoni A, Oldani L, Delvecchio G, Brambilla P. Pharmacological
properties of cannabidiol in the treatment of psychiatric disorders: a critical overview. Epidemiol
Psychiatr Sci. 2018;27:327–35.
Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O. Involvement of CB1 cannabinoid
receptors in emotional behaviour. Psychopharmacology. 2002;159:379–87.
Masataka N. Anxiolytic effects of repeated Cannabidiol treatment in teenagers with social anxiety
disorders. Front Psychol. 2019;10:2466.
McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, Taylor A, Wright
S. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized
controlled trial. Am J Psychiatry. 2018;175:225–31.
Meltzer HY, Arvanitis L, Bauer D, Rein W, Meta-Trial Study G. Placebo-controlled evaluation of
four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J
Psychiatry. 2004;161:975–84.
Moreira FA, Crippa JA. The psychiatric side-effects of rimonabant. Braz J Psychiatry. 2009;31:
145–53.
Morgan CJ, Das RK, Joye A, Curran HV, Kamboj SK. Cannabidiol reduces cigarette consumption
in tobacco smokers: preliminary findings. Addict Behav. 2013;38:2433–6.
Morrison MF, Ceesay P, Gantz I, Kaufman KD, Lines CR. Randomized, controlled, double-blind
trial of taranabant for smoking cessation. Psychopharmacology. 2010;209:245–53.
Muller-Vahl KR, Schneider U, Koblenz A, Jobges M, Kolbe H, Daldrup T, Emrich HM. Treatment
of Tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC): a randomized crossover trial.
Pharmacopsychiatry. 2002;35:57–61.
Muller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H, Daldrup T, Emrich HM. Delta
9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a
6-week randomized trial. J Clin Psychiatry. 2003;64:459–65.
Noel C. Evidence for the use of “medical marijuana” in psychiatric and neurologic disorders. Ment
Health Clin. 2017;7:29–38.
Nona CN, Hendershot CS, Le Foll B. Effects of cannabidiol on alcohol-related outcomes: a review
of preclinical and human research. Exp Clin Psychopharmacol. 2019;27:359–69.
Pamplona FA, Takahashi RN. Psychopharmacology of the endocannabinoids: far beyond ananda-
mide. J Psychopharmacol. 2012;26:7–22.
Panlilio LV, Justinova Z, Trigo JM, Le Foll B. Screening medications for the treatment of Cannabis
use disorder. Int Rev Neurobiol. 2016;126:87–120.
Parsons LH, Hurd YL. Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci.
2015;16:579–94.
Peball M, Krismer F, Knaus HG, Djamshidian A, Werkmann M, Carbone F, Ellmerer P,
Heim B, Marini K, Valent D, Goebel G, Ulmer H, Stockner H, Wenning GK, Stolz R,
Krejcy K, Poewe W, Seppi K, Collaborators of the Parkinson’s Disease Working Group,
I. Non-motor symptoms in Parkinson’s disease are reduced by Nabilone. Ann Neurol.
2020;88:712–22.
Pedrazzi JF, Issy AC, Gomes FV, Guimaraes FS, Del-Bel EA. Cannabidiol effects in the
prepulse inhibition disruption induced by amphetamine. Psychopharmacology. 2015;232:
3057–65.
Rabinak CA, Blanchette A, Zabik NL, Peters C, Marusak HA, Iadipaolo A, Elrahal F. Cannabinoid
modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study.
Psychopharmacology. 2020;237:1813–26.
Cannabinoid Drugs in Mental Health Disorders 1037

Raby WN, Carpenter KM, Rothenberg J, Brooks AC, Jiang H, Sullivan M, Bisaga A, Comer S,
Nunes EV. Intermittent marijuana use is associated with improved retention in naltrexone
treatment for opiate-dependence. Am J Addict. 2009;18:301–8.
Rigotti NA, Gonzales D, Dale LC, Lawrence D, Chang Y. A randomized controlled trial of adding
the nicotine patch to rimonabant for smoking cessation: efficacy, safety and weight gain.
Addiction. 2009;104:266–76.
Robinson JD, Cinciripini PM, Karam-Hage M, Aubin HJ, Dale LC, Niaura R, Anthenelli
RM. Pooled analysis of three randomized, double-blind, placebo controlled trials with
rimonabant for smoking cessation. Addict Biol. 2018;23:291–303.
Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J. Medicinal cannabis for psychiatric
disorders: a clinically-focused systematic review. BMC Psychiatry. 2020;20:24.
Sartim AG, Guimaraes FS, Joca SR. Antidepressant-like effect of cannabidiol injection into the
ventral medial prefrontal cortex-possible involvement of 5-HT1A and CB1 receptors. Behav
Brain Res. 2016;303:218–27.
Sarvet AL, Wall MM, Keyes KM, Olfson M, Cerda M, Hasin DS. Self-medication of mood and
anxiety disorders with marijuana: higher in states with medical marijuana laws. Drug Alcohol
Depend. 2018;186:10–5.
Schmidt ME, Liebowitz MR, Stein MB, Grunfeld J, Van Hove I, Simmons WK, Van Der Ark P,
Palmer JA, Saad ZS, Pemberton DJ, Van Nueten L, Drevets WC. The effects of inhibition of fatty
acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind,
randomized, placebo-controlled proof-of-concept study. Neuropsychopharmacology. 2021;46:
1004–10.
Schwarcz G, Karajgi B, McCarthy R. Synthetic delta-9-tetrahydrocannabinol (dronabinol) can
improve the symptoms of schizophrenia. J Clin Psychopharmacol. 2009;29:255–8.
Seeman P. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsy-
chotic clinical dose. Transl Psychiatry. 2016;6:e920.
Shalit N, Lev-Ran S. Does cannabis use increase anxiety disorders? A literature review. Curr Opin
Psychiatry. 2020;33:8–13.
Sloan ME, Gowin JL, Ramchandani VA, Hurd YL, Le Foll B. The endocannabinoid system as a
target for addiction treatment: trials and tribulations. Neuropharmacology. 2017;124:73–83.
Socías ME, Wood E, Lake S, Nolan S, Fairbairn N, Hayashi K, Shulha HP, Liu S, Kerr T, Milloy
MJ. High-intensity cannabis use is associated with retention in opioid agonist treatment: a
longitudinal analysis. Addiction. 2018;113:2250–8.
Soyka M, Koller G, Schmidt P, Lesch OM, Leweke M, Fehr C, Gann H, Mann KF. Cannabinoid
receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a
placebo-controlled, double-blind trial. J Clin Psychopharmacol. 2008;28:317–24.
Stanciu CN, Brunette MF, Teja N, Budney AJ. Evidence for use of cannabinoids in mood disorders,
anxiety disorders, and PTSD: a systematic review. Psychiatr Serv. 2021;72:appips202000189.
Suryadevara U, Bruijnzeel DM, Nuthi M, Jagnarine DA, Tandon R, Bruijnzeel AW. Pros and cons
of medical Cannabis use by people with chronic brain disorders. Curr Neuropharmacol.
2017;15:800–14.
Tonstad S, Aubin HJ. Efficacy of a dose range of surinabant, a cannabinoid receptor blocker, for
smoking cessation: a randomized controlled clinical trial. J Psychopharmacol. 2012;26:1003–9.
Trigo JM, Le Foll B. Inhibition of monoacylglycerol lipase (MAGL) enhances cue-induced
reinstatement of nicotine-seeking behavior in mice. Psychopharmacology. 2016;233:1815–22.
Trigo JM, Lagzdins D, Rehm J, Selby P, Gamaleddin I, Fischer B, Barnes AJ, Huestis MA, Le Foll
B. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Drug
Alcohol Depend. 2016a;161:298–306.
Trigo JM, Soliman A, Staios G, Quilty L, Fischer B, George TP, Rehm J, Selby P, Barnes AJ,
Huestis MA, Le Foll B. Sativex associated with behavioral-relapse prevention strategy as
treatment for Cannabis dependence: a case series. J Addict Med. 2016b;10:274–9.
Trigo JM, Soliman A, Quilty LC, Fischer B, Rehm J, Selby P, Barnes AJ, Huestis MA, George TP,
Streiner DL, Staios G, Le Foll B. Nabiximols combined with motivational enhancement/
1038 S. Kloiber et al.

cognitive behavioral therapy for the treatment of cannabis dependence: a pilot randomized
clinical trial. PLoS One. 2018;13:e0190768.
Vadhan NP, Corcoran CM, Bedi G, Keilp JG, Haney M. Acute effects of smoked marijuana in
marijuana smokers at clinical high-risk for psychosis: a preliminary study. Psychiatry Res.
2017;257:372–4.
van den Elsen GA, Ahmed AI, Verkes RJ, Kramers C, Feuth T, Rosenberg PB, van der Marck MA,
Olde Rikkert MG. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: a ran-
domized controlled trial. Neurology. 2015a;84:2338–46.
van den Elsen GAH, Ahmed AIA, Verkes RJ, Feuth T, van der Marck MA, Olde Rikkert MGM.
Tetrahydrocannabinol in behavioral disturbances in dementia: a crossover randomized con-
trolled Trial. Am J Geriatr Psychiatry. 2015b;23:1214–24.
Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects of dronabinol on anorexia and
disturbed behavior in patients with Alzheimer’s disease. Int J Geriatr Psychiatry. 1997;12:913–9.
Walsh Z, Gonzalez R, Crosby K, Thiessen MS, Carroll C, Bonn-Miller MO. Medical cannabis and
mental health: a guided systematic review. Clin Psychol Rev. 2017;51:15–29.
Walther S, Mahlberg R, Eichmann U, Kunz D. Delta-9-tetrahydrocannabinol for nighttime agitation
in severe dementia. Psychopharmacology. 2006;185:524–8.
Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S,
Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for medical use: a
systematic review and meta-analysis. JAMA. 2015;313:2456–73.
Wilkerson JL, Ghosh S, Mustafa M, Abdullah RA, Niphakis MJ, Cabrera R, Maldonado RL,
Cravatt BF, Lichtman AH. The endocannabinoid hydrolysis inhibitor SA-57: intrinsic anti-
nociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seek-
ing behavior in mice. Neuropharmacology. 2017;114:156–67.
Wycoff AM, Metrik J, Trull TJ. Affect and cannabis use in daily life: a review and recommenda-
tions for future research. Drug Alcohol Depend. 2018;191:223–33.
Zamberletti E, Rubino T, Parolaro D. The endocannabinoid system and schizophrenia: integration
of evidence. Curr Pharm Des. 2012;18:4980–90.
Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR. Antidepressant-like effects of
cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159:
122–8.
Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF, Musty RE, Crippa JA. Cannabidiol
monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006;20:683–6.
Cognitive Enhancement and American
Constitutional Law

Marc Jonathan Blitz

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040
Government Safety Interests and Limits on a Constitutional Right to Cognitive Liberty . . . . 1046
Tradition, Social Convention, and Limits on a Constitutional Right to Cognitive Liberty . . . 1050
Quasi-Constitutional Rights to Cognitive Liberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1056
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1057
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1058

Abstract
In recent years, there has been significant research and debate about whether
individuals can – and should be able to – improve their memory or other aspects
of their cognition with cognitive enhancement drugs.
This debate has largely been about ethics, but a debate has also emerged in legal
scholarship about whether, if constitutional systems give individuals the freedom
to shape their thinking in other ways (with books, conversations, software, or
games), it should also give them freedom to safely do so with cognitive enhance-
ment drugs. In the American context (which is the focus of this chapter), certain
scholars argue that individuals’ long-recognized right to “freedom of thought,”
under the First Amendment of the US Constitution, should, in the twenty-first
century, be understood as a broad right to “cognitive liberty,” allowing us to shape
our own minds medically as well as culturally.
This chapter provides an overview of this argument and then examines two
major reasons why American courts might resist it. One concerns the risks and
uncertainties about the safety of pharmacological cognitive enhancement. Indi-
viduals have constitutional freedom to take action that comes with at least some
risks to safety: Many forms of protest can involve physical action government has
M. J. Blitz (*)
Oklahoma City University School of Law, Okahoma City, OK, USA
e-mail: mblitz@okcu.edu

© Springer Nature Switzerland AG 2022 1039

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_383
1040 M. J. Blitz

cause to regulate. So it is not safety risks by themselves that weigh against finding
constitutional rights. It is rather because courts may well find, in analyzing laws
about cognition enhancement drugs, that it is harder to disentangle safety issues
(that government does have grounds to regulate) from liberty interests (that
government does not). A second reason courts may continue to treat different
forms of cognition enhancement differently is that historical tradition does so –
and traditional differences may, in rights jurisprudence, often override functional
similarities. The chapter ends by considering how, even when individuals lack
constitutional rights to use pharmacological means of cognitive enhancement,
legislatures can give them “quasi-constitutional” rights to do so.

Introduction

If I wish to improve my memory, there are a number of ways I might do so. I might
read a book on how to construct a “memory palace” or other mnemonic devices. I
can obtain a computer or Smartphone applications that let me tackle exercises that
challenge me to remember information – and perhaps build my capacity for doing so.
I might do a crossword puzzle. Each of these has been recommended as a way to
improve memory.
I also might conceivably do so by taking drugs – so-called “nootropics” substances
that can purportedly “boost creativity, memory, decision-making or other high-level
brain functions” (Heid 2019). These include substances individuals have long ingested
in common foods and beverages – such as caffeine (Dressler et al. 2019) or omega-3
oils in fish (Dressler et al. 2019; Luchtman and Song 2013). But they can also include
psychoactive drugs developed to treat illness – and repurposed to improve memory or
other cognitive functions in the “healthy.” To be sure, the benefits of such drugs remain
uncertain. Many have touted substances such as methylphenidate (or Ritalin) and
modafinil (or Provigil) as “smart pills.” Others have noted that acetylcholinesterase
inhibitors like those used to treat some Alzheimer’s patients may improve memory in
healthy adults as well – as might other drugs that increase levels of acetylcholine
(Farah et al. 2014). Others have argued that taking “microdoses” of LSD or mescaline
– doses too small to produce the hallucinatory experiences associated with those drugs
– improves individuals’ focus and creativity (Rose 2019).
But the research has been mixed. In a 2015 review of the literature on the
cognition-enhancing effects of these two substances, Veljko Dubljevic and Christo-
pher James Ryan found that there was as yet “little evidence that either methylphe-
nidate or modafinil are likely to provide any useful cognitive enhancement to those
who choose to use them” (Dubljevic and Ryan 2015). Dressler and his colleagues
similarly stress that “evidence for their efficacy for augmenting brain function and
cognition in healthy subjects is often markedly lower than assumed in theoretical
discussions” (Dressler et al. 2019; Luchtman and Song 2013). As Farah and her
colleagues stress, in a 2014 review of cognitive enhancement studies, “there are
surprisingly few generalizations about cognitive enhancement that can be stated with
confidence at present” (Farah et al. 2014). And Rose notes that when it comes to
Cognitive Enhancement and American Constitutional Law 1041

microdosing with LSD or mescaline, it has generally been “impossible to separate

truth from hype,” and although there has recently been intriguing research shedding
light on how microdosing might improve certain mental capacities, such research
“doesn’t prove that microdoses act as a novel cognitive enhancer” (Rose 2019).
But even if scientists have not yet developed effective cognitive enhancement
drugs, they may do so in the future. As Mehlman points out, “the new enhancement
drugs are only a first step” and future research is “bound to lead to the development
of more effective and safer modalities that produce enhancement effects in healthy
individuals” (Mehlman 2004). As Dubljevic and Ryan write, “further research may
reveal [that methylphenidate or modafinil] offer cognitive benefit or, perhaps more
likely, future research into other agents, not yet available, may offer the development
of proven ‘smart drugs’” (Dubljevic and Ryan 2015).
This raises an interesting question for ethicists, policy-makers, and legal scholars:
if we have a constitutionally protected freedom to shape our minds with books,
software applications, and crossword puzzles, do we similarly have the same
freedom to exercise mental autonomy by reshaping our minds pharmacologically?
If government may not stop me from using written mnemonic strategies, video
games, and crossword puzzles to improve my memory, if doing so would violate a
right I have to “freedom of thought,” why might it have a right to prevent me from
using modafinil or another biochemical agent for the same purpose? (Blitz 2016). In
fact, the same question may be asked not simply about our freedom to use drugs that
enhance cognition, but about our voluntary use of any drugs that alter cognition. If
government can’t prevent me from finding a sense of meaning or reshaping the way I
see the world by reading philosophy, why is it free to stop me when I use psilocybin
to generate a similar sense of meaning? (Griffith et al. 2008).
Some legal scholars have argued that government shouldn’t be able to do so – that
it should have to let individuals make their own decisions about how to use
pharmacology or other methods to safely reshape the way they think. The United
States Supreme Court said in the 1969 case, Stanley v. Georgia, that the government
“may not constitutionally premise legislation on the desirability of controlling a
person’s private thoughts” (Stanley v. Georgia 1969). It cannot, as the state of
Georgia did in Stanley, prosecute a person because the pornographic film he pos-
sesses might be used to generate feelings of sexual excitement. It cannot, as the state
of California did in enacting a recent law on violent video games, bar teenagers from
obtaining and playing such games because the state legislators disapprove of the
violence-filled fantasy the video games allow them to experience. As the Ninth
Circuit Court of Appeals wrote in finding that California law unconstitutional,
government may not restrict video game play “in order to control a minor’s
thoughts” (Video Software Deals Ass’n v. Schwarzenegger 2009). In short, such
court decisions have held, the First Amendment protects “freedom of speech” – and
this not only bars government from restricting our expression of thought, it also bars
it from restricting the formation of these thoughts that we engage with the aid of
books, films, or video games. In the same vein, one might argue officials should not
be able to criminalize the use of a certain drug simply because they disapprove of the
mental states such a drug can be used to generate.
1042 M. J. Blitz

Thus, in his treatise on Constitutional Law, Professor Lawrence Tribe draws an

analogy between censorship of films or reading materials, and prohibition or crim-
inalization of psychoactive drugs. “If the Stanleys of the world,” he says, “could
obtain from a new drug called ‘obscenamine’ the sensation that Stanley in fact
obtained from the obscene film,” it would seemingly be just as impermissible for
the government to bar someone from generating this sensation with such a drug as it
would be for government censor a film that produces it. If government violates our
First Amendment right when it restricts our private choices about what books to read
or what films to view, Tribe wrote, it may also do so when it “rummages through
[our] medicine chest, kitchen, and wine cellar to put together a picture of [our] oral
and chemical predilections.” (Tribe 1988).
Perhaps the most prominent contemporary variant of this legal argument comes
from Richard Glen Boire and Wrye Sententia, the founders of the Center for
Cognitive Liberty and Ethics (CCLE), an organization that has taken the leading
role in asking what form freedom of thought must take in the twenty-first century. As
Sententia defines it, cognitive liberty is “every person’s fundamental right to think
independently, to use the full spectrum of his or her mind, and to have autonomy
over his or her brain chemistry” (Sententia 2004). While judges may have conceived
of freedom of thought more narrowly in the past, says Sententia, the right to
“cognitive liberty” “updates notions of ‘freedom of thought’ for the 21st century
by taking into account the power we now have, and increasingly will have, to
monitor and manipulate cognitive function” (Sententia 2004). Boire similarly argues
that “the right to control one’s own consciousness is the quintessence of freedom”
(Boire 2000a) and that “drug prohibitions” are among the methods government uses
to “prohibit the experiencing of certain thought process” (Boire 2000b).1
A similar argument might be founded on a variant of the “parity principle” that
philosophers such as David Chalmers and Andy Clark, and more recently, Neil Levy,
have suggested should guide our conceptual and moral thinking about cognitive
enhancement. Chalmers and Clark do not deal specifically with the moral status of
psychopharmacology. They rather argue that when we think, we do so not only with
the biological equipment our brain provides for cognition, but also with various tools
outside of our body that we make a part of our “extended mind” (Clark and Chalmers
2008). When individuals rely consistently and automatically on a slide rule, a
notebook or a Smartphone app, such tools can serve precisely the same function
for us (from outside of our bodies) that certain parts of our neuronal processes play
inside of it. For example, both can play an essential role in the act of bringing

1
Other scholars have explored the implications of cognitive liberty in European law. Charlotte
Walsh argues that right to freedom of thought and cognitive liberty in the European Convention on
Human Rights justify decriminalization of psychedelics, and also argues that “should inform not
only defences raised in court but also the discourse of drug policy activism more broadly.” (Walsh
2016). Understanding the constitutional status of cognitive enhancement might also be informed by
a deeper exploration of scholarship on the ethics of cognitive enhancement in the United States and
Europe. (See e.g., Jotterand and Dubljevic 2016; Hildt and Franke 2013; Helmchen 2021; chapter
“▶ Ethical Issues in Neuropsychopharmacotherapy: US Perspective”).
Cognitive Enhancement and American Constitutional Law 1043

information to conscious memory. One consequence of this parity between internal

and external bases of our thoughts is that they may sometimes merit the same moral
treatment. Counterintuitively, our freedom of thought might extend into the world
beyond our minds: “[I]n some cases,” Chalmers and Clark write, “interfering with
someone’s environment will have the same moral significance as interfering with
their person” (Clark and Chalmers 2008). Interfering with a person’s Smartphone or
computer might damage thought to the same extent as psychosurgery (Carter and
Palermos 2016).
Levy develops this argument for moral or ethical parity, but uses it to push against
a very different moral intuition – one similar to that Boire objects to when he argues
that psychoactive drug use might sometimes merit the same constitutional protection
as we receive when we read a book or play a video game. If commentators worried
about psychosurgery tend to mistakenly confine freedom of thought to the inside of
our brain (leaving government free to damage equally essential tools of thought
outside of our bodies), American constitutional law, on Boire’s account, has made
the opposite mistake: It has secured our right to shape our minds with resources for
thinking that remain outside of our bodies – such as books or conversations – but has
provided no such protection for methods we might use to shape our thought from the
inside, by altering our brain chemistry (Boire 2000b). Levy does not address the
constitutional questions raised by Boire. But he does argue for ethical parity between
cognitive enhancement with books or other educational sources and cognitive
enhancement with drugs. More specifically, he argues that “[u]nless we can identify
ethically relevant differences between internal and external interventions and alter-
ations [in the mind], we ought to treat them on a par” (Levy 2007).
The parity principle has been subject to philosophical critique. For example,
Bublitz and Merkel argue that mental manipulation that occurs through “direct”
interventions into a person’s biology bypass reflection, and threaten autonomy, in a
way that “indirect” interventions, through books, conversations, or educational
processes do not (Bublitz and Merkel 2014).
But I want to focus here on the somewhat different debate over whether some-
thing like the parity principle has a place in the legal and political framework for use
of cognitive enhancement – and specifically, in constitutional law. What basis, if any,
do courts have for resisting the constitutional version of a parity principle? Why
shouldn’t they provide our shaping of our mental states with drugs at least some of
the same protection they provide to the shaping of our mental states with books? In
previous scholarship, I have defended importing a variation of the parity principle
into First Amendment law on the freedom of thought. (Blitz 2010; Blitz 2016). As
noted below, however, that position seems strongly at odds with the current juris-
prudence on regulation of psychopharmacology – so it is useful to understand the
arguments against a constitutional parity between pharmacological cognitive
enhancement (or alteration of consciousness) and cognitive enhancement or
reshaping that occurs through words or other cultural activity. Levy’s ethical argu-
ment leaves open the possibility that the presumption of parity can be overridden
where there are relevant differences between these two kinds of enhancement (Levy
2007). Is there then a legally relevant difference that justifies treating cognitive
1044 M. J. Blitz

enhancement or other changes of consciousness differently – under the US or other

constitution – depending on the means individuals use to obtain it?
Clearly, the American legal system – like most other legal systems – accords very
different treatment to these two modes of altering one’s mental functioning: In the
United States legal system, drug manufacture and use has been among the most
tightly regulated of human activities. No one may sell or manufacture a drug for
medical purposes until a governmental agency, the Federal Drug Administration (of
FDA) rigorously assesses the drugs “safety and efficacy” (21 United States Code
Annotated § 355; 21 Code of Federal Regulations § 312.23; Abigail All. for Better
Access to Developmental Drugs v. von Eschenbach 2007). Every organization that
wishes to sell or market a new drug in the United States must file a new drug
application (NDA) and gather data about the drug’s effects in animal studies and
human trials – process intended to enable the FDA to assure “drug is safe and
effective in its proposed use(s), and whether the benefits of the drug outweigh the
risks,” to assure that the labeling provides sufficient information, and what drug
manufacturing methods will be “adequate to preserve the drug’s identity, strength,
quality, and purity” (Skiadas v. Acer Therapeutics Inc. 2020).
In fact, not only has manufacture and use of drugs been tightly regulated. In the
United States and many other parts of the world, use of psychoactive and other drugs
has been outside of the legal framework. In the USA, many psychoactive drugs –
including drugs such as psilocybin, mescaline, LSD, and marijuana – are Schedule I
drugs under the legal regime created by the Controlled Substances Act (CSA): The
Act instructs the Secretary of Health and Human Services to classify a drug as being
in this category when it has a “high potential for abuse,” “no currently accepted
medical use in treatment in the United States,” and “a lack of accepted safety for use
of the drug or other substance under medical supervision” (21 United States Code §
812). Once a drug is classified as a Schedule I drug, the CSA makes it illegal to
“manufacture, distribute, or dispense,” it “or possess” it with intent to manufacture,
distribute, or dispense it (21 United States Code § 841(a)). The American “War on
Drugs” that began in the 1970s made government enforcement of such laws a high
priority – and led to the mass incarceration on the basis of drug use.
Other drugs, assigned to different schedules, can legally be used in certain
circumstances: Drugs are assigned to Schedule II, for example, when they have
“high potential for abuse which may lead to severe psychological or physical
dependence” but also “have medical value.” Schedule III, IV, V drugs are similar,
with each successive Schedule having lower potential for addiction or other safety
threats (21 United State Code §§ 821–831) (See also Sabet 2012).
Why, one might ask, are these efforts at drug regulation not subject to constitu-
tional constraints designed to assure that – even as the government protects individ-
uals from the risks that drugs pose to physical health and safety – it does not misuse
this power to bar individuals from safely altering their own mental states by
pharmacological means when they are able to do so?
The most common and obvious basis for finding an ethically and legally relevant
difference between altering one’s mind with drugs and altering one’s mind with
words (or other expression) is that drug use – as a general matter – presents a far
Cognitive Enhancement and American Constitutional Law 1045

greater threat to safety. In fact, even those who have advanced ethical arguments in
favor of permitting healthy individuals to use cognitive enhancement drugs have
emphasized they continue to believe that government regulation of such drugs is
necessary to assure safety. For example, in an editorial in Nature calling for the FDA
to permit use of cognition-enhancing drugs not only to treat sick patients but to
improve the healthy, Henry Greeley and other experts on law, ethics, or neuroscience
emphasize that while they believe cognitive enhancement drugs should be available
to mentally healthy individuals, this does not mean they should be unregulated:
“Cognitive enhancements,” they noted, “affect the most complex and important
human organ [the brain], and the risk of unintended side effects is therefore both
high and consequential” (Greely et al. 2008). Neil Levy likewise notes, before
examining the difference between internal and external interventions to the mind,
that “there are understandable safety concerns” linked to new technologies for
cognitive enhancements (Levy 2007).
But pointing to the safety risks of pharmacology is at best a partial answer to the
challenge raised by defenders of cognitive liberty. It explains that government has to
be left with power to protect individuals’ physical safety, but not why, once govern-
ment has imposed the regulation it needs to do so, individuals cannot then be left free
to engage in any kind of cognitive enhancement they wish to engage in, with drugs
or through other means, as long as it is consistent with such safety interests. Once
government has relied on its duty of protecting health and safety to claim its own
share of the “territory” encompassed by pharmacological enhancement, why isn’t
the rest of that “territory” constitutionally reserved for individuals?
After all, this is what already happens in free speech law and other areas of
American law where courts have to balance liberty and the need for government
measures to assure public safety: In free speech jurisprudence, for example, Amer-
ican courts allow the government to prevent protestors from blocking traffic or
inciting violence, but as long as individuals steer clear of preventing others’ freedom
of movement or threatening their safety, the First Amendment lets them say what
they wish. It does not allow government to restrict a form of protest that raises no
safety threat on the ground that government wishes to suppress the expression in that
protest (United States v. O’Brien 1968). Government, in other words, cannot use
traffic- or violence-prevention as a basis for suppressing certain ideas it doesn’t like.
Why then, one might ask, can courts not apply a variant of the same framework when
it addresses the exercise of cognitive liberty by changing mental states – and find that
government may regulate drug safety, but may not constitutionally use it as an
excuse to suppress individuals’ decisions about how to shape their consciousness?
In the remainder of this chapter, I will explore two possible answers to this
question. The first is that, when it comes to pharmacology, it is far harder (if not
impossible) for courts – or for government – to bracket safety considerations. To
continue using the spatial metaphor I discussed above: It’s not the case that safety
considerations only fill some of the territory of pharmacological enhancement or
alteration of cognition, leaving the rest as a sphere of individual liberty. Rather, one
might argue, safety considerations permeate all of this territory in a way they do not
in the realm of speech or cultural expression.
1046 M. J. Blitz

The second possible answer is that protecting physical health and safety is not the
sole reason that government receives the significant power it does to regulate and
restrict individuals’ use of drugs – whether for psychopharmacology or for other
purposes. Outside the realms of human behavior that are constitutionally reserved for
individual liberty, after all, government regulates myriad activities for many reasons
other than assuring safety: It enacts laws that promote education, economic well-
being, the aesthetic quality of our shared public spaces, and many other public
benefits. So one might argue that if the government is left unconstrained in the
territory that constitutes the realm of psychopharmacology, this is not necessarily
because safety concerns permeate all of this territory. It is rather because there are
other reasons that our constitutional tradition reserves a realm of speech and expres-
sion for cognitive liberty while failing to similarly insulate other spheres where such
cognitive liberty could potentially be at stake. To some extent, this division of
territory between a sphere of constitutional rights and a sphere of government leeway
to regulate may be as much a matter of tradition and social convention as of
principle. Government may face constitutional limitations in regulating one means
of cognitive enhancement (through speech) and not another (with pharmacology) not
because of any inherent difference between these two means of exercising control
over mental autonomy – but rather because the social and constitutional traditions of
the United States (and of other jurisdictions) have historically divided up the world
that way, and the division leaves us with sufficient freedom for mental autonomy.
Below, I examine each of these two possibilities more closely. Even if either or
both of these frameworks succeeds in justifying why the constitution does not
insulate psychopharmacology from government, this still leaves open the possibility
of what we might call “quasi-constitutional limitations” on regulations that limit
cognitive liberty. In other words, even if our liberty to shape our consciousness is not
fully protected by the United States Constitution, as Boire and others argue it should
be, the government can still deem itself bound to refrain from unnecessarily inter-
fering in such liberty even when it is free to do so. It can enact statutes that constrain
itself even when the Constitution doesn’t do so.

Government Safety Interests and Limits on a Constitutional Right

to Cognitive Liberty

As noted above, in Stanley v. Georgia, the Supreme Court writes that government
“may not constitutionally premise legislation on the desirability of controlling
a person’s private thoughts” (Stanley v. Georgia 1969). Why does this not present
a barrier to drug legislation that is premised on the “desirability” of preventing a
person from using such drugs to generate certain mental states?
One potential response by the courts is that – although such drug legislation
would raise constitutional concerns – this is not a possibility that arises, because all
restrictions on drugs in American law are premised at least in part on some
justification other than thought control – that is protecting patients’ health and safety.
The criteria that the Controlled Substance Act requires the FDA to use in classifying
Cognitive Enhancement and American Constitutional Law 1047

a drug as a Schedule I drug, after all, are safety-based: Such drugs have, among other
things, a “high potential for abuse,” and “a lack of accepted safety for use of the drug
or other substance under medical supervision.” 21 United States Code § 812. Since
concern for safety is always available as a justification for drug regulation, there are
never any cases where government is forced to concede that its true justification is to
limit individuals’ cognitive liberty.
But this isn’t a decisive objection. First, in both First and Fourteenth Amend-
ment law, courts are sometimes willing to show skepticism towards government’s
asserted justifications for enacting a law. They are willing to look behind govern-
ment claims that invoke justifiable grounds for government – to see if there are
constitutionally impermissible designs underlying the government’s action. Con-
sider the case of Sorrell v. IMS Health. That was a case not about drugs, but rather
speech about drugs: The State of Vermont regulated the practice of “detailing,”
wherein representatives of pharmaceutical companies attempt to convince physi-
cians to recommend and prescribe the medicines sold by those companies. When
making their sales pitch to physicians, these pharmaceutical company representa-
tives benefit from having information about the prescribing history of specific
physicians. The more they know about their audience, the better able they are to
convince them. Vermont was concerned that these sale pitches were convincing
physicians to prescribe expensive brand name drugs rather than generic drugs that
were just as effective. So they barred data-mining companies from sharing data on
physician prescribing practices with pharmaceutical company representatives.
Vermont said that their justification for doing so was to protect the privacy of
patients and doctors. But the Supreme Court was skeptical. It pointed out that
Vermont banned the sale of prescription data only to pharmaceutical company
representatives, but continued to let data-mining companies make it available to
numerous other entities, who could also use it in ways that threatened doctors’ or
patients’ privacy. The Court thus found that Vermont’s law seemed designed not to
protect patient safety but rather “to tilt public debate [about drugs] in a preferred
direction” – namely against argument for using brand name drugs and in favor of
using their generic equivalents (Sorrell v. IMS Health 2011).
The Court exhibited a similar kind of skepticism in a well-known case on freedom
of religion. In Lukumi Babalu Aye v City of Hialeah, Florida, the city of Hialeah had
banned the sacrifice of animals ostensibly in order to prevent cruelty to animals. But
the Court found that this justification was implausible because the ordinance
contained numerous exceptions that allowed the slaughter of animals (e.g., by
butchers). The only kind of animal slaughter occurring in the city that the exceptions
did not cover was that performed by the Santeria religious group as a part of their
religious ritual. Moreover, there had been numerous statements in city council
meetings expressing disdain for the Santeria. With the benefit of this background
information, the Court concluded that the only plausible explanation for the legal
ban on animal sacrifice was to prevent the Santeria from practicing their religion.
This purpose, to prevent members of a religious group from practicing their religion,
is an impermissible one under the US Constitution’s First Amendment protection for
religious liberty (Church of Lukumi Babalu Aye v. City of Hialeah, 1993).
1048 M. J. Blitz

So why shouldn’t courts engage in a similarly searching inquiry of laws that bar
pharmacological cognitive enhancement or other use of drugs to shape one’s mental
states? There are at least three different reasons one might offer.
One is that physical safety is always at stake when individuals ingest psychoac-
tive substances – and the state can thus always justify such regulation even when
certain government officials may have other motivations for preventing cognitive
enhancement. To quote the Nature editorial discussed earlier, psychoactive drugs all
affect “most complex and important human organ [the brain],” (Greely et al. 2008,
703) so, one might argue, the government’s safety justifications will never be
implausible in the way that the rejected justifications were in the above cases on
pharmaceutical company sales or animal slaughter. As Ricci notes, “the use of
methylphenidate, modafinil, amphetamine, and other prescription drugs involves
health risks, including dependence, tolerance, and cardiovascular, neurologic, and
psychological disorders” (Ricci 2020). Even when use of such drugs has a legitimate
medical purpose, the US government is not constitutionally bound to permit their
use. As Glannon points out, in a discussion of the ethics of cognitive enhancement
“adverse effects from using methylphenidate for cognitive enhancement intuitively
would be less acceptable than using it therapeutically” (Glannon 2015). As Bruhl et
al. point out, there are also safety risks associated with microdosing with LSD or
other hallucinogens: “Those who microdose incorrectly risk having unwanted, full-
blown trips or even experience unpleasant trips. There are some reports of psychosis-
like symptoms in certain vulnerable individuals who use LSD recreationally” (Bruhl
et al. 2019). Court may decide they are far less well-placed to second guess a safety
assessment by government than they are to second guess asserted justifications of
limiting speech or restrictions that burden religious activity.
In fact, courts may take the position that when chemicals affect brain structure
and function, it is permissible for government to begin by assuming that use of
cognitive enhancement drugs raises significant safety concerns – and then make their
use illegal until safety is proven. This, after all, is the stance that drug regulators
often take. When government claims it needs to restrict speech or religious practice
in order to promote safety, it has to provide powerful evidence of the safety
justification (and show it is real). But this approach is a poor fit for a system, like
that used by the US Food and Drug Administration that always begins with a
presumption that drugs that a company wishes to manufacture and market unsafe
until sufficient data show that it is safe and effective (21 United States Code
Annotated § 355; 21 Code of Federal Regulations § 312.23; Abigail All. for Better
Access to Developmental Drugs v. von Eschenbach, 2007). Numerous articles
emphasize how little is known about the long-term effects of many cognitive
enhancement drugs, so given this uncertainty, courts may simply refuse to scrutinize
government restrictions of pharmacological cognition enhancement. As Bruhl and
her co-authors stress, “there are no studies investigating the long-term effects of
cognitive enhancers in healthy people, where effects such as habituation or even a
potentiation of the beneficial effects, as well as different side effects (mental,
somatic), compared to a single dose could be detected” (Bruhl et al. 2019). And
past experiences with drugs “enthusiastically acclaimed for enhancing cognition and
Cognitive Enhancement and American Constitutional Law 1049

mood” provide reason for caution: “initial Golden Periods were followed by a
painful sobering, with the social and health–economic consequences still visible
today” (Bruhl et al. 2019).
To be sure, in debates over the ethics of cognitive enhancement, scholars have
pointed out that the mere existence of a health or safety risk is often not treated as
sufficient justification to ban an activity. Individuals are allowed to ski, climb
mountains, and participate in boxing matches and football games despite the risks
of these activities. They are allowed to eat high-cholesterol food that can increase
their risk of having a stroke or a heart attack. As Greely notes, “outside the world of
medicine we allow people to take non-trivial risks without requiring the government
to agree with consumers’ cost-benefit assessments” (Greely 2006). Of course,
an ethical or policy calculation is different from a constitutional rule: That govern-
ment tolerates certain risks when it leaves people free to engage in certain activities
(such as playing football) does not mean that government is constitutionally required
to tolerate such risks. Government is not constitutionally prohibited from banning
skiing or football, even though it is likely such a ban would be deeply unpopular in
the United States. One might thus argue that where shaping one’s mind with drugs
generates safety risks of any kind, it for democratic officials, not courts applying
constitutional law, to weigh the costs and benefits of each activity and decide
whether individuals should be left free to undertake it.
Second, one might argue that courts will be unable to distinguish permissible
safety-related justifications from (what one might argue are) impermissible designs
to constrain mental autonomy because these two interests are not entirely distinct.
Some of the worrisome side effects that patients, doctors, and government regulators
worry about are psychological. The FDA, for example, has issued warnings about
drugs that can cause depression as a side effect.2
If it is constitutionally permissible for government to prevent individuals from
ingesting chemicals on the grounds that doing so comes with a risk of severe
depression then it may be permissible for government to invoke health and safety
interests to prevent individuals from inducing other mental states, such as extreme
anxiety or paranoia. In fact, the Court has even found it constitutionally permissible
for prison officials to require that certain prisoners take antipsychotic medications in
order to treat certain psychological conditions that might be dangerous (Washington
v. Harper 1990, Riggins v. Nevada 1992). It has also suggested that authorities can
government may be able to forcibly medicate an inmate of a prison or psychiatric
facility in order to make that person “competent to stand trial,” where the govern-
ment can make certain showings. In Sell v. United States, the Court made clear that
the hurdle government has to meet to do so is a rather high one: Government must
show that “the treatment is medically appropriate, is substantially unlikely to have
side effects that may undermine the fairness of the trial, and, taking account of less

2
It did so, for example, with respect to smoking cessation drug, varenicline. See Food and Drug
Administration. FDA Drug Safety Communication: Safety review update of Chantix (varenicline)
and risk of neuropsychiatric adverse events.
1050 M. J. Blitz

intrusive alternatives, is necessary significantly to further important governmental

trial-related interests” (Sell v. United States 2003). Still, the Court clearly assumed
that changing a person’s psychological condition is sometimes a legitimate basis for
government-imposed medication – and if this is a justification for government to
impose chemical changes in person’s brain functioning, one might argue it can also
be a basis for the government to prevent chemical changes in a person’s brain
functioning generated by that person’s voluntary use of drugs.
Another consideration that will likely shape legal thinking about the above
considerations is the extent to which courts should think in categorical terms about
activities. For example, in one might ask whether – in asking whether the First
Amendment, Fifth, or Fourteenth Amendment can insulate psychopharmacological
cognitive enhancement from government restriction – we should answer this ques-
tion with a constitutional framework that applies to all such cognitive enhancement
in the same way, or that gives different forms of cognitive enhancement a different
constitutional status depending on the safety risks at stake. One might argue, for
example, that even if the United States Constitution imposes no limits at all on
government’s ability to bar individuals from administering psychoactive drugs to
themselves, it might impose limits on the government’s ability to restrict individuals’
to obtain such drugs under the supervision of an appropriate kind of physician
(which is presumably safer, as a general matter, than self-medication). But legal
scholars can also take a different stance. In marking a line between the sphere of
constitutionally shielded individual liberty and that where government has signifi-
cant leeway to regulate, courts – and the citizens who have to live with their rulings –
may prefer to make this line correspond to clear divisions between different spheres
of human conduct. They might therefore choose to exclude a category of often-risky
activity from the sphere of liberty (and leave it subject to government measures that
can address the risks) even if there are instances of such a category that carry much
lower risks.

Tradition, Social Convention, and Limits on a Constitutional Right

to Cognitive Liberty

In the preceding paragraphs, I have been assuming that – with respect to decisions
about psychopharmacology – where the government’s interest in guaranteeing safety
ends, constitutional cognitive liberty interests begin. But this isn’t the only possibil-
ity. It is also possible that constitutional freedom of thought protects not all the things
we do to shape our own thinking processes or mental, but only a subset of them. If
that is the case, our First Amendment freedom of thought – or Fifth and Fourteenth
Amendment liberty interests – may fall short of covering psychopharmacology not
because these protections have been pushed out of that territory to make room for
safety regulation, but because constitutional liberty never covered it in the first place.
Consider an analogy with another doctrine in First Amendment law: The right to
“receive information and ideas.” The Supreme Court has held that that the US
Constitution’s guarantee of free speech not only gives individuals a right to express
Cognitive Enhancement and American Constitutional Law 1051

ideas, but also a right to receive them from others – the right that is to be an audience,
and learn information (which they can then, of course, make the basis of their own
expression). (Martin v. City of Struthers 1943). But this right to receive information
has to have limits, as the Supreme Court emphasized in the 1965 case, Zemel v. Rusk.
This case arose when the United States State Department refused to validate the
passport of Louis Zemel for travel to Cuba. Zemel insisted that this violated his First
Amendment right to gather information: It was, he said, a “direct interference with
the First Amendment rights of citizens to travel abroad so that they might acquaint
themselves at first hand with the effects abroad of [the US] Government’s policies,
foreign and domestic, and with conditions abroad which might affect such policies.”
But the Court rejected Zemel’s claim. Treating the First Amendment as containing an
“unrestrained right to gather information,” said the Court, would stretch it to cover –
and shield from government regulation – virtually all human activity: “There are few
restrictions on action which could not be clothed by ingenious argument in the garb
of decreased data flow” (Zemel v. Rusk 1965).
The same argument might be made about freedom of thought. Every time we are
denied the chance to perceive a certain environment, we are denied the raw material
for a certain type of mental experience: Preventing Louis Zemel from visiting Cuba
not only prevented him from gathering information about Cuba. It prevented him
from having the kind of mental experiences that is difficult to have except when one
is in Cuba, perceiving the sights and sounds there. Freedom of thought, or cognitive
liberty, cannot plausibly entail a freedom to do anything one wishes to do in the
outside world – so that it will generate a particular kind of mental experience (See
Blitz 2010). There have to be limits on freedom of thought.
The Court of Appeals for the Seventh Circuit has attempted to identify such a
limit. In Doe v. City of Lafayette, it said that “only “governmental regulations
aimed at mere thought, and not thought plus conduct, trigger freedom of thought
protection” (Doe v. City of Lafayette, Indiana 2004). The problem with this
standard is that government regulations generally haven’t been aimed at “mere
thought” because, as Justice Murphy wrote in Jones v. Opelika, “the most tyran-
nical government” has generally been “powerless to control the inward workings
of the mind” (Jones v. Opelika 1942). One might argue that, with advances in
psychosurgery and greater understanding of pharmacological interventions, Mur-
phy’s generalization is no longer true: The government can control the inward
workings of the mind by controlling the functioning of the brain. But as a general
matter, when courts have raised worries that government action was violating or
threatening freedom of thought, they have focused on ways government does so
from the outside. For example, in Stanley v. Georgia, the Court worried that
government wished to control Stanley’s thoughts by restricting the films he
could possess and watch in his own home. One might argue that even here, the
government justified its limits on external conduct (watching a film) solely on the
basis of its effect on thinking (watching the film allowed the generation of a certain
mental state). But this begs the question of how courts can know a limit like that
imposed on Stanley is solely about targeting mental experiences rather than the
effects the government believes to flow from them.
1052 M. J. Blitz

Moreover, if Chalmers and Clark are right in arguing that the physical substrate
underlying our thinking includes not only our brain processes, but also the tools we
use outside of our bodies to store memories – from notebooks to Smartphones – then
many government regulations of these tools can potentially count as a restriction on
freedom of thought and at least incidentally burden it. The line between regulating
thought and regulating “conduct,” then, will not be entirely clear.
Perhaps for this reason, one might argue, the law’s answer to such a challenge
must often be based not only on principled line-drawing between categories, but on
history and on social conventions. More specifically, the reason that the constitu-
tional protections for freedom of thought cover only certain kinds of cognitive
enhancements and not others might be, in part, that (1) we need some protected
realm where we can exercise mental autonomy, even if we cannot exercise it in all
circumstances where it is possible and (2) the legal history of the United States has
marked out the realm of expression, and self-formation with cultural resources, as a
realm where individuals are generally free from state restriction as they shape and
reshape their own consciousness. Even if pharmacology is another tool that allows
us to similarly reshape our minds, it might lie outside of the sphere of tools that our
legal history has set aside for the exercise of mental autonomy. One might not
establish a constitutional right to pharmacological cognitive enhancement, then,
simply by showing that it is functionally analogous to cultural enhancement that is
already shielded by constitutional liberties. The parity principle that Levy defense
for ethics, in other words, may not translate to constitutional law – because even
when there is a functional parity between two forms of enhancement, social and
historical tradition may have classified them differently. Courts may treat this as
reason enough to continue treating them differently, so long as it leaves us with a
satisfactory amount of mental liberty, even if not the maximum amount conceivable.
In analyzing American doctrines of constitutional liberty, this account is best
elaborated in two steps. First, one might argue, to the extent the First Amendment’s
freedom of speech protects the thought underlying expression, this doesn’t necessarily
mean it protects all action we might take to shape the mental process that produce such
thought. Rodney Deaton has made an argument like this: The Supreme Court’s First
Amendment jurisprudence in Stanley v. Georgia, he argues, prevents government from
denying individuals the ability to generate particular beliefs or experiences. It bars
government from preventing individuals from obtaining the information or visual
experience that comes from watching a film (Deaton 2006). But when we ingest a
drug psilocybin or methylphenidate, this doesn’t generate a particular experience.
Outside of science fiction, an enhancement drug of that kind generally isn’t pro-
grammed to deliver us a custom-made dream or mental experience. Rather, it produces
certain changes in the way our brain operates (and, perhaps, in doing so, enhances
certain mental capacities). But that is different from delivering us particular informa-
tional or experiential content, and thus, it is different from the kind of thinking that is
arguably most closely to speech: namely, the mental formation of content that can then
be expressed (or that we find in others’ expression).
That a certain exercise of mental autonomy lies outside the realm of First
Amendment freedom of expression and the freedom of thought that makes it
Cognitive Enhancement and American Constitutional Law 1053

possible doesn’t mean that it lies outside the realm of constitutional liberties alto-
gether. In a series of cases, the Supreme Court has made it clear that pharmacological
alteration of a person’s brain function can implicate their constitutional rights – at
least when government forces such alteration on people against their will (Washing-
ton v. Harper 1990; Nevada v Riggins 1992; Sell v. United States 2003). The Court
found that government is subject to constitutional constraints when it requires
prisoners or inmates of psychiatric facilities to take antipsychotic medications to
make them less dangerous to themselves or others, or to make them competent to
stand trial. But the Court did so not on the grounds that compelled use of psycho-
active substances would violate the First Amendment’s right to “freedom of
thought,” but rather that it would violate the right that the Fifth and Fourteenth
Amendment “due process” clauses give each individuals to be free from government
coercion that invades their bodily autonomy or freedom to determine their own
medical treatment. The Court has never said that government might violate the
Constitution if, instead of compelling a person to take a psychoactive drug against
her will, it denied her the freedom to take a psychoactive drug voluntarily.
Even if it did, however, it may well conclude that if the right to reshape one’s
brain operations with a psychiatric medication or cognitive enhancement interven-
tion is a constitutional right – it is not a First Amendment right (to be analyzed under
doctrines similar to those that protect freedom of expression) but rather a Fifth or
Fourteenth Amendment right (to be analyzed under doctrines the protect our bodily
autonomy). This difference could have significance because, in certain respects,
constitutional protections for our right to bodily autonomy and medical treatment are
more limited than the First Amendment rights to advance these interests through the
adoption of a “clear and convincing” standard of proof to govern such autonomy in
the realm of expression and belief. The Supreme Court has suggested, for example,
that when individuals make decisions about whether to continue life-saving treat-
ment, such decisions are not completely insulated from government legal measures
furthering the state’s interest in “the preservation of human life” (Cruzan by Cruzan
v. Dir., Missouri Dep’t of Health 1990).
Second, courts might well not only reject arguments for shielding pharmacological
cognitive enhancement with First Amendment protections for freedom of thought, but
also arguments for shielding it with Fifth or Fourteenth Amendment protections. There
are a variety of reasons they might do so. But one form such a rejection is likely to take
in some legal argument is one that emphasizes the importance of social convention
and tradition in marking the boundaries of our right to physical liberty or bodily
autonomy. Many judges have argued that these boundaries are inherently vague –
because the United States Constitution, at least, says little about them. Courts have
rather implied them from the mention of the word “liberty” in the text of the due
process clauses of the Fifth and Fourteenth Amendments.
They have, primarily in the latter part of the twentieth century, found that certain
aspects of individuals’ “intimate conduct” occur within a constitutionally shielded
“zone of privacy” where state interference is generally out of place (Griswold v.
Connecticut 1965; Lawrence v. Texas 2003). This is the basis, for example, of the
decisions in which the Court has found unconstitutional laws that restrict
1054 M. J. Blitz

individuals’ reproductive decisions (including the decision of a woman to have an

abortion) (Roe v. Wade 1973; Planned Parenthood v. Casey 1992), or laws that
prohibit sexual relationships between individuals of the same sex (Lawrence v. Texas
2003). Different judges disagree about the role tradition or social convention should
play in defining what kinds of intimate conduct are insulated from state interference
– but most judges agree that it has some role to play in determining what kind of
conduct is and is not within the realm of constitutional liberty. In fact, that is one of
the central criteria – and for some judges, counts as the essential criterion – for
determining whether a particular activity is with the “zone of privacy” established by
the Fifth and Fourteenth Amendments: The Supreme Court has said that these
provisions give constitutional force to liberties that are “deeply rooted in this
Nation’s history and tradition” (Moore v. City of East Cleveland, 1977).
This isn’t the only criterion for identifying activities that are the subject of such
liberty. The Court has also said that the United States Constitution places certain
kinds of human conduct within a “zone of privacy” when they are the subject of a
right that is “implicit in the concept of ordered liberty” (Washington v. Glucksberg,
721). But the latter criterion, in the view of some judges, leaves too much to
interpretation – and gives courts too much power to remove certain types of conduct
from the realm of democratic decision-making. So, as Justice Scalia puts it in the
Court’s opinion Michael H v. Gerald D., judges should understand the Constitution
to protect only on those “interest[s] traditionally protected by our society” (Michael
H. v. Gerald D. 1989).
It is quite possible then that judges would find that even if individuals are
protected under the Fifth and Fourteenth Amendment against compelled use psy-
chiatric medications, that does not mean that they have a right to voluntary cognitive
enhancement. If historical tradition largely determines what actions are and are not
covered Fourteenth Amendment protection, it is possible that this tradition treats
coercive state medication or surgery as impermissible, while treating, as permissible,
state regulation of how people access (and when companies can produce) drugs that
individuals can use to modify the functioning of their brains and bodies. Even if a
philosopher, ethicist, or legal scholar views these two activities – imposing drugs on
a person or barring voluntary use of drugs by the same person – as two different ways
of limiting their cognitive liberty, American tradition might treat them differently.
Thus, in Abigail Alliance v. Von Eschenbach, the DC Circuit found that there is not
“a right to procure and use experimental drugs that is deeply rooted in our Nation’s
history and traditions. To the contrary, our Nation’s history evidences increasing
regulation of drugs as both the ability of government to address these risks has
increased and the risks associated with drugs have become apparent” (Abigail All.
for Better Access to Developmental Drugs v. von Eschenbach, 711). Although this
decision focused on experimental life-saving drugs, it is likely that courts would also
find that the same history of drug regulation makes it difficult to find that there is a
long tradition of shutting government out of regulating – and recognizing individual
freedom to use – cognition-enhancing drugs.
It is possible that American traditions would shield – at least to some extent –
cognitive enhancement that we undertake with certain biochemical agents that don’t
Cognitive Enhancement and American Constitutional Law 1055

intuitively count as drugs and have long been available to individuals without the
need for any prescription: It is conceivable, for example, the courts might be more
receptive to constitutional arguments against laws that which bar individuals from
using omega-3 fish oil for cognitive enhancement.

Quasi-Constitutional Rights to Cognitive Liberty

What implications does the foregoing analysis have for the constitutional status of
pharmacological cognitive enhancement? My central point is that when courts and
legal scholars analyzing American law confront the question of whether there is, or
should be, a constitutional right to shape our minds medically as well as with words,
they are not constrained to reach only one answer. Rather, they come to a fork in the
road. One can certainly make the argument that the logic of the First Amendment’s
cases on freedom of thought, or that on Fifth and Fourteenth Amendment liberty to
bodily autonomy and to freedom from state interference in one’s brain processes,
should prevent the state from restricting individuals’ decisions to use pharmacolog-
ical methods to enhance their cognition or otherwise alter their thinking patterns.
More specifically, one might argue that, except where the state has a valid safety-
based reason for limiting such activity, it should respect individuals’ right to
determine the content of their own consciousness. As noted above, Sententia and
Boire make an argument of this kind.
On the other hand, for the reasons I’ve given above, it’s also quite plausible for
courts to conclude that, when it comes to constitutional law at least, there isn’t parity
between cultural and pharmacological modes of cognitive enhancement. This could
be because concerns about physical health and safety permeate the latter and make it
impossible to shut government regulators out of this realm to the extent that
constitutional rights generally do shut government out of the spheres they protect.
Or it could be because the constitutional status of an activity (like enhancement)
depends not merely on what it does (and whether it is functionally analogous to those
covered by existing rights) but on how American tradition has classified it.
Even if pharmacological enhancement is not protected by a constitutional right, it
could still be protected by a quasi-constitutional right. That is, even if the US
Constitution does not establish a right of cognitive liberty that courts might invoke
to strike down legislative limits on certain types of cognitive enhancement, members
of the US Congress, or of state legislators, may still limit themselves – and those in
the federal and state government bound by their laws. This is what the US Congress
did with respect to religious liberty. The 2006 Supreme Court case, Gonzales v. O
Centro Espírita Beneficente União do Vegetal, provides an example of this. In that
case, the Supreme Court found that the federal government did not have a “compel-
ling interest” and thus could not legally seize a shipment of ayahuasca that the União
do Vegetal Church intended to use in its religious ceremonies. This was not,
however, because the religious liberty protection of the US Constitution itself barred
government from restricting religious use of a psychoactive substance (Gonzales v.
O Centro Espírita Beneficente União do Vegetal, 2006). On the contrary, the 1990
1056 M. J. Blitz

Supreme Court case of Employment Division, Oregon v. Smith had made it clear that
a “neutral law of general applicability” – for example, a law that bans the use of
mescaline or ayahuasca by all individuals – is constitutional even if, in imposing
such a ban, it incidentally burdens individuals who wish to use such practices as part
of their religious worship. But that wasn’t the end of the story: Although Smith gave
government virtually unlimited room to enact drug laws (or other laws) that inci-
dentally burdened religion, Congress then enacted a statute holding the federal
government to a higher standard: In the Religious Freedom Restoration Act
(RFRA), it barred any part of the federal government from burdening religion,
even incidentally, unless doing so was justified by a “compelling government
interest” (42 U.S.C. § 2000bb-bb4). This standard (known in American constitu-
tional law, as “strict scrutiny”) is a very high hurdle for government – so it is not
surprising that the government was unable to meet it when it tried to seize the
ayahuasca used by the União do Vegetal Church. In short, the religious liberty
protection that Supreme Court refused to impose on government in Employment
Division, Oregon v. Smith as a matter of constitutional law was imposed by the
federal government on itself in federal legislation (Employment Division v. Smith,
1990). Many states have followed this example and impose state law constraints on
their own government that mirror the religious liberty protections in RFRA. I call
such law “quasi-constitutional” here because it imposes rights-based restraints of a
kind courts often find in the Constitution, but locates those constraints in statutes
rather than in amendments to the Constitution (which are, in the US system, much
harder to enact, especially at the level of federal rather than state government).
RFRA only protects the use of psychoactive substances in religious worship. But
it is possible for Congress or state legislatures to enact other statutes that provide
broader quasi-constitutional protections for cognitive liberty. Even if government
may restrict even generally safe uses of cognitive enhancement drugs (for purposes
other than treating illness), Congress or state legislatures could adopt laws barring
any restriction that does have a justification rooted in health or physical security. As
Veljko Dubljevic writes, a state might instead institute a “gatekeeper” system in
which patients can only obtain and use cognition-enhancement drugs under the
supervision of a physician, and with educational programs that require them to
learn about safety risks and the safest methods of using such drugs (Dubljevic 2013).
Even if arguments for parity between pharmacological and cultural cognitive
enhancement don’t justify giving the two the same status as a matter of constitutional
law, they may justify – as a policy matter – legislation that results in both of them
being treated equally, that is, in such a way that the government does not unneces-
sarily restrict cognitive liberty.

Conclusion

In the past 20 years, the possibility of enhancing cognition – with drugs or medical
devices, such as transcranial direct current stimulation (tDCS) – has generated
debates among ethicists about whether it is ethical for a society to prohibit
Cognitive Enhancement and American Constitutional Law 1057

individuals from enhancing themselves in this way, or to bar psychiatrists and other
physicians from aiding in that enhancement.
Such debates are, in part, debates about liberty. They ask if individuals should
have the freedom to use this kind of cognition enhancement. This chapter has
considered whether, if such liberty exists, it should come in the form of a constitu-
tional right to “cognitive liberty.” Such questions are likely to arise in any jurisdic-
tion where there are constitutional protections for freedom of thought or belief. My
focus here, however, has been on American constitutional law. More specifically,
this chapter focuses specifically on whether there is a right to cognitive enhancement
included within the “freedom of thought” courts have found in the First Amend-
ment’s free speech guarantees or among the liberty rights they have found in the
Fifth and Fourteenth Amendment due process clauses.
Richard Glen Boire points out that the right to cognitive liberty “remains only
obliquely defined within the US legal system” (Boire 2000b). One reason for this is
simply that in the past, government has not easily been able to – in Justice
Murphy’s words – invade and control “the inward workings of the mind” (Jones
v. Opelika, 1942). It can’t know individuals’ unexpressed thoughts. Nor can it
control their thoughts as effectively as it can coerce physical behavior. But there are
two other reasons that the cognitive liberty Boire, Sententia, and other describe
might have remained ill-defined. One is that once our freedom to shape our own
consciousness extends beyond the realm of speech and expression, it enters a realm
where health and safety interests normally justify extensive government monitoring
and regulation of a kind that often has an uneasy coexistence with constitutional
rights (which push government power back). Another is that although there is a
long tradition in American law of limiting the government’s power to restrict
individuals’ speech, and the public discourse and shaping of culture to which it
contributes, there is not a similar tradition of insulating, against government
regulation, the chemical inputs to our consciousness. In American law, courts that
announce new constitutional rights – or announce that they are extending familiar
constitutional rights (such as freedom of speech or due process rights) into new
territory – often present themselves as formally endorsing, in law, constitutional
understandings that have already found in a place in America’s traditions or cultural
understandings about fundamental liberties. Where such a path for extending
constitutional rights has not already been carved by tradition or social change,
courts often leave it to democratic processes to do the carving: They might, for
example, refuse to find any general constitutional right to cognitive liberty and
leave, to Congress and state legislatures, the decision of whether to legislatively
establish quasi-constitutional rights.

Cross-References

▶ Ethical Issues in Neuropsychopharmacotherapy: US Perspective

▶ Ethics of Informed Consent: Coercive and Preventive Medication
1058 M. J. Blitz

References
Abigail All. for Better Access to Developmental Drugs v. von Eschenbach, 469 F.3d 129 (DC Cir.
2007) (Federal Reporter 3d, Vol. 469, 129–138).
Church of Lukumi Babalu Aye v. City of Hialeah, 508 U.S. 520 (1993) (United States Reports, Vol.
508, 520–580).
Clark, A. and Chalmers. D, The Extended Mind, in Clark. A., Supersizing the Mind: Embodiment,
Action, and Cognitive Experience (Oxford University Press 2008).
Cruzan by Cruzan v. Dir., Missouri Dep’t of Health, 497 U.S. 261 (1990) (United States Reports,
Vol. 497, 261–357).
Doe v. City of Lafayette, 377 F.3d 757 (7th Cir. 2004) (Federal Reporter 3d, Vol. 377, 757–785).
Gonzales v. O Centro Espírita Beneficente União do Vegetal, 546 U.S. 418 (2006) (United States
Reports, Vol. 564, 418–439).
Griswold v. Connecticut, 381 U.S. 479 (1965) (United States Reports, Vol. 381, 479–531).
Jones v. Opelika, 316 U.S. 584 (1942) (Murphy, J., dissenting) (United States Reports, Vol. 316,
584–624).
Lawrence v. Texas, 539 U.S. 558 (2003) (United States Reports, Vol. 539, 558–606).
Martin v. Struthers, 319 U.S. 141 (1943) (United States Reports, Vol. 319, 141–157).
Michael H. v. Gerald D., 491 U.S. 110 (1989) (United States Reports, Vol. 491, 110–163).
Moore v. City of East Cleveland, 431 U.S. 494 (1977) (United States Reports, Vol. 494, 431–552)
Planned Parenthood v. Casey, 505 U.S. 833 (1992) (United States Reports, Vol. 505, 883–1002).
Riggins v. Nevada, 504 U.S. 127 (1992) (United States Reports, Vol. 504, 127–157).
Roe v. Wade, 410 U.S. 113 (1973) (United States Reports, Vol. 410, 113–178).
Sell v. United States, 539 U.S. 166 (2003) (United States Reports, Vol. 539, 166–193) Skiadas v.
Acer Therapeutics Inc., No. 1:19-CV-6137-GHW, 2020 WL 3268495, *1-*17 (S.D.N.Y. June
16, 2020) Fed. Sec. L. Rep. P 100,848.
Sorrell v. IMS Health, 564 U.S. 552 (2011) (United States Reports, Vol. 564, 552–603).
Stanley v. Georgia, 394 U.S 557 (1969) (United States Reports, Vol. 394, 557–572).
United States v. O’Brien, 391 U.S. 367 (1968) (United States Reports, Vol. 391, 367–391).
Video Software Deals Ass’n v. Schwarzenegger, 556 F.3d 950 (2009). (Federal Reporter 3d, Vol.
556, 950–967).
Washington v. Glucksberg, 521 U.S. 702 (1997) (United States Reports, Vol. 521, 702–789).
Washington v. Harper, 494 U.S. 210 (1990) (United States Reports, Vol. 494, 210–258).
Zemel v. Rusk, 381 U.S. 1 (1965) (United States Reports, Vol. 381, 1–39).

Statutes
21 United States Code § 812.
21 United State Code §§ 821–831.

Articles, Book Chapters, and Books

Blitz MJ. Freedom of thought for the extended mind: cognitive enhancement and the constitution.
Wis L Rev. 2010;2010:1049–117.
Blitz MJ. A constitutional right to thought enhancing technology. In: Dubljevic V, Jotterand F,
editors. Cognitive enhancement: ethical and policy perspectives in international perspective:
Oxford University Press; 2016.
Boire RG. Cognitive liberty, Part I. J Cogn Lib. 2000a;1(1):1–3.
Boire RG. Cognitive liberty, Part II. J Cogn Lib. 2000b;1(2):1–6.
Cognitive Enhancement and American Constitutional Law 1059

Bruhl AB, Angelo CD, Sahakian B. Neuroethical issues in cognitive enhancement: modafinil as the
example of a workplace drug? Brain Neurosci Adv. 2019;3
Bublitz JC, Merkel R. Crimes against minds: on mental manipulations, harms, and human right to
mental self-determination. Crim L Phil. 2014;8:51–77.
Carter JA, Palermos SO. Is having your computer compromised a personal assault? The ethics of
extended cognition. J Am Phil Assoc. 2016;2(4):542–60.
Deaton RJS. Neuroscience and the in Corpore-ted first amendment. First Amendment L Rev.
2006;4:181–221.
Dressler M, Sandberg A, Bublitz C, Ohla K, Trenado C, Mroczko-Wąsowicz A, Kühn S, Repantis
D. Hacking the brain. ACS Chem Neurosci. 2019;10(3):1137–48.
Dubljevic V. Cognitive enhancement, rational choice and justification. Neuroethics. 2013;6:179–87.
Dubljevic V, Ryan C. Cognitive enhancement with methylphenidate and modafinil: conceptual
advances and societal implications. Neurosci Neuroecono. 2015;4:25–33.
Farah MJ, Smith M, Ilieva I, Hamilton R. Cognitive enhancement. Wiley Interdiscip Rev Cogn Sci.
2014;5(1):95–103.
Glannon W. Neuroethics: cognitive enhancement. In: Goldberg S, editor. Oxford philosophy
handbooks. New York: Oxford University Press; 2015. p. 1–13.
Greely HT. The social effects of advances in neuroscience: legal problems, legal perspectives. In:
Neuroethics: defining the issues in theory, practice, and policy, vol. 245. Judy Illes ed. Oxford:
Oxford University Press; 2006.
Greely HT, et al. Towards responsible use of cognitive-enhancing drugs by the healthy. Nature.
2008;456:702–5.
Griffith RR, et al. Mystical-type experiences occasioned by psilocybin mediate the attribution of
personal meaning and spiritual significance 14 months later. J Psychopharmacol. 2008;22
(6):621–32.
Heid M. Nootropics, or ‘Smart Drugs,’ are gaining popularity. But should you take them? Time.
2019;23
Helmchen H. Some remarks on the ethics of Psychopharmacotherapy from a European viewpoint.
In: Riederer P, Laux G, Le W, Nagatsu T, editors. NeuroPsychopharmacotherapy; 2021.
Hildt E, Franke AG, editors. Cognitive enhancement. An interdisciplinary perspective. Dordrecht:
Springer; 2013.
Jotterand F, Dubljevic V, editors. Cognitive enhancement: ethical and policy implications in
international perspectives. New York: Oxford University Press; 2016.
Levy N. Neuroethics: challenges for the 21st century. Cambridge: Cambridge University Press; 2007.
Luchtman DW, Song C. Cognitive enhancement by omega-3 fatty acids from child-hood to old age:
findings from animal and clinical studies. Neuropharmacology. 2013;64:550–65.
Mehlman MJ. Cognition enhancing drugs. Millbank Q. 2004;82(3):483–506.
Ricci G. Pharmacological human enhancement: an overview of the looming bioethical and regu-
latory challenges. Front Psych. 2020;11:–53.
Rose S. Do microdoses of LSD change your mind? Sci Am. 2019;161
Sabet KA. Much Ado about nothing: why rescheduling won’t solve advocates’ medical Marijuana
problem. Wayne L Rev. 2012;58:81–101.
Sententia W. Neuroethical considerations: cognitive liberty and converging technologies for
improving human cognition. Ann N Y Acad Sci. 2004;1013(1)
Tribe LH. American constitutional law. 2d ed. New York: Foundation Press; 1988.
Walsh C. Psychedelics and cognitive liberty: reimagining drug policy through the prism of human
rights. Int J Drug Policy. 2016;29:80–7.
Challenges of Parkinson’s Disease Care
in Southeast Asia

Roongroj Bhidayasiri, Sasivimol Virameteekul, Banon Sukoandari,

Tai Ngoc Tran, and Thien Thien Lim

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
Geography of Southeast Asia and Regional Epidemiology of Parkinson’s Disease . . . . . . . . . . 1063
Burden of Parkinson’s Disease in Southeast Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
Diagnostic Delay and Misdiagnosis of Parkinson’s Disease in Southeast Asia . . . . . . . . . . . . . . 1069
Knowledge Gaps of Parkinson’s Disease in Southeast Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
Parkinson’s Disease Treatment: Availabilities and Accessibilities in Southeast Asia . . . . . . . . 1071
Telehealth as a Solution for Specialist Parkinson’s Care in Southeast Asia . . . . . . . . . . . . . . . . . . 1075
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077

R. Bhidayasiri (*)
Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders, Department of
Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial
Hospital, Thai Red Cross Society, Bangkok, Thailand
The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
e-mail: rbh@chulapd.org
S. Virameteekul
Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders, Department of
Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial
Hospital, Thai Red Cross Society, Bangkok, Thailand
B. Sukoandari
Red Cross Hospital, Bogor, West Java, Indonesia
T. N. Tran
Movement Disorder Unit, Department of Neurology, University Medical Center, University of
Medicine and Pharmacy, Ho Chi Minh, Vietnam
T. T. Lim
Island Hospital, Penang, Malaysia

© Springer Nature Switzerland AG 2022 1061

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_442
1062 R. Bhidayasiri et al.

Abstract
When reviewing literature on Parkinson’s disease (PD), the focus tends to be on
Western studies where as this, historically, is where the majority of studies have
been undertaken. However, this bias is gradually changing as the prevalence of
PD is rising steeply in highly populous nations, which are mainly located in
Eastern hemisphere and including some within Southeast Asia (SEA). With this
rising demand for PD care in SEA, it is becoming apparent that there is a
mismatch of what healthcare resources are available across the region including
access to facilities, qualified personnel, approved and reimbursed therapeutic
options, or even knowledge of those who treat and those who receive the
treatments. This chapter looks at these challenges through the lens of a typical
case of PD patient in SEA, where various challenges are faced along the case
history, from diagnosis to advanced disease stage, with the intention of providing
real regional perspectives, supported by data or published literature when avail-
able. In addition, further insights on the practicalities of each challenge are sought
using individual authors’ clinical experience from within various countries of
SEA. It is unlikely that this chapter includes all challenges that PD patients face in
this region, but the authors have attempted to outline all those that are relevant in
clinical situations and provide rationales or solutions for some when available. It
is not the intention of the authors to fill this chapter with statistics or theoretical
approaches that, though seemingly ideal, have never been implemented in real
clinical scenarios. Rather, the authors want readers to be able to visualize the
challenges from a real clinical vignette typical of this region and to compare and
contrast these challenges with what is happening in the reader’s own environ-
ment. With the era of information technology and the “new” normal that we all
are facing, we all can benefit from information gained from any part of the world
and apply it appropriately in our clinical practice.

Introduction

Parkinson’s disease (PD) is a prototypical chronic neurodegenerative disorder that

is a leading cause of disability globally (GBD 2019 Diseases and Injuries Collab-
orators 2020). It typically has a long natural history, beginning in the prodromal
stage where patients are asymptomatic for motor symptoms, but troubled by
unrecognized non-motor symptoms (NMS), transitioning to the early stage,
when motor symptoms are mildly disabling, then progressing to the intermediate
and advanced stages, when burden of care accumulates not only to patient’s
families, but also the healthcare systems that are not designed to provide optimal
care for those with chronic disorders like PD. PD populations are projected to rise
rapidly, with more than 100% growth expected in countries with the most populous
nations like, for example, Indonesia in Southeast Asia (SEA), but this increase is
unmatched by the functioning of healthcare systems in such regions which are
Challenges of Parkinson’s Disease Care in Southeast Asia 1063

often fragmented, with poor interdisciplinary collaboration and a lack of timely

access to services and therapies (Dorsey et al. 2007; Bloem et al. 2020). Further-
more, complex problems that frequently occur in many advanced stage PD patients
are not optimally managed because of a lack of clinical expertise, with treatment
plans often focused on the disease, not patient as the individual (Bloem et al.
2020). Care in PD should be integrated, with a patient-centered perspective, and
include evidence-based solutions to improve healthcare delivery (Bloem et al.
2020). To achieve this goal, multidisciplinary and shared-care approaches are
needed alongside the use of patient-centered outcome measures. However, several
challenges to deliver patient-centered care in PD in Asia have recently been
highlighted by international experts in PD who issued a consensus on options
that could enhance patient-centered and personalized care in order for patients to
achieve the best possible outcomes, including improving knowledge about PD and
its treatment and increasing awareness of clinicians of PD heterogeneity and
treatment response (Bhidayasiri et al. 2020a). To follow on from this with a
focus on SEA, the authors would like to draw your attention to, first, the epidemi-
ology of PD and its disease burden in SEA compared to the rest of the world,
followed by the clinical vignette of a typical SEA PD patient, provided as sections
throughout this chapter to reflect different common clinical scenarios that we all
face as healthcare providers with a particular emphasis on SEA in relation to global
situations. Although in SEA specific data on PD may be limited in certain areas,
perspectives are provided by the authors that although reflect only our opinions,
are based on scientific data from published literature. While there is no perfect
situation where these challenges are met, it is important for healthcare providers to
recognize these difficulties and adapt to their individual situations in order to
deliver what is needed by most patients.

Geography of Southeast Asia and Regional Epidemiology of

Parkinson’s Disease

Southeast Asia (SEA) is a subregion of Asia, consisting of the countries south of

China, east of India and north of Australia. SEA consists of two geographical
regions: the Asian mainland that consists of Cambodia, Laos, Myanmar, Thai-
land, and Vietnam; and the maritime region that consists of Brunei, East Timor,
Indonesia, Malaysia, the Philippines, and Singapore. As of 2020, more than 670
million people live in the region, representing 8.5% of the total world population,
with more than a fifth of them (130 million) on the Indonesian island of Java, the
most densely populated large island in the world (2021b). SEA enjoys a diverse
distribution of religions and people with a mixture of various ethnic groups
including primarily descendants of Austronesian, Tai, Mon-Khmer, Arab, Chi-
nese, Indian, Polynesian, and Melanesian. Although the median age of SEA
population is 30.2 years old, there has been an increase of a mean life expectancy
from 63.4 years in the year 2000 to 71.4 years in 2019 (2021a). Indeed, the
1064 R. Bhidayasiri et al.

population of SEA is aging rapidly. While the proportion of people aged 60 or

above was 9.8% in 2017, it will increase to 13.7% and 20.3% by 2030 and 2050,
respectively (2021a). The health issues older people face are diverse including
noncommunicable diseases, mental health including dementia, and injuries
and disabilities due to declining functional ability, which could be partly as a
result of PD.
It is well accepted that PD is more common with increasing age and shows a
male predominance (Pringsheim et al. 2014; Muangpaisan et al. 2009). As
reported by Global Burden of Disease (GBD) Collaborators, the increase of PD
population from 2.5 million in 1990 to 6.1 million in 2016 is unlikely to be due to
aging population alone, but also as a result of longer disease duration and
environmental factors (GBD 2016 Parkinson’s Disease Collaborators 2018). PD
prevalence and incidence are found by most systematic reviews and meta-analysis
to be slightly lower in the East compared to the West even though varying
methodologies, diagnostic criteria, and case-finding strategies could potentially
contribute to this variation (Muangpaisan et al. 2009; Pringsheim et al. 2014;
Abbas et al. 2018). Although there is no dedicated study of PD epidemiology in
SEA, the estimates, as reported by GBD collaborators, identified 409,655 PD
patients in SEA with an overall 24.7% change in age-standardized rates between
1990 and 2016, with Thailand the highest (31.7%) among SEA nations (Fig. 1)
(GBD 2016 Parkinson’s Disease Collaborators 2018). In that report, the largest
increase in the number of PD patients was reported in countries with middle
Socio-Demographic Index, which includes Thailand and Malaysia as upper mid-
dle-income countries and Laos, Vietnam, Timor-Leste, Myanmar, Philippines,
and Indonesia as lower middle-income countries. Another study also projected
of an over 100% growth rate of PD populations in highly populous nations with
Indonesia being the representative country in SEA where the number of individ-
uals with PD over age 50 years is projected to double to 250,000 by the year 2030
(Dorsey et al. 2007). Prevalence studies conducted in individual SEA countries
are limited and comparison across studies is difficult because of the small number
and varying methodologies. However, in Singapore, the age-adjusted prevalence
of PD using a three-phase community survey was 0.30% for those aged 50 and
above, which is comparable to that of Western countries (Tan et al. 2004). No
significant difference of age-adjusted prevalence was observed among Chinese,
Malays, and Indians who reside in Singapore. In Thailand, prevalence of PD was
determined by the registry from physicians and self-reported patients using the
capture-recapture methodology, and revealing an age-adjusted prevalence of
0.42%, which was comparable to, or even higher than, the reported prevalence
of Western or other Asian countries (Bhidayasiri et al. 2011b). Both SEA studies
emphasized the role of environmental factors (e.g., pesticide exposure) in the
development of PD in this region (Bhidayasiri et al. 2011b; Tan et al. 2004). Other
acquired risk factors, including diabetes, chronic hepatitis C, and Helicobacter
Pylori infection, are also found to be more prevalent in Asian patients and may be
implicated as potential risk factors of PD in SEA (Lim et al. 2019). However,
specific studies in SEA to confirm these risk associations are still lacking.
 Challenges of Parkinson’s Disease Care in Southeast Asia
1065

Fig. 1 Map of Southeast Asia depicting statistical data on the number of Parkinson’s disease patients and neurologists
1066 R. Bhidayasiri et al.

Burden of Parkinson’s Disease in Southeast Asia

By definition, burden of disease refers to the total, cumulative consequences of a

defined disease (in our case, PD) or a range of harmful diseases with respect to
disabilities in a community. These consequences include health, social aspects, and
costs to the society. The gap between an ideal situation, where everyone lives free of
disease and disability, and the cumulated current health status is defined as the
burden of disease (Hessel 2008). In the setting of PD, the burden of disease is
estimated by adding together the number of years of life a person loses as a
consequence of dying early because of PD (Years of Life Lost, YLL) and the number
of years of life a person living with disability caused by PD (Years of Life Lived with
Disability, YLD) (Murray and Lopez 2013). Adding together the YLL and YLD
gives a single-figure estimate of disease burden, called the Disability Adjusted Life
Year (DALY). One DALY represents the loss of 1 year of life lived in full health.
Another indicator, Quality Adjusted Life Year (QALY), is a measure of the life
expectancy corrected for quality of that life caused by disease and disabilities. A year
of life in perfect health is given a QALY of 1 while a year of complete functional
impairment (e.g., death) has a QALY of 0. At a global level, PD represents a good
example of a noncommunicable neurological disorder (NCND) in which the
increase in absolute numbers juxtaposes with a significant decrease in age-standard-
ized rates, which is consistent with population aging and growth as the main drivers
of increased prevalence (GBD 2016 Neurology Collaborators 2019). It also suggests
that intervention strategies to reduce NCND, including PD, are not effective. Indeed,
PD was identified from the GBD 2015 as the fastest growing disease in prevalence,
disability, and deaths with the latest GBD 2016 report demonstrating the global
burden of PD of more than doubled over the past generation as a result of aging and
industrialization (GBD 2016 Neurology Collaborators 2019; GBD 2015 Neurolog-
ical Disorders Collaborator Group 2017).
According to the GBD 2016 report, PD caused 11,900 deaths (95% UI: 9,275-
14,966) and 213,332 DALYs (95% UI: 169,151-262,446) in SEA, which accounted
for 5.63% of global deaths and 6.59% of global DALYs, respectively (GBD 2016
Parkinson’s Disease Collaborators 2018). Although the number of deaths and DALYs
in SEA were still lower than those nations of high-income North America, high-
income Asia Pacific or Western Europe, the 24.7% increase in age-standardized rate
was higher than the 21.7% global increase in age-standardized rate, and more than
doubled the increase rates of high-income North America (12.8%) and Western
Europe (8.4%) (GBD 2016 Parkinson’s Disease Collaborators 2018). This figure
indicates that the increase in the number of PD patients was less pronounced in high
SDI countries, with the largest increase observed in middle SDI countries, which
constitutes the majority of SEA nations. Within SEA nations, Thailand has the highest
percentage increase of age-standardized rate (31.7%) while Indonesia has the highest
DALYs (70,145) and Cambodia has the highest percentage increase in age-standardized
death rate (57.6%) (GBD 2016 Parkinson’s Disease Collaborators 2018).
These findings have important health service implications. The increase in the PD
population in SEA implies a need for substantially increased resources for their
Challenges of Parkinson’s Disease Care in Southeast Asia 1067

management, particularly healthcare providers. Although conducted in the USA,

evidence suggests that neurologist care in PD is associated with improved clinical
outcomes, ranging from a reduced likelihood of placement in a skilled nursing
facility, a lower risk of hip fracture, and even a reduced likelihood of death (Willis
et al. 2011). By knowing the absolute numbers of new and existing cases of PD from
the GBD study, we can estimate annual requirements for first neurologist assess-
ments (total number of incident cases) and for follow-up neurological assessments
(assuming an average number of three follow-up visits per year), and, from these, the
number of neurologists required in SEA for appropriate outpatient management.
According to the GBD 2016 report, there were 409,655 prevalent cases of PD in
SEA (GBD 2016 Parkinson’s Disease Collaborators 2018). The incident cases were
estimated from the percentage change in age-standardized rates of each SEA nation
between 1990 and 2016, which accounted for 6,289 patients. Thus, the total time for
required first neurological assessments (6,289
0.75 h for a new clinic patient is
4,716.75 h) and neurology follow-ups (409,655
3
0.5 h for a follow-up is
614,482.5 h) was 619,199.25 h. By dividing 619,199.25 h by the average estimate of
neurologists’ working hours per year (40 h per week
48 weeks is 1920 h), one can
estimate that approximately 323 full-time equivalent (FTE) neurologists are required
to provide specialist neurological care for PD in SEA. This is a demanding figure of
FTE neurologists for only one disorder compared to a current number of 4,525 FTE
neurologists in SEA who are providing specialist care for various neurological
disorders, not limited to PD (Lim et al. 2019). The situation of neurological care in
SEA, as described by the WHO GBD analysis as a regional example of predominant
low and middle SDI countries, is like a double hit, whereby richer populations in
these countries are experiencing a higher prevalence of stroke, dementia, and PD as a
result of increasing life expectancy and behaviors that accompany rapid urbaniza-
tion, poorer populations are still suffering from many neurological infections
(Mohammadi 2011). With this analysis, the shortage of neurologists in SEA is likely
to get worse. Indeed, the lack of neurologists is a worldwide problem, not just in
SEA. Even high-income countries are affected, with a recent US report indicating
that an 11% rise of US neurologists between 2013 and 2025 was not matched by
a growing demand of 16% over the same period (Burton 2018). The situation in
SEA is likely to worsen as the number of neurologists in this area accounts for only
1.5–2.2% of the world’s neurologists (Tan 2015; Poungvarin 2007). An increased
shortage of neurologist also contributes to the burnout that neurologists face, partly
as a consequence of high workloads, particularly in large healthcare systems as
shown in two large survey conducted in the USA and China (Busis et al. 2017; Zhou
et al. 2017). This disparity on distribution of neurologists is evident in SEA, resulting
in an inaccessibility for PD patients for neurological care, with up to 80% of
Thai patients having never received a specialist neurological assessment
(Bhidayasiri et al. 2011a, b). This situation is likely to be similar across most
SEA nations, with the exception of Singapore, which has the lowest number
of populations per neurologist (58,000 population per one neurologist) (Lim et al.
2019). In most countries in SEA, care to PD patients is provided by general
physicians and it is also possible that there are unseen patients who have never
1068 R. Bhidayasiri et al.

been diagnosed, treated, or rely on traditional treatments. To compound the problem

further, the neurologist shortage is unlikely to be just the result of low numbers.
Where neurologists are few, like in many countries in SEA, they may also not be
working in places or milieux which optimize the use of their skills. In a report
conducted by the World Federation of Neurology Task Force on Neurological
Services, more than three quarters of neurologists who responded to the survey
worked in private practices, fewer than 25% work in a national health service or
academic settings (Bergen and World Federation of Neurology Task Force on
Neurological Services 2002). Moreover, there is also a major shortage of trained
nurses, paramedical staff, and rehabilitation services for PD patients in most coun-
tries in SEA.
When analyzing symptoms of PD, as another marker of disease burden, the
evidence from the SEA and Asia-Pacific regions suggests that patients experience
significant symptom burden and moderate unmet support needs even at the early and
intermediate stage of PD (Kwok et al. 2020). Two-thirds of PD participants rated a
range of NMS, encompassing constipation, fatigue, leg problem, and daytime som-
nolence as the most prevalent and burdensome symptoms. The study also observed
some variations on the types of support needed by PD patients as Hong Kong and
Taiwanese patients were more concerned on psychosocial and spiritual support,
whereas Thai patients prioritized physical needs and emotional concerns (Kwok et
al. 2020). Increasing symptom burden is likely to affect carers in SEA, particularly
when the disease is advanced to the point that patients are less able to take care of
themselves, or when assistance is required for unrecognized symptoms (e.g., nighttime
symptoms), and device-aided therapies (Tan et al. 2020; Viwattanakulvanid et al.
2014; Razali et al. 2011). In addition, PD is unlikely to occur in isolation. One large
study in SEA involving over 6,000 public primary care patients identified PD as one of
the common conditions that is associated with high comorbidities and low quality of
life (QoL) (Pengpid and Peltzer 2017). Importantly, PD was identified as the chronic
condition with the poorest QoL, worse than chronic obstructive pulmonary disease and
cardiovascular diseases in Cambodia, Myanmar, and Vietnam (Pengpid and Peltzer
2018a). To lessen patient and caregiver strain, timely referral of support care services
should be provided that encompass not only motor training, but also psychospiritual
and practical support. Moreover, planning for support care services should take into
consideration cultural and health service contexts.
Understanding the burden of PD is important at international or national levels for
health policy makers, but also vital as helpful guidance for clinicians on the
practicalities of measuring burden of PD enabling assessment of local healthcare
system performance, comparing actions and health gains, identifying at-risk PD
populations for certain outcomes (e.g., fall), and planning future needs. In the
following sections, we will present the clinical vignette of a typical SEA PD patient,
highlighting various challenges for patients and those who involve in the care of PD
patients, supported by data from SEA where available or elsewhere if relevant.

Clinical Vignette (Part 1) At the age of 63, the patient began to develop left
shoulder pain associated with dragging of her left foot during fast walking. She
Challenges of Parkinson’s Disease Care in Southeast Asia 1069

was initially treated for tendinitis by a general practitioner, internist, and orthopedic
surgeon for 2 years in her remote hometown without any improvement before being
referred to a neurologist in the university hospital located 250 km away where the
diagnosis of PD was made. (To be continued)

Diagnostic Delay and Misdiagnosis of Parkinson’s Disease in

Southeast Asia

In a recent survey of more than 2,000 PD patients conducted by Parkinson’s UK,

more than a quarter of patients were initially misdiagnosed, with a further 21%
having to see their general providers three times before being referred to a specialist,
suggesting that the problems of delayed diagnosis and misdiagnosis tend to occur
together in the sense that many patients received wrong diagnoses, and sometimes
more than one diagnosis, before PD was eventually diagnosed (Gavidia 2020).
Among participants who were misdiagnosed, 48% were given treatment for their
nonexistent conditions, with 36% receiving medication, 6% undergoing operations
or procedures with a decline in health documented in 34%. The time from symptom
onset to physician’s assessment was found to be significantly longer than the time
from physician’s assessment to PD diagnosis (Breen et al. 2013). These alarming
figures, documented in a developed country (UK), provided another piece of evi-
dence that diagnostic delay in PD is not a unique situation in SEA, but is likely to be
a global issue. While limited data is available in SEA, a census of movement
disorders at the tertiary referral center in Thailand showed that less than half of PD
patients were seen in this specialist center within 2 years of symptom onset while the
rest of patients were seen after 3 years of disease onset (Bhidayasiri et al. 2011a). The
delay in case referrals may be due to several reasons, including a delay in diagnosis,
initial misdiagnosis, or selective referrals for difficult cases only. In this report, the
most common misdiagnosis was vascular parkinsonism, followed by essential
tremor (ET), progressive supranuclear palsy, and corticobasal degeneration
(Bhidayasiri et al. 2011a). It is well recognized that tertiary neurological care is
not widely available in most SEA nations and there is inequality in terms of access
to these specialist centers across the populations (with probable exception of
Singapore) (Singhal and Khadilkar 2014). Therefore, it is not possible to generalize
these findings to the rest of SEA. Outside of specialist centers, PD patients are
managed by internists or general practitioners in which the diagnostic accuracy is
less than those performed by neurologists (Hughes et al. 2002). Moreover, most rural
health centers in SEA are manned by community nurses, general nurses, and medical
assistants who have to visit many patients, often more than 100 a day, with all sorts
of conditions. In this context, an individual with PD might be missed, either due to a
lack of knowledge about the symptoms or simply due to the overwhelming number
of patients that prevents healthcare professionals from performing proper
assessments.
When examining the problems of diagnostic delay and misdiagnosis of PD at a
global level, it is found not to be uncommon even in developed nations. Indeed, PD
1070 R. Bhidayasiri et al.

was identified in a systematic review as one of the common conditions that are
associated with diagnostic errors (overdiagnosis vs. underdiagnosis) in older patients
(Skinner et al. 2016). Specialists were found to less overdiagnose with a 1-PPV of
1.4–25% while overdiagnosis was more prevalent in patients with no bradykinesia,
rigidity, resting tremor, hypomimia, less severe disease, and higher scores on
cognitive testing (Schrag et al. 2002; Hughes et al. 2002; Newman et al. 2009).
Red flags for non-PD conditions include patients receiving low doses of anti-
parkinsonian medications, whose dose had not increased in 3 years, who had been
on monotherapy for 5 years, and who had neither a documented response to
dopaminergic medications nor clinical progression were more commonly over-
diagnosed (Newman et al. 2009; Schrag et al. 2002). In contrast, factors associated
with underdiagnosis included lower disease severity, shorter disease duration, living
in a nursing home, and absence of typical complications of PD and/or its treatment
(e.g., dyskinesia) (Schrag et al. 2002). Young-onset (defined in this study as the onset
between 21 and 45 years) was also associated with a delayed diagnosis and a
substantial proportion of young-onset patients were misdiagnosed with functional
disorders (Rana et al. 2012). Even in the hands of specialists, misdiagnosis can still
occur in the early stages of the disease due to subtle clinical features, absence of
typical presentations, and a lack of red flags for alternative diagnoses (Rizzo et al.
2016; Litvan et al. 2003; Bhidayasiri et al. 2019a). Conditions that were found to
mimic PD were similar across studies, including ET, drug-induced parkinsonism,
dementia with Lewy bodies, dystonic tremor, multiple system atrophy (MSA),
Alzheimer’s disease, and vascular parkinsonism (Breen et al. 2013; Bhidayasiri
et al. 2011a; Hughes et al. 1993). Symptom characteristics also influence the timing
of diagnosis in which gait disturbances were associated with the longest delay, while
tremor had the shortest (Breen et al. 2013).
Recent clinical diagnostic criteria proposed by the International Parkinson
and Movement Disorder Society (MDS) has incorporated normal functional
neuroimaging of the presynaptic dopaminergic system (e.g., 123I-2β-carbomethoxy-
3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane dopamine transporter single photon
emission computed tomography (123I-FP-CIT DAT SPECT), or L-3,4-dihydroxy-6-
(18F) fluoro-phenylalanine positron emission tomography (18FDOPA PET)) as one of
the absolute exclusion criteria for PD (Postuma et al. 2015). However, despite the
evidence supporting its use in the differential diagnosis of parkinsonism, its availability
and cost limits any widespread adoption in clinical practice in SEA, with its use here
mainly restricted to a few centers for research purposes (Mirpour et al. 2018; Bega et al.
2015; Bhidayasiri et al. 2012).

Knowledge Gaps of Parkinson’s Disease in Southeast Asia

Several factors are likely to contribute to diagnostic delay and misdiagnosis of PD,
encompassing disease characteristics, knowledge of both patients and physicians,
socioeconomic situations, availabilities of investigations (to support or refute the
diagnosis), and even misperceptions that PD was attributed to other nonmedical
Challenges of Parkinson’s Disease Care in Southeast Asia 1071

causes (e.g., cold weather, witchcraft), resulting in patients seeking treatment from
traditional healers, instead of healthcare professionals. One study in Thailand
documented significant knowledge gaps in PD among medical professionals, with
internists and general practitioners’ knowledge of pharmacotherapy and treatment
guidelines limited compared to neurologists (Bhidayasiri et al. 2014). However, an
intensive training program among healthcare professionals in Laos has been shown
to improve knowledge in PD even among those with limited existing knowledge
(Phokaewvarangkul et al. 2020). As for general public knowledge on PD, one large
study involving more than 1,000 responders in Malaysia found they still incorrectly
believe that PD is always associated with tremor and it can be cured (Tan et al. 2015).
Although patients were found to have superior knowledge to that of the general
public, less than half of PD patients in Malaysia recognized NMS as part of the
disease manifestations, with the least recognized reduced sense of smell, followed by
weight loss, and pain (Tan et al. 2015). Among Thai PD patients, younger age,
female gender, and higher disease duration were identified as predictors of a higher
level of PD knowledge and this group could potentially serve as patient advocates
for longitudinal patient educational programs within the country (Jitkritsadakul et al.
2017). The issue of stigma/shame was also observed in one-third of PD patients and
is recognized by several patient’s support groups within SEA where a recent public
education to break this stigma using integrated media has been shown to be effective
(Choo et al. 2020; Jagota et al. 2020).

Clinical Vignette (Part 2) The patient responded well to levodopa, taken four times
daily, to the point that she could return to her usual, pre-illness, activities. Due to a
long duration response, she cut back the frequency of levodopa to twice daily, but at
a higher dosage, to make her treatment regime more convenient. After only a year,
she started to develop motor fluctuations of predominantly wearing-off and peak-
dose dyskinesia. She required additional classes of dopaminergic medications to
improve her fluctuations, but these medications were not reimbursed and also not
available from her local health authority. Moreover, she did want to pursue deep
brain stimulation as this procedure was not available locally and she wished to stay
close to her family. As a result, she self-adjusted her own medications by increasing
the frequency of levodopa, leading to worsening dyskinesias. In addition, she
followed her neighbors’ suggestions to experiment with several herbal medicines
with the hope that her disease would be cured.

Parkinson’s Disease Treatment: Availabilities and Accessibilities

in Southeast Asia

While levodopa remains a gold standard for the treatment of PD, recent evidence has
indicated that there are subgroups of PD patients whose optimal treatment in the early
stage may not be necessarily levodopa, but other classes of dopaminergic medications
(De Bie et al. 2020). Moreover, as the disease progresses, it is likely that most PD
patients will require additional classes of dopaminergic medications alongside
1072 R. Bhidayasiri et al.

levodopa to treat symptoms of motor and non-motor fluctuations. While several

classes of dopaminergic medications, comprising of dopamine agonists (DAs), mono-
amine-oxidase B inhibitors (MAOBIs), catechol-O-methyltransferase inhibitor
(COMTI), in addition to levodopa, have been shown to be efficacious in the treatment
of motor fluctuations, they are not widely available within SEA (Fox et al. 2018;
Bhidayasiri et al. 2015). Table 1 provides updates of dopaminergic medications that
are available within SEA with the exceptions of Cambodia and East Timor where data
is unavailable. It is noted that the availabilities of these medications also vary across
SEA nations, with Singapore, Malaysia, Thailand, and Philippines having almost all
classes of dopaminergic medications available while Laos has only levodopa as their
treatment option. Another important consideration is also the accessibility of these
medications within a country. It is documented in the recent review that levodopa is
not universally available in two nations (Cambodia and Laos) in SEA (Lim et al.
2019). However, recent international supported programs, like the MDS, provides a
good demonstration of how collaboration within SEA nations (Thailand and Laos) can
result in better education as well as medication availability in underserved regions
(Phokaewvarangkul et al. 2020). Even in those countries where medications are shown
to be available, there is extreme diversity in accessibilities of different classes of
dopaminergic medications throughout the country. The recent study conducted in
Thailand demonstrated that although levodopa is available in all 77 provinces, acces-
sibility to other classes of dopaminergic medications is limited to only 17 provinces
(22%) (Sakdisornchai et al. 2017; Bhidayasiri et al. 2020b). Moreover, the hospitals
where all medication types are available are mostly located in the central region of the
country, with only 17% of hospitals in the south and 8% of hospitals in the north and
northeast of the country having complete availability of dopaminergic medications on
their hospital drug lists. Most hospitals with complete lists of dopaminergic medica-
tions are university teaching hospitals, main regional hospitals for referrals, or major
general hospitals in large cities in Thailand. Another study conducted in Philippines
provides a similar impression that inadequate healthcare delivery in PD is limited by
the patients’ accessibility to different classes of dopaminergic medications, which are
not included in the Philippine Department of Health’s program for significant cost
reduction (Jamora and Miyasaki 2017).
The situation around treatment availability within SEA is likely to be worse with
device-aided therapies. Among three types of device-aided therapies, deep brain
stimulation (DBS) is the most common available, followed by subcutaneous apo-
morphine infusion (SAI)/pen injector (Table 1). To the best of our knowledge, in the
whole of SEA, levodopa carbidopa intestinal gel (LCIG) is only available in
Thailand (Bhidayasiri et al. 2015). The availability of these device-aided therapies
is closely linked to the availability of well-trained healthcare professionals as the
successful delivery of these treatments requires a multidisciplinary team, comprising
of not only movement disorder neurologists, but also functional neurosurgeons, PD
specialist nurses, and technicians (Bhidayasiri et al. 2016, 2020b). Moreover,
follow-up assessments of these device-aided patients require more time, expertise,
personnel, and carer support, which increase the further workloads of healthcare
professionals and burden to families.
Table 1 Availability and formulations of Parkinson’s disease medications in Southeast Asia (Data from Cambodia and East Timor is unavailable)
Brunei Indonesia Laos Malaysia Philippines Singapore Thailand Vietnam
Levodopa
SR Y Y Y Y Y Y Y Y
CR N N N Y Y Y Y Y
COMTI
LCE N Y N Y Y Y Y Y
Entacapone Y Y N Y Y Y Y N
Ergot DAs
Bromocriptine N Y N Y Y Y Y N
Non-ergot DAs
Piribidil N N N Y Y Y Y Y
Pramipexole Y Y N Y Y Y Y Y
Ropinirole Y Y N Y Y Y Y N
Rotigotine N Y N Y Y Y Y Y
Apomorphine
Pen injection N N N Y Y Y Y N
Challenges of Parkinson’s Disease Care in Southeast Asia

SAI N N N N N N Y N
MAOBIs
Selegiline Y N N Y Y Y Y N
Rasagiline Y N N N Y N Y N
Amantadine Y N N Y Y Y N N
Zonisamide N Y N Y Y N Y N
LCIG N N N N N N Y N
DBS Y Y N Y Y Y Y Y
SR: standard-release; CR: controlled-release; COMTI: catechol-O-methyltransferase inhibitor; LCE: levodopa carbidopa entacapone; DAs: dopamine agonists;
SAI: subcutaneous apomorphine infusion; MAOBIs: monoamine-oxidase B inhibitors; LCIG: levodopa-carbidopa intestinal gel; DBS; deep brain stimulation;
N: Not available; Y; available
1073
1074 R. Bhidayasiri et al.

The financial burden of PD should not be underestimated and it is projected to grow

substantially over the next few decades, partly due to the growing size of the elderly
population. Economic burden is shown to be increasing in high-income Western
countries, so it is expected to follow a similar fashion in SEA (Kowal et al. 2013;
Yang et al. 2020). The difference is that medical insurance coverage for PD is scarce in
SEA, resulting in patients having to pay privately for treatment (Tan 2015). One study
in Singapore documented the annual total cost of PD care was 10,129 USD per patient
of which 38.5% accounted for direct cost (pharmacotherapy and home care) while the
rest (61.5%) was indirect costs, mainly related to productivity (Zhao et al. 2011).
Another study from the Philippines reported a total cost of 6,175 USD per patient with
similar distributions of direct (23%) and indirect (77%) costs to the Singaporean study
(Prado and Jamora 2020). These figures from two representative countries in SEA are
still considered much lower than the average direct medical cost in the USA of 24,439
USD per patient in 2017 (Yang et al. 2020). In most SEA countries (probably with the
exception of Singapore), the cost of PD treatment is prohibitive in relation to the
average income of patients, or their families, and is not reimbursed by national health
authorities. Moreover, having advanced PD alone was associated with a larger eco-
nomic burden compared to mild or moderate disease (Dahodwala et al. 2021). For
example, in the Philippines, PD medications are not reimbursed by the government
and patients have to rely on marketing strategies (e.g., discount coupons) to lower the
costs of their treatment (Jamora and Miyasaki 2017). In Thailand, only levodopa,
bromocriptine, entacapone, and ropinirole are included in national essential drug lists,
which entitles patients to full reimbursement if treated by specialists in government
public hospitals (Bhidayasiri et al. 2019b). The reimbursement schemes are similar,
but not identical in Malaysia and Indonesia where levodopa, entacapone, pramipexole,
and ropinirole are available for government reimbursement for limited quantities each
month (Personal communication). Therefore, reimbursement policies are likely to vary
by country within SEA with currently no shared policy adopted by all country
members of the Association of Southeast Asian Nations. As shown by the study in
Singapore, the cost of medication, and whether it is subsidized by the health authority
or not, significantly influence prescribing patterns of neurologists for their choice of
drugs for PD patients among other factors, including severity of symptoms, side
effects, and efficacy (Tan et al. 2005). Also, the high cost of device-aided therapies
probably limits the accessibility of patients in SEA to these treatments as demonstrated
by the low proportion of DBS patients to overall PD patients in the Philippines
(0.04%) compared to the global proportion (5–10%) (Diestro et al. 2018). In Vietnam,
only 94 PD patients had undergone DBS of the subthalamic nucleus since the launch in
2012 until February 2021 (Personal communication). Similarly, challenges to establish
apomorphine treatment in Thailand, as an example of a developing country, have been
outlined in a recent report, with suggested strategies to overcome problems including
the development of a coordinated approach to PD management throughout the country
to identify suitable patients and ensure treatment continuity (Bhidayasiri et al. 2020b).
When asking patients about the use of complementary and alternative medicine
(CAM), some PD patients may be reluctant to volunteer such an information as
they are concerned their participations with CAM may affect the doctor–patient
Challenges of Parkinson’s Disease Care in Southeast Asia 1075

relationship (Kim and Jeon 2012; Tan et al. 2006). While approximately 40% of
Western PD patients reported using at least one type of CAM methods, the rate is
probably much higher in Asian populations, as documented in 61% and 76% of
Singaporean and Korean PD patients, respectively (Kim et al. 2009; Tan et al. 2006).
CAM seems to be common practice among Asian population who believe that
Western medicine is toxic and CAM can help balance “Gi” for the promotion of
health. Evidence for CAM users in SEA is strong. In recent surveys, 6.4% of
Singaporeans and 32.9% of Indonesians reported using at least one CAM method
for their chronic conditions, ranging from mental illness, sleep disturbance, and
depression (Seet et al. 2020, Pengpid and Peltzer 2018b). In PD, patients with severe
motor dysfunction at onset are more likely to use CAM and it is often difficult to
determine a definite conclusion on the efficacy as most studies are limited by study
designs, inappropriate controlled settings, and inaccessible methods (Tan et al.
2006). However, an evidence-based review of CAM in PD ranging from natural
products (herbals, vitamins, minerals, and probiotics), mind and body practices
(acupuncture, massage, meditation, movement therapies, relaxation techniques, tai
chi, and yoga), and alternative systems (Korean and Chinese medicine, Ayurvedic,
and homeopathy) has shown some promising results that mind–body interventions
are effective forms of physical activity that are likely to foster good adherence and
may reduce disability related to PD (Bega and Zadikoff 2014). Another more recent
review also demonstrated beneficial effects of massage therapy on both motor and
NMS of PD along with safe techniques (Angelopoulou et al. 2020). Among the
studies included in this systematic review is a study from Thailand on the efficacy of
therapeutic Thai massage in improving upper limb motor strength in PD patients
(Miyahara et al. 2018).

Clinical Vignette (Part 3) The patient’s condition progressed to the point that
ambulation was only possible with a wheelchair. This protracted mobility further
limiting visits to her neurologist. At this stage, her husband acted as a 24-h full-time
carer so that medications were given to the patient at the right time and right dosage,
lessening the severity of dyskinesia and “off” episodes. However, he lost his job as a
mechanic, causing financial constraints and stress to himself and the family. Due to
her present condition and COVID-19 pandemic, the patient was evaluated by her
neurologist via teleclinic, providing convenient, specialist care, and a reduced risk
of contagion to the patient.

Telehealth as a Solution for Specialist Parkinson’s Care in

Southeast Asia

In the past, specialist consultations were only achievable by face-to-face visits. This
was particularly troublesome for PD patients who have impaired mobility and live
far from those practices, resulting in inconvenience, discomfort, and inadequate care
to patients. In SEA, most neurologists tend to congregate in large cities, providing
significant disadvantages to nonurban patients who lack access to specialist care
1076 R. Bhidayasiri et al.

either due to distance, disability, or absence of specialists locally (Tan 2015).

According to the NICE guideline, patients who are suspected of PD should be
referred to specialists for evaluation and regular assessments should be made at a
6- to 12-month interval National Institute for Health and Care Excellence (NICE)
(2017). With advances in telehealth technologies, it is currently possible to apply the
NICE recommendations to those patients who do not live in a close proximity of
specialist facilities, providing a practical solution for regular specialist assessments
of those with a later stage of the disease, limited resources for traveling, and living in
nursing homes. Telehealth can also open up new opportunities for many PD patients
in SEA to have remote specialist assessments for the first time as a majority of
patients have been identified as never having received a neurologist evaluation.
Benefits may also be extended to undiagnosed persons with PD in SEA and help
to address the growing need for assessment in this region with fast increasing rates of
PD (Dorsey et al. 2007). In addition to increased convenience, telehealth allows
patients to be evaluated from the comfort of their own homes, enabling neurologists
to virtually enter the home environment and to examine PD patients in their natural
settings, providing better insights into how individuals function in their daily lives as
well as social circumstances and patient-centered experiences (Bhidayasiri et al.
2020a; Maetzler et al. 2020). Despite various challenges, implementation of tele-
rehabilitation has also been demonstrated in the Philippines giving a model for
developing countries in its service, training, and research (Leochico et al. 2020).
As shown in this clinical vignette, advanced PD patients can particularly benefit
from telehealth during this COVID-19 pandemic as their risk for acquiring infection
is substantially reduced when they are neurologically assessed in their own safe
environments (Dorsey et al. 2020b). Indeed, as we all adjust to the new normal, we
should focus future care not on clinics, but on patients. Their needs, guided by
physicians, should determine how care is delivered, whether face-to-face in the
clinic, or remotely at home, or as a combination (Dorsey et al. 2020a). Importantly,
considerations need to take into account what can be implemented locally with
available resources.

Conclusion

Parkinson’s disease, whether in the form of number of patients or burden of disease,

is on the rise in SEA, posing significant challenges to healthcare sectors, personnel,
patients themselves, and families who are involved either directly or indirectly in the
care of PD. While PD as a disease is similar in anywhere in the world, difference can
be observed in the heterogeneity of clinical manifestations, etiological factors, and
its impact that the disease has on the patients, families, and the societies. The authors
believe that we are not ready, even at a global level, to tackle this disease effectively
as the number of patients is still on the rise without effective therapies to slow, halt,
or reverse disease progression, so it seems that PD will continue to be part of our
communities for the foreseeable future. Therefore, each of us as a healthcare
professional who is not only part of different local, national, regional societies, but
Challenges of Parkinson’s Disease Care in Southeast Asia 1077

also one global society, should be aware of the impact PD has on all levels of society.
This chapter examines various challenges, outlining the problems, statistics, litera-
ture, and even solutions for some that are prevalent in SEA in relation to the rest of
the World. Although challenges have been evident in SEA, we must also recognize
that healthcare professionals in our region do their utmost to overcome these
significant challenges in order to deliver to their patients their best diagnostic
abilities, treatment decisions, and multidisciplinary, interdisciplinary, or transdisci-
plinary management wherever possible. These efforts should not be forgotten, and
the authors believe that our community has made significant and positive changes to
the care of PD in SEA, but should still continue working together to bridge the gaps
to improve care for our patients.

Cross-References

▶ Health Economics for Neuropsychological Diseases in China

▶ Parkinsonian Drugs in China

Acknowledgments Roongroj Bhidayasiri is supported by Senior Research Scholar Grant

(RTA6280016) of the Thailand Science Research and Innovation (TSRI), International Research
Network Grant of the Thailand Research Fund (IRN59W0005), Chulalongkorn Academic
Advancement Fund into Its 2nd Century Project of Chulalongkorn University, and Centre of
Excellence grant of Chulalongkorn University (GCE 6100930004-1), Bangkok, Thailand.

Financial Disclosure Roongroj Bhidayasiri: receives salary from Chulalongkorn University and
stipend from the Royal Society of Thailand, has received consultancy and/or honoraria/lecture
fees from Abbott, Boehringer-Ingelheim, Britannia, Ipsen, Novartis, Teva-Lundbeck, Takeda,
and Otsuka pharmaceuticals; he has received research funding from the Newton Fund, the UK
Government, Thailand Science and Research Innovation Bureau, Thailand Research Fund,
Crown Property Bureau, Chulalongkorn University, and the National Science and Technology
Development Agency; he holds patents for laser-guided walking stick, portable tremor device,
nocturnal monitoring, and electronic Parkinson’s disease symptom diary as well as copyright on
Parkinson’s mascot, dopamine lyrics and teaching video clips for common nocturnal and gastroin-
testinal symptoms for Parkinson’s disease.
Other authors report no financial disclosure.

References
2021a. Global Health Observatory Data Repository (South-East Asia Region) [Online]. World Health
Organization. Available: https://apps.who.int/gho/data/view.main-searo.SDG2016LEXREGv?
lang¼en. Accessed 22 Jan 2021.
2021b. South Eastern Asian Population [Online]. Available: https://www.worldometers.info/world-
population/south-eastern-asia-population/#:~:text¼The%20current%20population%20of%
20South,of%20the%20total%20world%20population. Accessed.
Abbas MM, et al. Epidemiology of Parkinson’s disease-east versus west. Mov Disord Clin Pract.
2018;5:14–28.
Angelopoulou E, et al. Massage therapy as a complementary treatment for Parkinson’s disease: a
systematic literature review. Complement Ther Med. 2020;49:102340.
1078 R. Bhidayasiri et al.

Bega D, Zadikoff C. Complementary & alternative management of Parkinson’s disease: an evi-

dence-based review of eastern influenced practices. J Mov Disord. 2014;7:57–66.
Bega D, et al. Is there a role for DAT-SPECT imaging in a specialty movement disorders practice?
Neurodegener Dis. 2015;15:81–6.
Bergen DC, World Federation of Neurology Task Force on Neurological Services. Training and
distribution of neurologists worldwide. J Neurol Sci. 2002;198:3–7.
Bhidayasiri R, et al. A census of movement disorders at a Thai university hospital. J Neurol Sci.
2011a;301:31–4.
Bhidayasiri R, et al. A national registry to determine the distribution and prevalence of Parkinson’s
disease in Thailand: implications of urbanization and pesticides as risk factors for Parkinson’s
disease. Neuroepidemiology. 2011b;37:222–30.
Bhidayasiri R, et al. Boxing and Parkinson disease: a link or a myth? An 18F-FDOPA PET/CT
study in retired Thai traditional boxers. Parkinsonism Relat Disord. 2012;18:694–6.
Bhidayasiri R, et al. Identifying gaps in knowledge about Parkinson disease among medical
professionals in Thailand. Neurology. 2014;82:2238–40.
Bhidayasiri R, et al. Asian perspectives on the recognition and management of levodopa ‘wearing-
off’ in Parkinson’s disease. Expert Rev Neurother. 2015;15:1285–97.
Bhidayasiri R, et al. Understanding the role of the Parkinson’s disease nurse specialist in the
delivery of apomorphine therpy. Parkinsonism Relat Disord. 2016;33(Suppl 1):S49–55.
Bhidayasiri R, et al. Red flags phenotyping: a systematic review on clinical features in atypical
parkinsonian disorders. Parkinsonism Relat Disord. 2019a;59:82–92.
Bhidayasiri R, et al. Thai National Formulary 2019: drugs used in Parkinson’s disease. Bangkok:
Food and Drug Administration of Thailand; 2019b.
Bhidayasiri R, et al. Delivering patient-centered care in Parkinson’s disease: challenges and
consensus from an international panel. Parkinsonism Relat Disord. 2020a;72:82–7.
Bhidayasiri R, et al. Establishing apomorphine treatment in Thailand: understanding the challenges
and opportunities of Parkinson’s disease management in developing countries. Expert Rev
Neurother. 2020b;20:523–37.
Bloem BR, et al. Integrated and patient-centred management of Parkinson’s disease: a network
model for reshaping chronic neurological care. Lancet Neurol. 2020;19:623–34.
Breen DP, et al. Determinants of delayed diagnosis in Parkinson’s disease. J Neurol. 2013;260:
1978–81.
Burton A. How do we fix the shortage of neurologists? Lancet Neurol. 2018;17:502–3.
Busis NA, et al. Burnout, career satisfaction, and well-being among US neurologists in 2016.
Neurology. 2017;88:797–808.
Choo XY, et al. Understanding patients’ and caregivers’ perspectives and educational needs in
Parkinson’s disease: a multi-ethnic Asian study. Neurol Sci. 2020;41:2831.
Dahodwala N, et al. Burden of Parkinson’s disease by severity: health care costs in the U.S.
Medicare population. Mov Disord. 2021;36:133–42.
De Bie RMA, et al. Initiation of pharmacological therapy in Parkinson’s disease: when, why, and
how. Lancet Neurol. 2020;19:452–61.
Diestro JDB, et al. Deep brain stimulation for Parkinson disease in the Philippines: outcomes of the
Philippine Movement Disorder Surgery Center. World Neurosurg. 2018;115:e650–8.
Dorsey ER, et al. Projected number of people with Parkinson disease in the most populous nations,
2005 through 2030. Neurology. 2007;68:384–6.
Dorsey ER, et al. A new day: the role of telemedicine in reshaping care for persons with movement
disorders. Mov Disord. 2020a;35:1897–902.
Dorsey ER, et al. Care, convenience, comfort, confidentiality, and contagion: the 5 C’s that will
shape the future of telemedicine. J Parkinsons Dis. 2020b;10:893–7.
Fox SH, et al. International Parkinson and movement disorder society evidence-based medicine
review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord.
2018;33:1248–66.
Challenges of Parkinson’s Disease Care in Southeast Asia 1079

Gavidia M. Poll finds 1 in 4 people with Parkinson disease misdiagnosed [Online]. Am J Managed
Care. 2020. Available: https://www.ajmc.com/view/poll-finds-1-in-4-people-with-parkinson-
disease-misdiagnosed. Accessed 28 Jan 2021.
GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of
neurological disorders during 1990–2015: a systematic analysis for the Global Burden of
Disease Study 2015. Lancet Neurol. 2017;16:877–97.
GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disor-
ders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet
Neurol. 2019;18:459–80.
GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s
disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet
Neurol. 2018;17:939–53.
GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204
countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease
Study 2019. Lancet. 2020;396:1204–22.
Hessel F. Burden of disease. In: Kirch W, editor. Encyclopedia of public health. Dordrecht:
Springer; 2008.
Hughes AJ, et al. A clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol.
1993;50:140–8.
Hughes AJ, et al. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement
disorder service. Brain. 2002;125:861–70.
Jagota P, et al. If your patients were too embarrassed to go out in public, what would you do? –
public education to break the stigma on Parkinson’s disease using integrated media. Patient
Relat Outcome Meas. 2020;11:143–8.
Jamora RDG, Miyasaki JM. Treatment gaps in Parkinson’s disease care in the Philippines.
Neurodegener Dis Manag. 2017;7:245–51.
Jitkritsadakul O, et al. Knowledge, attitudes and perceptions of Parkinson’s disease: a cross-
sectional survey of Asian patients. J Neurol Sci. 2017;374:69–74.
Kim JY, Jeon BS. Complementary and alternative medicine in Parkinson’s disease patients in
Korea. Curr Neurol Neurosci Rep. 2012;12:631–2.
Kim SR, et al. Use of complementary and alternative medicine by Korean patients with Parkinson’s
disease. Clin Neurol Neurosurg. 2009;111:156–60.
Kowal SL, et al. The current and projected economic burden of Parkinson’s disease in the United
States. Mov Disord. 2013;28:311–8.
Kwok JYY, et al. Symptom burden and unmet support needs of patients with Parkinson’s disease: a
cross-sectional study in Asia-Pacific regions. J Am Med Dir Assoc. 2020;S1525–8610(20)
30795-7. https://doi.org/10.1016/j.jamda.2020.09.012. Online ahead of print.
Leochico CFD, et al. Challenges to the emergence of telerehabilitation in a developing country: a
systematic review. Front Neurol. 2020;11:1007.
Lim SY, et al. Parkinson’s disease in the Western Pacific region. Lancet Neurol. 2019;18:865–79.
Litvan I, et al. Movement disorders society scientific issues committee report: SIC
task force appraisal of clinical diagnostic criteria for parkinsonian disorders. Mov Disord.
2003;18:467–86.
Maetzler W, et al. Modernizing daily function assessment in Parkinson’s disease using capacity,
perception, and performance measures. Mov Disord. 2020;36(1):76–82. https://doi.org/10.
1002/mds.28377. Epub 2020 Nov 15.
Mirpour S, et al. Impact of DAT-SPECT on management of patients suspected of parkinsonism.
Clin Nucl Med. 2018;43:710–4.
Miyahara Y, et al. Can therapeutic Thai massage improve upper limb muscle strength in Parkinson’s
disease? An objective randomized-controlled trial. J Tradit Complement Med. 2018;8:261–6.
Mohammadi D. Neurology in resource-poor countries: fighting for funding. Lancet Neurol.
2011;10:953–4.
1080 R. Bhidayasiri et al.

Muangpaisan W, et al. Systematic review of the prevalence and incidence of Parkinson’s disease in
Asia. J Epidemiol. 2009;19:281–93.
Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med. 2013;369:448–57.
National Institute for Health and Care Excellence (NICE). Parkinson’s disease in adults. 2017.
https://www.nice.org.uk/guidance/ng71.
Newman EJ, et al. Accuracy of Parkinson’s disease diagnosis in 610 general practice patients in the
West of Scotland. Mov Disord. 2009;24:2379–85.
Pengpid S, Peltzer K. Multimorbidity in chronic conditions: public primary care patients in four
greater Mekong countries. Int J Environ Res Public Health. 2017;14:1019.
Pengpid S, Peltzer K. The impact of chronic diseases on the quality of life of primary care patients in
Cambodia, Myanmar and Vietnam. Iran J Public Health. 2018a;47:1308–16.
Pengpid S, Peltzer K. Utilization of traditional and complementary medicine in Indonesia: results of
a national survey in 2014–15. Complement Ther Clin Pract. 2018b;33:156–63.
Phokaewvarangkul O, et al. Addressing knowledge gaps in Parkinson’s disease: a report on
the Movement Disorder Society’s Centre-to-Centre initiative to improve Parkinson’s disease
services in Lao People’s Democratic Republic. BMC Med Educ. 2020;20:239.
Postuma RB, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord.
2015;30:1591–601.
Poungvarin N. Resources and organization of neurology care in South East Asia. Neurol Asia.
2007;12:41–6.
Prado M Jr, Jamora RD. Cost of Parkinson’s disease among Filipino patients seen at a public tertiary
hospital in Metro Manila. J Clin Neurosci. 2020;74:41–6.
Pringsheim T, et al. The prevalence of Parkinson’s disease: a systematic review and meta-analysis.
Mov Disord. 2014;29:1583–90.
Rana AQ, et al. Challenges in diagnosis of young onset Parkinson’s disease. J Neurol Sci. 2012;323:
113–6.
Razali R, et al. Burden of care among caregivers of patients with Parkinson disease: a cross-
sectional study. Clin Neurol Neurosurg. 2011;113:639–43.
Rizzo G, et al. Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-
analysis. Neurology. 2016;86:566–76.
Sakdisornchai K, et al. Availability of anti-parkinsonian drugs in Thailand. Mov Disord. 2017;32:
S512–4.
Schrag A, et al. How valid is the clinical diagnosis of Parkinson’s disease in the community? J
Neurol Neurosurg Psychiatry. 2002;73:529–34.
Seet V, et al. The use of complementary and alternative medicine in a multi-ethnic Asian population:
results from the 2016 Singapore Mental Health Study. BMC Complement Med Ther.
2020;20:52.
Singhal BS, Khadilkar SV. Neurology in the developing world. Handb Clin Neurol. 2014;121:
1773–82.
Skinner TR, et al. Diagnostic errors in older patients: a systematic review of incidence and potential
causes in seven prevalent diseases. Int J Gen Med. 2016;9:137–46.
Tan CT. Neurology in Asia. Neurology. 2015;84:623–5.
Tan LC, et al. Prevalence of Parkinson disease in Singapore: Chinese vs Malays vs Indians.
Neurology. 2004;62:1999–2004.
Tan EK, et al. Prescribing pattern in Parkinson’s disease: are cost and efficacy overriding factors?
Int J Clin Pract. 2005;59:511–4.
Tan LC, et al. Use of complementary therapies in patients with Parkinson’s disease in Singapore.
Mov Disord. 2006;21:86–9.
Tan AH, et al. Knowledge of Parkinson’s disease in a multiethnic urban Asian setting. J Parkinsons
Dis. 2015;5:865–79.
Tan SB, et al. Parkinson’s disease caregiver strain in Singapore. Front Neurol. 2020;11:455.
Viwattanakulvanid P, et al. The impact of the nocturnal disabilities of Parkinson’s disease on
caregivers’ burden: implications for interventions. J Neural Transm. 2014;121(Suppl 1):15–24.
Challenges of Parkinson’s Disease Care in Southeast Asia 1081

Willis AW, et al. Neurologist care in Parkinson disease: a utilization, outcomes, and survival study.
Neurology. 2011;77:851–7.
Yang W, et al. Current and projected future economic burden of Parkinson’s disease in the U.S. NPJ
Parkinsons Dis. 2020;6:15.
Zhao YJ, et al. Economic burden of Parkinson’s disease in Singapore. Eur J Neurol. 2011;18:519–26.
Zhou X, et al. Burnout, psychological morbidity, job stress, and job satisfaction in Chinese
neurologists. Neurology. 2017;88:1727–35.
Neuropsychopharmacotherapy:
Complementary Treatments

Hans Moises

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
Psychotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
Behavioral Activation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
Cognitive Behavioral Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
Problem-Solving Therapies (PST) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
First-Wave Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
Second-Wave Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
Third-Wave Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
Interpersonal Psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088
Psychodynamic Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088
Non-directive Supportive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088
Life Review Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
Exposure Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
Eye Movement Desensitization and Reprocessing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
The Dodo Bird Verdict . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
Common Factors Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091
Problems with Meta-Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094

Abstract
Psychotherapies are popular complementary treatments. These treatments include
behavioral activation therapy (BA), cognitive behavior therapy (CBT), problem-
solving therapies (PST), and self-examination therapy (SET); “third-wave” therapies

Hans Moises has retired.

H. Moises (*)
Department of Psychiatry and Psychotherapy, Kiel University Hospital, Kiel, Germany
e-mail: moises@icloud.com; hans.moises@alumni.uni-kiel.de

© Springer Nature Switzerland AG 2022 1083

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_23
1084 H. Moises

such as acceptance and commitment therapy (ACT), mindfulness-based CBT

(MBCT), cognitive behavioral analysis system of psychotherapy (CBASP), and
dialectic therapy (DBT); as well as interpersonal psychotherapy (IPT), psychody-
namic therapy, non-directive supportive therapy, life review therapy, exposure ther-
apy, and eye movement desensitization and reprocessing (EMDR). This chapter
presents the results of recent meta-analyses investigating the evidence for the efficacy
of 15 psychotherapies for depression. Progress in the field is hampered by method-
ological problems including the abundance of studies with small sample sizes and
insufficient power to detect differences between treatments. Several sources of bias
have been reported, including strong researcher allegiance to the therapy,
non-blinding of raters, improper randomization, selective outcome reporting, publi-
cation bias, waiting list control groups, problems with meta-analysis, and the placebo
effect. The “Dodo bird verdict” contends that meta-analyses have been unable, so far,
to find any significant difference between psychotherapeutic techniques, suggesting
that they are all equally effective. The common factors theory proposes that treatment
differences, the therapist’s competence, specific ingredients, and protocol adherence
are not responsible for the outcome of psychotherapies. But factors common to all
psychotherapies: foremost are the personality traits of the psychiatrist or psychother-
apist such as genuineness and empathy. Further commonalities include goal consen-
sus, collaboration, alliance, positive regard, and affirmation.

Introduction

Complementary treatments frequently employed alongside psychopharma-

cotherapy include psychotherapy, homeopathy, and acupuncture. Since the latter
two appear to be placebos (Derry et al. 2006; Grams 2019), this chapter will focus
on the effectiveness of psychotherapies. Before the advent of evidence-based
treatments, psychotherapy was performed by witchdoctors, shamans, and priests
(Torrey 1986). The main difference between these methods and current psycho-
therapies is in the scientific approach. Psychotherapies now have to prove in
randomized controlled trials (RCTs) that the treatment makes a significant differ-
ence compared to no treatment, such as being on a waiting list, or to treatment as
usual. Nevertheless, there are several sources of bias for RCTs (see “How to prove
that your therapy is effective, even when it is not,” (Cuijpers and Cristea 2016)).
The most interesting outcome measure of randomized controlled trials is not
simply the statistical significance but the magnitude of the effect of the treatment,
expressed as effect size (Cohen’s d or Hedges’s g). The effect size is determined by
taking the difference between the mean of the experimental group and the mean of
the control group divided by their standard deviation. Figure 1 shows the effect
sizes (Hedges’s g) of major psychotherapeutic methods for adult depression
obtained from meta-analyses of RCTs with low risk of bias and corrected for
publication bias (Cuijpers et al. 2019). The psychotherapies practiced today are
varied in the degree of scientific support for their efficacy, as assessed in recent
meta-analyses (Cuijpers et al. 2019).
Neuropsychopharmacotherapy: Complementary Treatments 1085

E ects of Psychotherapies from Studies with Low Risk of Bias

0.7
0.62
E ect Size (Hedges’ g

0.54
0.5
adjusted)

0.41
0.36 0.35
0.4 0.28
0.23 0.23 0.23 0.21 Clinically Irrelevant
0.2
Behavioral Activation Therapy

3rd Wave Therapies

CBT Coping with Depression

CBT by Beck

All Studies (low risk of bias)

CBT Generic

Self Examination Therapy

Psychodynamic - Generic

Problem-Solving Therapy
Fig. 1 Effects of psychotherapies compared to control groups in RCTs with low risk of bias. Data
from “Table V. The effects of fifteen evidence-supported therapies for adult depression: A meta-
analytic review.” (Cuijpers et al. 2019). The result for third-wave therapies is only based on RCTs of
ACT and MBCT. Insufficient numbers of studies were available for other types of third-wave therapies

Psychotherapies

Behavioral Activation Therapy

Behavioral activation therapy (BA) was developed by Peter Lewinsohn in 1974

based on B.F. Skinner’s operant conditioning model by reinforcement (Lewinsohn
1974; Dimidjian et al. 2006; Cuijpers et al. 2019). In contrast to CBT, the focus of
BA is not on the modification of thoughts but on changing the patient’s behavior by
increasing their pleasant activities in a stepwise manner so that they can experience
more positive social interactions (Dimidjian et al. 2006; Kanter et al. 2009). BA
appears to be one of the most effective psychotherapies for depression (see Fig. 1).
Importantly, CBT also includes a BA component developed by Jacobson and
Martell, which consists of activity scheduling, self-monitoring, graded task assign-
ment, role-playing, functional analysis, mental rehearsal, and mindfulness (Jacobson
et al. 2001; Martell et al. 2001; Cuijpers et al. 2019).

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) is based on the insight of ancient Stoic philos-
ophers that an individual’s emotions are strongly influenced by their thoughts
1086 H. Moises

(Evans, 2013). The focus of the cognitive behavioral therapist is on the pessimistic
and negative thoughts of the depressive patient, the so-called thinking errors. The
aim is to modify the cognitive distortions of the patient by challenging them to
question and investigate their reality (Cuijpers et al. 2019). The results of a recent
meta-analysis are shown in Fig. 1.

Problem-Solving Therapies (PST)

Extended Problem-Solving Therapy

Based on the observation that depressive patients are rather inefficient problem-
solvers, D’Zurilla and Nezu developed the most important form of extended
problem-solving therapy, social problem-solving therapy (Nezu 1986; D’Zurilla
et al. 2004).

Brief Problem-Solving Therapy

Brief problem-solving therapy has the advantage that trained members of the nursing
staff can apply it. It consists of nine sessions and focuses on key elements of
problem-solving strategies (Mynors-Wallis et al. 2000). The 2019 meta-analysis
by Cuijpers et al. shows a low ES for problem-solving therapies making them
clinically irrelevant (see Fig. 1).

Self-Examination Therapy
In self-examination therapy (SET), patients determine their major goals in life and
subsequently focus on employing problem-solving methods to achieve their prior-
ities. Patients learn to accept problems, which cannot be solved (Bowman et al.
1996; Cuijpers et al. 2019). The 2019 meta-analysis by Cuijpers et al. reveals a low
ES of 0.28 of self-examination therapy in depression (see Fig. 1).

First-Wave Therapies

The first generation of behavioral therapy was a reaction to the prevailing psycho-
analysis by Sigmund Freud, which was thought to have weak scientific support
(Hayes 2004). By contrast, behavioral therapy was based on the experimentally well-
established principles of learning theory. In the first wave of behavioral
therapy, anxiety was mainly treated by exposure to the feared stimuli. Cognition
was not taken into account. The primary purpose was to eliminate specific behaviors
(Wolpe 1958; Wolpe and Rachmann 1960; Hayes 2004, 2017).

Second-Wave Therapies

In the second wave, Aaron Beck developed CBT by targeting the content of thoughts
(Beck 1979; Hunot et al. 2013; Hayes 2017; Cuijpers and Cristea 2016).
Neuropsychopharmacotherapy: Complementary Treatments 1087

Third-Wave Therapies

The third-wave behavior therapies comprise a group of psychotherapies (acceptance

and commitment therapy, ACT; mindfulness-based CBT, MBCT; cognitive behav-
ioral analysis system of psychotherapy, CBASP; and dialectical behavior therapy,
DBT) that does not focus on the content of thoughts as in the second-wave CBT.
Instead, they focus on the process of thoughts and on motivating patients to accept
them (Hunot et al. 2013) by teaching skills such as mindfulness, emotion
regulation, acceptance, deepening of relationships, values, goals, and commitment
(Hayes 2004, 2017).

Acceptance and Commitment Therapy

ACT is based on a form of exposure therapy for anxieties and involves decreasing
experiential avoidance and focusing on the patient’s values and life goals (Hayes and
Wilson 1994; Hayes et al. 1999; Hayes 2004, 2016; Cuijpers et al. 2019). ACT
therapists ask their patients “What do you want your life to stand for?” and elaborate,
together with their patients, strategies for moving toward their patients’ goals (Hayes
2004). A 2014 meta-analysis revealed that despite its widespread acceptance, the
evidence for the efficiency of ACT is at best weak when compared to established
treatments (Coyne and Kok 2014). An evidence-based evaluation by Öst found that
ACT is not yet well-established for any disorder (Öst 2014). In contradiction to these
reports is a recent meta-analysis by Cuijpers et al. (2019), which revealed that ACT
is an effective psychotherapy for depression (shown in Fig. 1 as third-wave
therapies).

Mindfulness-Based CBT
MBCT combines meditation or mindfulness exercises with CBT. It was developed for
the prevention of relapse in people with recurrent depression by Mark Williams
(Oxford) together with John Teasdale (Cambridge) and Zindel Segal (Toronto)
based on the work by Jon Kabat-Zinn (Worcester, USA) on mindfulness-based stress
reduction (Segal et al. 2002, 2012). Even after remission, depressed patients tend to
react to negative mood by ruminating about their life situation. In MBCT, patients
learn to change their reaction to unwanted thoughts and feelings by no longer trying to
avoid them but to responding in a more detached way. MBCT is an 8-week group
program. A considerable number of studies have now examined the effects in patients
with acute depression and reported a significant effect (Cuijpers et al. 2019) (in Fig. 1
as third-wave therapies).

Cognitive Behavioral Analysis System of Psychotherapy

CBASP was developed by James P. McCullough Jr. in Richmond (USA) specifically
for the treatment of persistent forms of chronic depression. The disorder is thought to
be caused by psychological insults such as chronic interpersonal punishment, abuse,
or emotional neglect. The result is a generalized fear of others and interpersonal
avoidance behavior. This avoidance pattern prevents positive interpersonal experi-
ences and hence the improvement of their anxiety and depression. In modified
1088 H. Moises

exposure therapy, patients learn a new skill to confront the feared stimuli to achieve
their interpersonal goals (McCullough et al. 2014, 2015). Meta-analyses by Negt
et al. (2016) reported a moderate to high ES for CBASP when compared to treatment
as usual and interpersonal psychotherapy (ES ¼ 0.64–0.75, p < 0.05).

Dialectical Behavior Therapy

DBT was developed by Marsha Linehan for the treatment of highly suicidal patients
suffering from borderline personality disorder and combines CBT with meditation
(Linehan et al. 1991). Mindfulness is at the core of DBT and the foundation for the
acceptance of stress and powerful emotions. Patients are taught skills for emotion
regulation and distress tolerance (Linehan 2018). A recent meta-analysis showed a
small effect size of g ¼ 0.34 compared to controls and evidence for bias as well as for
publication bias (Cristea et al. 2017).

Interpersonal Psychotherapy

Interpersonal psychotherapy (IPT) was developed by Gerald Klerman and Myrna

Weissman in the 1980s (Weissman and Klerman 1985). It is a brief form of
psychotherapy using a highly structured manual to address the fact that depressions
mostly arise from four interpersonal difficulties: grief, interpersonal disputes, role
transitions, and interpersonal deficits. The therapist focuses on the patient’s primary
problems (Klerman and Weissman 1994; Cuijpers et al. 2019). A 2011 meta-analysis
found that IPT is an effective treatment for unipolar depression, although antide-
pressants show a greater efficacy compared to IPT. However, IPT adds to the effect
of pharmacotherapy (Cuijpers et al. 2011).

Psychodynamic Therapies

Psychodynamic therapies return to principles of Sigmund Freud’s psychoanalysis and

are based on the assumption that that the patient’s psychological problems are caused
by their childhood experiences and unresolved intrapsychic conflicts. To elucidate
these conflicts, the therapist explores the patient’s dreams, emotions, fantasies, and
wishes. In comparison to psychoanalytic psychotherapy, short-term psychodynamic
therapy is more focused and has time limitations (Cuijpers et al. 2019).
In a recent meta-analysis, the effect size for psychodynamic treatments of depres-
sion was not significant after adjusting for risk of bias and showed clinically
irrelevant ES of 0.23 (Cuijpers et al. 2019). See Fig. 1.

Non-directive Supportive Therapy

Non-directive supportive therapy (NDST) or counselling is a non-directive therapy

and uses no psychological technique. It is mainly based on the observation that
Neuropsychopharmacotherapy: Complementary Treatments 1089

talking to an empathetic listener about one’s experiences, emotions, and problems

frequently results in emotional relief. The aim of non-directive therapies is not to
provide solutions or acquire new skills (Cuijpers et al. 2019). In the treatment
of depression, NDST has a moderate ES of 0.58 and is as effective as other
psychotherapies provided that the data are adjusted for researcher allegiance
(Cuijpers et al. 2012).

Life Review Therapy

Life review therapy (LRT) employs reminiscence of the patient’s life to treat
depression in older adults. Patients are encouraged to systematically re-evaluate all
phases of their life and to try to resolve conflicts and to assess adaptive coping
responses (Lewis and Butler 1974; Cuijpers et al. 2019). A meta-analysis by
Bohlmeijer et al. (2003) obtained an ES of 0.84 for the treatment of depression in
the elderly following life review therapy. The ES was stronger in more severely
depressed patients (ES ¼ 1.23).

Exposure Therapy

Exposure treatment for phobia and other anxiety disorders was developed by Joseph
Wolpe (Wolpe 1958). Its foundation is the learning theory of Pavlov, Hull, and others
(Pavlov 1963; Hull 1943). Neuroses (as anxiety disorders were called at this time)
were thought to consist of learned behavior which can be unlearned by being
exposed to the feared stimuli (Wolpe 1954, 1958).
Exposure has become an essential part of many psychotherapies including CBT
(Sisemore 2012), DBT (Linehan 2018), ACT (Hayes 2004), prolonged exposure
therapy (PE) (Foa et al. 2007), and narrative exposure therapy (NE) for posttraumatic
stress disorder (PTSD), emotional exposure, or processing (Sisemore 2012).
In a meta-analysis, exposure therapy was directly compared to non-exposure
treatments. Exposure treatment led to significantly greater improvement at both
post-treatment (ES ¼ 0.44, p < 0.001) and follow-up (ES ¼ 0.35, p < 0.001),
contradicting the contention of the Dodo bird verdict that all psychotherapies are
equally effective (Wolitzky-Taylor et al. 2008).

Eye Movement Desensitization and Reprocessing

Eye movement desensitization and reprocessing (EMDR) was developed by

Francine Shapiro as psychotherapy for PTSD (Shapiro 1989, 1995). In EMDR, the
patient is asked to concentrate on an image of the traumatic event while simulta-
neously focusing the eyes on one finger of the therapist moving from side to side.
EMDR has been criticized as being a form of pseudoscience (Herbert et al. 2000).
Instead of building on the existing scientific concepts of habituation or extinction,
1090 H. Moises

Shapiro claims to have created an entirely novel paradigm, the “accelerated infor-
mation processing model,” to explain the effect of EMDR.
Scientific-sounding terms are employed; for example:

[The] valences of the neural receptors (synaptic potential) of the respective neuro networks,
which separately store various information plateaus and levels of adaptive information, are
represented by the letters Z through A. It is hypothesized that the high-valence target
network (Z) cannot link up with the more adaptive information, which is stored in networks
with a lower valence. That is, the synaptic potential is different for each level of effect held in
the various neuro networks. . .. (Shapiro 1995 as cited in Herbert et al. 2000)

Meta-analyses show that EMDR is an effective treatment for PTSD compared to

no treatment. However, it is not more effective than other exposure therapies, and the
eye movement component appears to be unnecessary (Herbert et al. 2000; Davidson
and Parker 2001; Bisson et al. 2013).

The Dodo Bird Verdict

The Dodo bird is a fictional character in Lewis Carroll’s novel Alice’s Adventures in
Wonderland. The Dodo proposes a race where no measurement is taken of how far or
for how long the competitors run, and at the end, he judges that “everyone has won
and all must have prizes.” This quote has come to represent one of the best-replicated
results of psychotherapy research: all psychotherapies are equally effective
(Luborsky et al. 1975). Despite numerous replications, this conclusion is controver-
sial among psychotherapists, and the possible causes of the Dodo bird verdict are
hotly debated (Budd and Hughes, 2009). Discussions of the controversy can be
found in “The dodo bird is extinct” (Beutler 2002) and “The Dodo Bird Verdict is
alive and well—mostly” (Luborsky et al. 2002). One of the possible explanations for
the Dodo bird verdict is that common factors across different psychotherapies may
be responsible for the equivalent efficacy of therapies (Luborsky 1995).

Common Factors Theory

The common factors theory is based on meta-analyses that have been unable to find a
significant difference in effectiveness between different psychotherapeutic methods
(Luborsky 1995; Cuijpers 2019). Figure 2 shows the effect sizes of meta-analyses of
psychotherapies investigating common and specific factors. Interestingly, neither
specific ingredients, protocol adherence, the competence of the therapist, nor treat-
ment differences have a clinically relevant influence of the effect of psychotherapies.
In contrast, the characteristics of the therapist – their genuineness, their positive
regard for and affirmation of the patient, and their empathy – and factors such as the
strength of the alliance between patient and therapist as well as the consensus of the
Neuropsychopharmacotherapy: Complementary Treatments 1091

Therapeutic Factors in Psychotherapy

0.80
0.8
0.70
0.63
0.6 0.57 0.56
0.55
E ect Size (d)

0.49

0.4
0.35
0.32

0.24
0.20 Clinially irrelevant
0.2
0.14

0.04
0.01
Therapist in RCTs

Treatment Di erences
Psychotherapy

Empathy

Alliance

Possitive Regard / A rmation

Therapist’s Competence
Goal Consensus / Collaboration

Genuineness
Therapists in Naturalistic Setting

Cultural Adaptation

Expectations

Protocol Adherence

Fig. 2 Effect sizes of common factors in different psychotherapies obtained from meta-analyses.
Data from Table 9.1 of “The Great Psychotherapy Debate – Evidence for What Makes Psychother-
apy Work” (Wampold and Imel 2015)

therapeutic goal and the collaboration to achieve that goal appear to be of major
importance for the outcome of the psychotherapy.
Even in antidepressant studies, there was significant variability in treatment
outcome between psychiatrists. In one study, psychiatrists accounted for 9.1% of
variability on the Beck Depression Inventory as compared to 3.4% accounted for by
the treatment. The best psychiatrists had better outcomes giving a placebo than the
worst psychiatrists had when giving the antidepressant (Wampold and Imel 2015).
Some psychiatrists and therapists consistently achieve better results than others.
For example, in one study the best therapists had a response rate of 80% compared to
a response rate of 20% for the lowest-performing therapists.

Discussion

Psychotherapy studies are criticized for being – on average – of low quality (Eysenck
1984; Coyne and Kok 2014; Cuijpers et al. 2019a) although there is some evidence
of improvement (Chen et al. 2014). For example, 65% of psychotherapy trials in
1092 H. Moises

depression employed improper randomization (Chen et al. 2014), and only 20% of
trials were found to have a low risk of bias (Cuijpers et al. 2019a). Typically,
psychotherapy studies are small and methodologically flawed, and non-blinded
raters with strong allegiances to one of the treatments under investigation evaluate
the results (Coyne and Kok 2014).
Studies employing proper blinding result in smaller effect sizes for psychotherapy
for depression (Cuijpers et al. 2010). Allegiance to the psychotherapy under inves-
tigation is a very strong predictor of outcome in RCTs (Miller et al. 2008; Munder
et al. 2013; Wampold and Imel 2015; Cuijpers and Cristea 2016).
There are more than 250 different psychotherapies (Herink 2012). All reported
improvements in patients treated by these different methods might be due to placebo
effects (Cuijpers and Cristea 2016). Placebos are thought to work by an increased
expectation of improvement or cure on the part of the patient (Colagiuri et al. 2015).
As long as patients expect the therapy to work, they will get better (Cuijpers and
Cristea 2016). The placebo effect might explain why some exotic treatments, such as
Mesmer’s animal magnetism (Lanska and Lanska 2007), acupuncture (Derry et al.
2006), homeopathy (Grams 2019), swimming with dolphins, or dancing the Argen-
tine tango, appear to be effective (Cuijpers and Cristea 2016).
Improper randomization can lead to larger reported effect sizes. In a meta-
analysis of psychotherapies for depression, Cuijpers and Cristea (2016) found
significant smaller effect sizes in studies using concealed assignment of patients to
the treatments compared to studies which did not use such a procedure.
In expectation of receiving psychotherapy, patients on waiting lists appear to do
nothing to solve their problems. (Cuijpers et al. 2010). In consequence, the outcome
of patients on waiting lists is worse than those receiving no treatment. For this
reason, waiting lists can be termed nocebos (Furukawa et al. 2014). Indeed, several
meta-analyses have found much larger effect sizes in studies using waiting list
control groups as compared to studies employing other control groups (Mohr et al.
2009, 2014; Barth et al. 2013).
The exclusion of drop-outs from the analysis of outcome results in larger effect
sizes (Cuijpers and Cristea 2016). Usually, multiple outcome measures are employed
in psychotherapeutic studies. Selective outcome reporting introduces a bias (Cuijpers
and Cristea 2016).
Small samples can produce better results than large samples due to an increased
chance of systematic differences between the groups under investigation (Cuijpers
et al. 2010; Gibertini et al. 2012; Cuijpers and Cristea 2016).
Trials involving hundreds or even thousands patients are required to find a small
difference between psychotherapies, and consequently, a large number of psycho-
therapeutic studies have insufficient power to report statistically robust outcomes
(Cuijpers and Cristea 2016).
A considerable publication bias exists in the field of psychotherapeutic research, as
demonstrated by the negative correlation between effect size and sample size, the
biased distribution of p values, an excess of significant findings, and the fact that a
considerable number of trials are never published (Kühberger et al. 2014; Flint et al.
2015; Cuijpers and Cristea 2016). Similar problems exist in antidepressant research
(Turner et al. 2008).
Neuropsychopharmacotherapy: Complementary Treatments 1093

Problems with Meta-Analyses

The results of meta-analyses have become a munition in the battle between psycho-
therapists advocating the Freudian and those favoring the Pavlovian paradigm. In
1977, the first meta-analysis of psychotherapy outcome studies was published by
Smith and Glass (Smith and Glass 1977; Smith et al. 1980). Combining the results of
nearly 400 controlled studies of different diagnoses, psychotherapies, and counselling,
they obtained an average ES of 0.68. Favoring the Pavlovian paradigm, Hans Eysenck
criticized such a meta-analysis as a meaningless exercise in adding apples and oranges.
He further claimed that certain excellent studies by prolific and prominent behavioral
researchers had been omitted, while others were included that were so flawed as to put
them beyond the pale of acceptability (Eysenck 1984, 1994). In his view, meta-
analysis muddies the waters in the majority of cases where it is being used and leads
to meaningless conclusions that are likely to hamper proper scientific research.
Thirty years later, Coyne and Kok observed that:

meta-analyses of psychotherapies are strongly biased toward concluding that treatments work,
especially when conducted by those who have undeclared conflicts of interest and investigator
allegiances. This includes developers and promoters of treatments that stand to gain financially
or otherwise from their branding as ‘evidence-supported’. (Coyne and Kok 2014)

These authors concluded that “psychotherapy literature is currently of too poor

quality to provide a reliable guide to clinicians, consumers, and policymakers” (Coyne
and Kok 2014).
Recently, Cuijpers et al. (2019b) concluded:

that meta-analyses that include all published trials, without taking into account the problems
of meta-analyses, heavily overestimate the effects of psychotherapies. This makes it highly
probable that Smith and Glass (1977) in their early meta-analysis considerably over-
estimated the effects of psychotherapy. . . . we found the overall effect of psychotherapy
was small but significant. (Cuijpers et al. 2019)

However,
because the effect sizes are relatively small, only a small change in the overall estimate,
caused by an unknown source of bias, can make this non-significant. . . The possibility that
psychotherapies do not have effects that are larger than spontaneous recovery cannot be
excluded. (Cuijpers et al. 2019b)

Conclusions

Psychotherapy is well accepted by patients and the general public alike. Having seen
recovery from anxiety and depression in patients following behavior therapy or other
forms of psychotherapy as well as antidepressants, it is difficult to imagine that these
improvements are purely the result of spontaneous remission. The significant role of
the therapist’s personality including their empathy and genuineness (see Fig. 2) is in
contradiction to the thesis of spontaneous recovery.
1094 H. Moises

Currently, the best evidence for the efficiency of psychotherapies is obtained from
meta-analyses of studies with low risk of bias. The results show that BA, the third
wave’s ACT and MBCT, and Beck’s CBT have the largest effect sizes (see Fig. 1).
In summary, meta-analyses suggest that all psychotherapies and antidepressants
are equivalently effective (Cuijpers 2016). For future psychotherapy research, the
reduction of biases and a considerable increase in sample sizes are of major impor-
tance to achieve further progress in this field. There are achievable strategies
available to researchers to reduce bias. As an example, blinding of raters is not
widely used, yet it can be achieved by recording video of patients during interviews,
editing the records to remove any hints to the psychotherapeutic treatment obtained,
and then presenting the videos to blinded raters in a randomized sequence.

Cross-References

▶ Randomized Controlled Trials and the Efficacy of Psychotropic Medications

References
Barth J, Munder T, Gerger H, et al. Comparative efficacy of seven psychotherapeutic interventions
for patients with depression: a network meta-analysis. PLoS Med. 2013;10:e1001454.
Beck AT. Cognitive therapy of depression. New York: Guilford Press; 1979.
Beutler LE. The dodo bird is extinct. Clin Psychol Sci Pract. 2002;9:30–4.
Bisson JI, Roberts NP, Andrew M, Cooper R, Lewis C. Psychological therapies for chronic post-
traumatic stress disorder (PTSD) in adults. Cochrane Database Syst Rev. 2013. CD003388.
Bohlmeijer E, Smit F, Cuijpers P. Effects of reminiscence and life review on late-life depression: a
meta-analysis. Int J Geriatr Psychiatry. 2003;18:1088–94.
Bowman V, Ward LC, Bowman D, Scogin F. Self-examination therapy as an adjunct treatment for
depressive symptoms in substance abusing patients. Addict Behav. 1996;21:129–33.
Budd R, Hughes I. The Dodo Bird Verdict – controversial, inevitable and important: a commentary
on 30 years of meta-analyses. Clin Psychol Psychother. 2009;16:510–22.
Chen P, Furukawa TA, Shinohara K, et al. Quantity and quality of psychotherapy trials for
depression in the past five decades. J Affect Disord. 2014;165:190–5.
Colagiuri B, Schenk LA, Kessler MD, Dorsey SG, Colloca L. The placebo effect: from concepts to
genes. Neuroscience. 2015;307:171–90.
Coyne JC, Kok RN. Salvaging psychotherapy research: a manifesto. J Evid Based Psychother.
2014;14:105–24.
Cristea IA, Gentili C, Cotet CD, Palomba D, Barbui C, Cuijpers P. Efficacy of psychotherapies for
borderline personality disorder: a systematic review and meta-analysis. JAMA Psychiat.
2017;74:319–28.
Cuijpers P. The future of psychotherapy research: stop the waste and focus on issues that matter.
Epidemiol Psychiatr Sci. 2016;25:291–4.
Cuijpers P. The role of common factors in psychotherapy outcomes. Annu Rev Clin Psychol.
2019;15:207.
Cuijpers P, Cristea IA. How to prove that your therapy is effective, even when it is not: a guideline.
Epidemiol Psychiatr Sci. 2016;25:428–35.
Cuijpers P, van Straten A, Bohlmeijer E, Hollon SD, Andersson G. The effects of psychotherapy for
adult depression are overestimated: a meta-analysis of study quality and effect size. Psychol
Med. 2010;40:211–23.
Neuropsychopharmacotherapy: Complementary Treatments 1095

Cuijpers P, Geraedts AS, van Oppen P, et al. Interpersonal psychotherapy for depression: a meta-
analysis. Am J Psychiatry. 2011;168:581–92.
Cuijpers P, Driessen E, Hollon SD, et al. The efficacy of non-directive supportive therapy for adult
depression: a meta-analysis. Clin Psychol Rev. 2012;32:280–91.
Cuijpers P, Karyotaki E, de Wit L, Ebert DD. The effects of fifteen evidence-supported therapies for
adult depression: a meta-analytic review. Psychother Res. 2019. p. 1–15.
Cuijpers P, Karyotaki E, Reijnders M, Ebert DD. Is psychotherapy effective? Pretending everything
is fine will not help the field forward. Epidemiol Psychiatr Sci. 2019a;28:56–357.
Cuijpers P, Karyotaki E, Reijnders M, Ebert DD. Was Eysenck right after all? A reassessment of the
effects of psychotherapy for adult depression. Epidemiol Psychiatr Sci. 2019b;28:21–30.
Davidson PR, Parker KCH. Eye movement desensitization and reprocessing (EMDR): a meta-
analysis. J Consult Clin Psychol. 2001;69:305–16.
Derry CJ, Derry S, McQuay HJ, Moore RA. Systematic review of systematic reviews of acupunc-
ture published 1996–2005. Clin Med (Lond). 2006;6:381–6.
Dimidjian S, Hollon SD, Dobson KS, et al. Randomized trial of behavioral activation, cognitive
therapy, and antidepressant medication in the acute treatment of adults with major depression.
J Consult Clin Psychol. 2006;74:658–70.
D’Zurilla TJ, Nezu AM, Maydeu-Olivares A. Social problem solving: theory and assessment. In:
Chang EC, D’Zurilla TJ, Sanna LJ, editors. Social problem solving: theory, research, and
training, American Psychological Association, vol. 2004; 2004. p. 11–27.
Evans J. Philosophy for life: and other dangerous situations. London: Rider; 2013.
Eysenck HJ. Meta-analysis: an abuse of research integration. J Spec Educ. 1984;18:41–59.
Eysenck HJ. Meta-analysis and its problems. BMJ. 1994;309:789–92.
Flint J, Cuijpers P, Horder J, Koole SL, Munafò MR. Is there an excess of significant findings in
published studies of psychotherapy for depression. Psychol Med. 2015;45:439–46.
Foa E, Hembree E, Rothbaum BO. Prolonged exposure therapy for PTSD. New York:
Oxford University Press; 2007.
Furukawa TA, Noma H, Caldwell DM, et al. Waiting list may be a nocebo condition in psychotherapy
trials: a contribution from network meta-analysis. Acta Psychiatr Scand. 2014;130:181–92.
Gibertini M, Nations KR, Whitaker JA. Obtained effect size as a function of sample size in
approved antidepressants: a real-world illustration in support of better trial design. Int Clin
Psychopharmacol. 2012;27:100–6.
Grams N. Homeopathy-where is the science? A current inventory on a pre-scientific artifact. EMBO
Rep. 2019. p. 20.
Hayes SC. Acceptance and commitment therapy, relational frame theory, and the third wave of
behavioral and cognitive therapies–republished article. Behav Ther. 2004;35:639–65.
Hayes SC. Acceptance and commitment therapy, relational frame theory, and the third wave of
behavioral and cognitive therapies – republished article. Behav Ther. 2016;47:869–85.
Hayes SC. The third wave of cognitive behavioral therapy and the rise of process-based care.
[editorial]. World Psychiatry. 2017;16(3):245.
Hayes SC, Wilson KG. Acceptance and commitment therapy: altering the verbal support for
experiential avoidance. Behav Anal. 1994;17:289–303.
Hayes SC, Strosahl K, Wilson KG. Acceptance and commitment therapy: understanding and
treating human suffering. New York: Guilford Press; 1999.
Herbert JD, Lilienfeld SO, Lohr JM, et al. Science and pseudoscience in the development of eye
movement desensitization and reprocessing: implications for clinical psychology. Clin Psychol
Rev. 2000;20:945–71.
Herink R. The psychotherapy guidebook. Martinsville: Fideli Publishing; 2012.
Hull CL. Principles of behavior. New York: Appleton; 1943.
Hunot V, Moore TH, Caldwell DM, et al. ‘Third wave’ cognitive and behavioural therapies versus
other psychological therapies for depression. Cochrane Database Syst Rev. 2013. CD008704.
Jacobson NS, Martell CR, Dimidjian S. Behavioral activation treatment for depression: returning to
contextual roots. Clin Psychol Sci Pract. 2001;8:255–70.
Kanter J, Busch AM, Rusch LC. Behavioral activation. Routledge; 2009.
1096 H. Moises

Klerman GL, Weissman MM. Interpersonal psychotherapy of depression. Lanham: Jason Aronson;
1994.
Kühberger A, Fritz A, Scherndl T. Publication bias in psychology: a diagnosis based on the
correlation between effect size and sample size. PLoS One. 2014;9:e105825.
Lanska DJ, Lanska JT. Franz Anton Mesmer and the rise and fall of animal magnetism: dramatic
cures, controversy, and ultimately a triumph for the scientific method. In: Whitaker H, Smith
CUM, Finger S, editors. Brain, mind and medicine: essays in eighteenth-century neuroscience.
Boston: Springer; 2007.
Lewinsohn PM. A behavioral approach to depression. Essential papers on depression. 1974.
p. 150–172.
Lewis MI, Butler RN. Life-review therapy. Putting memories to work in individual and group
psychotherapy. Geriatrics. 1974;29:165–73.
Linehan MM. Cognitive-behavioral treatment of borderline personality disorder. New York:
Guilford Publications; 2018.
Linehan MM, Armstrong HE, Suarez A, Allmon D, Heard HL. Cognitive-behavioral treatment of
chronically parasuicidal borderline patients. Arch Gen Psychiatry. 1991;48:1060–4.
Luborsky L. Are common factors across different psychotherapies the main explanation for the
dodo bird verdict that “everyone has won so all shall have prizes”. Clin Psychol Sci Pract.
1995;2:106–9.
Luborsky L, Singer B, Luborsky L. Comparative studies of psychotherapies. Is it true that
“everyone has won and all must have prizes”. Arch Gen Psychiatry. 1975;32:995–1008.
Luborsky L, Rosenthal R, Diguer L, et al. The Dodo Bird Verdict is alive and well – mostly. Clin
Psychol Sci Pract. 2002;9:2–12.
Martell CR, Addis ME, Jacobson NS. Depression in context: strategies for guided action.
New York: WW Norton & Co; 2001.
McCullough JP Jr, Schramm E, Penberthy JK. CBASP as a distinctive treatment for persistent
depressive disorder. London: Routledge; 2014. p. 152.
McCullough JP Jr, Schramm E, Penberthy K. CBASP – cognitive behavioral analysis system of
psychotherapy: Chronische Depressionen effektiv behandeln. Paderborn: Junfermann Verlag;
2015.
Miller S, Wampold B, Varhely K. Direct comparisons of treatment modalities for youth disorders: a
meta-analysis. Psychother Res. 2008;18:5–14.
Mohr DC, Spring B, Freedland KE, et al. The selection and design of control conditions for
randomized controlled trials of psychological interventions. Psychother Psychosom.
2009;78:275–84.
Mohr DC, Ho J, Hart TL, et al. Control condition design and implementation features in controlled
trials: a meta-analysis of trials evaluating psychotherapy for depression. Transl Behav Med.
2014;4:407–23.
Munder T, Brütsch O, Leonhart R, Gerger H, Barth J. Researcher allegiance in psychotherapy
outcome research: an overview of reviews. Clin Psychol Rev. 2013;33:501–11.
Mynors-Wallis LM, Gath DH, Day A, Baker F. Randomised controlled trial of problem solving
treatment, antidepressant medication, and combined treatment for major depression in primary
care. BMJ. 2000;320:26–30.
Negt P, Brakemeier EL, Michalak J, et al. The treatment of chronic depression with cognitive
behavioral analysis system of psychotherapy: a systematic review and meta-analysis of
randomized-controlled clinical trials. Brain Behav. 2016;6:e00486.
Nezu AM. Efficacy of a social problem-solving therapy approach for unipolar depression. J Consult
Clin Psychol. 1986;54:196.
Öst LG. The efficacy of acceptance and commitment therapy: an updated systematic review and
meta-analysis. Behav Res Ther. 2014;61:105–21.
Pavlov IP. Conditioned reflexes and psychiatry. Translation by W.H. Gantt. New York:
International Publishers; 1963.
Neuropsychopharmacotherapy: Complementary Treatments 1097

Segal ZV, Williams JMG, Teasdale JD. Mindfulness-based cognitive therapy for depression. 1st ed. -
New York: Guilford Press; 2002. p. 351.
Segal ZV, Williams JMG, Teasdale JD. Mindfulness-based cognitive therapy for depression.
New York: Guilford Press; 2012. p. 451.
Shapiro F. Eye movement desensitization: a new treatment for post-traumatic stress disorder.
J Behav Ther Exp Psychiatry. 1989;20:211–7.
Shapiro F. Eye movement desensitization and reprocessing. Guilford Publications; 1995. p. 398.
Sisemore TA. The clinician’s guide to exposure therapies for anxiety spectrum disorders. Oakland:
New Harbinger Publications; 2012.
Smith ML, Glass GV. Meta-analysis of psychotherapy outcome studies. Am Psychol.
1977;32:752–60.
Smith ML, Glass GV, Miller TI. The benefits of psychotherapy. Johns Hopkins University Press,
Baltimore; 1980. p. 269.
Torrey EF. Witchdoctors and psychiatrists: the common roots of psychotherapy and its future.
Northvale/London: Jason Aronson Inc.; 1986. p. 316.
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antide-
pressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:252–60.
Wampold BE, Imel ZE. The great psychotherapy debate. Routledge; 2015. p. 334.
Weissman MM, Klerman GL. Interpersonal psychotherapy and tricyclics for depression. In:
Psychiatry the state of the art. Heidelberg/New York: Springer; 1985. p. 99–104.
Wolitzky-Taylor KB, Horowitz JD, Powers MB, Telch MJ. Psychological approaches in the
treatment of specific phobias: a meta-analysis. Clin Psychol Rev. 2008;28:1021–37.
Wolpe J. Reciprocal inhibition as the main basis of psychotherapeutic effects. AMA Arch Neurol
Psychiatry. 1954;72:205–26.
Wolpe J. Psychotherapy by reciprocal inhibition. Stanford: Stanford University Press; 1958.
Wolpe J, Rachmann S. Psychoanalytic “evidence”: a critique based on Freud’s case of Little Hans.
J Nerv Ment Dis. 1960;131:135–48.
 Part III
Antidepressants

Hans-Jürgen Möller and Gerd Laux

Antidepressants: Definition, Classification,
Guidelines

Gerd Laux

Contents
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
New Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107

Abstract
Antidepressant effects of the monoamine oxidase inhibitor iproniazid and
imipramine have been discovered serendipitously 1957/1958. Their effects of sero-
tonergic and noradrenergic transmission led to hypotheses of the origin of depression.
Various tri- and tetracyclic substances have been synthesized; in the 1980s, seroto-
nin-selective inhibitors like fluoxetine got first-line antidepressants. Dual acting,
combined serotonin-noradrenaline-reuptake inhibitors like venlafaxine have been
developed, so classification of antidepressants nowadays includes these main groups.
Recently, a new nomenclature for neuropsychopharmacological CNS medications
(NbN), based on neuroscience regarding pharmacology and mode of action, has been
proposed. Guidelines have been proposed by international and national societies like
National Institute for Health and Clinical Excellence (NICE), World Federation
of Societies of Biological Psychiatry (WFSBP), The International College of

G. Laux (*)
Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich,
Germany
e-mail: ipm@ipm-laux.de

© Springer Nature Switzerland AG 2022 1101

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_24
1102 G. Laux

Neuropsychopharmacology (CINP), American Psychiatric Association (APA), and

German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN).

History

The modern antidepressants were discovered serendipitously. In 1954 investigators

noted that tuberculosis patients showed prolonged elevation of mood when treated
with iproniazid (Marsilid), a monoamine oxidase inhibitor (MAOI) thought to be an
antitubercular agent. Its impact on mood led to some of the earliest double-blind
studies in psychopharmacology, demonstrating that MAOIs were effective antide-
pressant agents. The biological and pharmacological observations that MAOIs were
antidepressants and that monoamine oxidase degraded norepinephrine and serotonin
(5-HT) became cornerstones of the so-called biogenic amine theories – serotonin and
catecholamine theory of depression (Ghaemi 2019).
The tricyclic antidepressants (TCAs) were also discovered serendipitously. In 1958
Kuhn in Switzerland reported his observation that the phenothiazine imipramine (Tofranil)
which was investigated as a treatment for schizophrenia produced improvement of mood.
The pharmaceutical industry developed further tri- and tetracyclic compounds in order to
improve efficacy and tolerability. The search for selective acting medications led to the
introduction of new classes of antidepressants, mainly the serotonin-selective inhibitors
(SSRIs) like fluoxetine. Dual acting, selective serotonin-norepinephrine reuptake inhibi-
tors (SNRIs) like venlafaxine have been developed. Modifications in mechanisms led to
α2-receptor antagonists, dopamine uptake inhibitors, and mixed 5-HT effects also com-
bined with melatonin effects. Selective and reversible inhibitors of monoamine oxidase A
(RIMAs) represent another attempt to render difficult-to-tolerate MAOIs in a more
manageable form. Despite the success of the newer classes of antidepressants in enhancing
safety and tolerability, there has been no appreciable success in improving the efficacy and
the latency of onset of the antidepressants (Schatzberg and Nemeroff 2017).

Definition

Antidepressants (Thymoleptics) are a category of psychotropic agents primarily used

for the treatment of depression. Primarily they have mood elevating and drive
normalizing effects after latency of onset compared to tranquilizers. Most of them
reveal also anxiolytic effects, so they can be used in treatment of anxiety and panic
disorders. Obsessive-compulsive symptoms are improved by serotonin-selective
agents (Baldwin et al. 2014). Therefore, the term antidepressants is somewhat
inconclusive and misleading (see below).

Classification

Antidepressant drugs are a heterogeneous group of compounds, fall into a wide

variety of chemical classes, and have a wide range of neuropsychopharmacological
effects. They are grouped after chemical classes, pharmacological/biochemical
effects, or clinical profiles (i.e., sedating and activating).
Antidepressants: Definition, Classification, Guidelines 1103

According chemical structure are distinguished: “Classical” tricyclic antidepres-

sants (TCAs), modified tri- und tetracyclic antidepressants, chemical different anti-
depressants (Stahl 2016).
Pharmacological-neurobiochemical classification according to their effects on
monoamine neurotransmitter system and receptor binding affinities regarding selec-
tivity can be distinguished:

1. Non-selective Monoamine (Noradrenaline-/Serotonin-) Reuptake Inhibitors

(NSMRI) (“Tricyclics”)
2. Selective Serotonin Reuptake Inhibitors (SSRIs)
3. Norepinephrine Reuptake Inhibitors (NRIs)
4. Selective Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)
5. Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)
6. Serotonin receptor antagonists and agonists, and α2-adrenergic receptor anta
gonists (NaSSA)
7. Monoamine Oxidase Inhibitors (MAOIs)
a) non-selective, irreversible
b) selective, reversible MAO-A (RIMA)
8. Melatonin agonist and 5-HT2-antagonist (Table 1)

So-called atypical antidepressants show no effects on norepinephrine and/or

serotonin. Examples are trimipramine and dopaminagonists like flupentixol and
sulpiride. Tianeptine is primarily a glutamate modulator.
Recently released is esketamine, mainly a N-Methyl-Aspartic Acid (NMDA)-
receptor antagonist and the GABA-A-receptor modulator brexanolone, a progester-
one-metabolite. In development are neuronale nicotine-receptor modulators and
glutamate/NMDA-receptor antagonists like Rapastinel. Innovative targets are mono-
clonal antibodies, antidiabetics, and antiinflammatory substances (like celecoxib), as
well as transcription factors (PPAR-ɣAgonists).

New Classification

Five international scientific associations (European College of Neuropsychophar-

macology (ECNP), American College of Neuropsychopharmacology (ACNP),
Asian College of Neuropsychopharmacology (AsCNP), International College
of Neuropsychopharmacology (CINP) and International Union of Basic & Clinical
Pharmacology (IUPHAR)) proposed a new nomenclature for neuropsychopharma-
cological CNS medications based on neuroscience regarding pharmacology and
mode of action (Zohar et al. 2018). Reason is that traditional terminology and
classification of psychotropic medications is primarily indication-related not
reflecting clinical use. Very often, that is, “antidepressants” are prescribed and
approved for anxiety or panic disorder. The neuroscience-based nomenclature
(NbN) is primarily related to domains and mechanism of action.
Regarding “antidepressants” classification according to pharmacology is as
follows:
 1104

Table 1 Pharmacological classification of antidepressants

Reuptake inhibition Receptor blockade
MAO-
Antidepressant Class Serotonin Noradrenalin Dopamin 5-HT2 5-HT3 α ACh H1 DA Inhibition
Agomelatine +++
Amitriptyline TCA ++ ++ + ++ + +++ +++ +++
Amoxapine TCA ++ ++
Bupropion + ++ + +
Citalopram SSRI +++
Clomipramine TCA +++ ++
Desvenlafaxine SNRI ++ + + + ++ ++ +
Dothiepin TCA ++ ++
Doxepin TCA + ++ ++ + +++ ++ +++
Duloxetine SNRI +++ ++ + +
Escitalopram SSRI +++
Fluoxetine SSRI +++ +
Fluvoxamine SSRI +++ +
Imipramine TCA ++ +++ + + + ++ ++ –
Isocarboxazid MAOI ++
St. John’s Wort + + +
Phyto +
Lofepramine TCA
Maprotiline tetracyclic ++ + + ++ ++
Mianserin tetracyclic +++ + +++ ++
Milnacipran SNRI ++ ++
G. Laux
Mirtazapine NaSSA +++ +++ +++ +++
Moclobemide MAOI/RIMA ++
Nortriptyline TCA + +++ + + ++ +
Paroxetine SSRI +++ + + + –
Phenelzine MAOI + ++ ++
Protriptyline TCA
Reboxetine NARI +++ + –
Selegiline MAOI ++
Sertraline SSRI +++ + + +
Sulpiride ++
Tianeptine Glutaminergic effects
Tranylcypromine MAOI – – +++
Trazodone + +
Trimipramine TCA ++ + ++ ++ +++ +
Venlafaxine SNRI +++ + –
Antidepressants: Definition, Classification, Guidelines

Vilazodone ++ +
Vortioxetine +++ + +
5-HT serotonin receptors, α α-adreno receptors, ACh muscarinic acetylcholine receptors, H1 histamine receptors, DA dopamine receptors
1105
1106 G. Laux

• Norepinephrine, for example, maprotiline and reboxetine

• Norepinephrine, dopamine bupropion
• Norepinephrine, serotonin milnacipran, mirtazapine
• Serotonin, for example, escitalopram, sertraline
• Serotonin, norepinephrine, for example, duloxetine, venlafaxine
• Serotonin, norepinephrine, dopamine, for example, moclobemide, phenelzine,
tranylcypromine

According to mode of action

• Enzyme inhibitor, for example, moclobemide, phenelzine, selegiline,

tranylcypromine
• Neurotransmitter releaser, for example, bupropion, tranylcypromine
• Receptor agonist, for example, agomelatine, trazodone
• Receptor antagonist, for example, amitriptyline, mirtazapine, trazodone, tri-
mipramine, vortioxetine
• Receptor partial agonist, for example, vortioxetine
• Reuptake inhibitors, for example, amitriptyline, bupropion, escitalopram, fluox-
etine, sertraline, venlafaxine, vortioxetine

Indications

Antidepressants are approved, indicated, and released for the treatment of

• Major depressive disorder

Some antidepressants are also effective and recommended for the treatment of

• Anxiety disorders (generalized anxiety disorder, panic disorder, and social anx-
iety disorder)
• Obsessive-compulsive disorder
• Chronic pain syndromes.

Possible effective are antidepressants in the treatment of bulimia nervosa, post-

traumatic stress disorder, premenstrual dysphoric syndromes, and organic mood
disorders.

Guidelines

Guidelines have been developed by international and national societies like the
British Association for Psychopharmacology, World Federation of Societies of
Biological Psychiatry (WFSBP), National Institute for Health and Clinical Excel-
lence (NICE), American Psychiatric Association (APA), Canadian Network for
Antidepressants: Definition, Classification, Guidelines 1107

Mood and Anxiety Treatments (CANMAT), the Australian and New Zealand
Guidelines, and the German S3 Guideline (Bauer et al. 2013, 2015; Cleare et al.
2015; DGPPN 2015).
Today SSRIs are seen as first-line antidepressants. Acute treatment is
recommended for 6–12 months, maintenance and relapse prevention for 2 years,
and longer depending from history of course (genetic load, and frequency of relapses
and recurrences).

Cross-References

▶ Agomelatine and Depressions

▶ Amitriptyline and Depressions
▶ Amoxapine and Depressions
▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and
Resistance to Therapy
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry
▶ Bupropion and Depressions
▶ Combination Therapies and Switching of Agents in Depression and Bipolar
Disorders
▶ Hypericum and Depression
▶ Monoamine Oxidase Inhibitors in Depressive Disorders
▶ Mianserine and Depressions
▶ Mirtazapine and Depressions
▶ Nortriptyline and Maprotiline for Depressions
▶ Psychopharmacotherapy of Depressive Disorders
▶ Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,
Desvenlafaxine, Duloxetine, Milnacipran, Levomilnacipran
▶ Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine,
Paroxetine, and Sertraline
▶ Trazodone and Depression
▶ Vilazodone and Depressions
▶ Vortioxetine and Depressions

References
Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety
disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the
2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol.
2014;28:403–39.
Bauer M, Pfennig A, Severus E, et al. World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update
2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol
Psychiatry. 2013;14:334–85.
1108 G. Laux

Bauer M, Severus E, Köhler S, et al. World Federation of Societies of Biological Psychiatry

(WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 2: mainte-
nance treatment of major depressive disorder update 2015. World J Biol Psychiatry. 2015;16:
76–95.
Cleare A, Pariante CM, Young AH, et al. Evidence-based guidelines for treating depressive
disorders with antidepressants: a revision of the 2008 British Association for Psychopharma-
cology guidelines. J Psychopharmacol. 2015;29:459–525.
DGPPN, BÄK, KBV, AWMF, et al. S3-Leitlinie/Nationale Versorgungsleitlinie Unipolare Depres-
sion. Berlin: Springer; 2015.
Ghaemi NS. Clinical psychopharmacology. Oxford, UK: Oxford University Press; 2019.
Schatzberg AF, Nemeroff CB. Textbook of psychopharmacology. 5th ed. Washington, DC: APA;
2017.
Stahl S. Essential psychopharmacology. The prescriber’s guide. Antidepressants. 5th ed. Cam-
bridge, UK: Cambridge University Press; 2016.
Zohar J, Blier P, Stahl S, Möller HJ, et al. NbN. Neuroscience-based nomenclature. 2nd ed. Utrecht:
ECNP; 2018.
Antidepressants: Pharmacology
and Biochemistry

Vanessa Efinger, Walter E. Müller, and Kristina Friedland

Contents
Biochemical Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
Effect on the Monoaminergic Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
Effects in the Entire Neuronal System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113
Reorganization Instead of Deficit Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113
Effect by Inhibition of Reuptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113
Effect on Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114
Effect by Delayed Decomposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1117
Clinical Efficacy Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1117
Effect on the Noradrenergic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
Effect on the Serotonergic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119
Effect on the Dopaminergic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
Effect on the Glutamatergic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121
Adaptive Changes with Prolonged Use of Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1124
Neuroplasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1124
Behavioural Pharmacological Effects of Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1128
Cross-references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1130

Abstract
The first antidepressants, discovered in the 1950s, and any successors directly
target the monoaminergic brain systems. Problems in this group, however, are
low effectiveness (only two-thirds of those treated responded to the therapy) and a

V. Efinger · K. Friedland (*)

Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University Mainz,
Mainz, Germany
e-mail: vefinger@uni-mainz.de; kfriedla@uni-mainz.de
W. E. Müller
Institute of Pharmacology and Clinical Pharmacy, Goehte University Frankfurt, Frankfurt,
Germany
e-mail: w.e.mueller@em.uni-frankfurt.de

© Springer Nature Switzerland AG 2022 1109

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_26
1110 V. Efinger et al.

significantly delayed onset of action of weeks to months. New findings on the

pathophysiology of depression affecting the GABAergic and glutamatergic sys-
tems give hope for the development of rapid-acting and effective antidepressants.
Only understanding the basics of antidepressant pharmacotherapy makes it
possible to comprehend new research approaches in this field. Moreover, the
specialist knowledge makes it easier for clinicians to make an adequate and
rational choice of the pharmaceuticals they use. By knowing the mechanism of
action and the route of decomposition of the antidepressant selected, adverse drug
reactions can be anticipated and avoided wherever possible.
For the reasons mentioned above, already known antidepressants (tricyclics,
SSRI, SNRI, NRI and MAO inhibitors), as well as newer antidepressant-acting
candidates (ketamine, scopolamine, rapastinel), will be discussed in this chapter
with regard to their pharmacology and biochemistry.

Abbreviations
5-HT 5-hydroxytryptamine/
serotonin
5-HT1A/5-HT1D/5-HT2/5-HT2A/5-HT2C/5-HT3 Serotonin receptors; subtypes
1A/1D/2/2A/2C/3
α1/α2/β Adrenergic receptors; subtypes
α1/α2/β
AC Adenylate cyclase
Akt Protein kinase B
AMP Adenosine monophosphate
AMPA α-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid
ATP Adenosine Triphosphate
BDNF Brain-derived neurotrophic
factor
CA Cornu ammonis
Ca2+ Calcium
CaMK Ca2+/calmodulin-dependent
protein kinase
cAMP Cyclic adenosine monophos
phate
Cl
Chloride
CNS Central Nervous System
COMT Catechol-O-methyltransferase
CREB cAMP response element-
binding protein
D1/D2 Dopamine receptors; subtypes
1/subtype 2
DA Dopamine
Antidepressants: Pharmacology and Biochemistry 1111

DDC DOPA decarboxylase

DG Dentate gyrus
DOPA L-3,4-dihydroxyphenylalanine/
levodopa
DOPAC 3,4-Dihydroxyphenylacetic acid
ECT Electroconvulsive therapy
eEF2 Eukaryotic elongation factor 2
Ent Entorhinal cortex
FDA U.S. Food and Drug
Administration
FST Forced swim test
GABA Gamma-Aminobutyric acid
GABAA GABA receptor; subtype A
H1 Histamine receptor; subtype 1
HVA Homovanillic acid
Ki Inhibition constant
LH Lethargic mouse model
LHb Lateral habenula
LTP Long-term potentiation
M Muscarinic acetylcholine
receptor
MAO-A/MAO-B Monoamine oxidase; subtypes
A/B
MAPK Mitogen-activated protein
kinase
MDD Major depressive disorder
mGluR2/3 Metabotropic glutamate recep-
tors; subtypes 2/3
mPFC Medial prefrontal cortex
MT Melatonin
MT1/MT2 Melatonin receptors; subtypes
1/2
mTORC1 Mammalian target of
rapamycin complex 1
Na+ Sodium
NDRI Norepinephrine dopamine
reuptake inhibitor
NE Norepinephrine
NGF Nerve growth factor
NMDA N-Methyl-D-aspartic acid
nmol Nanomolar
NRI Selective norepinephrine reup-
take inhibitor
1112 V. Efinger et al.

NSFT Near the individual spatial

frequency threshold
PDE-4 Phosphodiesterase
PKA/PKC Protein kinases; subtypes A/C
PLC Phospholipase C
RNA Ribonucleic acid
RR Blood pressure
RCT Randomised controlled trial
Rsk Ribosomal s6 kinase
SNRI Serotonin norepinephrine
reuptake inhibitor
SSA Succinate semialdehyde
SSRI Selective serotonin reuptake
inhibitor
TCA Tricyclic antidepressant
TH Tyrosine hydroxylase
TrkB Tropomyosin receptor kinase B
Tyr Tyrosine
VGCC Voltage-gated Ca2+ channel

Biochemical Mechanisms of Action

The mechanism of action of antidepressants has not yet been completely resolved
despite intensive research over the last 60 years. The neurobiochemical effects of
antidepressant substances are relatively well understood. However, there is still a
lack of clarity about the importance of these actions for the impact on depression,
since the biochemical basis of the disease itself has not yet been clarified due to the
lack of valid models of depression (Müller and Eckert 2017; Frazer 1997; Leonard
1995, 1996; Ebmeier et al. 2006).

Effect on the Monoaminergic Synapse

Since the discovery of the thymoleptic effect of imipramine over 50 years ago,
the transmission at monoaminergic synapses of the CNS is the centre of atten-
tion in the research on mechanisms of action of antidepressants. Initially, the
biochemical hypotheses about the causes of depression related to a lack of
transmitters in the synaptic cleft, later also to a reduced sensitivity of postsyn-
aptic receptors. The mode of action of antidepressants was considered to be a
specific effect (see below) on these hypothetical deficits. To this day, there is
virtually no effective antidepressant that does not also affect monoaminergic
synapses (Berton and Nestler 2006). An exception is the fast-acting substance
ketamine.
Antidepressants: Pharmacology and Biochemistry 1113

Effects in the Entire Neuronal System

The possibility that the effect of antidepressants cannot be ascribed to such specific
processes has lately been discussed increasingly. In 1983, Paioni et al. already
suspected that monoaminergic synapses are to be regarded as particularly favourable
intervention points for pharmacological influence on neuronal systems, namely, in
the sense of an impulse with the consequence of a slow normalization of the
previously disturbed overall regulatory system. This is supported by the detectable
adaptive changes in many neurotransmitter systems (see above) among all antide-
pressants and the fact that the central transmitters (norepinephrine, serotonin, dopa-
mine) triggered primarily by the antidepressants have a modulating action on many
different anatomical structures or many different functional processes of the CNS.
Stassen et al. (1996), likewise, conclude, based on the evaluation of the time courses
of antidepressants and placebo therapy, that the antidepressants tend to only accel-
erate a physiological normalization process.

Reorganization Instead of Deficit Regulation

This would mean that neither the acute pharmacological effects (amine reuptake
inhibition, MAO-inhibition) nor the latency-appearing adaptive changes in various
signal transduction mechanisms correct neurochemical deficits in depression but
rather are an expression of a rearrangement of certain functions of the central
neurotransmission, which ultimately lead to the resolution of the depression in the
patient. Since not only a lot of very different classes of substances (tricyclic drugs,
SSRIs, MAO-inhibitors, St. John’s wort extract) but also therapeutic measures like
electroconvulsive therapy (ECT) and rapidly effective interventions like sleep
deprivation and ketamine infusion converge on the level of adaptive changes,
this “reorganization hypothesis” could explain why many pharmacologically
very different antidepressant therapy options can show very similar clinical effects.
An important argument for this hypothesis is the fact that these adaptive changes
also exhibit a certain latency (1–2 weeks) in animal experiments, which in turn
better correlates with the delayed antidepressant action on the patient than the acute
effects.

Effect by Inhibition of Reuptake

The biochemical profile of the antidepressants is mainly derived from the acute
effects on the inhibition of NE and serotonin reuptake and the latency appearing
adaptive changes in certain central signal transduction mechanisms (Fig. 1 and
Table 1). We distinguish

• Selective norepinephrine reuptake inhibitors (NRIs, e.g. desipramine and espe-

cially reboxetine) resp.
1114 V. Efinger et al.

Fig. 1 Effects of different classes of antidepressants in (a) central noradrenergic and (b) central
serotonergic synapses (Müller and Eckert 2017)

• Highly selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine and

citalopram).
• Such antidepressants that have a mixed influence regarding those two systems,
partially also via an active metabolite (TCAs, e.g. amitriptyline, imipramine and
clomipramine or SNRIs, duloxetine and venlafaxine).

Bupropion, which is also approved for the treatment of depression, is the only
antidepressant that inhibits the dopamine reuptake to a relevant extent under
therapeutic conditions (Stahl et al. 2004). Another exception is St. John’s wort
extract, which inhibits the synaptosomal uptake of serotonin, norepinephrine and
dopamine to about the same extent via the most important ingredient hyperforin
(Müller 2003).

Effect on Receptors

Besides this characteristic, the action of the individual antidepressants on the pre-
and postsynaptic receptors needs to be considered for the profile. However, those are
less responsible for the antidepressant effect (exception α2-antagonsim, primary
mechanisms in mirtazapine) than for the desired – but especially for the many
undesired vegetative – side effects (sedation, anxiolysis) of the respective antide-
pressant (Table 2).
Agomelatine is the first melatonin receptor (MT1, MT2) agonist and simulta-
neously antagonist on the serotonin receptor subtype 5-HT2C, so that the substance at
least intervenes in the serotonergic neurotransmission like most other antidepres-
sants (Fuchs et al. 2006).
Table 1 Inhibition constants (Ki-values in nmol) and receptor profiles of typical antidepressants for the inhibition of neuronal reuptake of norepinephrine and
serotonin (Müller and Eckert 2017)
Drug NE uptake 5-HT uptake 5-HT selectivitya H1 receptor M receptor α1 receptor α2 receptor 5-HT2 receptor
TCA
Amitriptyline 14 84 0,17 1 10 24 940 18
Clomipramine 28 5 5,6 31 37 38 >1000 54
Desipramine 0,6 180 0,003 60 66 100 >1000 350
Doxepin 18 220 0,08 0,2 23 24 >1000 27
Imipramine 14 41 0,3 37 46 32 >1000 150
Mirtazapine >1000 >1000 – 0,5 500 500 10 5
Nortriptyline 2 154 0,01 6 37 55 >1000 41
Trimipramine 510 >1000 0,02 0,3 58 24 680 32
Viloxazine 170 >1000 0,01 >1000 1000 >1000 1000 >1000
SSRI
Antidepressants: Pharmacology and Biochemistry

Citalopram >1000 1 3076 470 >1000 >1000 >1000 >1000

Fluoxetine 143 14 10 >1000 590 >1000 >1000 280
Fluvoxamine 500 7 71 >1000 >1000 >1000 >1000 >1000
Paroxetine 33 0,7 47 >1000 110 >1000 >1000 >1000
Sertraline 220 3 73 >1000 630 380 >1000 >1000
Trazodone >1000 367 27 >1000 >1000 27 155b 35,6c
SNRI
Duloxetine 2,1 0,53 3,96 >1000 >1000 >1000 >1000 504c
Venlafaxine 210 39 5 >1000 >1000 >1000 >1000 >1000
a
The 5-HT selectivity ratio indicates how much the substance inhibits the serotonin uptake more than the norepinephrine uptake. Inhibition constants >1000
imply that this receptor type is not relevant
b
α2c
c
5-HT2A
1115
1116 V. Efinger et al.

Table 2 Possible adverse drug reactions of inhibition of neuronal reuptake systems and of
blockade of neuroreceptors (Müller and Eckert 2017)
Reuptake systems Adverse drug reactions
NE reuptake Enhancement of the effects of sympathomimetics
Tachycardia
RR "
Restlessness, tremor
Erectile and ejaculation dysfunctions
5-HT reuptake Gastrointestinal dysfunction, nausea, vomiting
Restlessness, sleep disturbances
Extrapyramidal motor symptoms (?)
Reduced appetite, weight loss
Headache
Sexual dysfunctions
DA reuptake Psychomotor activation
Triggering resp. reinforcement psychosis
Anti-Parkinson effect
Neuroreceptors Adverse drug reactions
M Dry mouth
Blurred vision, accommodative dysfunction
Sinus tachycardia
Obstipation
Urinary retention, voiding disorders
Disturbances of memory
H1 Sedation, fatigue, sleepiness
Enhancement of other central damping substances
Weight gain (?)
α1 Orthostasis, RR #
Dizziness, drowsiness, sedation
Reflex tachycardia (+ α2 blocking?)
Enhancement of the effect of other α1 inhibitors
D2 Extrapyramidal motor symptoms
Prolactin "
Sexual dysfunctions
5-HT2 Increased appetite, weight gain
RR #
5-HT3 Antiemetic effect
Anxiolysis (?)

Other substances occupying a special position in this concept are tianeptine, the
new substance vortioxetine, as well as ketamine (McEwen et al. 2010; Otte 2014;
Müller 2015). Paradoxically, tianeptine does not lead to inhibition but rather to an
increase in serotonin uptake. However, like other serotonergic antidepressants,
tianeptine has similar adaptive effects at the serotonergic synapse and shows very
distinct actions on neuroplasticity mechanisms. In addition, it directly modulates
glutamatergic neurotransmission, especially at the AMPA receptor (McEwen et al.
2010).
Antidepressants: Pharmacology and Biochemistry 1117

Vortioxetine inhibits serotonin reuptake and has agonistic and antagonistic effects
on various serotonin receptors, which synergistically contribute to the antidepressant
effect, explaining the positive effect on cognitive dysfunction in depressed patients.
This improvement of cognition distinguishes the substance from other antidepressants.
Ketamine, a drug from the class of narcotics, has an antagonistic effect on the
glutamatergic NMDA receptor complex. It inhibits the NMDA-dependent release of
acetylcholine and appears to possess an additional opioid-like active component.

Effect by Delayed Decomposition

In the human brain, serotonin, norepinephrine and dopamine are degraded by the
mitochondrial enzyme monoamine oxidase (MAO) via oxidative deamination. The
inhibition of this enzyme delays the decomposition of the above-mentioned neuro-
transmitters and thus leads to an increased synaptic availability (Figs. 1 and 3).
Currently, the substances tranylcypromine, an irreversible, non-selective inhibitor,
and moclobemide, a reversible, MAO-A-selective inhibitor, are of clinical relevance
in the treatment of depression. Because of the dietary restrictions required and the
significant risk of interaction, classical MAO inhibitors have been used mainly to
treat patients with atypical depression and treatment-resistant patients. Reversible
MAO inhibitors do not have these restrictions. They are therefore used for all forms
of depression (Riederer et al. 2002).

Clinical Efficacy Profiles

Given the considerable differences in pharmacological profiles between antidepres-

sants, the question inevitably arises to what extent these are relevant to the clinical
effects. Various authors have tried to differentiate these clinical profiles of the
antidepressants from one another. The best-known schematic diagram proposed by
Kielholz (1971) distinguishes three characteristics of action (increase of motivation,
lifting of mood and anxiolysis) of antidepressants. Clinical studies have not
succeeded in classifying antidepressants with different effect profiles for syn-
dromally different subgroups of depressed patients. Also, with regard to the mood-
lifting, i.e. actual antidepressant core effect, no quantitative differences have been
demonstrated.
The different effects are more related to the typical side effects than to their
therapeutic effects. In contrast to tricyclic drugs, SSRIs seem to be less sedative and
more likely to cause sleep disorders, inner restlessness and tremor. Nowadays, it is
therefore assumed that the antidepressants do not differ in their actual “antidepres-
sant” core effect, but can be subdivided according to their different primary sedative,
respectively sleep-inducing properties (Fig. 2). Only the sedating substances can be
used as primary hypnotics for certain indications, while all other substances only
improve sleep disorders as a symptom of the depressive syndrome.
1118 V. Efinger et al.

severe
medium
weak

missing

Amitriptyline Clomipramine Citalopram Tranylcypromine

Amitriptyline oxide Imipramine Desipramine
Dosulepin Lofepramine Dibenzepine
Doxepin Maprotiline Fluoxetine
Mianserin Fluvoxamine
Mirtazapine Moclobemide
Nefazodone Nortriptyline
Trazodone Paroxetine
Trimipramine Reboxetine
Sertraline
Venlafaxine
Viloxazine

Fig. 2 Initial sedative potency of antidepressants (Müller and Eckert 2017)

Some compounds also have positive actions on symptoms of the depressive

syndrome, which can occur independently of the antidepressant effect, such as
analgesic properties (amitriptyline, doxepin, clomipramine, duloxetine, venlafaxine)
and cognitive-enhancing (duloxetine, particularly vortioxetine) effects.

Effect on the Noradrenergic System

Early hypotheses already assumed that there is a deficiency of the neurotransmitter

norepinephrine (NE) in central noradrenergic synapses in depressed patients or in a
subgroup of depressed patients. In fact, there are several lines of evidence suggesting
the involvement of this neurotransmitter in the pathophysiology of depression. For
example, there are substantial functional biochemical differences in the NE system
in post-mortem brains from depressed patients and healthy controls. Moreover,
chemical manipulation that depletes the brain of norepinephrine increases the sus-
ceptibility of recovered depressed patients to a depressive relapse, whereas thera-
peutic agents which specifically increase norepinephrine activity are effective
antidepressants (Moret and Briley 2011). A higher concentration of NE can be
achieved medicinally in three ways (see below, Fig. 1a). However, the effects
mentioned above are presumably not directly correlated with antidepressant efficacy,
as they occur very rapidly, but antidepressant efficacy develops slowly over one to
three weeks (Müller 2016).
Antidepressants: Pharmacology and Biochemistry 1119

Reuptake inhibition. Various antidepressants inhibit the reuptake of norepi-

nephrine into the presynaptic nerve endings selectively (e.g. maprotiline, nor-
triptyline) or non-selectively (e.g. amitriptyline, clomipramine, imipramine and
venlafaxine).
Presynaptic α2 receptor blockade α2 receptors, as autoreceptors at the presynapse,
regulate the NE concentration in the synaptic cleft. If the NE concentration is too
high, α2 autoreceptors reduce the release and synthesis rate of norepinephrine in
subsequent nerve terminals. These receptors are blocked, for example, by the
antidepressant mianserin and even more specifically by mirtazapine.
Inhibition of decomposition. The decomposition of norepinephrine takes place
mainly via monoamine oxidase-(MAO-)A. If this enzyme is inhibited by selective
(moclobemide) and non-selective (tranylcypromine) inhibitors, more norepinephrine
remains in the synapse respectively in the synaptic cleft. However, there is no
unlimited increase in the concentration of NE in the synapse in any of these
interventions, as the synthesis rate of NE (even with α2 blockade) decreases due to
polysynaptic feedback mechanisms.

Effect on the Serotonergic System

Early hypotheses, now more than 50 years old, also assumed that serotonin defi-
ciency in the synaptic cleft in the CNS is part of the pathophysiology of depression.
Indeed, there is evidence that lowering the brain 5-HT concentration, by the so-called
tryptophan depletion, can cause clinical depressive symptomatology in those with
risk factors for depression (Cowen 2008). Moreover, post-mortem analysis and
positron-emission tomography showed findings of a reduction in serotonin trans-
porter binding density in the raphe nuclei, amygdala, and other brain areas in
depressed patients, especially suicidal individuals (Nemeroff and Owens 2009).
But it is still not clear whether the above-mentioned changes in the brain’s 5-HT
system is the cause of patients becoming depressed, for example, when they are
exposed to psychosocial stress, or whether these changes are remnants of earlier
acute depressive episodes and their treatment (Cowen 2008). Nevertheless, the
increased availability of synaptic serotonin seems to also be an important initial
mechanism of action of many antidepressants. In today’s often used group of SSRIs,
it is the sole initial effect. However, it is still important to bear in mind that the
increase in serotonin concentration is rapid, but the antidepressant effect only occurs
after some time. One assumption is therefore that in the successful therapy of
depressive patients, longer-lasting plastic processes are initiated or at least
influenced by serotonergic or noradrenergic signalling pathways that are associated
with the alteration of existing or the formation of new synaptic contacts and new
neurons (Riederer et al. 2002).
Reuptake inhibition. Various antidepressants selectively (e.g. SSRI) or
non-selectively (e.g. amitriptyline, clomipramine, imipramine and venlafaxine)
inhibit the reuptake of serotonin into the presynaptic nerve ending.
1120 V. Efinger et al.

5-HT1A receptor activation. There are also 5-HT1A autoreceptors in the serotoner-
gic system, which regulate the transmitter release analogously to the α2 receptors in the
noradrenergic system. In addition to the anxiolytic buspirone, there are some devel-
opmental substances (e.g. gepirone) that, as partial agonists, reduce the activity of the
serotonergic neurons by activating the 5-HT1A autoreceptors but directly activate
postsynaptic 5-HT1A receptors and have therefore been tested as antidepressants.
Inhibition of decomposition. The intra- and extraneuronal decomposition of
serotonin also occurs via MAO-A, whose inhibition by selective (moclobemide)
and non-selective (tranylcypromine) inhibitors leads to an increase in the concen-
tration of serotonin in the synapse respectively in the synaptic cleft.
Central α2 antagonism. These antagonists, e.g. mirtazapine, block the noradren-
ergic inhibition of serotonergic neurons and thus lead to an increased synaptic
activity of the serotonergic system.
5-HT2 antagonism. This antagonism, e.g. also mediated by mirtazapine, can lead
to an increase in the neuronal serotonin release and thus to an increased 5-HT1A
activation via interconnection mechanisms that have not yet been completely clar-
ified. This mechanism also applies to some atypical antipsychotics.
Reuptake activation. In contrast to most of the other antidepressants, which
influences the serotonergic system, tianeptine seems to enhance the reuptake of
serotonin into the presynapse, thus decreasing the serotonin concentration in the
synaptic cleft (Simoni et al. 1992). Nevertheless, tianeptine shows very good
antidepressant efficacy comparable to other substances (Kasper and McEwen 2008).

Effect on the Dopaminergic System

The dopaminergic system (Fig. 3) is very similar to the noradrenergic system (dopa-
mine is the precursor of norepinephrine; the synthesis pathway of the two neurotrans-
mitters is the same up to this stage!). The effects of antidepressants on this system and
their importance in influencing depression have not been well examined. Most of the
antidepressants have no relevant action on the neuronal DA reuptake. Two exceptions
are nomifensine and amineptine, which have been withdrawn from the market because
of serious side effects, and one newer substance: bupropion. St. John’s wort extract
also inhibits neuronal DA uptake to about the same extent as NE uptake (Müller 2003).
The following dopaminergic mechanisms are relevant for an antidepressant effect:
reuptake inhibition, inhibition of dopamine decomposition and presynaptic receptors.
Reuptake inhibition. Bupropion selectively inhibits the reuptake of dopamine and
norepinephrine. It has no effects on other reuptake systems or neurotransmitter
receptors; it is thus not associated with significant sedation, cognitive or anticholin-
ergic side effects. This pharmacologic profile is unique to bupropion, which is
currently the only available NDRI shown to increase the neurotransmission of
dopamine in humans at clinically relevant doses (Stahl et al. 2004).
Inhibition of decomposition. In humans, dopamine is degraded intra- and extra-
neuronally by MAO-A but mainly by MAO-B over oxidative deamination (Fritze
et al. 1989). Therefore, especially the older, non-selective MAO inhibitor
tranylcypromine leads to increased synaptic availability of dopamine.
Antidepressants: Pharmacology and Biochemistry 1121

Fig. 3 Dopaminergic synapse and the pharmacological influence of neuroleptics, antidepressants

and stimulants (Müller and Eckert 2017)

Inhibition of presynaptic receptors. In doses well below the antipsychotic doses,

antipsychotic drugs preferentially block presynaptic dopaminergic D2 autoreceptors
(Fig. 3), which regulate the release of transmitters analogously to the other systems.
The associated increased synaptic availability of dopamine is the basis for the use of
low-dose neuroleptics as anxiolytics or antidepressants (e.g. fluspirilene, sulpiride,
thioridazine) (Müller 1991). The same mechanism is likely also relevant for the
atypical tricyclic drug trimipramine, which is a relatively potent D2 antagonist.

Effect on the Glutamatergic System

The discovery of ketamine as a new, rapid-acting antidepressant has highlighted the

importance of the glutamatergic system and the NMDA receptor, to which ketamine
binds. As a result, this messenger system is now increasingly at the centre of
antidepressant drug development.
A first study by Berman et al. (2000) showed that even a single subanaesthetic
dose of ketamine (0.5 mg/kg; i.v. over 40 min) leads to antidepressant effects, which
1122 V. Efinger et al.

occur within a few hours and even in patients considered treatment-resistant lasting
up to one week. These findings were later confirmed in a double-blind, placebo-
controlled study by Zarate et al. (2006) and many other trials by different research
groups (Sanacora et al. 2017; Wilkinson et al. 2017; Newport et al. 2015). Thus,
ketamine represents a new chance of recovery, especially for therapy-resistant
depression patients. However, the widespread use of ketamine poses a problem
due to its side effects. Besides psychomimetic and dissociative effects, ketamine
has a high potential for abuse. Nevertheless, the findings can be used for the
development of ketamine-like drugs with fewer adverse reactions and a sustained
action, as well as agents that act at other sites within the glutamatergic system.
Examples of new developments are NMDA allosteric modulators (e.g. brexanolone
and SAGE-217) or mGluR2/3 autoreceptor inhibitors (notably LY341,495 and
MGS0039) (Duman 2018). It is believed that the rapid effect of ketamine is due to
the release of growth factors which promote the formation and function of synapses
in the hippocampus and layer V pyramidal neurons in the medial prefrontal cortex
(mPFC) (Björkholm and Monteggia 2016; Duman 2018). This restores connections
that have been broken down by stress mechanisms due to disease. The mechanism of
action is not yet fully understood. The assumption is that a rapid, transient increase in
glutamate (“glutamate burst”) occurs via disinhibition of the glutamatergic trans-
mission that is disturbed during depression. This disinhibition is achieved by
blocking NMDA receptors on GABAergic interneurons by ketamine. The increase
in glutamate in the synaptic cleft activates postsynaptic AMPA receptors, which in
turn leads to increased formation and release of BDNF. BDNF for its part activates
the protein mTORC1 via TrkB and Akt, which ultimately results in the effects
described above ((Duman 2014), Fig. 4). Another assumption suggests that
NMDA receptors on glutamatergic post-synapses are also inhibited by ketamine.
This inhibition leads to a deactivation of eEF2, which normally suppresses BDNF
levels (Krystal et al. 2019). In addition to its influence on the hippocampus and
mPFC, there is evidence that ketamine also has an effect on the lateral habenula
(LHb), a brain region that inhibits major reward centres (Yang et al. 2018). Blocking
the LHb with ketamine cancels out the anti-reward effect. Overall, it is postulated
that the actions on the lateral habenula lead to the rapid onset of antidepressant
effects, whereas the effects on the glutamatergic synapses in the hippocampus and
mPFC lead to the sustained actions of ketamine (Duman 2018). This postulate is
corroborated by the fact that ketamine has a half-life of only about 3 h, suggesting
that the long-lasting antidepressant effects are not mediated by NMDA receptor
blockade per se but rather by synaptic plasticity mechanisms (Björkholm and
Monteggia 2016).
Esketamine, the S-enantiomer of ketamine, has a three- to fourfold higher affinity
to NMDA receptors than R-ketamine. Two phase II RCTs were able to show that
intranasally administered esketamine diminished depressive symptoms already 4 h
post-dose and suicidal ideation in depressed patients. Based on the positive results,
the FDA granted a breakthrough therapy designation for intranasal esketamine, with
the result that it entered phase III development (Garay et al. 2017). In March 2019,
an esketamine nasal spray was approved by the FDA (U.S. Food and Drug
Antidepressants: Pharmacology and Biochemistry 1123

Fig. 4 Glutamatergic synapse and the therapeutic mechanisms of action of the rapid-acting
antidepressant ketamine. (Modified after Duman 2018; Krystal et al. 2019)

Administration 2019). Since the doses of esketamine required for depression may
cause dissociation and delirium, the approval is restricted for the therapy of
treatment-resistant patients with MDD in combination with an oral antidepressant
(Okada et al. 2020).
Scopolamine, a non-selective acetylcholine muscarinic receptor antagonist, also
exhibits promising antidepressant effects. Two clinical trials from 2006 and 2010
reported that a single low dose of scopolamine (4 μg/kg i.v.) already produces
antidepressant responses within the first 3 days (Furey and Drevets 2006; Drevets
and Furey 2010). A much earlier study from 1991 using other administration
(e.g. intramuscular) and dosing routes already suggested that scopolamine can
produce his antidepressant effect within several hours after treatment (Gillin et al.
1991). Moreover, it seems that the antidepressant actions of scopolamine are
increased with repeated administrations (Ellis et al. 2014). Interestingly, it seems
that scopolamine appears to mediate its rapid therapeutic action also via an increased
glutamatergic transmission (Duman 2014). Studies with rodent models were able to
show that scopolamine, just like ketamine, causes a burst of glutamate, with the
result of an increased release of BDNF and an increased mTORC1 signalling, so that
the synapse formation is ameliorated (Voleti et al. 2013; Ghosal et al. 2018).
Furthermore, there are findings that the effect of scopolamine also occurs via
disinhibition of the glutamatergic transmission through the blockage of M1 receptors
on GABAergic interneurons (Wohleb et al. 2016).
Besides (es)ketamine and scopolamine, rapastinel is a new substance of interest.
Rapastinel acts as a partial agonist at the allosteric glycine site of the NMDA
1124 V. Efinger et al.

receptor complex (Moskal et al. 2017). The consequences are an increase in synapse
number and functionality in the mFPC, as well as an increased BDNF release and
mTORC1 activation. In addition to preclinical studies in different rodent models
(including FST, NSFT, LH, chronic mild and social defeat stress), a double-blind
randomised trial showed that a single dose of rapastinel leads to antidepressant
effects lasting for about 7 days (Burgdorf et al. 2013; Kato et al. 2018; Preskorn
et al. 2015). Currently, it is in phase III clinical trials and has received breakthrough
classification.
Tianeptine also seems to influence the glutamatergic system, but in a modulating,
not in a direct, way. It has been shown that tianeptine leads, over various kinases, to
increased phosphorylation of the AMPA receptor subunit GInR1, which is partly
responsible for its antidepressant effect (Müller 2016).

Adaptive Changes with Prolonged Use of Antidepressants

Antidepressants have a number of different primary effects on the CNS. What all
these acute mechanisms of action have in common is that they occur immediately
after application and therefore do not correspond to the delayed development of the
antidepressant action in the patient. It is therefore assumed today that secondary to
these acute influences on the central neurotransmission, adaptive changes occur in
response to the acute intervention, especially at the level of receptors and receptor-
coupled transduction mechanisms. Here, a downregulation of the density and sen-
sitivity of central β-receptors has been best investigated (β-downregulation) but has
neither been found for all substances.
GABAergic mechanisms, glutamatergic mechanisms, the sensitivity of glucocor-
ticoid receptors and the regulation of transcription factors may also be affected by
such adaptive changes. To date, it is not possible to associate one of these adaptive
changes exclusively with the antidepressant efficacy, but rather see these changes,
which can be determined in animal experiments as an expression of an adaptation or
functional plasticity, which is possibly a direct correlate of the antidepressant effect
(Müller and Eckert 2017).

Neuroplasticity

Transcription factors. Previous studies on adaptive changes in mechanisms of

neurotransmission after chronic use of antidepressants had mainly concentrated on
changes in the density and sensitivity of neuronal receptors or secondary transmitters
directly downstream (e.g. cAMP). More recent studies, however, go a step or two
further on the cascade of mechanisms that ultimately control cellular functions under
the influence of signal transduction mechanisms. Various research groups were able
to show that as a possible consequence of influencing transmitters, various intracel-
lular transcription factors are influenced during chronic treatment with antidepres-
sants (Torres et al. 1998; Malberg and Blendy 2005). In the current discussion, the
Antidepressants: Pharmacology and Biochemistry 1125

transcription factor CREB (“cAMP response element-binding protein”), whose

central role in learning processes and synaptic plasticity has been very well
documented, is of particular importance, since there again is hope for a common
intracellular final path of different antidepressant classes (Fig. 5).
Although we now assume that CREB is activated as a result of the intracellular
formation of cAMP, current findings indicate an increase in CREB among antide-
pressants, although the concentration of cAMP is rather downregulated. Despite
these still unanswered questions, the activation of certain transcription factors that
specifically activate the reading of certain target genes and the formation of certain
target proteins is of great relevance today. Various authors have been able to
demonstrate that long-term antidepressant use, for example, leads to the upregulation
of CREB and other transcription factors (Duncan et al. 1993; Hope et al. 1994;
Morinobu et al. 1995). Furthermore, two important animal models of depression
(Posolt test and learned helplessness test) were used to show that the overexpression
of CREB in certain areas of the rat brain led to an antidepressant effect (Chen et al.
2001). Thus, an increase in the activity of the transcription factor CREB can be seen
as a possible common denominator of many antidepressants. However, one should
have learned from past experiences and also interpret these findings with a certain
critical distance until this possible common final path and its causal integration in the
antidepressant mechanism of action has actually been proven beyond doubt.
Structural changes. Structural plasticity is defined as an enlargement or reduction
of the synaptic contact surface or when entire synapses are built up, broken down or
remodelled. It can extend beyond the synapse and includes changes in spines
(in quantity, structure, density and/or morphology) and neurites (dendrites, axons).

Fig. 5 Molecular signalling

pathways of neuroplasticity,
which play an important role
in stress, depression and
antidepressant therapy.
Activation of neuroplasticity
as the common final route of
antidepressant action. After
activation of different targets
(including NMDA, BDNF or
classical neurotransmitter
receptors) on the cell surface,
various intracellular kinase
signalling pathways
ultimately lead to the
formation of pCREB, a
transcription factor for many
neurotrophic factors.
(Modified after Pittenger and
Duman 2008)
1126 V. Efinger et al.

Finally, the formation of new nerve cells, the neurogenesis, which in adult humans can
only be found in the olfactory bulb, the dentate gyrus (DG) of the hippocampus and the
subventricular zone, is also part of structural plasticity. CREB and other inducible
transcription factors induce effector genes that contribute to the stabilization of struc-
tural plasticity. The growth factor BDNF (“brain-derived neurotrophic factor”) is one
of the target genes or target proteins of CREB. Thus, BDNF not only can induce CREB
(Fig. 5) but also is itself a target of CREB induction. BDNF represents an important
growth factor for neuronal function in the CNS. Under the influence of BDNF, there is
dendrite and synapse growth of neuronal cells, whereas without the stimulating effect
of BDNF, atrophy up to the risk of cell death occurs. The fact that BDNF is also a target
gene of the transcription factor CREB has now led to the speculation that chronic
treatment with antidepressants may alter the concentration of BDNF. Interestingly, this
could be confirmed; various studies were able to show that under subchronic treatment
of different antidepressants, the BDNF-m-RNA is upregulated in various brain areas,
but mainly in the hippocampus (Duman et al. 1997, 1999; Duman 2014). Furthermore,
there are data which suggest that tianeptine increases the expression of BDNF and
other nerve growth factors in the hippocampus and amygdala and thus promotes
neuroplasticity (Alfonso et al. 2006; Reagan et al. 2007).
Neurodegenerative hypothesis of depression. Under normal conditions,
neurogenesis and normal growth of dendrites and synapses can be seen in the
adult brain. For many years now, there have been indications that chronic stress,
combined with upregulation of glucocorticoids, can lead along with other biochem-
ical changes to atrophic or degenerative changes, especially in the CA3 regions of the
hippocampus (Duman et al. 1999; Sapolsky et al. 1985). Seeing that the hippocam-
pus has been established to play an important role in processing psychological stress,
it immediately suggests itself to suppose that structural hippocampal changes under-
lie the pathophysiology of major depression (Dranovsky and Hen 2006). Together
with current findings from modern imaging clinical research, in which certain
indications of neurodegenerative changes, notably a decreased volume, in the
hippocampus of depressed patients are described, the finding mentioned above has
led to the so-called neurodegenerative hypothesis of depression, respectively, the
neurotrophic hypothesis of antidepressant effects (Rajkowska et al. 1999; Soares and
Mann 1997; Ebmeier et al. 2006). Interestingly – and this brings us back to the
growth factor BDNF – the hippocampal concentration of BDNF also tends to be
reduced under chronic stress. Other factors, especially genetic ones, which can be
relevant for depression as well, also seem to have a negative influence on the growth
of CA3 neurons. For example, the Met-allele, the result of the genetic polymorphism
Val/Met at codon 66, blocks the release of BDNF, with the consequence that the
carriers of this allele have an increased vulnerability to stress and depression
(Gerhard et al. 2016). But overall, it is still largely a matter of speculation as to
which factors interact in depressive patients.
Neurotrophic hypothesis of antidepressant effects. Under certain conditions, an
improved survival rate of hippocampal neurons with improved dendrite growth and
synapse formation and, in addition, a neoformation of nerve cells (neurogenesis)
have been seen under biological antidepressant therapies (Malberg et al. 2000).
Antidepressants: Pharmacology and Biochemistry 1127

It is known that serotonin over the 5-HT1A receptor and norepinephrine have
positive effects on hippocampal neurogenesis ((Santarelli et al. 2003; Dranovsky and
Hen 2006), Fig. 6d). It is therefore not surprising that SSRIs (e.g. fluoxetine)
increase neurogenesis in the ventral dentate gyrus (Duman 2004). A longitudinal
MRI study from 2013 could show that SSRI treatment over 8 weeks of patients with
major depression led to hippocampal growth, which is in consistency with the results
of a study using high-resolution MRI, where medicated patients with depression had
bigger dentate gyri than unmedicated patients (Huang et al. 2013; Arnone et al.
2013). There is also evidence from various other studies that, next to SSRIs, further
antidepressants (SNRIs, TCAs, MAO inhibitors and ketamine) increase
neurogenesis (Levy et al. 2018). In addition to their effects on neurogenesis,
antidepressants can also regulate other types of neuroplasticity (Fig. 6a–c). Chronic
mild stress has been shown to reduce volume as well as length and branching of
dendrites within the DG, CA3 region and the PFC in rats (Bessa et al. 2009). But
there is evidence that antidepressant treatment increases the variability and turnover
in the branches of dendrites and axons (Castrén and Hen 2013). The chronic use of
fluoxetine, for example, simultaneously increases the elongation and retraction of
branch tips in the mouse visual cortex (Chen et al. 2011). Moreover, imipramine and
tianeptine are able to restore dendritic arborisation to prestress levels (Patrício et al.
2015). Chronic stress also leads to the loss of dendritic spines and synaptic contacts
in the hippocampus and the PFC (McEwen 1999; Cerqueira et al. 2007; Hajszan
et al. 2010; Radley et al. 2006). Fluoxetine treatment, however, increased spine
number back to the baseline level (Chen et al. 2011). In addition to synapse number,
synaptic strength is also regulated by antidepressant drugs. Notably, fluoxetine and
tianeptine are able to modulate long-term potentiation (LTP) within the hippocampus

Fig. 6 Neuronal plasticity. In addition to synaptic plasticity at the level of signal transduction
(receptors, transporters, enzymes, etc.), neuronal plasticity also includes functional aspects of the
synapse such as (a) long-term potentiation (a mechanism of signal impregnation) and (b) histolog-
ically tangible changes (such as density and structure of postsynaptic spines), (c) length and
branching of neurites and (d) neoformation of neurons (neurogenesis), which is, however, mainly
reserved for two small areas of the hippocampus (Müller 2016)
1128 V. Efinger et al.

(Rocher et al. 2004; Wang et al. 2008). The presumption is that this finding may be
related to the “dematuration” process observed in the dentate granule neurons
(Kobayashi et al. 2010), indicating that antidepressant treatment reactivated
juvenile-like plasticity in the brain (Maya Vetencourt et al. 2008; Karpova et al.
2011).
Up to now, the effects of antidepressants on several mechanisms of neuroplasticity
were mainly seen as a consequence of the elevated synaptic concentrations of the amine
neurotransmitters leading to enhanced activation of postsynaptic receptors of the respec-
tive amine neurotransmitters (Fig. 5). However, there is increasing evidence that some
antidepressants may additionally affect neuroplasticity by directly activating the signal
cascades finally leading to enhanced levels of neurotrophic factors like BDNF (Fig. 5)
and NGF as shown for tianeptine (McEwen et al. 2010), fluvoxamine (Ishima et al.
2014) and fluoxetine (Levy et al. 2019). Similarly, several other drugs with antidepres-
sant properties have been shown to possess direct effects on neuroplasticity like
hyperforin, the main active ingredient of hypericum extract (Heiser et al. 2013) and
the special lavender oil Silexan (Friedland et al. 2021).
The results of all the studies mentioned above point towards that the adaptive
effects of antidepressants may repose on influencing the neuroplasticity in the
dentate gyrus and several other brain regions. Nevertheless, this hypothesis is still
not proven beyond doubt, and there are still a lot of unanswered questions, so further
experiments and clinical trials are needed. But the findings can help to better
understand the pathophysiology of major depression and to develop new
antidepressants.

Behavioural Pharmacological Effects of Antidepressants

Just like the chemical structure, the pharmacological properties of the preparations
used as antidepressants are quite different. The basic problem of research in this area
is the lack of an adequate animal model of depression. After about 30 years of
research, the following animal models are mainly used to assess the antidepressant
properties (Willner 1984). However, only some of these are actual “animal models of
depression,” while others are based on the pharmacological properties of tricyclics
and primarily record their NE- or serotonin-enhancing effects.
Spontaneous behaviour. Antidepressants, especially tricyclics, inhibit the spon-
taneous behaviour in animals, and they show centrally depressing actions at medium
and higher doses. So, this model tests sedative, but not antidepressant properties. In
contrast to neuroleptics, which produce similar effects, antidepressants cause a slight
to strong increase in excitability after increasing doses.
Reserpine antagonism. Antidepressants, particularly tricyclics, cancel out the
effects caused by reserpine (psychomotor inhibition, reduced autonomic reactions).
Potentiation of various catecholamine effects. Tricyclic antidepressants intensify,
probably by inhibiting the reabsorption of norepinephrine and the resulting increase
in the concentration at the receptor, the increases in blood pressure caused by this
transmitter.
Antidepressants: Pharmacology and Biochemistry 1129

Separation model. If young animals are socially isolated (separation from parent
animals), after some time, there is a considerable loss of activity and significant
changes in posture. These behaviours are reversed by antidepressants. However, this
model is not specific, as similar effects can also be achieved with alcohol, benzodi-
azepines and opioids.
Behavioural despair test. This “swimming test” determines how long the animals
swim after being immersed in a small water-filled container before they adopt an
immobile position. Antidepressants prolong the swimming phase, but this is also
achieved with antihistamines and anticholinergics.
Chronic stress test. In this experiment, rats or mice are exposed to chronic stress
(fasting, electric shocks, isolation, immersion in cold water) for a longer period of
time. The resulting reduced exploratory behaviour is increased again by antidepres-
sants, especially tricyclics.
Learned helplessness test. In this test, the animals learn “helplessness” through
unavoidable stimuli, which even after the experimental situation is ceased, no longer
enables them to influence tasks through their own behavioural reactions. This
helplessness is reversed by antidepressants, but not by neuroleptics and
tranquillizers.
Bulb ectomised rats. After surgical removal of the olfactory bulb, rats show
various behavioural changes that are similar to depression and can be corrected by
antidepressants.
None of these models is sufficient on their own to reliably predict an antidepres-
sant effect in humans. Though the hit rate can be significantly increased by a
combination of several of the tests mentioned above, all of which show a certain
“depression analogy.” However, to date, with all of these models, it has not yet been
possible to develop substances that exceed the usual approx. 70% response rate at
initial use.

Cross-references

▶ Agomelatine and Depressions

▶ Amitriptyline and Depressions
▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and
Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Molecular Aspects of SSRIs
▶ Bupropion and Depressions
▶ Hypericum and Depression
▶ Mianserine and Depressions
▶ Mirtazapine and Depressions
▶ Monoamine Oxidase Inhibitors in Depressive Disorders
▶ Nortriptyline and Maprotiline for Depressions
▶ Psychopharmacotherapy of Depressive Disorders
1130 V. Efinger et al.

▶ Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine,

Fluvoxamine, Paroxetine, and Sertraline
▶ Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,
Desvenlafaxine, Duloxetine, Milnacipran, Levomilnacipran
▶ Trazodone and Depression
▶ Vilazodone and Depressions
▶ Vortioxetine and Depressions

References
Alfonso J, Frick LR, Silberman DM, Palumbo ML, Genaro AM, Frasch AC. Regulation of
hippocampal gene expression is conserved in two species subjected to different stressors and
antidepressant treatments. Biol Psychiatry. 2006;59(3):244–51.
Arnone D, McKie S, Elliott R, Juhasz G, Thomas EJ, Downey D, et al. State-dependent changes in
hippocampal grey matter in depression. Mol Psychiatry. 2013;18(12):1265–72.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal
JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–4.
Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat
Rev Neurosci. 2006;7:137–51.
Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, et al. The mood-improving
actions of antidepressants do not depend on neurogenesis but are associated with neuronal
remodeling. Mol Psychiatry. 2009;14(8):764–73, 739.
Björkholm C, Monteggia LM. BDNF – a key transducer of antidepressant effects. Neuropharma-
cology. 2016;102:72–9.
Burgdorf J, Zhang X, Nicholson KL, Balster RL, Leander JD, Stanton PK, et al. GLYX-13, a
NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects
without ketamine-like side effects. Neuropsychopharmacology. 2013;38(5):729–42.
Castrén E, Hen R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 2013;36(5):
259–67.
Cerqueira JJ, Mailliet F, Almeida OFX, Jay TM, Sousa N. The prefrontal cortex as a key target of
the maladaptive response to stress. J Neurosci. 2007;27(11):2781–7.
Chen AC, Shirayama Y, Shin KH, Neve RL, Duman RS. Expression of the cAMP response element
binding protein (CREB) in hippocampus produces an antidepressant effect. Biol Psychiatry.
2001;49:753–62.
Chen JL, Lin WC, Cha JW, So PT, Kubota Y, Nedivi E. Structural basis for the role of inhibition in
facilitating adult brain plasticity. Nat Neurosci. 2011;14(5):587–94.
Cowen PJ. Serotonin and depression: pathophysiological mechanism or marketing myth? Trends
Pharmacol Sci. 2008;29(9):433–6.
de Simoni MG, de Luigi A, Clavenna A, Manfridi A. In vivo studies on the enhancement of
serotonin reuptake by tianeptine. Brain Res. 1992;574(1–2):93–7.
Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol
Psychiatry. 2006;59(12):1136–43.
Drevets WC, Furey ML. Replication of scopolamine’s antidepressant efficacy in major depressive
disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry. 2010;67(5):432–8.
Duman RS. Depression: a case of neuronal life and death? Biol Psychiatry. 2004;56(3):140–5.
Duman RS. Pathophysiology of depression and innovative treatments: remodeling glutamatergic
synaptic connections. Dialogues Clin Neurosci. 2014;16:11–27.
Duman RS. Ketamine and rapid-acting antidepressants: a new era in the battle against depression
and suicide. F1000Res. 2018;7:F1000.
Antidepressants: Pharmacology and Biochemistry 1131

Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen
Psychiatry. 1997;54:597–606.
Duman RS, Malberg J, Thorne J. Neural plasticity to stress and antidepressant treatment. Biol
Psychiatry. 1999;46:1181–91.
Duncan GE, Johnson KB, Breese GR. Topographic patterns of brain activity in response to swim
stress assessment by 2-deoxyglucose uptake and expression of fos-like immunreacivity. J
Neurosci. 1993;13:3932–4.
Ebmeier KP, Donaghex C, Steele JD. Recent developments and current controversies in depression.
Lancet. 2006;367:153–67.
Ellis JS, Zarate CA, Luckenbaugh DA, Furey ML. Antidepressant treatment history as a predictor of
response to scopolamine: clinical implications. J Affect Disord. 2014;162:39–42.
Frazer A. Antidepressants. J Clin Psychiatry. 1997;58(Suppl 6):9–25.
Friedland K, Silani G, Schuwald A, Stockburger C, Koch E, Nöldner M, Müller WE. Neurotrophic
properties of Silexan, an essential oil from the flowers of lavender-preclinical evidence for
antidepressant-like properties. Pharmacopsychiatry. 2021;54(1):37–46.
Fritze J, Koronakis P, Konradi C, Riederer P. Isoelectric focusing of monoamine oxidase subtypes
as identified by MAO inhibitors. Eur J Pharmacol Mol Pharmacol. 1989;172(2):147–54.
Fuchs E, Simon M, Schmelting B. Pharmacology of a new antidepressant: benefit of the implication
of the melatonergic system. Int Clin Psychopharmacol. 2006;21(Suppl 1):17–20.
Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a
randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63(10):1121–9.
Garay RP, Zarate CA, Charpeaud T, Citrome L, Correll CU, Hameg A, Llorca P-M. Investigational
drugs in recent clinical trials for treatment-resistant depression. Expert Rev Neurother. 2017;17
(6):593–609.
Gerhard DM, Wohleb ES, Duman RS. Emerging treatment mechanisms for depression: focus on
glutamate and synaptic plasticity. Drug Discov Today. 2016;21(3):454–64.
Ghosal S, Bang E, Yue W, Hare BD, Lepack AE, Girgenti MJ, Duman RS. Activity-dependent
brain-derived neurotrophic factor release is required for the rapid antidepressant actions of
scopolamine. Biol Psychiatry. 2018;83(1):29–37.
Gillin JC, Sutton L, Ruiz C, Darko D, Golshan S, Risch SC, Janowsky D. The effects of
scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal
comparison group. Biol Psychiatry. 1991;30(2):157–69.
Hajszan T, Szigeti-Buck K, Sallam NL, Bober J, Parducz A, Maclusky NJ, et al. Effects of estradiol
on learned helplessness and associated remodeling of hippocampal spine synapses in female
rats. Biol Psychiatry. 2010;67(2):168–74.
Heiser JH, Schuwald AM, Sillani G, Ye L, Müller WE, Leuner K. TRPC6 channel-mediated neurite
outgrowth in PC12 cells and hippocampal neurons involves activation of RAS/MEK/ERK,
PI3K, and CAMKIV signaling. J Neurochem. 2013;127(3):303–13.
Hope BT, Kelz MB, Duman RS, Nestler EJ. Chronic electroconvulsive seizure (ECS) treatment
results in expression of a long-lasting AP-1 complex in brain with altered composition and
characteristics. J Neurosci. 1994;14(7):4318–28.
Huang Y, Coupland NJ, Lebel RM, Carter R, Seres P, Wilman AH, Malykhin NV. Structural
changes in hippocampal subfields in major depressive disorder: a high-field magnetic resonance
imaging study. Biol Psychiatry. 2013;74(1):62–8.
Ishima T, Fujita Y, Hashimoto K. Interaction of new antidepressants with sigma-1 receptor
chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur J Pharmacol.
2014;727:167–73.
Karpova NN, Pickenhagen A, Lindholm J, Tiraboschi E, Kulesskaya N, Agústsdóttir A, et al. Fear
erasure in mice requires synergy between antidepressant drugs and extinction training. Science.
2011;334(6063):1731–4.
Kasper S, McEwen BS. Neurobiological and clinical effects of the antidepressant tianeptine. CNS
Drugs. 2008;22(1):15–26.
Kato T, Fogaça MV, Deyama S, Li X-Y, Fukumoto K, Duman RS. BDNF release and signaling are
required for the antidepressant actions of GLYX-13. Mol Psychiatry. 2018;23(10):2007–17.
1132 V. Efinger et al.

Kielholz P. Diagnose und Therapie der Depression für den Praktiker. 3rd ed. München: J. F.
Lehmanns Verlag; 1971.
Kobayashi K, Ikeda Y, Sakai A, Yamasaki N, Haneda E, Miyakawa T, Suzuki H. Reversal of
hippocampal neuronal maturation by serotonergic antidepressants. Proc Natl Acad Sci U S
A. 2010;107(18):8434–9.
Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: a paradigm shift for
depression research and treatment. Neuron. 2019;101(5):774–8.
Leonard BE. Mechanisms of action of antidepressants. CNS Drugs. 1995;4(Suppl 1):1–12.
Leonard BE. New approaches to the treatment of depression. J Clin Psychiatry. 1996;57(Suppl
4):26–33.
Levy MJF, Boulle F, Steinbusch HW, van den Hove DLA, Kenis G, Lanfumey L. Neurotrophic
factors and neuroplasticity pathways in the pathophysiology and treatment of depression.
Psychopharmacology. 2018;235(8):2195–220.
Levy MJF, Boulle F, Emerit MB, Poilbout C, Steinbusch HWM, van den Hove DLA, et al. 5-HTT
independent effects of fluoxetine on neuroplasticity. Sci Rep. 2019;9(1):6311.
Malberg JE, Blendy JA. Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci.
2005;26(12):631–8.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases
neurogenesis in adult rat hippocampus. J Neurosci. 2000;20(24):9104–10.
Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, de Pasquale R, O’Leary OF, et al. The
antidepressant fluoxetine restores plasticity in the adult visual cortex. Science. 2008;320
(5874):385–8.
McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105–22.
McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E. The
neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic
modulation. Mol Psychiatry. 2010;15(3):237–49.
Moret C, Briley M. The importance of norepinephrine in depression. Neuropsychiatr Dis Treat.
2011;7(Suppl 1):9–13.
Morinobu S, Nibuya M, Duman RS. Chronic antidepressant treatment down-regulates the induction
of c-fos mRNA in response to acute stress in rat frontal cortex. Neuropsychopharmacology.
1995;12(3):221–8.
Moskal JR, Burgdorf JS, Stanton PK, Kroes RA, Disterhoft JF, Burch RM, Khan MA. The
development of Rapastinel (formerly GLYX-13); a rapid acting and long lasting antidepressant.
Curr Neuropharmacol. 2017;15(1):47–56.
Müller WE. Wirkungsmechanismus niedrigdosierter Neuroleptika bei Angst und Depression. In:
Pöldinger W, editor. Niedrigdosierte Neuroleptika bei ängstlich-depressiven Zustandsbildern
und psychosomatischen Erkrankungen. Karlsruhe: Braun; 1991. p. 24–38.
Müller WE. Current St John’s wort research from mode of action to clinical efficacy. Pharmacol
Res. 2003;47(2):101–9.
Müller WE. Antidepressiva und kognitive Dysfunktion: die Rolle von Vortioxetin. Psychopharma-
kotherapie. 2015;22:177–88.
Müller WE. Normalisierung gestörter Neuroplastizitätsmechanismen als gemeinsame Endstrecke
im Wirkungsmechanismus von Antidepressiva: Die besondere Rolle von Tianeptin.
Psychopharmakotherapie. 2016;23(6):230–8.
Müller WE, Eckert A. Psychopharmakotherapie – pharmakologische Grundlagen. In: Möller H-J,
Laux G, Kapfhammer H-P, editors. Psychiatrie, Psychosomatik, Psychotherapie. 5th
ed. Springer; 2017. p. 749–93.
Nemeroff CB, Owens MJ. The role of serotonin in the pathophysiology of depression: as important
as ever. Clin Chem. 2009;55(8):1578–9.
Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine and
other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J
Psychiatry. 2015;172(10):950–66.
Antidepressants: Pharmacology and Biochemistry 1133

Okada M, Kawano Y, Fukuyama K, Motomura E, Shiroyama T. Candidate strategies for develop-

ment of a rapid-acting antidepressant class that does not result in neuropsychiatric adverse
effects: prevention of ketamine-induced neuropsychiatric adverse reactions. Int J Mol Sci.
2020;21(21):7951.
Otte C. Depression und kognitive Dysfunktion. Psychopharmakotherapie. 2014;21:40–9.
Patrício P, Mateus-Pinheiro A, Irmler M, Alves ND, Machado-Santos AR, Morais M, et al.
Differential and converging molecular mechanisms of antidepressants’ action in the hippocam-
pal dentate gyrus. Neuropsychopharmacology. 2015;40(2):338–49.
Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms.
Neuropsychopharmacology. 2008;33(1):88–109.
Preskorn S, Macaluso M, Mehra DOV, Zammit G, Moskal JR, Burch RM. Randomized proof of
concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major
depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract. 2015;21
(2):140–9.
Radley JJ, Rocher AB, Miller M, Janssen WGM, Liston C, Hof PR, et al. Repeated stress induces
dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16(3):313–20.
Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, et al. Morphometric
evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry.
1999;45(9):1085–98.
Reagan LP, Hendry RM, Reznikov LR, Piroli GG, Wood GE, McEwen BS, Grillo CA. Tianeptine
increases brain-derived neurotrophic factor expression in the rat amygdala. Eur J Pharmacol.
2007;565(1–3):68–75.
Riederer P, Laux G, Pöldinger W. Neuro-Psychopharmaka: Ein Therapie-Handbuch. 2nd
ed. Wien/New York: Springer; 2002.
Rocher C, Spedding M, Munoz C, Jay TM. Acute stress-induced changes in hippocampal/prefrontal
circuits in rats: effects of antidepressants. Cereb Cortex. 2004;14(2):224–9.
Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, et al. A consensus
statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiat. 2017;74
(4):399–405.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al. Requirement of hippo-
campal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301(5634):
805–9.
Sapolsky RM, Krey LC, McEwen BS. Prolonged glucocorticoid exposure reduces hippocampal
neuron number: implications for aging. J Neurosci. 1985;5(5):1222–7.
Soares JC, Mann JJ. The anatomy of mood disorders--review of structural neuroimaging studies.
Biol Psychiatry. 1997;41(1):86–106.
Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S. A review of the
neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor. Prim
Care Companion J Clin Psychiatry. 2004;6(4):159–66.
Stassen HH, Angst J, Delini-Stula A. Delayed onset of action of antidepressant drugs? Survey of
results of Zurich meta-analyses. Pharmacopsychiatry. 1996;29(3):87–96.
Torres G, Horowitz JM, Laflamme N, Rivest S. Fluoxetine induces the transcription of genes
encoding c-fos, corticotropin-releasing factor and its type 1 receptor in rat brain. Neuroscience.
1998;87(2):463–77.
U.S. Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant
depression. 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-
spray-medication-treatment-resistant-depression-available-only-certified. Accessed 26 Mar 2021.
Voleti B, Navarria A, Liu R-J, Banasr M, Li N, Terwilliger R, et al. Scopolamine rapidly increases
mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant
behavioral responses. Biol Psychiatry. 2013;74(10):742–9.
Wang J-W, David DJ, Monckton JE, Battaglia F, Hen R. Chronic fluoxetine stimulates maturation and
synaptic plasticity of adult-born hippocampal granule cells. J Neurosci. 2008;28(6):1374–84.
1134 V. Efinger et al.

Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G. A survey of the clinical,
off-label use of ketamine as a treatment for psychiatric disorders. Am J Psychiatry. 2017;174(7):
695–6.
Willner P. The validity of animal models of depression. Psychopharmacology. 1984;83(1):1–16.
Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR, Alreja M, Duman RS. GABA
interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Invest.
2016;126(7):2482–94.
Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H. Ketamine blocks bursting in the lateral habenula
to rapidly relieve depression. Nature. 2018;554(7692):317–22.
Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized
trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen
Psychiatry. 2006;63(8):856–64.
Antidepressants: Indications,
Contraindications, Interactions, and Side
Effects

Filippo Corponi, Chiara Fabbri, and Alessandro Serretti

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1138
Major Depressive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1138
Anxiety Disorders, Obsessive-Compulsive Disorder, Trauma- and Stressor-Related
Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1143
Other Approved Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144
Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1145
Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1145
Pregnancy and Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146
Liver and Kidney Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147
Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148
MAOIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148
TCAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150
SSRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150
SNRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151
Mirtazapine and Mianserin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
Reboxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
Bupropion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153
Agomelatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153
Vortioxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
Gastrointestinal System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
Genitourinary System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157
Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158

F. Corponi · A. Serretti (*)

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
e-mail: filippo.corponi@gmail.com; alessandro.serretti@unibo.it; alessandro.serretti@gmail.com
C. Fabbri
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and
Neuroscience, King’s College London, London, UK
e-mail: chiara.fabbri@yahoo.it

© Springer Nature Switzerland AG 2022 1135

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_29
1136 F. Corponi et al.

Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159

Weight Gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162
Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162
Hyperhidrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
Sleep Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
Discontinuation Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1164
Suicidality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165
SSRIs-Induced Emotional Indifference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165
Antidepressant-Induced Jitteriness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168

Abstract
Antidepressants are among the most largely prescribed medications worldwide.
They are the mainstay of depression treatment but are used for other conditions
too. As of today, over 40 medications are available. The history of new antide-
pressant development reflects an endeavor to reduce side effects while preserving
efficacy. In this perspective, newer agents have largely replaced monoamine
oxidase inhibitors and tricyclic antidepressants on the ground of higher tolerabil-
ity and similar efficacy. Considerations of safety, tolerability, comorbidities, and
possible drug interactions rather than efficacy generally guide antidepressant
choice. Personalized antidepressant choice should be implemented by matching
each patient’s symptom profile with the pharmacodynamic/pharmacokinetic pro-
file of available antidepressants. However, the use of clinical criteria to guide drug
choice does not prevent the occurrence of appreciable side effects, poor treatment
adherence, and insufficient response in a relevant proportion of patients. The need
of slow dose titration and the delayed development of the full antidepressant
action represent further issues. Several approaches can address these issues and
improve the outcomes of antidepressant treatment. These include the use of
genetic variants modulating antidepressant metabolism to guide drug choice
and dosing, as recommended by available guidelines. The validation of further
genetic and nongenetic biomarkers is expected in the next future. However, such
strategies merely capitalize on currently available medications which act on
substantially similar pathways and do not reflect the heterogeneity in depression
pathogenesis. The development of antidepressants with new mechanisms may
involve the modulation of endocrinological and immunological pathways, as well
as non-monoaminergic neurotransmission and metabolic regulation.

List of Abbreviations
5-HT Serotonin
ACT Anatomical Therapeutic Chemical
ADHH Attention deficit hyperactivity disorder
AIJ Antidepressant-induced jitteriness
BD Bipolar disorder
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1137

BDI Type I bipolar disorder

BDII Type II bipolar disorder
BN Bulimia nervosa
DILI Drug-induced liver injury
EMA European Medicines Agency
EPS Extrapyramidal symptoms
FDA Food and Drug Administration
ISBD International Society for Bipolar Disorders
KOR K-opioid receptor
MAO Monoamine oxidase
MAOIs Monoamine oxidase inhibitors
MDD Major depressive disorder
NbN Neuroscience-based Nomenclature
NE Norepinephrine
NMDA N-methyl-D-aspartate
OCD Obsessive-compulsive disorder
PTSD Post-traumatic stress disorder
RCTs Randomized clinical trials
REM Rapid eye movement
SMD Standardized mean difference
SNRIs Serotonin and noradrenaline reuptake inhibitors
SSRIs Selective serotonin reuptake inhibitors
TCAs Tricyclic antidepressants
TRD Treatment-resistant depression

Introduction

Depression is a highly recurrent disorder taking a heavy toll on both personal and
public health. It is the leading cause of disability worldwide and has been substan-
tially increasing over the past few decades, mainly driven by population growth and
ageing (Ahmad Kiadaliri 2016). With an estimated 350 million people affected
globally, the economic burden of depressive disorders in the USA alone has been
estimated to be more than US$210 billion (WHO 2017). Antidepressants are the
mainstay of depression treatment and rank among the top three most commonly used
therapeutic drug classes in the USA – in the 2011–2014 period, 12.7% of persons in
the USA aged 12 and over reported antidepressant use in the past month (Pratt et al.
2017). Antidepressants are prescribed for a wide range of conditions other than
major depression. It has been over 60 years since the serendipitous discovery of the
first antidepressant, when an antituberculosis drug, iproniazid, was observed to
improve mood in patients treated for tuberculosis. As of today, over 40 antidepres-
sants have been approved by regulatory agencies.
There are a number of non-pharmacological medical treatments for depression,
but it is beyond the scope of the present chapter to discuss them, and the reader can
refer to the relevant literature (Farah et al. 2016).
1138 F. Corponi et al.

Indications

While depression accounts for the majority of antidepressant prescription, this class
of drugs is also used to treat other conditions. Indications are established through
randomized clinical trials (RCTs), and being depression the most relevant and
prevalent disease, pharmaceutical companies tend to set up RCTs aimed at gaining
approval for this disorder in the first place. The relatively high rates of placebo
response (20–40%) have often represented a concern and contributed to failed trials
and delayed delivery of new medications to market. A number of factors purportedly
drive placebo response, including the randomization ratio, the expectation of receiv-
ing an active treatment, the therapeutic setting, the frequency of study visits, and the
entry criteria (e.g., milder forms of depression). These factors are potential causes for
an inflation of placebo response (Furukawa et al. 2016). However, antidepressants
are more efficacious than placebo in adults with major depressive disorder (MDD),
and although the overall effect size is statistically modest (standardized mean
difference (SMD) of 0.30 in acute treatment), statistical significance does not
equal to clinical significance (Cipriani et al. 2018).
The approval for indications other than MDD requires additional RCTs that
pharmaceutical companies may decide not to fund, resulting in common “off-
label” use of medications. By the same token, while not all drugs appear to be
equally effective in each condition, limited data on comparability across drugs is
available for cost reasons. At present, due to the absence of validated biomarkers to
guide treatment choice and dosing, treatment decisions rely to a great extent on
clinical factors. A comprehensive list of antidepressants licensed by the US Food and
Drug Administration (FDA) and European Medicines Agency (EMA) is reported in
Table 1.

Major Depressive Disorder

The recommended severity threshold to start an antidepressant treatment as first-line

intervention is a diagnosis of major depression of at least a moderate severity (Taylor
et al. 2018; Gelenberg et al. 2010; Kennedy et al. 2016; Baldwin et al. 2015). This is
typically defined as a 17-item Hamilton Depression Rating Scale (Hamilton
1980) > 17 or Montgomery-Asberg Depression Rating Scale (Montgomery and
Asberg 1979) > 20, which is indeed the entry criterion for most RCTs with a placebo
comparator. As a rule of thumb for the clinical practice, it has been suggested that the
diagnosis MDD according to the Diagnostic and Statistical Manual of Mental
Disorders fifth edition (American Psychiatric A 2013) per se should prompt initia-
tion of an antidepressant treatment. In case of milder episodes of disease, the
evidence in favor of antidepressant effectiveness is less robust, and psychotherapy
can be an alternative option. The preference of one intervention over the other should
be carefully balanced and discussed with the patient.
Once pharmacotherapy has been deemed as appropriate, the choice of the specific
drug is the following step. Monotherapy is recommended over polytherapy as
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1139

Table 1 Antidepressants indications approved by the US Food and Drug Administration (FDA)
and European Medicines Agency (EMA)
Drug FDA EMA
Fluoxetine MDD, OCD, BN, PD MDD, OCD, BN
Sertraline MDD, OCD, PD, PTSD, SAD, MDD, OCD, PD, PTSD, SAD
PMD
Paroxetine MDD, OCD, PD, SAD, GAD, MDD, OCD, PD, SAG, GAD,
PTSD PTSD
Fluvoxamine OCD MDD, OCD
Citalopram MDD MDD, PD
Escitaloprama MDD, GAD MDD, PD, SAD, OCD, GAD
Venlafaxine MDD, GAD, SAD, PD MDD
Duloxetine MDD, GAD, DPNP, FM, CMP MDD, GAD, DPNP
Milnacipram FM \
Vilazodone MDD \
Bupropiona MDD, SAD, SC MDD, SC
Reboxetinea \ MDD
Atomoxetine ADHD ADHD
Agomelatine \ MDD
Mirtazapine MDD MDD
Mianserina MDD
Trazodonea MDD MDD
Nefazodone Withdrawn due to incidence of Withdrawn due to incidence of
severe liver damage (1 in every severe liver damage (1 in every
250,000 to 300,000 patient-years) 250,000 to 300,000 patient-years)
Vortioxetine MDD MDD
Clomipraminea OCD MDD, OCD, PD, PTSD, SAD,
GAD
Nortriptylinea MDD MDD
Amitriptyline MDD MDD, NP, CTTH (prophylactic),
migraine (prophylactic), NE
Desipraminea MDD MDD
Tranylcyprominea MDD MDD
Doxepina MDD, insomnia characterized by MDD
difficulties with sleep maintenance
Imipraminea MDD, CE MDD, CE
ADHD attention-deficit/hyperactivity disorder, BN bulimia nervosa, CE childhood enuresis, CMP
chronic musculoskeletal pain, CTTH chronic tension-type headache, DPNP diabetic peripheral
neuropathic pain, FB fibromyalgia, GAD generalized anxiety disorder, MDD major depressive
disorder, NE nocturnal enuresis, NP neuropathic pain, OCD obsessive-compulsive disorder, PD
panic disorder, PMD premenstrual dysphoric disorder, PTSD post-traumatic stress disorder, SAD
social anxiety disorder, SC smoking cessation, VSM vasomotor symptoms associated with
menopause
a
Approved by individual European countries through a decentralized procedure – indications
licensed by the following national agencies are reported: Medicines and Healthcare Products
Regulatory Agency (MHRA); Federal Institute for Drugs and Medical Devices (BfArM);
Italian Medicines Agency (AIFA); Spanish Agency for Medicines and Health Products
(AEMPS); National Agency for the Safety of Medicine and Health Products (ANSM)
1140 F. Corponi et al.

first-line treatment, but evidence for superiority of one antidepressant over the other
is flimsy, making the identification of the most appropriate drug difficult. By and
large, effectiveness is comparable between classes and within classes of medications
and does not therefore stand as the main criterion of choice. However, differences in
the risk of causing particular side effects and drug interactions are better known.
Thus, considerations such as safety, tolerability, co-occurring medical conditions,
and potential for drugs interactions are usually recommended to guide the initial
selection of the antidepressant medication. Personal and familial history of prior
treatments should be investigated since an individual is more likely to respond to an
antidepressant to which himself/herself or a next of kin have responded in the past. In
addition, when choosing which antidepressant to prescribe, the specific pharmaco-
dynamic profile (i.e., pharmacological targets and binding affinity) should be con-
sidered in order to match the observed clinical profile (Serretti 2018). On these
premises, selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrena-
line reuptake inhibitors (SNRIs), mirtazapine, bupropion, and vortioxetine are con-
sidered the first-line medications in most cases (Gelenberg et al. 2010; Kennedy et al.
2016).
The elderly on the one hand, children and adolescents on the other represent
special populations. The elderly, particularly patients aged 65 and over, seem to
benefit less from antidepressants, in terms of both smaller drug-placebo difference
and later onset of antidepressant action. As comorbidity is frequent in this age range,
patients should be thoroughly evaluated for the presence of co-occurring medical
conditions which can precipitate depressive episodes and hamper antidepressant
action. There is no ideal antidepressant in the elderly, and they should be closely
monitored for potential side effects and drug interactions. SSRIs are generally better
tolerated than tricyclic antidepressants (TCAs). Agomelatine, sertraline,
vortioxetine, and duloxetine as well are effective and generally well-tolerated (Tay-
lor et al. 2018; Tedeschini et al. 2011). At the other end of the age spectrum,
fluoxetine is the only both FDA- and EMA-approved medication for the treatment
of depression in children and adolescents. Escitalopram carries FDA approval solely
for adolescent depression. Psychological interventions are considered first-line treat-
ment for child and adolescent depression, and pharmacotherapy should be used for
more severe episodes of disease in combination with psychological treatment. In
younger children (<13 years), antidepressant efficacy seems smaller (Birmaher et al.
2007).
Over the past decades, there has been an endeavor in psychiatric research to boost
precision medicine (Serretti 2018), which ultimately aims at therapies tailored to the
specific patient, on the basis of a deep genetic, environmental and psychological
characterization. Despite some initial promising results, no pharmacogenetic test has
become of common use in non-research clinical settings because of the lack of
definitive evidence of favorable cost/effectiveness ratio. Current clinical guidelines
and drug labels recommend genotyping of variants in two cytochrome genes
(CYP2D6 and CYP2C19) to guide choice and dosing of a number of antidepressants
(Consortium CPI 2017; FDA 2017). Indeed genetic polymorphisms in cytochrome
P450 (CYP450) genes, alongside other factors, affect drug plasma concentration and
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1141

consequently have an impact on clinical outcomes. In current clinical practice,

therapeutic drug monitoring (TDM) is often used instead of CYP450 genotyping
based on the assumption that clinical effects correlate better with blood levels than
doses, helping to optimize drug dosage (Hiemke et al. 2018). However, TDM can be
performed when the drug concentration reaches the steady state, while CYP450
genotyping can provide information to guide drug choice and dosing scheme at
baseline (Ostad Haji et al. 2012).
After the most appropriate antidepressant has been identified, treatment begins
with the acute phase (Fig. 1). The objective at this stage is a full return to the patient’s
baseline level of functioning, i.e., remission. This should always be vigorously
pursued since compelling evidence indicates that even mild residual symptoms,
besides hampering personal psychosocial functioning, are strongly associated with
a higher risk of relapse (i.e., return to the full criteria for MDD diagnosis before
recovery) and recurrence (i.e., development of a new MDD episode). Common
residual symptoms include cognitive, sleep, appetite/weight disturbances. Relapse
rate increases with the number of residual symptoms (Nierenberg et al. 2010). The
acute phase spans 4–6 weeks. Treatment guidelines recommend an antidepressant
trial of up to 4 weeks or longer before considering a change in treatment. However,
accumulating evidence suggests that the trend of improvement within the first
2 weeks predicts with high sensitivity later response and remission. Delaying
assessment of antidepressant efficacy may therefore not be cost/effective and may
also jeopardize treatment outcome. A
20% reduction in symptom severity at week
2 compared to baseline has been proposed as threshold to decide if the antidepressant
should be continued and titrated toward maximum recommend dose as tolerated.
Response, defined as a clinical improvement of at least 50%, is then evaluated at
week 4. In case of non-response at week 4 or of <20% improvement at week 2, a
change in treatment is warranted (Szegedi et al. 2009; Katzman et al. 2017). Three

Fig. 1 Phases of antidepressant treatment

1142 F. Corponi et al.

options are available: 1) maximizing the dose of medication, especially if the upper
limit dosage has not been reached; 2) switching to a different compound, considering
that the appropriateness of changing between or within classes is controversial; and
3) adding an adjunctive agent from an armamentarium comprising lithium, thyroid
hormones, another antidepressant, some anti-convulsants, some atypical antipsy-
chotics, and psychostimulants. Non-response to two or more antidepressants pre-
scribed at an adequate dose and duration is usually defined treatment-resistant
depression (TRD). A discussion of TRD and its management is beyond the scope
of this chapter. Overall, one-third of MDD patients will experience TRD. Approx-
imately one-third of patients on their first MDD episode will remit on their first
antidepressant trial after the acute phase of treatment. Unfortunately, for those who
fail to remit, chances of remission decrease with each successive trial.
In the continuation phase, antidepressant treatment should be continued at the
same therapeutic dose at which remission was reached for 6–9 months, unless
tolerability issues require a dose reduction. The goal of this phase is to forestall
relapse, which is defined as a return of symptoms to the full syndrome criteria for an
episode during remission but before recovery. Recovery is defined as remission
maintained for over 6 months, thus it is distinguished from remission by a temporal
criterion. Average rate of relapse in patients not going on continuation phase is 41%
compared with 18% on active treatment (Geddes et al. 2003), and thus continuation
should always be pursued. Even when antidepressant therapy is aptly administered
during the continuation phase, relapse may occur requiring a return to the acute
phase of treatment.
At the end of the continuation phase, a careful evaluation should be made as to
whether to maintain treatment or gradually go off medication(s). The aim of main-
tenance is to protect susceptible patients against recurrence, which is defined as the
appearance of a new episode after a period of recovery. A prior history of three or
more MDD episodes was associated with an above 90% recurrence rate (Angst et al.
1973; Lavori et al. 1994), thus it is the main condition that requires maintenance.
Presence of residual symptoms, ongoing psychosocial stressors, severity of prior
episodes, presence of side effects, and patient’s preference should be taken into
account when choosing between maintenance and discontinuation. In general, the
same medication dose of the continuation phase should be kept during maintenance,
especially if it is well-tolerated. Recurrence however will still happen in as many as
25% of individuals with adequate maintenance therapy.
On the other hand, in patients discontinuing antidepressants, it is important to
taper the medication over the course of some weeks in order to prevent discontin-
uation syndrome. The highest risk of relapse in these patients is in the first 2 months
after therapy cessation, thus a careful monitoring is recommended in this period
(Taylor et al. 2018; Gelenberg et al. 2010; Kennedy et al. 2016; Baldwin et al. 2015).
Of notice, as many as 50% of patients from psychiatric settings and primary care
prematurely discontinue antidepressant therapy on their own initiative for a number
of reasons, some of which are patient-related (e.g., side effects, misperceptions about
the medication), while others are clinician-related (e.g., poor instruction by the
clinician about the medication, lack of follow-up care). Poor treatment compliance
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1143

is indeed an issue of upmost importance that needs to be properly tackled: physicians

should educate patients about antidepressant treatment, explore questions and pos-
sible misperceptions that patients may have, and closely monitor patients for med-
ication adherence (Sansone and Sansone 2012).

Anxiety Disorders, Obsessive-Compulsive Disorder, Trauma- and

Stressor-Related Disorders

Antidepressants, alongside other psychotropic medications and various psychoso-

cial treatments, were proven effective in these disorders (Taylor et al. 2018;
Katzman et al. 2014; Baldwin et al. 2014). However, there is insufficient evidence
to conclusively recommend any proven efficacious psychological or pharmaco-
logical intervention over another or to systematically prefer a combined approach
over monotherapy. Consequently, the choice of psychological or pharmacological
treatment rests on factors such as patient’s preference and motivation, ability of the
patient to engage in the treatment, clinician’s skills and experience, patient’s
previous response to treatment, and co-occurrence of medical or psychiatric
conditions. SSRIs and SNRIs are widely recognized as the first-line pharmacolog-
ical approach across anxiety disorders, obsessive-compulsive disorder (OCD), and
post-traumatic stress disorder (PTSD). Certain TCAs and monoamine oxidase
inhibitors are efficacious treatments, but they are proposed as second-line drugs
since they are encumbered by a greater burden of side effects. In case of initial
treatment failure, common options are 1) raising the dosage, particularly if the
current dosage is well-tolerated, 2) switching to another evidence-based treatment,
3) combining evidence-based treatments when no contraindications exist, and 4)
combining evidence-based pharmacological and psychological interventions.
SSRIs and SNRIs can exacerbate anxiety as a side effect in some cases, especially
when too rapidly titrated. Therefore, when treating anxiety disorders and PTSD,
such medications should be initiated at half of the normal starting dose for the
treatment of depression. The dose should then be cautiously titrated upward into
the normal antidepressant dosage range as tolerated. The use of drops formulations
when available may be useful. Response to antidepressant is not immediate, indeed
a treatment period of up to 12 weeks may be needed to assess efficacy, but a
complete absence of clinical benefit within 2–4 weeks should be acknowledged as
a sign of non-response.
Until antidepressants exert their full action, co-prescription with benzodiaze-
pines is generally contraindicated and should be considered as last option for
short-term management of acute anxiety states, given their potential for depen-
dence and withdrawal symptoms. Benzodiazepines should be kept at minimum
effective dose for no longer than 4 weeks. Z-drugs (zaleplon, zolpidem, and
zopiclone) provide a better option for insomnia, due to lower potential to cause
dependence.
Although the optimal duration of antidepressant therapy is not clearly established,
treatment should continue for at least 1 year for generalized anxiety disorder, social
1144 F. Corponi et al.

phobia, and OCD and 6–8 months for panic disorder and PTSD. When discontinued,
antidepressants should be reduced slowly over several weeks to months to avoid
discontinuation syndrome.

Other Approved Indications

Approved indications for antidepressants comprise other neuropsychiatric dis-

eases. In some conditions, what is usually considered a side effect of an antide-
pressant can be used to deliver a therapeutic action (e.g., use of fluoxetine in
bulimia nervosa).
Atomoxetine was not licensed for the treatment of depression, although it belongs
to the antidepressant class of norepinephrine (NE) reuptake inhibitors. Its only
licensed indication is the treatment of attention deficit hyperactivity disorder
(ADHD) in children and adolescents, and it is the only medication licensed for use
in adults suffering from this condition. Atomoxetine is particularly useful for
patients at risk of substance abuse, as well as those who have comorbid anxiety or
tics, or who do not wish to take a controlled substance (as methylphenidate, although
it is usually the first choice for ADHD). The indication for any ADHD drug
treatment is the presence of severe impairment; in mild-to-moderate cases first-line
treatments are usually behavioral therapy and psychoeducation (Garnock-Jones and
Keating 2009).
Fluoxetine (60 mg/die) is approved for use in bulimia nervosa (BN) in adults, and
it is the only antidepressant licensed for eating disorders. Psychological interven-
tions however should be considered first-line for BN, and medications should not be
offered as the sole treatment (Hilbert et al. 2017). Fluoxetine effectively reduces
binge eating (reduction from pretreatment of 50–67% with active treatment vs.
18–33% with placebo) and vomiting (reduction from pretreatment of 50–56% with
active treatment vs. 5–21% with placebo) and reduces relapse risk (Goldstein et al.
1995; Romano et al. 2002). Early improvement at 3 weeks is a strong predictor of
overall response (Sysko et al. 2010).
Bupropion is licensed as a first-line pharmacotherapy for smoking cessation in
people aged 18 years and over. Quit rate with bupropion therapy is around 20% after
1 year of treatment. Bupropion reduces withdrawal symptoms as well as weight gain
during smoking cessation (Wilkes 2008).
Duloxetine is approved for the treatment of diabetic peripheral neuropathy,
fibromyalgia, and chronic musculoskeletal pain in adults. It seemingly exerts an
analgesic effect regardless of its action on mood and is suggested to specifically
address physical symptoms of depression. Milnacipram as well is licensed for
fibromyalgia in adults (Harada et al. 2016).
Treatment of neuropathic pain and prophylactic treatment of chronic tension-type
headache and migraine are approved indications of amitriptyline in adults. These
actions are independent of the presence of depression, and lower doses than those
used to treat depression are recommended. Amitriptyline is considered first-line
option in all these conditions (Moore et al. 2015).
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1145

Contraindications

Contraindications to the use of antidepressants arise from their interaction with a

comorbid or special condition of the patient or with other drugs or diet. Clinicians
may resort to contraindicated use of antidepressants if the expected benefits balance
the risks, but close monitoring is required; patients should be thoroughly informed of
the risk-benefit balance, and they should be actively engaged in the therapeutic plan.
Contraindications related to drug-drug interactions and to conditions in which
adverse effects from antidepressants are potentially more dangerous or more likely
to occur are discussed in sections “Interactions” and “Side Effects.”

Bipolar Disorder

Much of the concern about antidepressant safety in bipolar disorder (BD) regards the
possibility of affective switch to mania/hypomania. Although the empirical data are
arguably inconclusive (evidence level “C,” according to the the International Society
for Bipolar Disorders (ISBD)) (Pacchiarotti et al. 2013), current treatment guidelines
for BD (Taylor et al. 2018; Yatham et al. 2018) espouse this view and discourage the
use of antidepressant monotherapy. In fact, the risk of switch is significantly reduced
with a concurrent mood stabilizer compared to patients on antidepressant mono-
therapy: among patients treated with a concurrent mood stabilizer, no change in the
risk of (hypo)manic switch was observed during the 3 months after the start of an
antidepressant treatment, and a decreased risk was observed during the period
3–9 months after treatment initiation (hazard ratio = 0.63, 95% CI = 0.42; 0.93)
(Viktorin et al. 2014). Since a major depressive episode may be the initial presen-
tation of BD, clinicians are encouraged to screen for personal and familial history of
mania/hypomania. Patients should be monitored, particularly during the initial phase
of treatment, for activation indicators (Taylor et al. 2018; Yatham et al. 2018). The
highest risk of affective switch was associated with tricyclic antidepressants (TCAs)
and venlafaxine, while the lowest risk was reported for bupropion. Monoamine
oxidase inhibitors (MAOIs) may have a relatively low risk too. For BDII patients,
switch rate is lower, and when switch does occur, it is almost exclusively into
hypomania. Another controversial question is whether antidepressants can induce
rapid cycling (i.e.,
4 recurrences/year) in BD. The ISBD concluded that the overall
quality rating of the evidence on this topic is poor (evidence level “D”). On the flip
side, there is strong evidence that antidepressants are harmful in terms of switch rates
in patients with a history of rapid cycling, and thus their use should be discouraged in
this case. One last issue is whether antidepressant may alter the risk of suicidal
behavior in BD. Once again, quality of evidence was assessed as poor by the ISBD
(evidence level “D”) (Pacchiarotti et al. 2013).
Besides the aforementioned issues, evidence of antidepressant efficacy in bipolar
depression is poor. Consequently, treatment guidelines (Taylor et al. 2018; Yatham
et al. 2018) recommend the use of these medications as second/third-line option. In
particular, in individuals with a personal history of response to an antidepressant, the
1146 F. Corponi et al.

prescription of the same drug may be beneficial according to expert opinion

(Pacchiarotti et al. 2013). In case of type I bipolar disorder (BDI) depression,
adjunctive use of antidepressants, SSRIs, or bupropion specifically may be consid-
ered as a second-line add-on treatment for acute management. Antidepressants
should be discontinued 12 weeks after remission, and only fluoxetine has support
for use as second-line maintenance treatment but only in combination with the
antipsychotic olanzapine. The use of antidepressants as monotherapy should be
avoided also in type II bipolar disorder (BDII) depression. Recent evidence
suggested that monotherapy with sertraline may be a second-line option for the
acute treatment of BDII depression without mixed features, despite independent
confirmation of this finding is still lacking (Taylor et al. 2018; Yatham et al. 2018).

Pregnancy and Breastfeeding

The use of medications during pregnancy and breastfeeding raises safety concerns
about both the fetus/newborn and the mother. Antidepressants safety in these patient
groups cannot be clearly established since robust; prospective studies are lacking as
obviously unethical. Data are thus largely sparse and methodologically limited. If
antidepressants carry some known risks, untreated depression does too, for both the
fetus/newborn and the mother. Although minor forms of depression may respond
well to support or psychotherapy, major depression may benefit from the use of
antidepressants. Furthermore, pregnancy is not protective with respect to the risk of
depression relapse, contrary to what was once though, and relapse rates are high in
those with a history of depression who discontinue medications. In one study 68% of
women who were euthymic on antidepressant therapy and stopped treatment during
pregnancy relapsed, compared with 26% who continued antidepressants (Cohen et
al. 2006). Consequently, despite pregnancy and breastfeeding being relative contra-
indications, the use of antidepressants in such conditions is common in the clinical
practice, with around 8% of women in the USA being prescribed antidepressants at
some point during their pregnancy; this rate has shown a trend of increase over the
years, and SSRIs are the drugs class most commonly prescribed (Alwan et al. 2011).
Overall, antidepressants appear not to be major teratogens. Some rare birth
defects however have been observed to occur at higher rates in case of first trimester
exposure to specific compounds. Paroxetine in particular was specifically associated
with cardiac malformations. This resulted in labelling changes and treatment guide-
lines recommending that paroxetine should not be the first-line option when
selecting a new antidepressant for a pregnant patient (Berard et al. 2016). Sertraline
has the least degree of placental exposure and is recommended as first-line choice
during pregnancy (Hendrick et al. 2003).
Antidepressants were associated with spontaneous abortion, decreased gesta-
tional age, and decreased birth weight. It is possible however that any increased
risk may be related to depression, not the medication used to treat it. As regards
persistent pulmonary hypertension of the newborn, available studies make it
likewise difficult to differentiate the contribution of antidepressants from that of
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1147

depression itself, and if any risk exists, it was estimated to be less than 1% (t Jong
et al. 2012).
With third trimester antidepressant use, neonatal abstinence syndrome can occur.
This condition is the result of medication withdrawal from intra-uterus exposure and
entails transient symptoms such as jitteriness, tremor, sleep, and feeding distur-
bances. It may occur in as many as 30% of neonates exposed to SSRIs in utero,
but it is usually a mild and self-limiting condition. Paroxetine may be the SSRI most
likely to cause abstinence syndrome, allegedly due to its short half-life compara-
tively to other SSRIs and lack of active metabolites. Conversely, the long half-life of
fluoxetine and its active metabolite norfluoxetine, 2–4 days and 7–15 days, respec-
tively, make neonatal abstinence syndrome less likely with this medication
(Levinson-Castiel et al. 2006).
Women on antidepressants during pregnancy may be at increased risk of devel-
oping hypertension, preeclampsia, and postpartum hemorrhage. All these three
conditions are purportedly driven by serotonin (5-HT) and NE interference with
vascular tone and hemostasis.
Exposure to antidepressants via breast milk is substantially lower than in utero
exposure. Comparatively greater experience has been acquired for SSRIs, being the
class of drugs most commonly prescribed to breastfeeding women. Paroxetine and
sertraline should be considered first-line choices when needing to start an antide-
pressant treatment in nursing women. Contrariwise fluoxetine should be avoided
since accumulation may occur in the infant in consideration of the long elimination
half-life of fluoxetine and its primary active metabolite (Taylor et al. 2018).

Liver and Kidney Impairment

Antidepressants are highly protein bound, as lipophilic compounds, and are exten-
sively metabolized through the liver, primarily by CYP450 isoenzymes. Given the
crucial role the liver plays in the pharmacokinetics of antidepressants, it is unsur-
prising that various degrees of liver impairment have important consequences on
drug metabolism via a number of routes: decreased blood/plasma clearance by
hepatic metabolism or biliary excretion, reduced synthesis of transport proteins,
augmented distribution volume due to peripheral edemas and ascites, and reduced
first-pass metabolism as a result of portal-systemic shunts. Although kidneys are less
relevant to antidepressant metabolism, many active metabolites are excreted via this
route. Besides, patients with liver and/or kidney impairment, especially moderate to
severe forms, are prone to a number of comorbidities and are likely to receive
various medications. Thus the use of antidepressants in such patients requires
particular caution. There is a lack of clinical trials supporting effectiveness and
safety of antidepressants in liver and/or kidney impairment, since these conditions
usually stand as exclusion criteria. For the same reason, many drugs lack information
regarding pharmacokinetics and dosing adjustments in liver and/or kidney impair-
ment. The current consensus is that SSRIs are the safest antidepressants in both liver
and kidney impairment, principally based upon their generally high tolerability and
1148 F. Corponi et al.

wider therapeutic index. Lower starting/maintenance doses and slower titration are
recommended. Assessing hepatic and/or renal function is necessary so that dose
adjustment can be made. Creatinine clearance calculated with the Cockcroft-Gault
equation provides an estimation of the renal function, while the Child-Pugh score is
commonly used to establish the severity of liver impairment (Mullish et al. 2014;
Hedayati et al. 2012).

Interactions

Considering their large use (Pratt et al. 2017), antidepressants are very likely to be
co-prescribed with other drugs and to be encountered not only by mental health
specialists. Hence the evaluation of potential drug-drug interactions involving anti-
depressants is particularly relevant as well as the evaluation of the clinical signifi-
cance of such interactions. Drug-drug interactions are broadly classified as either
pharmacokinetic or pharmacodynamic. The former is the case of one drug interfering
with the absorption, distribution, metabolism, or elimination of another. This may
cause subtherapeutic effect or toxicity. The majority of the significant pharmacoki-
netic interactions with antidepressants involve druginduced changes in hepatic
metabolism, predominantly through cytochrome P450 (CYP450) isoenzymes.
While enzyme inhibition occurs rapidly, within 2–3 days, due to the offending
drug binding to the metabolizing enzyme, enzyme induction is generally a slower
process, hinging on protein expression reprogramming. Pharmacodynamic interac-
tions happen when one drug modulates the pharmacologic effect of another one
resulting in additive, synergistic, or antagonistic effects through action at the same
biochemical or molecular site, on the same target organ or on a different target that is
associated with the same physiological process. When considering the relevance and
significance of potential drug-drug interactions, taking into account patient’s char-
acteristics is of upmost importance: age, comorbidities, and genetic variability. In
particular, polymorphisms in CYP450 genes underlie differences in enzyme activity
that range from no enzyme activity (poor metabolizers), decreased (intermediate
metabolizers), normal (extensive metabolizers/wild type), to increased (ultra-rapid
metabolizers) enzyme activity. A common consequence of these different pheno-
types is therapeutic resistance or inefficacy due to insufficient plasma levels in ultra-
rapid metabolizers. In contrast, slow metabolism (poor metabolizers) may lead to
elevated plasma levels and side effects/toxicity. Of notice, most drug interactions are
detected after drug marketing (phase IV) and published either as single case reports
or case series (Taylor et al. 2018).

MAOIs

MAOIs are associated with the most clinically significant drug interactions among
all antidepressant classes. Despite decades of use, the pharmacokinetic interactions
of MAOIs are still poorly characterized but are certainly less problematic than
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1149

pharmacodynamics interactions. CYP2D6 and CYP3A4 are the isoenzymes mainly

involved in MAOIs metabolism; MAOIs themselves act as weak inhibitors of P450
isoenzymes, but this effect is not considered clinically relevant at therapeutic doses.
It has been reported that the antipsychotic phenothiazine may increase concentra-
tions of tranylcypromine, which is also an inhibitor of CYP2C19. Cimetidine has
been shown to diminish the clearance of moclobemide, and it is therefore
recommended that doses of moclobemide should be cut in half when using this
combination.
The central mechanisms responsible for MAOIs pharmacodynamic interactions
are the inhibition of the A isoform of the monoamine oxidase (MAO-A), an
enzyme that catalyzes the oxidative deamination of amines, such as NE and
5-HT, but also tyramine, a vasoactive amine that can be found in a range of
foods and beverages. Tyramine acts as releaser of systemic NE thereby elevating
blood pressure. Normally, the greatest part of dietary tyramine is inactivated by
MAO-A in the intestinal wall and in the liver before it enters systemic circulation,
and NE excess is removed by circulating MAO-A. MAOIs disrupt this protective
system, subsequently food high in tyramine may cause a hypertensive crisis in
patients on MAOIs. Since first reports of this adverse event were in connection to
cheese consumption (aged cheese in particular is rich in tyramine), the term
“cheese reaction” was coined. The average person is able to handle approximately
400 to 800 mg of ingested tyramine before blood pressure becomes elevated.
Under MAO-A irreversible inhibition, it may take as little as 10 mg of dietary
tyramine to increase blood pressure. Historically, an unnecessarily restrictive diet
was, and sometimes still is, imposed to patients taking MAOIs. In reality most
foods can be safely consumed if bought fresh and immediately cooked and
consumed in modest quantities. A tyramine content of less than 6 mg per serving
is generally considered safe. The following foods are marked as “absolutely
restricted”: aged cheeses, meats, banana peels, broad bean (such as fava) pods,
spoiled meats, marmite, sauerkraut, soybean products, and tap beer. Reversible
MAO-A inhibitors (e.g., moclobemide) carry less food restrictions.
While MAOIs are famous for their interaction with foods, drug-drug interac-
tions are more important in real clinical settings. There are two types of drug
interactions that warrant extreme caution in patients on MAOIs: one with sympa-
thomimetic agents leading to hypertensive crisis, the other with serotonergic drugs
leading to serotonin syndrome. Contraindicated sympathomimetic medications
include antidepressants with NE reuptake inhibition, decongestants which stimu-
late α1-adrenergic postsynaptic vascular receptors (phenylephrine and pseudo-
ephedrine), adrenergic stimulants (methylphenidate, amphetamine, modafinil,
and armodafinil), levodopa (except for approved combination with oral selegiline,
which is a selective irreversible MAO-B-Inhibitor), local anesthetics containing
vasoconstrictors, opioids inhibiting NE reuptake (tramadol and tapentadol), and
the anorectic drug phentermine. The risk of serotonergic syndrome contraindicates
5-HT enhancing antidepressants and opioids blocking 5-HT reuptake (meperidine,
tramadol, methadone, and dextromethorphan). Generally, a washout period of at
least 14 days is required after discontinuing an MAOI and before beginning a
1150 F. Corponi et al.

serotonergic agent and vice versa. Because fluoxetine has a particularly long
dynamic half-life, a washout period of more than 5 weeks may be needed
(Flockhart 2012).

TCAs

TCAs are primarily metabolized through the hepatic isoenzyme CYP2D6, with 1A2
and 3A4 as secondary routes; on the other hand, they do not cause enzyme inhibition
or induction. As a result, this class of drugs is not problematic itself in terms of
pharmacokinetic interactions, but, because of their narrow therapeutic index, TCAs
are susceptible to interactions when combined with inhibitors or inducers of the
aforementioned CYP450 enzymes.
Pharmacodynamic interactions on their part can exacerbate TCAs side effects.
Their sedative action due to H1 receptor agonism can be aggravated by sedative
drugs or alcohol, leading to respiratory depression in the worst case scenario.
Antihistamines and antipsychotics can precipitate anticholinergic effects, such as
blurred vision, dry mouth, constipation, urinary retention, and impaired cognition.
Adrenergic α1 blockers and antihypertensive drugs in general increase the risk of
orthostatic hypotension and subsequently of falls. Since TCAs lower the seizure
threshold, caution is needed with other proconvulsant drugs, e.g., antipsychotics,
particularly if the patient is being treated for epilepsy (higher doses of anti-convul-
sants may be required). Drugs that alter cardiac conduction either directly (e.g.,
antiarrhythmics or phenothiazines) or indirectly (e.g., diuretics via electrolyte dis-
turbances) should be used with caution in patients taking TCAs, in consideration of
the increased risk of QTc interval prolongation and arrhythmias. Lastly, combination
with drugs enhancing serotonergic transmission can result in serotonin syndrome
(Gillman 2007).

SSRIs

Differences in the potential of pharmacokinetic interactions involving SSRIs are

related to differences in their inhibitory potency toward CYP450 isoforms. Paroxetine,
fluoxetine, and its active metabolite norfluoxetine are potent inhibitors of CYP2D6;
fluvoxamine is a potent inhibitor of CYP1A2, CYP2C19, CYP3A4, and CYP2D6. On
the other hand, sertraline, citalopram, and escitalopram are weak inhibitors of
CYP2D6 and have little effect on other isoenzymes: these agents are thus unlikely
to give rise to significant pharmacokinetic interactions. Fluoxetine and paroxetine have
been shown to significantly increase the plasma levels of aripiprazole, atomoxetine,
carvedilol, clozapine (plasma levels increase of 30–42%), donepezil, galantamine,
metoprolol, most tricyclic antidepressants (for which a two to fivefold increase in
plasma levels has been reported), and risperidone. Furthermore, paroxetine and
possibly fluoxetine inhibit the metabolism of tamoxifen to its more active metabolites
by CYP2D6 enzyme, thereby decreasing its anticancer effect. These antidepressants
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1151

should thus be avoided in women taking tamoxifen for the treatment or prevention of
recurrence of breast cancer (Spina et al. 2012).
SSRIs are liable to a number of potential pharmacodynamics interactions which
make their side effects more likely to occur or more severe. Co-prescription with
other drugs raising serotonergic transmission can result in serotonin syndrome.
These include other 5-HT enhancing antidepressants (MAOIs and TCAs in partic-
ular), buspirone, linezolid, lithium, fentanyl, tramadol, and pethidine. Combination
with nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, or anti-
platelet drugs can lead to hemorrhagic risk, especially in patients with a pre-existing
hemorrhagic diathesis or undergoing major surgery. Antipsychotics can worsen
sexual dysfunction associated with SSRIs. Thiazide diuretics increase the risk of
hyponatremia. Medicines known to prolong QTc interval, such as most antipsy-
chotics and TCAs, warrant caution when used with citalopram in particular, for
which the risk of QTc prolongation seems the highest among SSRIs (Taylor et al.
2018; Gelenberg et al. 2010).

SNRIs

Venlafaxine is predominantly metabolized in the liver to a major active metabolite,

O-desmethylvenlafaxine (also referred to as desvenlafaxine) and, in parallel, to N-
desmethylvenlafaxine. CYP2D6 is the main enzyme responsible for the O-demeth-
ylation, while CYP3A4 is probably involved in the N-demethylation pathway.
Venlafaxine is a weaker inhibitor of CYP2D6 and has minimal or no effect on the
activity of CYP1A2, CYP2C9, and CYP3A4. Drugs that may increase venlafaxine
plasma levels, predominantly via CYP2D6 inhibition, include cimetidine, diphen-
hydramine, quinidine, terbinafine, bupropion, fluoxetine, and paroxetine.
Venlafaxine itself has a low propensity for pharmacokinetic interactions with co-
administered medications, and it may be safely used in combination with tamoxifen,
differently from paroxetine and fluoxetine. Similarly to its parent drug,
desvenlafaxine is unlikely to produce significant pharmacokinetic interactions as
consequence of its weak inhibitory effect on the hepatic CYP450 system. However,
drugs targeting CYP3A4 may affect desvenlafaxine metabolism. Duloxetine is
extensively metabolized in the liver primarily by CYP1A2 and, to a lesser extent,
by CYP2D6. It is itself considered to be a moderate inhibitor of CYP2D6 so it can
potentially increase the levels of drugs mainly metabolized through this route (e.g.,
TCAs, tolterodine, metoprolol, risperidone, and aripiprazole). Cigarette smoking is
associated with lower duloxetine plasma levels (via CYP1A2 induction).
Fluvoxamine and paroxetine have been shown to increase duloxetine levels.
Milnacipram disposition is unlikely to be affected by concomitant treatment with
CYP450 inhibitors or inducers, due to only limited oxidative metabolism of this
SNRI (mainly by CYP3A4). This antidepressant seemingly does not affect the
disposition of co-administered medications either. Milnacipram is in fact a weak
CYP3A4 inhibitor, and it has minimal inducing effects on the activity of the various
CYP450 isoforms (Spina et al. 2012).
1152 F. Corponi et al.

As for SSRIs, the most clinically relevant pharmacodynamic interactions involve

the risk of serotonin syndrome and bleeding. Since both duloxetine and warfarin are
highly bound to plasma proteins, displacement of warfarin from protein binding sites
is hypothesized as an additional mechanism for hemorrhagic risk (Chappell et al.
2009). Lastly, specific to SNRIs is an interference with antihypertensives.
Venlafaxine in particular was reported to reduce the blood pressure lowering effect
of metoprolol. Such an effect supposedly concerns the other SNRIs as well (Taylor et
al. 2018; Gelenberg et al. 2010).

Mirtazapine and Mianserin

Mirtazapine and mianserin have three main metabolic pathways, via CYP2D6, 1A2,
and 3A4, and have no appreciable inhibitory or inducing effects itself on the various
CYP450 isoforms. Thus, they seemingly carry a low risk of pharmacokinetic
interactions. However, the few interaction studies available showed that cimetidine,
fluvoxamine, and ketoconazole markedly increase plasma concentrations of both
drugs while carbamazepine and phenytoin (CYP3A4 inducers) reduce their plasma
concentrations. Smokers have significantly lower plasma mirtazapine and mianserin
concentration than nonsmokers, confirming the role of CYP1A2, which is induced
by cigarette smoking, in the metabolism of both drugs.
An additive sedative effect was documented when mirtazapine was co-adminis-
tered with diazepam or alcohol. The combinations likely to potentiate mirtazapine
sedative effect warrant caution, especially in the elderly. Likewise, mianserin may
potentiate the central nervous depressant action of alcohol, anxiolytics, and hyp-
notics. Weight gain is another common adverse effect of mirtazapine, which can
escalate when the drug is combined with antipsychotics (Spina et al. 2012). As
compared to both SSRIs and SNRIs, mirtazapine probably carries a lower risk of
serotonin syndrome and bleeding (Hauta-Aho et al. 2009). Lastly, the combined use
of mirtazapine with tramadol or dopamine-blocking agents could enhance the risk of
restless legs syndrome, possibly through a pharmacodynamic mechanism involving
5-HT2 receptor-mediated suppression of dopamine release and H1 receptor antag-
onism (Kim et al. 2008). Clinical experience has shown that mianserin does not
interact with the antihypertensives bethanidine, clonidine, guanethidine, or propran-
olol. There may be an enhanced hypotensive effect if mianserin is taken with
diazoxide, hydralazine, or nitroprusside (Kopera 1978).

Reboxetine

CYP3A4 is the main isoenzyme involved in reboxetine biotransformation. There-

fore, concomitant treatment with CYP3A4 inhibitors (e.g., ketoconazole) or inducers
(e.g., phenobarbital and carbamazepine) may affect plasma concentrations of
reboxetine. On the other hand, reboxetine itself has only weak inhibitory activity
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1153

on CYP2D6 and CYP3A4, unlikely to be relevant at the doses usually reached in the
clinical practice (Wienkers et al. 1999). Triiodothyronine, when co-administered as
an adjunctive treatment to reboxetine in MDD, was recorded to precipitate norad-
renergic effects such as anxiety, irritability, increased sweating, tremor, and sleep
disturbances (Cooper-Kazaz et al. 2010).

Bupropion

Bupropion is metabolized by CYP2B6, thus it is expected that co-administration of

CYP2B6 inhibitors (e.g., clopidogrel, orphenadrine, and ticlopidine) or inducers
(e.g., carbamazepine and ritonavir) may cause changes in plasma concentration of
bupropion and its metabolite hydroxybupropion, despite pharmacokinetic studies
focused on these possible interactions are not available. On the ground of the
moderate inhibitory effect of bupropion and its hydroxyl metabolite on CYP2D6
activity, relevant interactions may occur when bupropion is used in combination
with CYP2D6 substrates (e.g., desipramine, venlafaxine, and propagenone).
Although bupropion has lower inhibitory capacity on CYP2D6 compared to parox-
etine and fluoxetine, it is nonetheless best avoided in women taking tamoxifen.
Caution is required when bupropion is used in combination with other drugs that
share a lowering effect on the seizure threshold, including some other antidepres-
sants, antipsychotics, tramadol, and theophylline. Moreover, as bupropion boosts
dopaminergic activity, there is a potential risk for interactions with dopamine
agonists or antagonists. Adding bupropion to levodopa may indeed increase the
incidence of adverse effects of levodopa such as nausea, vomiting, and restlessness
(Spina et al. 2012).

Agomelatine

Agomelatine is extensively metabolized in the liver, primarily by CYP1A2 (90%)

and, to a lesser extent, by CYP2C9 and CYP2C19. It is not known to induce or
inhibit CYP450 isoenzymes, but its metabolism is profoundly affected by other
drugs or substances that impact on CYP1A2 activity. Fluoxetine, being a potent
CYP1A2 and a moderate CYP2C9 inhibitor, can lead to a 60-fold (range 12- to 412-
fold) increase in agomelatine plasma concentration when the two drugs are co-
administered. Ciprofloxacin, amiodarone, mexiletine, zileutin, and, to a lower
degree, estrogens are potent inhibitors of CYP1A2 and can thus significantly
increase agomelatine exposure. Conversely, cigarette smoking reduces plasma con-
centrations of agomelatine by three- to fourfold via CYP1A2 induction.
Since agomelatine has a significant potential for liver injury, caution is required
with other medications that can potentially impair liver functionality (e.g., clozapine,
MAOIs, and TCAs). Patients also need to be warned against interaction with
excessive alcohol consumption (Spina et al. 2012).
1154 F. Corponi et al.

Vortioxetine

CYP2D6 is the main CYP450 isoenzyme responsible for vortioxetine biotransfor-

mation, since CYP3A4/5 act as secondary routes. Vortioxetine itself does not either
induce or inhibit CYP450 isoenzymes but may be significantly affected by inhibitors
of CYP2D6 such as bupropion, fluoxetine, and paroxetine, wherein increased levels
would be expected. Likewise, CYP3A4 inhibitors (e.g., ketoconazole, fluconazole,
itraconazole, and clarithromycin) are expected to increase vortioxetine levels,
whereas lower exposure to vortioxetine may be caused by CYP3A4 inducers (e.g.,
carbamazepine, rifampicin, and phenytoin). The clinical significance of the CYP3A4
interaction is yet to be established however (Chen et al. 2013).
As with other antidepressants boosting serotonergic transmission, co-administra-
tion with other 5-HT enhancing agents may potentially cause serotonin syndrome
(Brintellix 2015).

Side Effects

Side effects of antidepressants limit compliance and are often the primary cause of
medication discontinuation or dose reduction. Roughly one-third to one-half of
patients discontinue pharmacological treatment, and a quarter of those patients
reported side effects as the reason for discontinuation (Lader et al. 2004). The history
of new antidepressant development reflects an effort by the pharmaceutical industry
to reduce side effects while preserving efficacy. In this perspective, TCAs and
MAOIs have come to be partially replaced by new generations of antidepressants
as these proved to be generally safer and better tolerated. The likelihood of different
side effects varies among drug classes, among individual agents, and, on the other
hand, among different subjects. Overall, side effects tend to manifest earlier than
therapeutic effects but they diminish over time with receptor desensitization. In
efficacy trials, an average of 63% of patients experienced at least one adverse
event during treatment (Gartlehner et al. 2011). Table 2 lists antidepressant side
effects and specifies more frequently associated and safer agents for each side effect.

Gastrointestinal System

Nausea, Vomiting, and Diarrhea

Approximately half of patients who start an SSRI or SNRI experience these distur-
bances (Uher et al. 2009). 5-HT exerts control over nausea and vomiting in the
hypothalamus and the brainstem (vomiting center of the chemoreceptor trigger
zone), and it influences gastrointestinal motility peripherally. Acute increase of
5-HT at these sites may explain the gastrointestinal disturbances experienced with
5-HT reuptake inhibition. These adverse events are generally dose-dependent and
tend to disappear over the first few weeks of treatment as receptor desensitization
kicks in.
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1155

Table 2 Antidepressant side effects with more frequently associated drugs and, where applicable,
drugs recognized as relatively safer
Side effect Drug(s) more frequently associated Safer drug(s)
Nausea Fluvoxamine, fluoxetine, venlafaxine, Escitalopram
vortioxetine, vilazodone
Vomiting Fluoxetine, venlafaxine Escitalopram
Diarrhea Sertraline, vilazodone \
Anorexia Fluoxetine Escitalopram
Xerostomia TCAs, SSRIs, SNRIs, bupropion Fluvoxamine,
vortioxetine
Constipation TCAs \
Drug-induced liver MAOIs, TCAs, nefazodone, bupropion, Citalopram,
injury duloxetine, agomelatine escitalopram, paroxetine,
fluvoxamine
Sexual dysfunction Paroxetine, venlafaxine Mirtazapine,
agomelatine,
vortioxetine, vilazodone
Urinary retention TCAs (particularly imipramine) \
QTc interval TCAs, citalopram Lofepramine
prolongation
Hypertension Venlafaxine, MAOIs
Orthostatic TCAs, mirtazapine
hypotension
" resting heart rate, # TCAs, SNRIs \
heart rate variability
Seizures TCAs, bupropion \
Extrapyramidal SSRIs \
symptoms
Blurred vision TCAs \
Angle-closure TCAs, paroxetine
glaucoma
Weight gain Paroxetine, amitriptyline Venlafaxine,
vortioxetine, vilazodone
Weight loss Fluoxetine, bupropion Escitalopram
Bleeding SSRIs, venlafaxine \
Hyponatremia SSRIs, venlafaxine TCAs, bupropion,
trazodone
Hyperhidrosis TCAs, sertraline, paroxetine Fluvoxamine, bupropion,
vortioxetine
Insomnia Bupropion, desvenlafaxine, duloxetine, Agomelatine, citalopram,
fluoxetine, fluvoxamine, reboxetine, escitalopram
sertraline, venlafaxine
Somnolence Fluvoxamine, mirtazapine, paroxetine, Bupropion
citalopram
Restless leg Mianserin, mirtazapine \
syndrome
Discontinuation Paroxetine, venlafaxine Agomelatine,
syndrome vortioxetine
(continued)
1156 F. Corponi et al.

Table 2 (continued)
Side effect Drug(s) more frequently associated Safer drug(s)
SSRI-induced Paroxetine Fluvoxamine
indifference
Switch to mania/ TCAs, venlafaxine Bupropion
hypomania
MAOIs monoamine oxidase inhibitors, REM rapid eye movement, SNRIs serotonin and noradren-
aline reuptake inhibitors, SSRIs selective serotonin reuptake inhibitors, TCAs tricyclic
antidepressants

Among SSRIs, nausea, vomiting, weight loss, and anorexia are more frequent in
fluvoxamine- and fluoxetine-treated patients, whereas they are less likely with
escitalopram. Venlafaxine consistently showed a higher rate of nausea and vomiting
than SSRIs, while sertraline has a higher incidence of diarrhea than other SSRIs and
venlafaxine. The data for the most recently approved antidepressants, i.e.,
vortioxetine and vilazodone, are comparatively limited. Nevertheless, nausea is
one of the most frequently reported side effect for both of them, and, as regards
vilazodone, diarrhea seems a common occurrence, reported by over 10% of patients,
with most cases being mild to moderate and only a very few leading to premature
discontinuation (Wang et al. 2018).

Xerostomia
Xerostomia, an unpleasant dry mouth sensation, is a common complaint with TCAs
use experienced by up to 27% patients on these medications. It is one of the
anticholinergic side effects of TCAs. In fact, antagonism of muscarinic M3 receptors
is responsible for decreasing salivary flow rate. Other antidepressants as well can
produce xerostomia, arguably through different pathogenetic mechanisms. In particu-
lar, significant risk of dry mouth is associated with SSRIs (relative risk = 1.64), SNRIs
(relative risk = 2.24), and bupropion (relative risk = 2.0). With regard to SNRIs, it is
hypothesized that xerostomia results from central accumulation of NE, which causes
activation of α2-receptors and concurrent inhibition of parasympathetic salivary
neurons in the brainstem leading to decreased salivary flow. On the other hand,
SSRIs, having less affinity for muscarinic cholinergic receptors, α-receptors, and NE
transporter, have less impact on salivary flow rate. Fluvoxamine and vortioxetine are
considered unencumbered by this adverse event (Cappetta et al. 2018).

Constipation
Constipation is another common anticholinergic side effect of TCAs. Cholinergic
receptors antagonism reduces the contractions propelling waste matter through the
digestive tract and the intestinal secretions lubricating. Incidence rate is generally
higher with TCAs compared to most SSRIs (Trindade et al. 1998).

Drug-Induced Liver Injury

The incidence of some degree of drug-induced liver injury (DILI) ranges from 0.5%
to 1% in patients on SSRIs and SNRIs, and it is 3% for MAOIs and TCAs. DILI can
manifest within a wide spectrum of clinical, laboratory, and histological
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1157

presentations but in most cases patients are clinically asymptomatic, and the alter-
ations identified in liver function tests are the only suggestive element of DILI.
Overall, the incidence of antidepressant-induced liver toxicity requiring hospitaliza-
tion is only 1.28–4 cases per 100,000 patient-years. The mechanism of DILI
associated with antidepressants can be immuno-allergic or metabolic. A hypersen-
sitivity syndrome (fever, rash, eosinophilia, and auto-antibodies) and a short latency
period (1 to 6 weeks) are earmarks of the former pathogenetic mechanism. On the
contrary, the absence of any hypersensitivity syndrome and a delayed onset (1 month
to 1 year) point to an immuno-allergic reaction. In most cases, liver damage is
unpredictable, dose-independent, and of the hepatocellular type rather than of the
cholestatic type. Old age and polytherapy with more than one drug targeting the
same CYP450 isoenzyme pathway are the main risk factors. Of notice, symptoms of
DILI can mimic neurovegetative manifestations of MDD. As a consequence of
misdiagnosis, clinicians may be tricked into increasing the antidepressant dosage
or into co-prescription. The drugs for which the frequency of reported DILI appears
to be highest are MAOIs, TCAs, nefazodone, bupropion, duloxetine, and
agomelatine. Those with apparently lower risk are citalopram, escitalopram, parox-
etine, and fluvoxamine. For nefazodone the risk of liver toxicity was considered
unacceptably high, and it was subsequently withdrawn from the market (Voican et al.
2014).

Genitourinary System

Sexual Dysfunction
The incidence of sexual dysfunction during antidepressant treatment can be high
(50–70%), mainly when the mechanism of antidepressant action is highly related to
5-HT reuptake blockade. On the contrary, drugs that predominantly decrease NE or
dopamine uptake have either fewer or null negative effects on sexual functioning.
5-HT2A receptor agonism at descending spinal cord synapses on sympathetic/
parasympathetic neurons is purportedly the main mechanism of sexual dysfunction,
and the side effect is likely to be dose-dependent. Other factors may play a role too:
sedation, hormonal changes, disturbance of cholinergic/adrenergic balance, periph-
eral α–adrenergic antagonism, and inhibition of nitric oxide. All phases of sexual
activity can be affected: sexual desire, arousal (including clitoral engorgement and
lubrication in women and erectile function in men), and orgasm with possible
differences between men and women. However, all these effects are reversible.
Despite the high frequency of sexual dysfunction, patients tend not to report it,
unless directly questioned. Moreover, impaired sexual functioning can be a result of
depression itself or a concurrent medical/psychological condition (Serretti and
Chiesa 2009).
Compared with other second-generation antidepressants, paroxetine has higher
rates of sexual dysfunction, up to 80% (Montejo et al. 2010), particularly ejaculatory
dysfunction. Bupropion has large evidence of showing no influence on sexual
dysfunction or slight improvement of sexual function both in depressed populations
and in healthy volunteers. Mirtazapine and agomelatine have a good sexual
1158 F. Corponi et al.

tolerability, similarly to the newer agents vortioxetine, at least in the lower dose
range, and vilazodone (Reichenpfader et al. 2014).
A relatively rare but important side effect with trazodone is priapism. It may be
most likely to occur within the first 28 days of treatment and that the majority of
cases occur with doses of 150 mg/day or less. All age groups appear to be vulnerable
to this adverse effect. Patients should be informed to discontinue the medication on
occurrence of any unusual erectile problem (Warner et al. 1987).

Urinary Disturbances
Urination is controlled by a complex mechanism that coordinates bladder storage,
emptying, and urinary sphincter activity by regulation of smooth muscle in the
bladder and urethra. TCAs have a significant association with urinary retention,
especially imipramine. However, when all TCAs are considered together, the risk is
very low (0.1%). TCAs may cause urinary retention through muscarinic cholinergic
receptors antagonism and, secondly, 5-HT and NE reuptake inhibition. Urinary
disturbances are rather rare events with newer antidepressants. Urinary retention
secondary to the use of SSRIs is supported only by case reports, and in most cases
SSRIs were used in combination with benzodiazepine and/or antipsychotics. 5-HT
may increase the central sympathetic outflow leading to urinary storage, and, at the
same time, it inhibits the parasympathetic flow that promotes voiding. SNRIs may
produce urinary retention via α1–adrenoreceptors stimulation as an additional mech-
anism. As with SSRIs, the association for SNRIs is likewise anecdotal and
documented only in case reports. Venlafaxine was associated with urinary inconti-
nence as well, the action on 5-HT4 receptors being allegedly the underlying mech-
anism (Dane et al. 2016; Faure Walker et al. 2016).

Cardiovascular System

QTc Interval Prolongation and Arrhythmias

Antidepressants have arrhythmogenic potential through variable inhibitory activities
at cardiac sodium and potassium channels. The electrocardiographic hallmark of
antidepressant impact on cardiac activity is QTc prolongation, i.e., prolongation of
the interval corresponding to the ventricular depolarization and repolarization. A
prolonged QTc interval is indeed an important risk factor for ventricular arrhythmias
and sudden cardiac death. SSRIs prolong QTc in a dose-dependent fashion and by a
mean of 6 ms comparatively to placebo. Such a measure may be of limited clinical
significance though. Among SSRIs, however, citalopram may cause a clinically
significant prolongation of the QTc interval; despite the causal association with
citalopram was deemed to be not definitive in the most part of cases and often
concomitant risk factors, overdose or doses >40 mg/day may have been implicated
(Tampi et al. 2015). This prompted FDA to put forth a recommendation regarding
citalopram and the risk of abnormal heart rhythms. TCAs impact on QTc prolonga-
tion to a greater extent than new-generation agents, with a mean QTc prolongation
vs. placebo of 7 ms. Lofepramine, however, despite its major metabolite being a
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1159

potent potassium channel blocker, seems to lack the arrhythmogenicity of other

TCAs (Beach et al. 2014).

Blood Pressure Abnormalities

SNRIs, due to NE reuptake inhibition, are associated with increased risk of hyper-
tension. Although all the three SNRIs carry the risk of increased blood pressure, such
an event is more likely with venlafaxine at doses greater than 300 mg daily, being the
noradrenergic activity more prominent over that threshold. In particular, venlafaxine
is associated with increases in blood pressure of up to 15 mm Hg from baseline.
MAOIs may give rise to a hypertensive crisis in case of interaction with some other
drugs and diet (see section “MAOIs”).
On the other hand, orthostatic hypotension is a well-known adverse effect of
TCAs because of their antagonistic α1-adrenergic receptor activity. This is of
particular concern in elderly patients since it may add up to comorbidities and
ongoing antihypertensive treatment resulting in falls and fractures. The TCA nor-
triptyline may be less likely to cause orthostatic hypotension. As for new-generation
antidepressants, paroxetine is the SSRI most frequently associated with postural
hypotension due to its anticholinergic activity. Mirtazapine may cause it in up to 7%
of patients having a moderate peripheral postsynaptic α1-adrenoreceptor blocking
activity. Some studies suggest a paradoxical hypotensive effect of venlafaxine in
patients aged over 60 years: hyperstimulation of presynaptic α2-adrenoreceptor,
mediating a negative feedback on NE release, is a proposed mechanism for this
phenomenon (Carvalho et al. 2016).

Heart Rate
Lastly, antidepressants unfavorably impact on resting-state heart rate and its vari-
ability. Increases in the former and decreases in the latter are associated with
substantial morbidity and mortality. All antidepressants, except possibly SSRIs,
were associated with increases in resting heart rate and decreased heart rate vari-
ability. These negative effects are more prominent in people treated with TCAs
(mean resting heart rate = 73.94 bpm) followed by SNRIs (mean resting heart
rate = 71.00 bpm) compared to those not on antidepressants (mean resting heart
rate = 66.87 bpm) (Kemp et al. 2014).

Nervous System

Serotonin Syndrome
The serotonin syndrome is a potentially life-threatening adverse reaction that can
result from therapeutic drug use, intentional self-poisoning, or inadvertent interac-
tion between drugs. This condition importantly is not an idiopathic drug reaction but
a predictable consequence of excessive serotonergic agonism at the central and
peripheral serotonergic receptors. The classic presentation is described as a clinical
triad of mental status changes, autonomic hyperactivity, and neuromuscular abnor-
malities, but clinical manifestations are highly variable and range from benign to
1160 F. Corponi et al.

life-threatening, reflecting the degree of 5-HT toxicity. Typically, symptoms develop

within 24 h after an increase in dosage, addition of a new serotonergic drug or
overdose. The diagnosis is based on clinical criteria with no laboratory test for
confirmation, although the assay of urinary levels of 5-HT may be useful. A number
of drugs can give rise to this condition: MAOIs, TCAs, SSRIs, opiate analgesics,
over-the-counter medicines, antibiotics, weight-reduction agents, antiemetics, anti-
migraine agents, drugs of abuse, and herbal products. Moreover, the addition of
drugs inhibiting cytochromes CYP3A4 and/or CYP2D6 to SSRIs is another mech-
anism for development of this condition. Risk of serotonin syndrome is particularly
high with MAOIs, especially when used in combination with meperidine, dextro-
methorphan, SSRIs, or methylenedioxymethamphetamine (MDMA or “ecstasy”).
The exact incidence of serotonin syndrome is unknown as many cases, especially
mild ones, go unrecognized. It is probably increasing reflecting the growing number
of serotonergic agents available and their increased use in clinical practice. Literature
reports an incidence of roughly 16% in patients who have a SSRIs overdose (Boyer
and Shannon 2005; Ables and Nagubilli 2010).

Seizures
Antidepressants can lower the seizure threshold. Epileptogenic risk is particularly
high for TCAs and bupropion which are indeed contraindicated in individuals with
seizure disorders. As regards bupropion, the use of immediate release formulation in
dosages over 450 mg may produce a tenfold increase of estimated seizure incidence.
However, with the development of sustained release, the incidence of seizure
dropped to 0.1% in a study including 3.094 patients (50–300 mg) (Dunner et al.
1998).

Extrapyramidal Symptoms
Case reports have associated the use of antidepressants with extrapyramidal symp-
toms (EPS). The whole spectrum of EPS has been reported over the years, but
dystonia appears to be the most common presentation. SSRIs are the most implicated
agents (80.2% of all cases). The putative pathogenetic mechanism would be a
disruption in dopaminergic neurons in the nigrostriatal and tuberoinfundibular
pathways caused by excessive levels of 5-HT. EPS usually arise within 30 days of
either treatment initiation or dose increase. Age, gender, dosing, and concurrent
antipsychotic treatment seemingly do not impact substantially on liability to EPS
during treatment with SSRIs (Hawthorne and Caley 2015).

Headache
Although a commonly listed side effect reported for second-generation antidepres-
sants, headache is much more likely to be coincidental than associated with medi-
cation use. Second-generation antidepressants emerged as either not associated with
an increased risk of headache or associated with a clinically inconsequential, albeit
statistically significant, risk in comparison to placebo. The only antidepressants that
were found to be significantly associated with increased risk of headache compared
to placebo were bupropion (RR = 1.22, 95% CI = 1.06–1.41) and escitalopram
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1161

(RR = 1.18, 95% CI = 1.01–1.37). Of interest, diagnostic indication, pharmacolog-

ical properties, and medication dosage did not affect the relative risk of headache
(Telang et al. 2018).

Ophthalmic Effects
Ophthalmic effects are more prominent with TCAs due to their anticholinergic
activity. Blurred vision occurs in roughly one-third of patients in the initial stages
of treatment with TCAs. Patients usually develop tolerance to this effect and vision
spontaneously return to normal after some time elapses. A more dangerous event is
angle-closure glaucoma, which TCAs may trigger through mydriasis and
cycloplegia. Pre-existing risk factors for angle-closure glaucoma indeed contraindi-
cate TCAs. SSRIs have been associated with mydriasis, increased intraocular pres-
sure, and angle-closure glaucoma via anticholinergic or noradrenergic effects (albeit
weak for the majority of SSRIs, especially in comparison to TCAs) and serotonergic
effects. Most of the reported glaucoma cases involved paroxetine, which compara-
tively to other SSRIs produces a relatively strong NE reuptake inhibition (Richa and
Yazbek 2010). Case reports have also associated venlafaxine with angle-closure
glaucoma (Richa and Yazbek 2010; Zhou et al. 2018; Ezra et al. 2006). In addition, a
nested case-control study found that that the risk of angle-closure glaucoma was
doubled among patients younger than 50 years taking bupropion (Symes et al. 2015).
New antidepressants thus do not appear to be completely safe from the risk of
glaucomatous attacks, even though well below the level of risk associated with
TCAs; baseline and follow-up ophthalmic consultations may be warranted in
patients with a higher risk for glaucoma (e.g., the elderly and those with a familial
high risk of glaucomatous diseases).

Weight Gain

Although weight loss can occur in the early stage of antidepressant treatment
(4–12 weeks), weight is often regained after 6 months and can be followed by
additional gain with long-term use. The interaction of a number of mechanisms is
likely to drive this phenomenon: 1) antagonism to histaminergic H1 receptors and
5-HT2C receptors; 2) diminished caloric expenditure due to sedative effects of
some antidepressants; 3) a shift in food preference; and 4) dry mouth, caused by
some antidepressants, may lead to an increased intake of caloric beverages
(Carvalho et al. 2016). Antidepressants markedly differ in their propensity to
induce changes in body weight, and overall the magnitude of effect is mild with
some notable exceptions. Paroxetine and amitriptyline are associated with a mean
weight gain after 4 months of 2.73 kg (95% CI = 0.78; 4.68) and 2.24 kg (95%
CI = 1.82; 2.66), respectively. Mirtazapine is the newer-generation antidepressant
most consistently associated with significant weight gain in the initial phases of
treatment with a mean weight gain of 1.74 kg between 4 and 12 weeks (95%
CI = 1.28; 2.20). Contrariwise, some weight loss occurs with fluoxetine and
bupropion, although the effect of fluoxetine appears to be limited to the acute
1162 F. Corponi et al.

phase of treatment (Serretti and Mandelli 2010). Venlafaxine is quite tolerable in

terms of weight gain, similarly to vortioxetine and vilazodone according to avail-
able evidence (Carvalho et al. 2016).

Bleeding

Antidepressants affect hemostasis primarily by interfering with the uptake of

blood 5-HT by platelets. 5-HT is released by platelets in response to vascular
injury and triggers vasoconstriction and platelet aggregation. Interestingly, 5-HT
increases gastric acidity, which may explain why most of the literature on
antidepressants-related bleeding addresses upper gastrointestinal bleeding.
Since the importance of 5-HT dysregulation in antidepressant-related bleeding,
this adverse event is limited to antidepressants with a high degree of 5-HT uptake
blockade, namely, SSRIs and venlafaxine, the most potent serotoninergic drug
among SNRIs. In a meta-analysis, paroxetine, fluoxetine, fluvoxamine, sertra-
line, and venlafaxine were found to carry comparable risks of bleeding
(ORs = 1.3–1.7), whereas higher odds were associated with citalopram and
escitalopram (OR > 2). Meta-analyses of observational studies have found OR
of 1.5 to 1.6 for risk of upper gastrointestinal bleeding with SSRIs and
venlafaxine (Jiang et al. 2015). However, in otherwise healthy subjects, compen-
satory mechanisms often prevent this side effect with a number needed to harm
(NNH) of 3177 per year in a low-risk population. The overall risks are substan-
tially higher among individuals on concomitant use of nonsteroidal anti-inflam-
matory agents/antiplatelet drugs or with pre-existing hemorrhagic diathesis due
to concurrent medical conditions including bleeding disorders, chronic liver
disease, acid peptic disease, and dental, obstetrical, and surgical events. Old
age per se is an additional risk factor. Under these circumstances, antidepressant
blocking 5-HT reuptake should be avoided if possible. Use of proton pump
inhibitors and acid suppressants may reduce this risk for gastrointestinal hemor-
rhage. Besides gastrointestinal bleeding, 5-HT reuptake inhibition increases the
risk of intracranial/intracerebral hemorrhage and increases the need of perioper-
ative blood transfusion (Andrade and Sharma 2016).

Hyponatremia

Hyponatremia is defined as a serum sodium level of less than 135 mEq/L by some
sources or of less than 130 mEq/L by others, the normal range being 135–145 mEq/L.
Clinical manifestations depend on the severity of hyponatremia. Minor reductions in
serum sodium level can remain clinically undetected, whereas, in case of a more
important drop in serum sodium level, symptoms range from nausea and malaise to
lethargy, decreased level of consciousness, headache, and, in severe cases, seizures
and coma. Overt neurologic symptoms are generally due to very low serum sodium
levels (usually <115 mEq/L) and result from intracerebral osmotic fluid shifts and
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1163

brain edema. The proposed mechanism of antidepressant-induced hyponatremia is the

syndrome of inappropriate secretion of antidiuretic hormone via serotonergic receptors
and α1-adrenergic receptors stimulation. Antidepressants may also increase renal
responsiveness to antidiuretic hormone. The risk of hyponatremia is significantly
higher among the elderly and in patients taking diuretics. The reported incidence
and prevalence of antidepressant-induced hyponatremia is controversial, and usually
studies are based on a serum sodium cut-off, not differentiating between symptomatic
and asymptomatic cases. Patients hospitalized due to hyponatremia have an OR of
around four for use of SSRIs. Seemingly, SSRIs and venlafaxine are the antidepres-
sants most frequently associated, whereas bupropion, trazodone, and TCAs are safer
agents with respect to this adverse event. Antidepressant-induced hyponatremia usu-
ally manifests within 30 days of starting treatment and may not be dose related
(Viramontes et al. 2016).

Hyperhidrosis

Hyperhidrosis, i.e., excessive sweating, is a common side effect of TCA treatment,

experienced by approximately 14% of the patients. A significantly increased risk of
hyperhidrosis compared to placebo is present with SSRIs (RR = 2.93, 95% CI:
2.46–3.47) and SNRIs (RR = 3.17, 95% CI: 2.63–3.82) as well. Among SSRIs
sertraline and paroxetine carry a higher risk, while fluvoxamine is safer. The atypical
agents bupropion and vortioxetine are not associated with a significantly higher risk
of hyperhidrosis. This side effect is dose-independent and may not remit with
continued treatment. Although the exact pathogenetic mechanism is unclear, it is
hypothesized to be related to 5-HT effects on thermoregulation in the hypothalamus
(Beyer et al. 2017).

Sleep Disturbances

Sleep disturbances are one of the hallmark manifestations of depression. Antide-

pressants themselves can affect sleep causing either insomnia or somnolence,
according to their pharmacodynamic profile; thus this side effect can be turned
into a desirable therapeutic action. Bupropion, desvenlafaxine, duloxetine,
escitalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, and
venlafaxine in decreasing order are associated with significantly higher rates of
insomnia as compared with placebo. Dopaminergic stimulation in substantia nigra
and ventral tegmental area, as well as α1-adrenoreceptors agonism, is the mecha-
nisms likely involved for bupropion. Agomelatine is the only new-generation
antidepressant with a lower likelihood of inducing insomnia compared with placebo.
Escitalopram, due to its high serotonergic specificity, and citalopram, on grounds of
its histaminergic stimulation, are associated with lower rates of insomnia compared
with other SSRIs. As for somnolence, higher risk than placebo was found in
decreasing order for fluvoxamine, mirtazapine, reboxetine, paroxetine,
1164 F. Corponi et al.

desvenlafaxine, duloxetine, venlafaxine, sertraline, citalopram, fluoxetine, and

escitalopram. The effect of fluvoxamine is probably related to the inhibition of
melatonin degradation. Bupropion is the only drug associated with a lower incidence
of this side effect than placebo (Alberti et al. 2015).
Antidepressants alter sleep structure as well. SSRIs, SNRIs, vortioxetine, and
activating TCAs increase rapid eye movement (REM) latency, suppress REM
sleep, and may impair sleep continuity. On the other hand, sedating antidepres-
sants, e.g., doxepin, mirtazapine, and trazodone, decrease sleep latency, improve
sleep efficiency, increase slow wave sleep, and usually have little or no effect on
REM sleep. Alterations in sleep structure tend to last only for the first few weeks of
treatment.
The use of antidepressants, also those with sedative properties, may impair sleep
due to the induction of sleep disorders or worsening already existing ones. Mianserin
and mirtazapine may induce restless legs syndrome in as many as 28% of patients.
Treatment-emergent restless legs syndrome has also been described for SSRIs and
venlafaxine (Wichniak et al. 2017).

Discontinuation Syndrome

The set of symptoms patients can experience on stopping an antidepressant treatment

are referred to as discontinuation syndrome. This term, as opposed to withdrawal
syndrome, is aimed at distancing antidepressants from drugs with a potential for
dependence. Clinical manifestations comprise flu-like symptoms, tremors, tachycar-
dia, shock-like sensations, paresthesia, myalgia, tinnitus, neuralgia, ataxia, vertigo,
sexual dysfunction, sleep disturbances, vivid dreams, nausea vomiting, diarrhea,
worsening anxiety, and mood instability. Despite discordant reports on incidence,
some discontinuation symptoms are experienced by at least a third of patients and are
seen to some extent with all antidepressant, with the possible exceptions of
agomelatine and vortioxetine. Most prominent symptoms are found in patients
treated with agents with shorter half-life, such as venlafaxine and paroxetine. High
antidepressant doses and 8 weeks or longer treatment duration increase the risk of
developing discontinuation syndrome. Clinical onset is typically within 3 days after
stopping antidepressant medication or initiating a medication taper. The exact
physiopathology of antidepressant discontinuation syndrome is not yet fully eluci-
dated, and a number of mechanisms have been put forward: a decrease in 5-HT
availability when treatment ends and a behavioral stress response that is associated
with increased hippocampal N-methyl-D-aspartate (NMDA) receptor density and
genetic vulnerabilities. Generally, to avoid discontinuation syndrome, antidepressant
therapy should be discontinued over at least a 4-week period, except for fluoxetine in
consideration of its particularly long dynamic half-life. Importantly, even medication
tapering does not guarantee against the occurrence of this adverse effect. Anyhow,
clinical manifestations are usually mild and resolve spontaneously in 1–2 weeks
(Gabriel and Sharma 2017).
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1165

Suicidality

The emergence of suicidality and self-harm behaviors upon antidepressant treatment

has been a highly debated topic. Since 2004 the FDA has issued a black box warning
concerning the risk of suicidality associated with the use of antidepressants in
children and adolescents. An increase in suicidal impulses as well as in the energy
to act on them preceding the onset of antidepressant therapeutic effect would
purportedly underlie the link between antidepressant and suicidality. Most authors
however agree that the risk/benefit ratio for antidepressants use in pediatric depres-
sion appears to be favorable, but careful monitoring is recommended (Birmaher et al.
2007; Wasserman et al. 2012).

SSRIs-Induced Emotional Indifference

Patients on SSRIs may develop diminished motivation and reduction in the intensity
and/or experience of all emotions, both positive and negative, with a subsequent
sense of emotional detachment. Since apathy is a feature of depression itself, SSRI-
induced indifference can be mistaken for a residual symptom of the illness. In SSRIs-
induced indifference, however, patients do not report emotional distress as with
depression, but, on the contrary, they report blunted emotional responsiveness; they
usually describe themselves as “just not caring.” While such a state of emotional
flattening can be in part desirable with regard to negative life events, it also limits
responsiveness to positive events and impairs interpersonal relationships, hindering
emotional resonance with beloved ones. SSRIs-induced indifference is dose-depen-
dent and completely reversible on drug discontinuation; usually a dose reduction is
sufficient. Onset is often insidious and delayed. Two putative mechanisms for
development of this side effect have been hypothesized: serotonergic effects on the
frontal lobes and/or serotonergic modulation of mid-brain dopaminergic systems,
which project to the prefrontal cortex. At present, data on epidemiology, effect of
gender, age and ethnicity, differential rate (if any) among SSRIs, and adjunctive risk
factors are lacking (Sansone and Sansone 2010). According to some findings
including animal models and healthy volunteers, SSRI-induced indifference could
be most pronounced with paroxetine, while fluvoxamine may be the least subject to
this effect (Serretti et al. 2010).

Antidepressant-Induced Jitteriness

Anxious or depressed patients who receive antidepressant medications often report

increased anxiety and related symptoms during the initial weeks of treatment. This
phenomenon is usually referred to as antidepressant-induced jitteriness (AIJ).
Despite being first described nearly 40 years ago, there are no validated, or com-
monly used, measures for AIJ. Although symptoms such as insomnia, anxiety,
1166 F. Corponi et al.

irritability, increased energy, and restlessness appear in most descriptions, consis-

tency is lacking, and no symptom is ubiquitous. As a result, comparability across
studies is limited and so is the overall level of evidence for any feature regarding this
condition. Moreover, the relationship and the boundaries between AIJ, akathisia, and
affective switch to mania/hypomania are poorly characterized. Importantly, it may
not be securely established whether AIJ results from antidepressant treatment or
whether it reflects a worsening of the underlying disease. Despite the potential
importance of the condition and its reception in guidelines, there has been only
one substantial review on the subject. Published incidences of AIJ vary considerably
(4–65%). Onset is typically early, within few weeks of treatment initiation, and the
majority of reports involved imipramine and fluoxetine (Sinclair et al. 2009).

Conclusions

Antidepressants are one of the most prescribed drug classes worldwide. Depression
accounts for the majority of antidepressant prescriptions; therefore for new drugs
pharmaceutical industries tend to set up RCTs aimed at gaining approval for this
condition in the first place. Additional RCTs to license drugs for other conditions
may not be funded, leaving a gray area of off-label prescriptions. Besides depression,
approved indications mainly comprise other psychiatric conditions in the realm of
anxiety spectrum disorders, obsessive-compulsive disorders, stressors-related disor-
ders, and medical painful syndromes. Whatever the illness, undertaking an antide-
pressant treatment is appropriate when some severity indicators are present.
Monotherapy is generally the first-line treatment, but evidence of superior efficacy
of one agent over another is scarce. Therefore, risk of different side effects and drug
interactions are usually recommended to guide antidepressant choice. Consequently,
considerations of safety, tolerability, co-occurring morbid conditions, and co-pre-
scribed medications rather than efficacy are the main criteria for antidepressant
choice.
The delayed development of the full antidepressant effect and the limited remis-
sion rate, with around 20–30% of patients considered treatment-resistant depression
(TRD), remain the most problematic issues of antidepressant therapy. Secondarily,
while newer antidepressants are safer and better tolerated, side effects are still a
major limit to compliance. A number of strategies can be applied in a bid to address
these still unmet needs. First, a clinical approach that matches clinical features (i.e.,
disease characteristics and vulnerability to side effects) with antidepressant specific-
ity (pharmacodynamic and pharmacokinetic profile) is a good option to personalize
treatment. This line of action can optimize efficacy and minimize side effects
(Serretti 2018), and it can be implemented more easily by using a recently proposed
new classification of psychotropic drugs based on pharmacological domains and
modes of action, the Neuroscience-based Nomenclature (NbN). Indeed the currently
applied Anatomical Therapeutic Chemical (ATC) classification classifies psychotro-
pic drugs by main indication, not including all potential clinical uses of a particular
agent. NbN aims to avoid confusion about drug indication, since patients and
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1167

caregivers may misunderstand the therapeutic indication of prescription when the

drug name does not match with the diagnosis and therefore not adhere to the
proposed treatment. Importantly, NbN also aims to provide clinicians the pharma-
cological information needed to make the most informed decisions regarding patient
care (Zohar et al. 2015). Besides a more rational and scientific nomenclature,
pharmacogenetics can assist in the delivery of patient-tailored treatments. The first
pharmacogenetic markers have entered guideline recommendations: Genotyping of
functional polymorphisms in CYP2C19 and CYP2D6 genes is recommended for
guiding drug choice and dose titration. However, the lack of evidence supporting the
cost/effectiveness of antidepressant pharmacogenetics has prevented the routine
clinical application as yet (Consortium CPI 2017; FDA 2017). In the future, bio-
markers hold the promise of aiding in diagnosis and treatment. Biomarkers involved
in inflammatory, neurotrophic, and metabolic processes, as well as neurotransmitter
and neuroendocrine systems represent highly promising candidates. However,
excessively contrasting evidence illustrates that there are a number of challenges
needing to be tackled before biomarker research can be applied to the clinical
practice, most importantly a lack of sensitivity, specificity, and consistent replication
(Strawbridge et al. 2017).
Despite precision medicine can significantly improve response and tolerability, a
fraction of patients might still not benefit from currently available treatments. These
indeed act on substantially similar pathways and do not reflect the heterogeneity in
MDD pathogenesis. In other words, some MDD subtypes may not be responsive to
antidepressants working through the modulation of monoamines availability, such
are the ones currently available. The construction of a scientifically verified concep-
tual framework for depression physiopathology and antidepressant action is needed
before more effective antidepressants can be developed. Recently, endocrinological
and immunological mechanisms, non-monoaminergic neurotransmission, metabolic
regulation, and genetic-environmental factors have been suggested as frameworks
for the development of new antidepressants, spawning new potential agents. A
popular example is ketamine, a noncompetitive NMDA receptor antagonist, that
produces rapid antidepressant action and leads to a swift resolution of suicidal
ideation, despite benefits tend to wane after some days (Harmer et al. 2017). Other
possible new antidepressants include monoclonal antibodies selectively targeting
relevant pro-inflammatory cytokines, antagonists at k-opioid receptor (KOR), and
agents geared to restore neurogenesis.
Despite antidepressants with really alternative mechanisms of action are still
not available, personalization of treatment should be already implemented by
matching each patient’s clinical profile with the pharmacodynamics/pharmaco-
kinetics of available drugs. Efforts toward the use of the whole armamentarium of
available antidepressant drugs should be pursued in order to personalize treat-
ment as much as possible. In addition to TDM, genotyping of functional variants
within CYP2D6/CYP2C19 has been already included in guidelines and can
provide useful information for antidepressant choice and dosing. Further bio-
markers are expected to improve personalization in drug choice and improve
clinical outcomes.
1168 F. Corponi et al.

References
Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam
Physician. 2010;81(9):1139–42.
Ahmad Kiadaliri A. Global, regional, and national disability-adjusted life-years (DALYs) for 315
diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for
the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1603–58.
Alberti S, Chiesa A, Andrisano C, Serretti A. Insomnia and somnolence associated with second-
generation antidepressants during the treatment of major depression: a meta-analysis. J Clin
Psychopharmacol. 2015;35(3):296–303.
Alwan S, Reefhuis J, Rasmussen SA, Friedman JM, National Birth Defects Prevention S. Patterns
of antidepressant medication use among pregnant women in a United States population. J Clin
Pharmacol. 2011;51(2):264–70.
American Psychiatric A. Diagnostic and statistical manual of mental disorders. Washington, DC:
American Psychiatric Association; 2013.
Andrade C, Sharma E. Serotonin reuptake inhibitors and risk of abnormal bleeding. Psychiatr Clin
North Am. 2016;39(3):413–26.
Angst J, Baastrup P, Grof P, Hippius H, Poldinger W, Weis P. The course of monopolar depression
and bipolar psychoses. Psychiatr Neurol Neurochir. 1973;76(6):489–500.
Baldwin DS, Anderson IM, Nutt DJ, Allgulander C, Bandelow B, den Boer JA, et al. Evidence-
based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obses-
sive-compulsive disorder: a revision of the 2005 guidelines from the British Association for
Psychopharmacology. J Psychopharmacol. 2014;28(5):403–39.
Baldwin D, Barnes T, Coghill D, Goodwin G, Hale T, Howard L, et al. Evidence-based guidelines
for treating depressive disorders with antidepressants: a revision of the 2008 British Association
for Psychopharmacology guidelines. J Psychopharmacol. 2015;29(295):459–525.
Beach SR, Kostis WJ, Celano CM, Januzzi JL, Ruskin JN, Noseworthy PA, et al. Meta-analysis of
selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry.
2014;75(5):e441–9.
Berard A, Iessa N, Chaabane S, Muanda FT, Boukhris T, Zhao JP. The risk of major cardiac
malformations associated with paroxetine use during the first trimester of pregnancy: a system-
atic review and meta-analysis. Br J Clin Pharmacol. 2016;81(4):589–604.
Beyer C, Cappetta K, Johnson JA, Bloch MH. Meta-analysis: risk of hyperhidrosis with second-
generation antidepressants. Depress Anxiety. 2017;34(12):1134–46.
Birmaher B, Brent D, Issues AWGoQ, Bernet W, Bukstein O, Walter H, et al. Practice parameter for
the assessment and treatment of children and adolescents with depressive disorders. J Am Acad
Child Adolesc Psychiatry. 2007;46(11):1503–26.
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112–20.
Brintellix (vortioxetine) Summary of product characteristics (online) Lundbeck Limited 2015.
www.medicines.org.uk/emc/medicine/30904. Accessed 15 Aug 2018.
Cappetta K, Beyer C, Johnson JA, Bloch MH. Meta-analysis: risk of dry mouth with second generation
antidepressants. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;84(Pt A):282–93.
Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks
associated with the use of newer generation antidepressant drugs: a critical review of the
literature. Psychother Psychosom. 2016;85(5):270–88.
Chappell J, He J, Knadler MP, Mitchell M, Lee D, Lobo E. Effects of duloxetine on the pharma-
codynamics and pharmacokinetics of warfarin at steady state in healthy subjects. J Clin
Pharmacol. 2009;49(12):1456–66.
Chen G, Lee R, Hojer AM, Buchbjerg JK, Serenko M, Zhao Z. Pharmacokinetic drug interactions
involving vortioxetine (Lu AA21004), a multimodal antidepressant. Clin Drug Investig.
2013;33(10):727–36.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy
and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive
disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357–66.
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1169

Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, et al. Relapse of major
depression during pregnancy in women who maintain or discontinue antidepressant treatment.
JAMA. 2006;295(5):499–507.
Consortium CPI. CPIC guidelines. 2017. Available at: https://cpicpgx.org/guidelines/. Accessed 24
July 2018.
Cooper-Kazaz R, Cohen A, Lerer B. Noradrenergic adverse effects due to combined treatment with
reboxetine and triiodothyronine. J Clin Psychopharmacol. 2010;30(2):211–2.
Dane KE, Gatewood SB, Peron EP. Antidepressant use and incident urinary incontinence: a
literature review. Consult Pharm. 2016;31(3):151–60.
Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety
surveillance study for bupropion sustained-release in the treatment of depression. J Clin
Psychiatry. 1998;59(7):366–73.
Ezra DG, Storoni M, Whitefield LA. Simultaneous bilateral acute angle closure glaucoma following
venlafaxine treatment. Eye (Lond). 2006;20(1):128–9.
Farah WH, Alsawas M, Mainou M, Alahdab F, Farah MH, Ahmed AT, et al. Non-pharmacological
treatment of depression: a systematic review and evidence map. Evid Based Med. 2016;21(6):214–21.
Faure Walker N, Brinchmann K, Batura D. Linking the evidence between urinary retention and
antipsychotic or antidepressant drugs: a systematic review. Neurourol Urodyn. 2016;35(8):866–74.
FDA. Table of pharmacogenomic biomarkers in drug labeling. 2017. Available at: https://www.fda.
gov/Drugs/ScienceResearch/ucm572698htm. Accessed 24 July 2018.
Flockhart DA. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an
update. J Clin Psychiatry. 2012;73(Suppl 1):17–24.
Furukawa TA, Cipriani A, Atkinson LZ, Leucht S, Ogawa Y, Takeshima N, et al. Placebo response
rates in antidepressant trials: a systematic review of published and unpublished double-blind
randomised controlled studies. Lancet Psychiatry. 2016;3(11):1059–66.
Gabriel M, Sharma V. Antidepressant discontinuation syndrome. CMAJ. 2017;189(21):E747.
Garnock-Jones KP, Keating GM. Atomoxetine: a review of its use in attention-deficit hyperactivity
disorder in children and adolescents. Paediatr Drugs. 2009;11(3):203–26.
Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, et al. Comparative benefits
and harms of second-generation antidepressants for treating major depressive disorder: an
updated meta-analysis. Ann Intern Med. 2011;155(11):772–85.
Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, et al. Relapse prevention
with antidepressant drug treatment in depressive disorders: a systematic review. Lancet.
2003;361(9358):653–61.
Gelenberg AJ, Marlene Freeman CP, Markowitz JC, Rosenbaum JF, Thase ME, Trivedi MH, et al.
Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Work
group on major depressive disorder. Virginia: American Psychiatric Association. 2010.
Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J
Pharmacol. 2007;151(6):737–48.
Goldstein DJ, Wilson MG, Thompson VL, Potvin JH, Rampey AH Jr. Long-term fluoxetine
treatment of bulimia nervosa. Fluoxetine Bulimia Nervosa Research Group. Br J Psychiatry.
1995;166(5):660–6.
Hamilton M. Rating depressive patients. J Clin Psychiatry. 1980;41(12 Pt 2):21–4.
Harada E, Tokuoka H, Fujikoshi S, Funai J, Wohlreich MM, Ossipov MH, et al. Is duloxetine's effect
on painful physical symptoms in depression an indirect result of improvement of depressive
symptoms? Pooled analyses of three randomized controlled trials. Pain. 2016;157(3):577–84.
Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining
future treatment approaches. Lancet Psychiatry. 2017;4(5):409–18.
Hauta-Aho M, Tirkkonen T, Vahlberg T, Laine K. The effect of drug interactions on bleeding risk
associated with warfarin therapy in hospitalized patients. Ann Med. 2009;41(8):619–28.
Hawthorne JM, Caley CF. Extrapyramidal reactions associated with serotonergic antidepressants.
Ann Pharmacother. 2015;49(10):1136–52.
Hedayati SS, Yalamanchili V, Finkelstein FO. A practical approach to the treatment of depression in
patients with chronic kidney disease and end-stage renal disease. Kidney Int. 2012;81(3):247–55.
1170 F. Corponi et al.

Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antide-
pressant medications. Am J Psychiatry. 2003;160(5):993–6.
Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Consensus
guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017.
Pharmacopsychiatry. 2018;51(1–02):9–62.
Hilbert A, Hoek HW, Schmidt R. Evidence-based clinical guidelines for eating disorders: interna-
tional comparison. Curr Opin Psychiatry. 2017;30(6):423.
Jiang HY, Chen HZ, Hu XJ, Yu ZH, Yang W, Deng M, et al. Use of selective serotonin reuptake
inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis.
Clin Gastroenterol Hepatol. 2015;13(1):42–50.e3.
Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, et al. Canadian clinical
practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compul-
sive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1.
Katzman MA, Nierenberg AA, Wajsbrot DB, Meier E, Prieto R, Pappadopulos E, et al. Speed of
improvement in symptoms of depression with desvenlafaxine 50 mg and 100 mg compared with
placebo in patients with major depressive disorder. J Clin Psychopharmacol. 2017;37(5):555–61.
Kemp AH, Brunoni AR, Santos IS, Nunes MA, Dantas EM, Carvalho de Figueiredo R, et al. Effects
of depression, anxiety, comorbidity, and antidepressants on resting-state heart rate and its
variability: an ELSA-Brasil cohort baseline study. Am J Psychiatry. 2014;171(12):1328–34.
Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for
Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of
adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatr
Rev Can Psychiatr. 2016;61(9):540–60.
Kim SW, Shin IS, Kim JM, Park KH, Youn T, Yoon JS. Factors potentiating the risk of mirtazapine-
associated restless legs syndrome. Hum Psychopharmacol. 2008;23(7):615–20.
Kopera H. Cardiovascular tolerance of mianserin and interactions of mianserin with other drugs.
Acta Psychiatr Belg. 1978;78(5):787–97.
Lader M, Stender K, Burger V, Nil R. Efficacy and tolerability of escitalopram in 12- and 24-week
treatment of social anxiety disorder: randomised, double-blind, placebo-controlled, fixed-dose
study. Depress Anxiety. 2004;19(4):241–8.
Lavori PW, Keller MB, Mueller TI, Scheftner W. Recurrence after recovery in unipolar MDD: an
observational follow-up study of clinical predictors and somatic treatment as a mediating factor.
Int J Methods Psychiatr Res. 1994;4(4):211–29.
Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in
utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc
Med. 2006;160(2):173–6.
Montejo AL, Prieto N, Terleira A, Matias J, Alonso S, Paniagua G, et al. Better sexual acceptability
of agomelatine (25 and 50 mg) compared with paroxetine (20 mg) in healthy male volunteers.
An 8-week, placebo-controlled study using the PRSEXDQ-SALSEX scale. J Psychopharmacol.
2010;24(1):111–20.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J
Psychiatry. 1979;134:382–9.
Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults.
Cochrane Database Syst Rev. 2015;7:CD008242.
Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepres-
sants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther.
2014;40(8):880–92.
Nierenberg AA, Husain MM, Trivedi MH, Fava M, Warden D, Wisniewski SR, et al. Residual
symptoms after remission of major depressive disorder with citalopram and risk of relapse: a
STARD report. Psychol Med. 2010;40(1):41–50.
Ostad Haji E, Hiemke C, Pfuhlmann B. Therapeutic drug monitoring for antidepressant drug
treatment. Curr Pharm Des. 2012;18(36):5818–27.
Antidepressants: Indications, Contraindications, Interactions, and Side Effects 1171

Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, et al. The International
Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disor-
ders. Am J Psychiatry. 2013;170(11):1249–62.
Pratt LA, Brody DJ, Gu Q. Antidepressant use among persons aged 12 and over: United States,
2011–2014: US Department of Health and Human Services, Centers for Disease Control and
Prevention, Atlanta: National Center for Health Statistics; 2017.
Reichenpfader U, Gartlehner G, Morgan LC, Greenblatt A, Nussbaumer B, Hansen RA, et al.
Sexual dysfunction associated with second-generation antidepressants in patients with major
depressive disorder: results from a systematic review with network meta-analysis. Drug Saf.
2014;37(1):19–31.
Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs.
2010;24(6):501–26.
Romano SJ, Halmi KA, Sarkar NP, Koke SC, Lee JS. A placebo-controlled study of fluoxetine in
continued treatment of bulimia nervosa after successful acute fluoxetine treatment. Am J
Psychiatry. 2002;159(1):96–102.
Sansone RA, Sansone LA. SSRI-induced indifference. Psychiatry (Edgmont). 2010;7(10):14–8.
Sansone RA, Sansone LA. Antidepressant adherence: are patients taking their medications? Innov
Clin Neurosci. 2012;9(5–6):41–6.
Serretti A. The present and future of precision medicine in psychiatry: focus on clinical psycho-
pharmacology of antidepressants. Clin Psychopharmacol Neurosci. 2018;16(1):1–6.
Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-
analysis. J Clin Psychopharmacol. 2009;29(3):259–66.
Serretti A, Mandelli L. Antidepressants and body weight: a comprehensive review and meta-
analysis. J Clin Psychiatry. 2010;71(10):1259–72.
Serretti A, Calati R, Goracci A, Di Simplicio M, Castrogiovanni P, De Ronchi D. Antidepressants in
healthy subjects: what are the psychotropic/psychological effects? Eur Neuropsychopharmacol.
2010;20(7):433–53.
Sinclair LI, Christmas DM, Hood SD, Potokar JP, Robertson A, Isaac A, et al. Antidepressant-
induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. 2009;194(6):483–90.
Spina E, Trifiro G, Caraci F. Clinically significant drug interactions with newer antidepressants.
CNS Drugs. 2012;26(1):39–67.
Strawbridge R, Young AH, Cleare AJ. Biomarkers for depression: recent insights, current chal-
lenges and future prospects. Neuropsychiatr Dis Treat. 2017;13:1245–62.
Symes RJ, Etminan M, Mikelberg FS. Risk of angle-closure glaucoma with bupropion and
topiramate. JAMA Ophthalmol. 2015;133(10):1187–9.
Sysko R, Sha N, Wang Y, Duan N, Walsh BT. Early response to antidepressant treatment in bulimia
nervosa. Psychol Med. 2010;40(6):999–1005.
Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME. Early
improvement in the first 2 weeks as a predictor of treatment outcome in patients with major
depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70(3):344–53.
t Jong GW, Einarson T, Koren G, Einarson A. Antidepressant use in pregnancy and persistent
pulmonary hypertension of the newborn (PPHN): a systematic review. Reprod Toxicol.
2012;34(3):293–7.
Tampi RR, Balderas M, Carter KV, Tampi DJ, Moca M, Knudsen A, et al. Citalopram, QTc
prolongation, and Torsades de pointes. Psychosomatics. 2015;56(1):36–43.
Taylor D, Barnes TE, Young A. The Maudsley prescribing guidelines in psychiatry 2018. Newark:
John Wiley & Sons. 2018.
Tedeschini E, Levkovitz Y, Iovieno N, Ameral VE, Nelson JC, Papakostas GI. Efficacy of
antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-con-
trolled randomized trials. J Clin Psychiatry. 2011;72(12):1660–8.
Telang S, Walton C, Olten B, Bloch MH. Meta-analysis: second generation antidepressants and
headache. J Affect Disord. 2018;236:60–8.
1172 F. Corponi et al.

Trindade E, Menon D, Topfer LA, Coloma C. Adverse effects associated with selective serotonin
reuptake inhibitors and tricyclic antidepressants: a meta-analysis. CMAJ. 1998;159(10):1245–52.
Uher R, Farmer A, Henigsberg N, Rietschel M, Mors O, Maier W, et al. Adverse reactions to
antidepressants. Br J Psychiatry. 2009;195(3):202–10.
Viktorin A, Lichtenstein P, Thase ME, Larsson H, Lundholm C, Magnusson PK, et al. The risk of
switch to mania in patients with bipolar disorder during treatment with an antidepressant alone
and in combination with a mood stabilizer. Am J Psychiatry. 2014;171(10):1067–73.
Viramontes TS, Truong H, Linnebur SA. Antidepressant-induced hyponatremia in older adults.
Consult Pharm. 2016;31(3):139–50.
Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for
clinicians. Am J Psychiatry. 2014;171(4):404–15.
Wang SM, Han C, Bahk WM, Lee SJ, Patkar AA, Masand PS, et al. Addressing the side effects of
contemporary antidepressant drugs: a comprehensive review. Chonnam Med J. 2018;54(2):101–12.
Warner MD, Peabody CA, Whiteford HA, Hollister LE. Trazodone and priapism. J Clin Psychiatry.
1987;48(6):244–5.
Wasserman D, Rihmer Z, Rujescu D, Sarchiapone M, Sokolowski M, Titelman D, et al. The
European Psychiatric Association (EPA) guidance on suicide treatment and prevention. Eur
Psychiatry. 2012;27(2):129–41.
WHO. Depression: fact sheet. Geneva: World Health Organisation. Available at: http://www.
whoint/mediacentre/factsheets/fs369/en/; 2017.
Wichniak A, Wierzbicka A, Walecka M, Jernajczyk W. Effects of antidepressants on sleep. Curr
Psychiatry Rep. 2017;19(9):63.
Wienkers LC, Allievi C, Hauer MJ, Wynalda MA. Cytochrome P-450-mediated metabolism of the
individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug
Metab Dispos. 1999;27(11):1334–40.
Wilkes S. The use of bupropion SR in cigarette smoking cessation. Int J Chron Obstruct Pulmon
Dis. 2008;3(1):45–53.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al. Canadian Network for
Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders
(ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord.
2018;20(2):97–170.
Zhou N, Zhao JX, Zhu YN, Zhang P, Zuo Y. Acute angle-closure glaucoma caused by venlafaxine.
Chin Med J. 2018;131(12):1502–3.
Zohar J, Stahl S, Moller HJ, Blier P, Kupfer D, Yamawaki S, et al. A review of the current
nomenclature for psychotropic agents and an introduction to the neuroscience-based nomencla-
ture. Eur Neuropsychopharmacol. 2015;25(12):2318–25.
Antidepressants: Course and Duration of
Therapy, Withdrawal Syndromes, and
Resistance to Therapy

Lasse Brandt, Andreas Heinz, and Jonathan Henssler

Contents
Course and Duration of Pharmacological Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174
Acute Treatment Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174
Continuation Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175
Recurrence Prevention Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175
Withdrawal Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176
Acute Discontinuation Syndrome/Withdrawal Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1177
Severe Cases of ADS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
Persistent Post-discontinuation Syndromes and Rebound Phenomena . . . . . . . . . . . . . . . . . . . . 1180
Basic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181
Treatment and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181
Resistance to Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182
Clinical Assessment of Resistance to Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185

Abstract
The course and duration of therapy, withdrawal syndromes, and resistance to
therapy are important clinical topics in antidepressant therapy. The reviewed
clinical evidence may help to guide clinicians and patients when planning the
pharmacological part of the therapy.
The treatment with antidepressants is typically divided into different phases
that each require specific considerations.
The recommended course and duration of treatment may vary depending on
the respective treatment phase, as well as on individual patient characteristics.
Insufficient treatment response occurs frequently and a series of therapeutic

L. Brandt · A. Heinz (*) · J. Henssler

Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité Universitätsmedizin
Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health,
Berlin, Germany
e-mail: lasse.brandt@charite.de; andreas.heinz@charite.de; jonathan.henssler@charite.de

© Springer Nature Switzerland AG 2022 1173

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_28
1174 L. Brandt et al.

options are available such as increase in dosage, combining the current antide-
pressant with an additional antidepressant, augmentation with another pharma-
cological substance, and switching to a different antidepressant.
When antidepressant therapy is discontinued, patients may experience with-
drawal symptoms/syndromes. Symptoms are generally mild and transient, but,
depending on the individual drug, can be severe and impairing for individual
patients. Recognizing discontinuation syndromes and differentiating those from
re-emergence of the primary disorder is of crucial importance and will have major
consequences for further treatment. Indications and guidance for gradual tapering
of antidepressants will be discussed.

Course and Duration of Pharmacological Therapy

The course of pharmacological treatment of unipolar depression is typically catego-

rized into three main phases: acute phase, continuation phase, and maintenance
phase (DGPPN et al. 2015; NICE 2009).

Acute Treatment Phase

Generally, medication can be used for reducing symptom severity in clinical depres-
sion, particularly for severe forms of major depression (Cipriani et al. 2018a).
Medication, if necessary, should be combined with psychotherapeutic interventions
and social support.
Important aims of the pharmacological treatment in the acute phase are to reduce
symptoms of depressions that are associated with a burden of distress for the
individual person, to reduce mortality, and to increase psychosocial functioning.
The acute phase typically lasts for 6–12 weeks until individual treatment aims have
been fully or partially reached.
The degree of symptom reduction, also known as treatment response, can be
measured quantitatively by standardized rating scales (e.g., Beck’s Depression
Inventory, Hamilton Depression Scale, Hospital Anxiety and Depression Scale, or
Montgomery–Åsberg Depression Rating Scale). “Response” to treatment is typi-
cally defined as a 50% reduction in depression severity, as measured by standardized
rating scales. A broadly implemented four-tier definition of treatment response
categorizes the symptom reduction in percentage according to standardized rating
scale: <20% ¼ no significant effect; 20–50% ¼ minimal effect; 51–99% partial
remission; 100% ¼ full remission (Crismon et al. 1999).
In the acute treatment phase, medication will be increased in dosage until a low
start dosage has been reached (Hiemke et al. 2011). Current treatment guidelines for
unipolar depression recommend to increase the dosage stepwise and keep this initial
phase of the treatment as long as needed with regard to tolerability of the medication
but as short as possible to prevent delays in reaching the low start dosage (DGPPN
et al. 2015). Older persons or persons with relevant comorbidities such as
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1175

cardiovascular illnesses or epilepsy may require smaller dosages (e.g., less than half
dosages of tricyclic antidepressants such as amitriptyline) and slower increases in
dosage to reduce the risk of adverse events (Arroll 2005; Leucht et al. 2012; Roose
and Spatz 1999). Patients should be well informed about critical factors such as
potential adverse events, planned course and duration of treatment, and potential
withdrawal phenomena prior to the start of the treatment. Regular clinical monitor-
ing with regard to occurrence of adverse events is of particular importance in this
first phase.
The time to treatment response may vary between individuals and according to
the specific antidepressant medication. In clinical routine, treatment response is often
assessed approximately four weeks after the beginning of the acute treatment phase
(DGPPN et al. 2015; NICE 2009). While a statistically significant and sustained
effect of antidepressant treatment can be found in clinical depression (Cipriani et al.
2018a; Henssler et al. 2018a), clinical significance of improvements are currently
under discussion (Cipriani et al. 2018b; Kirsch and Jakobsen 2018). Likewise, the
assumption that antidepressant efficacy is dependent on the severity of depression is
challenged by recent findings from patient-level data analyses (Rabinowitz et al.
2016).

Continuation Phase

The acute treatment phase is followed by the continuation phase that generally lasts
for 6–9 months (American Psychiatric Association (APA) 2000; Bauer et al. 2015):
As the name implies, the continuation phase is intended as a continuation of the
acute treatment with the same medication and dosage and the main aim is to
“stabilize” the response (i.e., avoid relapse of the depressive episode) that has been
reached in the acute treatment. It has been shown that the initial phase following the
acute treatment is characterized by an increased risk of relapse of the depressive
symptoms and withdrawal phenomena, and treatment during the continuation
phase may reduce the odds of relapse by 70% (Cipriani et al. 2018a; Geddes et al.
2003).

Recurrence Prevention Phase

Recurrence prevention is the third phase that may start after the continuation phase
and is generally considered to be indicated for persons with at least two recent
depressive episodes that caused functional deficits (Frank et al. 1990; Geddes et al.
2003). Pharmacological recurrence prevention is not indicated for all patients and
limited to persons with an increased risk of recurrence such as persons with
sustaining factors (e.g., residual symptoms from the last depressive episode, low
coping resources, increasing number of depressive episodes, decreasing time in
between episodes, severity of recent depressive episodes, a history of suicidality,
onset early in life, a family history of major depression in first degree relatives,
1176 L. Brandt et al.

“double depression” with concurrent dysthymic disorder, or concurrent substance

use or anxiety disorders) (Bauer et al. 2015; DGPPN et al. 2015; Hardeveld et al.
2010; Nierenberg et al. 2003; Petersen 2006). Individual response to previous
pharmacological treatment further guides the decision regarding recurrence preven-
tion: For example, medication that was effective and well tolerated during the acute
treatment may be the first choice during recurrence prevention as well (American
Psychiatric Association (APA) 2000). Affective disorders are often characterized by a
chronic (Spijker et al. 2002) or recurrent course of illness (Hardeveld et al. 2010;
Yiend et al. 2009), and a thorough delineation of the current and previous episodes,
including frequency, symptom severity, and characteristics, as well as applied phar-
macological treatment is of major importance in finding and developing optimal and
individually fitted treatment strategies. The National Institute of Mental Health Life
Chart Methodology (NIMH-LCMTM), developed for this purpose, provides an acces-
sible tool for clinicians and patients (Leverich and Post 1998). Several pharmacolog-
ical treatments have been shown to be effective in recurrence prevention such as
tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs), venlafaxine, and lith-
ium (Frank et al. 1990; Keller et al. 2007; Kocsis et al. 2007; Montgomery et al.
2004b; Paykel 2001; Reimherr et al. 1998). For example, in Germany, sertraline and
venlafaxine are approved for the purpose of recurrence prevention in unipolar depres-
sion, while lithium is considered second line for this purpose (Baethge et al. 2003;
Burgess et al. 2001; Souza and Goodwin 1991). Due to better tolerability, second-
generation antidepressants like SSRI or SNRI may be preferred over TCA for long-
term treatment (Bauer et al. 2015). Of note, lithium has been proven most effective in
reducing suicidal actions in persons with unipolar and bipolar affective episodes and
may therefore be of particular relevance for persons with increased risk of suicide
(Cipriani et al. 2005, 2013; Geddes et al. 2003; Guzzetta et al. 2007; Tondo et al.
2001). Overall, most studies on the effectiveness of antidepressants during recurrence
prevention provided data for up to two years of treatment and more research is needed
to investigate the effectiveness of recurrence prevention for longer periods.

Withdrawal Syndromes

Increasingly, adverse phenomena that occur following treatment discontinuation are

becoming the focus of attention. Though known as early on as in the early 1960s
(Kramer et al. 1961), withdrawal phenomena and adverse phenomena that occur
following treatment discontinuation of antidepressants have increasingly become the
focus of attention (Brandt et al. 2020b; Henssler et al. 2019), in clinical practice and
research as well as in the general public. Withdrawal phenomena are also known
from other psychiatric substances such as antipsychotics (Brandt et al. 2020a) and
nonpsychiatric substances such as beta-adrenergic receptor antagonists or alpha-2
adrenergic agents (Metz et al. 1987; Reidenberg 2011).
Patients frequently discontinue their antidepressant medication (Hotopf et al.
1997), often without consultation of their treating physician, and inquiries from
patients concerning antidepressant discontinuation phenomena are common
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1177

(Van Geffen et al. 2007). It seems essential to provide patients with relevant
information on possible withdrawal phenomena already at treatment initiation
(Brandt et al. 2020b).
In clinical practice, when facing a patient who experiences newly emergent
symptoms after discontinuation of dose reduction of an antidepressant, the following
possible differential diagnoses have to be distinguished:

• Withdrawal syndrome/Antidepressant discontinuation syndrome

– characterized by: rapid onset; transient, usually self-limiting; rapid improve-
ment following resumption of the medication; typically accompanied by
nonspecific somatic symptoms
• Rebound
– re-emergence of symptoms of the primary disorder to a greater extent than
prior to medication and/or higher risk for relapse compared to patients not
receiving antidepressants
• Relapse/Recurrence
– re-emergence of the same disease episode/of a new episode of the same
recurring primary disorder due to loss of psychopharmacological effect with
medication discontinuation

Adequate differential diagnosis will have major clinical consequences, poten-

tially resulting in either necessary resumption of the antidepressant treatment in
recurrence of the primary disorder, or proposing a wait-and-see approach, or symp-
tomatic treatment in the case of withdrawal phenomena.

Acute Discontinuation Syndrome/Withdrawal Syndrome

Antidepressant discontinuation syndrome (ADS) is now defined as a separate

syndrome in relation to antidepressants. The discontinuation-emergent signs and
symptoms (DESS) checklist is the current standard to assess withdrawal symptoms.
It is being applied in major studies on this topic and lists the symptoms that have
meanwhile been identified and updated through research (Baldwin et al. 2006;
Rosenbaum et al. 1998).
Table 1 provides a detailed listing of possible clinical presentations of ADS.
While the most common symptoms represent unspecific physical symptoms, ADS
also may resemble symptoms of the primary disorder (i.e., mood disturbances,
anxiety or suicidal thoughts). Other symptoms, however, clearly can be differenti-
ated from the disorder (e.g., electric shock-like paresthesia, diarrhea, intense
dreams).
For a facilitated and rapid identification of ADS, the mnemonic aid “FINISH”
(Berber 1998) may particularly be helpful and pragmatic:

• Flu-like symptoms
• Insomnia (disturbed sleep, vivid dreams/nightmares)
1178 L. Brandt et al.

Table 1 Individual symptoms of antidepressant discontinuation syndrome

Systemic, Dizziness/drowsiness, impaired balance, fatigue, headache, flu-like
cardiac symptoms, weakness, tachycardia, dyspnea
Gastrointestinal Nausea, vomiting, diarrhea, anorexia, abdominal pain
Sleep Insomnia, nightmares, vivid dreams, hypersomnia
Affective Irritability, anxiety, agitation, depressive mood, panic, impulsivity, tension,
mood swings, sudden crying, outbursts of anger, mania, increased drive,
derealization, depersonalization, increased suicidal thoughts
Vasomotor Perspiration, impaired temperature regulation, flushing, chills
Cognitive Confusion, disorientation, amnesia
Sensory Paresthesia, dysesthesia, itch, tinnitus, altered taste, blurred vision, visual
changes, electric shock-like sensations (“brain-zapps/body-zapps”)
Neuromuscular Tremor, ataxia, muscle tension, myalgia, neuralgia
Sexual Premature ejaculation, genital hyperarousal
Psychotic Visual and auditory hallucinations
Delirium Specifically with tranylcypromine
Individual symptoms of antidepressant discontinuation syndrome. Symptoms shown in bold occur
frequently. (Adapted from (Chouinard and Chouinard (2015), Fava et al. (2015), Henssler et al.
(2019))

• Nausea
• Imbalance (vertigo, light-headedness)
• Sensory disturbances (electric shock-like sensations, dysesthesia)
• Hyperarousal (anxiety, agitation, irritability, etc.)

Further characteristics of ADS that were identified through a comprehensive and

structured literature search (Henssler et al. 2019) are:

• Rapid onset mostly within 1 week following discontinuation (generally peaking

after 36–96 h), after approximately 3–5 half-lives
• Usually spontaneous resolution within 2 (–6) weeks (depending on half-life)
• Predominantly mild, reversible symptoms
• Rapid and generally complete resolution if medication is resumed

ADS is typically predominated by nonspecific physical symptoms and the most

common symptoms are nausea, dizziness, headache, insomnia, irritability or emo-
tional lability.
The frequency and severity of ADS following discontinuation or dose reduction
vary strongly depending on the individual antidepressant and class of antidepressant.
MAO inhibitors: While evidence on ADS associated with MAO-I is particularly
sparse and mostly of low methodological quality, these agents appear to be associ-
ated with a particularly high risk for frequent and severe cases of ADS (Gahr et al.
2013; McGrath et al. 1993; Tyrer 1984). In this vein, in case reports on withdrawal
syndromes following discontinuation of tranylcypromine, delirium was described in
50% of all cases (Gahr et al. 2013), potentially due to their strong effect on dopamine
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1179

neurotransmission (Ainsworth et al. 1998; Heinz et al. 2011). Addictive-like con-

sumption was reported in single case reports (Westermeyer 1989) and associated
neurobiological adaptions may contribute to withdrawal symptoms (Henssler et al.
2019).
Tricyclic antidepressants (TCA): The evidence on tricyclic antidepressants (TCA)
is limited, and there are only a handful of methodologically high-quality studies
available concerning tricyclic antidepressants (TCA). Thus, evidence on ADS after
discontinuation of TCA is limited, prevailing evidence, however, suggests a high
risk for ADS. Even with gradual tapering, 80% of patients exhibited symptoms with
amitriptyline, albeit primarily mild and self-limiting (Giller et al. 1985), and ADS
from imipramine was comparable to that of paroxetine (GlaxoSmithKline 1992).
Following methodologically low quality studies and case series, TCA also appears to
carry an elevated risk for the development of severe withdrawal symptoms (Charney
et al. 1982). As a general clinical characteristic, ADS from TCA typically resembles
symptoms of cholinergic overdrive (Dilsaver and Greden 1984).
Selective serotonin reuptake inhibitors: ADS after discontinuation of selective
serotonin reuptake inhibitors (SSRI) is well studied and has been subject to a large
number of trials, including many of high methodological rigor. Fluoxetine has
proven to be rather unproblematic, even in the case of abrupt discontinuation
(Michelson et al. 2000; Zajecka et al. 1998), presumably due to its particularly
long half-life. Sertraline, citalopram, and escitalopram seem to inherit a low risk for
ADS with abrupt discontinuation (approximately 20% compared to 10% with
continuation of medication) (Markowitz et al. 2000; Montgomery et al. 2005),
while tapered withdrawal was not significantly associated with more withdrawal
symptoms compared to continuation (Allgulander et al. 2006).
Paroxetine, on the contrary, is – concerning severity as well as frequency –
associated with a particularly high risk for ADS. Following abrupt discontinuation,
withdrawal symptoms are seen in more than in one-third of patients (Kaufman et al.
2003; Michelson et al. 2000; Montgomery et al. 2004c). Concerning severity and
also clinical presentation, ADS after discontinuation of paroxetine resembles that
seen with tricyclic antidepressants (GlaxoSmithKline 1992). Typically, ADS after
discontinuation of SSRI (excluding paroxetine) is rather mild and self-limiting.
Selective serotonin and noradrenaline reuptake inhibitors: Withdrawal syn-
dromes after serotonin and noradrenaline reuptake inhibitors (SNRIs) discontinua-
tion are well studied in a number of methodologically rigorous trials. Venlafaxine
(and desvenlafaxine) holds a higher risk for ADS, when directly compared to SSRI
(escitalopram and sertraline) (Montgomery et al. 2004c; Montgomery and Andersen
2006; Ninan et al. 2015; Sir et al. 2005). Also, venlafaxine is associated with more
severe cases of ADS (Sir et al. 2005) and a particularly early onset of symptoms, in
some patients as early as after only one delayed dose. Duloxetine, on the contrary,
carries a comparably low risk for ADS in comparison (Hartford et al. 2007), but risk
increases with treatment in the high-dose range (120 mg/day) (Perahia et al. 2005).
Concerning the third SNRI, milnacipran, there is evidence resulting from studies of
high methodological rigor, indicating a low risk of ADS, even following abrupt
discontinuation of the antidepressant (Saxe et al. 2012; Vandel et al. 2004).
1180 L. Brandt et al.

Agomelatine: There is abundant evidence resulting from studies of high method-

ological rigor showing that withdrawal symptoms do not occur with agomelatine,
even following abrupt discontinuation (Goodwin et al. 2009; Montgomery et al.
2004a; Stein et al. 2012).
Mirtazapine and Bupropion: Evidence concerning ADS after discontinuation of
mirtazapine and bupropion is particularly sparse and lacks rigorous studies.
A handful of case reports suggest that discontinuation of mirtazapine and bupropion
can also cause ADS (Berigan 2002; Fauchere 2004; MacCall and Callender 1999).

Severe Cases of ADS

Generally, controlled and methodologically sound studies point toward a predomi-

nantly self-limiting course of ADS, mainly involving mild symptoms. Symptoms
classified as more severe in these studies primarily were nervousness, anxiety, and
sleep disturbances (Khan et al. 2014). While (online) surveys and uncontrolled
studies suggest higher rates of severe cases and overall higher incidence rates of
ADS (Davies and Read 2018), limitations have to be considered. The danger of
overestimation and attribution of causality is demonstrated by the fact that in blinded
randomized controlled trials, over 30% of all patients in control arms, that is, those
continuously taking antidepressant medication, reported withdrawal symptoms
(Allgulander et al. 2006; Ninan et al. 2015). Methodologically weaker studies and
case reports described extrapyramidal motor symptoms (such as parkinsonism and
akathisia) or paradoxical activation up to full-scale manic syndromes as withdrawal
symptoms. TCA, venlafaxine, and paroxetine have mainly been associated with
these more severe cases of ADS, but they also are reported with other SSRI
(Stoukides and Stoukides 1991) and mirtazapine (MacCall and Callender 1999).
The development of suicidal thought in severe cases of ADS is of high clinical
relevance (Tint et al. 2008), and the particular high risk of a severe course with
delirium after discontinuation of tranylcypromine has been mentioned above. A
special symptom that is experienced as particularly impairing by patients and has
been reported particularly after discontinuation of venlafaxine (and SSRI) are so-
called body-zapps or brain-zapps – electric “shock-like” sensations (Ellison 1994;
Reeves et al. 2003).

Persistent Post-discontinuation Syndromes and Rebound

Phenomena

It has been proposed to define withdrawal symptoms that persist for over more than 6
weeks as “persistent post-discontinuation syndromes” (Chouinard and Chouinard
2015). Also, mood and anxiety symptoms have been reported to re-emerge after
discontinuation to a greater extent than prior to initiation of the antidepressant (Fava
et al. 2007). These rebound phenomena are thought to represent an organism’s
increased susceptibility and vulnerability following drug discontinuation, most
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1181

likely due to previous counter-regulatory neuroadaptation to neuropsychopharma-

cological effects of the substance (Heinz et al. 2019; Henssler et al. 2019). Data on
persistent withdrawal syndromes and rebound phenomena are particularly sparse
and evidence results from case reports and one open and uncontrolled study only.
Paroxetine again seems to inherit a particularly high risk in this regard (Fava et al.
2007). Symptoms that have been reported to persist for more than 6 weeks after
withdrawal or to re-emerge with greater severity are anxiety symptoms, sleep
disorders, and cyclothymic syndromes (Fava et al. 2007). However, it seems partic-
ularly challenging to causally attribute these symptoms to an increased susceptibility
of the organism after discontinuation of the antidepressant and differentiate them
from a relapse or recurrence from the primary disorder, even more so, as the natural
course of mood disorders is likely to include changes of symptoms and severity over
time. In this vein, anxiety and depressive disorders are often combined, and manic
symptoms often emerge later than depressive episodes in the course of bipolar
disorders (Boschloo et al. 2014; Wittchen et al. 2003). Thus, patients later diagnosed
as bipolar may initially be thought of as suffering from unipolar depressive disorder,
and attribution of manic symptoms to drug discontinuation may be wrong.

Basic Principles

Generally, the risk of ADS seems to appear with a minimum treatment duration of
4 weeks (Hohagen et al. 1994); robust data exists after 8 weeks. Afterwards, it
appears that the risk of ADS does not further increase with longer treatment
duration. ADS has been reported irrespective of the primary disorder, for which
the antidepressant treatment was initiated (Baldwin et al. 2007; Bogetto et al.
2002). As described above, incidence and severity of ADS are different between
single agents and classes of ADs. Additionally, plasma elimination time of the AD
plays a major role. In this vein, ADs with shorter elimination time inherit a
relatively higher risk of severe and frequent discontinuation symptoms. It has
been reported that ADS occurs after approximately 3–5 half-lives following
discontinuation or dose-reduction (Montgomery 2002). Discontinuation symp-
toms occur independent of medication dose within the normal therapeutic dosing
range, but have been reported to appear more frequently after high-dose treatment
(e.g., duloxetine 120 mg/day; escitalopram 20 mg/day) (Baldwin et al. 2007;
Markowitz et al. 2000; Perahia et al. 2005).

Treatment and Prevention

Prior to treating symptoms that appear after discontinuation of antidepressant med-

ication, it is of major clinical importance to differentiate withdrawal syndromes from
a re-emergence of the primary disorder (Brandt et al. 2020b). In the latter case, re-
initiation of the antidepressant might be necessary, while in the case of ADS, a
watch-and-wait procedure or slower tapering of the antidepressant may be adequate.
1182 L. Brandt et al.

Unfortunately, there is considerable overlap in clinical presentation between with-

drawal syndromes and depressive and anxiety disorders, potentially even (hypo-)
manic episodes. This might even lead to the misdiagnosis of a bipolar affective
disorder when misinterpreting arousal in ADS (falsely) as a manic episode.
Nevertheless, as stated above, ADS is strongly characterized by somatic symp-
toms or some particular, almost pathognomonic symptoms like vivid dreams and
sensory disturbances (“brain-zapps”), which are untypical for depression. The time
course of symptom emergence may also be helpful for differentiating ADS from
depression, with ADS typically occurring within one week following discontinua-
tion or dose reduction and gradual amelioration in the second week, generally being
more fluctuating and transient than the re-emergence of the affective disorder, and
with relapse in depression usually occurring after one to three months following
discontinuation of the antidepressant (at least in previously remitted patients) (Har-
vey and Slabbert 2014; Montgomery et al. 2004a).
When having identified ADS, a watch-and-wait strategy including patient
education will often be sufficient, as symptoms are mostly mild and self-limiting.
Symptomatic treatment including hypnotic agents or anti-muscarinic drugs in the
case of TCA and cholinergic rebound has proven to be of help (Dilsaver et al.
1983). Re-administration of the antidepressant generally leads to complete remis-
sion of withdrawal symptoms within 1–2 days. This may be necessary as a first step
in the case of severe symptoms. Afterwards, the antidepressant can gradually be
tapered. Several case reports point to the usefulness of Fluoxetine as a “rescue”
substance for ADS from Venlafaxine (Giakas and Davis 1997) or other SSRI
(Keuthen et al. 1994). Instead of discontinuation, the initial antidepressant can
first be switched to Fluoxetine, which may then be discontinued after several
weeks with a lower risk of ADS. Gradual tapering has proven to reduce the severity
of ADS and increase the probability of complete and persistent discontinuation of
the antidepressant (Groot and van Os 2020). Evidence indicates that tapering – in
order to be successful – has to be particularly slow and following hyperbolic dose
reduction, with increasingly little steps the lower the dose (Horowitz and Taylor
2019). Indicators for an a priori decision to taper the antidepressant and also to
taper over longer periods may include the individual risk of the antidepressant (as
stated above) and the use of high initial doses of the antidepressant. Also, when
patients report previous experiences of withdrawal symptoms or the experience of
incipient symptoms even after only one or two missed doses of the antidepressant,
there is a high risk of the occurrence of ADS following discontinuation of dose
reduction of the antidepressant.

Resistance to Therapy

Treatment response is typically assessed after four weeks of pharmacological treat-

ment. A significant proportion of patients that achieve treatment response are
showing the response during the first two to four weeks (DGPPN et al. 2015;
NICE 2009). Generally, improvement of depressive symptoms can be expected for
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1183

up to 12 weeks with ongoing monotherapy. Between 8 and 12 weeks, however, the

incremental benefit is relatively small (Henssler et al. 2018b). About a third of
persons will not show a sufficient response to the first antidepressant medication,
and about half of patients will not achieve full remission, even after 12 weeks
(Cowen 1998; Henssler et al. 2018b). Over the last two decades, the European
Group for the Study of Resistant Depression (GSRD) has studied correlates of
outcomes in major depressive episodes. They identified the lifetime number of
depressive episodes, symptom severity, suicidality, and comorbid anxiety as the
most important factors in prediction models of treatment resistance (Bartova et al.
2019).

Clinical Assessment of Resistance to Therapy

In addition to irregular intake of medication, a lack of treatment response may be

caused by a series of individual factors: For example, comedications, comorbidities,
and genetically determined metabolic factors influence plasma levels of antidepres-
sant medication and may lead to insufficient effectiveness with standard therapeutic
dosages. Standard therapeutic dosages have been established for most antidepres-
sants and corresponding therapeutic plasma levels have been published previously
(Baumann et al. 2004; Möller et al. 2000). Plasma levels may be determined at
steady state if treatment response is insufficient after an appropriate treatment
duration and dosage, for example, after four weeks with an established therapeutic
dosage. Assessment of plasma levels can be particularly relevant for persons with
comorbidities, comedications, high dosage treatments, irregular intake of medica-
tion, and metabolically relevant changes in the activity of hepatic isoenzymes
(Baumann et al. 2004; Hiemke et al. 2011; Kirchheiner et al. 2001, 2004). The
Maudsley Staging Method has been developed as a tool to define and stage treat-
ment-resistance in unipolar depression, and has been enhanced by a standardized
rating guidance. It has also shown predictive validity in short- and long-term out-
comes (Fekadu et al. 2009, 2018). In case of nonresponse, several options are
recommended in the current treatment guidelines: increase in dosage, switching to
a different antidepressant, combining the current antidepressant with an additional
antidepressant, “augmentation” with another pharmacological substance, and com-
bining the pharmacological treatment with intensive psychotherapy (DGPPN et al.
2015; NICE 2009).
An increase in the dosage of the antidepressant is commonly tested in case of
initial nonresponse to tricyclic antidepressants, venlafaxine, and tranylcypromine.
However, evidence for the efficacy of dose increases in nonresponders is sparse
(Bartova et al. 2019). In particular, selective serotonin reuptake inhibitors are not
characterized by a positive dose-response relationship and will generally not show
better effectiveness after an increase in dosage (Adli et al. 2005; Licht and Qvitzau
2002; Rink et al. 2018). Switching from one antidepressant to another (e.g., to a
MAO-inhibitor) in case of nonresponse may be done if the switch occurs between
different substance classes. Less interactions can be expected from switching
1184 L. Brandt et al.

compared to augmentation or combinations with additional antidepressants, pro-

vided appropriate switching strategies are implemented (e.g., tapered discontinua-
tion strategies and sufficient time gap between discontinuation of monoamine
oxidase inhibitors and serotonin agonists). However, switching is not considered
to be the first option in nonresponse, since several studies, albeit not all, did not show
improved efficacy after switching compared to continued treatment with the same
antidepressant (Bartova et al. 2019; Bschor et al. 2018). The combination of two
antidepressants has proven to increase efficacy in a number of trials, but may be
accompanied by a higher risk of interactions and adverse events compared to
monotherapy. Specifically, combining a monoamine reuptake inhibitor (SSRI,
venlafaxine, tricyclic antidepressants) with mirtazapine, trazodone, or mianserine
currently is supported by the highest level of evidence and was shown to be
particularly effective and equally tolerated compared to monotherapy (Henssler
et al. 2016).
“Augmentation” refers to the use of a pharmacological substance that is not
categorized as an antidepressant to augment the effectiveness of another antidepres-
sant. For instance, evidence is strong for the effect of lithium augmentation and it is
an approved option in case of nonresponse to an antidepressant (Bauer et al. 2003;
Bauer and Döpfmer 1999). The effect of lithium augmentation may be assessed after
two to four weeks and, if proven effective for the individual person, may be
continued for more than six months (DGPPN et al. 2015). The antipsychotics
quetiapine, aripiprazole, risperidone, and olanzapine are listed as augmentary
options by the NICE guidelines (NICE 2009) and the DGPPN guidelines (DGPPN
et al. 2015), while the World Federation of Societies of Biological Psychiatry
(WFSB) (Bauer et al. 2013) limits its recommendations to quetiapine and
aripiprazole (Edwards et al. 2013; Komossa et al. 2010; Spielmans et al. 2013).
The antipsychotic quetiapine is approved for augmentation in Germany, and the
antipsychotics aripiprazole, risperidone, and olanzapine may be used off-label
(DGPPN et al. 2015). The use of antipsychotics for this purpose should take into
account that the risk of adverse events is significantly increased compared to
monotherapy with an antidepressant (Komossa et al. 2010), and that the longtime
effects as well as the effects on quality of life and social functioning are not well
established. A Cochrane Review found augmentation with an antipsychotic to be
more effective compared to antidepressant monotherapy in treatment resistant
depression, but augmentation treatment was associated with more drop-outs, mostly
due to side effects and adverse events (Davies et al. 2019). Other substances such as
antiepileptic drugs, thyroid hormones, dopamine-agonists, and psychostimulants are
not routinely used for augmentation, which is partly due to less established effec-
tiveness and potential interactions with the antidepressant (Bauer et al. 2004).
Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has
shown promising efficacy as an augmenting agent in treatment-resistant depression
(Carter et al. 2020).
In summary, insufficient response to pharmacological treatment occurs frequently
and it requires consideration in clinical practice. Beyond intensive psychotherapy
and psychosocial interventions, pharmacological treatment options include increase
in dosages, combinations, augmentation, and switching.
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1185

Cross-References

▶ Agomelatine and Depressions

▶ Amitriptyline and Depressions
▶ Amoxapine and Depressions
▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and
Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry
▶ Bupropion and Depressions
▶ Ginseng and Ginsenosides in Depression
▶ Hypericum and Depression
▶ Mianserine and Depressions
▶ Mirtazapine and Depressions
▶ Monoamine Oxidase Inhibitors in Depressive Disorders
▶ Nortriptyline and Maprotiline for Depressions
▶ Psychopharmacotherapy of Depressive Disorders
▶ Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine,
Fluvoxamine, Paroxetine, and Sertraline
▶ Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,
Desvenlafaxine, Duloxetine, Milnacipran, Levomilnacipran
▶ Trazodone and Depression
▶ Vilazodone and Depressions
▶ Vortioxetine and Depressions

References
Adli M, Baethge C, Heinz A, Langlitz N, Bauer M. Is dose escalation of antidepressants a rational
strategy after a medium–dose treatment has failed? Eur Arch Psychiatry Clin Neurosci.
2005;255(6):387–400.
Ainsworth K, Smith SE, Zetterström TSC, Pei Q, Franklin M, Sharp T. Effect of antidepressant
drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus
accumbens of the rat. Psychopharmacology. 1998;140(4):470–7.
Allgulander C, Florea I, Huusom A. Prevention of relapse in generalized anxiety disorder by
escitalopram treatment. Int J Neuropsychopharmacol. 2006;9(5):495–505.
American Psychiatric Association (APA). Practice guideline for the treatment of patients with major
depressive disorder. In: American Psychiatric Association, editor. Practice guidelines for the
treatment of people with psychiatric disorders. Washington, DC: American Psychiatric Associ-
ation (APA). Guideline Central; 2000. p. 413–96.
Arroll B. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for
treatment of depression in primary care: a meta-analysis. Ann Fam Med. 2005;3(5):449–56.
Baethge C, Gruschka P, Smolka MN, Berghöfer A, Bschor T, Müller-Oerlinghausen B, et al.
Effectiveness and outcome predictors of long-term lithium prophylaxis in unipolar major
depressive disorder. J Psychiatry Neurosci. 2003;28(5):355–61.
Baldwin DS, Cooper JA, Huusom AKT, Hindmarch I. A double-blind, randomized, parallel-group,
flexible-dose study to evaluate the tolerability, efficacy and effects of treatment discontinuation
1186 L. Brandt et al.

with escitalopram and paroxetine in patients with major depressive disorder. Int Clin
Psychopharmacol. 2006;21(3):159–69.
Baldwin DS, Montgomery SA, Nil R, Lader M. Discontinuation symptoms in depression and
anxiety disorders. Int J Neuropsychopharmacol. 2007;10(1):73–84.
Bartova L, Dold M, Kautzky A, Fabbri C, Spies M, Serretti A, et al. Results of the European Group
for the Study of Resistant Depression (GSRD) – basis for further research and clinical practice.
The World. J Biol Psychiatry. Taylor & Francis. 2019;20(6):427–48.
Bauer M, Döpfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of
placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427–34.
Bauer M, Adli M, Baethge C, Berghöfer A, Sasse J, Heinz A, et al. Lithium augmentation therapy in
refractory depression: clinical evidence and neurobiological mechanisms. Can J Psychiatr.
2003;48(7):440–8.
Bauer M, Whybrow PC, Angst J, Versiani M, Möller HJ. Biologische Behandlung unipolarer
depressiver Störungen: Behandlungslinien der World of Federation of Societies of Biological
Psychiatry. 1st ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2004.
Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller H-J, et al. World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar
depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar
depressive disorders. World J Biol Psychiatry. 2013;14(5):334–85.
Bauer M, Severus E, Köhler S, Whybrow PC, Angst J, Möller H-J, et al. World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar
depressive disorders. Part 2: maintenance treatment of major depressive disorder-update 2015.
World J Biol Psychiatry. Taylor & Francis. 2015;16(2):76–95.
Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, et al. The AGNP-TDM
expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacop-
sychiatry. 2004;37(6):243–65.
Berber MJ. FINISH: remembering the discontinuation syndrome. Flu-like symptoms, Insomnia,
Nausea, Imbalance, Sensory disturbances, and Hyperarousal (anxiety/agitation). J Clin Psychi-
atry. 1998;59(5):255.
Berigan TR. Bupropion-associated withdrawal symptoms revisited: a case report. Prim Care
Companion J Clin Psychiatry. 2002;4(2):78.
Bogetto F, Bellino S, Revello RB, Patria L. Discontinuation syndrome in dysthymic patients treated with
selective serotonin reuptake inhibitors: a clinical investigation. CNS Drugs. 2002;16(4):273–83.
Boschloo L, Spijker AT, Hoencamp E, Kupka R, Nolen WA, Schoevers RA, et al. Predictors of the
onset of manic symptoms and a (hypo) manic episode in patients with major depressive disorder.
PLoS One. 2014;9(9):e106871.
Brandt L, Bschor T, Henssler J, Müller M, Hasan A, Heinz A, et al. Antipsychotic withdrawal
symptoms: a systematic review and meta-analysis. Front Psych. 2020a;11:569912.
Brandt L, Henssler J, Gutwinski S. Entstehung, Merkmale, Prävention und Behandlung von
Absetzphänomenen. InFo Neurologie. 2020b;22(3):26–35.
Bschor T, Kern H, Henssler J, Baethge C. Switching the antidepressant after nonresponse in adults
with major depression: a systematic literature search and meta-analysis. J Clin Psychiatry.
2018;79(1):16r10749.
Burgess SS, Geddes J, Hawton KK, Taylor MJ, Townsend E, Jamison K, et al. Lithium for
maintenance treatment of mood disorders. Cochrane Database Syst Rev [Internet]. 2001[cited
2020 Nov 10];2001(3). Available from https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC7005360/
Carter B, Strawbridge R, Husain MI, Jones BDM, Short R, Cleare AJ, et al. Relative effectiveness
of augmentation treatments for treatment-resistant depression: a systematic review and network
meta-analysis. Int Rev Psychiatry. Taylor & Francis; 2020;32(5–6):477–90.
Charney DS, Heninger GR, Sternberg DE, Landis H. Abrupt discontinuation of tricyclic antide-
pressant drugs: evidence for noradrenergic hyperactivity. Br J Psychiatry J Ment Sci. 1982;141:
377–86.
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1187

Chouinard G, Chouinard V-A. New classification of selective serotonin reuptake inhibitor with-
drawal. Psychother Psychosom. 2015;84(2):63–71.
Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-
cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J
Psychiatry. 2005;15:1805–1819.
Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood
disorders: updated systematic review and meta-analysis. BMJ. 2013;346(4):f3646.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy
and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive
disorder: a systematic review and network meta-analysis. Lancet. 2018a;391(10128):1357–66.
Cipriani A, Salanti G, Furukawa TA, Turner E, Ioannidis JPA, Geddes JR. Network meta-analysis
of antidepressants – authors’ reply. Lancet. 2018b;392(10152):1012–3.
Cowen PJ. Pharmacological management of treatment-resistant depression. Adv Psychiatr Treat.
1998;4:320–7.
Crismon ML, Trivedi M, Pigott T, Rush J, Hirschfeld R, Kahn D, et al. The Texas Medication
Algorithm Project: report of the Texas Consensus Conference Panel on medication treatment of
major depressive disorder. J Clin Psychiatry. 1999;15:142–156.
Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant
withdrawal effects: are guidelines evidence-based? Addict Behav. 2018;97:111–121.
Davies P, Ijaz S, Williams CJ, Kessler D, Lewis G, Wiles N. Pharmacological interventions for
treatment-resistant depression in adults. Cochrane Database Syst Rev. 2019;12:CD010557.
DGPPN, BÄK, KBV, AWMF. S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression –
Langfassung, 2. Auflage [Internet]. Deutsche Gesellschaft für Psychiatrie, Psychotherapie und
Nervenheilkunde (DGPPN); Bundesärztekammer (BÄK); Kassenärztliche Bundesvereinigung
(KBV); Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften
(AWMF); 2015 [cited 2020 Nov 3]. Available from http://www.leitlinien.de/mdb/downloads/
nvl/depression/depression-2aufl-vers5-lang.pdf
Dilsaver SC, Greden JF. Antidepressant withdrawal phenomena. Biol Psychiatry. 1984;19(2):
237–56.
Dilsaver SC, Feinberg M, Greden JF. Antidepressant withdrawal symptoms treated with anticho-
linergic agents. Am J Psychiatry. 1983;140(2):249–51.
Edwards S, Hamilton V, Nherera L, Trevor N. Lithium or an atypical antipsychotic drug in the
management of treatment-resistant depression: a systematic review and economic evaluation.
Health Technol Assess. 2013;17(54):1.
Ellison JM. SSRI withdrawal buzz. J Clin Psychiatry. 1994;55(12):544–5.
Fauchere PA. Recurrent, persisting panic attacks after sudden discontinuation of mirtazapine
treatment: a case report. Int J Psychiatry Clin Pract. 2004;8(2):127–9.
Fava GA, Bernardi M, Tomba E, Rafanelli C. Effects of gradual discontinuation of selective
serotonin reuptake inhibitors in panic disorder with agoraphobia. Int J Neuropsychopharmacol.
2007;10(6):835–8.
Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal symptoms after selective serotonin
reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom. 2015;84(2):
72–81.
Fekadu A, Wooderson S, Donaldson C, Markopoulou K, Masterson B, Poon L, et al. A multi-
dimensional tool to quantify treatment resistance in depression: the Maudsley staging method. J
Clin Psychiatry. 2009;70(2):177–84.
Fekadu A, Donocik JG, Cleare AJ. Standardisation framework for the Maudsley staging method for
treatment resistance in depression. BMC Psychiatry. 2018;18(1):100.
Frank E, Kupfer D, Perel J. Three-year outcomes for maintenance therapies in recurrent depression.
Arch Gen Psychiatry. 1990;47(12):1093.
Gahr M, Schonfeldt-Lecuona C, Kolle MA, Freudenmann RW. Withdrawal and discontinuation
phenomena associated with tranylcypromine: a systematic review. Pharmacopsychiatry.
2013;46(4):123–9.
1188 L. Brandt et al.

Geddes JR, Carney S, Davies C, Furukawa T, Kupfer D, Frank E, et al. Relapse prevention with
antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003;361:
653–1.
Giakas WJ, Davis JM. Intractable withdrawal from venlafaxine treated with fluoxetine. Psychiatr
Ann. 1997;27(2):85–92.
Giller E, Bialos D, Harkness L, Jatlow P, Waldo M. Long-term amitriptyline in chronic depression.
Hillside J Clin Psychiatry. 1985;7(1):16–33.
GlaxoSmithKline. A double-blind comparative study of withdrawal effects following abrupt dis-
continuation of treatment with paroxetine in low or high dose or imipramine. GSK – clinical
study register. https://www.gsk-clinicalstudyregister.com. 1992.
Goodwin G, Emsley R, Rembry S, Rouillon F. Agomelatine prevents relapse in patients with major
depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized,
double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(8):1128–37.
Groot PC, van Os J. Outcome of antidepressant drug discontinuation with tapering strips after 1–5
years. Ther Adv Psychopharmacol. 2020;10:2045125320954609.
Guzzetta F, Tondo L, Centorrino F, Baldessarini R. Lithium treatment reduces suicide risk in
recurrent major depressive disorder. J Clin Psychiatry. 2007;4:380–383.
Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman ATF. Prevalence and predictors of
recurrence of major depressive disorder in the adult population. Acta Psychiatr Scand.
2010;122(3):184–91.
Hartford J, Kornstein S, Liebowitz M, Pigott T, Russell J, Detke M, et al. Duloxetine as an SNRI
treatment for generalized anxiety disorder: results from a placebo and active-controlled trial. Int
Clin Psychopharmacol. 2007;22(3):167–74.
Harvey BH, Slabbert FN. New insights on the antidepressant discontinuation syndrome. Human
Psychopharmacol. 2014;29(6):503–16.
Heinz AJ, Beck A, Meyer-Lindenberg A, Sterzer P, Heinz A. Cognitive and neurobiological
mechanisms of alcohol-related aggression. Nat Rev Neurosci. Nature Publishing Group;
2011;12(7):400–13.
Heinz, A., Daedelow, L., Wackerhagen, C., Di Chiara, G. Addiction theory matters – why there is
no dependence on caffeine or antidepressant medication. Addict Biol. 2019;25(2):e12735. (in
press).
Henssler J, Bschor T, Baethge C. Combining antidepressants in acute treatment of depression: a
meta-analysis of 38 studies including 4511 patients. Can J Psychiatr. 2016;61(1):29–43.
Henssler J, Kurschus M, Franklin J, Bschor T, Baethge C. Long-term acute-phase treatment with
antidepressants, 8 weeks and beyond: a systematic review and meta-analysis of randomized,
placebo-controlled trials. J Clin Psychiatry. 2018a;79(1):15r10545.
Henssler J, Kurschus M, Franklin J, Bschor T, Baethge C. Trajectories of acute antidepressant
efficacy: how long to wait for response? A systematic review and meta-analysis of long-term,
placebo-controlled acute treatment trials. J Clin Psychiatry. 2018b;79(3):17r11470.
Henssler J, Heinz A, Brandt L, Bschor T. Antidepressant withdrawal and rebound phenomena.
Dtsch Arztebl Int. 2019;116(20):355–61.
Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, et al. AGNP consensus
guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry.
2011;44(06):195–235.
Hohagen F, Montero RF, Weiss E, Lis S, Schonbrunn E, Dressing H, et al. Treatment of primary
insomnia with trimipramine: An alternative to benzodiazepine hypnotics? Eur Arch Psychiatry
Clin Neurosci. 1994;244(2):65–72.
Horowitz MA, Taylor D. Tapering of SSRI treatment to mitigate withdrawal symptoms. Lancet
Psychiatry. 2019;6(6):538–46.
Hotopf M, Hardy R, Lewis G. Discontinuation rates of SSRIs and tricyclic antidepressants: a meta-
analysis and investigation of heterogeneity. Br J Psychiatry. 1997;170(2):120–7.
Kaufman MJ, Henry ME, Frederick B, Hennen J, Villafuerte RA, Stoddard EP, et al. Selective
serotonin reuptake inhibitor discontinuation syndrome is associated with a rostral anterior
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1189

cingulate choline metabolite decrease: a proton magnetic resonance spectroscopic imaging

study. Biol Psychiatry. 2003;54(5):534–9.
Keller MB, Trivedi MH, Thase ME, Shelton RC, Kornstein SG, Nemeroff CB, et al. The prevention
of recurrent episodes of depression with venlafaxine for two years (PREVENT) study: outcomes
from the acute and continuation phases. Biol Psychiatry. 2007;62(12):1371–9.
Keuthen NJ, Cyr P, Ricciardi JA, Minichiello WE, Buttolph ML, Jenike MA. Medication with-
drawal symptoms in obsessive-compulsive disorder patients treated with paroxetine. J Clin
Psychopharmacol. 1994;14(3):206–7.
Khan A, Musgnung J, Ramey T, Messig M, Buckley G, Ninan PT. Abrupt discontinuation
compared with a 1-week taper regimen in depressed outpatients treated for 24 weeks with
desvenlafaxine 50 mg/d. J Clin Psychopharmacol. 2014;34(3):365–8.
Kirchheiner J, Brøsen K, Dahl ML, Gram LF, Kasper S, Roots I, et al. CYP2D6 and CYP2C19
genotype-based dose recommendations for antidepressants: a first step towards subpopulation-
specific dosages. Acta Psychiatr Scand. 2001;104(3):173–92.
Kirchheiner J, Nickchen K, Bauer M, Wong M-L, Licinio J, Roots I, et al. Pharmacogenetics of
antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of
drug response. Mol Psychiatry. Nature Publishing Group. 2004;9(5):442–73.
Kirsch I, Jakobsen JC. Network meta-analysis of antidepressants. Lancet. 2018;392(10152):1010.
Kocsis JH, Kornstein SG, Ahmed S, Ferdousi T, Musgnung J, Thase M, et al. Two years of
maintenance treatment with venlafaxine xr 75–225 mg/d: efficacy in patients with recurrent
unipolar major depression. Eur Psychiatry. Cambridge University Press; 2007;22(S1):S239–40.
Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S. Second-generation antipsychotics
for major depressive disorder and dysthymia. Cochrane Database Syst Rev [Internet]. Wiley;
2010 [cited 2020 Nov 10];(12). Available from https://www.cochranelibrary.com/cdsr/doi/10.
1002/14651858.CD008121.pub2/full
Kramer JC, Klein DF, Fink M. Withdrawal symptoms following discontinuation of imipramine
therapy. Am J Psychiatry. 1961;118:549–50.
Leucht C, Huhn M, Leucht S. Amitriptyline versus placebo for major depressive disorder. Cochrane
Database Syst Rev [Internet]. 2012 [cited 2020 Nov 3];(12). Available from https://www.
readcube.com/articles/10.1002/14651858.CD009138.pub2
Leverich GS, Post RM. Life charting of affective disorders. CNS Spectr. Cambridge University
Press; 1998;3(5):21–37.
Licht RW, Qvitzau S. Treatment strategies in patients with major depression not responding to first-
line sertraline treatment. Psychopharmacology. 2002;161(2):143–51.
MacCall C, Callender J. Mirtazapine withdrawal causing hypomania. Br J Psychiatry J Ment Sci.
1999;175:390.
Markowitz J, DeVane C, Liston H, Montgomery S. An assessment of selective serotonin reuptake
inhibitor discontinuation symptoms with citalopram. Int Clin Psychopharmacol. 2000;15(6):329–33.
McGrath PJ, Stewart JW, Tricamo E, Nunes EN, Quitkin FM. Paradoxical mood shifts to euthymia
or hypomania upon withdrawal of antidepressant agents. J Clin Psychopharmacol. 1993;13(3):
224–5.
Metz S, Klein C, Morton N. Rebound hypertension after discontinuation of transdermal clonidine
therapy. Am J Med. 1987;82(1):17–9.
Michelson D, Amsterdam J, Apter J, Fava M, Londborg P, Tamura R, et al. Hormonal markers of
stress response following interruption of selective serotonin reuptake inhibitor treatment.
Psychoneuroendocrinology. 2000;25(2):169–77.
Möller H-J, Glaser K, Leverkus F, Göbel C. Double-blind, multicenter comparative study of
sertraline versus amitriptyline in outpatients with major depression. Pharmacopsychiatry.
2000;33(6):206–12.
Montgomery D. ECNP Guidelines for investigating efficacy in GAD. Eur Neuropsychopharmacol.
2002;12(1):81–7.
Montgomery SA, Andersen HF. Escitalopram versus venlafaxine XR in the treatment of depression.
Int Clin Psychopharmacol. 2006;21(5):297–309.
1190 L. Brandt et al.

Montgomery S, Kennedy S, Burrows G, Lejoyeux M, Hindmarch I. Absence of discontinuation

symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a
randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol.
2004a;19(5):271–80.
Montgomery SA, Huusom AKT, Bothmer J. A randomized study comparing escitalopram with
venlafaxine XR in primary care patients with major depressive disorder. Neuropsychobiology .
Karger Publishers. 2004b;50(1):57–64.
Montgomery SA, Huusom AKT, Bothmer J. A randomised study comparing escitalopram with
venlafaxine XR in primary care patients with major depressive disorder. Neuropsychobiology.
2004c;50(1):57–64.
Montgomery SA, Nil R, Dürr-Pal N, Loft H, Boulenger J-P. A 24-week randomized, double-blind,
placebo-controlled study of escitalopram for the prevention of generalized social anxiety
disorder. J Clin Psychiatry. 2005;66(10):1270–8.
NICE. Depression: the treatment and management of depression in adults (update) [Internet]. NICE;
2009 [cited 2020 Nov 10]. Available from https://www.nice.org.uk/guidance/CG90
Nierenberg A, Petersen T, Alpert J. Prevention of relapse and recurrence in depression: the role of
long-term pharmacotherapy and psychotherapy. J Clin Psychiatry. 2003;64:13–7.
Ninan PT, Musgnung J, Messig M, Buckley G, Guico-Pabia CJ, Ramey TS. Incidence and timing of
taper/posttherapy-emergent adverse events following discontinuation of desvenlafaxine 50 mg/
d in patients with major depressive disorder. Prim Care Companion CNS Disord 2015;17(1).
https://doi.org/10.4088/PCC.14m01715
Paykel ES. Continuation and maintenance therapy in depression. Br Med Bull. 2001;57(1):145–59.
Perahia DG, Kajdasz DK, Desaiah D, Haddad PM. Symptoms following abrupt discontinuation of
duloxetine treatment in patients with major depressive disorder. J Affect Disord. 2005;89
(1–3):207–12.
Petersen TJ. Enhancing the efficacy of antidepressants with psychotherapy. J Psychopharmacol.
Sage Publications Ltd STM. 2006;20(3):19–28.
Rabinowitz J, Werbeloff N, Mandel FS, Menard F, Marangell L, Kapur S. Initial depression severity
and response to antidepressants v. placebo: patient-level data analysis from 34 randomised
controlled trials. Br J Psychiatry. Cambridge University Press;. 2016;209(5):427–8.
Reeves RR, Mack JE, Beddingfield JJ. Shock-like sensations during venlafaxine withdrawal.
Pharmacotherapy. 2003;23(5):678–81.
Reidenberg MM. Drug discontinuation effects are part of the pharmacology of a drug. J Pharmacol
Exp Ther. 2011;339(2):324–8.
Reimherr FW, Amsterdam JD, Quitkin FM, Rosenbaum JF, Fava M, Zajecka J, et al. Optimal length
of continuation therapy in depression: a prospective assessment during long-term fluoxetine
treatment. Am J Psychiatr. American Psychiatric Publishing. 1998;155(9):1247–53.
Rink L, Braun C, Bschor T, Henssler J, Franklin J, Baethge C. Dose increase versus unchanged
continuation of antidepressants after initial antidepressant treatment failure in patients with
major depressive disorder: a systematic review and meta-analysis of randomized, double-blind
trials. J Clin Psychiatry. 2018;79(3):17r11693.
Roose S, Spatz E. Treatment of depression in patients with heart disease. J Clin Psychiatry. 1999;60:
34–7.
Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor
discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77–87.
Saxe P, Arnold L, Palmer R, Gendreau R, Chen W. Short-term (2-week) effects of discontinuing
milnacipran in patients with fibromyalgia. Curr Med Res Opin. 2012;28(5):815–21.
Sir A, D’Souza RF, Uguz S, George T, Vahip S, Hopwood M, et al. Randomized trial of sertraline
versus venlafaxine XR in major depression: efficacy and discontinuation symptoms. J Clin
Psychiatry. 2005;66(10):1312–20.
Souza FGM, Goodwin GM. Lithium treatment and prophylaxis in unipolar depression: a meta-
analysis. Br J Psychiatry. 1991;158(5):666–75.
Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC. Adjunctive atypical
antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of
life, and safety outcomes. PLoS Med. 2013;10(3):e1001403.
Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and . . . 1191

Spijker J, de Graaf R, Bijl RV, Beekman ATF, Ormel J, Nolen WA. Duration of major depressive
episodes in the general population: results from The Netherlands Mental Health Survey and
Incidence Study (NEMESIS). Br J Psychiatry. 2002;181:208–13.
Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C. Agomelatine prevents relapse in
generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discon-
tinuation study. J Clin Psychiatry. 2012;73(7):1002–8.
Stoukides JA, Stoukides CA. Extrapyramidal symptoms upon discontinuation of fluoxetine. Am J
Psychiatry. 1991;148(9):1263.
Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant tapering on the incidence of
discontinuation symptoms: a randomised study. J Psychopharmacol (Oxford, England). 2008;22
(3):330–2.
Tondo L, Hennen J, Baldessarini RJ. Lower suicide risk with long-term lithium treatment in major
affective illness: a meta-analysis. Acta Psychiatr Scand. 2001;104(3):163–72.
Tyrer P. Clinical effects of abrupt withdrawal from tri-cyclic antidepressants and monoamine
oxidase inhibitors after long-term treatment. J Affect Disord. 1984;6(1):1–7.
Van Geffen ECG, Brugman M, Van Hulten R, Bouvy ML, Egberts ACG, Heerdink ER. Patients’
concerns about and problems experienced with discontinuation of antidepressants. Int J Pharm
Pract. 2007;15(4):291–3.
Vandel P, Sechter D, Weiller E, Pezous N, Cabanac F, Tournoux A, et al. Post-treatment emergent
adverse events in depressed patients following treatment with milnacipran and paroxetine.
Human Psychopharmacol. 2004;19(8):585–6.
Westermeyer J. Addiction to tranylcypromine (Parnate): a case report. Am J Drug Alcohol Abuse.
Taylor & Francis;. 1989;15(3):345–50.
Wittchen H-U, Beesdo K, Bittner A, Goodwin RD. Depressive episodes–evidence for a causal role
of primary anxiety disorders? Eur Psychiatry. 2003;18(8):384–93.
Yiend J, Paykel E, Merritt R, Lester K, Doll H, Burns T. Long term outcome of primary care
depression. J Affect Disord. 2009;118(1–3):79–86.
Zajecka J, Fawcett J, Amsterdam J, Quitkin F, Reimherr F, Rosenbaum J, et al. Safety of abrupt
discontinuation of fluoxetine: a randomized, placebo-controlled study. J Clin Psychopharmacol.
1998;18(3):193–7.
Tricyclics: Imipramine, Clomipramine,
Trimipramine (Dibenzazepines)

Hans-Peter Volz and Gerd Laux

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195
Pharmacodynamics/Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1197
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1197
Side Effects/Adverse Reactions and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1198
Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1200
Combination Therapies, Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201

Abstract
Imipramine was the first tricyclic antidepressant (TCA), discovered serendipi-
tously being the prototype of antidepressants for long time. Clomipramine and
trimipramine are further developed dibenzazepine TCAs belonging to the
tertiary-amine tricyclics. Numerous randomized clinical trials (RCTs) have pro-
ved the antidepressive efficacy for acute and long-term treatment of depressions.
For clomipramine some studies and clinical experience claim higher efficacy in

H.-P. Volz
Krankenhaus für Psychiatrie, Psychotherapie und Psychosomatische Medizin Schloss Werneck,
Werneck, Germany
G. Laux (*)
Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich,
Germany
e-mail: ipm@ipm-laux.de

© Springer Nature Switzerland AG 2022 1193

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_385
1194 H.-P. Volz and G. Laux

inpatients and severe, therapy-resistant depressions compared with modern anti-

depressants, i.e., SSRIs. Further indications are anxiety and panic disorders and
obsessive-compulsive disorders (Clomipramine) and insomnia (trimipramine) as
well as neuropathic/chronic pain. Tolerability is limited by anticholinergic and
cardiovascular side effects mainly. Special attention is required regard toxicity at
higher doses.

Chemistry, Developmental History

Tricyclics have a central three-ring structure, hence the name tertiary-amine tricyclics
being representatives of a chemical group in which two benzene rings are fused to a
central, nitrogen-containing seven-membered ring, the 1H-azepine (Dibenzoazepines).
Examples are imipramine, clomipramine, and trimipramine, but also the anxio-
lytic opipramol or the anti-convulsant carbamazepine. Figure 1 shows the chemical
structure of imipramine as an example.
Imipramine was the first TCA to be developed by Ciba in 1951, as an antihista-
mine. In 1957 the Swiss psychiatrist Roland Kuhn observed that imipramine ame-
liorated symptoms in depressed patients, so serendipitously antidepressant effects
have been discovered. Subsequently, imipramine was introduced for the treatment of
depression in Europe in 1958 and in the United States in 1959 being the prototypical
drug for the development of the later-released TCAs. The discoveries of imipramine,
the first TCA, and iproniazid, the first monoamine oxidase inhibitor (MAOI), were
results of astute and rather fortuitous clinical observations and did not emerge form
systematic pharmacological development (Humble 2000).
Clomipramine was developed by Geigy as a chlorinated derivative of Imipramine.
It was first referenced in the literature in 1961 and was patented in 1963, approved for
medical use in Europe in the treatment of depression in 1970. Clomipramine remains
the only TCA in the United States that is not approved for the treatment of depression,
in spite of the fact that it is a highly effective antidepressant. It has been approved in
the United States for the treatment of OCD in 1989 and became available in 1990. It
was the first drug to be investigated and found effective in the treatment of OCD. It is
on the World Health Organization’s List of Essential Medicines.
Trimipramine was developed by Rhône-Poulenc, patented in 1959 and first
introduced for medical use in 1966 in Europe. It was not introduced in the United
States, is available worldwide except Australia (Heal 1997).

Fig. 1 Structural formulas of imipramine, clomipramine and trimipramine

Tricyclics: Imipramine, Clomipramine, Trimipramine (Dibenzazepines) 1195

Table 1 Main pharmacokinetic parameters of important Dibenzazepines (oral application)

(Balant-Gorgia et al. 1991, Sallee and Pollock 1990, mediq.ch/substances. Accessed February
20, 2020, Hiemke et al. 2018)
Absolute Dose Therapeutic
bioavailability (oral (mg) [maximal plasma levels
application) [%] t1/2 [h] tmax [h] dose] (ng/ml)
Imipramine 22–77 19 2.2 50–150 [300] 175–300
Clomipramine 50 21 3–4 50–150 [300] 230–450
Trimipramine 40 24 appr. 3 50–300 [400] 150–300

Pharmacology

Pharmacokinetics

The most important pharmacokinetic parameters of the mentioned dibenzazepines

are summarized in Table 1. Imipramine is metabolized to desipramine, a presynaptic
norepinephrine reuptake inhibitor (Hiemke et al. 2018; Stahl 2017).

Pharmacodynamics/Mechanism of Action

The most important pharmacodynamic property of tricyclics are the inhibition of the
reuptake of noradrenaline or serotonin at the presynaptic site. However, this is only
true for clomipramine and imipramine, whereas trimipramine exerts nearly no
inhibiting effect on the presynaptic noradrenaline and serotonin transporter. Clomip-
ramine acts mainly on the serotonin transporter, imipramine has a nearly balanced
inhibiting potential (Richelson and Nelson 1984; Owens et al. 1997; Humble 2000).
However, the compounds do not only exhibit activities on the presynaptically
located noradrenaline and serotonin transporter but also at different receptor sites
located in the CNS but also in the periphery. The most important receptors which
those compounds usually block are the muscarinergic-acetylcholine receptor
(AchR), the histamine-1-receptor (H1R), the alpha-1-adrenoreceptor (α1R), and the
Serotonin-2(A)-Receptor (5HT2[A] (Gillman 2007, Haenisch et al. 2011).).
Trimipramine is described as an atypical or “second-generation” TCA because,
unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor
Similarly to other TCAs however, trimipramine does have antihistamine, anti-
serotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities. Its
well-documented antidepressant action cannot be explained by noradrenaline or
serotonin reuptake inhibition or by a down-regulation of beta-adrenoceptors. Fur-
thermore, its receptor affinity profile – trimipramine is the only antidepressant
showing also activity at the Dopamine-2-receptor (D2) – resembles more that of
clozapine, a neuroleptic/antipsychotic drug, than that of tricyclic antidepressants
(Gastpar 1989). Trimipramine does not reduce, but rather increases, rapid eye
movement sleep. It stimulates nocturnal prolactin secretion and inhibits nocturnal
1196 H.-P. Volz and G. Laux

cortisol secretion and may act at the level of the hypothalamus on corticotropin-
releasing hormone secretion (Berger and Gastpar 1996).
In Table 2 the respective activities of imipramine, clomipramine, and tri-
mipramine are summarized qualitatively.
The different receptor profiles are shown in Fig. 2:

Table 2 Affinity to different receptors (mediq.ch/substances. Accessed February 15, 2020)

Imipramine Clomipramine Trimipramine
5-HT2A + (strong ant.) ++ (strong ant.) +++ (no effect)
α1 + (strong ant.) ++ (strong ant.) +++ (strong ant.)
D2 0 + (low ant.) ++ (medium ant.)
H1 ++ (strong ant.) ++ (strong ant.) +++ (strong ant.)
Ach + (strong ant.) ++ (strong ant.) ++ (strong ant.)
0 no, + low, ++ medium, +++ high affinity, ant antagonistic

Legend Imipramine

5HT2
5HT2 9%
NE-receptor NE-receptor
5HT1 5HT-receptor 17%
AChM
29%
5HT-receptor
D2 DA-receptor 11%
α1 2%

AChM α1

H2 α2 H1 32%

Clomipramine Trimipramine

5HT2
D2 NE-receptor
7%
1% 5%
AChM
13%

H1
10% H1
α1 5HT-receptor
3%
61%

Fig. 2 Receptor binding profiles of imipramine, clomipramine, and trimipramine. (Adapted from
Fritze 2002)
Tricyclics: Imipramine, Clomipramine, Trimipramine (Dibenzazepines) 1197

Indications

Imipramine, Clomipramine, and trimipramine are mainly used in the treatment of

depressive disorders.
Imipramine has additional indications for the treatment of panic attacks, chronic
pain, and Kleine-Levin syndrome. It has also been used to treat nocturnal enuresis
because of its ability to shorten the time of delta wave stage sleep, where wetting
occurs.
Clomipramine is used for the treatment of obsessive–compulsive disorder, panic
disorder, major depressive disorder, and chronic pain. Clomipramine is well
established in the treatment of depressive illness, particularly treatment-resistant
depression. However, in addition to its role as an antidepressant, attention is being
focused on the use of clomipramine in two other areas of psychiatry: obsessive
compulsive disorder and panic disorder.
Trimipramine is also used for its sedative, anxiolytic, and weak antipsychotic
effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively.

Clinical Studies

The efficacy of tricyclic compounds in major depression is well established (see

Morris and Beck 1974; Gillman 2007). TCAs were also effective in late-life depres-
sion, i.e., older patients’ response rates appeared to be lower than in nonelderly
patients, however (Gerson et al. 1988). When the SSRIs were introduced a large
meta-analysis of 102 RCTs (10,706 pts.) found TCAs and SSRIs in general have
comparable efficacy. TCAs appeared to be more effective in in-patients (Anderson
2000).
Fayez and Gupta (2021) give an actual overview to imipramine.
In the (conventional) meta-analysis of Möller et al. (1994), a total of 90 random-
ized, controlled trials (RCTs) using imipramine as the reference compound investi-
gating the efficacy (and tolerability) of other, more modern antidepressants
(maprotiline, mianserin, viloxazine, trazodone, nomifensine, fluvoxamine, fluoxe-
tine) have been included. Overall, there was no difference regarding efficacy
between imipramine and the mentioned comparative compounds.
In severe depressed inpatients, clomipramine was more effective than the SSRI
citalopram (Danish University Study Group 1986). Clomipramine belongs to the
antidepressants with superior efficacy (Montgomery et al. 2007).
Clomipramine is established in the therapy of obsessive compulsive and panic
disorders (Peters et al. 1990; McTavish and Benfield 1990), benefits are limited due
to drop rates as a result of adverse reactions, however (Papp et al. 1997). In a meta-
analysis of various trials involving fluoxetine, fluvoxamine, and sertraline to test
their relative efficacies in treating OCD, clomipramine was found to be the most
effective (Greist et al. 1995). Clomipramine nonetheless retains a significant effec-
tiveness advantage relative to SSRIs. SSRIs are treatment of choice in OCD today, in
case of refractory OCD clomipramine could be used (Del Casale et al. 2019). Further
1198 H.-P. Volz and G. Laux

positive results have been reported in chronic pain syndromes (Nilsson and von
Knorring 1989).
According to his atypical pharmacological properties trimipramine is effective in
the therapy of insomnia and psychotic, delusional depression (Pecknold and Luthe
1989; Gross et al. 1991; Sonntag et al. 1996; Berger and Gastpar 1996; Riemann
et al. 2002; Künzel et al. 2009).
Table 3 gives a summary of important controlled clinical studies:
Thus, overall, there seems to be no major efficacy difference of the tricyclics
compared to other antidepressants.

Side Effects/Adverse Reactions and Toxicology

Most side effects of imipramine and clomipramine can be explained by their

pharmacodynamic properties (Fritze 2002; Stahl 2017). Thus, the presynaptic
noradrenaline-reuptake-inhibiting property can lead to agitation, restlessness,
and sometimes – if the α1R-blocking activity is low – to hypertension and
tachycardia.
The presynaptic serotonin-reuptake-inhibiting property might result in gastroin-
testinal disturbances like nausea and even vomiting, but also in headache.
The blockade of the AchR can result in peripheral anticholinergic effects like
accommodation disorders, blurred vision, constipation, mydriasis, dryness of mouth,
sinus tachycardia and urine retention, but also to central anticholinergic effects like
cognitive disturbances.
The central and peripheral blockade of H1R might lead to increased appetite
resulting in some cases in weight gain.
The blockade of central and peripheral α1R can lead to (orthostatic) hypotension
and sedation.
The blockade of 5HT2R can lead to increased appetite and weight increase.
By blocking the voltage dependent sodium and potassium channels the cardiac
conduction might be decelerated resulting in AV-blocks, QTc-prolongation, and
even torsade de points might occur. This pharmacodynamic property is also respon-
sible for the lowered seizure threshold. Incidence of seizures under clomipramine is
dose related, occurring in 0.48% of all pts. receiving lower and 2.1% of pts.
receiving higher doses >250 mg/d (McTavish and Benfield 1990).
+Trimipramine has a different side effect profile compared to other TCAs and in
general with fewer side effects, chiefly due to its lack of norepinephrine reuptake
inhibition and relatively lower anticholinergic effects. Somnolence is the most
common side effect of the drug. Dry mouth is the most common anticholinergic
side effect, but others like constipation, urinary retention, and blurred vision are also
present. It leads not to orthostatic hypotension and is less cardiotoxic than other
TCAs (Pecknold et al. 1985; Lapierre 1989; Berger and Gastpar 1996; Stahl 2017).
The respective compounds exhibit these side effect in relation to their potential at
the different sites (Table 4).
Tricyclics: Imipramine, Clomipramine, Trimipramine (Dibenzazepines) 1199

Table 3 Surveys Review RCTs of imipramine (I), clomipramine (C) and trimipramine (T) in
depression
Study arms, Results Relevant and
N, Patients comparators, (Response-rate Dropout severe side
Study Duration Placebo RR) rates effects
Prien et al. N ¼ 77 I N ¼ 38 Relapse rates
(1973) 20 months Pl N ¼ 39 I 37%
RCT Pl 67%
Frank et al. N ¼ 128 I N ¼ 28 Relapse rates
(1990) 3 years IPT þ I N ¼ 25 21%
RCT IPT þ Pl N ¼ 26 24%
IPT N ¼ 26 66%
Pl N ¼ 23 62%
78%
Effective
relapse
prevention of I
at 200 mg/d
Wehmeier N ¼ 41 T N ¼ 21,150 mg/d T ¼ F T¼F
et al. (2005) geriatric Fluoxetine (F)
RCT MDD pts N ¼ 20 20 mg/d
6 weeks
Pecknold et al. N ¼ 39 T N ¼ 20, T ¼ M in M>T
(1985) Anxiety- 150 mg/d depression and M weight gain, T
RCT depression Maprotiline anxiety scales # RR, lower
5 weeks (M) N ¼ 19, anticholinergic,
150 mg/d neurologic and
cardiovascular
effects
Greist et al. N ¼ 1520 C N ¼ 520 C > F, Fl,
(1995) Fluoxetine (F) N ¼ S > Pl
Meta-analysis 355
4 multicenter, Fluvoxamine
placebo- (Fl) N ¼ 320
controlled Sertraline (S) N ¼
studies 325
Arroll et al. Primary TCAs vs Pl RR TCA 60% NNH TCA 5–11
(2005) care pts. Pl 45%
Meta-analysis 6–8 weeks NNT TCA 4
12 RCT Low dose also
studies effective
Sonntag et al. N ¼ 20 T vs I T enhanced
(1996) male inpts REM and slow
RCT Sleep wave sleep,
EEG, total sleep time
nocturnal increased
hormone with T, cortisol
secretion secretion
decreased
with T
(continued)
1200 H.-P. Volz and G. Laux

Table 3 (continued)
Study arms, Results Relevant and
N, Patients comparators, (Response-rate Dropout severe side
Study Duration Placebo RR) rates effects
Künzel et al. N ¼ 94 T N ¼ 33 Ø RR: T 84.8% Not reported
(2009) Delusional 356 mg/d A/H 70.8%
RCT depression Amitriptyline/ Decrease of
haloperidol (A/H) cortisol and
N ¼ 24 Ø ACTH
184/6 mg/d response in the
Dex/CRH test
in both groups
Note > more effective or more frequent than
NNT number needed to treat, NNH number needed to harm, Randomized Controlled Trial (RCT)

Table 4 Side-effect profile of imipramine, trimipramine, and clomipramine (according to Fritze

2002)
Imipramine Clomipramine Trimipramine
Anticholinergic +++ +++ +
Sedation +++ +++ ++++
Agitation, sleep disturbances +  
Orthostatic reaction ++++ +++ +++
Arrhythmia +++ +++ +++
Weight increase +++ ++ +++
Sexual dysfunctions ++ ++++ +
Nausea + + 
Headache ++ + +
Diarrhea +  
Epileptic seizures   
 no, + low, ++ medium, +++ high, ++++ very high

Toxicity

TCAs have greater toxicity than SSRIs, SNRIs, or mirtazapine (Hawton et al. 2010).
Clomipramine was associated with a significant degree of toxicity in overdose,
trimipramine is relatively safe in overdose (White et al. 2008).
Contraindications for tricyclics include recent myocardial infarction, heart block
or other cardiac arrhythmias, severe liver disease, narrow angle glaucoma, and
urinary retention.
Pregnancy: For imipramine positive evidence of risk to human fetus (risk cate-
gory D), for clomipramine and trimipramine risk category C (no controlled studies in
humans, some animal studies show adverse effects).
Withdrawal symptoms may occur during gradual or particularly abrupt with-
drawal of tricyclic antidepressant drugs. Possible symptoms include: nausea,
vomiting, abdominal pain, diarrhea, insomnia, headache, nervousness, anxiety,
dizziness and worsening of psychiatric status.
Tricyclics: Imipramine, Clomipramine, Trimipramine (Dibenzazepines) 1201

Combination Therapies, Interactions

If combined with a strong inhibitor or inducer of CYP2D6, CYP1A2, or CYP3A4

elevated or reduced plasma levels might result. There is a potential pharmacokinetic
interaction with quinidine due to the fact that clomipramine is metabolized by
CYP2D6, diuretics (due to the potential for hypokalaemia which increases the risk
for QT interval prolongation and torsades de pointes), serotonergic agents like the
selective serotonin reuptake inhibitors (SSRIs), tramadol and triptans; due to poten-
tial additive serotonergic effects leading to serotonin syndrome. Regarding pharma-
codynamic interactions, special attention is required if tricyclics are combined with
compounds blocking H1R (e.g., some antipsychotics like quetiapine, olanzapine,
clozapine) or AchR (e.g. some antihistamines, cimetidine, antipsychotics like clo-
zapine, olanzapine) since the respective side-effects induced by blocking these
receptors might be considerably worsened. Also, compounds lowering the seizure
threshold (e.g. some antipsychotics) or decreasing cardiac conduction
(e.g. antiarrhythmics, phenothiazines) should be avoided. Trimipramine can be
safely combined with MAOIs apparently without risk of serotonin syndrome or
hypertensive crisis.

Cross-References

▶ Antidepressants: Definition, Classification, Guidelines

▶ Antidepressants: Pharmacology and Biochemistry
▶ Antidepressants: Indications, Contraindications, Interactions, and Side effects

References
Anderson I. Selective serotonin reuptake inhibitors versus tricyclic antidepressants; a meta-analysis
of efficacy and tolerability. J Affect Disord. 2000;58:19–36.
Arroll B, Macgillivray S, Ogston S, et al. Efficacy and tolerability of tricyclic antidepressants and
SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann
Fam Med. 2005;3:449–56.
Balant-Gorgia AE, Gex-Fabry M, Balant LP. Clinical pharmacokinetics of clomipramine. Clin
Pharmacokinet. 1991;20:447–62.
Berger M, Gastpar M. Trimipramine: a challenge to current concepts on antidepressives. Eur Arch
Psychiatry Clin Neurosci. 1996;246:235–9.
Danish University Antidepressant Group. Citalopram: clinical effectprofile in comparison with
clomipramine: a controlled multicenter study. Psychopharmacology. 1986;90:131–8.
Del Casale A, Sorice S, Padovano A, et al. Psychopharmacological treatment of obsessive-
compulsive disorder (OCD). Curr Neuropharmacol. 2019;17:710–36.
Fayez R, Gupta V. Imipramine. StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2021.
Frank E, Kupfer DJ, Perel JM, et al. Three-year outcomes for maintenance therapies in recurrent
depression. Arch Gen Psychiatry. 1990;47:1093–9.
Fritze J. Unerwünschte Wirkungen, Kontraindikationen, Überdosierung, Intoxikation. In:
Riederer P, Laux G, Pöldinger W, editors. Neuropsychopharmaka. Ein Therapiehandbuch.
Band 3: Antidepressiva, Phasenprophylaktika und Stimmungsstabilisierer. Wien: Springer;
2002. p. 162–82.
1202 H.-P. Volz and G. Laux

Gastpar M. Clinical originality and new biology of trimipramine. Drugs. 1989;38(Suppl 1):43–8.
Gerson SC, Plotkin DA, Jarvik LF. Antidepressant drug studies 1964 to 1986: empirical evidence
for aging patients. J Clin Psychopharmacol. 1988;8:311–22.
Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br
J Pharmacol. 2007;151:737–48.
Greist JH, Jefferson JW, Kobak KA, et al. Efficacy and tolerability of serotonin transport inhibitors
in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatr. 1995;52:53–60.
Gross G, Xin X, Gastpar M. Trimipramine: pharmacological reevaluation and comparison with
clozapine. Neuropharmacology. 1991;30:1159–6.
Haenisch B, Hiemke C, Bönisch H. Inhibitory potencies of trimipramine and its main metabolites at
human monoamine and organic cation transporters. Psychopharmacology. 2011;217:289–95.
Hawton K, Bergen H, Simkin S, Cooper J, et al. Toxicity of antidepressants: rates of suicide relative
to prescribing and non-fatal overdose. Br J Psychiatry. 2010;196:354–8.
Heal D. The antidepressant era. Harvard University Press; 1997. ISBN 9780674039575
Hiemke C, Bergemann N, Clement HW, Conca A, et al. Consensus guidelines for therapeutic drug
monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Humble M. Noradrenaline and serotonin reuptake inhibition as clinical principles: a review of
antidepressant efficacy. Acta Psychiatr Scand Suppl. 2000;402:28–36.
Künzel HE, Ackl N, Hatzinger M, et al. Outcome in delusional depression comparing trimipramine
monotherapy with a combination of amitriptyline and haloperidol – a double-blind multicentre
trial. L Psyhiatr Res. 2009;43:702–10.
Lapierre YD. A review of trimipramine. 30 years of clinical use. Drugs. 1989;38(suppl 1):17–24.
McTavish D, Benfield P. Clomipramine. An overview of its pharmacological properties and a
review of its therapeutic use in obsessive compulsive disorder and panic disorder. Drugs.
1990;39:136–53.
Mediq.ch. Accessed 15 Feb 2020.
Möller HJ, Fuger J, Kasper S. Efficacy of new generation antidepressants: meta-analysis of
imipramine-controlled studies. Pharmacopsychiatry. 1994;27:215–23.
Montgomery SA, Baldwin DS, Blier P, et al. Which antidepressants have demonstrated superior
efficacy? A review of the evidence. Int Clin Psychopharmacol. 2007;22:323–9.
Morris JB, Beck AT. The efficacy of antidepressant drugs. A review of research (1958-1972). Arch
Gen Psychiatry. 1974;30:667–74.
Nilsson HL, von Knorring L. Review. Clomipramine in acute and chronic pain syndrome. Nord
Psykiatr Tidsskr. 1989;43:101–13.
Owens MJ, Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding
profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997;283:1305–22.
Papp LA, Schneier FR, Fyer AJ, et al. Clomipramine treatment of panic disorder: pros and cons.
J Clin Psychiatry. 1997;58:423–5.
Pecknold JC, Luthe L. Trimipramine, anxiety, depression and sleep. Drugs. 1989;38(Suppl
1):25–31.
Pecknold JC, Familamiri P, McClure DJ, Elie R, Chang H. Trimipramine and maprotiline: antide-
pressant, anxiolytic, and cardiotoxic comparison. J Clin Psychiatry. 1985;46:166–71.
Peters MD, Davis SK, Austin LS. Clomipramine: an antiobsessional tricyclic antidepressant. Clin
Pharm. 1990;9:165–78.
Prien RF, Klett CJ, Caffey EM Jr. Lithium carbonate and imipramine in prevention of affective
episodes. A comparison in recurrent affective illness. Arch Gen Psychiatry. 1973;29:420–5.
Psiac.de. Accessed 15 Feb 2020.
Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal
human brain in vitro. J Pharmacol Exp Ther. 1984;230:94–102.
Riemann D, Voderholzer U, Cohrs S, et al. Trimipramine in primary insomnia: results of a
polysomnographic double-blind controlled study. Pharmacopsychiatry. 2002;35:165–74.
Sallee FR, Pollock BG. Clinical pharmacokinetics of imipramine and desipramine. Clin
Pharmacokinet. 1990;18:346–64.
Tricyclics: Imipramine, Clomipramine, Trimipramine (Dibenzazepines) 1203

Sonntag A, Rothe B, Guldner J, et al. Trimipramine and imipramine exert different effects on the
sleep EEG and on nocturnal hormone secretion during treatment of major depression. Depres-
sion. 1996;4:1–13.
Stahl SM. Stahl’s essential psychopharmacology. In: The prescriber’s guide. Antidepressants. 6th
ed. Cambridge University Press; 2017.
Wehmeier PM, Kluge M, Maras A, Riemann D, et al. Fluoxetine versus trimipramine in the
treatment of depression in geriatric patients. Pharmacopsychiatry. 2005;38:13–6.
White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by
antidepressant type. J Med Toxicol. 2008;4(4):238–50.
Amitriptyline and Depressions

Mellar P. Davis

Contents
Chemistry, Developmental History, and Chemical Graphics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206
Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1208
Indication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1209
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1210
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1210
Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1212
Amitriptyline and Migraines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214
Amitriptyline and Pain: Recent Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214
Amitriptyline and Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1215
Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1215
Drug Interactions and Drug Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1217
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1218

Abstract
Amitriptyline was the second tricyclic antidepressant to be introduced into
practice in the United States. In a network meta-analysis, amitriptyline is equiv-
alent to selective serotonin reuptake inhibitors (SSRIs) and is superior to trazo-
done, fluoxetine, and reboxetine in efficacy. Dropouts for reasons of adverse
effects were higher than for most antidepressants particularly in the outpatient
setting. Therapeutic drug monitoring improves clinical utility since there are
wide individual differences in serum drug levels per dose. Drug interactions are
a result of competitive inhibition with the mixed function oxidases CYP2D6 and

M. P. Davis (*)
Department of Palliative Care, Geisinger Medical Center, Danville, PA, USA
e-mail: mdavis2@geisinger.edu

© Springer Nature Switzerland AG 2022 1205

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_81
1206 M. P. Davis

Fig 1 Molecular Structure of

Amitriptyline

CYP2C19. Amitriptyline is effective in treating melancholic depression and

psychotic depression if combined with an antipsychotic in the latter instance
but increases the risk of mania in bipolar disorders. Amitriptyline adverse effects
are largely related to antimuscarinic side effects. Overdoses are highly lethal due
to arrhythmias.

Chemistry, Developmental History, and Chemical Graphics

Amitriptyline was synthesized in 1960 and introduced into the United States in 1961
and in the United Kingdom in 1962 (Pressman and Weiss 1961). It was the second
tricyclic antidepressant to be introduced for the treatment of depression. Imipramine
was the first which was available in 1957. Amitriptyline is a dibenzocycloheptadiene
(Fig. 1). The chemical name is 3-(10,11)-dihydro-5H-dibenzo [a, d] cycloheptene-5-
y(diene)-N, N-dimethyl-propan-1-amine.

Pharmacology

Pharmacodynamics

Amitriptyline has a high affinity for norepinephrine and serotonin transporters but
very low affinity for dopamine transporters. It binds to and inhibits adrenergic,
histaminergic, and muscarinic receptors which are largely responsible for side effects
associated with amitriptyline. Amitriptyline also binds to certain serotonin receptors
(5HT1B, 5HT2A, 5HT2B, and 5HT2C) (Vaishnavi et al. 2004; Mestres et al. 2011;
Giros et al. 1992) (Table 1). The hypnotic effects of amitriptyline are thought to be
due to histamine receptors (H1, H2) and certain serotonin receptors (5HT2A and
5HT2C) (Atkin et al. 2018).
Several recent studies demonstrated amitriptyline effects beyond monoamine
receptor and transporter interactions. The hippocampus plays a major role in depres-
sion. Reductions in neurogenesis within the hippocampus are associated with major
depression disorders. The Janus kinase 3 (Jak-3) is induced in stress-related major
depression which causes inhibition of neurogenesis within the hippocampus as
described in animal models. Amitriptyline reduces Jak-3 expression through the
Amitriptyline and Depressions 1207

Table 1 Affinity of amitriptyline for transporters and receptors (Vaishnavi et al. 2004; Mestres
et al. 2011)
Transporter/receptor K1 (nM) IC50(nM)
Norepinephrine transporter 13.3 63
Serotonin transporter 3.13 47
Dopamine transporter 2580 7500
Norepinephrine receptor 24 690
Muscarinic receptor 7.2 –
Histamine receptor – 26(H1)
Serotonin-5HT1B – 40
Serotonin-5HT2A – 4
Sertonin-5HT2B – 40
Serotonin-5HT2C – 6
Ki-binding constant of the protein in concentration
IC50-concentration at which 50% of the protein function is inhibited

inhibition of sphingomyelinase. This is associated with reduced stress-induced

depression in mice (Gulbins et al. 2016).
Pharmacodynamically, there may be benefits to combinations of antidepressants
rather than starting with monotherapy. Single antidepressants can cause neuronal
oxidative stress which leads to double-stranded DNA breaks, whereas treatment
with combined antidepressants (amitriptyline/imipramine + fluoxetine) initiates
p16-dependent cell cycle arrest, overexpression of telomere maintenance proteins,
and restoration of cellular proliferation (Solek et al. 2019). The cytotoxicity
of monotherapy is efficiently blocked by an inhibitor of p38 MAPK (Lirk et al.
2006).
The interactions of amitriptyline with opioids is rather complex. In rhesus
macaques amitriptyline (0.32–1 mg/kg) administered prior to heroin significantly
shifted the heroin dose-effect curve leftward (Nilges et al. 2019). One hypothesis is
that amitriptyline produces analgesia by blocking serotonin uptake and therefore
enhancing the action of serotonin at the spinal terminals of an opioid-mediated
intrinsic analgesia system (Botney and Fields 1983). Early studies suggested treat-
ment prolonged morphine analgesia by increasing the sensitivity of the central
nervous system to morphine rather than by changing morphine pharmacokinetics
(Liu and Wang 1981). Amitriptyline/morphine co-infusion restores the anti-
nociceptive effect of morphine and upregulates glutamate transporters (GLAST
and GLT-1 expression) and restores transporter excitatory amino acid carrier
1 (EAAC1 expression) to baseline levels, thus improving morphine analgesia (Tai
et al. 2008). This “left shift” in analgesia may not lead to greater clinical utility of the
combination of morphine and amitriptyline. In rabbits, pretreatment with amitripty-
line increases morphine-induced hypercarbia through pharmacodynamic processes
(Kozer et al. 2008).
In the same stress-induced depression animal model, heavy neurofilament
phosphorylation is reduced resulting in reduced hippocampus neurogenesis.
Amitriptyline increases heavy neurofilament phosphorylation which is associated
1208 M. P. Davis

with reduced stress-induced depression. Interestingly, citalopram does not prevent

dephosphorylation or increase neurofilament phosphorylation suggesting that this is
a unique mechanism of action (Sanna et al. 2017).
FK506-binding protein 51 (FKBP51) is necessary for autophagy and is also a
HSP-90 co-chaperone which regulates glucocorticoid receptors. Antidepressants as
a class of medications are dependent on the expression of FKBP51 for antidepressant
activity which is lost in FKBP51 knockout mice (Gassen et al. 2014, 2015).
In humans, antidepressant benefits are predicted by the expression of FKBP51 and
autophagy observed in circulating leukocytes (Gassen et al. 2014). The correlation of
response to FKBP51 expression is quite significant (r = 0.416).
Antidepressants also reduce neuroinflammation as a mechanism of its action.
Neuroinflammation has been associated with depression and pain. Amitriptyline
reduces neuroinflammation and expression of inflammatory mediators, NLRP3,
interleukin 1B, and interleukin 18. This neuroinflammatory action is autophagy
dependent. The presence of NLRP3 inflammasomes are a biomarker of antidepres-
sant responses (Alcocer-Gomez et al. 2014, 2017).
Amitriptyline has smooth muscle effects which may reduce bladder spasm and
facilitate the passage of kidney stones caught in the bladder. This may be thought to
be due to its anticholinergic properties, but in fact it is by another mechanism.
Amitriptyline relaxes urinary tract smooth muscle by opening of voltage-dependent
potassium channels (Achar et al. 2003).

Pharmacokinetics

Amitriptyline is well absorbed (Rudorfer and Potter 1999). Bioavailability is 45%

(95% confidence intervals [CI] 42.8 to 45.9%) with a time to maximum drug
concentrations of 3.6 h (range 2.2–4.7 h) (Schulz et al. 1985). The volume of
distribution in the central compartment is 1.4 l/kg largely because amitriptyline is
lipophilic. In the brain, amitriptyline levels are 43% of the total area under the curve
of serum concentrations, and nortriptyline is 29% which are the most abundant
central drug and metabolites as measured in mice, indicating fairly good blood-brain
barrier penetration (Coudore et al. 1994). Amitriptyline is not a substrate for
P-glycoprotein (O’brien et al. 2013). Amitriptyline-free fraction in plasma is 5.7%
(range 3.6–7 0.8%) indicating a high degree of protein binding. Total-body plasma
clearance on average is 1300 mL/min but with a wide range (1019–2531) (Schulz
et al. 1985). Amitriptyline levels per dose are reportedly increased with age and
female gender (Preskorn and Mac 1985). Plasma clearance is 2–5 times slower in the
elderly than in the healthy young. The ratio of nortriptyline (which is the major
amitriptyline metabolite) to amitriptyline does not differ from the healthy young
indicating that delayed clearance in the elderly is not related to cytochrome metab-
olism. However, there are other studies which do indicate a delayed conversion
of amitriptyline to nortriptyline with age (Baumann et al. 1986; Baumann 1986).
Amitriptyline is demethylated to nortriptyline which is an active metabolite.
Amitriptyline and Depressions 1209

Amitriptyline also undergoes N-oxidation, aromatic and aliphatic hydroxylation,

dealkylation, and glucuronidation (Furlanut and Benetello 1990).
Therapeutic drug monitoring has been recommended largely for safety reasons
though a therapeutic range has been established (Roy and Dawling 1987). Patient
populations that benefit from monitoring are children and adolescents, pregnant
women, elderly patients, individuals with intellectual disabilities, patients with
substance abuse disorders, forensic psychiatric patients, or patients with known or
suspected pharmacokinetic abnormalities (Hiemke et al. 2018). Non-response at
therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharma-
cokinetic drug-drug interactions are typical indications for TDM (Hiemke et al.
2018). In multiple early studies, depression responses did not correlate with
amitriptyline or nortriptyline blood levels (Monteleone and Fabrazzo 1994;
Baumann et al. 1986). Others have found that though there is an 8–10-full
difference in amitriptyline concentrations between individuals using a standard
dose (150 mg), there was a linear dose to plasma concentration relationship for a
single individual, and non-responders in general had lower plasma levels (Rao
et al. 1996). Still others have described a complex relationship between nortripty-
line and amitriptyline plasma levels and depression responses (Franke et al. 2003).
This study found that a nortriptyline to amitriptyline plasma concentration ratio of
<1 predicted a better response at 4 weeks (75%) versus a ratio greater than
1 (52.2%). Individuals with amitriptyline levels less than or equal to 110 ng per
mL were responders if the ratio was <1. A meta-analysis has clarified the rela-
tionship of plasma levels to depression responses. This study involved 23 different
trials with pooled data of serum concentrations and therapeutic effect relationships
(Ulrich and Lauter 2002). The mean effect size for response was determined for
those individuals within the therapeutic range as opposed to those outside of the
therapeutic range. The therapeutic range was the sum of amitriptyline and nortrip-
tyline plasma concentrations between 80 and 200 ng per mL. The effect size for
response for individuals within the therapeutic range was 0.538 (95% CI
0.167–0.909). A second study found that the combined amitriptyline plus nortrip-
tyline plasma levels between 93 and 140 ng /mL was a reasonable therapeutic
(Perry et al. 1994).
The terminal half-life of amitriptyline ranges between 12.5 and 36 h. Approxi-
mately 25–50% of the dose is excreted in the urine within 24 h as the metabolites
with a small proportion excreted in feces (von Moltke et al. 1993).
Amitriptyline clearance is significantly influenced by CYP2C19 and CYP2D6
genotypes. Recommendations have been made by the Clinical Pharmacogenetic
Implementation Consortium which is outlined on Table 2. (Dean 2017)

Indication

Indications for amitripyline are for depressive symptoms. Endogenous depression is

more responsive than other forms of depression
1210 M. P. Davis

Table 2 Recommendations for amitriptyline dosing by the Clinical Pharmacogenetic Implemen-

tation Consortium
1. Amitriptyline dosing should be based on CYP2D6 and CYP2C19 genotype.
2. If an individual is an ultrarapid metabolizer (CYP2D6 genotype>2 alleles), tricyclic
antidepressants should not be used due to lack of efficacy.
3. If tricyclic antidepressants are used to treat depression in ultrarapid metabolizer at therapeutic
dose monitoring should be used and higher than usual and of amitriptyline will be needed to reach
therapeutic levels.
4. If an individual is an intermediate metabolizer (equivalent to one functional allele), consider
using 75% of initial doses due to delayed clearance.
5. Avoid tricyclic antidepressants in poor metabolizers.
6. For ultrarapid CYP2C19 metabolizers, avoid amitriptyline due to a suboptimal response, and
consider using nortriptyline or desipramine which is not metabolized by CYP2C19.
7. Avoid amitriptyline in CYP2C19 poor metabolizers due to suboptimal responses secondary to
lack of conversion to nortriptyline.
8. If a tertiary amine tricyclic antidepressant is considered in CYP2C19 poor metabolizer, start
amitriptyline at 50% of doses due to amitriptyline accumulation.
Dean (2017)

Clinical Studies

Depression

Table 3 is a synopsis of five systematic reviews and meta-analysis of amitriptyline

versus placebo, amitriptyline in the elderly, and amitriptyline versus other antide-
pressants for major depression disorders. In the network meta-analysis published in
2018, amitriptyline was better than placebo in responses with an odds ratio (OR) of
2.13 and remissions OR 1.98 (Cipriani et al. 2018). Amitriptyline was superior to
reboxetine, trazodone, and fluoxetine. All-cause dropout rates were not different
when comparing amitriptyline to placebo. However, dropout for adverse effects was
greater with amitriptyline with an OR of 3.11. Agomelatine and escitalopram were
better tolerated.
Amitriptyline was as effective as selective serotonin reuptake inhibitors (SSRIs)
in a second review (Mottram et al. 2006). Although amitriptyline was as effective
SSRIs, more patients withdrew from amitriptyline therapy overall with a relative
risk (RR) of 1.23 and withdrew for adverse effects with a RR of 1.36. The lead
adverse effect was a dry mouth which is largely due to amitriptyline anticholinergic
effects.
Two meta-analyses by the same author compared amitriptyline to other antide-
pressants (Barbui et al. 2004; Guaiana et al. 2007). Amitriptyline responses were
higher in those who were inpatients (OR 1.22) but were not significantly higher
in outpatients (OR 1.01). Adverse effects with amitriptyline were greater in out-
patients with the comparator antidepressant (OR 0.9) with the opposite occurring in
inpatients (comparator OR 1.09).
Table 3 Systematic reviews and meta-analysis of amitriptyline randomized trials for major depression disorders
Author/ N, patients
year N, RCT Comparator Results Dropouts Adverse effects
Cipirani/ N = 116,477 Placebo, AMT > placebo, response For AE AMT> Placebo Agomelatine, escitalopram, vortioxetine
2018 RCT-522 21 antidepressants OR 2.13, remission OR-3.11 >AMT
OR-1.98, SMD 0.48 All-cause AMT>
AMT>trazodone, agomelatine, escitalopram
fluoxetine,
reboxetine
Leucht/ N,3509 Placebo AMT>placebo OR- 2.67 Lack of efficacy AMT>Placebo; tachycardia,
Amitriptyline and Depressions

2012 RCT-39 response Placebo>AMT OR- 0.2, AE nervousness, sedation, tremor,

AMT > placebo OR- 4.15 dyspepsia, sexual dysfunction, weight
gain
Mottram/ N,1154 Classical tricyclics Similar response RR -1.07 Overall tricyclics>SSRIs Tricyclics>SSRI hypotension, dry
2009 RCT-10 (includes AMT) RR- 1.24 mouth, constipation, drowsiness,
versus SSRIs somnolence, dizziness
Guaiana/ N,81 per trial Tricyclic, AMT > comparator AMT = comparator Comparator<AMT OR-0.66
2007 (mean) heterocyclic, OR-1.12, OR-0.96 NNH -8
RCT-194 SSRIs NNT-50, SMD- 0.13 AMT = tricyclics OR -1.07 Tricyclics< AMT SMD 0.67
AMT > other tricyclics AMT > SSRIs OR 0.84 NNH -9.5
SMD 0.18 NNH 40 SSRIs< AMT OR 0.65,
AMT = SSRIs OR -1.14, NNH -10
SMD 0.09
Barbui/ N, 14,790 Tricyclic, AMT > comparator OR Inpatients –
2004 RCT-181 heterocyclic, -1.22 AMT = tricyclic = SSRIs
SSRIs AMT > tricyclics for Outpatients
inpatients OR -1.20, SMD SSRI<AMT OR -0.77
0.28 AMT = tricyclics
AMT = SSRIs inpatient
AMT = tricyclics
outpatient
1211

AMT, amitriptyline; RCT, randomized control trials; OR, odds ratio; RR, relative risk; SSRIs, selective serotonin reuptake inhibitors; SMD, standard mean
difference
1212 M. P. Davis

A meta-analysis of trials involving comparisons between amitriptyline and pla-

cebo was published in 2012 (Leucht et al. 2012). Acute antidepressant responses
were superior with amitriptyline within the first 6 weeks (OR 2.67). Withdrawal due
to lack of efficacy was less with amitriptyline (OR 0.2), but withdrawal due to side
effects was greater (OR 4.15). Side effects were significantly more prevalent than
placebo which included tachycardia, nervousness, sedation, tremor, dyspepsia, sex-
ual dysfunction, and weight gain.

Other Studies

Other studies have bearing on amitriptyline utility and are worth reviewing. These
studies include patients with comorbidities as well as major depression disorders.
Patients with melancholic depression, depression, and panic disorders or psychotic
depression have not been included in randomized trials reviewed in the previous
section. An important study has analyzed whether lower doses of tricyclic antide-
pressants can be used and still maintain a response but have fewer side effects.
In a Cochrane Collaboration review, low doses (<100 mg/d) of tricyclic antide-
pressants as a drug class were compared to standard doses using response (>50%
decrease) in the Hamilton Assessment of Major Depression Rating Scale (HAMD)
(Furukawa et al. 2003). Low-dose tricyclic antidepressants as a class were superior
to placebo at 4 weeks (OR 1.65, 95% CI 1.36–2.0) and at 8 weeks (OR 1.47, 95%CI
1.12–1.94). Adverse effects were 63% higher than placebo, and dropout were 111%
higher than placebo. However, low-dose tricyclics were 55% less likely to produce
dropouts than standard doses.
A systematic review and meta-analysis of 41 trials involving antidepressants in
the treatment of panic disorders found that tricyclic antidepressants as a class were
superior to SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs)
(Bighelli et al. 2018). However, tricyclics also produced greater numbers of dropout.
Definitions of response in the study was “very much or much improved” on the
Clinical Global Impression by investigators or more than 40% reduction in Panic
Disorder Severity scale or 50% decrease in Fear Questionnaire Agoraphobia sub-
scale. The tricyclic antidepressants involved in trials were imipramine, clomipra-
mine, and desipramine but not amitriptyline.
Though tricyclic antidepressants have been used frequently in certain countries to
treat childhood depression, a meta-analysis of 14 studies found that the tricyclics as a
class did not improve depression (RR for response 1.07, 95%CI 0.91–1.29) (Hazell
and Mirzaie 2013). Some reduction in depression symptoms did occur (standard
mean differences [SMD], 0.32,95%CI 0.59 to 0.04). Adverse effects were
significantly worse with tricyclics relative to placebo in children. The risk of vertigo
(RR 2.76, 95%CI 1.73–4.43), orthostatic hypotension (RR 4.86, 95%CI1.69–13.97),
tremors (RR 5.53, 95%CI 1.64–17.98), and dry mouth (RR 3.35, 95%CI 1.98–5.64).
SSRIs were deemed safer due to potential overdose deaths associated with tricyclic
antidepressants. The wide confidence intervals demonstrate the imprecision in the
analysis secondary to low numbers of participants in the studies.
Amitriptyline and Depressions 1213

Antidepressants in managing depression in patients with cancer have recently

been reviewed in a meta-analysis. Tricyclic antidepressants as a class were no better
than placebo for response (SMD 0.45, 95%CI 1.01 to 0.11) (Ostuzzi et al. 2018).
SSRIs did not fare better, and dropouts were the same between drug classes. Only ten
randomized trials could be found which involved 885 patients and no trial went
beyond 12 weeks. Only one trial involved amitriptyline. A second systematic review
and meta-analysis found that only mianserin was effective in patients with cancer
(SMD relative to placebo 0.6,95%CI 0.24 to 0.95), and amitriptyline was not (Riblet
et al. 2014). It would be assumed as a result that mianserin and mirtazapine as a drug
class would be better choices for treating patients with cancer and depression.
A systematic review and meta-analysis were done on trials of antidepressants in
patients receiving palliative care. Patient has had cancer and non-cancer diagnoses.
The review involved 25 randomized controlled trials of which 6 trials involved
tricyclic antidepressants (nortriptyline, imipramine, and desipramine) (Rayner et al.
2011). Responses for antidepressants occurred at 4–5 weeks (OR 1.93, 95%CI
1.15–3.42), 6–8 weeks (OR 2.25, 95%CI 1.38), and between 9 and 12 weeks
(OR 2.71, 95%CI 1.50–3.67). Tricyclic antidepressants as a drug class were superior
to SSRIs and placebo before week 9. However, mianserin and mirtazapine were
superior to both SSRIs and tricyclic antidepressants (OR 3.56, 95%CI 1.24–10.23).
Tricyclic antidepressant dropout rates were greater than for placebos after 9 weeks.
Dry mouth was the major side effect (OR 5.33, 95%CI 2.23–12.73).
Tricyclic antidepressants were found not to be effective in treating depression
associated with Parkinson’s disease (Rocha et al. 2013). Tricyclic antidepressants
improve depression symptoms (SMD 0.59, 95%CI 0.21 to 0.96) but not response
rates or remissions in patients with HIV infections and depression. Mirtazapine
appeared to produce greater responses than SSRIs or tricyclic antidepressants
(mean difference 9 points on HAMD, 95%CI 3.61–14.39). However, the evidence
was low quality (Eshun-Wilson et al. 2018).
Six of eight randomized studies that used antidepressants in patients with rheu-
matoid arthritis and depression involved tricyclic antidepressants (Richards et al.
2011). Tricyclics were of no benefits regarding pain, and tricyclics failed to improve
depression in the first week. There was conflicting evidence for benefit in longer
trials. Adverse effects were greater with tricyclic antidepressants than placebo
(RR 2.27, 95%CI 1.17–4.42) even though there were no differences in dropout rates.
Depression associated with end-stage kidney disease is poorly studied. There are
only 4 randomized trials with a total of 170 patients. Studies involved fluoxetine,
sertraline, citalopram, and escitalopram, but there were no tricyclic antidepressants
studied in this population (Palmer et al. 2016). By case report amitriptyline has been
associated with acute kidney injury (Chen et al. 2019).
Psychiatric disorders are common in alcoholics, particularly depression.
Antidepressants as a class increased the number of abstinent (RR 1.69, 95% CI
1.18 to 2.43) and reduced the number of drinks per drinking days (MD -1.21 number
of drinks per drinking days, 95% CI 1.91 to 0.51). Antidepressants had positive
effects on certain relevant outcomes related to depression and alcohol use (Agabio
et al. 2018).
1214 M. P. Davis

In summary amitriptyline is as effective as other classes of antidepressants in

managing major depression disorders. Amitriptyline is superior to trazodone,
reboxetine, and fluoxetine but less well tolerated than agomelatine and escitalopram.
Overall dropout rates are the same as placebo, but dropouts differ as to whether it is
for lack of efficacy or side effects. Tricyclics and by extension amitriptyline reduce
panic and appear to be effective in a palliative population though mirtazapine and
mianserin may be preferred. There appears to be little benefit to tricyclic antidepres-
sants in multiple medical conditions; mirtazapine or mianserin may be preferred.
There is little evidence that tricyclic antidepressants improve childhood depression,
and I would assume the same is true for amitriptyline though there are very few trials
on which to base this conclusion. Amitriptyline doses less than 100 mg may be
effective with reduced side effects assuming that this is a drug class effect. Unfor-
tunately, there are no head-to-head trials of amitriptyline.

Amitriptyline and Migraines

A recent review of antidepressants to prevent migraines found that amitriptyline has

the best evidence for use in migraine prevention. Nortriptyline is an alternative in
patients who may not tolerate amitriptyline (Burch 2019). Currently, the only
FDA-approved medical treatment option for preventive therapy in chronic migraine
in adolescents is topiramate. The Childhood and Adolescent Migraine Prevention
Study (CHAMP) did not find superiority of topiramate or amitriptyline over placebo
(Qureshi et al. 2019; Powers et al. 2017). Children with migraines receiving ami-
triptyline plus cognitive behavioral therapy are more likely than those receiving
amitriptyline plus headache education to have a reduction in headache frequency
(Oskoui et al. 2019). It is likely that the bulk of the benefit is related to the cognitive
behavioral therapy.

Amitriptyline and Pain: Recent Studies

In adults with chronic, nonspecific, low back pain, low-dose amitriptyline (25 mg/d)
or an active comparator (benztropine mesylate, 1 mg/d) for 6 months. There were no
significant improvements in outcomes including pain intensity at 6 months, but there
was a reduction in disability at 3 months (Urquhart et al. 2018). For masticatory
myofascial pain, nortriptyline and amitriptyline were compared in a randomized
trial. The 50% improvement rate with nortriptyline was better (P = 0.036) (Haviv
et al. 2019). Depression and chronic pain often coexist. Of 1166 people prescribed
opioids for chronic non-cancer pain, half the cohort (N = 637, 54.6%) used antide-
pressants. Three hundred twenty-nine (51.7%) reported moderate to severe depres-
sion. Amitriptyline was the most commonly used antidepressant (17.3%) (Gisev
et al. 2019). Patients with chronic neck pain were randomized between amitriptyline
at night and placebo. Amitriptyline significantly lowers pain scores greater than
in the placebo group (3.34 +/ 1.45 vs. 6.12 +/ 0.92; p < 0.0001), which
Amitriptyline and Depressions 1215

corresponded to a 53.06 +/ 20.29% of improvement from baseline pain as com-

pared to 14.41 +/ 11.05%, respectively ( p < 0.0001), with placebo (Maarrawi et al.
2018). This illustrates the clinical use of amitriptyline as both an adjuvant analgesic
and antidepressant. Physicians often use amitriptyline for both purposes.

Amitriptyline and Insomnia

Many drugs are used off-label for treatment of insomnia. The most common are
antidepressants such as trazodone, mirtazapine, and amitriptyline. There is little
evidence that these drugs are effective in treating insomnia not associated with
depression (2018). There was no evidence for amitriptyline use for primary insomnia
(Everitt et al. 2018). Sertraline, fluoxetine, and amitriptyline appear to increase
periodic limb movements that do not disrupt sleep (Kolla et al. 2018).

Adverse Effects

One of the difficulties in measuring side effects is that antidepressant side effects can
be learned using a conditioning paradigm and evoked via a placebo pill. This may
result in a crossover effect with placebo side effects looking very similar to active
treatment. This should inform us when we read about side effects (Rheker et al.
2017). In systematic reviews of randomized trials comparing amitriptyline to pla-
cebo, side effects experienced significantly more often were largely related to
anticholinergic toxicities: tachycardia, nervousness, sedation, tremor, dyspepsia,
sexual dysfunction, and weight gain (Leucht et al. 2012). Anticholinergic adverse
effects may be worse at the time of peak plasma concentrations. In a study dividing
the dose of amitriptyline to every 8 h appears to reduce dry mouth and sedation
compared to a single-dose bedtime dose which is the usual dosing strategy (Gupta
et al. 1999). Individuals starting out on amitriptyline are better at recognizing
treatment-emerging side effects. However, individuals on long-term amitriptyline
may eventually complain of anticholinergic side effects they did not recognize with
initial therapy. Patients may initially tolerate amitriptyline anticholinergic effects and
not recognize symptoms as side effects, and yet over time tolerance diminishes at a
threshold at which the symptom is recognized as a side effect (Bryant et al. 1987).
In early studies, the incidence of side effects recognized by patients occurred in
15.4%. Major adverse effects described in an early study were psychosis, halluci-
nations, disorientation, and agitation in 4.6% of a group of patients treated in the
Boston Collaborative Drug Surveillance Program (Jick et al. 1972). However, these
severe adverse effects have not been described in recent trials and may have been
related to treating psychotic depression or bipolar disorders with amitriptyline; both
of which are poorly responsive to amitriptyline alone. Amitriptyline converts depres-
sion to mania in 42% of individuals treated for bipolar depression (Koszewska and
Rybakowski 2009).
1216 M. P. Davis

Amitriptyline sexual dysfunction occurs more commonly in men and adversely

influences the early phases of a sexual encounter, that is, arousal and libido
more than orgasm and ejaculation. Symptoms of insomnia, somnolence, and nausea
predict the presence of sexual dysfunction. Sexual dysfunction does improve over
time (Chen et al. 2018).
Amitriptyline causes a prolonged QTC interval on electrocardiogram. In a group
of veterans treated for post-traumatic stress syndrome, a prolonged QTC interval
from baseline occurred in 23% which placed them at risk for sudden death (hazard
ratio 1.6, 95% confidence interval 1.04 to 2.44) (Stock et al. 2018). QTC prolonga-
tion correlates with the combined serum concentrations of amitriptyline plus nor-
triptyline (r = 0.918) (Hefner et al. 2018). QTC prolongation is relatively minor if
serum levels were in the therapeutic range (80 to 200 nanometer g per mL) but
significantly increase if serum levels are above therapeutic (Unterecker et al. 2015).
In the elderly, cardiac side effects related to amitriptyline can occur at therapeutic
doses; therefore careful monitoring of cardiac status is warranted when considering
amitriptyline therapy (Rodstein and Oei 1979).
Amitriptyline adverse effects on memory are greater than that seen with SSRIs
and SNRIs. The SMD is 0.58 (95%CI 0.31 to 0.84) favoring SSRIs and SNRIs
(Rosenblat et al. 2015).
Amitriptyline overdoses are highly lethal unlike SSRIs and mirtazapine (Paksu
et al. 2014). Overdoses are associated with seizures, arrhythmias, and respiratory
depression. This is particularly dangerous in pediatric overdoses. The severity
of these complications directly relates to the combined amitriptyline and nortripty-
line blood levels. The most common electrolyte abnormality is hyponatremia.
Thirty-nine percent of adults and 53% of pediatric patients will present with
hyponatremia. A low Glasgow Coma Score and a pathologic ECG tracing at
presentation predict seizures, cardiac arrest, and poor prognosis (Paksu et al.
2014). A sequela of overdose may be a prolonged delirium and an abdominal
compartmental syndrome secondary to anticholinergic side effects. The prolonged
delirium may respond to physostigmine (Gomolin and Melmed 1983). Irreversible
structural damages have been described and involve the frontal and insular cortex
(Nishimura et al. 2017).
This serotonin syndrome can occur particularly when amitriptyline is combined
with other antidepressants or its clearance is delayed due to drug interactions.
Factors associated with the serotonin syndrome include advanced age, high doses,
and concomitantly use of medications which are potent inhibitors of CYP2D6 (Park
et al. 2014).
Antidepressant exposure particularly in the first trimester of pregnancy may risk
congenital malformations. Citalopram has a significant risk of all the antidepres-
sants (OR 1.36, 95%CI 1.08–1.73). Amitriptyline does not have major organ
adverse effects but may influence the eye, ear, face, neck, and digestive system
development (OR 2.45 to 2.55) (Berard et al. 2017). Antidepressant use during
pregnancy can increase the risk of gestational diabetes. Amitriptyline (adjusted OR
1.52, 95% CI 1.25 to 1.84) is associated with an increased risk of gestational
diabetes (Dandjinou et al. 2019). Antidepressants as a class increase the risk of
Amitriptyline and Depressions 1217

neonatal seizures. Antidepressants in the third trimester of pregnancy appeared to

be particularly associated more with neonatal seizures compared with earlier
exposure (Uguz 2019).

Drug Interactions and Drug Combinations

There has been concern that hormonal contraceptives may increase amitriptyline
exposure through pharmacokinetic interactions (Berry-Bibee et al. 2016). The com-
bined use of carbamazepine with amitriptyline reduces mean amitriptyline levels by
42% and nortriptyline by 40% (Leinonen et al. 1991). Valproic acid has been
combined with amitriptyline to treat refractory depression. Valproic acid signifi-
cantly increases amitriptyline serum levels (Unterecker et al. 2013). On the other
hand, the combination of mirtazapine (30 mg) and amitriptyline (75 mg) has minor
and clinically insignificant interactions. Mirtazapine may in fact prevent this sero-
tonin syndrome by blocking postsynaptic serotonin receptors (Sennef et al. 2003).
The combination of citalopram with amitriptyline has been used for individuals with
depression and either migraine or tension headaches who have not responded to
either drug alone. There are no increases in major side effects or serotonergic adverse
effects with the combination (Rampello et al. 2004). However, citalopram and
escitalopram like amitriptyline prolongs the QTC interval and may cause torsades
de pointes. The combination, if used, should be monitored by ECG (Tampi et al.
2015). The risk appears to be related to the CYP2C19 genotype and not citalopram
blood levels (Kumar et al. 2014). CYP2C19 poor metabolizers will be at particular
risk with the combination (Chang et al. 2014).
Antidepressants have been augmented with coadministration of atypical antipsy-
chotics, most commonly aripiprazole, quetiapine, and olanzapine, for treatment of
refractory depression, psychotic depression, and depression associated with schizo-
phrenia or anxiety (Katzman et al. 2008; Brawman-Mintzer et al. 2005). The most
common combination consists of a SSRI and an atypical antipsychotic. Drug-drug
interactions are a risk when combining atypical antipsychotics with amitriptyline.
For instance, risperidone and aripiprazole are both metabolized through CYP2D6
and could competitively inhibit amitriptyline clearance. Delayed clearance of both
drugs increases the risk for extrapyramidal side effects (Berman et al. 2009; Wright
et al. 2013). One systematic review of augmentation therapy with atypical antipsy-
chotics for depression included 35 studies, and no combinations included amitrip-
tyline (Wright et al. 2013).
A small study found the combination of olanzapine in average dose 6.5 mg plus
amitriptyline effectively treated melancholic depression which had failed to respond
to amitriptyline alone. The response (50% reduction in score) based on the
Montgomery-Asberg Depression Rating Scale (MADRS) occurred in 10 of 23 avail-
able patients. The combination appeared to be effective and safe; however, the study
was not a randomized trial and was of short duration (Takahashi et al. 2008).
Amitriptyline has also been combined with another antipsychotic, haloperidol (aver-
age dose 9 mg) and compared with risperidone for patients with schizoaffective
1218 M. P. Davis

disorders and depression (Muller-Siecheneder et al. 1998). The average amitriptyline

dose was 180 mg per day in 61 of 123 individuals randomized to the combination.
Responses by the Positive and Negative Syndrome Scale-derived Brief Psychiatric
Rating Scale were better with the combination (51%) as compared with risperidone
alone (37%). Individuals with more depression symptoms were more likely to
respond to the combination. Interestingly, extrapyramidal symptoms were not
worse with the combination (31% vs. 37%). Amitriptyline has also been combined
with haloperidol and compared with trimipramine in patients with delusional depres-
sion (Kunzel et al. 2009). The response rate was quite high for both treatment arms as
measured by the HAMD (70% for the combination and 84.8% for trimipramine).
Remissions were equivalent at 45.8% versus 54.5%. There appears to be no advan-
tage to the combination. A systematic review of treatment for psychotic depression
found three trials involving amitriptyline (Wijkstra et al. 2015). Amitriptyline
was equally effective as perphenazine (RR 2.09, 95%CI 0.64–6.82) for response
(RR 1.79, 95% CI 0.18–18.02) for dropouts. The combination of amitriptyline plus
perphenazine was superior to perphenazine alone (RR 3.61, 95%CI 1.23–10.56)
with no difference in dropouts. The wide confidence intervals reflect the small trial
sizes.
Lithium has been used to augment tricyclic antidepressant efficacy. In an open-
label study involving elderly patients with depression not responding to tricyclic
antidepressants, lithium improved depression, whereas a switch to a monoamine
oxidase inhibitor did not. The combination of a tricyclic antidepressant and lithium
was associated with increased tremors (Kok et al. 2007). A second study compared
lithium augmentation in patients on paroxetine or amitriptyline. The paroxetine
augmented patient had a better response than those on amitriptyline (Bauer and
Dopfmer 1999).
A systematic review surveyed trials of combinations of antidepressants as an
ischial therapy for depression. Only five randomized trials were found in the
literature review (Rocha et al. 2012). Tricyclic antidepressants as a drug class (trials
included nortriptyline and desipramine) plus SSRIs produced better remissions by
the HAMD (RR 8.58,95%CI 1.70–43.32) and responses (RR 1.78, 95%CI
1.07–2.93) than SSRIs alone. Dropout did not increase with the combination.
There were no trials which compared amitriptyline plus SSRIs to SSRIs alone as
initial treatment for major depression.

References
Achar E, Achar RA, Paiva TB, Campos AH, Schor N. Amitriptyline eliminates calculi through
urinary tract smooth muscle relaxation. Kidney Int. 2003;64:1356–64.
Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co-occurring
depression and alcohol dependence. Cochrane Database Syst Rev. 2018;4:CD008581.
Alcocer-Gomez E, De Miguel M, Casas-Barquero N, Nunez-Vasco J, Sanchez-Alcazar JA,
Fernandez-Rodriguez A, Cordero MD. NLRP3 inflammasome is activated in mononuclear
blood cells from patients with major depressive disorder. Brain Behav Immun. 2014;36:111–7.
Amitriptyline and Depressions 1219

Alcocer-Gomez E, Casas-Barquero N, Williams MR, Romero-Guillena SL, Canadas-Lozano D,

Bullon P, Sanchez-Alcazar JA, Navarro-Pando JM, Cordero MD. Antidepressants induce
autophagy dependent-NLRP3-inflammasome inhibition in Major depressive disorder.
Pharmacol Res. 2017;121:114–21.
Atkin T, Comai S, Gobbi G. Drugs for insomnia beyond benzodiazepines: pharmacology, clinical
applications, and discovery. Pharmacol Rev. 2018;70:197–245.
Barbui C, Guaiana G, Hotopf M. Amitriptyline for inpatients and SSRIs for outpatients with
depression? Systematic review and meta-regression analysis. Pharmacopsychiatry. 2004;37:93–7.
Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of
placebo-controlled studies. J Clin Psychopharmacol. 1999;19:427–34.
Baumann P. New aspects in research on blood levels and bioavailability of antidepressants.
Psychopathology. 1986;19(Suppl 2):79–84.
Baumann P, Jonzier-Perey M, Koeb L, Le PK, Tinguely D, Schopf J. Amitriptyline pharmacoki-
netics and clinical response: I. Free and total plasma amitriptyline and nortriptyline. Int Clin
Psychopharmacol. 1986;1:89–101.
Berard A, Zhao JP, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital
malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec
Pregnancy Cohort. BMJ Open. 2017;7:e013372.
Berman RM, Fava M, Thase ME, Trivedi MH, Swanink R, Mcquade RD, Carson WH, Adson D,
Taylor L, Hazel J, Marcus RN. Aripiprazole augmentation in major depressive disorder: a
double-blind, placebo-controlled study in patients with inadequate response to antidepressants.
CNS Spectr. 2009;14:197–206.
Berry-Bibee EN, Kim MJ, Simmons KB, Tepper NK, Riley HE, Pagano HP, Curtis
KM. Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic
review. Contraception. 2016;94:650–67.
Bighelli I, Castellazzi M, Cipriani A, Girlanda F, Guaiana G, Koesters M, Turrini G, Furukawa TA,
Barbui C. Antidepressants versus placebo for panic disorder in adults. Cochrane Database Syst
Rev. 2018;4:CD010676.
Botney M, Fields HL. Amitriptyline potentiates morphine analgesia by a direct action on the central
nervous system. Ann Neurol. 1983;13:160–4.
Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disor-
der: a double-blind, placebo-controlled study. J Clin Psychiatry. 2005;66:1321–5.
Bryant SG, Fisher S, Kluge RM. Long-term versus short-term amitriptyline side effects as measured
by a postmarketing surveillance system. J Clin Psychopharmacol. 1987;7:78–82.
Burch R. Antidepressants for preventive treatment of migraine. Curr Treat Options Neurol.
2019;21:18.
Chang M, Tybring G, Dahl ML, Lindh JD. Impact of cytochrome P450 2C19 polymorphisms on
citalopram/escitalopram exposure: a systematic review and meta-analysis. Clin Pharmacokinet.
2014;53:801–11.
Chen LW, Chen MY, Lian ZP, Lin HS, Chien CC, Yin HL, Chu YH, Chen KY. Amitriptyline and
sexual function: a systematic review updated for sexual health practice. Am J Mens Health.
2018;12:370–9.
Chen TY, Tzeng NS, Tai YM. Amitriptyline-induced acute kidney injury and acute hepatitis: a case
report. Am J Ther. 2019;0:1–2.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG,
Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A,
Ioannidis JPA, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for
the acute treatment of adults with major depressive disorder: a systematic review and network
meta-analysis. Lancet. 2018;391:1357–66.
Coudore F, Fialip J, Eschalier A, Lavarenne J. Plasma and brain pharmacokinetics of amitriptyline
and its demethylated and hydroxylated metabolites after acute intraperitoneal injection in mice.
Eur J Drug Metab Pharmacokinet. 1994;19:5–11.
Dandjinou M, Sheehy O, Berard A. Antidepressant use during pregnancy and the risk of gestational
diabetes mellitus: a nested case-control study. BMJ Open. 2019;9:e025908.
1220 M. P. Davis

Dean L. Amitriptyline therapy and CYP2D6 and CYP2C19 Genotype. In: Pratt V, McLeod H,
Rubinstein W, Dean L, Malheiro A, editors. Medical genetics summaries [Internet]. Bethesda:
National Center for Biotechnology Information (US); 2017; 2012-.2017 Mar 23.
Drugs for chronic insomnia. Med Lett Drugs Ther. 2018;60:201–205.
Eshun-Wilson I, Siegfried N, Akena DH, Stein DJ, Obuku EA, Joska JA. Antidepressants for
depression in adults with HIV infection. Cochrane Database Syst Rev. 2018;1:CD008525.
Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia AL, Manson CC, Wilson
S. Antidepressants for insomnia in adults. Cochrane Database Syst Rev. 2018;5:CD010753.
Franke L, Schewe HJ, Uebelhack R, Muller-Oerlinghausen B. Predictors of therapeutic effects in
amitriptyline treatment – 1. Plasma drug levels. Pharmacopsychiatry. 2003;36:134–42.
Furlanut M, Benetello P. The pharmacokinetics of tricyclic antidepressant drugs in the elderly.
Pharmacol Res. 1990;22:15–25.
Furukawa T, McGuire H Barbui C. Low dosage tricyclic antidepressants for depression. Cochrane
Database Syst Rev. 2003;(3):CD003197.
Gassen NC, Hartmann J, Zschocke J, Stepan J, Hafner K, Zellner A, Kirmeier T,
Kollmannsberger L, Wagner KV, Dedic N, Balsevich G, Deussing JM, Kloiber S, Lucae S,
Holsboer F, Eder M, Uhr M, Ising M, Schmidt MV, Rein T. Association of FKBP51 with
priming of autophagy pathways and mediation of antidepressant treatment response: evidence in
cells, mice, and humans. PLoS Med. 2014;11:e1001755.
Gassen NC, Hartmann J, Schmidt MV, Rein T. FKBP5/FKBP51 enhances autophagy to synergize
with antidepressant action. Autophagy. 2015;11:578–80.
Giros B, El Mestikawy S, Godinot N, Zheng K, Han H, Yang-Feng T, Caron MG. Cloning,
pharmacological characterization, and chromosome assignment of the human dopamine trans-
porter. Mol Pharmacol. 1992;42:383–90.
Gisev N, Nielsen S, Campbell G, Santo T, Mant A, Bruno R, Cohen M, Hall WD, Larance B,
Lintzeris N, Farrell M, Degenhardt L. Antidepressant use among people prescribed opioids for
chronic noncancer pain. Pain Med. 2019;20:2450–8.
Gomolin IH, Melmed CA. Prolonged delirium without anticholinergic signs following amitriptyline
overdose. Can Med Assoc J. 1983;129:1203–4.
Guaiana G, Barbui C, Hotopf M. Amitriptyline for depression. Cochrane Database Syst Rev.
2007;18:CD004186.
Gulbins A, Grassme H, Hoehn R, Kohnen M, Edwards MJ, Kornhuber J, Gulbins E. Role of Janus-
kinases in major depressive disorder. Neurosignals. 2016;24:71–80.
Gupta SK, Shah JC, Hwang SS. Pharmacokinetic and pharmacodynamic characterization of OROS
and immediate-release amitriptyline. Br J Clin Pharmacol. 1999;48:71–8.
Haviv Y, Zini A, Sharav Y, Almoznino G, Benoliel R. Nortriptyline compared to amitriptyline for
the treatment of persistent masticatory myofascial pain. J Oral Facial Pain Headache.
2019;33:7–13.
Hazell P, Mirzaie M. Tricyclic drugs for depression in children and adolescents. Cochrane Database
Syst Rev. 2013;CD002317.
Hefner G, Hahn M, Hohner M, Roll SC, Klimke A, Hiemke C. QTc time correlates
with amitriptyline and venlafaxine serum levels in elderly psychiatric inpatients.
Pharmacopsychiatry. 2018;52:38–43.
Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G,
Egberts K, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, Hefner G,
Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T, Mossner R, Muller MJ, Paulzen M,
Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS,
Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G,
Zurek G, Baumann P. Consensus guidelines for therapeutic drug monitoring in neuropsycho-
pharmacology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Jick H, et al. Adverse reactions to the tricyclic-antidepressant drugs. Report from Boston Collab-
orative Drug Surveillance Program. Lancet. 1972;1:529–31.
Katzman MA, Vermani M, Jacobs L, Marcus M, Kong B, Lessard S, Galarraga W, Struzik L,
Gendron A. Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting
Amitriptyline and Depressions 1221

generalized anxiety disorder: a flexible-dose, open-label pilot trial. J Anxiety Disord.

2008;22:1480–6.
Kok RM, Vink D, Heeren TJ, Nolen WA. Lithium augmentation compared with phenelzine in
treatment-resistant depression in the elderly: an open, randomized, controlled trial. J Clin
Psychiatry. 2007;68:1177–85.
Kolla BP, Mansukhani MP, Bostwick JM. The influence of antidepressants on restless legs
syndrome and periodic limb movements: a systematic review. Sleep Med Rev. 2018;38:131–40.
Koszewska I, Rybakowski JK. Antidepressant-induced mood conversions in bipolar disorder: a
retrospective study of tricyclic versus non-tricyclic antidepressant drugs. Neuropsychobiology.
2009;59:12–6.
Kozer E, Levichek Z, Hoshino N, Kapur B, Leombruno J, Taguchi N, Garcia-Bournissen F,
Koren G, Ito S. The effect of amitriptyline, gabapentin, and carbamazepine on morphine-
induced hypercarbia in rabbits. Anesth Analg. 2008;107:1216–22.
Kumar Y, Kung S, Shinozaki G. CYP2C19 variation, not citalopram dose nor serum level, is
associated with QTc prolongation. J Psychopharmacol. 2014;28:1143–8.
Kunzel HE, Ackl N, Hatzinger M, Held K, Holsboer-Trachsler E, Ising M, Kaschka W, Kasper S,
Konstantinidis A, Sonntag A, Uhr M, Yassouridis A, Holsboer F, Steiger A. Outcome in
delusional depression comparing trimipramine monotherapy with a combination of amitripty-
line and haloperidol – a double-blind multicenter trial. J Psychiatr Res. 2009;43:702–10.
Leinonen E, Lillsunde P, Laukkanen V, Ylitalo P. Effects of carbamazepine on serum antidepressant
concentrations in psychiatric patients. J Clin Psychopharmacol. 1991;11:313–8.
Leucht C, Huhn M, Leucht S. Amitriptyline versus placebo for major depressive disorder. Cochrane
Database Syst Rev. 2012;12:CD009138.
Lirk P, Haller I, Myers RR, Klimaschewski L, Kau YC, Hung YC, Gerner P. Mitigation of direct
neurotoxic effects of lidocaine and amitriptyline by inhibition of p38 mitogen-activated protein
kinase in vitro and in vivo. Anesthesiology. 2006;104:1266–73.
Liu SJ, Wang RI. Increased sensitivity of the central nervous system to morphine analgesia by
amitriptyline in naive and morphine-tolerant rats. Biochem Pharmacol. 1981;30:2103–9.
Maarrawi J, Abdel Hay J, Kobaiter-Maarrawi S, Tabet P, Peyron R, Garcia-Larrea L. Randomized
double-blind controlled study of bedtime low-dose amitriptyline in chronic neck pain. Eur J
Pain. 2018;22:1180–7.
Mestres J, Seifert SA, Oprea TI. Linking pharmacology to clinical reports: cyclobenzaprine and its
possible association with serotonin syndrome. Clin Pharmacol Ther. 2011;90:662–5.
Monteleone P, Fabrazzo M. Blood levels of mianserin and amitriptyline and clinical response in
aged depressed patients. Pharmacopsychiatry. 1994;27:238–41.
Mottram P, Wilson K, Strobl J. Antidepressants for depressed elderly. Cochrane Database Syst Rev.
2006;25:CD003491.
Muller-Siecheneder F, Muller MJ, Hillert A, Szegedi A, Wetzel H, Benkert O. Risperidone versus
haloperidol and amitriptyline in the treatment of patients with a combined psychotic and
depressive syndrome. J Clin Psychopharmacol. 1998;18:111–20.
Nilges MR, Bondy ZB, Grace JA, Winsauer PJ. Opioid-enhancing antinociceptive effects of delta-
9-tetrahydrocannabinol and amitriptyline in rhesus macaques. Exp Clin Psychopharmacol. 2019
https://doi.org/10.1037/pha0000313.
Nishimura T, Maruguchi H, Nakao A, Nakayama S. Unusual complications from amitriptyline
intoxication. BMJ Case Rep 2017;2017. https://doi.org/10.1136/bcr-2017-219257.
O’brien FE, Clarke G, Dinan TG, Cryan JF, Griffin BT. Human P-glycoprotein differentially affects
antidepressant drug transport: relevance to blood-brain barrier permeability. Int J Neuropsycho-
pharmacol. 2013;16:2259–72.
Oskoui M, Pringsheim T, Billinghurst L, Potrebic S, Gersz EM, Gloss D, Holler-Managan Y,
Leininger E, Licking N, Mack K, Powers SW, Sowell M, Cristina Victorio M, Yonker M,
Zanitsch H, Hershey AD. Practice guideline update summary: pharmacologic treatment
for pediatric migraine prevention: report of the Guideline Development, Dissemination, and
Implementation Subcommittee of the American Academy of Neurology and the American
Headache Society. Headache. 2019;59:1144–57.
1222 M. P. Davis

Ostuzzi G, Matcham F, Dauchy S, Barbui C, Hotopf M. Antidepressants for the treatment of

depression in people with cancer. Cochrane Database Syst Rev. 2018;4:CD011006.
Paksu S, Duran L, Altuntas M, Zengin H, Salis O, Ozsevik SN, Albayrak H, Murat N, Guzel A,
Paksu MS. Amitriptyline overdose in emergency department of university hospital: evaluation
of 250 patients. Hum Exp Toxicol. 2014;33:980–90.
Palmer SC, Natale P, Ruospo M, Saglimbene VM, Rabindranath KS, Craig JC, Strippoli
GF. Antidepressants for treating depression in adults with end-stage kidney disease treated
with dialysis Cochrane Database Syst Rev. 2016;May 23;(5):CD004541. https://doi.org/
10.1002/14651858.CD004541.pub3.
Park SH, Wackernah RC, Stimmel GL. Serotonin syndrome: is it a reason to avoid the use of
tramadol with antidepressants? J Pharm Pract. 2014;27:71–8.
Perry PJ, Zeilmann C, Arndt S. Tricyclic antidepressant concentrations in plasma: an estimate of
their sensitivity and specificity as a predictor of response. J Clin Psychopharmacol.
1994;14:230–40.
Powers SW, Coffey CS, Chamberlin LA, Ecklund DJ, Klingner EA, Yankey JW, Korbee LL, Porter
LL, Hershey AD, Investigators C. Trial of amitriptyline, topiramate, and placebo for pediatric
migraine. N Engl J Med. 2017;376:115–24.
Preskorn SH, Mac DS. Plasma levels of amitriptyline: effect of age and sex. J Clin Psychiatry.
1985;46:276–7.
Pressman MD, Weiss LB. Experiences with Elavil: treatment of fifty-one cases of depression. Am J
Psychiatry. 1961;118:74–5.
Qureshi MH, Esper GJ, Bashir FF. When to consider prophylactic antimigraine therapy in children
with migraine. Curr Treat Options Neurol. 2019;21:15.
Rampello L, Alvano A, Chiechio S, Malaguarnera M, Raffaele R, Vecchio I, Nicoletti F. Evaluation
of the prophylactic efficacy of amitriptyline and citalopram, alone or in combination, in patients
with comorbidity of depression, migraine, and tension-type headache. Neuropsychobiology.
2004;50:322–8.
Rao ML, Deister A, Laux G, Staberock U, Hoflich G, Moller HJ. Low serum levels of tricyclic
antidepressants in amitriptyline- and doxepin-treated inpatients with depressive syndromes are
associated with nonresponse. Pharmacopsychiatry. 1996;29:97–102.
Rayner L, Price A, Evans A, Valsraj K, Hotopf M, Higginson IJ. Antidepressants for the treatment
of depression in palliative care: systematic review and meta-analysis. Palliat Med.
2011;25:36–51.
Rheker J, Winkler A, Doering BK, Rief W. Learning to experience side effects after antidepressant
intake – results from a randomized, controlled, double-blind study. Psychopharmacology.
2017;234:329–38.
Riblet N, Larson R, Watts BV, Holtzheimer P. Reevaluating the role of antidepressants in cancer-
related depression: a systematic review and meta-analysis. Gen Hosp Psychiatry.
2014;36:466–73.
Richards BL, Whittle SL, Buchbinder R. Antidepressants for pain management in rheumatoid
arthritis. Cochrane Database Syst Rev. 2011;Nov 9;(11):CD008920. https://doi.org/10.1002/
14651858.CD008920.pub2.
Rocha FL, Fuzikawa C, Riera R, Hara C. Combination of antidepressants in the treatment of major
depressive disorder: a systematic review and meta-analysis. J Clin Psychopharmacol.
2012;32:278–81.
Rocha FL, Murad MG, Stumpf BP, Hara C, Fuzikawa C. Antidepressants for depression in
Parkinson’s disease: systematic review and meta-analysis. J Psychopharmacol.
2013;27:417–23.
Rodstein M, Oei LS. Cardiovascular side effects of long-term therapy with tricyclic antidepressants
in the aged. J Am Geriatr Soc. 1979;27:231–4.
Rosenblat JD, Kakar R, Mcintyre RS. The cognitive effects of antidepressants in major depressive
disorder: a systematic review and meta-analysis of randomized clinical trials. Int J Neuropsy-
chopharmacol. 2015;19. pii: pyv082. https://doi.org/10.1136/10.1093/ijnp/pyv082
Amitriptyline and Depressions 1223

Roy D, Dawling S. Application of an individually predicted dosage of amitriptyline to the treatment

of depression. Int Clin Psychopharmacol. 1987;2:307–15.
Rudorfer MV, Potter WZ. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol.
1999;19:373–409.
Sanna MD, Ghelardini C, Galeotti N. Effect of amitriptyline treatment on neurofilament-H protein
in an experimental model of depression. Brain Res Bull. 2017;128:1–6.
Schulz P, Dick P, Blaschke TF, Hollister L. Discrepancies between pharmacokinetic studies of
amitriptyline. Clin Pharmacokinet. 1985;10:257–68.
Sennef C, Timmer CJ, Sitsen JM. Mirtazapine in combination with amitriptyline: a drug-drug
interaction study in healthy subjects. Hum Psychopharmacol. 2003;18:91–101.
Solek P, Koszla O, Mytych J, Badura J, Chelminiak Z, Cuprys M, Fraczek J, Tabecka-Lonczynska-
A, Koziorowski M. Neuronal life or death linked to depression treatment: the interplay between
drugs and their stress-related outcomes relate to single or combined drug therapies. Apoptosis.
2019;24:773–84.
Stock EM, Zeber JE, Mcneal CJ, Banchs JE, Copeland LA. Psychotropic pharmacotherapy
associated with QT prolongation among veterans with posttraumatic stress disorder. Ann
Pharmacother. 2018; https://doi.org/10.1177/1060028018769425.
Tai YH, Tsai RY, Wang YH, Cherng CH, Tao PL, Liu TM, Wong CS. Amitriptyline induces nuclear
transcription factor-kappaB-dependent glutamate transporter upregulation in chronic morphine-
infused rats. Neuroscience. 2008;153:823–31.
Takahashi H, Kamata M, Yoshida K, Higuchi H, Ishigooka J. Augmentation with olanzapine in
TCA-refractory depression with melancholic features: a consecutive case series. Hum
Psychopharmacol. 2008;23:217–20.
Tampi RR, Balderas M, Carter KV, Tampi DJ, Moca M, Knudsen A, May J. Citalopram, QTc
prolongation, and torsades de pointes. Psychosomatics. 2015;56:36–43.
Uguz F. The use of antidepressant medications during pregnancy and the risk of neonatal seizures: a
systematic review. J Clin Psychopharmacol. 2019;39:479–84.
Ulrich S, Lauter J. Comprehensive survey of the relationship between serum concentration and
therapeutic effect of amitriptyline in depression. Clin Pharmacokinet. 2002;41:853–76.
Unterecker S, Burger R, Hohage A, Deckert J, Pfuhlmann B. Interaction of valproic acid and
amitriptyline: analysis of therapeutic drug monitoring data under naturalistic conditions. J Clin
Psychopharmacol. 2013;33:561–4.
Unterecker S, Pfuhlmann B, Kopf J, Kittel-Schneider S, Reif A, Deckert J. Increase of heart rate and
QTc by amitriptyline, but not by venlafaxine, is correlated to serum concentration. J Clin
Psychopharmacol. 2015;35:460–3.
Urquhart DM, Wluka AE, van Tulder M, Heritier S, Forbes A, Fong C, Wang Y, Sim MR, Gibson
SJ, Arnold C, Cicuttini FM. Efficacy of low-dose amitriptyline for chronic low back pain: a
randomized clinical trial. JAMA Intern Med. 2018;178:1474–81.
Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJ. Milnacipran: a comparative
analysis of human monoamine uptake and transporter binding affinity. Biol Psychiatry.
2004;55:320–2.
von Moltke LL, Greenblatt DJ, Shader RI. Clinical pharmacokinetics of antidepressants in the
elderly. Therapeutic implications. Clin Pharmacokinet. 1993;24:141–60.
Wijkstra J, Lijmer J, Burger H, Cipriani A, Geddes J, Nolen WA. Pharmacological treatment for
psychotic depression. Cochrane Database Syst Rev. 2015;30:CD004044.
Wright BM, Eiland EH 3rd, Lorenz R. Augmentation with atypical antipsychotics for depression: a
review of evidence-based support from the medical literature. Pharmacotherapy.
2013;33:344–59.
Amoxapine and Depressions

Dan Rujescu, Stephan Röttig, and Tim Johannes Krause

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226
Indications (of Marketed Products) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226
Side Effects/Adverse Reactions and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1231
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1231
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1232

Abstract
Amoxapine is a tricyclic antidepressant (TCA) and used in the treatment of major
depressive disorder. It is a norepinephrine and serotonin reuptake inhibitor. A
more rapid onset of action is discussed in comparison to other antidepressants.
There are notable, especially anticholinergic, side effects such as constipation and
paralytic ileus, urinary retention, and ECG changes. Amoxapine is potentially
lethal when overdosed.

Chemistry, Developmental History

Amoxapine is a tricyclic antidepressant belonging to the dibenzoxazepine class. It is

the N-demethylated derivative of loxapine.

D. Rujescu (*) · S. Röttig · T. J. Krause

Department of Psychiatry, Psychotherapy and Psychosomatics, Martin Luther University of Halle-
Wittenberg, Halle/Saale, Germany
e-mail: dan.rujescu@uk-halle.de; stephan.roettig@uk-halle.de; tim.krause@uk-halle.de

© Springer Nature Switzerland AG 2022 1225

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_82
1226 D. Rujescu et al.

Amoxapine was introduced in the United States in 1992; in Europe it is approved

in France only.

Pharmacology

Pharmacokinetics

The absorption of amoxapine is rapid and almost complete from the GI tract. It is
extensively metabolized by hepatic hydroxylation resulting in the active metabolites
7-hydroxyamoxapine and 8-hydroxyamoxapine. These metabolites are conjugated
to form glucuronides (Uptodate.com, 12/12/2018). The time to peak serum levels is
1.5 h. Half-life of amoxapine is 8 h and of the metabolite 8-hydroxyamoxapine 30 h
(Jue et al. 1982). It is excreted predominantly in urine as conjugated metabolites
(drugs.com, 12/12/2018).

Mechanism of Action

Amoxapine is primarily a strong reuptake inhibitor of norepinephrine and to a little

lesser degree of serotonin (Tatsumi et al. 1997). It also blocks dopamine receptors.
The metabolite 7-hydroxyamoxapine is a stronger serotonin reuptake inhibitor. A
positron emission tomography investigation analyzed dopamine D2 and serotonin 5-
HT2 receptor occupancy. The study revealed that at all doses, 5-HT2 occupancy
exceeded D2 occupancy; the profile of amoxapine was described as similar to the
one of atypical antipsychotics (Kapur et al. 1999). Besides, amoxapine is an antag-
onist at the muscarinic acetylcholine receptor M1 (drugbank.ca, 12/11/2019; Buck-
ley and McManus 1998).

Indications (of Marketed Products)

Amoxapine is approved by the US Food and Drug Administration (FDA) in patients

with neurotic or reactive depressive disorder, endogenous or psychotic depression,
and depression accompanied by anxiety or agitation. In past decades, it was also
prescribed for patients with anxiety, insomnia, and neuropathic or chronic pain
(Stahl 2017).

Clinical Studies

Already in 1978, Hekimian et al. compared the therapeutic efficacy and the onset of
action of amoxapine and amitriptyline. This double-blind study showed for a smaller
number of patients that amoxapine was as effective as amitriptyline and had an
earlier onset of action (Hekimian et al. 1978).
Amoxapine and Depressions 1227

A further comparison with amitriptyline in a double-blind trial was published in

the following year. Amoxapine-treated patients were more content concerning
efficacy in unipolar depression (Fruensgaard et al. 1979).
A first review of the literature on amoxapine was published in 1980 by Ban et al. In
ten uncontrolled clinical trials, amoxapine had antidepressant effects in doses of
100–300 mg per day. In ten published standard, and placebo and standard controlled
clinical studies, amoxapine was superior to placebo and in overall therapeutic efficacy
equals to the standard antidepressants imipramine and amitriptyline (Ban et al. 1980).
In 1982, Jue et al. reviewed the pharmacology and efficacy of amoxapine. Again,
in comparison with standard antidepressants, amoxapine was of comparable effi-
cacy. A more rapid onset of improvement of several symptoms of depressions was
discussed (Jue et al. 1982). Kinney and Evans Jr. described this result as well and
mentioned a time period of 1 or 2 weeks after initiation of therapy, but they also
pointed toward the inconsistency of the literature (Kinney and Evans Jr 1982).
In 1993, Davies et al. showed a nonsignificant efficacy advantage of amoxapine
compared with older tricyclic antidepressants (Davis et al. 1993).
Several years later, in the early 2000s, amoxapine was discussed as an atypical
antipsychotic due to its pharmacology. One double-blind trial compared amoxapine
with risperidone. Both treatments had equivalent improvement in positive, negative,
and depressive symptoms. Amoxapine was associated with less extrapyramidal
symptoms and less prolactin elevation than risperidone (Apiquian et al. 2005).
Another double-blind trial did not support the antipsychotic effectiveness of
amoxapine. The trial of Fitzgerald et al. compared amoxapine and olanzapine. In
the beginning, five patients were randomized to each study arm. None of the patients
receiving amoxapine completed the 8 weeks of the study. Four patients were
withdrawn because of a lack of efficacy and an interim analysis was performed.
Finally, the study was unblinded, and the trial stopped (Fitzgerald et al. 2004).
Another trial examined the antipsychotic effect and side effect profile of amoxapine
in comparison to haloperidol in a double-blind study in patients with schizophrenia.
Altogether, 36 patients completed the 6 weeks of follow-up. Both groups had
significant improvement in symptom scales (Chaudhry et al. 2007) (Table 1).

Side Effects/Adverse Reactions and Toxicology

Most of the side effects seem to be explained by anticholinergic activity.

Drowsiness (14%), xerostomia (14%), and constipation (12%) are considered as
the most common side effects (Uptodate.com, 14/12/2018). Paralytic ileus can be a
life-threatening consequence. Blurred vision is frequent as well. Because of the risk
of urinary retention, amoxapine should be used with caution in patients with benign
prostatic hyperplasia. Kinney and Evans Jr. described a very high rate of hypotension
(42%, Kinney and Evans Jr. 1982); this percentage was lower in following publica-
tions. Dizziness and hypotension might be caused by blockade of alpha adrenergic 1
receptors (Stahl 2017). Amoxapine might lead to pupillary dilation, which can result
in narrow-angle glaucoma (Uptodate.com, 14/12/2018).
Table 1 “Surveys review”
1228

Study (RCT, meta-

analysis, NIS; Study arms,
name/acronym, N, patients comparators, Results (scores, response/ Relevant and severe side
authors, year Country(ies) placebo remissions rates) Dropout rates effects
A comparison of 61 Amoxapine max. Same effectiveness, Loss of libido: Amoxapine
the onset of action 300 mg, amoxapine earlier onset of 8 patients, amitriptyline 3
and therapeutic amitriptyline action patients
efficacy of max. 150 mg
amoxapine and
amitriptyline;
Hekimian et al.
1978
Amoxapine versus 48 Amoxapine, HAM-D Frequency of side effects
amitriptyline in amitriptyline Nosie such as tremor and dizziness
endogenous CGI considerably lower in
depression. A Patient’s self-evaluation amoxapine group
double-blind study; HAM-D considerably
Fruensgaard et al. reduced in majority of
1979 patients
Amoxapine: a Ten reports on Amoxapine BDI Similar to reference drug
review of the uncontrolled clinical 100–300 mg, BPRS amitriptyline and imipramine
literature; Ban et al. studies placebo, CGI Various anticholinergic
1980 Ten published reports on amitriptyline, HAM-D effects, orthostatic
standard, and placebo and imipramine IMPS hypotension, changes of the
standard controlled NOSIE electrocardiogram
clinical studies Self-rating symptoms scale
ZSDS
Uncontrolled clinical
studies: Therapeutic
changes in depressive
symptoms
D. Rujescu et al.
 Standard, and placebo and
standard controlled studies
Amoxapine superior to
placebo, equal in overall
therapeutic efficacy to
amitriptyline and
imipramine
A quantitative 784 Meta-analysis of Amoxapine: 79%
analysis of clinical 19 studies responders TCA: 73%
Amoxapine and Depressions

drug trials for the responders

treatment of
affective disorders;
Davis et al. 1993
Amoxapine as an 48 Amoxapine max. PANSS F = 1.39, df 1, 9 patients
atypical 250 mg p = 0.24
antipsychotic: a Risperidone max. CDSS F = 0.74, df 1,
comparative study 5 mg p = 0.39
vs risperidone; Clinical scales
Apiquian et al. Laboratory tests
2005 Body weight F = 1.36, df
1, p = 0.25
QTc prolongation
F = 0.82, df 1, p = 0.36
Amoxapine in 10 Amoxapine PANSS 4 of 5 patients of
schizophrenia: a 150–300 mg, MADRS the amoxapine
negative double- olanzapine SAS group due to lack
blind controlled 10–20 mg BAS of efficacy
trial; Fitzgerald
et al. 2004
(continued)
1229
 1230

Table 1 (continued)
Study (RCT, meta-
analysis, NIS; Study arms,
name/acronym, N, patients comparators, Results (scores, response/ Relevant and severe side
authors, year Country(ies) placebo remissions rates) Dropout rates effects
Amoxapine as an 54 Amoxapine PANSS: Total score mean 18 of 54 No fewer extrapyramidal
antipsychotic: 150–250 mg, difference amoxapine side effects in amoxapine
comparative study haloperidol 15.74, haloperidol 13.41 group
versus haloperidol; 5–15 mg CGI
Chaudhry et al. CDSS
2007.
BAS barnes akathisia rating scale, BDI beck depression inventory, BPRS brief psychiatric rating scale, CDSS calgary depression scale for schizophrenia, CGI
clinical global impression scale, HAM-D hamilton rating scale for depression, IMPS inpatient multidimensional psychiatric rating scale, MADRS montgomery-
asberg depression rating scale, NOSIE nurses’ observation scale for inpatient evaluation, PANSS positive and negative syndrome scale, SAS simpson-angus scale
for extrapyramidal symptoms, ZSDS zung self-rating depression scale
D. Rujescu et al.
Amoxapine and Depressions 1231

QT prolongation is documented as well. Amoxapine is contraindicated in the

acute recovery period after a myocardial infarction. Hepatic insufficiency, hepatitis,
and hepatic failure are described. Weight gain is common.
Amoxapine can also cause extrapyramidal symptoms like acute dystonic reac-
tions, akathisia, pseudoparkinsonism, and tardive dyskinesia (Neuroscience based
Nomenclature, www.nbn2com, 14/12/2018). Amoxapine lowers the seizure thresh-
old; in recommended dosages, seizures are rarely seen.
In overdosage, amoxapine is toxic and potentially lethal. Amoxapine-related deaths
were reported already in 1984 (Winek et al. 1984). Toxic effects differ from other
tricyclic antidepressants (drugbank.ca, 14/12/2018). A comparative analysis of 25
antidepressants revealed the toxicity of amoxapine in overdosage (White et al. 2008).
Medical outcome differences were calculated by a hazard index. The highest hazard
index was measured for amoxapine. Even compared with other tricyclic antidepressants,
amoxapine was distinguished by high rates of cardiovascular effects including cardiac
arrest, multiple seizures and status epilepticus, renal failure, hyperventilation, respiratory
depression or arrest, acidosis, and fever or hypothermia (White et al. 2008). Renal failure
might develop 2–5 days after toxic overdose (drugbank.ca, 14/12/2018).

Combination Therapy: Interactions

Many drug interactions are known for amoxapine.

It is mainly metabolized by CYP2D6 (NbN2.com, 14/12/2018). Strong CYP2D6
inhibitors like fluoxetine and paroxetine might increase amoxapine blood levels. In
these cases, lower doses should be considered. Serum levels of tricyclic antidepres-
sants have been reported to be significantly increased when cimetidine is given
contemporaneously (Food and Drug Administration, 16/12/2018). Higher doses may
be necessary in ultrarapid metabolizers. Plasma levels should be checked whenever
another drug which is known to be an inhibitor of CYP2D6 is co-administered.
It is recommended to start other antidepressants with caution up to 2 weeks after
stopping amoxapine. It should not be used together with monoamine oxidase
inhibitors (MAOIs); allow at least 14 days to pass between discontinuing an
MAOI and initiation of amoxapine (Stahl 2017). Hyperthermia and seizures have
occurred in patients receiving tricyclic antidepressants and monoamine oxidase
inhibitors simultaneously. Since TCAs can prolong QT interval, amoxapine should
be used with caution in patients taking drugs that might induce bradycardia like beta-
blockers, digitalis, or clonidine (Stahl 2017).

Cross-References

▶ Antidepressants: Definition, Classification, Guidelines

▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry
1232 D. Rujescu et al.

References
Apiquian R, Fresan A, Ulloa RE, de la Fuente-Sandoval C, Herrera-Estrella M, Vazquez A, Nicolini
H, Kapur S. Amoxapine as an atypical antipsychotic: a comparative study vs risperidone.
Neuropsychopharmacology. 2005;30:2236–44.
Ban TA, Wilson WH, McEvoy JP. Amoxapine: a review of literature. Int Pharmacopsychiatry.
1980;15:166–70.
Buckley NA, McManus PR. Can the fatal toxicity of antidepressant drugs be predicted with
pharmacological and toxicological data? Drug Saf. 1998;18:369–81.
Chaudhry IB, Husain N, Khan S, Badshah S, Deakin B, Kapur S. Amoxapine as an antipsychotic:
comparative study versus haloperidol. J Clin Psychopharmacol. 2007;27:575–81.
Davis JM, Wang Z, Janicak PG. A quantitative analysis of clinical drug trials for the treatment of
affective disorders. Psychopharmacol Bull. 1993;29:175–81.
Drugbank.ca. https://www.drugbank.ca/drugs/DB00543. Accessed 12 Nov 2019.
Fitzgerald PB, Filia S, De Castella A, McBain N, Kapur S, Kulkarni J. Amoxapine in schizophrenia:
a negative double-blind controlled trial. J Clin Psychopharmacol. 2004;24:448–50.
Food and Drug Administration (FDA). https://www.accessdata.fda.gov/drugsatfda_docs/label/
2014/072691s036lbl.pdf. Accessed 16 Dec 2018.
Fruensgaard K, Hansen CE, Korsgaard S, Nymgaard K, Vaag UH. Amoxapine versus amitriptyline
in endogenous depression. A double-blind study. Acta Psychiatr Scand. 1979;59:502–8.
Hekimian LJ, Friedhoff AJ, Deever E. A comparison of the onset of action and therapeutic efficacy
of amoxapine and amitriptyline. J Clin Psychiatry. 1978;39:633–7.
Jue SG, Dawson GW, Brogden RN. Amoxapine: a review of its pharmacology and efficacy in
depressed states. Drugs. 1982;24:1–23.
Kapur S, Cho R, Jones C, McKay G, Zipursky RB. Is amoxapine an atypical antipsychotic?
Positron-emission tomography investigation of its dopamine2 and serotonin2 occupancy. Biol
Psychiatry. 1999;45:1217–20.
Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B,
Zaslavsky L, Zhang J, Bolton EE. PubChem 2019 update: improved access to chemical data.
Nucleic Acids Res. 2019;47(D1):D1102–9.
Kinney JL, Evans RL Jr. Evaluation of amoxapine. Clin Pharm. 1982;1:417–24.
Neuroscience based Nomenclature. http://www.nbn2.com/search#drug/6. Accessed 14 Dec 2018.
Stahl SM. Prescriber’s guide. 6th ed. Cambridge, MA: Cambridge University Press; 2017.
Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and
related compounds at human monoamine transporters. Eur J Pharmacol. 1997;11:249–58.
Uptodate.com. Accessed 14 Dec 2018.
White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by
antidepressant type. J Med Toxicol. 2008;4:238–50.
Winek CL, Wahba WW, Rozin L. Amoxapine fatalities: three case studies. Forensic Sci Int.
1984;26:33–8.
Nortriptyline and Maprotiline
for Depressions

Gerd Laux

Contents
Chemistry and Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1234
Pharmacology and Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1234
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1235
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1235
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1236
Side Effects, Adverse Reactions, and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1238
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1238

Abstract
Nortriptyline is a tricyclic antidepressant compound (TCA) methylated of the
parent amitriptyline. It is a serotonin and norepinephrine reuptake inhibitor. The
drug has a “therapeutic window,” that is, a curvilinear relationship between
therapeutic response and plasma levels.
Maprotiline is a tetracyclic compound closely related to nortriptyline
exhibiting strong effects as a norepinephrine reuptake inhibitor showing a high
degree of selectivity.
Both are released for treatment of major depressions, they are also used off-label
for the treatment of panic disorder, chronic pain/neuralgia, and neuropathic pain.
The most common side effects of nortriptyline include dry mouth, sedation,
constipation, increased appetite, blurred vision, and tinnitus. Maprotiline causes

G. Laux (*)
Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich,
Germany
e-mail: ipm@ipm-laux.de

© Springer Nature Switzerland AG 2022 1233

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_436
1234 G. Laux

Nortriptyline
Maprotiline

Fig. 1 Chemical formulas of nortriptyline and maprotiline

also anticholinergic side effects (dry mouth, constipation, confusion, tachycardia)

with a lower incidence than amitriptyline and antihistamine effects like sedation.
Contraindications for both are hypertrophy of the prostate gland with urine hesitancy,
closed angle glaucoma, serious cardiovascular conditions, and epileptic seizures.
Nortriptyline may interact with antiarrhythmics like flecainide, propafenone or
quinidine, cimetidine, guanethidine and monoamine oxidase (MAO) inhibitors,
maprotiline with anticholinergics, sympathomimetics, and antihypertensives.

Chemistry and Developmental History

Nortriptyline is a tricyclic antidepressant compound (TCA), specifically a

dibenzocycloheptadiene, a secondary amine TCA, with its N-methylated parent
amitriptyline.
Maprotiline is a tetracyclic compound very similar to that of secondary amine TCAs,
so it could also or alternatively be considered to be a TCA. Maprotiline is closely related
to other secondary amine TCAs like nortriptyline (Nelson 2017; Stahl 2017).
Nortriptyline was developed by Geigy. It first appeared in the literature and was
patented in 1962, first introduced for the treatment of depression in 1963, approved
in Europe and the United States in 1964. Generics are worldwide available.
Maprotiline was patented in 1966, first described in the literature in 1969,
introduced for medical use in 1973. Maprotiline is marketed throughout the world
mainly under the brand name Ludiomil, generics are widely available (Fig. 1).

Pharmacology and Pharmacokinetics

Nortriptyline is an active metabolite of amitriptyline by demethylation in the liver,

metabolized by the hepatic enzyme CYP2D6. Genetic variations within the gene
coding for this enzyme can affect its metabolism leading to changes in the concen-
trations of the drug (plasma level) (Pinder et al. 1977; Nelson 2017).
Nortriptyline and Maprotiline for Depressions 1235

NE-Uptake
alpha-adrenerg
histaminerg
anticholinerg

Nortriptyline Maprotiline

Fig. 2 Receptor binding profiles of nortriptyline and maprotiline

Maximal plasma concentration is reached 6–8 h after use depending from

CYP2D6 activity. The terminal half-life averages 36 h. The drug has a “therapeutic
window,” that is, a curvilinear relationship between therapeutic response and plasma
levels ranging between 125 and 200 ng/ml (Asberg et al. 1971; Perry et al. 1994).
Peak plasma concentration of maprotiline is reached 8–24 h after oral intake, and
terminal half-life is on average 51 h depending from CYP2D6 activity (Wells and
Gelenberg 1981).
The different receptor binding profiles of both substances are shown in Fig. 2
(Richelson and Nelson 1984; Tatsumi et al. 1997).

Mechanism of Action

Nortriptyline is a norepinephrine and serotonin reuptake inhibitor, which compared

to other TCAs has weaker anticholinergic effects (Cusack et al. 1994).
Maprotiline exhibits strong effects as a norepinephrine reuptake inhibitor show-
ing a high degree of selectivity (Baumann and Maitre 1979). It is also an antagonist
of the H1 receptor. The pharmacological profile of maprotiline explains its antide-
pressant, sedative, anxiolytic, and sympathomimetic activities by blocking reuptake
of norepinephrine.

Indications

Nortriptyline is released for treatment of major depressions. It is also used

off-label for the treatment of panic disorder, smoking cessation, and chronic
pain/neuralgia. Effectiveness in neuropathic pain has been shown in RCTs
(Derry and Moore 2015).
Maprotiline is used for the treatment of depressions of all forms and severities
(endogenous, psychotic, involutional, and neurotic) especially for depression asso-
ciated with agitation or anxiety. In some countries maprotiline is used off label for
treatment of panic disorder, irritable bowel syndrome, neuralgia and symptomatic
1236 G. Laux

relief of anxiety, attention deficit hyperactivity disorder (ADHD), smoking cessa-

tion, tension, or insomnia. Although not approved by the FDA for neuropathic pain,
randomized controlled trials have demonstrated the effectiveness of TCA. (Open)
clinical studies have shown effects in the treatment of somatized depressions (Kuhn
1973) and pain depression (Lindsay and Olsen 1985).

Clinical Studies

The clinical efficacy of nortriptyline in major depression is well established (Nelson

2017; Ghaemi 2019). Some authors recommend nortriptyline in the treatment of
depression in Parkinson’s disease (Seppi et al. 2011). More recently in a 12 week
RCT the relative efficacy of escitalopram was superior to nortriptyline (Power et al.
2012). Only a few studies of TCAs are available for elderly depressed patients
(Mulsant et al. 2014), and nortriptyline was effective in acute and continuation
treatment recommended as the tricyclic-of-first-choice in treatment of elderly
patients with major depression (McCue 1992). Georgotas et al. (1986) reported
after 5 week treatment a response rate of 65%, and Flint and Rifat (1996) found in
101 late life depressives after 6 weeks treatment with nortriptyline in recommended
plasma levels (50–150 ng/ml) remission in 60 to 75% of the intent-to-treat or
completers sample. Tertiary-amine TCAs should be avoided in elderly persons
according to Beers Criteria, and the secondary amine nortriptyline can be used in
some cases (Mulsant et al. 2014).
A maintenance study comparing long-term effects of interpersonal psychotherapy
with nortriptyline in recurrent major depression showed equal efficacy of both
treatments. Nortriptyline or interpersonal psychotherapy in recurrent depressions
was superior to placebo in preventing or delaying recurrence. Combined treatment
using both appears to be the optimal clinical strategy in preserving recovery
(Reynolds 1999).
A review including over 900 patients spanning 13 countries of double-blind
comparisons of maprotiline and TCAs showed no statistical significant differences
like an outpatient RCT maprotiline vs. amitriptyline (Weissman et al. 1975).
Reviews of maprotiline are given by Pinder et al. (1977) and Grüter and Pöldinger
(1982). The antidepressant effect of maprotiline was compared with that of imipra-
mine in a 4-week, double-blind, placebo-controlled study with neurotic depressives.
On all factors of the Hamilton Depression Rating Scale and on most items of the
Zung Self-Rating Scales for Depression and Anxiety, maprotiline appeared slightly
more effective than imipramine and showed a faster onset of action. In addition, it
appeared to cause fewer anticholinergic side effects (van der Velde 1981). Treating
geriatric depressions therapeutic superiority of maprotiline versus doxepin has been
reported (Gwirtsman et al. 1983).
A long-term multicenter study (130 psychiatrists including 1.141 patients)
showed relapse rates at 1 year for maprotiline 75 mg 16%, 37.5 mg 24%, for placebo
32%. In addition, the tolerance of maprotiline was satisfactory with prolonged
prescription (Rouillon et al. 1989).
Nortriptyline and Maprotiline for Depressions 1237

Side Effects, Adverse Reactions, and Toxicology

The most common side effects of nortriptyline are central and peripheral
anticholinergic effects like dry mouth, sedation, constipation, urinary hesitancy,
increased appetite, blurred vision, and tinnitus. Cardiovascular effects like ortho-
static hypotension are less pronounced compared to other TCAs; however,
quinide-like effects on cardiac conduction are possible. From a clinical point of
view the substance was well tolerated also in elderly patients (Rosen et al. 1993).
Maprotiline causes a strong initial sedation (first 2–3 weeks of therapy) and is
therefore indicated to treat agitated patients. It can cause anticholinergic side effects
(dry mouth, constipation, confusion, tachycardia) with a lower incidence than ami-
triptyline. Most often seen are antihistamine effects like sedation, dizziness, drowsi-
ness, increased appetite, and weight gain. Leukopenia and skin reactions occur more
often with maprotiline than with comparable drugs like amitriptyline. Maprotiline
caused a significant prolongation of atrioventricular and intraventricular conduction
and a rise in heart rate. Although these effects were not clinically relevant in samples of
patients without overt heart disease, they should be taken into account when treating
depressed patients with concomitant cardiac disease (Hewer et al. 1995). Under higher
doses (>200 mg/d) the risk of seizures is increased (Molnar 1993).
Nortriptyline should not be used in the acute recovery phase after myocardial
infarction, hypertrophy of the prostate gland with urine hesitancy, closed angle
glaucoma, and along with a monoamine oxidase (MAO) inhibitor.
A nortriptyline overdose is considered a medical emergency and frequently
results in death. Symptoms of overdose include irregular heartbeat, seizures, coma,
confusion, hallucination, widened pupils, drowsiness, agitation, fever, low body
temperature, stiff muscles, and vomiting.
Nortriptyline may cause problems if taken during pregnancy. Use during
breastfeeding appears to be relatively safe.
Contraindications for maprotiline are hypertrophy of the prostate gland with urine
hesitancy, closed angle glaucoma, serious cardiovascular conditions, and epilepsy.
During pregnancy it should be used only if clearly needed, and it is excreted in breast
milk corresponding closely to blood concentrations.
Overdose (>1 g) can be toxic and fatal due to cardiac arrhythmias and CNS
depression.

Combination Therapy: Interactions

Nortriptyline may interact with antiarrhythmics like flecainide, propafenone

or quinidine, cimetidine, and guanethidine as well as with anticholinergic
drugs. Alcohol may exacerbate some of its side effects. MAOIs are
contraindicated.
Maprotiline may interact with anticholinergics, sympathomimetics, antihyper-
tensives (clonidine, guanethidine), type 1a antiarrhythmics – QT prolonging agents
1238 G. Laux

(quinidine, diltiazem), CYP2D6 inhibitors, cimetidine, methylphenidate, and

MAOIs.

Cross-References

▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and

Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry
▶ Combination Therapies and Switching of Agents in Depression and Bipolar
Disorders
▶ Psychopharmacotherapy of Depressive Disorders

References
Asberg M, Cronholm B, Sjöqvist F, Tuck D. Relationship between plasma level and therapeutic
effect of nortriptyline. Br Med J. 1971;3:331–4.
Baumann PA, Maitre L. Neurobiochemical aspects of maprotiline (Ludiomil). J Int Med Res.
1979;7:391–400.
Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on
newer generation compounds. Psychopharmacology. 1994;114:559–65.
Derry SW, Moore AD. Nortriptyline for neuropathic pains in adults. Cochrane Database Syst Rev.
2015; https://doi.org/10.1002/14651858.CD011605.
Flint A, Rifat S. The effect of sequential antidepressant treatment on geriatric depression. J Affect
Disord. 1996;36:95–105.
Georgotas A, McCue RE, Hapworth W, et al. Comparative efficacy and safety of MAOIs versus
TCAs in treating depression in the elderly. Biol Psychiatry. 1986;21:1155–66.
Ghaemi NS. Clinical psychopharmacology. Oxford: Oxford University Press; 2019.
Grüter W, Pöldinger W. Maprotiline. Mod Probl Pharmacopsychiatry. 1982;18:1–30.
Gwirtsman HE, Ahles S, Halaris A, et al. Therapeutic superiority of maprotiline versus doxepin in
geriatric depression. J Clin Psychiatry. 1983;44:449–53.
Hewer W, Rost W, Gattaz F. Cardiovascular effects of fluvoxamine and maprotiline in depressed
patients. Eur Arch Psychiatry Clin Neurosci. 1995;246:1–6.
Kuhn R. Die Therapie der larvierten Depression. In: Kielholz P, editor. Die larvierte Depression.
Bern: Huber; 1973. p. 194–203.
Lindsay PG, Olsen RB. Maprotiline in pain depression. J Clin Psychiatry. 1985;46:226–8.
McCue RE. Using tricyclic antidepressants in the elderly. Clin Geriatr Med. 1992;8:323–34.
Molnar G. Seizures associated with high maprotiline serum concentrations. Can J Psychiatr.
1993;28:555–6.
Mulsant BH, Blumberger DM, Ismail Z, et al. A systematic approach to the pharmacotherapy of
geriatric major depression. Clin Geriatr Med. 2014;30:517–34.
Nelson JC. Tricyclic and tetracyclic drugs. In: Schatzberg AF, Nemeroff CB, editors. Textbook of
psychopharmacology. 5th ed. Washington, DC: American Psychiatric Publishing; 2017.
Perry PJ, Zeilmann C, Arndt S. Tricyclic antidepressant concentrations in plasma: an estimate of
their sensitivity and specificity as a predictor of response. J Clin Psychopharmacol. 1994;14:
230–40.
Nortriptyline and Maprotiline for Depressions 1239

Pinder RM, Brogden RN, Speight TM, Avery GS. Maprotiline: a review of its pharmacological
properties and therapeutic efficacy in mental depressive states. Drugs. 1977;13:321–52.
Power RA, Muthen B, Henigsberg N, et al. Non-random drop-out and the relative efficacy of
escitalopram and nortriptyline in treating major depressive disorder. Psychiatry Res. 2012;46:
1333–8.
Reynolds CF. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent
major depression. JAMA. 1999;281:39–45.
Richelson E, Nelson A. Antagonism of antidepressants of neurotransmitter receptors of normal
human brain in vitro. J Pharmacol Exp Ther. 1984;230:94–102.
Rosen J, Sweet R, Pollock BG, et al. Nortriptyline in the hospitalized elderly: tolerance and side
effect reduction. Psychopharmacol Bull. 1993;29:327–31.
Rouillon F, Serrurier PR, et al. Recurrence of unipolar depression and efficacy of maprotiline.
L'Encéphale. 1989;15:527–34.
Seppi K, Weintraub D, Coelho M, et al. The movement disorder society evidence-based medicine
review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord.
2011;26:S42–80.
Stahl S. Essential psychopharmacology. The prescriber's guide. Antidepressants. 6th
ed. Cambridge: Cambridge University Press; 2017.
Tatsumi M, GroshanK BRD, Richelson E. Pharmacological profile of antidepressants and related
compounds at human monoamine transporters. Eur J Pharmacol. 1997;340:249–58.
Van der Velde CD. Maprotiline versus imipramine and placebo in neurotic depression. J Clin
Psychiatry. 1981;42:138–41.
Weissman MM, Lieb J, Prusoff B, Bothwell S. A double-blind trial of maprotiline (Ludiomil) and
amitriptyline in depressed outpatients. Acta Psychiatr Scand. 1975;52:225–36.
Wells BG, Gelenberg AJ. Chemistry, pharmacology, pharmacokinetics, adverse effects, and effi-
cacy of the antidepressant maprotiline hydrochloride. Pharmacotherapy. 1981;1:121–39.
Mianserine and Depressions

Frank Faltraco and Johannes Thome

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1241
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1242
Indications (of Marketed Products) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1242
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243
Side Effects/Adverse Reactions and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1246
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1246
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1246

Abstract
Mianserine is a mood-enhancing and anxiety-relieving tetracyclic antidepressant,
which enhances noradrenergic neurotransmission and interacts with serotonin
receptors.

Chemistry, Developmental History

Mianserine (2-Methyl-1,2,3,4,10,14-hexahydrodibenzol-pyrazino-1,2-azepin, Fig. 1)

was originally designed as an antiallergic drug; however, early trials suggested mood-
elevating qualities. In 1972, antidepressant-like central nervous system activity was
detected by computerized electroencephalographic studies (Itil et al. 1972).
Mianserine is a tetracyclic antidepressant and a CYP3A4 substrate. Two strate-
gies for the synthesis of mianserine exist: structure of the 7-ring through
2-benzylaniline or through methylene group.

F. Faltraco (*) · J. Thome

Department of Psychiatry and Psychotherapy, University Medical Centre Rostock, Rostock,
Germany
e-mail: frank.faltraco@med.uni-rostock.de; johannes.thome@med.uni-rostock.de

© Springer Nature Switzerland AG 2022 1241

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_100
1242 F. Faltraco and J. Thome

Fig. 1 Graph of the chemical

structure of mianserine.
(Reference: https://pubchem.
ncbi.nlm.nih.gov/compound/
Mianserin#section¼2D-
Structure, 02 Nov 2021)

The dibenzoazepine is built up via an imide-chloride from the corresponding

chloroacetanilide with phosphorus-oxychloride. The piperazine ring of the tetra-
cyclic ring system of mianserine is closed from the 1,2-diamine formed by reaction
with methylamine using oxalic-acid-diethylester and subsequent reduction of the
piperazinedione intermediate with diborane.
Synthesis of mianserine by reaction of styrene-oxide with N-methylaminoethanol,
followed by subsequent chlorination and reaction with 2-aminobenzyl-alcohol
resulting in diphenylpiperazine intermediate and ring closure with polyphosphoric
acid (Kleemann et al. 2000; Van der Burg et al. 1970).
Mianserine is formulated as mianserinehydrochlorid, which is a racemate and
physical crystalline. The solubility of mianserinehydrochlorid in water is low.

Pharmacology

Mianserine is absorbed after oral administration with peak plasma concentrations being
attained 2–3 h after ingestion. Plasma concentration increases progressively during
continued treatment, reaching possible steady state after 2 weeks. The maximum
antidepressant effect occurs after a delay within 2–4 weeks (Brogden et al. 1978).
The profile of action differs from that of tricyclic antidepressants. Mianserine
enhances noradrenergic neurotransmission by presynaptic α-adrenoceptor-blocking
activity and interacts with serotonin receptors but has no central anticholinergic
activity. It is a histamine, alpha1 and alpha2 antagonist (Brogden et al. 1978).

Indications (of Marketed Products)

Mianserine is approved for the treatment of depression and depression-associated

anxiety. It has mood-enhancing, anxiety-relieving, sedative, and sleep-promoting
effects (Brogden et al. 1978).
Mianserine is given as tablets as a single dose in the evening. Usually, the intake
is done before going to bed, because of its calming properties. Studies reported that
mianserine has antidepressive activity at dosages of 30–120 mg daily in divided
Mianserine and Depressions 1243

doses or as a single bedtime dose of 60 mg. The treatment is started gradually, and
the withdrawal should take place gradually as well to prevent withdrawal symptoms
(Brogden et al. 1978).
Mianserine should not be used in case of hypersensitivity, mania, and severe liver
disease as well as in combination with monoaminooxidase (MAO) inhibitors. It was
approved in Switzerland in 1981 and is commercially available as film-coated tablets
(Generika). The original Tolvon ® is no longer marketed.

Clinical Studies

In therapeutic dosage, mianserine has no effect on peripheral noradrenaline uptake in

the tyramine pressor test. Animal studies investigated that mianserine is less liable to
cause cardiotoxicity compared to other tricyclic drugs, e.g., amitriptyline. Studies
reported that mianserine did not produce postural hypotension or adverse cardiovas-
cular (ECG) effects. Other studies with limited numbers of patients with depressive
disorders reported that the profile of activity of mianserine differs compared to
amitriptyline, but larger sample sizes are needed for confirmation. A comparison
between mianserine and imipramine did not result in a significant difference in
therapeutic efficacy. Comparing studies with mianserine and diazepam stated that
mianserine may be useful in mixed depression anxiety syndromes; however, further
studies are needed for confirmation (Brogden et al. 1978; Wakeling 1983).
Depression has a prevalence of 24% in patients diagnosed with cancer. However,
only little knowledge about the efficacy of antidepressants in patients diagnosed with
cancer exists. van Heeringen and Zivkov (1996) reported that mianserine treatment
resulted in a significant improvement in depressive symptoms (van Heeringen and
Zivkov 1996). Depression in old age is associated with neurodegenerative changes
in the hyppocampus similar to dementia. Karlsson et al. (2000) reported that
mianserine is an effective and well-tolerated treatment for older patients with
dementia (Karlsson et al. 2000). Moreover, Mizuki et al. (1992) reported that the
negative symptoms of schizophrenia are partly improved by treatment with
mianserine (Mizuki et al. 1992) (Table 1).

Side Effects/Adverse Reactions and Toxicology

Mianserine in combination with other antidepressants or alcohol leads to an increase

of undesirable effects. The most common possible adverse effects of mianserine
include weight gain, depression, edema, and elevated liver enzymes (may affect up
to 1 of 10 persons treated). Mianserine rarely can cause agranulocytosis (may affect
up to 1 of 1000 persons treated) and has not been associated with adverse cardio-
vascular effects at therapeutic doses or on overdose (Brogden et al. 1978; Haine et al.
2006; Wakeling 1983). Bonne et al. (1995) reported that mianserine resulted in
delirium in five elderly patients with depression caused by its anticholinergic activity
(Bonne et al. 1995). A case report presented delirium manifestations appearing after
 1244

Table 1 “Surveys review”

Study (RCT, meta-
analysis, NIS; name/
acronym, authors, Study arms, comparators, Results (scores, response-/ Dropout Relevant and severe side
year n, patients, country/ies placebo remissions rates) rates effects
Brogden et al. Results of open and Dosages of 30–120 mg Psychiatric symptom- Generally mild and tend to
(1978) controlled trials in patients daily in divided doses or as rating scales, particularly disappear as treatment
with depressive illness a single bedtime dose of the Hamilton Rating Scale continues, anticholinergic
60 mg for depression side effects
The majority of double-
blind studies have compared
mianserine with
amitriptyline
Wakeling (1983) Three placebo-controlled Comparison with Sedative properties and
trials and 11 double- amitriptyline, imipramine, drowsiness
blinded trials and clomipramine; daily
dosage ranged from 20 to
30 mg for mianserine and
75 to 300 mg for the
tricyclics
van Heeringen and Total 55 depressed women Hamilton Rating Scale for
Zivkov (1996) with breast cancer (stage I Depression and the
or II and without known number of responders
metastases), in a
randomized, double-blind,
6-week, placebo-
controlled study
F. Faltraco and J. Thome
Karlsson et al. Total 336 elderly, Either citalopram Montgomery-Asberg Five fatal and 12 nonfatal
(2000) depressed patients with or 20  40 mg/day or Depression Rating Scale serious adverse events
without dementia mianserine 30  60 mg/day (MADRS) total score
for 12 weeks
Mizuki et al. (1992) Twenty inpatients with Fixed doses of 60 mg/day of BPRS and plasma
schizophrenia mianserine for 2 weeks and monoamine metabolites
flexible doses for 4 weeks
were given orally in an open
study for 6 consecutive
Mianserine and Depressions

weeks, and no treatment

followed for 1 additional
week
1245
1246 F. Faltraco and J. Thome

using mianserine. The delirium manifestation vanished upon discontinuation of the

drug (Berilgen 2010).

Combination Therapy: Interactions

Mianserine should not be combined with MAO inhibitors. Blood pressure should be
monitored if antihypertensive drugs are administered simultaneously. Mianserine has
an EEG and clinical activity profile similar to that of amitriptyline. It is a substrate of
CYP3A4, and corresponding drug interactions with inducers and inhibitors are pos-
sible. Interactions with vitamin K antagonists are also described (Brogden et al. 1978).

Cross-References

▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and

Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry

References
Berilgen MS. Delirium associated with mianserine in demented patients. J Clin Psychopharmacol.
2010;30(4):467–8.
Bonne O, Shalev AY, Bloch M. Delirium associated with mianserine. Eur Neuropsychopharmacol.
1995;5(2):147–9.
Brogden RN, Heel RC, Speight TM, Avery GS. Mianserine: a review of its pharmacological
properties and therapeutic efficacy in depressive illness. Drugs. 1978;16(4):273–301.
Haine SE, Miljoen HP, Blankoff I, Vrints CJ. Mianserine and ventricular tachycardia: case report
and review of the literature. Cardiology. 2006;106(4):195–8.
Itil TM, Polvan N, Hsu W. Clinical and EEG effects of GB-94, a “tetracyclic” antidepressant (EEG
model in discovery of a new psychotropic drug). Curr Ther Res Clin Exp. 1972;14(7):395–413.
Karlsson I, Godderis J, Augusto De Mendonca Lima C, Nygaard H, Simanyi M, Taal M, et al. A
randomised, double-blind comparison of the efficacy and safety of citalopram compared to
mianserine in elderly, depressed patients with or without mild to moderate dementia. Int
J Geriatr Psychiatry. 2000;15(4):295–305.
Kleemann A, Engel J, Kutscher B, Reichert D. Pharmaceutical substances, 2 Bände. 4th
ed. Stuttgart: Thieme-Verlag; 2000. ISBN 978-1-58890-031-9
Mizuki Y, Kajimura N, Kai S, Suetsugi M, Ushijima I, Yamada M. Effects of mianserine in chronic
schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 1992;16(4):517–28.
Van der Burg WJ, Bonta IL, Delobelle J, Ramon C, Vargaftig B. Novel type of substituted
piperazine with high antiserotonin potency. J Med Chem. 1970;13:35. https://doi.org/10.1021/
jm00295a010.
van Heeringen K, Zivkov M. Pharmacological treatment of depression in cancer patients. A
placebo-controlled study of mianserine. Br J Psychiatry. 1996;169(4):440–3.
Wakeling A. Efficacy and side effects of mianserine, a tetracyclic antidepressant. Postgrad Med
J. 1983;59(690):229–31.
Trazodone and Depression

Gerd Laux

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1248
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1248
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1248
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1249
Indications (of Marketed Products) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1249
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1249
Side Effects, Adverse Reactions, and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1252
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1253
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1254
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1254

Abstract
Trazodone is a multimodal, multifunctional antidepressant working as an antag-
onist of 5-HT2A and 5-HT2B receptors, as a weak 5-HT-reuptake inhibitor and a
partial agonist of the 5-HT1A receptor, and an antagonist of the α1- and α2-
adrenergic and histamine receptors. Trazodone has shown antidepressant efficacy
and effectiveness in randomized placebo-controlled clinical studies (RCTs) and
noninterventional studies; long-term studies are missing, however. Frequently
low-dose trazodone is used off-label in the treatment of insomnia. Common side
effects include sedation, dizziness, somnolence, and orthostatic hypotension; a
relatively rare side effect associated with trazodone is priapism.

G. Laux (*)
Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich,
Germany
e-mail: ipm@ipm-laux.de

© Springer Nature Switzerland AG 2022 1247

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_111
1248 G. Laux

Fig. 1 Chemical formula of

trazodone

Chemistry, Developmental History

Trazodone is a triazolopyridine derivative and a phenylpiperazine that is chemically

related to nefazodone and etoperidone. The chemical formula of trazodone is shown
in Fig. 1.
Trazodone was developed in Italy, in the 1960s, by Angelini Research Laborato-
ries as a second-generation antidepressant. Trazodone was patented and marketed in
many countries all over the world. It was approved by the Food and Drug Admin-
istration (FDA) in 1981 and was the first nontricyclic or MAOI antidepressant
approved in the USA. It is available as a generic medication.

Pharmacology

Trazodone is the first member of the serotonin antagonist and reuptake inhibitor
(SARI) class, described as a multimodal, multifunctional antidepressant (Stahl
2009). Trazodone is an antagonist of 5-HT2A and 5-HT2B receptors, a weak
5-HT-reuptake inhibitor and a partial agonist of the 5-HT1A receptor, and an antag-
onist of the α1- and α2-adrenergic and histamine receptors (Cusack et al. 1994;
Tatsumi et al. 1997; Richelson 2002; Stahl 2009).

Pharmacokinetics

Trazodone is metabolized by several liver enzymes, including CYP3A4, CYP2D6,

and CYP1A2, with large interindividual variations in the metabolism. Trazodone has
a minor active metabolite, meta-chlorophenylpiperazine (mCPP), and this metabo-
lite may contribute to some degree to the pharmacological properties of trazodone.
The mean blood elimination half-life of trazodone is biphasic: The first phase’s half-
life is 3 to 6 hours, and the following phase’s half-life is 5 to 9 hours (Jauch et al.
1976; Stahl 2017).
Recommended therapeutic reference range (plasma levels) is 700–1000 ng/ml.
Trazodone levels were 30% lower in smokers (Hiemke et al. 2018).
Trazodone and Depression 1249

Mechanism of Action

Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its

therapeutic benefits against anxiety and depression. Sedating properties are associ-
ated with histamine-receptor antagonism; trazodone exerts no β-adrenergic receptor
antagonism. Trazodone reduces REM-latency and makes suppression of
REM-sleeps (Haria et al. 1994; Ghaemi 2019).

Indications (of Marketed Products)

Trazodone is approved, released, and marketed in several countries worldwide to

treat major depressive disorders (MDD) in adult patients.
Trazodone is characterized as a wide spectrum antidepressant, often used in
multiple clinical conditions such as insomnia, anxiety disorders, post-traumatic
stress disorder, obsessive compulsive disorder, feeding and eating disorders, sub-
stance use disorders, alcohol postwithdrawal syndrome, aggression, behavioral
disturbances associated with cognitive dysfunction, sexual dysfunction, certain
pain conditions, and tremors and rehabilitation after acute ischemic stroke (Brogden
et al. 1981). Controlled clinical trials are needed to confirm its efficacy in these
disorders (Khouzam 2017). Positive studies in generalized anxiety disorders imip-
ramine, trazodone versus placebo exist (Rickels et al. 1993).
Additionally, it is used as an augmenting agent to various psychotropic drugs
including antidepressants.
Frequently low-dose trazodone is used off-label in the treatment of insomnia.
Trazodone is usually used at a dosage of 200 to 400 mg/day for the treatment
of depression, 100 mg in the evening initially. Higher doses up to 600 mg/day
have been used in more severe cases of depression, for instance, in hospitalized
patients. Trazodone is used at doses in the range of 25 to 150 mg/day for
insomnia.

Clinical Studies

Data from open and double-blind trials suggest the antidepressant efficacy of
trazodone is comparable to that of TCAs (amitriptyline, doxepin, and imipramine),
mianserin, and SSRIs (Fagiolini et al. 2012). Three double-blind studies reported
trazodone has antidepressant efficacy similar to that of other antidepressants in
geriatric patients being helpful for severe agitation and insomnia mainly (Gerner
1987). Comparative studies in a total of 320 evaluable elderly patients with major
depression suggest that trazodone at therapeutic doses is superior to placebo and as
effective as amitriptyline, imipramine, fluoxetine, and mianserin in relieving depres-
sive symptoms (Haria et al. 1994). A survey review of important studies is given in
Table 1.
 1250

Table 1 Survey review trazodone (T) studies in MÝ

Drop out,
N patients Results discontinuation Relevant side
Study Duration Study arms, comparators, placebo Response-(R)/ Remission-Rate (RR) rates effects
Goldberg and N ¼ 184 T 150–400 mg/day T ¼A T >A
Finnerty amitriptyline (A) 75–200 mg/d T > Pl
(1980) Pl
RCT
Gershon et al. N ¼ 263 N ¼ 91 T 200–600 mg/d versus T ¼ I > Pl Pl > T > I
(1981) N ¼ 100 imipramine
RCT (I) 100–300 mg/d, versus Pl
Moises et al. N ¼ 43 T versus amitriptyline A >T
(1981) Inpatients T sedative and some anxiolytic
RCT properties, negligible antidepressant
efficacy
Kerr et al. N ¼ 74 N ¼ 25 T 150–300 mg/d versus T ¼A T N ¼ 11, T >A
(1984) Inpatients N ¼ 29 amitriptyline 75–225 mg/d AN¼9
RCT 6 weeks
Murasaki N ¼ 205 N ¼ 101 T 100–450 mg/d versus T ¼A T >A
et al. (1990) N ¼ 104 A 50–225 mg/d
RCT
Tsutsui et al. N ¼ 184 N ¼ 93 T 75–225 mg/d versus T (>) M T¼M
(1990) N ¼ 91 maprotiline
RCT (M) 30–90 mg/d
G. Laux
Beasley Jr N ¼ 126 N ¼ 61 T 100–400 mg/d versus T¼F T¼F
et al. (1991) N ¼ 65 fluoxetine (F) 20–60 mg/d
RCT
Cunningham N ¼ 225 T 300 mg/d versus venlafaxine T, V > Pl 33% V nausea, T
et al. (1994) 6 weeks (V) 160 mg/d versus Pl V better in cognitive factors and dizziness,
N ¼ 96 responders retardation, T in sleep disturbance somnolence
1 year continuation
Weisler et al. N ¼ 124 N ¼ 63 bupropion R: B 58% B anorexia,
(1994) T 46%
Trazodone and Depression

(B) 225–450 mg/d versus N ¼ 61 T T somnolence, "

RCT 150–400 mg/d appetite
v. van N ¼ 200 T 150–450 mg/day versus M>T M>T
Moffaert et al. mirtazapine (M) 24–72 mg/day
(1995)
RCT
Entsuah et al. N ¼ 304 N ¼ 185 V, V > I, T Completers V
(1996) 12 months N ¼ 62 imipra-mine (I), N ¼ 30 Relapse rates 38%, Pl 26%
Pool analysis trazodone (T), N ¼ 119 Pl V 20%, I 31%, T 29%, Pl 34%
4 RCTs
Fagiolini et al. N ¼ 324 N ¼ 166 T (Ø 311 mg/d) versus V>T T dizziness,
(2020) 8 weeks N ¼ 158 venlafaxine (V) (Ø R: T 65,4%, somnolence
RCT 84 mg/d) V 76,3% V nausea, and
RR: T 37,7%, headache
V 52,0%
Note > significantly more effective than or better as, ¼ not significantly different, Pl ¼ placebo
1251
1252 G. Laux

Treatment guidelines issued by the National Institute of Health and Clinical

Excellence (NICE), the American Psychiatric Association (APA), and the German
Association of Psychiatry, Psychotherapy and Psychosomatics (DGPPN) reflect the
viewpoint of equal efficacy of antidepressants. However, as shown in Table 1, some
studies and reviews reported higher efficacy of amitriptyline, mirtazapine, or
venlafaxine compared with trazodone. In a network meta-analysis comparing 21 anti-
depressants regarding efficacy (response rate) and acceptability (dropout rate),
trazodone was ranking place 18 regarding efficacy and acceptability (Cipriani
et al. 2018).
Studies regarding long-term prophylactic therapy for recurrent depression are
missing.
In an RCT comparing imipramine, trazodone, diazepam, and placebo in general-
ized anxiety disorders (GAD), response rates of 73% versus 69% versus 66% versus
47% have been found (Rickels et al. 1993).
Systematic reviews and meta-analyses have found trazodone to be a significantly
effective medication for insomnia, both in depressed and nondepressed individuals,
in primary as well as secondary insomnia (Jaffer et al. 2017; Yi et al. 2018). For
example, seventeen depressed patients who had insomnia while taking fluoxetine or
bupropion were given either trazodone or placebo in a double-blind crossover trial.
A total of 67% experienced overall improvement in sleep with trazodone according
to a priori criteria, whereas only 13% experienced improvement with placebo
(Nierenberg et al. 1994). However, having the widespread use in mind, a careful
review reported very limited evidence for the efficacy of trazodone in treating
insomnia and a high incidence of discontinuation due to side effects as well as
tolerance effects (Mendelson 2005).

Side Effects, Adverse Reactions, and Toxicology

Common side effects include sedation, dizziness, nausea, feeling faint, vomiting, dry
mouth, and headache. More serious side effects may include suicide, mania, irregular
heart rate (arrhythmogenic), pathologically prolonged erections, and orthostatic hypo-
tension, which may cause dizziness and increase the risk of falling, and can have
devastating consequences for elderly patients mainly. Most frequent side effects in a
recent study were dizziness (11,2%) and somnolence (8,7%) (Fagiolini et al. 2020).
A relatively rare side effect associated with trazodone is priapism, likely due to its
antagonism at α-adrenergic receptors. More than 200 cases have been reported, and
the manufacturer estimated that the incidence of any abnormal erectile function is
about one in 6000 male patients treated with trazodone. The risk for this side effect
appears to be greatest during the first month of treatment at low dosages
(i.e., <150 mg/day). Early recognition of any abnormal erectile function is impor-
tant, including prolonged or inappropriate erections, and should prompt discontin-
uation of trazodone. In females, increased libido has been reported (Abber et al.
1987; Clayton et al. 2002).
Trazodone and Depression 1253

Induction of suicidality by antidepressants is a point of frequent scientific and

medical discussion. Meta-analyses of randomized clinical trials (RCTs) indicate a
small increased risk for suicidal events in adolescents and young adults, but a
protective effect in older adults. In contrast, pharmaco-epidemiologic studies show
a protective effect across the life span (Brent 2016).
Trazodone appears to be relatively safer than TCAs, MAOIs, and a few of the
other second-generation antidepressants in overdose situations, especially when it is
the only agent taken. Fatalities are rare, and uneventful recoveries have been
reported after ingestion of doses as high as 6000–9200 mg (Buckley and McManus
2002).
A comparative analysis of suicidal antidepressant overdoses by antidepressant
type showed a very low Hazard index for trazodone (White et al. 2008).
Pregnancy, breast feeding. A multicenter prospective-controlled study to deter-
mine the safety of trazodone during pregnancy found no increased rates of major
malformations above the baseline rate of 1% to 3% (Einarson et al. 2003). However,
use during first trimester is not recommended. If child becomes sedated,
breastfeeding or drug may need to be discontinued.
Contraindications are MAOIs due to the potential for serotonin syndrome.
Caution is advisable in patients with instable heart function and liver diseases.
Discontinuation symptoms. Symptoms occur within a few days from drug dis-
continuation, are mild, and last a few weeks; variations are possible, however
(Davies and Read 2019).Typical symptoms can be summarized with the acronym
FINISH: Flu-like, Insomnia, Nausea, Imbalance, Sensory disturbance,
Hyperarousal-like nightmares, vivid dreams, dizziness, and feelings of electricity
in the body (Gabriel and Sharma 2017). Data regarding frequency, intensity, and
duration vary. Frequently, intake is terminated by patients’ own decision without
symptoms.

Combination Therapy: Interactions

Trazodone should not be taken with serotonergic agents like SSRIs, tramadol,
fentanyl, dextro-methorphane, pethidine, St John’s wort, tryptophan, or 5-HTP as
the resulting drug interaction could lead to serotonin syndrome. Use with caution in
patients with history of seizures.
CYP3A4 inhibitors such as clarithromycin, erythromycin, fluvoxamine,
grapefruit juice, ketoconazole, and ritonavir may lead to increased concentrations
of trazodone, CYP3A4 inducers like carbamazepine, phenytoin, and St. John’s
wort may result in decreased trazodone concentrations. CYP2D6 inhibitors
(bupropion, cannabidiol, and metoclopramide) may result in increased concen-
trations of both trazodone and mCPP. CYP1A2 inhibitors (ciprofloxacin) may
increase trazodone concentrations while CYP1A2 inducers (rifampin, ritonavir,
and tobacco) may decrease trazodone concentrations (Fagiolini et al. 2012; Stahl
2017; Ghaemi 2019).
1254 G. Laux

Cross-References

▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and

Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry
▶ Combination Therapies and Switching of Agents in Depression and Bipolar
Disorders
▶ Psychopharmacotherapy of Depressive Disorders

References
Abber JC, Lue TF, Luo JA, Juenemann KP, Tanagho EA. Priapism induced by chlorpromazine and
trazodone: mechanism of action. J Urol. 1987;137:1039–42.
Beasley CM Jr, Dornseif BE, Pultz JA, Bosomworth JC, Sayler ME. Fluoxetine versus trazodone:
efficacy and activating-sedating effects. J Clin Psychiatry. 1991;52:294–9.
Brent DA. Antidepressants and suicidality. Psychiatr Clin North Am. 2016;39:503–12.
Brogden RN, Heel RC, Speight TM, Avery GS. Trazodone: a review of its pharmacological
properties and therapeutic use in depression and anxiety. Drugs. 1981;21:401–29. https://doi.
org/10.2165/00003495-198121060-00001.
Buckley NA, McManus PR. Fatal toxicity of serotonergic and other antidepressant drugs: analysis
of United Kingdom mortality data. Br Med J. 2002;325:1332–3.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, et al. Comparative efficacy and acceptability of
21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a
systematic review and network meta-analysis. Lancet. 2018;391:1357–66.
Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antide-
pressants. J Clin Psychiatry. 2002;63:357–66.
Cunningham LA, Borison RL, Carman JS, Chouinard G, et al. A comparison of venlafaxine,
trazodone, and placebo in major depression. J Clin Psychopharmacol. 1994;14:99–106.
Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on
newer generation compounds. Psychopharmacology. 1994;114:559–65.
Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant
withdrawal effects: are guidelines evidence-based? Addict Behav. 2019;97:111–21.
Einarson A, Bonari L, Voyer-Lavigne S, et al. A multicentre prospective controlled study to
determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatr.
2003;48:106–10.
Entsuah AR, Rudolph RI, Hackett D et al. Efficacy of venlafaxine and placebo during long-term
treatment of depression: a pooled analysis of relapse rates. Int Clin Psychopharmacol.
1996;11:137–145.
Fagiolini A, Comandini A, Catena Dell’Osso M, Kasper S. Rediscovering trazodone for the
treatment of major depressive disorder. CNS Drugs. 2012;26:1033–49.
Fagiolini A, Albert U, Ferrando L, Herman E, et al. A randomized, double-blind study comparing
the efficacy and safety of trazodone once-a-day and venlafaxine extended-release for the
treatment of patients with major depressive disorder. Int Clin Psychopharmacol. 2020;35:
137–46. https://doi.org/10.1097/YIC.0000000000000304.
Gabriel M, Sharma V. Antidepressant discontinuation syndrome. CMAJ. 2017;189:E747. https://
doi.org/10.1503/cmaj.160991.
Gerner RH. Geriatric depression and treatment with trazodone. Psychopathology. 1987;20:82–91.
Trazodone and Depression 1255

Gershon S, Mann J, Newton R, Gunther BJ. Evaluation of trazodone in the treatment of endogenous
depression: results of a multicenter double-blind study. J Clin Psychopharmacol. 1981;Suppl 6:
39–44.
Ghaemi NS. Clinical psychopharmacology. Oxford, 2019.
Goldberg HL, Finnerty RJ. Trazodone in the treatment of neurotic depression. J Clin Psychiatry.
1980;41:430–4.
Haria M, Fitton A, Trazodone MTD. A review of its pharmacology, therapeutic use in depression
and therapeutic potential in other disorders. Drugs Aging. 1994;4:331–55.
Hiemke C, Bergemann N, Clement HW, Conca A, et al. Consensus guidelines for therapeutic drug
monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Jaffer KY, Chang T, Vanle B, et al. Trazodone for insomnia: A systematic review. Innov Clin
Neurosci. 2017;14:24–34.
Jauch R, Kopitar Z, Prox A, Zimmer A. Pharmacokinetics and metabolism of trazodone in man
(author’s transl). Arzneimittel-Forsch. 1976;26:2084–9.
Kerr TA, McClelland HA, Stephens DA, Trazodone ASI. A comparative clinical and predictive study.
Acta Psychiatr Scand. 1984;70:573–7. https://doi.org/10.1111/j.1600-0447.1984.tb01251.x.
Khouzam HR. A review of trazodone use in psychiatric and medical conditions. Postgrad Med.
2017;129:140–8.
Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia.
J Clin Psychiatry. 2005;66:469–76. https://doi.org/10.4088/jcp.v66n0409.
Moises HW, Kasper S, Beckmann H. Trazodone and amitriptyline in treatment of depressed
inpatients. A double-blind study. Pharmacopsychiatria. 1981;14:167–71. https://doi.org/10.
1055/s-2007-1019592.
Murasaki M, Kurihara M, Takahashi R, Mori A, Hasegawa K, et al. Clinical effects of trazodone
(KB-831) on depression – a double-blind comparative study using amitriptyline as a standard
drug. Rinsho Hiyoka (Jpn). 1990;18:279–313.
Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-
associated insomnia. Amer J Psychiatry. 1994;151:1069–72.
Richelson E. The clinical relevance of antidepressant interaction with neurotransmitter transporters
and receptors. Psychopharmacol Bull. 2002;36:133–50.
Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized
anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam.
Arch Gen Psychiatry. 1993;50:884–95. https://doi.org/10.1001/archpsyc.1993.
01820230054005.
Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009;14:536–46.
Stahl S. Essential psychopharmacology. The Prescriber’s guide. Antidepressants. 6th
ed. Cambridge: Cambridge University Press; 2017.
Tatsumi M, GroshanK BRD, Richelson E. Pharmacological profile of antidepressants and related
compounds at human monoamine transporters. Eur J Pharmacol. 1997;340:249–58.
Tsutsui S, Nakano K, Tsuboi K, Tahara K, Igarashi M, et al. Clinical evaluation of trazodone
hydrochloride, a new antidepressant, in the field of medicine – a double-blind controlled study
in comparison with maprotiline hydrochloride. Rinsho Iyaku (Jpn). 1990;6:1193–214.
van Moffaert M, de Wilde J, Vereecken A, Dierick M, et al. Mirtazapine is more effective than
trazodone: a double-blind controlled study in hospitalized patients with major depression. Int
Clin Psychopharmacol. 1995;10:3–9.
Weisler RH, Johnston JA, Lineberry CG, Samara B, et al. Comparison of bupropion and trazodone
for the treatment of major depression. J Clin Psychopharmacol. 1994;14:170–9.
White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by
antidepressant type. J Med Toxicol. 2008;4:238–50.
Yi XY, Ni SF, Ghadami MR, et al. Trazodone for the treatment of insomnia: a meta-analysis of
randomized placebo-controlled trials. Sleep Med. 2018;45:25–32.
Serotonin Reuptake Inhibitors: Citalopram,
Escitalopram, Fluoxetine, Fluvoxamine,
Paroxetine, and Sertraline

Gerd Laux

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1258
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1259
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1259
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1259
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1260
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1260
Side Effects, Adverse Reactions, and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1265
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1266
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1266
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1267

Abstract
Selective serotonin reuptake inhibitors (SSRIs) are the first-line antidepressants today
showing similar efficacy as nonselective monoamine reuptake inhibitors (NSMRIs,
“classical” tricyclic antidepressants) with lower side effects, however. So long, six
substances are approved and marketed – citalopram, escitalopram, fluoxetine,
fluvoxamine, paroxetine, and sertraline. Indications are major depressive disorder,
generalized anxiety disorder, panic disorder, social anxiety disorder, and obsessive-
compulsive disorder mainly. They differ regarding pharmacokinetic properties (half-
life, metabolism) mainly. Numerous randomized placebo-controlled clinical studies
(RCTs) and noninterventional studies have shown efficacy and effectiveness. Typical
side effects are nausea, troubled sleeping, and sexual dysfunction.

G. Laux (*)
Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich,
Germany
e-mail: ipm@ipm-laux.de

© Springer Nature Switzerland AG 2022 1257

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_413
1258 G. Laux

Chemistry, Developmental History

Selective serotonin reuptake inhibitors (SSRIs) have been developed and introduced
as antidepressants between 1972 and 2003. Zimelidine (INN) developed by Arvid
Carlsson was the first to be marketed; rare case reports of immunotoxic effects
(Guillain–Barré syndrome) appeared to be caused by the drug, prompting its man-
ufacturer to withdraw it from the market in 1983. After its withdrawal, it was
succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphen-
hydramine). Fluvoxamine was introduced in Switzerland in 1983, in the USA in
1994, and in Japan in 1999. Fluoxetine was discovered by Eli Lilly in 1972; in 1975,
it was given the official chemical name fluoxetine and was marketed in Belgium in
1986; Lilly began marketing it in the USA in 1988 with the trade name Prozac, a
cultural icon and symbol of blockbuster and medicalization problem. It is on the
World Health Organization’s List of Essential Medicines. Paroxetine was approved
for medical use in the United States in 1992. Citalopram was first synthesized in
1972, first marketed in 1989 in Denmark, and approved for medical use in the United
States in 1998. Lundbeck now markets the (S)-(+) enantiomer escitalopram. FDA
issued the approval of escitalopram for major depression in 2002 and for generalized
anxiety disorder in 2003. Sertraline was approved by the FDA for medical use in the
United States in 1991 (Ciraulo and Shader 2011; Ghaemi 2019).
The chemical formulas of the SSRIs available are shown in Fig. 1.

Fig. 1 Chemical formulas of SSRIs

Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine,. . . 1259

Pharmacology

Pharmacokinetics

The six SSRIs differ mainly regarding elimination half-life and liver metabolism
via cytochrome P450 isoenzymes shown in Table 1. Great genetic variability in
the function of 2D6 enzyme among people should be mentioned. Range of
therapeutic plasma levels also vary. Paroxetine is the most potent 2D6 inhibitor
(DeVane et al. 2002; Hiemke and Härtter 2000; Kaye et al. 1989, Sanchez et al.
2014).

Mechanism of Action

SSRIs share common features, increase 5-HT, and enhance serotonergic neuro-
transmission through blockade of the serotonin transporter so blocking 5-HT
reuptake. 5-HT1A and 5-HT2 receptor density among patients with depression is
normalized (Cusack et al. 1994; Richelson and Nelson 1984; Tatsumi et al.
1997).
Fluvoxamine is a potent selective serotonin reuptake inhibitor with around
100-fold affinity for the serotonin transporter. Additionally, it behaves as a
potent σ1 receptor-agonist (Wilde et al. 1993). Fluoxetine delays the reuptake
of serotonin, resulting in serotonin persisting longer when it is released;
norfluoxetine is the primary active metabolite. Fluoxetine has been shown to
inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives
ceramide from sphingomyelin (Benfield et al. 1986). Escitalopram has the
highest selectivity for the serotonin transporter (SERT) (Sanchez et al. 2014).
Paroxetine has mild anticholinergic effects and is also a relatively potent nor-
epinephrine reuptake inhibitor (Kaye et al. 1989). Sertraline also shows rela-
tively high activity as an inhibitor of the dopamine transporter (DAT) and
antagonist of the sigma σ1 receptor (DeVane et al. 2002).The unique effect of
sertraline on dopaminergic neurotransmission may be related to these effects on
cognition and vigilance.

Table 1 Summary of SSRIs pharmacokinetics

CYP450
inhibition Therapeutic plasma 5-HT uptake
t ½ (hrs) 2D6 3A4 1A2 level (ng/ml) inhibition
Citalopram 33 +

50–110 1.8
Escitalopram 30 +

15–80 1
Fluoxetine 4–6 days +++ ++ + 120–500 25
Fluvoxamine 15–22
+ +++ 60–230 6.2
Paroxetine 10–21 +++

20–65 1.1
Sertraline 26–32 +

10–150 7.3
1260 G. Laux

Indications

SSRIs have a broad spectrum of indications. They are used and in many countries
released for the treatment of major depressive disorder, anxiety disorders, such as
panic disorder, social anxiety disorder, obsessive-compulsive disorder (OCD),
bulimia nervosa, and premenstrual dysphoric disorder (PMDD). Fluoxetine is also
approved for treatment of major depressive disorder in adolescents and children (Lee
et al. 2016; Stahl 2017; Ghaemi 2019).
For subtypes of depressive disorders such as poststroke depression and postpar-
tum/postnatal depressions, SSRIs are also first-line medications (Villa et al. 2018;
Deng et al. 2018).
Efficacy in the treatment of post-traumatic stress disorder (PTSD) is also evidence
based (Ipser and Stein 2012), e.g., sertraline is approved for the treatment of PTSD.
There is evidence that paroxetine may be effective in the treatment of compulsive
gambling, and fluoxetine in impulsive aggression (Kim et al. 2002; Felthous and
Stanford 2021). Escitalopram has shown positive effects regarding cognitive func-
tions including driving ability (Montgomery and Möller 2009). Anti-inflammatory
effects of fluvoxamine are being researched for potential use in Covid-19.

Clinical Studies

Multiple RCTs proved SSRIs superior to placebo required for approval; they are as
effective as tricyclic antidepressants, but better tolerated (Undurraga and
Baldessarini 2017; Ciraulo and Shader 2011; Ghaemi 2019). Table 2 gives a
selection of RCTs between SSRIs and TCAs and within SSRIs as well as some
major noninterventional/surveillance/observational studies (NIS). In conclusion,
efficacy and effectiveness of SSRIs is established.
A review concluded that second-generation antidepressants appear equally effec-
tive, although they may differ in efficacy (response rates) and acceptance (dropout
rates) (Cipriani et al. 2018). Treatment guidelines issued by the National Institute of
Health and Clinical Excellence, the American Psychiatric Association, and the
German Association of Psychiatry, Psychotherapy and Psychosomatics reflect the
viewpoint of equal efficacy.
Efficacy of fluoxetine for acute and maintenance treatment of major depressive
disorder in adults as well as children and adolescents (8–18 years) was established in
multiple clinical trials (Rossi et al. 2004; Magni et al. 2013). Efficacy for geriatric
depression was also demonstrated in placebo-controlled trials. It seems less effective
than sertraline, mirtazapine, and venlafaxine. The efficacy in the treatment of
obsessive-compulsive disorder (OCD) was demonstrated in two randomized multi-
center phase III clinical trials. The pooled results of these trials demonstrated that
47% of completers treated with the highest dose were “much improved” or “very
much improved” after 13 weeks of treatment, compared to 11% in the placebo arm of
the trial. The efficacy in panic disorder was demonstrated in two 12-week-random-
ized multicenter phase III clinical trials that enrolled patients diagnosed with panic
Table 2 Survey review SSRIs studies in MDD
Study arms, comparators, and Results Dropout
Study N patients placebo response-/remission-rate rates Relevant side effects
Citalopram (C) 316 pts C 103, 20–60 mg/d 62%
Stahl (2000) S 106, 50–150 mg/d 57%
RCT 24 weeks Pl 107 40%
Bougerol et al. 296 in-/out-pts C 147, 40 mg/d 69%
(1997) Flu 149 20 mg/d 73%
RCT
Escitalopram (E) 1282 pts E 12,6 mg/d 55,5%
Auquier et al. (2003) C 26,4 mg/d 50,8%
Meta-analysis
4 RCTs
Moore et al. (2005) 294 pts E versus C E 76% /56% C>E C 2,8%
RCT C 61%/44% E 0,7%
Holsboer-Trachsler 5.649 pts 52% Nausea 7%
et al. (2011) Depression
NIS and anxiety
Möller et al. (2007) 11.760 pts MADRS 6,7%
NIS initial 31,8 Nausea 1,7%,
week 8 12, and 4 anxiety 0,7%,
two suicides
Fluoxetine (FLU) 65 inpts Flu 40–80 mg/d versus maprotiline Flu ¼ M Four each Flu nausea
Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine,. . .

DeJonghe et al. (M) 50–150 mg/d group M dry mouth

(1991)
RCT
Feighner and Cohn 175 older pts Flu
80 mg/d Flu 49% Flu 47% Flu agitation, insomnia,
(1985) doxepin (D) D 48% D 61% nausea
RCT
200 mg/d D sedation, and
anticholinergic symptoms
(continued)
1261
 1262

Table 2 (continued)
Study arms, comparators, and Results Dropout
Study N patients placebo response-/remission-rate rates Relevant side effects
Newhouse et al. 236 older pts Flu 20–40 mg/d Flu 71% S lower cognitive
(2000) S 50–100 mg/d S 73% symptoms
RCT
Magni et al. (2013) 171 studies Flu ¼ TCAs Flu better tolerated than
Review RCTs 24.868 pts Flu < sertraline, mirtazapine, TCAs
and venlafaxine
Fluvoxamine (F) 84 inpts F 100–300 mg/d F¼C F>C F nausea
Coleman and Block clomipramine (C) 100–300 mg/d C tremor, and
(1982) anticholinergic symptoms
RCT
Nemeroff et al. 95 pts F 124 mg/d F¼S F 31% nausea
(1995) S 137 mg/d S 35% insomnia
RCT
Paroxetine (P) 258 pts P 125, 20–30 mg/d P 60,0%
Bignamini and Ami 133, 75–150 mg/d Ami 65,4%
Rapisarda (1992)
RCT
Möller et al. (1993) 160 inpts P 84, 30 mg/d P 74,0%
RCT Ami 76, 150 mg/d Ami 87,0%
G. Laux
Ravindran et al. 953 pts P 479, 20–40 mg/d P 68,5%
(1997) 8–12 weeks Clo 474, 75–150 mg/d Clo 66,9%
RCT
Sertraline (S) 448 pts S 149, 50–200 mg/d S 61,1%
Reimherr et al. Ami 149, 50–150 mg/d Ami 70,5%
(1990) Pl 150 Pl 38,3%
RCT S ¼ Ami > Pl
Lydiard et al. (1997) 392 pts S 132, 50–200 mg/d S 55%
RCT Ami 131, 50–150 mg/d Ami 53%
Pl 129 Pl 37%
Sechter et al. (1999) 238 pts S 118, 50–150 mg/d S 74%
RCT 24 weeks Flu 120, 20–60 mg/d Flu 64%
Möller et al. (2000) 205 pts S 100, 50–100 mg/d S 66,3%
RCT Ami 105, 75–150 mg/d Ami 65,9%
Note > ¼ significantly more effective or better as, ¼ not significant different, MADRS¼ Montgomery Asberg Depression Rating Scale, Pl¼ Placebo, TCA¼
Tricyclic Antidepressants
Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine,. . .
1263
1264 G. Laux

disorder, with or without agoraphobia. A 2011 systematic review discussed seven

trials which compared fluoxetine to a placebo in the treatment of bulimia nervosa, six
of which found a statistically significant reduction in symptoms such as vomiting
and binge eating. Fluoxetine reduced low-intensity aggressive behavior in patients in
intermittent aggressive disorder and borderline personality disorder (Felthous and
Stanford 2021).
A variety of meta-analyses have been conducted to evaluate the efficacy of
paroxetine in depression; there was no clear evidence that paroxetine was better or
worse compared with other antidepressants (Purgato et al. 2014; Nevels et al.
2016). Comparative efficacy of paroxetine is equivalent to that of clomipramine
and venlafaxine in OCD (Wagstaff et al. 2002). Paroxetine was efficacious com-
pared to placebo and safe in the treatment of pathological gambling (Kim et al.
2002).
Regarding citalopram, various reviews and balances over 10 years of experi-
ence in Europe and the USA exist (Parker and Brown 2000; Keller 2000).
Comparative trials concluded that escitalopram is modestly superior to
citalopram in efficacy and tolerability (Kennedy et al. 2006; Montgomery and
Möller 2009; Pastoor and Gobburu 2014). Meta-analyses found escitalopram
more effective than paroxetine or sertraline (Sanchez et al. 2014) and superior
efficacy and tolerability after 6 months treatment with 10 to 20 mg/day compared
with other SSRIs, bupropion and serotonin-norepinephrine-selective re-uptake
inhibitors (SNRIs). The remission rate was 51,7% vs. 45,6% of the comparators,
the drop-out rate 15,9% vs. 23.9% (Favre 2012). Escitalopram appears to be
effective in treating general anxiety disorder, with relapse on escitalopram at
20% rather than placebo at 50% as well as social anxiety disorder (Baldwin et al.
2016).
Multiple controlled clinical trials established efficacy of sertraline for the treat-
ment of depression (Muijsers et al. 2002; Sheehan and Kamijima 2009). In several
double-blind studies, sertraline was consistently more effective than psychotherapy
for dysthymia (Stahl 2017). Continuing sertraline treatment helps prevent relapses of
OCD with long-term data supporting its use for up to 24 months. Frequency of
anxiety and panic attacks decreased by about 80% (vs. 45% for placebo) and resulted
in improvement of quality of life on most parameters (Hirschfeld 2000). A
Ccochrane systematic review of 59 studies concluded sertraline to be equal effective
to TCAs, maprotiline and other newer antidepressants, but lower effective than
mirtazapine. It was characterized as strong candidate as the initial choice of antide-
pressants (Cipriani et al. 2010). National Institute of Clinical Excellence recom-
mends it for patients who prefer drug treatment to a psychological one. A 2019
systematic review suggested that sertraline may be a good way to control anger,
irritability, and hostility in depressed patients and patients with other comorbidities
(Romero-Martinez et al. 2019).
It is generally accepted that the dosages necessary for the effective treatment of
OCD are higher than the usual dosage for depression. The onset of action is also
slower for OCD than for depression.
Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine,. . . 1265

Side Effects, Adverse Reactions, and Toxicology

SSRIs have much lower rates of adverse effects than TCAs (Undurraga et al. 2017;
Stahl 2017; Ghaemi 2019). Common side effects mainly include gastrointestinal
side effects such as nausea, loss of appetite, vomiting, diarrhea, and CNS effects
such as trouble sleeping, sexual problems, shakiness, feeling tired, excessive yawn-
ing, severe tinnitus, and sexual dysfunction. Rates vary depending if spontaneous
reporting or direct questioning is applied.
SSRIs are associated with a modest increase in the QTc interval although to a
lesser extent than TCAs.
Citalopram and escitalopram are associated with more dose-dependent QT inter-
val prolongation, so maximum daily doses are limited at 40 resp.20 mg for adults
and 20/10 mg for those older than 65 years or pts. with liver impairment (Beach et al.
2014).
Rare are hyponatremia and SIADH (syndrome of inappropriate antidiuretic
hormone secretion).
Serious side effects include serotonin syndrome and blood-thinning effects with
increased risk of bleeding especially when combined with anticoagulants or NSAIDs
(Andrade and Sharma 2016).
An increased risk of suicidal behavior in people under 25 years has been claimed.
Newer analyses conclude among adults a reduction in mean rating of suicidality in
patients receiving an SSRI; in young adults, SSRI treatment neither reduced nor
increased suicidality ratings relative to placebo (Brent 2016; Näslund et al. 2018).
Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most
prone to causing insomnia and agitation). It also appears to be the most prone of the
SSRIs for producing dermatologic reactions (e.g., urticaria, rash, and itchiness).
Fluvoxamine is associated with nausea and sedation mainly. Paroxetine has a higher
incidence of anticholinergic effects (e.g., dry mouth, constipation, and blurred
vision) and sedation. Sertraline has higher incidence of diarrhea and can have
activating effects.
Regarding safety of overdose, SSRIs have low-hazard indices compared to
TCAs and MAOIs (White et al. 2008). Acute overdosage is often manifested by
emesis, lethargy, ataxia, disturbances in heart rhythm, tremor, amnesia, confusion,
coma, or convulsions.
Pregnancy. Data regarding teratogenic effects of SSRIs are controversial. Risk of
treatment (first trimester fetal development, third trimester newborn delivery) must
be weighed against risk of recurrence of depression (Fischer et al. 2019). Increased
risk of pulmonary hypertension has been associated with paroxetine mainly, so it is
not recommended for use in pregnancy (Berard et al. 2017; De Vries et al. 2021). In
sum, evidence suggests a generally small risk of congenital malformations and
argues against a substantial teratogenic effect of SSRIs (Gao et al. 2018).
Contraindications are MAOIs due to the potential for serotonin syndrome.
Use of citalopram, escitalopram, fluoxetine, or sertraline is permitted for pilots
with authorization from an aviation medical examiner by Federal Aviation
1266 G. Laux

Administration, US Department of Transportation (FAA), and European Union

Aviation Safety Agency (EASA).
Discontinuation symptoms typically occur within a few days from drug discon-
tinuation, are mild, and last a few weeks; variations are possible, however (Fava et al.
2015).
Typical symptoms can be summarized with the acronym FINISH: Flu-like,
Insomnia, Nausea, Imbalance, Sensory disturbance, Hyperarousal-like night-
mares, vivid dreams, dizziness, and feelings of electricity in the body (Gabriel
and Sharma 2017). A review of 14 studies with more than 4.000 patients reported
discontinuation symptoms in 27–86% (56% on average) of patients treated with
antidepressants. Nearly half of the patients reported severe symptoms (Davies
and Read 2019). Data regarding frequency, intensity, and duration vary however.
Frequently, intake is terminated by patients’ own decision without symptoms.
Discontinuation syndrome is less likely to occur with fluoxetine due to its long
half-life.

Combination Therapy: Interactions

Concomitant use of serotonergic drugs such as triptans, tramadol, and buspiron must
be monitored, and dose must be reduced by half when strong inhibitors of CYP2D6
are coadministered. Concomitant use of aspirin, nonsteroidal anti-inflammatory
drugs (NSAIDs), and anticoagulants can result in gastrointestinal and other bleeding.
SSRIs should not be taken with St John’s wort, tryptophan, or 5-HTP as the resulting
drug interaction could lead to serotonin syndrome.
Fluvoxamine has been observed to increase serum concentrations of mirtazapine,
which is mainly metabolized by CYP1A2, CYP2D6, and CYP3A4 (Wilde et al.
1993).
Paroxetine interacts with CYP2D6CYP2B6 and reaches a steady state in 7–14 days
(Kaye et al. 1989).
Taking citalopram with omeprazole may cause higher blood levels of citalopram
(Hiemke et al. 2018).

Cross-References

▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and

Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry
▶ Combination Therapies and Switching of Agents in Depression and Bipolar
Disorders
▶ Psychopharmacotherapy of Depressive Disorders
Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine,. . . 1267

References
Andrade C, Sharma E. Serotonin reuptake inhibitors and risk of abnormal bleeding. Psychiatr Clin
North Am. 2016;39:413–26.
Auquier P, Robitail S, Llorca PM, Rive B. Comparison of escitalopram and citalopram efficacy: a
meta-analysis. Int J Psych Clin Pract. 2003;7:259–68.
Baldwin DS, Asakura S, Koyama T, Hayano T, Hagino A, Reines E, Larsen K. Efficacy of
escitalopram in the treatment of social anxiety disorder: a meta-analysis versus placebo. Eur
Neuropsychopharmacol. 2016;26:1062–9.
Beach SR, Kostis WJ, Celano CM, et al. Meta-analysis of selective serotonin reuptake inhibitor-
associated QTc prolongation. J Clin Psychiatry. 2014;75:441–9.
Benfield P, Heel RC, Lewis SP. Fluoxetine. A review of its pharmacodynamic and pharmacokinetic
properties, and therapeutic efficacy in depressive illness. Drugs. 1986;32:481–508.
Bérard A, Sheehy O, Zhao JP, Vinet É, Bernatsky S, Abrahamowicz M. SSRI and SNRI use during
pregnancy and the risk of persistent pulmonary hypertension of the newborn. Br J Clin
Pharmacol. 2017;83:1126–33.
Bignamini A, Rapisarda V. A double-blind multicenter study of paroxetine and amitriptyline in
depressed outpatients. Int Clin Psychopharmacol. 1992;6(Suppl 4):37–41.
Bougerol T, Scotto JC, Patris FM, et al. Citalopram and fluoxetine in major depression: comparison
of two clinical trials in a psychiatrist setting and in general practice. Clin Drug Invest. 1997;14:
77–89.
Brent DA. Antidepressants and suicidality. Psychiatr Clin North Am. 2016;39:503–12.
Cipriani A, La Ferla T, Furukawa TA, Signoretti A, et al. Sertraline versus other antidepressive
agents for depression. Cochrane Database Syst Rev. 2010;2:CD006117.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, et al. Comparative efficacy and acceptability of
21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a
systematic review and network meta-analysis. Lancet. 2018;391:1357–66.
Ciraulo DA, Shader RI, editors. Pharmacotherapy of depression. 2nd ed. New York: Humana Press/
Springer; 2011.
Coleman BS, Block BA. Fluvoxamine maleate, a serotonergic antidepressant: a comparison with
chlorimipramine. Prog Neuro-Psychopharmacol Biol Psychiatry. 1982;6:475–8.
Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on
newer generation compounds. Psychopharmacology. 1994;114:559–65.
Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant
withdrawal effects: are guidelines evidence-based? Addict Behav. 2019;97:111–21.
De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E. A systematic review and meta-
analysis considering the risk for congenital heart defects of antidepressant classes and individual
antidepressants. Drug Saf. 2021;44:291–312.
DeJonghe F, Swinkels J, Tuyman-Qua H. Randomized double-blind study of fluvoxamine and
maprotiline in treatment of depression. Pharmacopsychiatry. 1991;24:21–7.
Deng L, Qiu S, Yang Y, et al. Efficacy and tolerability of pharmacotherapy for post-stroke
depression: a network meta-analysis. Oncotarget. 2018;9:23718–28.
DeVane CL, Liston HL, Markowitz JS. Clinical pharmacokinetics of sertraline. Clin
Pharmacokinet. 2002;41:1247–66.
Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal symptoms after selective serotonin
reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom. 2015;84:72–81.
Favré P. Clinical efficacy and achievement of a complete remission in depression: increasing
interest in treatment with escitalopram. L’Encephale. 2012;38:86–96.
Feighner J, Cohn JB. Double-blind comparative trials of fluoxetine and doxepine in geriatric
patients with major depressive disorder. J Clin Psychiatry. 1985;46:20–5.
Felthous A, Stanford M. The pharmacotherapy of impulsive aggression in psychopathic disorders.
In: Felthous A, Sass H, editors. The Wiley international handbook on psychopathic disorders
and the law. 2nd ed. Wiley; 2021. p. 810–3.
1268 G. Laux

Fischer Fumeaux CJ, Morisod Harari M, Weisskopf E, Eap CB, Epiney M, Vial Y, Csajka C, Bickle
Graz M, Panchaud A. Risk-benefit balance assessment of SSRI antidepressant use during
pregnancy and lactation based on best available evidence – an update. Expert Opin Drug Saf.
2019;18:949–63.
Gabriel M, Sharma V. Antidepressant discontinuation syndrome. Can Med Assoc J. 2017;189:747.
Gao SY, Wu QJ, Sun C, Zhang TN, Shen ZQ, et al. Selective serotonin reuptake inhibitor use during
early pregnancy and congenital malformations: a systematic review and meta-analysis of cohort
studies of more than 9 million births. BMC Med. 2018;16:205.
Ghaemi NS. Clinical psychopharmacology. Oxford: Oxford University Press; 2019.
Hiemke C, Härtter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther.
2000;85:11–28.
Hiemke C, Bergemann N, Clement HW, Conca A, et al. Consensus guidelines for therapeutic drug
monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Hirschfeld RM. Sertraline in the treatment of anxiety disorders. Depress Anxiety. 2000;11:139–57.
Holsboer-Trachsler E, Baumann P, Höck P, et al. Escitalopram in clinical practice: results of an
observational study in patients with depression and anxiety. Psychopharmakotherapie. 2011;18:
59–65.
Ipser JC, Stein DJ. Evidence-based pharmacotherapy of post-traumatic stress disorder (PTSD). Int J
Neuropsychopharmacol. 2012;15:825–40.
Kaye CM, Haddock RE, Langley PF, Mellows G, et al. A review of the metabolism and pharma-
cokinetics of paroxetine in man. Acta Psychiatr Scand Suppl. 1989;350:60–75.
Keller MB. Citalopram therapy for depression: a review of 10 years of European experience and
data from U.S. clinical trials. J Clin Psychiatry. 2000;61:896–908.
Kennedy SH, Andersen HF, Lam RW. Efficacy of escitalopram in the treatment of major depressive
disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine
XR: a meta-analysis. J Psychiatry Neurosci. 2006;31:122–31.
Kim SW, Grant JE, Adson DE, Shin YC, Zaninelli R. A double-blind placebo-controlled study of
the efficacy and safety of paroxetine in the treatment of pathological gambling. J Clin Psychi-
atry. 2002;63:501–7.
Lee DJ, Schnitzlein CW, Wolf JP, Vythilingam M, et al. Psychotherapy versus pharmacotherapy for
posttraumatic stress disorder: systemic review and meta-analyses to determine first-line treat-
ments. Depress Anxiety. 2016;33:792–806.
Lydiard RB, Stahl SM, Hertzman M, Harrison WM. A double-blind, placebo-controlled study
comparing the effects of sertraline versus amitriptyline in the treatment of major depression. J
Clin Psychiatry. 1997;58:484–91.
Magni LR, Purgato M, Gastaldon C, Papola D, Furukawa TA, Cipriani A, Barbui C. Fluoxetine
versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev. 2013;7:
CD004185.
Möller HJ, Berzewski H, Eckmann F, Gonzalves N, Kissling W, Knorr W, Ressler P, Rudolf GA,
Steinmeyer EM, Magyar I, et al. Double-blind multicenter study of paroxetine and amitriptyline
in depressed inpatients. Pharmacopsychiatry. 1993;26:75–8.
Möller HJ, Glaser K, Leverkus F, Göbel C. Double-blind, multicenter comparative study of
sertraline versus amitriptyline in outpatients with major depression. Pharmacopsychiatry.
2000;33:206–12.
Möller HJ, Friede M, Schmauß M. Treatment of depression with escitalopram: results of a large
post-marketing surveillance study. Psychopharmakotherapie. 2007;14:149–56.
Montgomery SA, Möller HJ. Is the significant superiority of escitalopram compared with other
antidepressants clinically relevant? Int Clin Psychopharmacol. 2009;24:111–8.
Moore N, Verdoux H, Fantino B. Prospective, multicenter, randomized, double-blind study of the
efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder.
Int Clin Psychopharmacol. 2005;20:131–7.
Muijsers RB, Plosker GL, Noble S. Sertraline: a review of its use in the management of major
depressive disorder in elderly patients. Drugs Aging. 2002;19:377–92.
Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine,. . . 1269

Näslund J, Hieronymus F, Lisinski A, Nilsson S, Eriksson E. Effects of selective serotonin reuptake

inhibitors on rating-scale-assessed suicidality in adults with depression. Br J Psychiatry.
2018;212:148–54.
Nemeroff C, Ninan PT, Ballenger J, et al. Double-blind multicenter comparison of fluvoxamine
versus sertraline in the treatment of depressed outpatients. Depression. 1995;3:163–9.
Nevels RM, Gontkovsky ST, Williams BE. Paroxetine-the antidepressant from hell? Probably not,
but caution required. Psychopharmacol Bull. 2016;46:77–104.
Newhouse PA, Krishnan KR, Doraiswamy PM, Richer EM, et al. A double-blind comparison of
sertraline and fluoxetine in depressed elderly outpatients. J Clin Psychiatry. 2000;61:559–68.
Parker NG, Brown CS. Citalopram in the treatment of depression. Ann Pharmacother. 2000;34:
761–71.
Pastoor D, Gobburu J. Clinical pharmacology review of escitalopram for the treatment of depres-
sion. Expert Opin Drug Metab Toxicol. 2014;10:121–8.
Purgato M, Papola D, Gastaldon C, Trespidi C, et al. Paroxetine versus other anti-depressive agents
for depression. Cochrane Database Syst Rev. 2014;4:CD006531.
Ravindran AV, Judge R, Hunter BN, Bray J, Morton NH. A double-blind, multicenter study in
primary care comparing paroxetine and clomipramine in patients with depression and associated
anxiety. Paroxetine Study Group. J Clin Psychiatry. 1997;58:112–8.
Reimherr FW, Chouinard G, Cohn CK, Cole JO, Itil TM, LaPierre YD, Masco HL, Mendels
J. Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled,
multicenter comparison study in outpatients with major depression. J Clin Psychiatry. 1990;51
(Suppl B):18–27.
Richelson E, Nelson A. Antagonism of antidepressants of neurotransmitter receptors of normal
human brain in vitro. J Pharmacol Exp Ther. 1984;230:94–102.
Romero-Martínez Á, Murciano-Martí S, Moya-Albiol L. Is sertraline a good pharmacological
strategy to control anger? Results of a systematic review. Behav Sci (Basel). 2019;9:57.
Rossi A, Barraco A, Donda P. Fluoxetine: a review on evidence based medicine. Ann Gen Hosp
Psychiatry. 2004;3:2.
Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and
sertraline: are they all alike? Int Clin Psychopharmacol. 2014;29:185–96.
Sechter D, Troy S, Paternetti S, Boyer P. A double-blind comparison of sertraline and fluoxetine in
the treatment of major depressive episode in outpatients. Eur Psychiatry. 1999;14:41–8.
Sheehan DV, Kamijima K. An evidence-based review of the clinical use of sertraline in mood and
anxiety disorders. Int Clin Psychopharmacol. 2009;24:43–60.
Stahl SM. Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram
and sertraline. Biol Psychiatry. 2000;48:894–901.
Stahl S. Essential psychopharmacology. The prescriber’s guide. Antidepressants. 6th
ed. Cambridge: Cambridge University Press; 2017.
Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and
related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340:249–58.
Undurraga J, Baldessarini RJ. Direct comparison of tricyclic and serotonin-reuptake inhibitor
antidepressants in randomized head-to-head trials in acute major depression: systematic review
and meta-analysis. J Psychopharmacol. 2017;31:1184–9.
Villa RF, Ferrari F, Moretti A. Post-stroke depression: mechanisms and pharmacological treatment.
Pharmacol Ther. 2018;184:131–44.
Wagstaff AJ, Cheer SM, Matheson AJ, Ormrod D, Goa KL. Paroxetine: an update of its use in
psychiatric disorders in adults. Drugs. 2002;62:655–703.
White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by
antidepressant type. J Med Toxicol. 2008;4:238–50.
Wilde MI, Plosker GL, Benfield P. Fluvoxamine. An updated review of its pharmacology, and
therapeutic use in depressive illness. Drugs. 1993;46:895–924.
Bupropion and Depressions

Dan Rujescu, Stephan Röttig, and Tim Johannes Krause

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272
Indications (of Marketed Products) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272
Side Effects/Adverse Reactions and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1273
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1278
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1279
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1279

Abstract
Bupropion is a norepinephrine and dopamine reuptake inhibitor. It is indi-
cated for the treatment of major depressive disorder, for the prevention of
major depressive episodes in patients with seasonal affective disorder, and for
the treatment of nicotine addiction (Food and Drug Administration, FDA).
Positive effects on fatigue and hypersomnia have been described. Compared
to other antidepressants, it has a positive side effect profile especially
concerning the risk of weight gain, sexual dysfunction, and QT prolongation.
At higher doses, there is an increased risk of seizures. Due to its unique
pharmacology, it might be used for pharmacological augmentation of seroto-
nergic antidepressants.

D. Rujescu (*) · S. Röttig · T. J. Krause

Department of Psychiatry, Psychotherapy and Psychosomatics, Martin Luther University of Halle-
Wittenberg, Halle/Saale, Germany
e-mail: dan.rujescu@uk-halle.de; stephan.roettig@uk-halle.de; tim.krause@uk-halle.de

© Springer Nature Switzerland AG 2022 1271

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_83
1272 D. Rujescu et al.

Chemistry, Developmental History

Bupropion belongs to the class of the phenethylamines. It is a unicyclic aminoketone

unrelated to other known antidepressants.
Bupropion was invented by chemist and pharmacologist Nariman B. Mehta in
1969. The FDA approved bupropion as an antidepressant in 1985. Due to reports of
seizures, the approval was withdrawn in the following year. The relationship to
epileptic seizures was proved to be highly dose related, and the drug was introduced
again in 1989 with a lower maximum dose. Eight years later, it was FDA-approved
for the treatment of nicotine addiction and in 2006 for seasonal affective disorder.

Pharmacology

Pharmacokinetics

The absorption of bupropion is rapid. Immediate-release bupropion reaches peak

plasma levels within 2 h of oral administration. For sustained release formulations,
peak levels are measured within 3 h (https://pubchem.ncbi.nlm.nih.gov/compound/
444#section=ATC-Code, 01/12/2018). The metabolism is extensively hepatic via
the cytochrome P450 isoenzyme CYP2B6. Three metabolites have been shown to be
active. The half-life of bupropion is ranging from 12 to 30 h. The excretion is almost
90% urinary, primarily as metabolites.

Mechanism of Action

The mechanism of action is not fully understood. Bupropion blocks the norepineph-
rine and the dopamine reuptake pump. That is why it presumably increases norepi-
nephrine and dopaminergic neurotransmission (Stahl 2017).

Indications (of Marketed Products)

The indications for bupropion are the treatment of major depressive disorder, the
prevention of major depressive episodes in patients with seasonal affective disorder,
and the treatment of nicotine addiction.
Positive effects on fatigue and hypersomnia are described. In clinical practice
bupropion is also used as augmentation of serotonergic antidepressants like selective
serotonergic reuptake inhibitors (SSRIs).

Clinical Studies

Patel et al. published a systematic review and meta-analysis on the effectiveness of

bupropion as an antidepressant and analyzed 51 prior studies (Patel et al. 2016).
Bupropion was superior to placebo and of equivalent effectiveness compared to
Bupropion and Depressions 1273

other antidepressants, though some of the head-to-head antidepressant trials were

hindered by the absence of a placebo arm. A subgroup of only five studies revealed
sufficient data for a meta-analysis, and two of these were industry-sponsored.
Compared with placebo, a consistent effect was shown favoring bupropion
(Hedge’s g = 2.02, df = 4, p < 0.001, 95% confidence interval [CI] 2.93–1.11).
However, the meta-analysis exposed the heterogeneity of study findings
( p = 0.001, I2 = 79.4%, τ2 = 0.832) that is reflected in a large prediction interval
(PI 5.28 to 1.24). Additionally, both Egger’s ( p = 0.043) and Begg’s ( p = 0.027)
tests for publication bias provided significant results. Consequently, the authors
stated that the strength of evidence of this meta-analysis has to be considered with
caution (Patel et al. 2016).
In 2009 bupropion was part of a meta-analysis comparing 12 new-generation
antidepressants (Cipriani et al. 2009). One hundred and seventeen randomized
controlled trials from 1991 to 2007 were reviewed. Fourteen trials included
bupropion. Bupropion had comparable efficacy to other antidepressants. It seemed
to be better tolerated than some other compounds.
In a systematic review and network meta-analysis in 2018, the previous publica-
tion was updated and extended (Cipriani et al. 2018). Five hundred and twenty two
antidepressant randomized controlled trials comprising 116.477 participants were
reviewed, 33 trials included bupropion. Compared with placebo, bupropion had a
significantly better response rate [OR 1.58 (1.35–1.86] and was of average efficacy
compared to other antidepressants. The acceptability was similar to placebo [OR
0.96 (0.81–1.14)]. In head-to-head comparisons, bupropion had a significantly better
efficacy than reboxetine [response OR 1.65 (1.05–2.60)] and trazodone [response
OR 1.56 (1.04–2.31)], but a low quality of evidence was stated for both results. It
was also mentioned that smaller and older publications showed larger effects of the
active intervention versus placebo and bupropion and three other antidepressants
were particularly noted (Cipriani et al. 2018).
A meta-analysis of FDA reviews of second-generation antidepressants was
conducted and published in 2018 (Monden et al. 2018). Data of phase 2 and 3 trials
for 16 antidepressants including bupropion were extracted from FDA reviews. It was
considered that this approach was less liable to reporting biases. Meta-analytic Bayes
factors, quantifying the strength of evidence for efficacy, were calculated. This
comparative meta-analysis of second-generation antidepressants revealed relatively
low effect sizes and lower evidence for the efficacy of bupropion in comparison to 15
other antidepressants, with a lower effect size only calculated for vilazodone
(Monden et al. 2018) (Table 1).

Side Effects/Adverse Reactions and Toxicology

Most side effects seem to be linked to norepinephrine and dopamine. Most common
are headache, dry mouth, and transient insomnia. Increased restlessness, anxiety, and
agitation were repeatedly reported shortly after initiation of treatment. The rate of
insomnia for bupropion is higher than for placebo but similar to the rate associated
with SSRIs (Fava et al. 2005).
Table 1 “Surveys review”
1274

Study (RCT, meta-

analysis, NIS; Relevant and
name/acronym, N, patients Results (scores, response/remission Dropout severe side
authors, year Country(ies) Study arms, comparators, placebo rates) rates effects
Extended-release Bupropion 135, Extended-release bupropion Bupropion XL superior to placebo Body weight loss
bupropion for placebo 139 (bupropion XL) and placebo in reducing the IDS-IVR-30 score
patients with ( p = 0.018)
major depressive Response: IDS-IVR-30
disorder Bupropion: 53%
presenting with Placebo: 45%
symptoms of Remission: IDS-IVR-30
reduced energy, Bupropion: 41%
pleasure, and Placebo: 27%
interest: findings
from a
randomized,
double-blind,
placebo-controlled
study, Jefferson
et al. 2006
Bupropion Bupropion: 276 Bupropion 300–450 mg, escitalopram HAM-D-17
extended release Escitalopram: 281 10–20 mg, placebo Response:
compared with Placebo: 273 Bupropion: 62%
escitalopram: Escitalopram: 65%
effects on sexual Placebo: 52%
functioning and Remission:
antidepressant Bupropion: 43%
efficacy in 2 Escitalopram: 45%
randomized, Placebo: 34%
double-blind,
placebo-controlled
D. Rujescu et al.
studies, Clayton
et al. 2006
Double-blind, Bupropion: 211 Bupropion 150–300 mg, placebo Statistically significant
placebo-controlled Placebo: 207 improvement on MADRS scores
evaluation of compared with placebo ( p = 0.033)
extended-release Response:
bupropion in Bupropion: 53%
elderly patients Placebo: 43%
with major Remission:
Bupropion and Depressions

depressive Bupropion: 38%

disorder, Hewett Placebo: 33%
et al. 2010a
Double-blind, Bupropion: 204 Bupropion 150 mg, venlafaxine MADRS Dry mouth,
placebo-controlled Venlafaxine: 198 75 mg, placebo Response: insomnia,
comparison of the Placebo: 189 Bupropion: 57% hyperhidrosis
antidepressant Venlafaxine: 66%
efficacy and Placebo: 49%
tolerability of Remission:
bupropion XR and Bupropion: 45%
venlafaxine XR, Venlafaxine: 56%
Hewett et al. Placebo: 38%
2010b
The efficacy and Bupropion Bupropion 150 mg, 300 mg, and MADRS total score at week 8: Nasopharyngitis,
safety of 150 mg: 190, placebo Bupropion 150 mg 14.4, dry mouth,
bupropion bupropion 300 mg bupropion 300 mg 12.9, placebo headache
sustained-release 188, placebo 186; 13.9
formulation for the Japan and South Response:
treatment of major Korea Bupropion 150 mg: 51.6%,
depressive Bupropion 300 mg: 43.6%
disorder: A Placebo: 46.2%
multicenter, Remission:
randomized, Bupropion 150 mg: 31.6%
1275

(continued)
 1276

Table 1 (continued)
Study (RCT, meta-
analysis, NIS; Relevant and
name/acronym, N, patients Results (scores, response/remission Dropout severe side
authors, year Country(ies) Study arms, comparators, placebo rates) rates effects
double-blind, Bupropion 300 mg: 29.8%
placebo-controlled Placebo: 28.5%
study in Asian
patients, Koshino
et al. 2013
Systematic review 14,372 records Meta-analysis bupropion and placebo Hedge’s g < 0: Favoring bupropion
and meta-analysis identified by Hedge’s g > 0: Favoring placebo
Bupropion: a database Overall:
systematic review searching, five Hedge’s g = 2.02, df = 4,
and meta-analysis studies eligible for p < 0.001, CI -2.93 – 1.11
of effectiveness as inclusion in High heterogeneity of study findings
an Antidepressant meta-analysis ( p =0.001, I2 = 79.4%,
Patel et al. 2016 τ2 = 0.832), prediction interval
(PI 5.28 to 1.24).
Egger’s test p = 0.043 and Begg’s
test p = 0.027 for publication bias
D. Rujescu et al.
Comparative Review of 117 Bupropion 150–450 mg compared Efficacy (response rate) OR (95%
efficacy and randomized with new-generation antidepressants CI) 0,93 (0,77–1,11)
acceptability of 12 controlled trials Acceptability (dropout rate) OR
new-generation (25,928 (95% CI) 1,12 (0,92–1,36)
antidepressants: a participants)
multiple-
treatments meta-
analysis, Cipriani
et al. 2009
Bupropion and Depressions

Comparative Review of 522 Bupropion and placebo Efficacy (response rate) compared to
efficacy and trials comprising Bupropion and 20 antidepressants placebo (95% CrI) 1,58 (1,35–1,86)
acceptability of 21 116,477 Acceptability (dropout rate)
antidepressant participants, 33 compared to placebo (95% CrI) 0,96
drugs for the acute trials including (0,81–1,14)
treatment of adults bupropion
with major
depressive
disorder: a
systematic review
and network meta-
analysis, Cipriani
et al. 2018
HAM-D Hamilton rating scale for depression, IDS-IVR Inventory of depressive symptomatology self-reported, MADRS Montgomery-Asberg depression rating
scale
1277
1278 D. Rujescu et al.

Bupropion is contraindicated in patients with a seizure disorder. For the immedi-

ate-release formulation, the risk of seizures is slightly elevated, and it increases
considerably at higher doses. The risk of seizures is reduced by lower doses and slow
release formulations (Steinert and Fröscher 2018). Prior to the prescription, patients
should be screened for the presence of comorbidities, clinical conditions, or other
medication that might lower seizure threshold (Fava et al. 2005).
Anaphylactic reactions that are characterized by symptoms like pruritus, urticaria,
and dyspnea have been conveyed in clinical trials with bupropion (FDA 2018).
There were rare reports of erythema multiforme, Stevens-Johnson syndrome, and
anaphylactic shock associated with bupropion.
Weight gain is very unusual; weight loss is more common. A review on weight
considerations and psychotropic drugs stated that there may be modest weight loss
with bupropion (Hasnain and Vieweg 2013). This is an advantage compared to many
other antidepressants like tricyclics, but this has to be considered in underweight and
anorectic patients. Bupropion is not associated with QT prolongation in ECG. It does
not differ significantly from placebo concerning sexual dysfunction. As an advan-
tage of bupropion, it has repeatedly been associated with significantly less sexual
dysfunction than SSRIs.
Similar to other antidepressants, bupropion can lead to hypomanic or manic
episodes in patients with bipolar disorder. This risk might be lower compared with
antidepressants like venlafaxine (Post et al. 2006).
A systematic review analyzed the use of bupropion during pregnancy. Eight
studies were included. While a small elevation in the risk of cardiovascular defects
was associated with the use of bupropion in the first months of pregnancy, the
absolute risk was calculated as low. Though in one study the risk of miscarriage
was higher than that of controls, it remained within the general population rate. The
review concludes that while more studies are needed, current research suggests that
bupropion might be a reasonable treatment option for depressed pregnant women
who require pharmacotherapy (Hendrick et al. 2017). A German database recom-
mends preferring sertraline or citalopram during pregnancy (embryotox.de 2019).
Findings regarding antidepressants and the risk of suicide are controversial. In one
major study, bupropion had lower risks than several antidepressants in conventional
Cox regression models but not in marginal structural models (Valenstein et al. 2012).
An overdose with bupropion is seldom lethal. Symptoms of overdose include
seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest
(drugbank.ca 2018). In a comparative analysis by antidepressant type, bupropion
revealed the highest rate of seizures and a high rate of hallucinations with otherwise
relatively mild side effects compared to other antidepressants (White et al. 2008).

Combination Therapy: Interactions

As bupropion is metabolized by CYP2B6, plasma levels will be higher in CYP2B6

slow metabolizers which are more frequent in Asian populations (about 20%)
(NbN2.org 2018). In combination with CYP2B6 inhibitors such as fluoxetine or
Bupropion and Depressions 1279

paroxetine, a potential increase of bupropion levels has to be considered. Combined

with CYP2B6 inducers like carbamazepine or St John’s wort, decreased bupropion
levels might be expected. Furthermore, bupropion is an inhibitor of CYP2D6. This
might interfere with the clearance of other medications, and it could cause, for
example, increased plasma levels of several beta-blockers. In combination with
tramadol, the risk of seizures can be elevated.
The concomitant administration of bupropion and a monoamine oxidase inhibitor
(MAOI) is contraindicated. Allow 14 days to pass between discontinuing an MAOI
and initiation of bupropion and vice versa (FDA 16/01/2019). One major reason is
the increased risk of hypertensive reaction.
Bupropion is appropriate for combination therapy with SSRIs or SNRIs
(serotonin–norepinephrine reuptake inhibitors). Adverse drug reactions of this com-
bination therapy might increase blood pressure and tremor. In combination therapies,
the maximum dose of bupropion is 300 mg per day because of the increasing risk of
seizures.

Cross-References

▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects

▶ Antidepressants: Pharmacology and Biochemistry

References
Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa
A, Omori IM, McGuire H, Tansella M, Barbui C. Comparative efficacy and acceptability of 12
new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746–58.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG,
Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A,
Ioannidis JPA, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for
the acute treatment of adults with major depressive disorder: a systematic review and network
meta-analysis. Lancet. 2018;391:1357–66.
Clayton AH, Croft HA, Horrigan JP, Wightman DS, Krishen A, Richard NE, Modell JG. Bupropion
extended release compared with escitalopram: effects on sexual functioning and antidepressant
efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry.
2006;67:736–46.
Drugbank.ca. 2018. https://www.drugbank.ca/drugs/DB01156. Accessed 03 Dec 2018.
Embroytox.de. 2019. https://www.embryotox.de/arzneimittel/details/bupropion/. Accessed 11 Nov
2019.
Fava M, Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, Johnston JA. 15 years of clinical
experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care
Companion J Clin Psychiatry. 2005;7:106–13.
Food and Drug Administration (FDA). 2018. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2011/021515s026s027lbl.pdf. Accessed 03 Dec 2018.
Hasnain M, Vieweg WV. Weight considerations in psychotropic drug prescribing and switching.
Postgrad Med. 2013;125:117–29.
Hendrick V, Suri R, Gitlin MJ, Ortiz-Portillo E. Bupropion use during pregnancy: a systematic
review. Prim Care Companion CNS Disord. 2017;19(5) https://doi.org/10.4088/PCC.17r02160.
1280 D. Rujescu et al.

Hewett K, Chrzanowski W, Jokinen R, Felgentreff R, Shrivastava RK, Gee MD, Wightman DS,
O'Leary MC, Millen LS, Leon MC, Briggs MA, Krishen A, Modell JG. Double-blind, placebo-
controlled evaluation of extended-release bupropion in elderly patients with major depressive
disorder. J Psychopharmacol. 2010a;24:521–9.
Hewett K, Gee MD, Krishen A, Wunderlich HP, Le Clus A, Evoniuk G, Modell JG. Double-blind,
placebo-controlled comparison of the antidepressant efficacy and tolerability of bupropion XR
and venlafaxine XR. J Psychopharmacol. 2010b;24:1209–16.
Jefferson JW, Rush AJ, Nelson JC, VanMeter SA, Krishen A, Hampton KD, Wightman DS, Modell
JG. Extended-release bupropion for patients with major depressive disorder presenting with
symptoms of reduced energy, pleasure, and interest: findings from a randomized, double-blind,
placebo-controlled study. J Clin Psychiatry. 2006;67:865–73.
Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B,
Zaslavsky L, Zhang J, Bolton EE. PubChem 2019 update: improved access to chemical data.
Nucleic Acids Res. 2019;47(D1):D1102–9. https://doi.org/10.1093/nar/gky1033. [PubMed
PMID: 30371825]
Koshino Y, Bahk W, Sakai H, Kobayashi T. The efficacy and safety of bupropion sustained-release
formulation for the treatment of major depressive disorder: a multi-center, randomized, double-
blind, placebo-controlled study in Asian patients. Neuropsychiat Dis Treat. 2013;9:1273–80.
Monden R, Roest AM, van Ravenzwaaij D, Wagenmakers EJ, Morey R, Wardenaar KJ, de Jonge P.
The comparative evidence basis for the efficacy of second-generation antidepressants in the
treatment of depression in the US: a Bayesian meta-analysis of food and drug administration
reviews. J Affect Disord. 2018;235:393–8.
Neuroscience based Nomenclature. 2018. http://www.nbn2.org/search#drug/15. Accessed 03 Dec
2018.
Patel K, Allen S, Hague MN, Angelescu I, Baumeister D, Tracy DK. Bupropion: a systematic
review and meta-analysis of effectiveness as an antidepressant. Ther Adv Psychopharmacol.
2016;6:99–144.
Post RM, Altshuler LL, Leverich GS, Frye MA, Nolen WA, Kupka RW, Suppes T, McElroy S,
Keck PE, Denicoff KD, Grunze H, Walden J, Kitchen CM, Mintz J. Mood switch in bipolar
depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry.
2006;189:124–31.
Stahl SM. Prescriber’s guide. 6th ed. Cambridge, MA: Cambridge University Press; 2017.
Steinert T, Fröscher W. Epileptic seizures under antidepressive drug treatment: systematic review.
Pharmacopsychiatry. 2018;51:121–35.
Valenstein M, Kim HM, Ganoczy D, Eisenberg D, Pfeiffer PN, Downing K, Hoggatt K, Ilgen M,
Austin KL, Zivin K, Blow FC, McCarthy JF. Antidepressant agents and suicide death among US
Department of Veterans Affairs patients in depression treatment. J Clin Psychopharmacol.
2012;32:346–53.
White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by
antidepressant type. J Med Toxicol. 2008;4:238–50.
Mirtazapine and Depressions

Mellar P. Davis

Contents
Chemistry and Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282
Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284
Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284
Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284
Hepatic Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284
Pharmacodynamics: Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1286
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1286
Mirtazapine Compared with Placebo and Amitriptyline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1286
Other Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1290
Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1291
General Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1294
Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1294
Side Effects and Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1294
Drug Interactions and Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297
Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297
Drug Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1298
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1300

Abstract
Mirtazapine was introduced into the United States in 1996 as a norepinephrine
and specific serotonergic antidepressant which would have a broad spectrum of
activity and hopefully fewer side effects compared with selective serotonin
reuptake inhibitors. Mirtazapine consists of S- and R-enantiomers which are
metabolized by cytochromes CYP1A2, CYP2D6, and CYP3A4 which are then

M. P. Davis (*)
Department of Palliative Care, Geisinger Medical Center, Danville, PA, USA
e-mail: mdavis2@geisinger.edu

© Springer Nature Switzerland AG 2022 1281

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_102
1282 M. P. Davis

Fig. 1 Mirtazapine

glucuronidated. Metabolites account for only 10% of mirtazapine antidepressant

activity. Oral bioavailability is approximately 50% and half-life 20–40 h.
Mirtazapine inhibits presynaptic alpha-2 adrenergic autoreceptors, presynaptic
alpha-2 adrenergic heteroreceptors, and two postsynaptic serotonin receptors, 5
HT-2 and 5 HT-3. Mirtazapine labeled indication for treatment of outpatient
major depressive disorder. Mirtazapine responses were noted to occur within
1 week of starting therapy and differ significantly from placebo. Responses are
equivalent to amitriptyline and, in some reviews, superior to selective serotonin
reuptake inhibitors. Mirtazapine appears to be a very cost-effective antidepressant
when weighing, response, tolerance, and drug costs. Major side effects are
sedation and weight gain. Mirtazapine transiently impairs driving skills. Hypo-
natremia, sexual dysfunction, and seizure risks are lower with mirtazapine than
seen with SSRIs. There are relatively few drug-drug interactions. Mirtazapine has
been combined with SSRIs to augment SSRI antidepressant responses. It is the
most frequently used antidepressant by survey used to treat depression in cancer.

Chemistry and Developmental History

Mirtazapine [(R, S) 1,2,3,4,10,14b-hexahydro-2-methylpyrazino(2,1-a) pyrido (2,3-

c) benzazepine] is a dual function norepinephrine and specific serotonergic antide-
pressant (Fig. 1). It was initially developed in the Netherlands and then introduced
into the United States in 1996. The patent expired in 2004 and generic versions are
now available. Mirtazapine was developed to give a broader spectrum of action than
selective serotonin reuptake inhibitors (SSRIs) with reduced side effects (Anttila and
Leinonen 2001).

Pharmacology

Pharmacokinetics

Oral by availability is 49.7%  9.8% which does not change with chronic dosing
and is not significantly altered by food (Fawcett and Barkin 1998b). The mean
time to maximum concentration is 1.8  0.7 h for single dose and a bit shorter
Mirtazapine and Depressions 1283

(1.5 h) with multiple doses (Timmer et al. 2000). Peak plasma levels for a single
15 mg dose are 31.6  12.8 ng/mL and for multiple doses 41.8  7.7 ng/mL.
Dose proportional increases in plasma levels occur with doses between 5 and
75 mg. Serum half-life is 16.4  4.6 h which remains the same at steady state
(Timmer et al. 1996, 1997, Timmer et al. 2000). Mirtazapine is 85% protein
bound, a central volume of distribution of 107  42 L and at steady state a total
volume of distribution of 339  125 L or about 4.5 l/kg (Fawcett and Barkin
1998b).
Mirtazapine is metabolized in the gut wall and then hepatic first-pass clearance
through multiple mixed function oxidases (cytochromes). Cytochromes
CYP1A2, CYP2D6, and CYP3A4 are largely responsible for metabolism with
CYP2D6 and CYP1A2 involved in the formation of the 8-hydroxy metabolite
and CYP3A4 responsible for the formation of the N-desmethyl and N-oxide
metabolite (Dodd et al. 2001). Mirtazapine is also glucuronidated. Metabolites
are active but contribute only 3–10% to antidepressant efficacy (Timmer et al.
2000; Sandker et al. 1994; Delbressine et al. 1998; Kasper 1995, 1997). The
R-enantiomer has higher plasma levels than the S-enantiomer and a longer half-
life. However, the S-enantiomer serum levels are increased in CYP2D6 poor
metabolizers, while the R-enantiomer levels are unchanged (Delbressine et al.
1998; Hayashi et al. 2015). A multicenter study compared clinical effectiveness
of mirtazapine with pharmacokinetics and pharmacokinetics (Jaquenoud Sirot et
al. 2012). Smokers had lower mirtazapine and metabolites serum levels, while
women had higher levels. And although CYP1A2 and CYP2D6 genotype influ-
ences the parent drug and metabolite level, neither cytochrome influences effi-
cacy (Okubo et al. 2015; Kirchheiner et al. 2004). However, CYP2B6 genotype
influences R-hydroxy metabolites which have some correlation with depression
responses. The authors found that a S-mirtazapine levels greater than 5 ng/mL
had a 77% probability of response with a specificity of 50% and a sensitivity of
91%. On the other hand, there is no relationship between pharmacokinetic
parameters and adverse effects. At low drug concentrations, the three major
cytochromes each contribute approximately 25–45% to mirtazapine metabolism,
whereas at high drug concentrations, CYP3A4 contributes 70% to metabolism.
However, complete inhibition of one cytochrome enzyme is unlikely to influence
mirtazapine clearance to significant degree (Stormer et al. 2000). Unlike tricyclic
antidepressants, CYP2D6 genotype does not influence drug levels (Lind et al.
2009). In general, despite the abovementioned study, serum levels do not corre-
late with antidepressant efficacy (Timmer et al. 2000). Therapeutic drug moni-
toring is not recommended as it is with amitriptyline. Mirtazapine does not inhibit
cytochromes to any significant degree and is less subject to drug-drug interac-
tions than SSRIs and tricyclic antidepressants (Barkin et al. 1999; Stormer et al.
2000).
Mirtazapine and metabolites are mainly eliminated in the urine (75%) with 15%
eliminated in stool. Mirtazapine is nearly completely eliminated within 3–4 days.
The eliminations half-life is 20–40 h. It is longer in women (37 h) than men (26 h)
(Timmer et al. 2000).
1284 M. P. Davis

Special Populations

Elderly

Mirtazapine clearance is subject to age. Clearance is reduced in the elderly compared

to the young. The difference is particularly significant in males with a 40% lower
clearance in elderly males compared to young males. The difference between elderly
females and young females is only 10% (Timmer et al. 2000; Stimmel et al. 1997).
No dose modifications are recommended for the elderly, but it is probably wise to
start low and go slow.

Renal Failure

Mirtazapine elimination correlates with creatinine clearance. Total body clearance is

reduced by 30% in those with moderate renal failure (creatinine clearance between
11 and 39 mL/min per 1.73 m2) and 50% in those with a creatinine clearance of less
than 10 mL per 1.73 m2 (Stimmel et al. 1997). Though caution is advised when using
mirtazapine in renal failure, there is evidence that adverse effects are not increased
by using standard doses (Dev et al. 2014).

Hepatic Failure

Mirtazapine clearance is decreased by approximately 30% in hepatic impaired

patients. The drug half-life increases 40%, and the area under the curve for plasma
concentrations increases 57% (Anttila and Leinonen 2001). Lower doses may be
advisable in those with advanced liver disease.

Pharmacodynamics: Mechanisms of Action

Mirtazapine has four main mechanisms of action: inhibition of presynaptic alpha-2

adrenergic autoreceptors, inhibition of presynaptic alpha-2 adrenergic hetero-
receptors, and inhibition of two postsynaptic serotonin receptors, 5 HT-2 and 5
HT-3 (Anttila and Leinonen 2001). The R-enantiomer blocks alpha-2 autoreceptors
and heteroreceptors as well as 5 HT-2 postsynaptic receptors, while the S- enantio-
mer blocks alpha-2 autoreceptors and 5 HT-3 postsynaptic receptors (de Boer 1995).
Mirtazapine increases norepinephrine neurotransmission by blocking negative feed-
back on alpha-2 autoreceptors. Serotonergic neurotransmission is increased by
blocking negative feedback of norepinephrine on alpha-2 heteroreceptor found on
serotonergic neurons (de Boer 1996; De Boer et al. 1994, 1996; Holm and Markham
1999). Mirtazapine affinity for presynaptic alpha-2 adrenergic receptors is tenfold
greater than for alpha-2 adrenergic postsynaptic receptors or peripheral alpha-2
adrenergic receptors (de Boer 1995). The affinity for alpha-2 adrenergic
Mirtazapine and Depressions 1285

autoreceptors is 30-fold greater than for central and peripheral alpha-1 adrenergic
receptors (de Boer 1995). Norepinephrine inhibits hippocampal serotonergic neuron
release of serotonin by binding to presynaptic alpha-2 heteroreceptors which is
prevented by mirtazapine. At the same time, norepinephrine release is amplified
by mirtazapine binding to alpha-2 autoreceptors. Subsequently norepinephrine binds
to alpha-1 adrenergic receptors on brainstem raphe neurons which facilitate seroto-
nin release (Fawcett and Barkin 1998b). By blocking postsynaptic 5HT-2 and 5HT-3
receptors, mirtazapine reduces nausea and anorexia commonly seen with SSRIs and
reduces the risk of a serotonin syndrome (Fawcett and Barkin 1998b). Serotonin
released by raphe neurons is directed to 5HT-1 receptors and away from 5HT-2
receptors which contribute to mirtazapine’s anti-anxiolytic activity (Fawcett and
Barkin 1998b). Blockade of 5 HT-3 receptors in the limbic system may be important
in treating clinical states associated with increased dopaminergic tone such as
emesis, schizophrenia, manic, and substance abuse (Dubovsky 1994). This may be
the reason for reduced extrapyramidal effects when mirtazapine is combined with an
antipsychotic.
Mirtazapine has low affinity for muscarinic and dopaminergic receptors such that
anticholinergic side effects are significantly less than that seen with tricyclic antide-
pressants (Nutt 1997; de Boer et al. 1988b). The high affinity for histamine (H-1)
receptors is responsible for sedation and improves sleep and weight gain commonly
seen with mirtazapine (Salvi et al. 2016; Holm and Markham 1999).
Mirtazapine has very weak and clinically insignificant norepinephrine reuptake
inhibition. It is a 1000-fold less avid for transporters compared with desipramine and
100-fold less than imipramine (de Boer et al. 1988a).
Mirtazapine responses are associated with plasma brain-derived neurotrophic
factor (BDNF) and reduced plasma tumor necrosis factor-alpha (TNF-alpha)
suggesting that mirtazapine has some anti-neuroinflammatory activity which con-
tributes to its antidepressant efficacy (Gupta et al. 2016; Deuschle et al. 2013).
Weight gain is common in the first 4 weeks of mirtazapine therapy. Weight gain is
associated with an increase leptin serum level. Tricyclic antidepressants are also
associated with weight gain, but this is not related to serum leptin levels unlike
mirtazapine (Kraus et al. 2002; Goodnick et al. 1999; Fava 2000).
Mirtazapine has less sexual dysfunction associated with it compared with SSRIs
and, in fact, reverses SSRI sexual dysfunction. This may be related to reduced effects
on the hypothalamic pituitary axis. Mirtazapine does not increase prolactin levels or
reduced growth hormone levels; although mirtazapine transiently reduces cortisol
levels, the clinical significance of this is unknown (Farah 1998, 1999; Laakmann
et al. 1999, 2000).
Several studies have attempted to use pharmacogenetics to predict mirtazapine
responders. The short form of the monoamine oxidase A promoter region has been
reported to predict mirtazapine responses (Tzeng et al. 2009). Monoamine oxidase A
polymorphism T941G is reported to predict antidepressant responses only in females
(Tadic et al. 2007). The catechol-o-methyl transferase gene Val/Val and Val/Met
predicts responses with mirtazapine but not paroxetine (Szegedi et al. 2005). Certain
polymorphisms of the 5HT-2A receptor predict improved insomnia but not
1286 M. P. Davis

depression (Kang et al. 2007). The adrenergic alpha 2a receptor-1291C/G polymor-

phism is associated with weight gain and treatment response to mirtazapine in
patients with major depressive disorder (Lee et al. 2009). Finally polymorphism of
beta-arrestin (Lt1) influences downstream signaling of G-protein-coupled receptors
and is associated with mirtazapine responses (Chang et al. 2015).

Indications

Mirtazapine has a labeled indication for treatment of outpatient management of

major depression disorder. The efficacy was established in a series of 6-week
randomized controlled trials of outpatients whose diagnosis was consistent with
major depression by the Diagnostic and statistical Manual of Mental Disorders,
Third Edition (DSM-III).

Clinical Studies

Randomized trials compare antidepressants or an antidepressant to placebo. Many

studies do not consider patient predictors of response (this may account for variabil-
ity in response and differences in effect sizes between comparators). The higher the
guilt subscale score of the baseline Hamilton Rating Scale (HAMD) for Depression),
the greater difference in reduction in depression severity between antidepressants
and placebo at 6 weeks of a study, while the older the current age or the age at onset
of depression, the smaller the difference. At week 8 of a study, the guilt subscale
score of HAMD, the presence of suicidal ideation at baseline predicted greater, and
the anhedonia subscale and insomnia subscale scores of HRSD and early response at
week 2 predicted smaller difference in reduction of depression (Noma et al. 2019).
Subthreshold hypomanic symptoms are associated with lower remission rates with
venlafaxine-plus-mirtazapine combinations but not with the bupropion-plus-
escitalopram combinations (Jha et al. 2018). Systematic reviews and meta-analysis
of mirtazapine trials are summarized on Table 1. Almost all early trials compared to
mirtazapine with placebo or the active comparator amitriptyline. Several systematic
reviews have compared mirtazapine to other antidepressants, mostly SSRIs. Two
network meta-analyses have been published.

Mirtazapine Compared with Placebo and Amitriptyline

Responses in randomized trials are defined as a 50% reduction in the Hamilton

Depression Rating Scale either 17- or 21-item (HAMD). Remission is defined as a
HAMD <7. Some studies used the Montgomery-Asberg Depression Rating Scale
(MADRS) or the Clinical Global Impression (CGI) scale. Comparisons were either
response, remission, or standard mean differences (SMD) between depression
scales. Mirtazapine responses were noted to occur within 1 week of starting therapy
Table 1 Systematic reviews and meta-analysis of mirtazapine for major depression disorder
N, Patients Study arms/
Author/year N, RCT comparators Results Dropout rates Adverse effects
Cipriani, N = 116,477 21 MIR > placebo response; OR 1.89, Overall Clomipramine > MIR, (OR 1.42)
2018 RCT = 522 antidepressants SMD improvement 0.99, remission MIR = placebo MIR = SSRIs
(OR 1.75) Placebo > MIR for MIR > escitalopram
MIR > trazodone lack of efficacy
MIR = SSRIs MIR > placebo for
Remission at 7 months (range AE
Mirtazapine and Depressions

41.8–46.6%), response (range

57.4–59.4%)
Khoo, 2015 RCT = 76 MIR, SSRIs, Remission/response Duloxetine > MIR MIR > agomelatine (OR2.21)
SNRIs, MIR > SSRIs, SNRIs, trazodone (OR 0.47)
trazodone, (OR range 1.37–1.56)
agomelatine Efficacy plus tolerability,
MIR = agomelatine = escitalopram
Cost-effectiveness,
MIR > agomelatine, escitalopram
Watanabe, N = 4974 MIR, other 2-week response Same for all MIR > SSRIs
2011 RCT = 29 antidepressants MIR = tricyclics > SSRIs, (OR antidepressants Dry mouth, weight gain, fatigue,
1.57), somnolence
6-week response SSRIs > MIR
MIR > SSRIs Sweating, nausea, diarrhea, sexual
(OR1.19) dysfunction, headache, tremor, sleep
MIR = tricyclics disturbances
MIR > venlafaxine at 2 weeks and 6
weeks (OR 2.29, OR 1.53)
Thase, 2010 N = 2971 MIR Remission, MIR > SSRIs MIR 31.3%
RCT = 15 SSRIs Week 1 NNT 56 SSRIs 27.8%,
Week 4 NNT 12 p = 0.02
Week 8 NNT 23
1287

(continued)
Table 1 (continued)
1288

N, Patients Study arms/

Author/year N, RCT comparators Results Dropout rates Adverse effects
Remissions 8 weeks
MIR 51.8%, SSRIs 47.5%
Papakostas, N = 1904 MIR Response MIR = SSRIs, SSRIs. MIR insomnia (RR 0.5), nausea
2008 RCT = 10 Fluoxetine MIR = SSRIs same for AE and (RR 0.3)
Paroxetine (RR 1.07) lack of efficacy MIR > SSRIs, fatigue (RR 1.5),
Sertraline sleepiness (RR 1.3), weight gain (RR
Citalopram 3.8), dry mouth (RR 1.8)
Watanabe, RCT = 25 MIR vs. other Responses, No difference
2008 antidepressants Remissions between
2 weeks, MIR = tricyclic > SSRIs antidepressants
(RR 1.36, 1.68)
6 weeks MIR = SSRIs
Response
MIR > paroxetine (RR 2.02)
MIR > venlafaxine (RR 1.77)
Bech 2001 N = 665 MIR, HAMD change,6 weeks, MIR Completion rate
RCT = 7 amitriptyline, 11.08, placebo 7.32, MIR 82%
placebo (SMD 0.49) Amitriptyline 80%
HAMD depression items MIR Placebo 75%
5.06, placebo 3.28, (upper limits)
(SMD 0.42)
MIR = amitriptyline
(SMD 0.4 vs. 0.57)
Zivkov, N = 580 MIR HAMD change 6-weeks MIR 38% MIR > amitriptyline
1997 RCT = 5 Amitriptyline MIR 13.3, amitriptyline 14.8 Amitriptyline 33% Sedation
Placebo Placebo 8.4 Placebo 43% Weight gain
AE dropouts
M. P. Davis
 MIR 10%
Amitriptyline 17%
Fawcett, RCT = 11 MIR, Response 6 weeks, MIR 48%, MIR 4.9% Placebo 76%
1998 Amitriptyline, placebo 20% MIR 76%
placebo, MIR > placebo
trazodone Drowsiness, sedation, weight gain,
appetite, headache
Kasper N = 495 Placebo HAMD change 6 weeks MIR 13.5%
1995 RCT = 5 MIR MIR 14 Placebo 21.5%
Mirtazapine and Depressions

Placebo 10
MIR response 51%
Kasper N = 732 MIR HAMD change 6 weeks
1995 RCT = 5 Amitriptyline MIR 15.7
Amitriptyline 16.1
Responses MIR 72%
Amitriptyline 71%
Kasper N = 265 MIR HAMD change 6 weeks
RCT = 3 Doxepin MIR 18.1
Trazodone Clomipramine 18.1
Clomipramine MIR 13.6
Doxepin 14.7
MIR 18.7
Trazodone 15.7
MIR = clomipramine,
doxepin > trazodone
HAMD Hamilton Depression Rating Scale, MIR mirtazapine, n number, NNT number needed to treat, OR odds ratio, RR relative risks, RCT randomized
controlled trial, SMD standard mean difference
1289
1290 M. P. Davis

which differed significantly from placebo and SSRIs but not amitriptyline. At
6 weeks the magnitude of change was 14 points for mirtazapine and 10 points for
placebo (Kasper 1995). Responders overall in this review were 51% for mirtazapine
and 33% for placebo. Overall dropouts were 13.7% for mirtazapine and 21.5% for
placebo. Mirtazapine maintenance therapy after remission-maintained remissions
was better than placebo at 2 years (77% versus 43.9%, p < 0.001) (Montgomery
1995). One of the original studies found that difference in the HAMD between
mirtazapine and placebo to be 3.5 at 6 weeks favoring mirtazapine. Responses
were 63% for mirtazapine and 30% for placebo (Smith et al. 1990). A fourth review
found that mirtazapine decreased the HAMD by 11.1 points versus 6.9 points for
placebo at 6 weeks (Stahl et al. 1997). A fifth review found that the SMD in the
HAMD between mirtazapine and placebo was 0.49 (95% confidence interval (CI),
0.33–0.64) and reduction in the HAMD was 11.08 for mirtazapine versus 7.21
for placebo (Bech 2001). If only the depression subscale was compared, the differ-
ence was 1.78 in favor of mirtazapine with a SMD of 0.42 (95% CI, 0.28–0.57).
Dropouts were not different between placebo and mirtazapine. Reasons for dropouts
were adverse effects for mirtazapine and lack of efficacy for placebo (Cipriani et al.
2018a). In a network meta-analysis, mirtazapine was superior to placebo with an
odds ratio (OR) of 1.89 (95% CI, 1.64–2.2) (Cipriani et al. 2018a). The overall
number needed to treat to benefit a single patient (NNT) with mirtazapine is 4.
In all the comparisons of mirtazapine with amitriptyline in particular and with
other classes of antidepressants in general, mirtazapine was not inferior in the
primary endpoints which included improvement, responses, and remissions
(Cipriani et al. 2018a; Montgomery et al. 1998; Stahl et al. 1997; Smith et al.
1990; Fawcett and Barkin 1998a; Bech 2001; Kasper 1995; Watanabe et al. 2008,
2011; Papakostas et al. 2008; Thase et al. 2010; Khoo et al. 2015). In fact,
mirtazapine was better tolerated than amitriptyline with fewer side effects and was
found to be the most cost-effective antidepressant of any drug class. In the original
trials, there tended to be less dropout with mirtazapine compared with amitriptyline
(Montgomery et al. 1998; Montgomery 1995).

Other Antidepressants

There have been several systematic reviews and meta-analysis which have compared
mirtazapine to other antidepressants. Cipriani and colleagues in their network meta-
analysis found that mirtazapine responses ranged between 57.4% and 59.4% and
remissions ranged between 41.8% and 46.6% at 7 months (Cipriani et al. 2018a).
Mirtazapine produced similar responses as SSRIs but was superior to reboxetine and
trazodone. Clomipramine was less well tolerated, and escitalopram was better
tolerated than mirtazapine. In the two meta-analyses published by Watanabe and
colleagues, mirtazapine produced equivalent responses and remissions as tricyclic
antidepressants within the first 2 weeks of therapy, whereas SSRI responses did not
occur until later and matched mirtazapine efficacy at only at 6 weeks (Watanabe et al.
2008, 2011). In addition, mirtazapine responses were superior to venlafaxine and
Mirtazapine and Depressions 1291

paroxetine. Sweating, diarrhea, nausea, sexual dysfunction, headache, tremor, and

sleep disturbances were less frequent with mirtazapine compared with SSRIs, while
mirtazapine was associated with an increase in dry mouth, weight gain, fatigue, and
somnolence (Watanabe et al. 2008, 2011). Similar findings were reported by
Papakostas and colleagues (2008).
A meta-analysis by Thase and colleagues found that mirtazapine was superior in
efficacy to SSRIs (Thase et al. 2010). The NNT (number needed to treat) at week 1
was 56, at week 4, 12, and at week 8, 23. Remissions at 8 weeks were 51.8% for
mirtazapine and 47.5% for SSRIs. Time to remission was quicker with mirtazapine
than for SSRIs (OR 1.2, 95% CI 1.12–1.39). On the downside, mirtazapine dropouts
were greater than for SSRIs (31.3% versus 27.8%, p = 0.02).
A large meta-analysis of trials published in 2015 measured efficacy, tolerability,
and cost-effectiveness. Mirtazapine was superior to SSRIs and agomelatine for
efficacy, but escitalopram and agomelatine were better tolerated. Mirtazapine was
the most cost-effective antidepressant (Khoo et al. 2015).
An evidence review of second-generation antidepressants used FDA reviews of
phase 2 and 3 clinical trials for 16 antidepressants: levomilnacipran, desvenlafaxine,
duloxetine, venlafaxine, paroxetine, escitalopram, vortioxetine, mirtazapine,
venlafaxine XR, sertraline, fluoxetine, citalopram, paroxetine CR, nefazodone,
bupropion, and vilazodone. Effect size and the evidence load for efficacy of treat-
ment employed Bayesian statistics. The effect size for mirtazapine was between 0.3
and 0.4 (Hedges’ g) which is a moderate benefit. Posterior effect size distributions
had the highest estimated effect size for venlafaxine followed by paroxetine and the
lowest for bupropion and vilazodone (Monden et al. 2018).

Other Studies

Mirtazapine has been used to treat refractory depression defined as failure to respond
to two consecutive medical treatments. Remissions by the HAMD were 12% (Fava
et al. 2006). However, patients who have not responded to a SSRI alone will respond
to mirtazapine nearly 50% of the time (48%) (Fava et al. 2001). Patients who have
impaired sexual function on an SSRI will have a return of sexual function when
switched to mirtazapine (Gelenberg et al. 2000; Koutouvidis et al. 1999).
Mirtazapine is particularly effective in patients with depression and anxiety or
those with a general anxiety disorder (Falkai 1999; Nutt 1999; Croom et al. 2009).
Mirtazapine is equally effective as amitriptyline and clomipramine when treating
melancholic depression (Kasper 1997). In a randomized trial, mirtazapine produced
a higher remission rate than venlafaxine when treating melancholic depression and a
higher completion percentage (76.9% vs. 64.6%) with fewer dropouts (5.1% vs.
15.3%). Sleep disturbances were also improved with mirtazapine in this group of
patients (Guelfi et al. 2001).
In a prospective study which compared doses of sertraline and mirtazapine as an
“add-on” or “switch” for patients not responding to sertraline, there was no statis-
tically significant difference in the adjusted PHQ-9 score at week 9 between the
1292 M. P. Davis

50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), –
0.58 to 1.07, P = 0.55). In step 2, participants not remitted by week 3 were
randomized to continue sertraline and add mirtazapine) or to switch to mirtazapine.
At week 9, adding mirtazapine reduced the PHQ-9 scores by 0.99 point (0.43–1.55,
P = 0.0012); switching reduced it by 1.01 points (0.46–1.56, P = 0.0012), relative to
continuing sertraline (Kato et al. 2018). It appears that if patients have no response
to sertraline using 50 mg a day for 3 weeks, there may be a modest advantage to
switching to mirtazapine.
Mirtazapine prevents poststroke depression. In a randomized trial, 2 of 35
patients developed depression on mirtazapine, whereas 14 of 35 placebo-treated
patients developed depression. Mirtazapine was effective treating depression in
those who developed depression on placebo in the crossover (Niedermaier et al.
2004). Mirtazapine has been used to treat post-traumatic stress disorders (PTSD).
However, mirtazapine is less effective than SSRIs as a drug class and venlafaxine for
PTSD (Cipriani et al. 2018b).
Mirtazapine has been used to treat patients with substance use and depression.
Patients who use cocaine have improved depression but not reduced cocaine use
(Afshar et al. 2012). The benefits of mirtazapine in reducing depression in patients
with alcohol abuse have been confirmed in two studies. However the evidence for
reducing alcohol use in this population is mixed (Cornelius et al. 2016; Altintoprak
et al. 2008).
Chronic pain and depression co-occur with a high degree of frequency. In an
observational study of 594 patients, mirtazapine improved depression and pain
severity independent of age and type of pain syndrome (Freynhagen et al. 2006).
Sleep disturbances due to pain were also improved. Dropouts (18%) were largely
due to lack of efficacy. Eighty percent elected to continue mirtazapine beyond the 6-
week trial period. Adverse effects were fatigue and weight gain.
Responses in post-traumatic stress syndrome (PTSD) to antidepressants are
mixed (Mcgrane and Shuman 2018). While placebo-controlled trials are few, avail-
able data suggest that mirtazapine produces only a small benefit in civilians with
PTSD as either monotherapy or as adjunct to sertraline (Davidson et al. 2003). As
one would anticipate, open-label studies demonstrate improved outcomes in combat-
related PTSD populations relative to placebo-controlled studies (Chung et al. 2004).
Open-label trials bias responses toward favorable outcomes which may not be
validated or confirmed by double-blind randomized trials. Though uncommon,
worsening anxiety has been experienced secondary to mirtazapine; thus, mirtazapine
should be used with caution in patients with PTSD (Davidson et al. 2003; Connor et
al. 1999; Alderman et al. 2009).
Depression in Alzheimer’s disease is much less responsive to antidepressants
than major depression disorder (Orgeta et al. 2017). Mirtazapine, imipramine clo-
mipramine, and sertraline responses are the same as placebo (OR 1.08, 95% CI
0.69–1.69). Mirtazapine improvement in depression by the Cornell Scale for Depres-
sion in Dementia was discouraging (SMD of 0.01, 95% CI 1.37 to +1.38)
(Banerjee et al. 2013). Mirtazapine worsened daytime sleeping patterns without
improving night time sleep (Scoralick et al. 2017). In general, classical
Mirtazapine and Depressions 1293

antidepressants for treating Alzheimer’s related depression show only modest to no

benefits compared with placebo. Antipsychotics, acetylcholinesterase inhibitors,
anti-convulsants, and hormone replacement therapy have proven to be unhelpful.
Studies using novel glutamatergic drugs are ongoing, suggesting that many
demented patients may benefit from agents affecting glutamate transmission
(Lozupone et al. 2018).
A recent review compared antidepressants in patients with HIV infections and
depression. There was some evidence that mirtazapine resulted in a greater improve-
ment in depression compared to an SSRI (MD 9.00, 95% CI 3.61–14.39; partici-
pants = 70; studies = 1); however, this was not consistent for all measures of
depression in this single study; therefore the evidence is quite low (Eshun-Wilson
et al. 2018).
Mirtazapine has been combined with antipsychotics to treat depression in schizo-
phrenia. In a systematic review of nine randomized trials which compared
mirtazapine to placebo, mirtazapine did not improve negative symptoms but did
improve the mental state of patients (RR 0.69, 95% CI 0.51–0.92) relative to
placebo. There was no improvement in the CGI scale, but mirtazapine did reduce
the frequency of akathisia (RR 0.33, 95% CI 0.2–0.5) (Perry et al. 2018). There was
no improvement in quality of life or days in hospital relative to placebo. Adverse
effects were weight gain (RR 3.19, 95% CI 1.47–8.65) and sedation (RR 1.64, 95%
CI 1.01–7.68). Isolated studies have demonstrated some benefit in treating the
negative symptoms of schizophrenia. A second systematic review of seven studies
by Vidal and colleagues used the Positive and Negative Symptom Scale as the
primary outcome and found that mirtazapine was superior to placebo (SMD 1.0,
95% CI 0.08–1.92) (Vidal et al. 2015). The wide confidence interval in both
systematic reviews suggests that studies were small and heterogeneity between trials
may have been a factor for the difference (Vidal et al. 2015). It is difficult to make
firm conclusions about benefits in this clinical situation.
Mirtazapine reduces experimental transient insomnia. Sleep time is increased,
waking after sleep onset is reduced by a 35–40%, and increases occur in stages 3 and
4 slow-wave sleep without increases in rapid eye movement sleep (REMS) (Karsten
et al. 2017). Mirtazapine, however, does cause daytime sleepiness in a subset of
individuals. In a small group of depressed patients, mirtazapine shortened sleep
latency, sleep time was increased, efficiency was improved, and REMS remained
unchanged (Winokur et al. 2003). Mirtazapine significantly improved insomnia and
suicide ideation in a small group of male patients (Gandotra et al. 2018). In contrast,
fluoxetine did not improve sleep latency or efficiency but did reduce waking after
sleep onset.
Mirtazapine is effective in reducing depression in the elderly with comorbid
illnesses (Varia et al. 2007). One of the advantages of mirtazapine is it is cardiac
safety. There are no adverse effects on heart rate, blood pressure, electrocardiogram,
and cardiac rhythm unlike tricyclic antidepressants. There are few drug interactions.
Mirtazapine is superior to placebo in treating post-myocardial infarction depression
(Honig et al. 2007). Mirtazapine is superior to imipramine and placebo in treating
insomnia, anxiety, and depression in cancer patients (Cankurtaran et al. 2008). In a
1294 M. P. Davis

recent survey, mirtazapine was the most common in a depressant prescribed for
depression in cancer patients because of its multiple benefits (appetite, weight gain,
sleep, pain, and depression) (Sanjida et al. 2018).

General Anxiety Disorders

A recent network meta-analysis compared various medications in the management

of general anxiety disorders. The search included publications between 1992 and
2017 and included 89 studies and over 25,000 participants. Duloxetine (MD 3.13,
95% credible interval [CrI] 4.13 to 2.13), pregabalin (MD 2.79, 95% CrI
3.69 to 1.91), venlafaxine (MD 2.69, 95% CrI 3.50 to 1.89), and
escitalopram (MD 2.45, 95% CrI 3.27 to 1.63) were better than placebo.
Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also beneficial
but limited by small sample sizes. Quetiapine (MD 3.60 95% CrI 4.83 to 2.39)
had the largest effect on HAMD-A but poorly tolerated (odds ratio 1.44, 95% CrI
1.16–1.80). Paroxetine and benzodiazepines were effective but poorly tolerated
(Slee et al. 2019).

Pain

Mirtazapine has been used in patients with pain, depressed mood, and/or insomnia.
The beneficial effects are present, but the mechanism for analgesia is unknown. It is
unclear whether the reduction of pain, the enhancement of the depressed mood, or
the combination of both effects leads to analgesia (Freynhagen et al. 2006). In animal
models there is evidence that mirtazapine has direct analgesic benefits (Bomholt et
al. 2005). Analgesia appears to be at the supraspinal level and not spinal (Kilic et al.
2011). In an open-label crossover study, mirtazapine analgesia was assessed by the
Memorial Pain Assessment Scale items for pain, pain relief (Theobald et al. 2002).
Low-dose pregabalin and mirtazapine improved pain from bone metastases better
than pregabalin alone in a randomized trial. The rationale behind the combination is
that a subset with bone metastases suffer from neuropathic pain from damage to
trabecular nerve-free endings (Nishihara et al. 2013). A meta-analysis of fibromyal-
gia pain found that mirtazapine potential benefits were outweighed by its potential
harms (Welsch et al. 2018). A systematic review published the same year as the
meta-analyses found that patients with fibromyalgia, treated with mirtazapine, had
improved pain, sleep, and quality of life. Study durations ranged from 6 to 13 weeks,
and studies used varying dosing strategies for mirtazapine (Ottman et al. 2018).

Side Effects and Adverse Effects

A summary of side effects relative to placebo are listed on Table 2, and the side
effects relative to SSRIs are summarized on Table 3.
Mirtazapine and Depressions 1295

Table 2 Side effects of mirtazapine compared with placebo

Side effect Mirtazapine (%) Placebo (%)
Drowsiness 23.4 14.2
Sedation 18.7 5.2
Insomnia 9.5 2.3
Appetite 10.6 2.1
Weight gain 10.3 1.2
Dry mouth 25.3 15.9
Fatigue 16.2 11.9

Table 3 Mirtazapine side effects compared with SSRIs as a drug class

Side effect Mirtazapine
Dry mouth OR 1.80, 95% CI 1.37–2.36
Weight gain OR 4.23, 95% CI 2.93–6.11
Fatigue OR 1.53, 95% CI 1.08–2.15
Somnolence OR 1.81, 95% CI 1.39–2.37
Sweating OR 0.25, 95% CI 0.15–0.44
Diarrhea OR 0.57, 95% CI 0.41–0.80
Nausea/vomiting OR 0.33, 95% CI 0.26–0.43
Sexual dysfunction OR 0.31, 95% CI 0.13–0.74
Headache OR 0.69, 95% CI 0.56–0.86
Tremor OR 0.34, 95% CI 0.18–0.66
Sleep disturbances OR 0.52, 95% CI 0.31–0.86

Mirtazapine is associated with hyponatremia as are most antidepressants

(Farmand et al. 2018). The incidence ratio for hyponatremia is 2.95 (95% CI
2.71–3.21) (Leth-Moller et al. 2016). In a subset of patients on mirtazapine, the
hyponatremia will become symptomatic (Ladino et al. 2006). On the other hand, the
risk of hyponatremia is lower than that of duloxetine, escitalopram, and paroxetine
(Gandhi et al. 2017). Transient hypocortisolism is described with mirtazapine which
is unique and not seen with tricyclic antidepressants or SSRIs (Horstmann et al.
2009; Schule et al. 2003; Laakmann et al. 2003). The clinical significance of this is
not known. Neutropenia (<1500 neutrophils/cmm) is seen in 1.6% of mirtazapine-
treated patients and 1.1% of placebo-treated individuals (Nelson 1997). Agranulo-
cytosis has been reported in 2 individuals per 4 million treated patients in one study
and per 3.1 million treated patients in another (Anttila and Leinonen 2001;
Meyboom et al. 1999).
Mirtazapine, 15 mg at night, produces mild but statistically important impairment
of driving skills the next day. In fact, mirtazapine has been used as a positive control
for driving ability. A 15-mg dose is equivalent to a 0.05% alcohol blood level which
is the legal limit for driving in many countries (Verster et al. 2015; Iwamoto et al.
2013; Ramaekers et al. 2011). The impairment is not dose related and resolves in
1–2 weeks. However, individuals on other medications such as opioids may have
1296 M. P. Davis

significant impairment, and individuals with marginal driving ability may become
dangerously impaired on mirtazapine. Trazodone which is also given at night for
sleep does not impair driving skills (Sasada et al. 2013).
Antidepressants as a drug class can lower seizure threshold. However, seizures
are very rare with mirtazapine (less than 0.1%). In one study incidence of seizures
with mirtazapine was 0.04% compared with tricyclic antidepressants which was as
high as 4% (Steinert and Froscher 2018; Kasper 1997). Mirtazapine occasionally
produces nightmares and has been associated with the restless leg syndrome and
periodic limb movements (Menon and Madhavapuri 2017; Kolla et al. 2018).
Mirtazapine does not adversely affect blood pressure or heart rate (Montgomery
1995). However SSRIs are significantly associated with lower all-cause mortality in
patients with cardiovascular disease (OR 0.37, 95% CI 0.19–0.71, p = 0.0028) in a
group of veterans; mirtazapine was significantly associated with higher prevalence
of heart failure (OR 3.26, 95% CI 1.029–10.38, p = 0.0445) (Acharya et al. 2013).
This may be related to weight gain and increase fat on mirtazapine (Lee et al. 2016;
Laimer et al. 2006; Kraus et al. 2002). Depression has been associated with increased
heart rate and reduced respiratory sinus arrhythmia (a sign of reduced vagal tone)
(Hage et al. 2017). Mirtazapine reduces heart rate variability further. The
sympathovagal imbalance of depression is not reversed by mirtazapine (Terhardt
et al. 2013).
Mirtazapine reduces nausea, retching, and reduced appetite and can increase
weight in patients with functional dyspepsia and gastroparesis (Tack and Carbone
2017; Malamood et al. 2017; Yin et al. 2014; Kim et al. 2006). Topical mirtazapine is
well absorbed and has been associated with weight gain in cats with unintended
weight loss (Poole et al. 2019). This may be an attractive option in those suffering
from cancer-related anorexia, thus seen more as a benefit then a side effect. The
benefits may be related to neuroendocrine changes. Serum neuropeptide Y, ghrelin,
and motilin are increased, while serotonin and cholecystokinin are reduced (Jiang et
al. 2016). The downside into mirtazapine like other antidepressants is the increased
risk of gastrointestinal bleeding (OR 1.17, 95% CI 1.01–1.38) (Na et al. 2018).
Mirtazapine has been associated with the serotonin syndrome. In one case report,
the combination of metoclopramide and mirtazapine leads to serotonin-related
toxicity (Harada et al. 2017). This has also been reported with olanzapine plus
mirtazapine and escitalopram plus mirtazapine and mirtazapine plus venlafaxine
(Wu et al. 2015; Ansermot et al. 2014; Decoutere et al. 2012). On the other hand,
mirtazapine has been used to treat the serotonin syndrome since it blocks postsyn-
aptic serotonin receptors (Hoes and Zeijpveld 1996).
Antidepressants have been associated with sleep bruxism. Duloxetine (odds ratio
[OR] = 2.16; 95% confidence interval [95% CI] = 1.12–4.17), paroxetine
(OR = 3.63; 95% CI = 2.15–6.13), and venlafaxine (OR = 2.28; 95%
CI = 1.34–3.86) are associated with sleep bruxism, whereas mirtazapine is not
(Melo et al. 2018).
Mirtazapine treats pruritus of various causes, those resulting from spinal mor-
phine, related to cancer and dermatological diseases (Kouwenhoven et al. 2017;
Yosipovitch and Bernhard 2013; Hundley and Yosipovitch 2004; Davis et al. 2003).
Mirtazapine and Depressions 1297

Edema occurs in 1% of individuals on mirtazapine which is not dose related (Anttila

and Leinonen 2001). Mirtazapine is associated with an increased risk of Stevens-
Johnson syndrome/toxic epidermal necrolysis (Frey et al. 2019).
In a rat model, there was a suggestion that prolonged use of mirtazapine may have
a negative effect on the synthesis of the bone and on its mechanical strength (Fekete
et al. 2015). To the authors’ knowledge, there is no evidence pro or con that
mirtazapine accelerates osteoporosis. Depression is associated with increased frac-
tures. Twenty-three studies from a meta-analysis found that depression was associ-
ated with 26% increase in fracture risk (HR = 1.26, 95% CI, 1.10–1.43, p < 0.001)
(Wu et al. 2018). The overall association between SSRI use and fracture risk is weak
(RR, 1.40; 95% CI [1.22, 1.61] (Wu et al. 2012). Also, tricyclics may be associated
with an increased risk of fracture, independent of depression and bone mineral
density (Wu et al. 2013).
Mirtazapine increases the risk for preterm births but not spontaneous abortions,
major malformations, or stillbirths. There is a near significant or trend toward
neonatal respiratory problems and hypoglycemia in neonates whose mothers are
on mirtazapine. There appears to be no significant problems with breastfeeding.
Mirtazapine exposure through breast milk is 1.9%. There are no adverse effects on
neurobehavioral development in infants exposed to mirtazapine in utero (Smit et al.
2015, 2016).
Abrupt withdrawal of mirtazapine causes dizziness, nausea, insomnia, anxiety,
and panic attacks (Benazzi 1998a). Fatal drug overdoses with mirtazapine are rare
and are usually not related to mirtazapine but polypharmacy (Bremner et al. 1998).
Symptoms of overdose are somnolence and tachycardia. Doses as high as
10–30-fold greater than therapeutic doses have not been associated with respiratory
depression or arrhythmia (Lovecchio et al. 2008; Waring et al. 2007).

Drug Interactions and Combinations

Drug Interactions

Mirtazapine blocks the antihypertensive effects of clonidine by inhibiting central

alpha-2 adrenergic receptors and by subsequently increasing norepinephrine levels
(Abo-Zena et al. 2000). Although there are no interactions between mirtazapine with
lithium, combining carbamazepine with mirtazapine results in reduced mirtazapine
serum levels and lack of augmentation due to increased mirtazapine clearance
through upregulation of CYP3A4 (Schule et al. 2009; Sitsen et al. 2001). Phenytoin
with mirtazapine results in a decrease of the plasma concentrations of mirtazapine by
46% (Spaans et al. 2002). Amitriptyline increases mirtazapine serum levels modestly
but not to a clinically significant degree (Timmer et al. 2000; Sennef et al. 2003). Of
the SSRIs, fluvoxamine has the most severe interactions. Serum levels of
mirtazapine are increased two- to fourfold (Anttila et al. 2001). The serotonin
syndrome has been reported with the combination of SSRIs, SNRIs, tramadol, and
mirtazapine (Gnanadesigan et al. 2005; Houlihan 2004; Dimellis 2002; Demers and
1298 M. P. Davis

Malone 2001; Benazzi 1998b). Benzodiazepines do not interfere with mirtazapine

clearance but add to sedation (Mattila et al. 1989). Mirtazapine does not interfere
with alcohol clearance but does add to alcohol sedation (Arora and Vohora 2016).
Risperidone and olanzapine have no interactions with mirtazapine and can be used to
augment antidepressant activity (Anttila and Leinonen 2001; Loonen et al. 1999;
Botts et al. 2008). However, atypical antipsychotics can severely aggravate
mirtazapine-induced weight-related problems (Seo et al. 2009). There are case
reports of seizures occurring with the combination of olanzapine and mirtazapine
(Spyridi et al. 2009). Also the combination has been reported to cause the serotonin
syndrome (Wu et al. 2015). Cimetidine, an inhibitor of CYP 3A4, increases
mirtazapine serum levels by 22% which appears not to be clinically important.
Antidepressants can have drug-drug interactions with statins. Second-generation
antidepressants, in particular citalopram, escitalopram, mirtazapine, reboxetine, and
venlafaxine, have weak inhibitory effects on various cytochrome (CYP) isozymes
and less likely to be a problem (Palleria et al. 2019).

Drug Combinations

Combinations of antidepressants or antidepressants and antipsychotics are often

recommended by physicians for patients poorly responding to a single antidepres-
sant. People who are already taking one antidepressant are reluctant to take a second,
being wary of side effects, and unconvinced of the logic of such a combination.
People describe being in a state of equilibrium, thus reluctant to change, feeling that
the present equilibrium is hard enough to achieve and thus unwilling to risk being
destabilized by additional medications (Chew-Graham et al. 2018).
Attempts have been made to use combination antidepressants as initial therapy
for major depression disorders. A 12-week trial of escitalopram plus placebo was
compared with escitalopram plus bupropion and mirtazapine plus venlafaxine and
found no benefit with the combinations. Remissions ranged between 41.8 and 46.1%
and responses 57.4–59.4% without differences between treatment arms. The
mirtazapine plus venlafaxine combination was associated with greater side effects
(Warden et al. 2014; Rush et al. 2011). Aripiprazole augmentation does not improve
the initial treatment response compared with mirtazapine alone but does improve
treatment-resistant depression (Schule et al. 2007). Mirtazapine reduces aripiprazole
extrapyramidal side effects. The addition of lithium, but not carbamazepine, signif-
icantly augments the efficacy of mirtazapine in depressed patients who had received
2 weeks of mirtazapine prior to randomization (Schule et al. 2009).
Recent studies have found that mirtazapine does not augment antidepressant
activity in those not responding to monotherapy. An open-design randomized
study for treatment of moderate to severe unipolar major depressive episodes
after a 10-week unsuccessful venlafaxine regimen (225–300 mg/d) assessed the
effectiveness of switching to imipramine (adjusted to plasma levels) compared
with add-on mirtazapine (30 mg/d). Percentage of remitters (71.43% vs. 39.28%)
and the mean reduction of the HAMD score (76.94% vs. 50.72%) were greater in
Mirtazapine and Depressions 1299

the imipramine subgroup (Navarro et al. 2019). A second study did not find
evidence of important benefits to adding mirtazapine to an SSRI or SNRI over
placebo in a treatment-resistant group of primary care patients with depression
(Kessler et al. 2018).
Mirtazapine has been combined with methylphenidate to treat depression in
cancer patients. Depression was significantly better by day 3 as measured by the
MADRS ( 5.29 versus 1.02), and responses to the combination were greater at
day 9 (20.5% versus 6.8%) and day 14 (29.5% versus 6.8%) (Zaini et al. 2018).
Adverse effects were the same as mirtazapine alone. In contrast, aripiprazole aug-
mentation therapy appears to be effective and safe in patients who do not respond to
SSRIs or SNRIs (Kamijima et al. 2018).
Early studies reported that mirtazapine did augment monotherapy activity in
those with resistant depression. Mirtazapine has been used to augment antidepres-
sant responses in patients not responding to monotherapy. Patients not responding at
4 weeks to a standard antidepressant were randomized to continued monotherapy or
mirtazapine augmentation using 15–30 mg/d. Responses at 4 weeks were 64% for
the combination versus 20% for monotherapy and remissions 45.4% versus 13.3%
(Carpenter et al. 1999, 2002). A study which compared mirtazapine augmentation of
SSRIs (paroxetine, sertraline) versus SSRI augmentation of mirtazapine in patients
failing to respond to 4 weeks of monotherapy found that mirtazapine improved
responses but adding SSRIs to mirtazapine failed to improve responses. When
mirtazapine was added to SSRIs non-responders after 4 weeks, the remission rate
increased by 5% and HAMD score improved by 4 points. While for mirtazapine
non-responders, the addition of a SSRIs was not effective (Kato et al. 2017). This
begs the question of whether mirtazapine should be used first line or second line or as
augmentation to SSRI therapy.
Two systematic reviews shed some light on the question. Upfront combinations
of mirtazapine plus a SSRI are superior to SSRI monotherapy for remissions (RR
1.88, 95% CI 1.06–3.33) but not responses. Weight gain was the major side effect
with the combination (Rocha et al. 2012). The second systematic review had safety
as the primary outcome. The combination of mirtazapine plus an SSRI was associ-
ated with greater overall side effects than SSRI monotherapy (RR 1.65, 95% CI
1.19–2.33). Sedation (RR 3.22, 95% CI 2.16–4.08) and weight gain (RR 3.81, 95%
CI 1.37–10.55) were the most prominent additional side effects with the combination
(Galling et al. 2015).
Citalopram has been used to treat obsessive-compulsive disorders. In a ran-
domized trial, the combination of mirtazapine plus citalopram produced
responses at 4 weeks which took 8 weeks for citalopram (Pallanti et al. 2004).
The combination of mirtazapine plus sertraline produced greater PTSD remis-
sions than sertraline alone (OR 4.7, 95% CI 1.1–19.9, NNT 3.5). Depression was
significantly better with the combination at 24 weeks ( p = 0.023) (Schneier et al.
2015).
Prolonged release melatonin (2 mg) has been added to mirtazapine as it was being
withdrawn for a group of premenopausal women treated for insomnia but suffered
from weight gain. Mirtazapine was withdrawn over 1–3 months, and so there was a
1300 M. P. Davis

1–3-month overlap. Sleep quality improved 103% with the combination and further
improved 180% with the withdrawal of mirtazapine. Weight decreased with the
withdrawal of mirtazapine (Dolev 2011).

References
Abo-Zena RA, Bobek MB, Dweik RA. Hypertensive urgency induced by an interaction of
mirtazapine and clonidine. Pharmacotherapy. 2000;20:476–8.
Acharya T, Acharya S, Tringali S, Huang J. Association of antidepressant and atypical antipsychotic
use with cardiovascular events and mortality in a veteran population. Pharmacotherapy.
2013;33:1053–61.
Afshar M, Knapp CM, Sarid-Segal O, Devine E, Colaneri LS, Tozier L, Waters ME, Putnam MA,
Ciraulo DA. The efficacy of mirtazapine in the treatment of cocaine dependence with comorbid
depression. Am J Drug Alcohol Abuse. 2012;38:181–6.
Alderman CP, Condon JT, Gilbert AL. An open-label study of mirtazapine as treatment for combat-
related PTSD. Ann Pharmacother. 2009;43:1220–6.
Altintoprak AE, Zorlu N, Coskunol H, Akdeniz F, Kitapcioglu G. Effectiveness and tolerability of
mirtazapine and amitriptyline in alcoholic patients with co-morbid depressive disorder: a
randomized, double-blind study. Hum Psychopharmacol. 2008;23:313–9.
Ansermot N, Hodel PF, Eap CB. Serotonin toxicity after addition of mirtazapine to escitalopram. J
Clin Psychopharmacol. 2014;34:540–1.
Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS
Drug Rev. 2001;7:249–64.
Anttila AK, Rasanen L, Leinonen EV. Fluvoxamine augmentation increases serum mirtazapine
concentrations three- to fourfold. Ann Pharmacother. 2001;35:1221–3.
Arora S, Vohora D. Comparative evaluation of partial alpha2 -adrenoceptor agonist and pure alpha2
-adrenoceptor antagonist on the behavioural symptoms of withdrawal after chronic alcohol
administration in mice. Basic Clin Pharmacol Toxicol. 2016;119:202–9.
Banerjee S, Hellier J, Romeo R, Dewey M, Knapp M, Ballard C, Baldwin R, Bentham P, Fox C,
Holmes C, Katona C, Lawton C, Lindesay J, Livingston G, Mccrae N, Moniz-Cook E, Murray J,
Nurock S, Orrell M, O’brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Burns A. Study of
the use of antidepressants for depression in dementia: the HTA-SADD trial – a multicentre,
randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effec-
tiveness of sertraline and mirtazapine. Health Technol Assess. 2013;17:1–166.
Barkin RL, Chor PN, Braun BG, Schwer WA. A trilogy case review highlighting the clinical and
pharmacologic applications of mirtazapine in reducing polypharmacy for anxiety, agitation,
insomnia, depression, and sexual dysfunction. Prim Care Companion J Clin Psychiatry.
1999;1:142–5.
Bech P. Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the
Hamilton Depression Scale as evidence of a pure antidepressive effect in the short-term
treatment of major depression. Int J Neuropsychopharmacol. 2001;4:337–45.
Benazzi F. Mirtazapine withdrawal symptoms. Can J Psychiatr. 1998a;43:525.
Benazzi F. Serotonin syndrome with mirtazapine-fluoxetine combination. Int J Geriatr Psychiatry.
1998b;13:495–6.
Bomholt SF, Mikkelsen JD, Blackburn-Munro G. Antinociceptive effects of the antidepressants
amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and
neuropathic pain. Neuropharmacology. 2005;48:252–63.
Botts S, Diaz FJ, Santoro V, Spina E, Muscatello MR, Cogollo M, Castro FE, De Leon J. Estimating
the effects of co-medications on plasma olanzapine concentrations by using a mixed model.
Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32:1453–8.
Mirtazapine and Depressions 1301

Bremner JD, Wingard P, Walshe TA. Safety of mirtazapine in overdose. J Clin Psychiatry.
1998;59:233–5.
Cankurtaran ES, Ozalp E, Soygur H, Akbiyik DI, Turhan L, Alkis N. Mirtazapine improves sleep
and lowers anxiety and depression in cancer patients: superiority over imipramine. Support Care
Cancer. 2008;16:1291–8.
Carpenter LL, Jocic Z, Hall JM, Rasmussen SA, Price LH. Mirtazapine augmentation in the
treatment of refractory depression. J Clin Psychiatry. 1999;60:45–9.
Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant
augmentation with mirtazapine. Biol Psychiatry. 2002;51:183–8.
Chang HS, Won ES, Lee HY, Ham BJ, Kim YG, Lee MS. Association of ARRB1 polymorphisms
with the risk of major depressive disorder and with treatment response to mirtazapine. J
Psychopharmacol. 2015;29:615–22.
Chew-Graham CA, Shepherd T, Burroughs H, Dixon K, Kessler D. The value of an embedded
qualitative study in a trial of a second antidepressant for people who had not responded to one
antidepressant: understanding the perspectives of patients and general practitioners. BMC Fam
Pract. 2018;19:197.
Chung MY, Min KH, Jun YJ, Kim SS, Kim WC, Jun EM. Efficacy and tolerability of mirtazapine
and sertraline in Korean veterans with posttraumatic stress disorder: a randomized open label
trial. Hum Psychopharmacol. 2004;19:489–94.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG,
Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A,
Ioannidis JPA, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for
the acute treatment of adults with major depressive disorder: a systematic review and network
meta-analysis. Lancet. 2018a;391:1357–66.
Cipriani A, Williams T, Nikolakopoulou A, Salanti G, Chaimani A, Ipser J, Cowen PJ, Geddes JR,
Stein DJ. Comparative efficacy and acceptability of pharmacological treatments for post-
traumatic stress disorder in adults: a network meta-analysis. Psychol Med. 2018b;48:1975–84.
Connor KM, Davidson JR, Weisler RH, Ahearn E. A pilot study of mirtazapine in post-traumatic
stress disorder. Int Clin Psychopharmacol. 1999;14:29–31.
Cornelius JR, Chung TA, Douaihy AB, Kirisci L, Glance J, Kmiec J, Wesesky MA, Fitzgerald D,
Salloum I. A review of the literature of mirtazapine in co-occurring depression and an alcohol use
disorder. J Addict Behav Ther Rehabil. 2016;5. https://doi.org/10.4172/2324-9005.1000159.
Croom KF, Perry CM, Plosker GL. Mirtazapine: a review of its use in major depression and other
psychiatric disorders. CNS Drugs. 2009;23:427–52.
Davidson JR, Weisler RH, Butterfield MI, Casat CD, Connor KM, Barnett S, Van Meter S.
Mirtazapine vs. placebo in posttraumatic stress disorder: a pilot trial. Biol Psychiatry.
2003;53:188–91.
Davis MP, Frandsen JL, Walsh D, Andresen S, Taylor S. Mirtazapine for pruritus. J Pain Symptom
Manag. 2003;25:288–91.
De Boer T. The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission.
Int Clin Psychopharmacol. 1995;10(Suppl 4):19–23.
De Boer T. The pharmacologic profile of mirtazapine. J Clin Psychiatry. 1996;57(Suppl 4):19–25.
De Boer T, Broekkamp CL, Gower A, De Graaf JS, De Vos CJ, Rae D, Van Delft AM. The
pharmacological profile of Org 6906, a potential non-sedative antidepressant that combines
monoamine uptake inhibition with alpha 2-adrenolytic activity. Neuropharmacology.
1988a;27:251–60.
De Boer TH, Maura G, Raiteri M, De Vos CJ, Wieringa J, Pinder RM. Neurochemical and
autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its
enantiomers. Neuropharmacology. 1988b;27:399–408.
De Boer T, Nefkens F, Van Helvoirt A. The alpha 2-adrenoceptor antagonist Org 3770 enhances
serotonin transmission in vivo. Eur J Pharmacol. 1994;253:R5–6.
De Boer TH, Nefkens F, Van Helvoirt A, Van Delft AM. Differences in modulation of noradrenergic
and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin
and idazoxan. J Pharmacol Exp Ther. 1996;277:852–60.
1302 M. P. Davis

Decoutere L, De Winter S, Vander Weyden L, Spriet I, Schrooten M, Tournoy J, Fagard K. A

venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and re-challenge. Int
J Clin Pharm. 2012;34:686–8.
Delbressine LP, Moonen ME, Kaspersen FM, Wagenaars GN, Jacobs PL, Timmer CJ, Paanakker
JE, Van Hal HJ, Voortman G. Pharmacokinetics and biotransformation of mirtazapine in human
volunteers. Clin Drug Investig. 1998;15:45–55.
Demers JC, Malone M. Serotonin syndrome induced by fluvoxamine and mirtazapine. Ann
Pharmacother. 2001;35:1217–20.
Deuschle M, Gilles M, Scharnholz B, Lederbogen F, Lang UE, Hellweg R. Changes of serum
concentrations of brain-derived neurotrophic factor (BDNF) during treatment with venlafaxine
and mirtazapine: role of medication and response to treatment. Pharmacopsychiatry.
2013;46:54–8.
Dev V, Dixon SN, Fleet JL, Gandhi S, Gomes T, Harel Z, Jain AK, Shariff SZ, Tawadrous D, Weir
MA, Garg AX. Higher anti-depressant dose and major adverse outcomes in moderate chronic
kidney disease: a retrospective population-based study. BMC Nephrol. 2014;15:79.
Dimellis D. Serotonin syndrome produced by a combination of venlafaxine and mirtazapine. World
J Biol Psychiatry. 2002;3:167.
Dodd S, Boulton DW, Burrows GD, De Vane CL, Norman TR. In vitro metabolism of mirtazapine
enantiomers by human cytochrome P450 enzymes. Hum Psychopharmacol. 2001;16:541–4.
Dolev Z. Case series of perimenopausal women with insomnia treated with mirtazapine followed by
prolonged-release melatonin add-on and monotherapy. Arch Womens Ment Health.
2011;14:269–73.
Dubovsky SL. Beyond the serotonin reuptake inhibitors: rationales for the development of new
serotonergic agents. J Clin Psychiatry. 1994;55(Suppl):34–44.
Eshun-Wilson I, Siegfried N, Akena DH, Stein DJ, Obuku EA, Joska JA. Antidepressants for
depression in adults with HIV infection. Cochrane Database Syst Rev. 2018;1:CD008525.
Falkai P. Mirtazapine: other indications. J Clin Psychiatry. 1999;60(Suppl 17):36–40; discussion
46–8
Farah A. Lack of sexual adverse effects with mirtazapine. Am J Health Syst Pharm.
1998;55:2195–6.
Farah A. Relief of SSRI-induced sexual dysfunction with mirtazapine treatment. J Clin Psychiatry.
1999;60:260–1.
Farmand S, Lindh JD, Calissendorff J, Skov J, Falhammar H, Nathanson D, Mannheimer B.
Differences in associations of antidepressants and hospitalization due to hyponatremia. Am J
Med. 2018;131:56–63.
Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000;61(Suppl 11):37–41.
Fava M, Dunner DL, Greist JH, Preskorn SH, Trivedi MH, Zajecka J, Cohen M. Efficacy and safety
of mirtazapine in major depressive disorder patients after SSRI treatment failure: an open-label
trial. J Clin Psychiatry. 2001;62:413–20.
Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, Mcgrath PJ, Thase ME, Warden D,
Biggs M, Luther JF, Niederehe G, Ritz L, Trivedi MH. A comparison of mirtazapine and
nortriptyline following two consecutive failed medication treatments for depressed outpatients:
a STARD report. Am J Psychiatry. 2006;163:1161–72.
Fawcett J, Barkin RL. A meta-analysis of eight randomized, double-blind, controlled clinical trials
of mirtazapine for the treatment of patients with major depression and symptoms of anxiety. J
Clin Psychiatry. 1998a;59:123–7.
Fawcett J, Barkin RL. Review of the results from clinical studies on the efficacy, safety and
tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord.
1998b;51:267–85.
Fekete S, Simko J, Mzik M, Karesova I, Zivna H, Pavlikova L, Palicka V. Effect of mirtazapine on
rat bone tissue after orchidectomy. Pharmacology. 2015;95:166–72.
Frey N, Bodmer M, Bircher A, Jick SS, Meier CR, Spoendlin J. Stevens-Johnson syndrome and
toxic epidermal necrolysis in association with commonly prescribed drugs in outpatient care
Mirtazapine and Depressions 1303

other than anti-epileptic drugs and antibiotics: a population-based case-control study. Drug Saf.
2019;42:55–66.
Freynhagen R, Muth-Selbach U, Lipfert P, Stevens MF, Zacharowski K, Tolle TR, Von Giesen HJ.
The effect of mirtazapine in patients with chronic pain and concomitant depression. Curr Med
Res Opin. 2006;22:257–64.
Galling B, Calsina Ferrer A, Abi Zeid Daou M, Sangroula D, Hagi K, Correll CU. Safety and
tolerability of antidepressant co-treatment in acute major depressive disorder: results from a
systematic review and exploratory meta-analysis. Expert Opin Drug Saf. 2015;14:1587–608.
Gandhi S, Shariff SZ, Al-Jaishi A, Reiss JP, Mamdani MM, Hackam DG, Li L, Mcarthur E, Weir
MA, Garg AX. Second-generation antidepressants and hyponatremia risk: a population-based
cohort study of older adults. Am J Kidney Dis. 2017;69:87–96.
Gandotra K, Chen P, Jaskiw GE, Konicki PE, Strohl KP. Effective treatment of insomnia with
mirtazapine attenuates concomitant suicidal ideation. J Clin Sleep Med. 2018;14:901–2.
Gelenberg AJ, Mcgahuey C, Laukes C, Okayli G, Moreno F, Zentner L, Delgado P. Mirtazapine
substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry. 2000;61:356–60.
Gnanadesigan N, Espinoza RT, Smith R, Israel M, Reuben DB. Interaction of serotonergic
antidepressants and opioid analgesics: is serotonin syndrome going undetected? J Am Med
Dir Assoc. 2005;6:265–9.
Goodnick PJ, Puig A, Devane CL, Freund BV. Mirtazapine in major depression with comorbid
generalized anxiety disorder. J Clin Psychiatry. 1999;60:446–8.
Guelfi JD, Ansseau M, Timmerman L, Korsgaard S, Mirtazapine-Venlafaxine Study G. Mirtazapine
versus venlafaxine in hospitalized severely depressed patients with melancholic features. J Clin
Psychopharmacol. 2001;21:425–31.
Gupta R, Gupta K, Tripathi AK, Bhatia MS, Gupta LK. Effect of mirtazapine treatment on serum
levels of brain-derived neurotrophic factor and tumor necrosis factor-alpha in patients of major
depressive disorder with severe depression. Pharmacology. 2016;97:184–8.
Hage B, Britton B, Daniels D, Heilman K, Porges SW, Halaris A. Low cardiac vagal tone index by
heart rate variability differentiates bipolar from major depression. World J Biol Psychiatry.
2019;20(5):359–367. https://doi.org/10.1080/15622975.2017.1376113. Epub 2017 Oct 5.
Harada T, Hirosawa T, Morinaga K, Shimizu T. Metoclopramide-induced Serotonin Syndrome.
Intern Med. 2017;56:737–9.
Hayashi Y, Watanabe T, Aoki A, Ishiguro S, Ueda M, Akiyama K, Kato K, Inoue Y, Tsuchimine S,
Yasui-Furukori N, Shimoda K. Factors affecting steady-state plasma concentrations of enantio-
meric mirtazapine and its desmethylated metabolites in Japanese psychiatric patients.
Pharmacopsychiatry. 2015;48:279–85.
Hoes MJ, Zeijpveld JH. Mirtazapine as treatment for serotonin syndrome. Pharmacopsychiatry.
1996;29:81.
Holm KJ, Markham A. Mirtazapine: a review of its use in major depression. Drugs.
1999;57:607–31.
Honig A, Kuyper AM, Schene AH, Van Melle JP, De Jonge P, Tulner DM, Schins A, Crijns HJ,
Kuijpers PM, Vossen H, Lousberg R, Ormel J, MIND-IT Investigators. Treatment of post-
myocardial infarction depressive disorder: a randomized, placebo-controlled trial with
mirtazapine. Psychosom Med. 2007;69:606–13.
Horstmann S, Dose T, Lucae S, Kloiber S, Menke A, Hennings J, Spieler D, Uhr M, Holsboer F, Ising
M. Suppressive effect of mirtazapine on the HPA system in acutely depressed women seems to be
transient and not related to antidepressant action. Psychoneuroendocrinology. 2009;34:238–48.
Houlihan DJ. Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and
mirtazapine. Ann Pharmacother. 2004;38:411–3.
Hundley JL, Yosipovitch G. Mirtazapine for reducing nocturnal itch in patients with chronic
pruritus: a pilot study. J Am Acad Dermatol. 2004;50:889–91.
Iwamoto K, Kawano N, Sasada K, Kohmura K, Yamamoto M, Ebe K, Noda Y, Ozaki N. Effects of
low-dose mirtazapine on driving performance in healthy volunteers. Hum Psychopharmacol.
2013;28:523–8.
1304 M. P. Davis

Jaquenoud Sirot E, Harenberg S, Vandel P, Lima CA, Perrenoud P, Kemmerling K, Zullino DF,
Hilleret H, Crettol S, Jonzier-Perey M, Golay KP, Brocard M, Eap CB, Baumann P. Multicenter
study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in
depression. J Clin Psychopharmacol. 2012;32:622–9.
Jha MK, Malchow AL, Grannemann BD, Rush AJ, Trivedi MH. Do baseline sub-threshold
hypomanic symptoms affect acute-phase antidepressant outcome in outpatients with major
depressive disorder? Preliminary findings from the randomized CO-MED trial. Neuropsycho-
pharmacology. 2018;43:2197–203.
Jiang SM, Jia L, Liu J, Shi MM, Xu MZ. Beneficial effects of antidepressant mirtazapine in
functional dyspepsia patients with weight loss. World J Gastroenterol. 2016;22:5260–6.
Kamijima K, Yasuda M, Yamamura K, Fukuta Y. Real-world effectiveness and safety of
aripiprazole augmentation therapy in patients with major depressive disorder. Curr Med Res
Opin. 2018;34:2105–12.
Kang RH, Choi MJ, Paik JW, Hahn SW, Lee MS. Effect of serotonin receptor 2A gene polymor-
phism on mirtazapine response in major depression. Int J Psychiatry Med. 2007;37:315–29.
Karsten J, Hagenauw LA, Kamphuis J, Lancel M. Low doses of mirtazapine or quetiapine for
transient insomnia: a randomised, double-blind, cross-over, placebo-controlled trial. J
Psychopharmacol. 2017;31:327–37.
Kasper S. Clinical efficacy of mirtazapine: a review of meta-analyses of pooled data. Int Clin
Psychopharmacol. 1995;10(Suppl 4):25–35.
Kasper S. Efficacy of antidepressants in the treatment of severe depression: the place of mirtazapine.
J Clin Psychopharmacol. 1997;17(Suppl 1):19S–28S.
Kato M, Takekita Y, Koshikawa Y, Sakai S, Bandou H, Nishida K, Sunada N, Onohara A, Hatashita
Y, Serretti A, Kinoshita T. Non response at week 4 as clinically useful indicator for antidepressant
combination in major depressive disorder. A sequential RCT. J Psychiatr Res. 2017;89:97–104.
Kato T, Furukawa TA, Mantani A, Kurata K, Kubouchi H, Hirota S, Sato H, Sugishita K, Chino B,
Itoh K, Ikeda Y, Shinagawa Y, Kondo M, Okamoto Y, Fujita H, Suga M, Yasumoto S, Tsujino N,
Inoue T, Fujise N, Akechi T, Yamada M, Shimodera S, Watanabe N, Inagaki M, Miki K, Ogawa
Y, Takeshima N, Hayasaka Y, Tajika A, Shinohara K, Yonemoto N, Tanaka S, Zhou Q, Guyatt
GH, SUND Investigators. Optimising first- and second-line treatment strategies for untreated
major depressive disorder – the SUND study: a pragmatic, multi-centre, assessor-blinded
randomised controlled trial. BMC Med. 2018;16:103.
Kessler DS, Macneill SJ, Tallon D, Lewis G, Peters TJ, Hollingworth W, Round J, Burns A, Chew-
Graham CA, Anderson IM, Shepherd T, Campbell J, Dickens CM, Carter M, Jenkinson C,
Macleod U, Gibson H, Davies S, Wiles NJ. Mirtazapine added to SSRIs or SNRIs for treatment
resistant depression in primary care: phase III randomised placebo controlled trial (MIR). BMJ.
2018;363:k4218.
Khoo AL, Zhou HJ, Teng M, Lin L, Zhao YJ, Soh LB, Mok YM, Lim BP, Gwee KP. Network meta-
analysis and cost-effectiveness analysis of new generation antidepressants. CNS Drugs.
2015;29:695–712.
Kilic FS, Dogan AE, Baydemir C, Erol K. The acute effects of mirtazapine on pain related behavior
in healthy animals. Neurosciences (Riyadh). 2011;16:217–23.
Kim SW, Shin IS, Kim JM, Kang HC, Mun JU, Yang SJ, Yoon JS. Mirtazapine for severe
gastroparesis unresponsive to conventional prokinetic treatment. Psychosomatics.
2006;47:440–2.
Kirchheiner J, Henckel HB, Meineke I, Roots I, Brockmoller J. Impact of the CYP2D6 ultrarapid
metabolizer genotype on mirtazapine pharmacokinetics and adverse events in healthy volun-
teers. J Clin Psychopharmacol. 2004;24:647–52.
Kolla BP, Mansukhani MP, Bostwick JM. The influence of antidepressants on restless legs
syndrome and periodic limb movements: a systematic review. Sleep Med Rev. 2018;38:131–40.
Koutouvidis N, Pratikakis M, Fotiadou A. The use of mirtazapine in a group of 11 patients
following poor compliance to selective serotonin reuptake inhibitor treatment due to sexual
dysfunction. Int Clin Psychopharmacol. 1999;14:253–5.
Mirtazapine and Depressions 1305

Kouwenhoven TA, Van De Kerkhof PCM, Kamsteeg M. Use of oral antidepressants in patients with
chronic pruritus: a systematic review. J Am Acad Dermatol. 2017;77:1068–1073.e7.
Kraus T, Haack M, Schuld A, Hinze-Selch D, Koethe D, Pollmacher T. Body weight, the tumor
necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine.
Pharmacopsychiatry. 2002;35:220–5.
Laakmann G, Schule C, Baghai T, Waldvogel E. Effects of mirtazapine on growth hormone,
prolactin, and cortisol secretion in healthy male subjects. Psychoneuroendocrinology.
1999;24:769–84.
Laakmann G, Schule C, Baghai T, Waldvogel E, Bidlingmaier M, Strasburger C. Mirtazapine: an
inhibitor of cortisol secretion that does not influence growth hormone and prolactin secretion. J
Clin Psychopharmacol. 2000;20:101–3.
Laakmann G, Hennig J, Baghai T, Schule C. Influence of mirtazapine on salivary cortisol in
depressed patients. Neuropsychobiology. 2003;47:31–6.
Ladino M, Guardiola VD, Paniagua M. Mirtazapine-induced hyponatremia in an elderly hospice
patient. J Palliat Med. 2006;9:258–60.
Laimer M, Kramer-Reinstadler K, Rauchenzauner M, Lechner-Schoner T, Strauss R, Engl J,
Deisenhammer EA, Hinterhuber H, Patsch JR, Ebenbichler CF. Effect of mirtazapine treatment
on body composition and metabolism. J Clin Psychiatry. 2006;67:421–4.
Lee HY, Kang RH, Paik JW, Jeong YJ, Chang HS, Han SW, Lee MS. Association of the adrenergic
alpha 2a receptor – 1291C/G polymorphism with weight change and treatment response to
mirtazapine in patients with major depressive disorder. Brain Res. 2009;1262:1–6.
Lee SH, Paz-Filho G, Mastronardi C, Licinio J, Wong ML. Is increased antidepressant exposure a
contributory factor to the obesity pandemic? Transl Psychiatry. 2016;6:e759.
Leth-Moller KB, Hansen AH, Torstensson M, Andersen SE, Odum L, Gislasson G, Torp-Pedersen
C, Holm EA. Antidepressants and the risk of hyponatremia: a Danish register-based population
study. BMJ Open. 2016;6:e011200.
Lind AB, Reis M, Bengtsson F, Jonzier-Perey M, Powell Golay K, Ahlner J, Baumann P, Dahl ML.
Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine
and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behav-
iour. Clin Pharmacokinet. 2009;48:63–70.
Loonen AJ, Doorschot CH, Oostelbos MC, Sitsen JM. Lack of drug interactions between
mirtazapine and risperidone in psychiatric patients: a pilot study. Eur Neuropsychopharmacol.
1999;10:51–7.
Lovecchio F, Riley B, Pizon A, Brown M. Outcomes after isolated mirtazapine (Remeron)
supratherapeutic ingestions. J Emerg Med. 2008;34:77–8.
Lozupone M, La Montagna M, D’urso F, Piccininni C, Sardone R, Dibello V, Giannelli G, Solfrizzi
V, Greco A, Daniele A, Quaranta N, Seripa D, Bellomo A, Logroscino G, Panza F. Pharmaco-
therapy for the treatment of depression in patients with Alzheimer’s disease: a treatment-
resistant depressive disorder. Expert Opin Pharmacother. 2018;19:823–42.
Malamood M, Roberts A, Kataria R, Parkman HP, Schey R. Mirtazapine for symptom control in
refractory gastroparesis. Drug Des Devel Ther. 2017;11:1035–41.
Mattila M, Mattila MJ, Vrijmoed-De Vries M, Kuitunen T. Actions and interactions of psychotropic
drugs on human performance and mood: single doses of ORG 3770, amitriptyline, and
diazepam. Pharmacol Toxicol. 1989;65:81–8.
Mcgrane IR, Shuman MD. Mirtazapine therapy for posttraumatic stress disorder: implications of
alpha-adrenergic pharmacology on the startle response. Harv Rev Psychiatry. 2018;26:36–41.
Melo G, Dutra KL, Rodrigues Filho R, Ortega AOL, Porporatti AL, Dick B, Flores-Mir C, De Luca
Canto G. Association between psychotropic medications and presence of sleep bruxism: a
systematic review. J Oral Rehabil. 2018;45:545–54.
Menon V, Madhavapuri P. Low-dose mirtazapine-induced nightmares necessitating its discontinu-
ation in a young adult female. J Pharmacol Pharmacother. 2017;8:182–4.
Meyboom RH, Edwards IR, Egberts AC. Mirtazapine and the granulocytes – so far so good. N Z
Med J. 1999;112:104.
1306 M. P. Davis

Mirtazapine – a new antidepressant. Med Lett Drugs Ther. 1996;38:113–4.

Monden R, Roest AM, Van Ravenzwaaij D, Wagenmakers EJ, Morey R, Wardenaar KJ, De Jonge
P. The comparative evidence basis for the efficacy of second-generation antidepressants in the
treatment of depression in the US: a Bayesian meta-analysis of Food and Drug Administration
reviews. J Affect Disord. 2018;235:393–8.
Montgomery SA. Safety of mirtazapine: a review. Int Clin Psychopharmacol. 1995;10(Suppl
4):37–45.
Montgomery SA, Reimitz PE, Zivkov M. Mirtazapine versus amitriptyline in the long-term
treatment of depression: a double-blind placebo-controlled study. Int Clin Psychopharmacol.
1998;13:63–73.
Na KS, Jung HY, Cho SJ, Cho SE. Can we recommend mirtazapine and bupropion for patients at
risk for bleeding?: a systematic review and meta-analysis. J Affect Disord. 2018;225:221–6.
Navarro V, Boulahfa I, Obach A, Jerez D, Diaz-Ricart M, Gasto C, Guarch J. Switching to
imipramine versus add-on mirtazapine in venlafaxine-resistant major depression: a 10-week
randomized open study. J Clin Psychopharmacol. 2019;39:63–6.
Nelson JC. Safety and tolerability of the new antidepressants. J Clin Psychiatry. 1997;58(Suppl
6):26–31.
Niedermaier N, Bohrer E, Schulte K, Schlattmann P, Heuser I. Prevention and treatment of
poststroke depression with mirtazapine in patients with acute stroke. J Clin Psychiatry.
2004;65:1619–23.
Nishihara M, Arai YC, Yamamoto Y, Nishida K, Arakawa M, Ushida T, Ikeuchi M. Combinations
of low-dose antidepressants and low-dose pregabalin as useful adjuvants to opioids for intrac-
table, painful bone metastases. Pain Physician. 2013;16:E547–52.
Noma H, Furukawa TA, Maruo K, Imai H, Shinohara K, Tanaka S, Ikeda K, Yamawaki S, Cipriani
A. Exploratory analyses of effect modifiers in the antidepressant treatment of major depression:
individual-participant data meta-analysis of 2803 participants in seven placebo-controlled
randomized trials. J Affect Disord. 2019;250:419–24.
Nutt D. Mirtazapine: pharmacology in relation to adverse effects. Acta Psychiatr Scand Suppl.
1997;391:31–7.
Nutt DJ. Care of depressed patients with anxiety symptoms. J Clin Psychiatry. 1999;60(Suppl
17):23–7; discussion 46–8
Okubo M, Murayama N, Miura J, Chiba Y, Yamazaki H. Effects of cytochrome P450 2D6 and 3A5
genotypes and possible coadministered medicines on the metabolic clearance of antidepressant
mirtazapine in Japanese patients. Biochem Pharmacol. 2015;93:104–9.
Orgeta V, Tabet N, Nilforooshan R, Howard R. Efficacy of antidepressants for depression in
Alzheimer’s disease: systematic review and meta-analysis. J Alzheimer’s Dis. 2017;58:725–33.
Ottman AA, Warner CB, Brown JN. The role of mirtazapine in patients with fibromyalgia: a
systematic review. Rheumatol Int. 2018;38:2217–24.
Pallanti S, Quercioli L, Bruscoli M. Response acceleration with mirtazapine augmentation of
citalopram in obsessive-compulsive disorder patients without comorbid depression: a pilot
study. J Clin Psychiatry. 2004;65:1394–9.
Palleria C, Roberti R, Iannone LF, Tallarico M, Barbieri MA, Vero A, Manti A, De Sarro G, Spina
E, Russo E. Clinically relevant drug interactions between statins and antidepressants. J Clin
Pharm Ther. 2019; https://doi.org/10.1111/jcpt.13058.
Papakostas GI, Homberger CH, Fava M. A meta-analysis of clinical trials comparing mirtazapine
with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. J
Psychopharmacol. 2008;22:843–8.
Perry LA, Ramson D, Stricklin S. Mirtazapine adjunct for people with schizophrenia. Cochrane
Database Syst Rev. 2018;5:CD011943.
Poole M, Quimby JM, Hu T, Labelle D, Buhles W. A double-blind, placebo-controlled, randomized
study to evaluate the weight gain drug, mirtazapine transdermal ointment, in cats with
unintended weight loss. J Vet Pharmacol Ther. 2019;42:179–88.
Mirtazapine and Depressions 1307

Ramaekers JG, Conen S, De Kam PJ, Braat S, Peeters P, Theunissen EL, Ivgy-May N. Residual
effects of mirtazapine on actual driving performance: overall findings and an exploratory
analysis into the role of CYP2D6 phenotype. Psychopharmacology (Berl). 2011;215:321–32.
Rocha FL, Fuzikawa C, Riera R, Hara C. Combination of antidepressants in the treatment of major
depressive disorder: a systematic review and meta-analysis. J Clin Psychopharmacol.
2012;32:278–81.
Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, Warden D, Morris DW,
Luther JF, Husain MM, Cook IA, Shelton RC, Lesser IM, Kornstein SG, Wisniewski SR.
Combining medications to enhance depression outcomes (CO-MED): acute and long-term
outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168:689–701.
Salvi V, Mencacci C, Barone-Adesi F. H1-histamine receptor affinity predicts weight gain with
antidepressants. Eur Neuropsychopharmacol. 2016;26:1673–7.
Sandker GW, Vos RM, Delbressine LP, Slooff MJ, Meijer DK, Groothuis GM. Metabolism of three
pharmacologically active drugs in isolated human and rat hepatocytes: analysis of interspecies
variability and comparison with metabolism in vivo. Xenobiotica. 1994;24:143–55.
Sanjida S, Mulvogue K, Shaw J, Couper J, Kissane D, Pearson SA, Price MA, Janda M. What type
and dose of antidepressants are cancer and non-cancer inpatients being prescribed: a retrospec-
tive case-control study at an Australian tertiary hospital. Support Care Cancer. 2018;26:625–34.
Sasada K, Iwamoto K, Kawano N, Kohmura K, Yamamoto M, Aleksic B, Ebe K, Noda Y, Ozaki N.
Effects of repeated dosing with mirtazapine, trazodone, or placebo on driving performance and
cognitive function in healthy volunteers. Hum Psychopharmacol. 2013;28:281–6.
Schneier FR, Campeas R, Carcamo J, Glass A, Lewis-Fernandez R, Neria Y, Sanchez-Lacay A,
Vermes D, Wall MM. Combined mirtazapine and SSRI treatment of PTSD: a placebo-controlled
trial. Depress Anxiety. 2015;32:570–9.
Schule C, Baghai T, Rackwitz C, Laakmann G. Influence of mirtazapine on urinary free cortisol
excretion in depressed patients. Psychiatry Res. 2003;120:257–64.
Schule C, Baghai TC, Eser D, Hecht S, Hermisson I, Born C, Hafner S, Nothdurfter C, Rupprecht
R. Mirtazapine monotherapy versus combination therapy with mirtazapine and aripiprazole in
depressed patients without psychotic features: a 4-week open-label parallel-group study. World J
Biol Psychiatry. 2007;8:112–22.
Schule C, Baghai TC, Eser D, Nothdurfter C, Rupprecht R. Lithium but not carbamazepine
augments antidepressant efficacy of mirtazapine in unipolar depression: an open-label study.
World J Biol Psychiatry. 2009;10:390–9.
Scoralick FM, Louzada LL, Quintas JL, Naves JO, Camargos EF, Nobrega OT. Mirtazapine does
not improve sleep disorders in Alzheimer’s disease: results from a double-blind, placebo-
controlled pilot study. Psychogeriatrics. 2017;17:89–96.
Sennef C, Timmer CJ, Sitsen JM. Mirtazapine in combination with amitriptyline: a drug-drug
interaction study in healthy subjects. Hum Psychopharmacol. 2003;18:91–101.
Seo HJ, Jung YE, Woo YS, Jun TY, Chae JH, Bahk WM. Effect of augmented atypical antipsy-
chotics on weight change in patients with major depressive disorder in a naturalistic setting.
Hum Psychopharmacol. 2009;24:135–43.
Sitsen J, Maris F, Timmer C. Drug-drug interaction studies with mirtazapine and carbamazepine in
healthy male subjects. Eur J Drug Metab Pharmacokinet. 2001;26:109–21.
Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N. Pharmacological treatments for
generalised anxiety disorder: a systematic review and network meta-analysis. Lancet.
2019;393:768–77.
Smit M, Dolman KM, Honig A. Mirtazapine in pregnancy and lactation – a systematic review. Eur
Neuropsychopharmacol. 2016;26:126–35.
Smit M, Wennink H, Heres M, Dolman KM, Honig A. Mirtazapine in pregnancy and lactation: data
from a case series. J Clin Psychopharmacol. 2015;35:163–7.
Smith WT, Glaudin V, Panagides J, Gilvary E. Mirtazapine vs. amitriptyline vs. placebo in the
treatment of major depressive disorder. Psychopharmacol Bull. 1990;26:191–6.
1308 M. P. Davis

Spaans E, Van Den Heuvel MW, Schnabel PG, Peeters PA, Chin-Kon-Sung UG, Colbers EP, Sitsen
JM. Concomitant use of mirtazapine and phenytoin: a drug-drug interaction study in healthy
male subjects. Eur J Clin Pharmacol. 2002;58:423–9.
Spyridi S, Sokolaki S, Nimatoudis J, Iacovides A, Kaprinis G. Status epilepticus in a patient treated
with olanzapine and mirtazapine. Int J Clin Pharmacol Ther. 2009;47:120–3.
Stahl S, Zivkov M, Reimitz PE, Panagides J, Hoff W. Meta-analysis of randomized, double-blind,
placebo-controlled, efficacy and safety studies of mirtazapine versus amitriptyline in major
depression. Acta Psychiatr Scand Suppl. 1997;391:22–30.
Steinert T, Froscher W. Epileptic seizures under antidepressive drug treatment: systematic review.
Pharmacopsychiatry. 2018;51:121–35.
Stimmel GL, Dopheide JA, Stahl SM. Mirtazapine: an antidepressant with noradrenergic and
specific serotonergic effects. Pharmacotherapy. 1997;17:10–21.
Stormer E, Von Moltke LL, Shader RI, Greenblatt DJ. Metabolism of the antidepressant mirtazapine
in vitro: contribution of cytochromes P-450 1A2, 2D6, and 3A4. Drug Metab Dispos.
2000;28:1168–75.
Szegedi A, Rujescu D, Tadic A, Muller MJ, Kohnen R, Stassen HH, Dahmen N. The catechol-O-
methyltransferase Val108/158Met polymorphism affects short-term treatment response to
mirtazapine, but not to paroxetine in major depression. Pharmacogenomics J. 2005;5:49–53.
Tack J, Carbone F. Functional dyspepsia and gastroparesis. Curr Opin Gastroenterol.
2017;33:446–54.
Tadic A, Muller MJ, Rujescu D, Kohnen R, Stassen HH, Dahmen N, Szegedi A. The MAOA
T941G polymorphism and short-term treatment response to mirtazapine and paroxetine in major
depression. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:325–31.
Terhardt J, Lederbogen F, Feuerhack A, Hamann-Weber B, Gilles M, Schilling C, Lecei O,
Deuschle M. Heart rate variability during antidepressant treatment with venlafaxine and
mirtazapine. Clin Neuropharmacol. 2013;36:198–202.
Thase ME, Nierenberg AA, Vrijland P, Van Oers HJ, Schutte AJ, Simmons JH. Remission with
mirtazapine and selective serotonin reuptake inhibitors: a meta-analysis of individual patient
data from 15 controlled trials of acute phase treatment of major depression. Int Clin
Psychopharmacol. 2010;25:189–98.
Theobald DE, Kirsh KL, Holtsclaw E, Donaghy K, Passik SD. An open-label, crossover trial of
mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms. J Pain
Symptom Manag. 2002;23:442–7.
Timmer CJ, Paanakker JE, Vrijmoed-De Vries M. Mirtazapine pharmacokinetics with two dosage
regimens and two pharmaceutical formulations. Pharm Res. 1997;14:98–102.
Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin
Pharmacokinet. 2000;38:461–74.
Tzeng DS, Chien CC, Lung FW, Yang CY. MAOA gene polymorphisms and response to
mirtazapine in major depression. Hum Psychopharmacol. 2009;24:293–300.
Varia I, Venkataraman S, Hellegers C, Gersing K, Doraiswamy PM. Effect of mirtazapine orally
disintegrating tablets on health-related quality of life in elderly depressed patients with comor-
bid medical disorders: a pilot study. Psychopharmacol Bull. 2007;40:47–56.
Verster JC, Van De Loo AJ, Roth T. Mirtazapine as positive control drug in studies examining the
effects of antidepressants on driving ability. Eur J Pharmacol. 2015;753:252–6.
Vidal C, Reese C, Fischer BA, Chiapelli J, Himelhoch S. Meta-analysis of efficacy of mirtazapine as
an adjunctive treatment of negative symptoms in schizophrenia. Clin Schizophr Relat Psycho-
ses. 2015;9:88–95.
Warden D, Trivedi MH, Carmody T, Toups M, Zisook S, Lesser I, Myers A, Kurian KR, Morris D,
Rush AJ. Adherence to antidepressant combinations and monotherapy for major depressive
disorder: a CO-MED report of measurement-based care. J Psychiatr Pract. 2014;20:118–32.
Waring WS, Good AM, Bateman DN. Lack of significant toxicity after mirtazapine overdose: a
five-year review of cases admitted to a regional toxicology unit. Clin Toxicol (Phila).
2007;45:45–50.
Mirtazapine and Depressions 1309

Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, Churchill R, Furukawa TA.

Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev.
2011;CD006528.
Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, Mcguire H, Churchill R, Furukawa
TA, Multiple Meta-Analyses of New Generation Antidepressants Study Group. Mirtazapine
versus other antidepressants in the acute-phase treatment of adults with major depression:
systematic review and meta-analysis. J Clin Psychiatry. 2008;69:1404–15.
Welsch P, Bernardy K, Derry S, Moore RA, Hauser W. Mirtazapine for fibromyalgia in adults.
Cochrane Database Syst Rev. 2018;8:CD012708.
Winokur A, Demartinis NA 3rd, Mcnally DP, Gary EM, Cormier JL, Gary KA. Comparative effects
of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression
and insomnia. J Clin Psychiatry. 2003;64:1224–9.
Wu CS, Tong SH, Ong CT, Sung SF. Serotonin syndrome induced by combined use of mirtazapine
and olanzapine complicated with rhabdomyolysis, acute renal failure, and acute pulmonary
edema-a case report. Acta Neurol Taiwanica. 2015;24:117–21.
Wu Q, Bencaz AF, Hentz JG, Crowell MD. Selective serotonin reuptake inhibitor treatment and risk
of fractures: a meta-analysis of cohort and case-control studies. Osteoporos Int. 2012;23:365–75.
Wu Q, Liu B, Tonmoy S. Depression and risk of fracture and bone loss: an updated meta-analysis of
prospective studies. Osteoporos Int. 2018;29:1303–12.
Wu Q, Qu W, Crowell MD, Hentz JG, Frey KA. Tricyclic antidepressant use and risk of fractures: a
meta-analysis of cohort and case-control studies. J Bone Miner Res. 2013;28:753–63.
Yin J, Song J, Lei Y, Xu X, Chen JD. Prokinetic effects of mirtazapine on gastrointestinal transit.
Am J Physiol Gastrointest Liver Physiol. 2014;306:G796–801.
Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med. 2013;368:1625–34.
Zaini S, Guan NGC, Sulaiman AH, Zainal NZ, Huri HZ, Shamsudin SH. The use of antidepressants
for physical and psychological symptoms in cancer. Curr Drug Targets. 2018;19:1431.
Vilazodone and Depressions

Frank Faltraco and Johannes Thome

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312
Indications (of Marketed Products) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316
Side Effects/Adverse Reactions and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317

Abstract
Vilazodone is an antidepressant, which enhances the serotonin concentration in
the synapse and also is a partial agonist for 5-HT1A-receptors.

Chemistry, Developmental History

The synthesis of vilazodone proceeds via two synthetic pathways. The first synthetic
pathway starts from indole-5-carbonitrile, which first reacts with
4-chlorobutyrochloride. A reduction of the keto-function results in the precursor
3-(4-chlorobutyl)-1H-indole-5-carbonitrile. In the second synthetic pathway,
5-nitrobenzofuran-2-carboxylic-acid-ethyl-ester is first reduced in a catalytic hydro-
genation to amine intermediate. The piperidine structure is built up by reaction with
bis(2-chloroethyl)amine. The condensation of the precursors of both synthesis
pathways results in vilazodone (Sorbera et al. 2001; Heinrich et al. 2004).

F. Faltraco · J. Thome (*)

Department of Psychiatry and Psychotherapy, University Medical Centre Rostock, Rostock,
Germany
e-mail: frank.faltraco@med.uni-rostock.de; johannes.thome@med.uni-rostock.de

© Springer Nature Switzerland AG 2022 1311

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_113
1312 F. Faltraco and J. Thome

Fig. 1 Graph of the chemical H

structure of vilazodone. N
(Reference: https://pubchem.
ncbi.nlm.nih.gov/compound/ N
Vilazodone#section¼2D-
Structure) N O
C
N O N H
H

Hu and Su investigated an alternative pathway to synthesize vilazodone: The

output substances are 4-cyanoaniline and 5-bromo-2-hydroxybenzaldehyde.
3-(4-chlorobutyl)-1H-indole-5-carbonitrile is synthesized via diazotization of
4-cyanoaniline, followed by Fischer indole cyclization with 6-chlorohexanal. Then
5-(piperazin-1-yl)benzofuran-2-carboxamide is generated via aromatic nucleophilic
substitution of 5-bromobenzofuran-2-carboxamide with piperazine. Vilazodone is
synthesized via nucleophilic substitution of the two intermediates by treatment with
Triethylamine-potassium-carbonate (Et3N/K2CO3) (Hu and Su 2019).
Vilazodone (5-(4-(4-(5-Cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-
carboxamid) is an antidepressant (Fig. 1). Vilazodon-hydrochloride is used medi-
cally and was developed as well as patented by Merck KGaA in 1993. It was
approved by the US Food and Drug Administration (FDA) under the name Viibryd
in 2011 and in Canada in 2018 (Traynor 2011).

Pharmacology

Vilazodone is absorbed after oral administration and has a plasma half-life of 20–24 h.
When vilazodone is taken with food, the drug’s absolute bioavailability is 72%. It loses
50% of its bioavailability if this drug is taken without food (Cruz 2012; Schwartz et al.
2011; Wang et al. 2013). Steady state is achieved after approximately 4 days. It is a
selective serotonin reuptake inhibitor as well as a selective partial agonist for 5-HT1A-
receptors. Vilazodone blocks the serotonin reuptake pump (serotonin transporter),
desensitizes serotonin receptors (5-HT1A), and therefore presumably increases seroto-
nergic neurotransmission (Schwartz et al. 2011).
Vilazodone is metabolized extensively by the hepatic CYP3A4 enzyme. Its dose
should be reduced to 20 mg/day with concomitant use of any potent CYP3A4
inhibitors (Schwartz et al. 2011).

Indications (of Marketed Products)

Vilazodone is approved for the treatment of major depressive disorder. It is admin-

istrated orally as tablets in 10, 20, or 40 mg dosage. The maintenance dose is 40 mg
once daily. It should be titrated, starting with an initial dosage of 10 mg once daily
Table 1 “Surveys review”
Study (RCT,
meta-analysis,
NIS; name/
acronym, authors, Study arms, comparators, Results (scores, response/ Dropout Relevant and severe side
year n, patients, country/ies and placebo remissions rates) rates effects
Rickels et al. Total 410 randomly assigned Vilazodone was titrated Hamilton Rating Scale for Adverse events with
(2009) patients, 198 receiving from 10 to 40 mg once a Depression (HAM-D-17), vilazodone included
vilazodone and day over 2 weeks Montgomery-Asberg diarrhea, nausea, and
Vilazodone and Depressions

199 receiving placebo Depression Rating Scale somnolence; most adverse

(MADRS), Hamilton Rating events were of mild or
Scale for Anxiety, Clinical moderate intensity
Global Impressions-Severity
of Illness (CGI-S) and
-Improvement (CGI-I)
scales
Khan et al. (2011) Total 481 adults with Vilazodone (titrated to Montgomery-Asberg Most common adverse
DSM-IV-TR-defined MDD 40 mg/day) or placebo Depression Rating Scale events (vilazodone versus
(MADRS), 17-item placebo) were diarrhea (31%
Hamilton Depression Rating versus 11%), nausea (26%
Scale (HDRS-17), Hamilton versus 6%), and headache
Anxiety Rating Scale (13% versus 10%)
(HARS), Clinical Global
Impressions-Severity of
Illness (CGI-S), and Clinical
Global Impressions-
Improvement (CGI-I) scores
Khan et al. (2014) Data from two phase III, Montgomery-Åsberg
8-week, randomized, Depression Rating Scale
double-blind, placebo- (MADRS) and the 17-item
controlled trials were pooled Hamilton Depression Rating
for analysis, 40 mg/day Scale
1313

(continued)
Table 1 (continued)
1314

Study (RCT,
meta-analysis,
NIS; name/
acronym, authors, Study arms, comparators, Results (scores, response/ Dropout Relevant and severe side
year n, patients, country/ies and placebo remissions rates) rates effects
vilazodone for the treatment
of MDD in adults
Jain et al. (2014) Post hoc analyses were Vilazodone 40 mg/day or Montgomery-Åsberg
conducted on pooled data placebo in adult patients Depression Rating Scale
from two phase III, with major depressive (MADRS)
multicenter, 8-week, double- disorder
blind, randomized,
controlled trials (RCTs)
Croft et al. (2014) Eight-week, randomized (1: Vilazodone 40 mg/day Montgomery-Asberg Diarrhea and nausea; most
1), double-blind, placebo- with placebo in Depression Rating Scale incidences were mild in
controlled, parallel-group, outpatients with (MADRS) severity
fixed-dose study (placebo ¼ DSM-IV-TR-diagnosed
252, vilazodone ¼ 253) MDD
Mathews et al. Ten-week, multicenter, Vilazodone 20 or Montgomery-Åsberg Most common adverse
(2015) double-blind, placebo- 40 mg/day, citalopram Depression Rating Scale events (5% of vilazodone
controlled and active- 40 mg/day, or placebo (MADRS), Clinical Global patients, twice the rate of
controlled, fixed-dose trial, Impressions-Severity and placebo) were diarrhea,
1133 patients, (placebo ¼ sustained response nausea, vomiting
281; vilazodone (vilazodone 40 mg/day
20 mg/day ¼ 288; only), and insomnia
vilazodone 40 mg/day ¼
284; and citalopram ¼ 280)
Wang et al. (2013) Two pivotal 8-week, Dose titration up to Early onset of action, fewer
randomized, double- 2 weeks to reach a target sexual side effects, the
dose of 40 mg/day absence of known cardiac
F. Faltraco and J. Thome
 blinded, placebo-controlled toxicity, and minimal effect
studies on weight gain
Zareifopoulos and Three RCTs (comprising Vilazodone (20-40 mg, HAMA reduction at week
Dylja (2017) 1453 patients), meta- mean dose ¼ 31.42 mg) 8, CGI-S reduction at week
analysis of all relevant 8, and CGI-I score at week 8
randomized controlled trials,
clinical trials on the use of
vilazodone in the treatment
of generalized anxiety
Vilazodone and Depressions

disorder GAD, total of three

well-designed randomized
controlled trials with a
duration of 10 weeks, total
of 844 (intent to treat
population) randomized to
vilazodone, and 618 to
placebo
1315
1316 F. Faltraco and J. Thome

for 7 days, followed by 20 mg once daily for additional 7 days, and then an increase
to 40 mg once daily (Cruz 2012; Schwartz et al. 2011).

Clinical Studies

Two phase III studies enabled approval of vilazodone for treatment of major
depressive disorder and reported that vilazodone (40 mg/day) showed significant
superior efficacy over placebo (Rickels et al. 2009; Khan et al. 2011).
One pooled analysis aimed to assess the efficacy of vilazodone across a range of
symptoms and severities of depression. The study reported about significantly
improvement in depressive symptoms for the vilazodone-treated group compared
to placebo (Khan et al. 2014). A second study investigated the timing of depressive
symptom improvement and reported about vilazodone’s superior efficacy over
placebo in response rates (Jain et al. 2014). Two phase IV clinical trials confirmed
the efficacy and safety (Croft et al. 2014; Mathews et al. 2015).
Wang et al. reported that vilazodone exerts an antidepressive response after
1 week of treatment. After 8 weeks, it resulted in a 13% higher response compared
to placebo (Wang et al. 2013). Development for generalized anxiety disorder has
been stopped in 2017, because of the small benefit and high number of side effects
(Zareifopoulos and Dylja 2017) (Table 1).

Side Effects/Adverse Reactions and Toxicology

Major side effects of vilazodone are diarrhea, nausea, headache, and dry mouth (may
affect up to 1 of 10 persons treated). Vilazodone carries an increased lethality
warning in young adult patients (may affect up to 1 of 1000 persons treated).
Adverse effects in relation to sexual dysfunction are reported, but the effects were
minimal with 1–2% over placebo rates (Howland 2011; Schwartz et al. 2011).

Combination Therapy: Interactions

Vilazodone should not be combined with monoaminooxidase (MAO) inhibitors as

well as other serotonergic drugs. It is primarily metabolized via CYP3A4; therefore,
the manufacturer recommends that the vilazodone dose should not exceed 20 mg if it
is given with strong CYP3A4 inhibitors (Cruz 2012).

Cross-References

▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and

Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
Vilazodone and Depressions 1317

▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects

▶ Antidepressants: Pharmacology and Biochemistry

References
Croft HA, Pomara N, Gommoll C, Chen D, Nunez R, Mathews M. Efficacy and safety of
vilazodone in major depressive disorder: a randomized, double-blind, placebo-controlled trial.
J Clin Psychiatry. 2014;75(11):e1291–8.
Cruz MP. Vilazodone HCl (Viibryd): a serotonin partial agonist and reuptake inhibitor for the
treatment of major depressive disorder. P T. 2012;37(1):28–31.
Heinrich T, Böttcher H, Gericke R, Bartoszyk GD, Anzali S, Seyfried CA, Greiner HE, van
Amsterdam C. Synthesis and structure–activity relationship in a class of indolebutylpiperazines
as dual 5-HT1A receptor agonists and serotonin reuptake inhibitors. J Med Chem. 2004;47:
4684–92. https://doi.org/10.1021/jm040793q.
Howland RH. Vilazodone: another novel atypical antidepressant drug. J Psychosoc Nurs Ment
Health Serv. 2011;49(3):19–22.
Hu F, Su W. An investigation of the synthesis of vilazodone. J Chem Res. 2019; https://doi.org/10.
1177/1747519819893293.
Jain R, Chen D, Edwards J, Mathews M. Early and sustained improvement with vilazodone in adult
patients with major depressive disorder: post hoc analyses of two phase III trials. Curr Med Res
Opin. 2014;30(2):263–70.
Khan A, Cutler AJ, Kajdasz DK, Gallipoli S, Athanasiou M, Robinson DS, et al. A randomized,
double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the
treatment of major depressive disorder. J Clin Psychiatry. 2011;72(4):441–7.
Khan A, Sambunaris A, Edwards J, Ruth A, Robinson DS. Vilazodone in the treatment of major
depressive disorder: efficacy across symptoms and severity of depression. Int Clin
Psychopharmacol. 2014;29(2):86–92.
Mathews M, Gommoll C, Chen D, Nunez R, Khan A. Efficacy and safety of vilazodone 20 and
40 mg in major depressive disorder: a randomized, double-blind, placebo-controlled trial. Int
Clin Psychopharmacol. 2015;30(2):67–74.
Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. Evidence for efficacy
and tolerability of vilazodone in the treatment of major depressive disorder: a randomized,
double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(3):326–33.
Schwartz TL, Siddiqui UA, Stahl SM. Vilazodone: a brief pharmacological and clinical review of
the novel serotonin partial agonist and reuptake inhibitor. Ther Adv Psychopharmacol.
2011;1(3):81–7.
Sorbera LA, Rabasseda X, Silvestre J, Castaner J. Vilazodone hydrochloride. Antidepressant,
5-HT1A partial agonist, 5-HT reuptake inhibitor. Drugs Future. 2001;36:247–52.
Traynor K. Vilazodone approved for major depression. Am J Health Syst Pharm. 2011;68(5):366.
Wang SM, Han C, Lee SJ, Patkar AA, Masand PS, Pae CU. A review of current evidence for
vilazodone in major depressive disorder. Int J Psychiatry Clin Pract. 2013;17(3):160–9.
Zareifopoulos N, Dylja I. Efficacy and tolerability of vilazodone for the acute treatment of
generalized anxiety disorder: a meta-analysis. Asian J Psychiatr. 2017;26:115–22.
Serotonin-Norepinephrine Reuptake
Inhibitors (SNRIs): Venlafaxine,
Desvenlafaxine, Duloxetine, Milnacipran,
Levomilnacipran

Gerd Laux and Ansgar Klimke

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322
Indications (of Marketed Products) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324
Desvenlafaxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335
Duloxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335
Milnacipran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335
Levomilnacipran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336
Side Effects, Adverse Reactions, Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336
Desvenlafaxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337
Duloxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337
Milnacipran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337
Levomilnacipran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337
Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1338
Discontinuation Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1338
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1338
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339

G. Laux (*)
Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich,
Germany
e-mail: ipm@ipm-laux.de
A. Klimke
Vitos Waldkrankenhaus Köppern, Friedrichsdorf, Germany

© Springer Nature Switzerland AG 2022 1319

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_414
1320 G. Laux and A. Klimke

Abstract
Approved members of the selective serotonin (5-HT) and norepinephrine
(NE) reuptake inhibitor (SNRI) class so long are venlafaxine, desvenlafaxine,
duloxetine, milnacipran, and levomilnacipran. They differ regarding binding
affinity to 5-HT/NE-transporter binding and uptake inhibition, pharmacokinetic
properties (half-life, metabolism), and clinical profile (e.g., analgesic properties).
Numerous randomized placebo-controlled clinical studies (RCTs) and
non-interventional studies have shown efficacy and effectiveness. Some studies
reported higher efficacy compared to serotonin selective antidepressants (SSRIs)
proposing these drugs for severe and so-called therapy-resistant depressions.
Typical side effects are nausea, trouble sleeping, and sexual dysfunction.

Chemistry, Developmental History

Venlafaxine is a bicyclic phenylethylamine compound.

Desvenlafaxine is a synthetic form of the isolated major active metabolite of
venlafaxine.
Duloxetine’s chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-
hiophenepropylamine hydrochloride.
Milnacipran and levomilnacipran are cyclopropancarbamides.
Venlafaxine was approved for medical use in the USA in 1993, marketed in most
of the world; generic venlafaxine has been available since around 2008 and extended
release since around 2010.
Desvenlafaxine was approved for major depression (MDD) in the USA and
Australia in 2008, in 2009 in Canada. Its application was denied by the European
Medicine Agency (EMA) in 2009. Generic forms are available since 2017.
Duloxetine was created by Eli Lilly, first published 1988. In 2003 US Food and
Drug Administration (FDA) recommended the application as not approvable, 2004
duloxetine was FDA and EMA approved for depression and diabetic neuropathy,
2007 for the treatment of generalized anxiety disorder, same year in Canada. In 2004
duloxetine was approved for use of stress urinary incontinence in the EU.
Milnacipran was first approved for the treatment of major depressive episodes in
France in 1996. It is currently marketed for this indication in over 45 countries
worldwide including several European states, Japan and Mexico. 2009 the
U.S. Food and Drug Administration (FDA) approved milnacipran only for the
treatment of fibromyalgia, the European Medicines Agency (EMA) refused market-
ing for the treatment of fibromyalgia in 2009.
The chemical formulas of the SNRIs available are shown in Fig. 1.

Pharmacology

All SNRIs are more potent 5-HT than NE reuptake inhibitors (Cusack et al. 1994;
Harvey et al. 2000; Richelson 2002). Venlafaxine and its active metabolite
O-desmethylvenlafaxine (Desvenlafaxine) inhibit the neural uptake of 5-HT, NE
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . . 1321

Duloxetine Venlafaxine Desvenlafaxine

Milnacipran Levomilnacipran

Fig. 1 Chemical formulas of SNRIs

and with lower potency dopamine and has very low affinity for muscarinic, alpha
adrenergic, or histamine receptors (Bymaster et al. 2001).
Duloxetine and milnacipran inhibit 5-HT and NE uptake, duloxetine has weak
affinity for the dopamine transporter, both have weak or no significant affinity for
muscarinic, α-adrenergic, histaminergic, opioid, glutamate, and GABA receptors.
Analgesic properties are associated to sodium ion channel blockade.
Milnacipran exerts no significant actions on H1, α1, D1, D2, and mACh receptors
(Puozzo et al. 2002).

Pharmacokinetics

Venlafaxine has linear kinetics, is metabolized in the liver via the CYP2D6 isoen-
zyme to the active metabolite O-desmethylvenlafaxine (desvenlafaxine). When most
normal metabolizers take venlafaxine, approximately 70% of the dose is metabo-
lized into desvenlafaxine (Ereshefsky and Dugan 2000).
Duloxetine is a moderate CYP2D6 inhibitor (Knadler et al. 2011). Smoking is
associated with a decrease in duloxetine concentration (Fric et al. 2008).
1322 G. Laux and A. Klimke

Table 1 Pharmacological parameters of different SNRIs

CYP450 Therapeutic Relation 5-HT/
t½ Inhibition plasma level NE uptake
(hrs) 2D6 3A4 1A2 (ng/ml) inhibition
Duloxetine 12 +
+ 50–110 1.8
Milnacipran 8


120–500 25
Venlafaxine 14 +

15–80 1
Desvenlafaxine 15–22
+ +++ 60–230 6.2

Milnacipran has a linear dose-related kinetic, is not metabolized by cytochrome P450

(Spencer and Wilde 1998). The elimination half-life of milnacipran is not increased by
liver impairment and old age, but by significant renal disease (Puozzo et al. 2002).
The five SNRIs differ mainly regarding elimination half-life (t1/2) and liver
metabolism via cytochrome P450 isoenzymes shown in Table 1. Great genetic
variability in the function of 2D6 enzyme among people should be mentioned.
Range of therapeutic plasma levels also vary (Hiemke et al. 2018).

Mechanism of Action

SNRIs share common features, increase 5-HT, enhance serotonergic neurotransmis-

sion through blockade of the serotonin transporter so blocking 5-HT reuptake and
increase NE by NE reuptake inhibition (Cusack et al. 1994; Tatsumi et al. 1997;
Sansone and Sansone 2014).
Venlafaxine is a more potent inhibitor of serotonin reuptake than norepinephrine
reuptake. It exerts rapid β receptor desensitization. Venlafaxine is a substrate of
P-glycoprotein (P-gp), which pumps it out of the brain. The gene encoding P-gp,
ABCB1, has been associated with treatment remission.
Desvenlafaxine is approximately 10 times more potent at inhibiting serotonin
uptake than norepinephrine uptake.
Duloxetine and milnacipran block serotonin and norepinephrine transporter and
desensitize serotonin 1A and β adrenergic receptors (Delini-Stula 2000).
Relation of 5-HT and NE-activity of the SNRIs venlafaxine, duloxetine, and
milnacipran is shown in Fig. 2. Milnacipran has nearly equal 5-HT and NE reuptake
(“dual”), Venlafaxine in lower doses is a SSRI essentially, NE-reuptake inhibition is
increasing with doses >150–225 mg/day (Bymaster et al. 2001). see Figure 2.

Indications (of Marketed Products)

SNRIs have a broad spectrum of indications. They are used and in many countries
released for the treatment of major depressive disorder, anxiety disorders, such as
panic disorder, social anxiety disorder, obsessive-compulsive disorder (OCD), bulimia
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . . 1323

Venlafaxine Duloxetine Milnacipran

1
1
1

9 1,6
30*-3

NE 5 - HT-Relations; *Venlafaxine dose-related

Fig. 2 Serotonergic and noradrenergic activity of different SNRIs

nervosa, and premenstrual dysphoric disorder (PMDD) (Stahl 2017; Shelton 2018;
Ghaemi 2019).
Venlafaxine is approved to treat major depressive disorder (MDD), general-
ized anxiety disorder (GAD), panic disorder, and social phobia. Off-label,
venlafaxine can be used for attention deficit disorder, fibromyalgia, diabetic
neuropathy, complex pain syndromes, hot flashes, migraine prevention, post-
traumatic stress disorder, obsessive-compulsive disorder, and premenstrual dys-
phoric disorder.
Starting dose in MDD is 75 mg/day, approved maximum doses are up to
375 mg/day in absence of response to lower doses due to wide inter-individual
differences in blood levels. Dose should be reduced in case of hepatic or renal
impairment.
Desvenlafaxine is approved for MDD in USA. Doses of 10 to 400 mg/day were
studied in clinical trials. There is no evidence that doses greater than 50 mg per day
provide additional benefit.
Duloxetine is used to treat major depressive disorder, generalized anxiety disor-
der, fibromyalgia, neuropathic pain, and stress urinary incontinence. Duloxetine was
approved for the pain associated with diabetic peripheral neuropathy. 2010 FDA
approved duloxetine to treat chronic musculoskeletal pain, including discomfort
from osteoarthritis and chronic lower back pain.
Starting dose for MDD is 60 mg/day, recommended maximal doses are 120 mg/day.
Milnacipran is prescribed for major depressive disorder, fibromyalgia, and neu-
ropathic pain/chronic pain.
Usual dosage is 50 mg b.i.d., begin at 25 mg b.i.d. increase up to 100 mg twice
daily, diminished in case of renal dysfunction.
Levomilnacipran initial dose is 20 mg orally once a day for 2 days, then increase
to 40 mg orally once a day. Maintenance dose: 40 to 120 mg orally once a day,
maximum dose: 120 mg/day.
1324 G. Laux and A. Klimke

Clinical Studies

Multiple RCTs proved SNRIs superior to placebo required for approvement (e.g.,
Khan et al. 1991; Entsuah et al. 1996 for venlafaxine), they are as effective as
tricyclic antidepressants but better tolerated (Shelton 2018; Ghaemi 2019). Table 2
gives a selection of RCTs between SNRIs and TCAs and SSRIs as well as some
major non-interventional/surveillance/observational studies (NIS). In conclusion,
efficacy and effectiveness of SNRIs is established.
A review concluded that second-generation antidepressants appear equally effec-
tive, although they may differ in efficacy (response rates) and acceptance (dropout
rates). In a network meta-analysis comparing 21 major antidepressants beside
amitriptyline, mirtazapine, and paroxetine the SNRIs venlafaxine, duloxetine, and
milnacipran are on the top 6 ranking regarding efficacy (Cipriani et al. 2018).
Treatment guidelines issued by the National Institute of Health and Clinical
Excellence (NICE), the American Psychiatric Association (APA), and the German
Association of Psychiatry, Psychotherapy and Psychosomatics (DGPPN) reflect the
viewpoint of equal efficacy.
However, some studies and reviews reported higher efficacy of venlafaxine
compared with SSRIs (Clerc et al. 1994; Smith et al. 2002), it was at least as
effective or more effective as the TCAs (Einarson et al. 1999; Stahl et al. 2002). A
re-evaluation of studies reported no better efficacy or tolerability conpared with
SSRIs (Weinmann et al. 2008).
According the Cochrane Collaboration Depression, Anxiety and Neurosis Review
Group Controlled Trials Register all RCTs comparing fluoxetine with any other AD
for patients with unipolar major depressive disorder 171 studies were included in the
analysis (24,868 participants). Fluoxetine was as effective as the TCAs, less effective
than venlafaxine which was more effective than milnacipran (Magni et al. 2013).
Efficacy of venlafaxine for the treatment of Generalized Anxiety Disorder (GAD)
has been established in various RCTs (e.g., Gelenberg et al. 2000; Rickels et al.
2000; Allgulander et al. 2001). Efficacy in the treatment of panic disorder has been
compared with paroxetine and placebo in 664 non-depressed adult outpatients; 75%
of patients were responders, nearly 45% achieved remission under 75 or150 mg/day
venlafaxine or paroxetine 40 mg/day. Venlafaxine and paroxetine showed greater
improvement than placebo. Panic-free rates after 12 weeks were 54% to 61%
compared with 35% for placebo, 75% of patients given active treatments were
responders, nearly 45% achieved remission. Placebo response rate was 55%, remis-
sion near 25% (Pollack et al. 1996).
N ¼ 440 adult outpatients with DSM-IV generalized social anxiety disorder were
randomly assigned for 6 months or longer to receive venlafaxine mean daily dose
202 mg, paroxetine (46 mg/day), or placebo for 12 weeks. Response rates were 58.6%
for venlafaxine, 62.5% for paroxetine, and 36.1% for placebo (Liebowitz et al. 2005).
A systematic review and network meta-analysis including 67 RCTs found superior
response compared to placebo for paroxetine mainly, escitalopram and sertraline.
Venlafaxine performed worse due to adverse events dropouts (Williams et al.
2020). Effects regarding neuropathic pain have been reported (Gallagher et al. 2015).
Table 2 Survey review SNRIs studies in MDD
Dropout rates,
N patients Study arms, comparators, Results Response-(R)/Remission-Rate Dis-continuation Relevant side
Study Duration Placebo (RR) rates effects
Venlafaxine (V)
Schweizer et al. N ¼ 60 V 75 mg/day, 225 mg/day, V > Pl all doses V nervousness,
1991 6 weeks 375 mg/day R: V 68%, Pl 31% sweating, nausea
RCT vs. Pl
Cunningham N ¼ 225 V vs. Trazodone (T) vs. Pl V, T > Pl 33% V nausea, T
et al. 1994 6 weeks V better in cognitive factors and dizziness,
N ¼ 96 retardation, T in sleep disturbance somnolence
Responders
1 year
continuation
Schweizer et al. N ¼ 224 V Ø182 mg/day R: V 90%, I 79% V 16%,
1994 6 weeks Imipramine (I) 176 mg/day Pl 53% I 25%
RCT Pl
Nierenberg et al. N ¼ 84 R: 30–40% according to HAMD,
1994 treatment- MADRS
Open study resistant out- Maintained for 3 months
and inpts.
12 weeks
Entsuah et al. N ¼ 304 N ¼ 185 V, N ¼ 62 Imipra- Relapse rates V 20%, I 31%, T 29%, Pl Completers V
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . .

1996 12 months mine (I), N ¼ 30 Trazodone 34% 38%, Pl 26%

Pool analysis (T), N ¼ 119 Pl
4 RCTs
Thase 1997 N ¼ 191 N ¼ 91 V vs. N ¼ 100 Pl V > Pl beginning at week 2 V nausea,
RCT 8 weeks insomnia,
somnolence
(continued)
1325
 1326

Table 2 (continued)
Dropout rates,
N patients Study arms, comparators, Results Response-(R)/Remission-Rate Dis-continuation Relevant side
Study Duration Placebo (RR) rates effects
Costa e Silva N ¼ 382 V 75–150 mg/ V ¼ F, higher V doses (>) F V Nausea,
et al. 1998 8 weeks day vs. Fluoxetine dizziness, F
RCT (F) 20–40 mg/day Nausea, insomnia
Samuelian and N ¼ 102 V or Clomipramine R: V 59–62%, V 13%, C 20% C anticholinergic
Hackett 1998 43 days (C) 150 mg/day C 43–54% TEAE,
RCT tachycardia,
#blood pressure
Einarson et al. N ¼ 4033 V vs. SSRIs citalopram, V > SSRIs, TCAs
1999 HAMD>15, fluoxetine, fluvoxamine, R: V 73.7%, SSRIs 61.1%, TCAs
Meta-analysis MADRS>18 paroxetine, sertraline vs. TCAs 57.9%
RCTs 44 trials amitriptyline, imipramine,
desipramine, nortriptyline
Rudolph and N ¼ 232 N ¼ 100 V 75–225 mg/ RR: V 37%, F 22%, Pl 18% V 6%, F 9%
Feiger 1999 8 weeks d vs. N ¼ 103 Fluoxetine
RCT (F) 20–60 mg/day
N ¼ 98 Pl
Poirier and N ¼ 122 V 200–300 mg/day, Paroxetine R: V 51.9%, P 32,7% V¼P
Boyer 1999 Treatment- (P) 30–40 mg/day RR: V 42.3%, P 20.0%
RCT resistant
depressions
Ballus et al. N ¼ 84 N ¼ 41 V 75–150 mg/ R: V 55%, P 29% V 39%, V Nausea (28%),
2000 HAMD > 17, day vs. N ¼ 43 Paroxetine RR: V 59%, P 31% P 26% P Headache (40%)
RCT Dysthymia (P) 20–40 mg/day
12 weeks
G. Laux and A. Klimke
Tzanakaki et al. N ¼ 109 N ¼ 55 V 75–225 mg/ V>F 22% Nausea V 5.5%, F
2000 Inpts with day vs. N ¼ 54 Fluoxetine R: V V 70%, F 66% Due to side 14.8%
RCT melancholia (F) 20–60 mg/day RR: V 41%, F 36% effects V 5%, F
HAMD >25 9%
6 weeks
Mehtonen et al. N ¼ 147 N ¼ 75 V 75–150 mg/ V>S V 21% V Nausea,
2000 8 weeks day, vs. N ¼ 72 Sertraline R: V 83%, S 68% S 17% sweating
RCT (S) 50–100 mg/day RR: V 67%, S 36% S Nausea, diarrhea
Thase et al. 2001 N ¼ 2045 N ¼ 851 V vs. N ¼ 748 SSRIs V > SSRIs
Pool analysis (Fluoxetine, paroxetine, RR: V 45%, SSRIs 35%,
8 RCTs fluvoxamine Pl 25%
vs. N ¼ 446 Pl
Entsuah and N ¼ 301 N ¼ 100 V 75–225 mg/ Response benefit: V 66%, F 53%, Pl
Gorman 2002 day vs. N ¼ 103 Fluoxetine 52%
Retrospective (F) 20–60 mg/day vs. N ¼ 98 Remission benefit: V 34%, F 19%, Pl
Global benefit- Pl 19%
risk (GBR)
Stahl et al. 2002 8 weeks V vs. SSRIs vs. Pl V > SSRIs > Pl R: V 67–71%, SSRIs
8 RCTs Pool 59–64%
analysis Pl 41–50%
Sauer et al. 2003 N ¼ 160 N ¼ 60 V 75–150 mg/day V ¼A A due to dry V >A
RCT 6 weeks N ¼ 57Amitriptyline Performance d2 test V > A mouth
(A) 75–150 mg/day
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . .

Montgomery N ¼ 235 N ¼ 109 V 100–200 mg/ Relapse V 22%, Pl 55% V 21%, Pl 48%
et al. 2004 1 year day vs. N ¼ 116 Pl due to lack of
efficacy
Bielski et al. N ¼ 197 N ¼ 98 V 225 mg/day V¼E E>V
2004 8 weeks N ¼ 97 Escitalopram R: V 48.0%
RCT (E) 20 mg/day E 58.8%
RR: V 36.7%
E 41.2%
1327

(continued)
 1328

Table 2 (continued)
Dropout rates,
N patients Study arms, comparators, Results Response-(R)/Remission-Rate Dis-continuation Relevant side
Study Duration Placebo (RR) rates effects
Thase et al. 2006 N ¼ 348 V 150–225 mg/ RR: V 33%, B 46% V more sexual
RCT 12 weeks day vs. Bupropion dysfunction
(B) 300–450 mg/day
Keller et al. N ¼ 258 V Ø 224.7 mg/day vs. Pl Recurrence V 28%, Pl 63%
2007/Kocsis 1 and 2 years 1 year V 23%, Pl 42%
et al. 2007/ 2 years V 28%
Kornstein et al. Pl 47%
2008
PREVENT-
Study, RCT
Nemeroff et al. N ¼ 8744 N ¼ 4191 V V > Fluoxetine Due to adverse
2008 Ø 151 mg/day RR difference 5.9% favoring V effects V 11%,
34 RCTs Meta- N ¼ 3621 SSRIs Drug-placebo differences V 13%, SSRIs 9%
analysis N ¼ 932 Pl SSRIs 6%
Schueler et al. N ¼ 18.180 N ¼ 12.816 V, N ¼ 4.528 V and D > Pl V, D > Pl V, D > Pl
2011 Duloxetine (D), different R and RR: SSRIs > V
54 RCTs Meta- SSRIs V>D V ¼ TCAs
analysis V ¼ TCAs D < SSRIs, V
Thase et al. 2011 N ¼ 259 N ¼ 160 V, Non-recurrence V 71.9%
PREVENT Recurrence N ¼ 99 Fluoxetine (F) F 55.8%
Study 2 years
RCT
Thase et al. 2016 N ¼ 1087 V 75–225 mg/day vs. Pl V > Pl at week 2, no sign. interaction V 9.4%,
Meta-analysis with baseline HAMD-scores Pl 3.6%
5 RCTs
G. Laux and A. Klimke
Fagiolini et al. N ¼ 324 N ¼ 158 V vs. N ¼ 166 V HAMD-total score – 16.4, V nausea
2020 8 weeks Trazodone (T) T – 15.4 T dizziness,
RCT somnolence
Desvenlafaxine (Dv)
Thase et al. 2009 N ¼ 2913 N ¼ 1805 Dv R: Dv 53% Pl 41% Dv 4–18%
Meta-analysis 8 weeks N ¼ 1108 Pl RR: Dv 32%, Pl 23% (increase with
9 RCTs dose)
Pl 3%
Meta-analysis
RCT
Laoutidis and 17 trials Dv 50,100,200, 400 mg/day Risk ratio for response 1.24, for Risk ratio 1.16 Risk ratio 1.98
Kioulos 2015 Pl Fluoxetine, Venlafaxine remission 1.29 vs. Pl, 0.90 or 0.82 in
Review, Meta- head-to-head trials. Not as efficacious
analysis RCTs as other antidepressants
Duloxetine (D)
Goldstein et al. N ¼ 160 D 40 mg/day vs. D 80 mg/ D 40 and 80 mg/day > Pl Depression Insomnia D
2004 8 weeks day vs. Paroxetine (P) 20 mg/ scores and pain severity 19.8%, P 8%
RCT day vs. Pl P ¼ Pl
RR D 80 mg/day 57%, P 34%
Nelson et al. N ¼ 90 N ¼ 47 D 60 mg/day RR: D 44.1% D 21.0%
2005 >55 years N ¼ 43 Pl Pl 16.1% Pl 6.7%
RCT 9 weeks Pain reduction D > Pl
Eckert and 22 studies D N ¼ 1280 vs. Fluoxetine D¼F D¼F
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . .

Lançon 2006 5–12 weeks (F) N ¼ 2078 V>D D>V

Meta-regression and vs. Venlafaxine
analysis for (V) N ¼ 768, Pl N ¼ 918
indirect
comparisons
(continued)
1329
 1330

Table 2 (continued)
Dropout rates,
N patients Study arms, comparators, Results Response-(R)/Remission-Rate Dis-continuation Relevant side
Study Duration Placebo (RR) rates effects
Perahia et al. N ¼ 392 N ¼ 93 D 80 mg/day D 80 and 120 mg/day > Pl D¼P
2006 8 months N ¼ 103 D120 mg/day D¼P
RCT N ¼ 97 P 20 mg/day
N ¼ 99 Pl
Perahia et al. N ¼ 288 D60–120 mg/day vs. Pl Relapse rate D ¼ Pl due to D ¼ Pl
2009 52 weeks D 14.4%, adverse events,
RCT Relapse Pl 33.1% vital signs, or
prevention weight
43 centers
(France,
Germany,
Italy, Russia,
Sweden,
USA)
Oakes et al. N ¼ 681 N ¼ 456 D 60 mg/day D > Pl at 4,8,16 and 20 weeks (not at D 15.3% Dry mouth,
2013 >65 years N ¼ 225 Pl 12 weeks) in depression and pain scales Pl 5.8% constipation,
Robinson et al. 12/24 weeks nausea, diarrhea,
2014 USA, France, fatigue
RCT Mexico, 2x > Pl
Puerto Rico
Cipriani et al. N ¼ 5735 pts D vs. Paroxetine, Escitalopram E and V > D D higher dropout
2012 (E), Fluoxetine, Venlafaxine, as E and V
Review 16 RCTs desvenlafaxine
G. Laux and A. Klimke
Milnacipran (M)
Macher et al. N ¼ 58 M 2 50 mg/day vs. Pl M > Pl M 10.3%, Pl M¼P
1989 Severe 55.2%
RCT depressions
(MADRS
>25)
5 weeks
Ansseau et al. N ¼ 45 M 50 mg/day vs. 100 mg/day M 100 ¼ A > M 50 More
1989 5 weeks vs. Amitriptyline (A) 150 mg/d anticholinergic
side effects,
weight gain, #
blood pressure
Kasper et al. N ¼ 842 M 2 50 mg/day vs. TCAs R: M 64%, TCA 67% M > TCAs,
1996 4–12 weeks Imipramine and Clomipramine RR: M 39%, TCAs 42% dysuria M
Meta-analysis 2 75 mg/day (2.1%) > TCAs
7 studies
Lopez-Ibor et al. M 250 mg/day vs. Fluoxetine M > SSRIs M fewer
1996 20 mg/days, Fluvoxamine R: M 64%, SSRIs 50% gastrointestinal
Meta-analysis 2100 mg/day RR: M 39%, SSRIs 28% side effects, M
RCTs more dysuria
Puech et al. 1997 N ¼ 1032 M 2 50 mg/ M ¼ I, > SSRIs M>I
Meta-analysis day vs. SSRIs, vs. Imipramine R: M 64%, SSRIS 50% M more dysuria, I
(I) more
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . .

anticholinergic
side effects, SSRIs
nausea
Leinonen et al. N ¼ 107 N ¼ 52 M 200 mg/ C>M Due to TEAE M M insomnia
1997 26 weeks day vs. N ¼ 55 Clomipramine R; M 58%, C 72% 21%, C 38%; C dry mouth
RCT (C) 150 mg/day RR: M 45%, C 63% due to lack of
efficacy M 19%,
C 7%
1331

(continued)
 1332

Table 2 (continued)
Dropout rates,
N patients Study arms, comparators, Results Response-(R)/Remission-Rate Dis-continuation Relevant side
Study Duration Placebo (RR) rates effects
Steen and Den Therapy- M 100–200 mg/ M¼C
Bour 1997 resistant day, vs. Clomipramine Poor antide-pressant activity
RCT depressions (C) 150 mg/day R: 30%
6 months
10 hospitals
NL
Tignol et al. N ¼ 219 M 2 50 mg/day M¼I 72 pts. I anticholinergic
1998 Elderly pts. Imipramine (I) 250 mg/day side effects
8 weeks
Guelfi et al. N ¼ 289 M 100 or 200 mg/ M¼F M more " heart
1998 inpatients day vs. Fluoxetine (F) 20 mg/ rate, F weight loss
RCT 12 weeks day
Rouillon et al. N ¼ 204 N ¼ 104 M 2 50 mg/ Recurrence M 16.3%, Pl 23.6% M 18%,
2000 1 year day vs. N ¼ 110 Pl Pl 25%
RCT
Clerc 2001 N ¼ 113 M 2 50 mg/day vs. Fluvox- R: M 78.9%, F 60.7% F tremor,
RCT 6 weeks amine (F) 2 100 mg/day drowsiness
Van Amerongen N ¼ 109 N ¼ 53 M 100 mg/ M¼I I>M M>I
et al. 2002 6 weeks day vs. N ¼ 56 Imipramine
RCT (I) 150 mg/day
Sechter et al. N ¼ 300 M 100 mg/day vs. Paroxetine M¼P P more
2004 6 weeks (P) 20 mg/day R: M 62.8%, P 64.9% discontinu-ation
RCT symptoms
G. Laux and A. Klimke
Papakostas et al. N ¼ 17.036 SNRIs vs. SSRIs SNRIs (>) SSRIs
2007 R: SNRIs 63.6%, SSRIs 59.3%
Meta-analysis
93 trials
Nakagawa et al. N ¼ 2.277 M vs. SSRIs, other SNRIs, M ¼ other AD M > TCAs due M < sedation,
2009 TCAs to side effects dizziness,
Cochrane meta- constipation, dry
analysis mouth
16 RCTs
Olie et al. 2010 N ¼ 195 M and Venlafaxine R: 70% M, 77% V 31% 72% M, 74% V
RCT 24 weeks (V) 100–200 mg/day RR: 52.2% M, 62.1% V (mild)Nausea,
dizziness,
hyperhidrosis,
dysuria (♂ M),
sexual dysfunction
(V)
Levomilnacipran (Lm)
Asnis et al. 2013 N ¼ 724 N ¼ 179 Pl, N ¼ 181 Lm40 R: Pl 29.1%, Lm 40 36.4%, Lm Pl 21.6%, Lm40 TEAEs Lm > Pl:
RCT outpatients mg/day, N ¼ 181 Lm 80 mg/ 80 37.3%, Lm 120 41.5% 27%, Lm Headache, nausea,
8 weeks day, N ¼ 83 Lm 120 mg/day RR: 80 32.4%, constipation,
19.4% vs. 21.6%, vs. 20.9% vs. 20.5% Lm120 35% hyperhidrosis,
vomiting, urinary
hesitation
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . .

Montgomery N ¼ 553 N ¼ 276 Lm 75 or 100 mg/day, R: Lm 59.1%; Pl 42.2% Lm 9.4%, Pl Lm > Pl: Hyper-
et al. 2013 Outpatients N ¼ 277 Pl RR: 46.4% vs. 26.0% 6.5% due to hidrosis,
RCT 10 weeks MADRS adverse events constipation,
diarrhea,
tachycardia,
hypertension
(continued)
1333
 1334

Table 2 (continued)
Dropout rates,
N patients Study arms, comparators, Results Response-(R)/Remission-Rate Dis-continuation Relevant side
Study Duration Placebo (RR) rates effects
Sambunaris N ¼ 434 Lm 40–120 mg/day Lm > Pl Pl 61.8%
et al. 2014 10 weeks vs. Pl Lm 81.6%
RCT Nausea, dizziness,
constipation,
tachycardia,
hypertension,
urinary hesitation,
hyperhidrosis,
insomnia,
ejaculation
disorder
Note: > significantly more effective than or better as or more frequent as, ¼ not significantly different, HAMD Hamilton Depression Scale, MADRS
Montgomery Asberg Depression Rating Scale, Pl ¼ Placebo, TEAE ¼ Treatment Emergent Adverse Events
G. Laux and A. Klimke
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . . 1335

Desvenlafaxine

An integrated analysis compared 50 and 100 mg/day with placebo in adult out-
patients from 4317 pts. Statistically significant improvements versus placebo were
observed for all efficacy endpoints (Carrasco et al. 2016). An indirect comparison
meta-analysis showed no differences between Dv and venlafaxine regarding effi-
cacy, nausea, and dropout rates favored Dv (Coleman and Xavier 2012).

Duloxetine

A 2012 Cochrane Review did not find greater efficacy of duloxetine compared to
SSRIs and newer antidepressants. Additionally, the review found evidence that
duloxetine has increased side effects and reduced tolerability compared to other
antidepressants. It thus did not recommend duloxetine as a firstline treatment for
major depressive disorder. Duloxetine appears less tolerable than some other anti-
depressants (Cipriani et al. 2012).
Duloxetine is more effective than placebo in the treatment of generalized anxiety
disorder (GAD) (Carter and McCormack 2009). In a relapse prevention study (N ¼ 887;
mean age ¼ 43.3 years) over 26 weeks placebo-treated patients relapsed more fre-
quently (41.8%) than duloxetine-treated patients (13.7%) (Davidson et al. 2008).
Duloxetine is used in pain and stress urinary incontinence treatment.
One review of duloxetine found that it reduced pain and fatigue, and improved
physical and mental performance in fibromyalgia compared to placebo (Acuna
2008). Another systematic review noted that tricyclic antidepressants (imipramine
and amitriptyline), traditional anti-convulsants and opioids have better efficacy in
painful diabetic neuropathy than duloxetine (Wong et al. 2007). The comparative
data collected by reviewers in BMC Neurology indicated that amitriptyline, other
tricyclic antidepressants, and venlafaxine may be more effective for painful diabetic
neuropathy and fibromyalgia (Sultan et al. 2008). A newer review based on the
Cochrane Neuromuscular Group Specialized Register analyzed benefits and harms
of duloxetine for treating painful neuropathy and different types of chronic pain.
Eighteen trials with 6407 participants were included. Doses of 60 mg and 120 mg
daily were efficacious for treating pain in diabetic peripheral neuropathy, the effect in
fibromyalgia was attributed to greater improvement in mental symptoms than in
somatic physical pain. Minor side effects were common, direct comparisons of
duloxetine with other antidepressants and with other drugs, such as pregabalin
were recommended (Lunn et al. 2014).

Milnacipran

The clinical properties are summarized by Lecrubier 1997. A meta-analysis of six

studies involving more than 1000 patients showed no distinction between
milnacipran and SSRIs in efficacy or discontinuation rates, including
1336 G. Laux and A. Klimke

discontinuation for side effects or lack of efficacy (Papakostas et al. 2007). A meta-
analysis of a total of 16 randomized controlled trials with more than 2200 patients
concluded that there were no statistically significant differences in efficacy, accept-
ability, and tolerability when comparing milnacipran with other antidepressant
agents. However, compared with TCAs, significantly fewer patients taking
milnacipran dropped out due to adverse events (Ansseau et al. 1989; Nakagawa
et al. 2008, 2009).
A systematic review in 2015 showed moderate relief for a minority of people with
fibromyalgia. Milnacipran was associated with increased adverse events when
discontinuing use of the drug (Cording et al. 2015).

Levomilnacipran

A systematic review of all available clinical studies reported superiority over placebo
with a NNT for response vs. placebo of 9 and for remission 14. Improvement in
social functioning was also demonstrated (Citrome 2013). A review of seven RCTs
found Lm more effective than placebo in reducing depression as well as improving
functional impairment. In the placebo-controlled long-term study Lm was not
significantly superior to placebo (Asnis and Henderson 2015).

Side Effects, Adverse Reactions, Toxicology

Common side effects of SNRIs are similar to SSRIs and mainly include gastroin-
testinal side-effects like nausea, loss of appetite, vomiting, diarrhea, and CNS
effects like trouble sleeping, shakiness, feeling tired, excessive yawning, severe
tinnitus, and sexual dysfunction (Clayton et al. 2002). Rates vary depending if
spontaneous reporting or direct questioning is applied.
Induction of suicidality by antidepressants is a point of frequent scientific and
medical discussion. Meta-analyses of randomized clinical trials (RCTs) indicate a
small increased risk for suicidal events in adolescents and young adults, but a
protective effect in older adults. In contrast, pharmacoepidemiologic studies show
a protective effect across the life span (Brent 2016).
Most commonly reported adverse effects of Venlafaxine are nausea, dizziness,
sweating, nervousness, and insomnia. It can cause abnormal bleeding, altered
platelet function, and in higher doses because of norepinephrine reuptake inhibition
tachycardia, tremor, and elevated blood pressure (Rudolph and Derivan 1996).
Serotonin syndromes have been reported rarely.
At lower doses the adverse effect profile of venlafaxine is similar to SSRIs, at
higher doses venlafaxine can produce adverse effects because of norepinephrine
reuptake inhibition: diaphoresis, tachycardia, tremors, anxiety, and mild but
sustained hypertension (Nelson 1997; Preskorn 1995). The elevated blood pressure
is a dose-dependent effect, doses of 300 mg per day or higher have a rate of 13%
(Feighner 1995; Thase 1998).
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . . 1337

A 2014 meta-analysis of 21 clinical trials of venlafaxine for the treatment of

depression in adults found that compared to placebo, venlafaxine reduced the risk of
suicidal thoughts and behavior. An analysis of clinical trials by the FDA statisticians
showed the incidence of suicidal behavior among the adults on venlafaxine to be not
significantly different from fluoxetine or placebo, however, venlafaxine caused a
statistically significant five-fold increase in suicidal ideation and behavior in persons
younger than 25 (Gibbons et al. 2012).

Desvenlafaxine

50 and 100 mg/day was generally safe and well tolerated (Carrasco et al. 2016).

Duloxetine

Nausea, somnolence, insomnia, decreased libido/sexual dysfunction, loss of appe-

tite, and dizziness are the main side effects, reported by about 10 to 35% of patients
(Perahia et al. 2006b; Nelson et al. 2006). The frequency of treatment-emergent
sexual dysfunction was similar for duloxetine and SSRIs when compared in a
6-month observational study in depressed patients (Dueñas et al. 2011).

Milnacipran

The most frequently occurring adverse reactions (5% and greater than placebo)
were nausea, headache, constipation, dizziness, insomnia, hot flush, and hyperten-
sion. Effects on weight, QTc, or sexual functions are missing. A study with N ¼ 1871
pts. reported 7.9% dry mouth, 4.3% sweating, 2.1% dysuria (Lopez-Ibor et al. 1996).
In summary, side effects are comparable to SSRIS with fewer nausea but more
dysuria (Puech et al. 1997).

Levomilnacipran

The most commonly encountered AEs (incidence >5%) were nausea, hyperhidrosis,
tachycardia, and mild increase of blood pressure (Citrome 2013). Lm was weight
neutral, did not cause QTc prolongation, pulse and blood pressure were significantly
elevated, nausea and hyperhidrosis occurred in 17% vs. 6% under Pl and 9% vs. 2%
under Pl, respectively (Asnis and Henderson 2015).
Regarding safety of overdose SNRIs have low hazard indices compared to TCAs
and MAOIs (White et al. 2008). Acute overdosage is often manifested by emesis,
lethargy, ataxia, disturbances in heart rhythm, tremor, amnesia, confusion, coma, or
convulsions. The fatal toxicity index (deaths due to acute overdose) was reported to
be higher with venlafaxine than with SSRIs (Buckley and McManus 2002).
1338 G. Laux and A. Klimke

During clinical trials, patients survived acute ingestion of over 6750 mg of

venlafaxine without serious effects. Most acute overdoses required no specific
therapeutic interventions other than observation.

Pregnancy

Venlafaxine should only be used during pregnancy if clearly needed. Venlafaxine

can potentially pass into breast milk and cause side effects in breastfed children and
should not be used in breastfeeding (Einarson et al. 2001).
Duloxetine: Benefit must be weighed against potential fetal risk. Breastfeeding is
not recommended.
Milnacipran should not be used during pregnancy and during lactation.
Contraindications for all SNRIs are MAOIs due to the potential for serotonin
syndrome.
Caution is advisable in heart failure patients, hyperthyroidism, and those with
recent myocardial infarctions or instable heart function as they can raise blood
pressure and increase heart rate. SNRIs raise the risk of seizures, and prescribers
should avoid the drugs in patients with epilepsy.
Duloxetine: MAOIs, liver diseases; use with caution in patients with history of
seizures and urogenital disorders (prostatahyperplasia). For overview see Hayes
et al. 2012; Berard et al. 2017; De Vries et al. 2021.

Discontinuation Symptoms

Symptoms occur within a few days from drug discontinuation, are mild and last a
few weeks, variations are possible, however (Fava et al. 2018).
Typical symptoms can be summarized with the acronym FINISH: Flu-like,
Insomnia, Nausea, Imbalance, Sensory disturbance, Hyperarousal like nightmares,
vivid dreams, dizziness, feelings of electricity in the body (Gabriel and Sharma
2017). A review of 14 studies with more than 4000 patients reported discontinuation
symptoms in 27–86% (56% on average) of patients treated with antidepressants.
Nearly half of the patients reported severe symptoms (Davies and Read 2019). Data
regarding frequency, intensity, and duration vary however. Frequently intake is
terminated by patients’ own decision without symptoms.
People stopping venlafaxine commonly experience discontinuation symptoms
such as dysphoria, headaches, nausea, irritability, emotional lability, sensation of
electric shocks, and sleep disturbance. Venlafaxine has a higher rate of moderate to
severe discontinuation symptoms relative to other antidepressants.

Combination Therapy: Interactions

SNRIs should not be taken with serotonergic agents like SSRIs, tramadol, fentanyl,
dextro-methorphane, pethidine, St John’s wort, tryptophan, or 5-HTP as the resulting
drug interaction could lead to serotonin syndrome. Concomitant use of serotonergic
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . . 1339

drugs like triptans, tramadol, buspiron must be monitored, dose must be reduced by
half when strong inhibitors of CYP2D6 are coadministered.
SSRIs and SNRIs: Concomitant use of aspirin, nonsteroidal anti-inflammatory
drugs (NSAIDs), and anticoagulants can result in gastrointestinal and other bleeding
events.
Duloxetine: CYP1A2 inhibitors (Fluvoxamine, ciprofloxazine, enoxacine);
smoking.
Milnacipran: Clonidine, sympathomimetics (Spencer and Wilde 1998).
Levomilnacipran shows minimal drug–drug interactions.

Cross-References

▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and

Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry
▶ Combination Therapies and Switching of Agents in Depression and Bipolar
Disorders
▶ Psychopharmacotherapy of Depressive Disorders

References
Acuna C. Duloxetine for the treatment of fibromyalgia. Drugs Today. 2008;44:725–34.
Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ER) in the treatment of
generalized anxiety disorder: twenty-four-week placebo-controlled dose-ranging study. Br J
Psychiatry. 2001;179:15–22.
Ansseau M, von Frenckell R, Mertens C, de Wilde J, et al. Controlled comparison of two doses of
milnacipran (F 2207) and amitriptyline in major depressive inpatients. Psychopharmacology.
1989;98:163–8.
Ansseau M, Papart P, Troisfontaines B, Bartholome F, et al. Controlled comparison of milnacipran
and fluoxetine in major depression. Psychopharmacology. 1994;114:131–7.
Asnis GM, Bose A, Gommoll CP, Chen C, Greenberg WM. Efficacy and safety of levomilnacipran
sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized,
double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74:242–8.
Asnis GM, Henderson MA. Levomilnacipran for the treatment of major depressive disorder: a
review. Neuropsychiatr Dis Treat. 2015;11:125–35.
Ballus C, Quiros G, De Flores T, et al. The efficacy and tolerability of venlafaxine and paroxetine in
outpatients with depressive disorders or dysthymia. Int Clin Psychopharmacol. 2000;15:43–8.
Bérard A, Sheehy O, Zhao JP, Vinet É, et al. SSRI and SNRI use during pregnancy and the risk of
persistent pulmonary hypertension of the newborn. Br J Clin Pharmacol. 2017;83:1126–33.
Bielski RJ, Ventura D, Chang CC. A double-blind comparison of escitalopram and venlafaxine
extended release in the treatment of major depressive disorder. J Clin Psychiatry. 2004;65:
1190–6.
Brent DA. Antidepressants and suicidality. Psychiatr Clin North Am. 2016;39:503–12.
Buckley NA, McManus PR. Fatal toxicity of serotonergic and other antidepressant drugs: analysis
of United Kingdom mortality data. Br Med J. 2002;325:1332–3.
1340 G. Laux and A. Klimke

Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL. Comparative affinity of duloxetine
and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human
serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology.
2001;25:871–80.
Carrasco JL, Kornstein SG, McIntyre RS, et al. An integrated analysis of the efficacy and safety of
desvenlafaxine in the treatment of major depressive disorder. Int Clin Psychopharmacol.
2016;31:134–46.
Carter NJ, McCormack PL. Duloxetine: a review of its use in the treatment of generalized anxiety
disorder. CNS Drugs. 2009;23:523–41.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, et al. Comparative efficacy and acceptability of
21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a
systematic review and network meta-analysis. Lancet. 2018;391:1357–66.
Cipriani A, Koesters M, Furukawa TA, Nosè M, et al. Duloxetine versus other antidepressive agents
for depression. Cochrane Database Syst Rev. 2012;10:CD006533.
Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and
safety profile for this newly approved antidepressant—what is the number needed to treat, number
needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2013;67:1089–104.
Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antide-
pressants. J Clin Psychiatry. 2002;63:357–66.
Clerc G. Antidepressant efficacy and tolerability of milnacipran, a dual serotonin and noradrenaline
reuptake inhibitor: a comparison with fluvoxamine. Int Clin Psychopharmacol. 2001;16:145–51.
Clerc GE, Ruimy P, Verdeau-Palles J. A double-blind comparison of venlafaxine and fluoxetine in
patients hospitalized for major depression and melancholia. The Venlafaxine French Inpatient
Study Group. Int Clin Psychopharmacol. 1994;9:139–43.
Coleman KA, Xavier VY. An indirect comparison of the efficacy and safety of desvenlafaxine and
venlafaxine using placebo as the common comparator. CNS Spectr. 2012;17:131–41.
Cording M, Derry S, Phillips T, Moore RA, Wiffen PJ. Milnacipran for pain in fibromyalgia in
adults. Cochrane Database Syst Rev. 2015;10:CD008244.
Costa e Silva J. Randomized, double-blind comparison of venlafaxine and fluoxetine in outpatients
with major depression. J Clin Psychiatry. 1998;59:352–7.
Cunningham LA, Borison RL, Carman JS, Chouinard G, et al. A comparison of venlafaxine,
trazodone, and placebo in major depression. J Clin Psychopharmacol. 1994;14:99–106.
Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on
newer generation compounds. Psychopharmacology. 1994;114:559–65.
Davidson JRT, Wittchen HU, Llorca PM, et al. Duloxetine treatment for relapse prevention in adults
with generalized anxiety disorder: a double-blind placebo-controlled trial. Eur Neuropsycho-
pharmacol. 2008;18:673–81.
Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant
withdrawal effects: are guidelines evidence-based? Addict behaviors. 2019;97:111–21.
Delini-Stula A. Milnacipran: an antidepressant with dual selectivity of action on noradrenaline and
serotonin uptake. Hum Psychopharmacol. 2000;15:255–60.
De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E. A systematic review and meta-
analysis considering the risk for congenital heart defects of antidepressant classes and individual
antidepressants. Drug Saf. 2021;44:291–312.
Dueñas H, Brnabic AJ, Lee A, Montejo AL. Treatment-emergent sexual dysfunction with SSRIs
and duloxetine: effectiveness and functional outcomes over a 6-month observational period. Int
J Psychiatry Clin Pract. 2011;15:242–54.
Eckert L, Lançon C. Duloxetine compared with fluoxetine and venlafaxine: use of meta-regression
analysis for indirect comparisons. BMC Psychiatry. 2006;6:30.
Einarson TR, Arikian SR, Casciano J, Doyle JJ. Comparison of extended-release venlafaxine,
selective serotonin reuptake inhibitors, and tricyclic antidepressants in the treatment of depres-
sion: a meta-analysis of randomized controlled trials. Clin Ther. 1999;21:296–308.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . . 1341

Einarson A, Fatoye B, Sarkar M, et al. Pregnancy outcome following gestational exposure to

venlafaxine: a multicenter prospective controlled study. Am J Psychiatry. 2001;158:1728–30.
Entsuah AR, Rudolph RL, Hackett D, Miska S. Efficacy of venlafaxine and placebo during long-
term treatment of depression: a pooled analysis of relapse rates. Int Clin Psychopharmacol.
1996;11:137–45.
Entsuah R, Gorman JM. Global benefit-risk assessment of antidepressants: venlafaxine XR and
fluoxetine. J Psychiatr Res. 2002;36:111–8.
Ereshefsky L, Dugan D. Review of the pharmacokinetics, pharmacogenetics, and drug interaction
potential of antidepressants: focus on venlafaxine. Depress Anxiety. 2000;12(Suppl 1):30–44.
Fagiolini A, Albert U, Ferrando L, Herman E. A randomized, double-blind study comparing the
efficacy and safety of trazodone once-a-day and venlafaxine extended-release for the treatment
of patients with major depressive disorder. Int Clin Psychopharmacol. 2020;35:137–46.
Fava M. Somatic symptoms, depression, and antidepressant treatment. J Clin Psychiatry. 2002;63:
305–7.
Fava GA, Benasi G, Lucente M, Offidani E, Cosci F, Guidi J. Withdrawal symptoms after
serotonin-noradrenaline reuptake inhibitor discontinuation: systematic review. Psychother
Psychosom. 2018;87:195–203.
Feighner JP. Cardiovascular safety in depressed patients: focus on venlafaxine. J Clin Psychiatry.
1995;56:574–9.
Feighner JP, Entsuah AR, McPherson MK. Efficacy of once-daily venlafaxine extended release
(XR) for symptoms of anxiety in depressed outpatients. J Affect Disord. 1998;47:55–62.
Fric M, Pfuhlmann B, Laux G, Riederer P, et al. The influence of smoking on the serum level of
duloxetine. Pharmacopsychiatry. 2008;41:151–5.
Gabriel M, Sharma V. Antidepressant discontinuation syndrome. CMAJ 2017;189:E747.
Gallagher HC, Gallagher RM, Butler M, Buggy DJ, Henman MC. Venlafaxine for neuropathic pain
in adults. Cochrane Database Syst Rev. 2015;8:CD011091.
Gelenberg AJ, Lydiard RB, Rudolph RL, et al. Efficacy of venlafaxine extended-release capsules in
nondepressed outpatients with generalized anxiety disorders. 6-month randomized controlled
trial. JAMA. 2000;283:3082–8.
Ghaemi NS. Clinical psychopharmacology. Oxford; 2019.
Gibbons RD, Brown CH, Hur K, Davis J, Mann JJ. Suicidal thoughts and behavior with antide-
pressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and
venlafaxine. Arch Gen Psychiatry. 2012;69:580–7.
Goldstein DJ, Lu Y, Detke MJ, et al. Duloxetine in the treatment of depression: a double-blind
placebo-controlled comparison with paroxetine. J Clin Psychopharmacol. 2004;24:389–99.
Guelfi JD, Ansseau M, Corruble E, Samuelian JC, Tournoux A, Pletan Y. A double-blind compar-
ison of the efficacy and safety of milnacipran and fluoxetine in depressed patients. Int Clin
Psychopharmacol. 1998;3:121–8.
Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine.
Arch Gen Psychiatry. 2000;57:503–9.
Hayes RM, Wu P, Shelton RC, Cooper WO, et al. Maternal antidepressant use and adverse
outcomes: a cohort study of 228,876 pregnancies. Am J Obstet Gynecol. 2012;207:49.e41–9.
Hiemke C, Bergemann N, Clement HW, Conca A, et al. Consensus guidelines for therapeutic drug
monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Kasper S, Pletan Y, Solles A, Tournoux A. Comparative studies with milnacipran and tricyclic
antidepressants in the treatment of patients with major depression: a summary of clinical trial
results. Int Clin Psychopharmacol. 1996;11(Suppl 4):35–9.
Keller MB, Trivedi MH, Thase ME, Shelton RC, et al. The prevention of recurrent episodes of
depression with venlafaxine for two years (PREVENT) study: outcomes from the 2-year and
combined maintenance phases. J Clin Psychiatry. 2007;68:1246–56.
Khan A, Fabre LF, Rudolph R. Venlafaxine in depressed outpatients. Psychopharmacol Bull.
1991;27:141–4.
1342 G. Laux and A. Klimke

Knadler MP, Lobo E, Chappell J, Bergstrom R. Duloxetine: clinical pharmacokinetics and drug
interactions. Clin Pharmacokinetics. 2011;50:281–94.
Kocsis JH, Thase ME, Trivedi MH, Shelton RC, et al. Prevention of recurrent episodes of
depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT study.
J Clin Psychiatry. 2007;68:1014–23.
Kornstein SG, Kocsis JH, Ahmed S et al. Assessing the efficacy of 2 years of maintenance treatment
with venlafaxine extended release in patients with recurrent major depression: a secondary
analysis of data from the prevent study. Int Clin Psychopharmacol 2008;23:357–63.
Laoutidis ZG, Kioulos KT. Desvenlafaxine for the acute treatment of depression: a systematic
review and meta-analysis. Pharmacopsychiatry. 2015;48:187–99.
Lecrubier Y. Milnacipran: the clinical properties of a selective serotonin and noradrenaline reuptake
inhibitor (SNRI). Hum Psychopharmacol. 1997;12:127–34.
Leinonen E, Leopola U, Mehtonen H, Rimon O-P. Long-term efficacy and safety of milnacipran
compared to clomipramine in patients with major depression. Acta Psychiatr Scand. 1997;96:
497–504.
Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended release vs placebo and paroxetine
in social anxiety disorder. Arch Gen Psychiatry. 2005;62:190–8.
Lopez-Ibor J, Guelfi JD, Pletan Y, Tournoux A, Prost JF. Milnacipran and selective serotonin
reuptake inhibitors in major depression. Int Clin Psychopharmacol. 1996;11(Suppl 4):41–6.
Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or
fibromyalgia. Cochrane Database Syst Rev. 2014;1:CD007115.
Macher JP, Sichel JP, Serre C, von Frenckell R, Huck JC, Demares JP. Double-blind placebo-
controlled study of milnacipran in hospitalized patients with major depressive disorders.
Neuropsychobiology. 1989;22:77–82.
Magni LR, Purgato M, Gastaldon C, Papola D, et al. Fluoxetine versus other types of pharmaco-
therapy for depression. Cochrane Database Syst Rev. 2013;17:CD004185.
Mehtonen OP, Sogaard J, Roponen P, Behnke K. Randomized, double-blind comparison of
venlafaxine and sertraline in outpatients with major depressive disorder. Venlafaxine
631 Study Group. J Clin Psychiatry. 2000;61:95–100.
Montgomery SA, Entsuah R, Hackett D, Kunz NR, Rudolph RL. Venlafaxine versus placebo in the
preventive treatment of recurrent major depression. J Clin Psychiatry. 2004;65:328–36.
Montgomery SA, Mansuy L, Ruth A, Bose A, et al. Efficacy and safety of levomilnacipran
sustained release in moderate to severe major depressive disorder: a randomized, double-
blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2013;74:363–9.
Nakagawa A, Watanabe N, Omori IM, Barbui C, et al. Efficacy and tolerability of milnacipran in the
treatment of major depression in comparison with other antidepressants: a systematic review and
meta-analysis. CNS Drugs. 2008;22:587–602.
Nakagawa A, Watanabe N, Omori IM, Barbui C, et al. Milnacipran versus other antidepressive
agents for depression. Cochrane Database Syst Rev. 2009;8:CD006529.
Nelson JC. Safety and tolerability of the new antidepressants. J Clin Psychiatry. 1997;58(6):26–31.
Nelson JC, Lu Pritchett Y, Martynov O, Yu JY, Mallinckrodt CH, Detke MJ. The safety and
tolerability of duloxetine compared with paroxetine and placebo: a pooled analysis of 4 clinical
trials. Prim Care Companion J Clin Psychiatry. 2006;8:212–9.
Nelson JC, Wohlreich MM, Mallinckrodt CH, Detke MJ, et al. Duloxetine for the treatment of
major depressive disorder in older patients. Am J Geriatr Psychiatry. 2005;13:227–35.
Nemeroff CB, Entsuah R, Benattia I, et al. Comprehensive analysis of remission (COMPARE) with
venlafaxine versus SSRIs. Biol Psychiatry. 2008;63:424–34.
Nierenberg AA, Feighner JP, Rudolph R, Cole J, Sullivan J. Venlafaxine for treatment-resistant
depression. J Clin Psychopharmacol. 1994;14:419–23.
Oakes TM, Katona C, Liu P, Robinson M, et al. Safety and tolerability of duloxetine in elderly
patients with major depressive disorder: a pooled analysis of two placebo-controlled studies. Int
Clin Psychopharmacol. 2013;28:1–11.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . . 1343

Olie JP, Gourion D, Montagne A, Rostin M, Poirier MF. Milnacipran and venlafaxine at flexible
doses (up to 200 mg/day) in the outpatient treatment of adults with moderate-to-severe major
depressive disorder: a 24-week randomized, double-blind exploratory study. Neuropsychiatr Dis
Treat. 2010;6:71–9.
Papakostas GI, Fava M. A meta-analysis of clinical trials comparing milnacipran, a serotonin—
norepinephrine reuptake inhibitor, with a selective serotonin reuptake inhibitor for the treatment
of major depressive disorder. Eur Neuropsychopharmacol. 2007;17:32–6.
Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. Are antidepressant drugs that combine
serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin
reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer
agents. Biol Psychiatry. 2007;62:1217–27.
Perahia DGS, Wang F, Mallinckrodt CH, Walker DJ, Detke MJ. Duloxetine in the treatment of
major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Psychiatry. 2006a;21:
367–78.
Perahia DGS, Pritchett YL, Desaiah D, Raskin J. Efficacy of duloxetine in painful symptoms: an
analgesic or antidepressant effect? Int Clin Psychopharmacol 2006b;21:311–7.
Perahia DGS, Maina G, Thase ME, et al. Duloxetine in the prevention of depressive recurrences: a
randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70:706–16.
Poirier MF, Boyer F. Venlafaxine and paroxetine in treatment-resistant depression: double-blind,
randomized comparison. Br J Psychiatry. 1999;175:12–6.
Pollack MH, Worthington JJ, Otto MW, et al. Venlafaxine for panic disorder: results from a double-
blind, placebo-controlled study. Psychopharmacol Bull. 1996;32:667–70.
Preskorn SH. Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone,
paroxetine, sertraline, and venlafaxine. J Clin Psychiatry. 1995;56:12–21.
Puech A, Montgomery SA, Prost JF, Solles A, Briley M. Milnacipran, a new serotonin and
norepinephrine reuptake inhibitor: an overview of its antidepressant activity and clinical toler-
ability. Int Clin Psychopharmacol. 1997;12:99–108.
Puozzo C, Panconi E, Deprez D. Pharmacology and pharmacokinetics of milnacipran. Int Clin
Psychopharmacology. 2002;17(Suppl 1):S25–35.
Richelson E. The clinical relevance of antidepressant interaction with neurotransmitter transporters
and receptors. Psychopharmacol Bull. 2002;36:133–50.
Rickels K, Pollack MH, Sheehan DV, Haskins JT. Efficacy of extended-release venlafaxine in
nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry. 2000;157:
968–74.
Robinson M, Oakes TM, Raskin J, et al. Acute and long-term treatment of late-life major depressive
disorder: duloxetine versus placebo. Am J Geriatr Psychiatry. 2014;22:34–45.
Rouillon F, Warner B, Pezous N, Bisserbe JC. Milnacipran efficacy in the prevention of recurrent
depression: a 12-month placebo-controlled study. Int Clin Psychopharmacol. 2000;15:133–40.
Rudolph RL, Derivan AT. The safety and tolerability of venlafaxine hydrochloride: analysis of the
clinical trials database. J Clin Psychopharmacol. 1996;16(suppl 2):54S–9S.
Rudolph RL, Feiger AD. A double-blind, randomized, placebo-controlled trial of once-daily
venlafaxine extended release (XR) and fluoxetine for the treatment of depression. J Affect
Disord. 1999;56:171–81.
Sambunaris A, Bose A, Gommoll CP, Chen C, et al. A phase III, double-blind, placebo-controlled,
flexible-dose study of levomilnacipran extended-release in patients with major depressive
disorder. J Clin Psychopharmacol. 2014;34:47–56.
Samuelian JC, Hackett D. A randomized, double-blind, parallel-group comparison of venlafaxine
and clomipramine in outpatients with major depression. J Psychopharmacol. 1998;12:273–8.
Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological com-
parison. Innov Clin Neurosci. 2014;11:37–42.
Sauer H, Huppertz-Helmhold S, Dierkes W. Efficacy and safety of venlafaxine ER vs. amitriptyline
ER in patients with major depression of moderate severity. Pharmacopsychiatry. 2003;36:169–75.
1344 G. Laux and A. Klimke

Schueler YB, Koesters M, Wieseler B, Grouven U, et al. A systematic review of duloxetine and
venlafaxine in major depression, including unpublished data. Acta Psychiatr Scand. 2011;123:
247–65.
Schweizer E, Feighner J, Mandos LA, Rickels K. Comparison of venlafaxine and imipramine in the
acute treatment of major depression in outpatients. J Clin Psychiatry. 1994;55:104–8.
Schweizer E, Weise C, Clary C, Fox I, Rickels K. Placebo-controlled trial of venlafaxine for the
treatment of major depression. J Clin Psychopharmacol. 1991;11:233–6.
Sechter D, Vandel P, Weiller E, Pezous N, Cabanac F, Tournoux A. A comparative study of
milnacipran and paroxetine in outpatients with major depression. J Affect Disord. 2004;83:
233–6.
Shelton RC. Serotonin norepinephrine reuptake inhibitors. In: Macaluso M, Preskorn SH, editors.
Antidepressants. Handbook of experimental pharmacology, vol. 250. Springer Nature; 2018.
Smith D, Dempster C, Glanville J, Freemantle N, Anderson I. Efficacy and tolerability of
venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a
meta-analysis. Br J Psychiatry. 2002;180:396–404.
Spencer CM, Wilde MI. Milnacipran. A review of its use in depression. Drugs. 1998;56:405–27.
Stahl S. Essential psychopharmacology. The prescriber’s guide. Antidepressants. 6th
ed. Cambridge: Cambridge University Press; 2017.
Stahl SM, Entsuah R, Rudolph RL. Comparative efficacy between venlafaxine and SSRIs: a pooled
analysis of patients with depression. Biol Psychiatry. 2002;52:1166–74.
Steen A, Den Bour JA. A double-blind, six-month comparative study of milnacipran and clomip-
ramine in major depressive disorder. Int Clin Pharmacol. 1997;12:269–81.
Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and
fibromyalgia pain: systematic review of randomised trials. BMC Neurol. 2008;8:29.
Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and
related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340:249–58.
Thase ME. Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients
with major depression. The Venlafaxine XR 209 Study Group. J Clin Psychiatry. 1997;58:
393–8.
Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744
depressed patients. J Clin Psychiatry. 1998;59:502–8.
Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or
selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234–41.
Thase ME, Clayton AH, Haight BR, Thompson AH, et al. A double-blind comparison between
bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability.
J Clin Psychopharmacol. 2006;26:482–8.
Thase ME, Kornstein SG, Germain JM, Jiang Q, et al. An integrated analysis of the efficacy of
desvenlafaxine compared with placebo in patients with major depressive disorder. CNS Spectr.
2009;14:144–54.
Thase ME, Gelenberg A, Kornstein SG, Kocsis JH, et al. Comparing venlafaxine extended release
and fluoxetine for preventing the recurrence of major depression: results from the PREVENT
study. J Psychiatr Res. 2011;45:412–20.
Thase ME, Asami Y, Wajsbrot D, Dorries K, et al. A meta-analysis of the efficacy of venlafaxine
extended release 75–225 mg/day for the treatment of major depressive disorder. Curr Med Res
Opin. 2016;33:317–26.
Tignol J, Pujol-Domenech J, Chartres JP, Leger JM, et al. Double-blind study of the efficacy and
safety of milnacipran and imipramine in elderly patients with major depressive episode. Acta
Psychiatr Scand. 1998;97:157–65.
Tzanakaki M, Guazelli M, Nimatoudis I, et al. Increased remission rates with venlafaxine compared
with fluoxetine in hospitalized patients with major depression and melancholia. Int Clin
Psychopharmacol. 2000;15:29–34.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine,. . . 1345

Van Amerongen AP, Ferrey G, Tournoux A. A randomized, double-blind comparison of

milnacipran and imipramine in the treatment of depression. J Affect Disord. 2002;72:21–31.
Weinmann S, Becker T, Koesters M. Re-evaluation of the efficacy and tolerability of venlafaxine
vs SSRI: meta-analysis. Psychopharmacology. 2008;196:511–20.
White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by
antidepressant type. J Med Toxicol. 2008;4:238–50.
Williams T, McCaul M, Guido Schwarzer G, et al. Pharmacological treatments for social anxiety
disorder in adults: a systematic review and network meta-analysis. Acta Neuropsychiatr.
2020;32:169–76.
Wong MC, Chung JW, Wong TK. Effects of treatments for symptoms of painful diabetic neurop-
athy: systematic review. BMJ. 2007;335(7610):87.
Monoamine Oxidase Inhibitors
in Depressive Disorders

Jeffrey H. Meyer, Dmitriy Matveychuk, Andrew Holt,

Apitharani Santhirakumar, and Glen B. Baker

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1348
Clinical Applications of MAOIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1349
Pharmacokinetics/Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1351
Adverse Effects of MAOIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1364
Drug-Drug Interactions with MAOIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1366
Use of Drugs in Combination with MAOIs to Treat Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1367
Pharmacological and Neurochemical Actions of MAOIs in Addition to Inhibition
of MAO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1368
Target Matching of MAOIs in Major Depressive Disorder (MDD) . . . . . . . . . . . . . . . . . . . . . . . 1369
Revitalization of Interest in MAOIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1370
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1370
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1371

Abstract
Monoamine oxidase inhibitors (MAOIs) first came into use as antidepressants in the
1950s and 1960s but were soon replaced as first-line drugs by tricyclic antidepressants
and then later by drugs like selective serotonin reuptake inhibitors (SSRIs). However,
there is a strong feeling among many prominent health professionals that the MAOIs
are effective antidepressants (and anxiolytics in some cases) that are underutilized
because of concerns about potential adverse effects, including food-drug and drug-
drug interactions, even though these are often avoidable and/or manageable. In this

J. H. Meyer · A. Santhirakumar
Centre for Addiction and Mental Health (CAMH) and Department of Psychiatry, University of
Toronto, Toronto, ON, Canada
e-mail: jeffrey.meyer@utoronto.ca; apitharani.santhirakumar@mail.utoronto.ca;
apitharani.santhirakumar@camh.ca
D. Matveychuk · A. Holt · G. B. Baker (*)
Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB,
Canada
e-mail: dmitriym@ualberta.ca; aholt@ualberta.ca; glen.baker@ualberta.ca

© Springer Nature Switzerland AG 2022 1347

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_98
1348 J. H. Meyer et al.

review, we discuss various aspects of MAOIs including pharmacology, clinical

applications, pharmacokinetics/metabolism, adverse effects, food-drug and drug-
drug interactions and combinations with other drugs for pharmacotherapy. Several
of the MAOIs are multifaceted, and their actions in addition to inhibition of MAO are
discussed briefly, as are the concerns about the underutilization, current availability
and inadequate education about these drugs in academic settings.

Introduction

Monoamine oxidase (MAO) enzymes catalyze the oxidation of several important

amines, including the biogenic amine neurotransmitters noradrenaline, serotonin
(5-hydroxytryptamine, 5-HT) and dopamine. MAO enzymes contain a covalently-
bound flavin adenine dinucleotide (FAD) cofactor (Binda et al. 2002), and the two
isozymes MAO-A and MAO-B (Johnston 1968) have 70% sequence homology
(Bach et al. 1988). Noradrenaline and serotonin are preferred substrates for MAO-A
and β-phenylethylamine is a preferred substrate for MAO-B (Johnston 1968;
Youdim et al. 1972). Dopamine has similar affinity for both isozymes (O’Carroll
et al. 1983). Several MAO inhibitors (MAOIs) have been used as antidepressants,
and this paper provides an overview of these drugs. Although there are numerous
MAOIs available (see Riederer et al. 2004 and Kennedy et al. 2009 for lists), only
five are currently used clinically as antidepressants. These are phenelzine,
tranylcypromine, isocarboxazid, moclobemide, and (
)-deprenyl (selegiline; admin-
istered orally in Parkinson’s disease and as a patch for treating depression).
Serendipity played a major role in the development of the MAOIs (Lopez-Munoz
and Alamo 2009). The hydrazine-based drugs isoniazid and iproniazid were used
initially in the treatment of tuberculosis in the 1950s. It was reported that the mood of
some of the tuberculosis patients seemed to improve while taking iproniazid
(Entzeroth and Ratty 2017), and it was determined thereafter that this drug also
inhibited MAO, reducing catabolism of noradrenaline and serotonin. Around the
same time, accumulating research revealed a functional deficiency of these two
biogenic amines at specific brain synapses in depression (review: Baker and
Dewhurst 1985). Iproniazid was then licensed for use as an antidepressant but was
withdrawn later because of hepatotoxicity. β-Phenylethylhydrazine (phenelzine) was
marketed as an antidepressant beginning in the early 1960s and is still marketed for
that purpose. Another hydrazine derivative, isocarboxazid, was also developed as an
antidepressant and is still commercially available. Tranylcypromine, a cyclized
derivative of amphetamine, became available at about the same time and is still
used clinically as an antidepressant. All of the drugs mentioned above are
non-selective MAOIs, inhibiting both MAO-A and -B, and are also irreversible.
Because of reports of increased blood pressure that occur when these drugs were
taken in conjunction with foods containing tyramine (a substrate for MAO-A in the
gut) or other sympathomimetic substances (see later section on adverse effects of
MAOIs), selegiline (an irreversible MAO-B inhibitor) and moclobemide
Monoamine Oxidase Inhibitors in Depressive Disorders 1349

Fig. 1 Structures of MAOIs

currently used as
antidepressants: phenelzine
(a), isocarboxazid (b),
tranylcypromine (c),
moclobemide (d), deprenyl (e)

(a reversible MAO-A inhibitor) were tested as antidepressants. The structures of the

above-mentioned drugs are shown in Fig. 1. Since all MAO inhibitors used for major
depressive disorder (MDD) have some level of MAO-A inhibition, it is clear that the
inhibition of MAO-A provides antidepressant activity, while the inhibition of
MAO-B is implicated in broader effects such as neuroprotective actions and inter-
vention in apoptosis (Riederer and Muller 2017).

Clinical Applications of MAOIs

Although MAOIs are no longer first-line drugs, there is general agreement that they
should definitely be considered for use in atypical depression (characterized by
pathological sensitivity to interpersonal loss or rejection, prominent anergia and
increased appetite, weight or sleep but lacking catatonic or melancholic features)
(Quitkin et al. 1993; Henkel et al. 2006; Ricken et al. 2017; Ulrich et al. 2017) and in
treatment-refractory depression (McGrath et al. 1987; Birkenhager et al. 2004;
Fiedorowicz and Swartz 2004; Amsterdam and Shults 2005: Kim et al. 2019).
However, there are numerous reports indicating that MAOIs are also effective in
the treatment of melancholic depression (endogenous depression) that is not
treatment-refractory (McGrath et al. 1984; Davidson et al. 1988; Gillman et al.
2020). In a systematic review comparing tranylcypromine and tricyclic
1350 J. H. Meyer et al.

antidepressants, Ulrich et al. (2020) concluded that tranylcypromine and tricyclics

are equally effective in depressed patients demonstrating mixed psychomotor symp-
toms and that tranylcypromine might be superior to the tricyclic antidepressants in
anergic (psychomotor-retarded) depression. Tranylcypromine and phenelzine have
also been reported to be effective in the treatment of bipolar depression
(Himmelhoch et al. 1982; Mallinger et al. 2009; Vazquez et al. 2013). Dysthymic
disorder (now called persistent depressive disorder) is characterized by chronic and
persistent mild depression, and it has been reported that MAOIs, tricyclics and
SSRIs are all equally effective treatments, but that SSRIs may be better tolerated
(De Lima and Hotopf 2003; Ishizaki and Mimura 2011).
The usual recommended doses of MAOIs as antidepressants in adults for mono-
therapy are as follows, but these may have to be adjusted if concurrent medication is
being taken or the elderly are being treated. The doses represent oral doses except in
the case of selegiline, where the drug is administered as a patch. The drugs may have
to be administered for up to 6 weeks at full dose for a clinical effect to be obtained.
While some trials have used three times daily dosing to address rapid blood plasma
clearance, it is well known that dosing frequency above twice daily is unlikely to
have adequate compliance, and it is also now known that antidepressants typically
have much slower pharmacokinetics in the brain than in plasma. Hence, oral dosing
is typically divided into two doses per day. Isocarboxazid: 10 mg daily is given
initially, increasing by 10 mg per day every 2–4 days or longer as tolerated up to
40 mg per day over one to 3 weeks; if the clinical trial is unsuccessful, the dose may
be similarly titrated to higher levels, with a maximum of 60 mg per day which may
be applied for maintenance. Phenelzine: The usual starting dose is 15 mg daily,
raised by 15 mg every 4 to 7 days, given across two dosing times per day, increasing
to 45 to 60 mg per day depending on patient tolerance. If after a 6-week trial, the
medication is well tolerated and there is no response, a higher dose such as 75 mg
may be considered. This is in accord with the clinical trials which typically show
positive results at total daily doses of 45 to 60 mg, with somewhat higher levels of
response and attrition at higher doses. It may be considered necessary to increase the
dose up to a maximum of 90 mg per day if tolerability permits. Tranylcypromine: A
starting dose of 10 mg per day is usually used, and then the dose is titrated by 10 mg
every 4 to 7 days, up to 30 mg daily, or preferably 40 mg daily across two doses as
tolerated. If there is inadequate response after 6 weeks, and tolerability is good, the
dose can be increased similarly in increments of 10 mg per day to assess the effect of
a 50 mg total daily dose or a maximum dose of 60 mg per day (30 mg twice daily).
Moclobemide: The usual initial dose is 300 mg per day in two divided doses after
meals. Tolerability tends to be excellent, and the dose is usually increased to 600 mg
per day in divided doses after the first week of treatment. Then treatment of 4 to
6 weeks is required in order to determine the efficacy. If an effect is obtained, the
dose is continued for maintenance. Selegiline transdermal patch (EMSAM): Initially,
a patch of 6 mg per 24 h is applied daily for a 6-week trial. If there is a non-response
and the patient is willing to complete the required dietary restriction, the dose may be
increased by 3 mg per day at 1- to 2-week intervals to a maximum dose of 12 mg
per day.
Monoamine Oxidase Inhibitors in Depressive Disorders 1351

Table 1 is a summary table that lists several important references that provide
information on many of the clinical studies that have been done on the use of MAOIs
in depression. Tables 2, 3, 4 and 5 list specific clinical studies for the most commonly
used MAOIs, i.e. phenelzine, tranylcypromine, moclobemide and EMSAM.
There are also reports in the literature on the effectiveness of MAOIs in treating
panic disorder, social anxiety disorder and post-traumatic stress disorder (Sheehan
et al. 1980; Stein et al. 2002; Versiani et al. 1996; Riederer et al. 2004; Zhang and
Davidson 2007; Baldwin et al. 2014; Cipriani et al. 2018; Williams et al. 2020;
Chamberlain et al. 2020).

Pharmacokinetics/Metabolism

Although phenelzine and tranylcypromine have been commercially available for

about 60 years, there is still a paucity of information about their metabolism.
Originally, it was assumed that phenelzine was metabolized primarily by N-acety-
lation, and it was even thought that acetylation status might be a predictor of
response to phenelzine, but it is now known that acetylation is a very minor
metabolic route for phenelzine (Robinson et al. 1985). Significant metabolites
include β-phenylethylamine, phenylacetic acid, p-hydroxyphenylacetic acid,
β-phenylethylidenehydrazine (PEH), phenylethyldiazene and phenylacetaldehyde
(Clineschmidt and Horita 1969; Tipton and Spires 1972; Robinson et al. 1985;
Kennedy et al. 2009). There is now considerable evidence that PEH is an active
metabolite that contributes to actions of phenelzine other than inhibition of MAO.
These include inhibition of GABA transaminase, inhibition of primary amine oxi-
dase and sequestration of toxic reactive aldehydes, actions which suggest that
phenelzine is a multifaceted drug with properties that extend beyond its antidepres-
sant effects (Song et al. 2013; Baker et al. 2019; Matveychuk et al. 2021). Phenelzine
is absorbed rapidly from the gastrointestinal tract (GIT); the time to peak plasma
concentration is less than an hour, and the elimination half-life is about 10 h (Kallem
et al. 2016). Steady-state MAO-A occupancy with positron emission tomography
(PET) imaging, that is, the change in MAO-A enzyme available to 11C-harmine, is
typically greater than 90% (Chiuccariello et al. 2016). Importantly, phenelzine, in
addition to being an inhibitor of MAO, is also metabolized by MAO (Tipton and
Spires 1972). Inhibiting MAO prior to administering phenelzine reduces the GABA-
elevating effect of the drug (Popov and Matthies 1969), suggesting that PEH,
responsible for the effects on GABA, is a major metabolite formed by
MAO-mediated oxidation of phenelzine. Catabolism of isocarboxazid is primarily
through hydrolysis in the liver by carboxylesterase (Larsen et al. 2016).
Despite being suggested in several papers and textbooks that tranylcypromine is
metabolized to amphetamine, most findings indicate that this is not a route of
metabolism of this drug (Baker et al. 1999). Hydroxylation and acetylation have
been reported as other routes of metabolism of tranylcypromine (Baker et al. 1999).
Tranylcypromine has a tmax of 1–2 h and a half-life of about 2 h (Ulrich et al. 2017).
Moclobemide is absorbed well from the GIT, the time to peak plasma concentration
1352 J. H. Meyer et al.

Table 1 Selected examples of important papers discussing the use of MAOIs in depression
White and Simpson 1981: Review of the literature on MAOI TCA combinations
Davidson et al. 1988: RCT on efficacy of isocarboxazid
Quitkin et al. 1993: Review of several double-blind studies comparing efficacy of phenelzine and
imipramine in atypical depression
Thase et al. 1995: Comprehensive review and meta-analysis of effectiveness of phenelzine,
tranylcypromine and isocarboxazid compared to TCAs
De Lima and Hotopf 2003: Systematic review of RCTs comparing two or more active drug
treatments for dysthymia (now called persistent depressive disorder). Comparisons of MAOIs and
TCAs were included
Bonnet 2003. Overview of clinical trials with moclobemide and its interactions with CYP
enzymes
Fiedorowicz and Swartz 2004: Review of the use of MAOIs in atypical depression, bipolar
depression and TRD
Riederer et al. 2004: Review of clinical applications of MAOIs which includes detailed tables on
RCTs with tranylcypromine and moclobemide in treatment of depressive disorders
Amsterdam and Shults 2005: Retrospective study on efficacy and safety of MAOIs in early and
advanced TRD
Henkel et al. 2006: Meta-analysis of evidence regarding treatment of atypical depression. MAOIs
(phenelzine and moclobemide) were compared to TCAs and SSRIs
Mallinger et al. 2009. Retrospective study on use of MAOIs and the SSRI paroxetine in bipolar
depression
Shulman et al. 2013: Review of the historical background and use of the MAOIs (phenelzine,
isocarboxazid, tranylcypromine, moclobemide and selegiline) in treatment of depression
Thomas et al. 2015: Literature review and retrospective study on combining MAOIs (phenelzine,
tranylcypromine, isocarboxazid, selegiline) with other antidepressants or stimulants for
management of TRD
Entzeroth and Ratty 2017: Review of the following aspects of MAOIs; historical background,
pharmacology, potential adverse effects and potential use in a number of disorders, with a focus on
moclobemide in the section on depressive disorders
Ricken et al. 2017: Detailed review and meta-analysis containing extensive text and tables on the
studies of the use of tranylcypromine to treat subtypes of depression
Chockalingam et al. 2018: Literature review on MAOIs covering historical background,
comparison of effectiveness of MAOIs and TCAs in depressive disorders and the
underprescribing of MAOIs and TCAs
Amsterdam and Kim 2019: Retrospective study on effectiveness of MAOI-TCA combination
therapy for TRD
Gillman 2019: An overview of MAOI and TCA interactions which includes a detailed list of
references to studies on the use and safety of MAOI-TCA combinations for treating depressive
disorders
Kim et al. 2019: Retrospective review comparing effectiveness of MAOIs versus TCAs as
monotherapy for early stage and advanced TRD
Ulrich et al. 2020: Meta-analysis comparing tranylcypromine and TCAs in the treatment of
depression
Abbreviations: MAOI monoamine oxidase inhibitor, RCT randomized controlled trial, SSRI selec-
tive serotonin reuptake inhibitor, TRD treatment resistant depression
Table 2 Acute phase trials of phenelzine (PHZ) in depression
Methods
Diagnostic system, duration Randomized (n)/
Author diagnostic method (weeks) RX cells (dosages) completers (n) Comments
Agnew et al. DSM-I, CLIN Random, DB PHZ (45 mg/d) 4/4 Inpatients; mixed depressive diagnoses; PHZ ¼
(1961) (3 weeks) ISO 6/6 IMI > PBO
IMI (75 mg/d) 6/6
PBO 5/5
Rees and “Diagnostic Random, DB PHZ (90 mg/d) 20/20 Inpatients; PHZ > PBO
Davies (1961) Criteria of Royal (3 weeks) PBO 21/20
Bethlehem Hospital”
Leitch and CLIN Random, DB PHZ (45 mg/d) 24/22 Inpatients; endogenous depression; PHZ ¼ IMI
Seager (1963) (4 weeks) IMI (150 mg/d) 26/25
Martin (1963) No systematic Random, DB PHZ (45–60 mg/d) NR/47 In- (n ¼ 79) and outpatients (n ¼ 16); endogenous
criteria reported, (4 weeks) IMI (150–200 NR/49 depression;
CLIN mg/d) IMI  PHZ
Glick (1964) Depression Random, DB PHZ (x ¼ 55 mg/d) NR/4 Outpatients;
Monoamine Oxidase Inhibitors in Depressive Disorders

Rating Scale (4 weeks) TRP NR/6 PHZ ¼ TCP > PBO

And Global PBO NR/6
Rating, CLIN
Greenblatt DSM-I, CLIN Random PHZ (60–75 mg/d) NR/38 Inpatients; mixed depressive diagnoses; 3-site
et al.a (1964) (Rx only), IMI (200–250 NR/73 collaborative study; PHZ ¼ PBO  IMI < ECT
DB mg/d) NR/68
(3 weeks) ISO NR/39
PBO NR/63
ECT (>
9 treatments)
Imlah et al. No systematic Random, PHZ (45 mg/d) 50/40 Outpatients;
(1964) criteria reported, single-blind IMI (150 mg/d) 40/41 PHZ ¼ IMI
CLIN (6 weeks)
1353

(continued)
Table 2 (continued)
1354

Methods
Diagnostic system, duration Randomized (n)/
Author diagnostic method (weeks) RX cells (dosages) completers (n) Comments
Schildkraut DSM-I, CLIN Random PHZ (45–60 6/6 Inpatients; PHZ ¼ IMI > PBO
et al. (1964) (3 weeks) mg/d) 6/6
IMI (100–200 5/5
mg/d)
PBO
Brit. Med. Res. No systematic Random PHZ (60 mg/d) 65/50 Inpatients; predominantly endogenous;
Coun. (1965) criteria reported, (Rx only), IMI (200 mg/d) 65/58 PHZ ¼ PBO < IMI < ECT
CLIN DB PBO 65/51
(4 weeks) ECT (4–8 65/58
treatments)
Kay et al. Newcastle Random, DB PHZ (45 mg/d) 31/27 Outpatients; non-endogenous depression;
(1973) Rating Scale, (4 weeks) AMI (150 mg/d) 31/18 PHZ ¼ IMI (intention to threat); PHZ  AMI
CLIN completers only
Robinson et al. Structured Random, DB PHZ (x ¼ 58.5 44/33 Outpatients with
(1973) Interview (6 weeks) mg/d) 43/27 nonendogenous depression;
Depression, DSM-II PBO PHZ > PBO
Raskin et al. DSM-II, CLIN Random, DB PHZ (x ¼ 45.5 110/78 Inpatients; mixed
(1974) (4 weeks) mg/d) 111/81 diagnoses; 9 site
PBO collaborative study; PHZ ¼ PBO
Ravaris et al. Structured Random, DB PHZ (total) 41/30 Outpatients; predominantly nonendogenous;
(1976) Diagnostic (6 weeks) 60 mg/d 20/14 PHZ (60 mg) > PBO ¼ PHZ (30 mg)
Interview, 30 mg/d 21/16
CLIN AMI (150 mg/d) 21/19
Davidson et al. Criteria of Random, DB PHZ (90 mg/d) 4/4 Inpatients;
(1977) Feighner et al., CLIN (3 weeks) IMI (150 mg/d) 6/6 PHZ ¼ IMI
Ravaris et al. SDI, RDC Random, DB PHZ (60 mg/d) 68/55 Outpatients;
(1980) (6 weeks) AMI (150 mg/d) 61/49 predominantly nonendogenous; PHZ ¼ AMI
J. H. Meyer et al.
Hamilton Criteria of Random (Rx PHZ (45–90 mg/d) NR/65 Mixed in- and
(1982) Feighner et al., CLIN only), open IMI (150–225 NR/65 outpatients (majority of Rx cases are outpatients);
label mg/d) NR/146 melancholia; newly referred depressed;
ECT (6–12 PHZ  IMI < ECT
treatments)
Rowan et al. RDC, Random, DB PHZ (x ¼ 75 mg/d) 58/42 Outpatients; non-endogenous;
(1982) Newcastle Rating (6 weeks) AMI (x ¼ 62/44 PHZ ¼ AMI > PBO
Scale, 188 mg/d) 56/45
CLIN PBO
Kayser et al. RDC, SDI Random, DB PHZ (60 mg/d) NR/23 Outpatients; PHZ ¼ AMI; In “hysteroid
(1985) (6 weeks) AMI (150 mg/d) NR/24 dysphoria,” PHZ (9/9) > AMI (3/5)
Georgotas et al. RDC, CLIN Random, DB PHZ (x ¼ 54 mg/d) 30/20 Outpatients; age
(1986) (6 weeks) NTP (x ¼ 79 mg/d) 30/23 55–75; PHZ ¼ NTP > PBO
PBO 30/19
Kayser et al. DSM-III, SDI Random, DB PHZ (60 mg/d) NR/12 Outpatients; DSM-III melancholia;
(1988) (6 weeks) AMI (150 mg/d) NR/12 PHZ ¼ AMI
Liebowitz et al. RDC, CLIN Random, DB PHZ (x ¼ 73 mg/d) 56/34 Outpatients;
(1988) (6 weeks) IMI (x ¼ 52/38 atypical major and minor depression;
Monoamine Oxidase Inhibitors in Depressive Disorders

255 mg/d) 55/47 PHZ > IMI > PBO

PBO
Quitkin et al.b RDC, CLIN Random, DB PHZ (x ¼ 72 mg/d) 24/17 Outpatients; probably atypical major and minor
(1988) (6 weeks) IMI (x ¼ 23/19 depression; PHZ  IMI ¼ PBO;
267 mg/d) 27/24 PHZ > PBO
PBO
Quitkin et al.b RDC, CLIN Random, DB PHZ (x ¼ 71 mg/d) 26/20 Outpatients; mood reactive, major and minor
(1989) (6 weeks) IMI (x ¼ 27/19 depression;
259 mg/d) 27/20 PHZ ¼ IMI > PBO
PBO
(continued)
1355
 1356

Table 2 (continued)
Methods
Diagnostic system, duration Randomized (n)/
Author diagnostic method (weeks) RX cells (dosages) completers (n) Comments
Quitkin et al.b RDC, CLIN Random, DB PHZ (x ¼ 73 mg/d) 33/30 Outpatients;
(1990) (6 weeks) IMI (x ¼ 37/34 atypical major and minor depression;
270 mg/d) 34/26 PHZ > IMI  PBO
PBO
Quitkin et al.b RDC, CLIN Random, DB PHZ (x ¼ 69 mg/d) 43/35 Outpatients;
(1991) (6 weeks) IMI (x ¼ 37/29 atypical major and minor depression patients who
276 mg/d) failed 6 weeks of placebo treatment;
PHZ > IMI
McGrath et al. RDC, CLIN Random, DB PHZ (x ¼ 56/45 Outpatients; probable or definite atypical major
(1993) (6 weeks) 75 mg/dc) 33/22 and minor depression patients who failed
IMI (x ¼ treatment with the other compound;
274 mg/dc) PHZ > IMI
Table adapted from Thase et al. (1995); copyright clearance from Springer Nature was obtained
Abbreviations: DSM Diagnostic and Statistical Manual of Mental Disorders, RDC Research Diagnostic Criteria, SDI Structured Depression Interview, DB
double blind, CLIN clinical assessment, PHZ phenelzine, ISO isocarboxazid, IMI imipramine, PBO placebo, TCP tranylcypromine, ECT electroconvulsive
therapy, AMI amitriptyline, NTP nortriptyline, NR not reported
a
Marked improvement only as employed in this study (the moderate improvement rating does not appear to correspond to the contemporary use of CGI score
of 2)
b
Patients completing >4 weeks are considered completers
c
Dosages reported only for nonresponders
J. H. Meyer et al.
Table 3 Acute phase trials of tranylcypromine (TCP) in depression
Diagnostic system, Methods duration Randomized (n)/
Author diagnostic method (weeks) RX cells (dosages) completers (n) Comments
Bartholomew No systematic Random, DB TCP (x ¼ 43 mg/d) 51/42 Outpatients;
(1962) diagnostic criteria, (6 weeks) PBO 51/49 TCP > PBO
CLIN
Gottfries No systematic Random, DB TCP (30 mg/d) NR/25 Inpatients;
(1963) method, CLIN (15 days) PBO NR/25 TCP ¼ PBO
Glick (1964) Depression Random, DB TCP (37 mg/d) NR/4 Outpatients;
Rating Scale and (14 weeks) PHZ NR/6 sample too small to ascertain significance
Global Rating, PBO NR/6
CLIN
Richmond and No systematic Random, DB TCP (40 mg/d) NR/20 Outpatients;
Roberts (1964) criteria, CLIN (3 weeks) ISO 38/20 TCP > AMI + IMI
AMI (150 mg/d) NR/20
IMI (225 mg/d) NR/20
Monoamine Oxidase Inhibitors in Depressive Disorders

Spear et al. No systematic Random, DB TCP (30 mg/d) 37/34 Inpatients and
(1964) criteria, CLIN (3 weeks) IMI (150 mg/d) 41/36 outpatients (proportion not specified);
TCP ¼ IMI
Himmelhoch RDC, SADS Random, DB TCP (40 mg/d) 28/22 Outpatients;
et al. (1982) (6 weeksa) PBO 31/17 predominantly bipolar; anergic
depression;
TCP > PBO
Razani et al. DSM-III, CLIN Random, DB TCP (40 mg/d) 25/21 Inpatients (57%)
(1983) (4 weeks) AMI (293 mg/d) 28/20 and outpatients (43%);
TCP ¼ AMI
White et al. RDC, CLIN Random, DB TCP (x ¼ 44 mg/d) 63/37 Outpatients;
(1984) (4 weeks) NTP (109 mg/d) 61/40 TCP ¼ NTP  PBO;
PBO 59/45 TCP > PBO
1357

(continued)
Table 3 (continued)
1358

Diagnostic system, Methods duration Randomized (n)/

Author diagnostic method (weeks) RX cells (dosages) completers (n) Comments
Nolen et al. DSM-III, CLIN Random, open First phase 14/14 Inpatients; resistant to serial trials of
(1985) (4 weeks) TCP (x ¼ 82 mg/d) 12/12 tricyclics, oxaprotiline, fluvoxamine, and
5-HTP (x ¼ 12/12 sleep deprivation; TCP > 5-HTP
182 mg/d) 5/5
Crossover of 26/26
failures 17/17
TCP
5-HTP
Pooled
TCP
5-HTP
Nolen et al. DSM-III, CLIN Random, DB TCP (x ¼ 78 11/11 Inpatients; resistant to serial trials of
(1988) (4 weeks) mg/d) 10/10 tricyclics, oxaprotiline, fluvoxamine, and
Nomifensine sleep deprivation;
(x ¼ 235 mg/d) TCP > NOM
Himmelhoch DSM-III, RDC, Random, DB TCP (x ¼ 36.8 28/26 Outpatients;
et al. (1991) CLIN (6 weeksa) mg/d) 28/21 anergic bipolar depression;
IMI (246 mg/d) TCP > IMI
Thase et al. DSM-III, RDC, Up to 6 weeksa TCP (x ¼ 39.2 12/10 Outpatients;
(1992) CLIN DB for non-responders mg/d) 4/3 anergic bipolar depression crossover;
of Himmelhoch et al. IMI (x ¼ 150 TCP > IMI
1991 mg/d)
Table adapted from Thase et al. (1995); copyright clearance from Springer Nature was obtained
Abbreviations: DSM Diagnostic and Statistical Manual of Mental Disorders, RDC Research Diagnostic Criteria, DB double blind, CLIN clinical assessment,
PHZ phenelzine, ISO isocarboxazid, IMI imipramine, PBO placebo, TCP tranylcypromine, AMI amitriptyline, NTP nortriptyline, NOM nomifensine, 5-HTP
5-hydroxytryptophan, NR not reported
a
4 weeks of treatment required to be considered as a completer
J. H. Meyer et al.
Table 4 Acute phase trials of moclobemide (MOC) in depression
Methods
Diagnostic system, diagnostic duration Randomized (n)/
Author method (weeks) RX cells (dosages) completers (n) Comments
Baumhackl et al. DSM-III, HAM-D, CLIN Random, DB MOC (300–600 mg/d) 189/154a Inpatients (n = 122, MOC; n = 120,
(1989) (4 weeks) IMI (100–200 mg/d) 192/161a IMI), outpatients (n = 37, MOC; n =
36, IMI), in- and out-patients (n = 30,
MOC; n = 36, IMI); 17 centres;
adverse effects greater in IMI; MOC
= IMI
Laux et al. DSM-III, Newcastle Rating Random, DB MOC (x̄ = 327 mg/d) 20a/15 Inpatients; predominantly
(1989) Scale, RDC (4 weeks) MAP (x̄ = 169 mg/d) 20a/20b endogenous depression; MOC =
CLIN MAP
Versiani et al. DSM-III, HAM-D, CLIN Random, DB MOC (300–600 mg/d) 164/138a Outpatients; MOC = IMI > PBO
(1989) (6 weeks) IMI (100–200 mg/d) 164/135a
PBO 162/126a
Classen and No specified diagnostic Random, DB MOC (x̄ = 300 mg/d) 13/13b Inpatients; assessed treatment of
Laux (1990) criteria (4 weeks) MAP (x̄ = 150 mg/d) 18/18b psychometric alterations (motor and
Monoamine Oxidase Inhibitors in Depressive Disorders

sensorimotor performance);
psychomotor performance: MOC <
MAP, in nonresponders
Dierick et al. No specified diagnostic Random, DB MOC (300–600 mg/d) 32/29 Patient type not specified; MOC =
(1990) criteria (4 weeks) CLO (75–150 mg/d) 31/22 CLO; difficulty interpreting results
due to small numbers and
concomitant medication
Laux et al. No specified diagnostic Random, DB MOC (x̄ = 327 mg/d) 20a/15 Inpatients; predominantly
(1990) criteria (4 weeks) MAP (x̄ = 169 mg/d) 20a/20b endogenous depression; MOC =
MAP
(continued)
1359
 1360

Table 4 (continued)
Methods
Diagnostic system, diagnostic duration Randomized (n)/
Author method (weeks) RX cells (dosages) completers (n) Comments
Lecrubier and DSM-III, CLIN Random, DB MOC (300–600 mg/d) 164/146c Outpatients; multicenter study; 50%
Guelfi (1990) (6 weeks) IMI (100–200 mg/d) 164/145c of patients endogenously depressed;
PBO 162/120c MOC = IMI > PBO
Larsen et al. Newcastle II Scale, HAM-D, Random, DB MOC (300–600 mg/d) 59/41 Outpatients; atypical, endogenous,
(1991) QSAD, DSM-III, CLIN (6 weeks) CLO (150–200 mg/d) 57/39 and reactive depression; MOC < ISO
ISO (30–40 mg/d) 51/39 < CLO
Bakish et al. DSM-III-R, HAM-D, CLIN Random, DB MOC (200–600 mg/d) 58/40 Outpatients; multi center study; MOC
(1992) (6 weeks) AMI (50–150 mg/d) 59/39 = AMI > PBO
PBO 56/28
Evans et al. DSM-III, HAM-D, CLIN Random, DB MOC (x̄ = 325 mg/d) 24/19 In- (n = 4) and outpatients (n = 44);
(1992) (4 weeks) AMI (x̄ = 123 mg/d) 24/17 multicenter study; MOC = AMI
Guelfi et al. Newcastle Rating Scale, ICD- Random, DB MOC (300–600 mg/d) 62/47 Inpatients; endogenous depression;
(1992) 9, MADRS, DSM-III, CLIN (6 weeks) CLO (100–200 mg/d) 67/56 MOC = CLO
DUAG (1993) DUAG diagnostic depression Random, DB MOC (400 mg/d) 57/51d Inpatients; MOC < CLO
scale, HAM-D, CLIN (6 weeks) CLO (150 mg/d) 58/56d
Philipp et al. Research diagnostic criteria, Random, DB MOC (400–500 mg/d) 118/94e Outpatients; MOC = DOX; MOC
(1993) HAM-D, CLIN (6 weeks) DOX (100–125 mg/d) 119/89e better tolerated
Rimon et al. DSM-III, HAM-D, CLIN Random, DB MOC (150–525 mg/d) 62/55 Inpatients and outpatients (proportion
(1993) (4 weeks) IMI (50–175 mg/d) 65/58 not specified); MOC = IMI
Williams et al. DSM-III, HAM-D, CLIN Random, DB MOC (300–600 mg/d) 62/49 In- (21% MOC, 33% FLU) and
(1993) (6 weeks) FLU (20–40 mg/d) 60/43 outpatient (79% MOC, 67% FLU);
MOC = FLU
J. H. Meyer et al.
UK DSM-III, HAM-D, CLIN Random, DB MOC (450 mg/d) NR/56 Patient type not specified; multi-
Moclobemide (6 weeks) IMI (150 mg/d) NR/50 center study; MOC = IMI = PBO
Study Group PBO NR/54
(1994)
Gachoud et al. DSM-III, HAM-D, CLIN Random, DB, MOC (300–400 mg/d) 66/54 Outpatients; MOC = MAP
(1994) (4 weeks) MAP (75–100 mg/d) 64/55
Lonnqvist et al. DSM-III-R, HAM-D, CLIN Random, DB MOC (300–450 mg/d) 102/84 Inpatients and outpatients (84%
(1994) (6 weeks) FLU (20–40 mg/d) 107/85 MOC, 79% FLU); MOC = FLU
Kragh-Sorensen DSM-III-R, HAM-D, CLIN Random, DB MOC (400 mg/d) 48/39a,f Patient type not specified; MOC =
et al. (1995) (6 weeks) CLO (150 mg/d) 48/30a,f CLO
Lecrubier et al. DSM-III, HAM-D, CLIN Random, DB MOC (400–600 mg/d) 98/68a Outpatients; nonmelancholic,
(1995) (12 weeks) CLO (100–150 mg/d) 93/62a nonpsychotic major depression MOC
= CLO
Nair et al. (1995) DSM-III-R, CLIN Random, DB MOC (400 mg/d) 36/15a Inpatients and outpatients; ages > 60;
(7 weeks) NOR (75 mg/d) 38/20a 3 inter-national sites; MOC  PBO;
PBO 35/20a NOR > PBO
Reynaert et al. DSM-III-R, HAM-D, CLIN Random, DB MOC (300–600 mg/d) 51/38 In- (n = 65) and outpatients (n = 34);
(1995) (6 weeks) FLU (20–40 mg/d) 50/42 MOC = FLU
Monoamine Oxidase Inhibitors in Depressive Disorders

Lapierre et al. DSM-III-R, HAM-D, CLIN Random, DB MOC (x̄ = 440  123 66/53 Outpatients; MOC = FLU
(1997) (6 weeks) mg/d) 62/54
FLU (x̄ = 35  8 mg/
d)
Jouvent et al. MADRS, DSM-III-R, Random, DB MOC (450 mg/d) 65/62a Inpatients; MOC  CLO
(1998) Abrams-Taylor Scale, ERD, (4 weeks) CLO (150 mg/d) 59/54a
CLIN
Sogaard et al. Random, DB MOC (300–450 mg/d) 97/84 Outpatients; atypical depression;
(1999) (12 weeks) SER (50–100 mg/d) 100/83 MOC  SER
(continued)
1361
 1362

Table 4 (continued)
Methods
Diagnostic system, diagnostic duration Randomized (n)/
Author method (weeks) RX cells (dosages) completers (n) Comments
Atypical Depression
Diagnostic Scale, HAM-D,
DSM-III-R, CLIN
Table adapted from Riederer et al. (2004)
Abbreviations: DSM = Diagnostic and Statistical Manual of Mental Disorders; HAM-D = Hamilton Depression Rating Scale; QSAD = Quantitative Scale for
Atypical Depression; ICD = International Classification of Diseases; MADRS = Montgomery-Asberg Depression Rating Scale; RDC = Research Diagnostic
Criteria; DUAG = Danish University Antidepressant Group; ERD = échelle de ralentissement dépressif; DB = double blind; CLIN = clinical assessment; MOC
= moclobemide; AMI = amitriptyline; PBO = placebo; CLO = clomipramine; ISO = isocarboxazid; DOX = doxepin; IMI = imipramine; FLU = fluoxetine; MAP
= maprotiline; NOR = nortriptyline; SER = sertraline
a
Data estimated from published figure
b
Patient dropout numbers not specified
c
Completers calculated with the percentages of dropouts mentioned in article
d
Number of randomizers and completers during active treatment
e
Additional 14 patients from both groups (proportion not specified) were withdrawn from study for protocol violation (169 valid completers)
f
Patients with HAM-D scores  16
J. H. Meyer et al.
Monoamine Oxidase Inhibitors in Depressive Disorders 1363

Table 5 Acute phase trials of selegiline transdermal system (STS; EMSAM) in depressiona
Diagnostic
system, Methods
diagnostic duration RX cells Randomized (n)/
Author method (weeks) (dosages) completers (n) Comments
Bodkin and DSM-IV, Random, STS 89/79 Outpatients;
Amsterdam HAM-D, DB (20 mg/d) 88/73 six-site
(2002) CLIN (6 weeks) PBO collaboration
study; tyramine-
restricted diet
during trial and
2 weeks
following end of
treatment;
STS > PBO
Amsterdam DSM-IV, Random, STS 149/108b Outpatients;
(2003) HAM-D, DB, (6 mg/d) 152/111b 16 investigative
CLIN (8 weeks) PBO sites; no dietary
restrictions;
STS > PBO
Feiger et al. DSM-IV, Random, STS 132/100 Patient type not
(2006) Mini DB, (6–12 133/106 specified; no
International (8 weeks) mg/d) dietary
Neuropsy- PBO restrictions;
chiatric STS > PBO
Interview,
HAM-D,
CGI-S,
CLIN
Table adapted from Jessen et al. (2008).
Abbreviations: STS selegiline transdermal system, DSM Diagnostic and Statistical Manual of
Mental Disorders, HAM-D Hamilton Depression Rating Scale, CGI-S Clinical Global Impressions
Scale, DB double blind, CLIN clinical assessment, PBO placebo
a
Only includes studies that targeted patients ages 18 and above
b
41 patients from each group discontinued; completers (n) calculated by subtracting 41 from
randomized (n)

is 0.3–2 h, and the elimination half-life after oral administration is around 2 h (Nair
et al. 1993). Chronic dosing of total daily doses of 300 mg to 1200 mg is associated
with MAO-A occupancies of 75% to 85% (Chiuccariello et al. 2016). Moclobemide
is metabolized extensively in the liver (Jauch et al. 1990), and at least, part of that
metabolism appears to be catalyzed by CYP2C19 (Waldmeier et al. 1994). In
addition, moclobemide is an inhibitor of CYPs 2C19, 2D6 and 1A2 (Gram et al.
1995; Bonnet 2003). Two major metabolites appearing in the plasma are a pharma-
cologically inactive lactam formed by oxidation of the morpholine moiety and the
N-oxide which retains weak MAO-A-inhibiting activity (Jauch et al. 1990). There
has been a great deal of research on the metabolism of selegiline, with extensive
metabolism to the (
) isomers of methamphetamine, amphetamine,
N-propargylamphetamine and selegiline-N-oxide reported (Heinonen et al. 1989),
1364 J. H. Meyer et al.

and much of this metabolism is catalyzed by several CYP enzymes (Salonen et al.
2003; Meyer 2017). Because of their long-lasting inhibition of MAO, the pharma-
codynamic half-life of the irreversible MAOIs is very much longer than their
pharmacokinetic half-life.

Adverse Effects of MAOIs

One of the most widely described adverse effects of irreversible MAOIs is the
“cheese effect,” which is actually a food-drug interaction. An increase in blood
pressure, the result of irreversible inhibitors of MAO-A (e.g., phenelzine,
tranylcypromine, isocarboxazid) preventing the oxidation of sympathomimetic
amines, primarily tyramine, in foodstuffs ingested while the patient is taking the
MAOI, may result in symptoms ranging from a headache to a full-blown hyperten-
sive crisis. Tyramine, a sympathomimetic amine that is present at relatively high
concentrations in some foods, is normally metabolized by MAO-A in the gut.
However, when such foods are ingested by patients taking irreversible,
non-selective MAOIs, the tyramine is not metabolized and enters sympathetic
varicosities supplying the vasculature. Displacement and release of noradrenaline,
which may itself be present in vesicles at elevated concentrations due to inhibition of
MAO-A, results in intense vasoconstriction. This effect is called the cheese effect
because in early studies on this phenomenon, one of the proposed food culprits was
aged cheese. The awareness of this effect means that patients receiving these drugs
receive a list of foods that should be avoided while taking these medications. This
adverse effect has been widely described in medical textbooks and has been respon-
sible in large part for the underutilization of MAOIs as antidepressants. However, as
indicated in numerous papers (e.g., Grady and Stahl 2012; Meyer 2017; Gillman
2018), many of the foods on the list do not contain as much tyramine as in past years
because of improved food processing. Although clinicians and patients should be
aware of this food-drug interaction, it is generally felt to be manageable with correct
dietary instructions (Gillman 2018), and the list of culprit foods has now been
updated (see Grady and Stahl 2012; Meyer 2017; and Chockalingam et al. 2018
for current information).
Nevertheless, concern about this adverse effect did lead to the development of
reversible inhibitors of MAO-A (RIMAs) (Nair et al. 1993; Waldmeier et al. 1994;
Fulton and Benfield 1996; Riederer et al. 2004), one of which, moclobemide, is used
in many countries, although not approved in the USA. Unlike phenelzine,
tranylcypromine and isocarboxazid, moclobemide is not an irreversible inhibitor of
MAO-A, but rather competes reversibly with substrates (including tyramine) for
access to the active site. Moclobemide retains antidepressant properties through
reducing the inactivation of noradrenaline and serotonin, but tyramine may still
compete for access to the enzyme, thereby minimizing risk of an increase in levels of
the dietary amine. Moclobemide also has the advantage that in situations where it is
decided to stop the MAOI, it is not necessary to wait for about 2 weeks while new
enzyme is synthesized before starting another drug; the drug change can be made
Monoamine Oxidase Inhibitors in Depressive Disorders 1365

after a much shorter time in the case of moclobemide. Brofaromine, a RIMA that
also has modest effects as a serotonin reuptake inhibitor, has also been reported to be
an effective antidepressant (Laux et al. 1990; Chouinard et al. 1993; Volz et al. 1996;
Lotufo-Neto et al. 1999; Entzeroth and Ratty 2017), but was not marketed for what
were apparently commercial reasons.
In another effort to deal with the cheese effect, the drug (
)-deprenyl (selegiline)
a selective, irreversible MAO-B inhibitor, was tested as an antidepressant. Deprenyl
was actually synthesized in the 1960s as a potential psychic energizer, and it was
subsequently discovered that the (
) enantiomer (selegiline) was a strong selective
MAO-B inhibitor at low doses (Knoll and Magyar 1972). Early clinical studies with
oral selegiline, alone or in combination with the amino acids L-5-hydroxytryptophan
or L-phenylalanine, reported antidepressant activity (Mendlewicz and Youdim 1978,
1983; Birkmayer et al. 1984). Mendlewicz and Youdim (1983) reported, in a double-
blind placebo-controlled study, that oral selegiline at 15 mg/day for 40 days pro-
duced an improvement in Hamilton scores beginning at 8 days and a marked
improvement by 40 days of administration. Mann et al. (1989), also in a double-
blind placebo-controlled study, compared the effects of doses of selegiline of 10 mg/
day and 30 mg/day (the latter dose inhibits MAO-A as well as MAO-B), each dose
administered for 3 weeks; they found an antidepressant effect with the higher dose,
but not with the lower dose. In addition, plasma levels of selegiline fluctuate
considerably after oral dosing (Azzaro et al. 2007); so, in order to take advantage
of the potential antidepressant effect of selegiline and achieve consistent blood
plasma levels, it has been administered topically, as a patch (Bodkin and Amsterdam
2002: Tabi et al. 2020), minimizing inhibition in the gut while causing an antide-
pressant effect due to inhibition of MAO-A (and -B) in brain, a consequence of the
high brain-blood concentration ratio achieved. Fowler et al. (2015), in a [11C]
clorgyline PET study of patients treated with the selegiline patch for 28 days,
demonstrated a modest occupancy of brain MAO-A of 33 per cent. The transdermal
patch is marketed under the proprietary name, EMSAM. Oral selegiline and
rasagiline, another selective inhibitor of MAO-B, are used in the treatment of
Parkinson’s disease (Riederer et al. 2004; Riederer and Muller 2017;Tabi et al.
2020).
Although the cheese effect and hypertension have received a great deal of
attention, MAOIs administered under conditions in which there is not concomitant
consumption of potentially interacting foods or sympathomimetic drugs are more
likely to produce hypotension and associated dizziness (Fiedorowicz and Swartz
2004; Meyer 2017; Ricken et al. 2017; Kiani 2020). Although not well documented,
tranylcypromine may produce transient paradoxical hypertension in some patients in
an hour or two after administration (Gillman 2018). Weight gain and sexual dys-
function may occur with phenelzine and isocarboxazid, but these adverse effects
appear much less frequently with tranylcypromine and moclobemide (Ricken et al.
2017; Meyer 2017; Kiani 2020). Insomnia and dry mouth occur more often with
tranylcypromine than with the hydrazine MAOIs (Kiani 2020). Pyridoxine defi-
ciency and rare cases of hepatotoxicity have been reported with phenelzine
(Fiedorowicz and Swartz 2004). In a systematic review and meta-analysis
1366 J. H. Meyer et al.

comparing tranylcypromine and tricyclic antidepressants in treatment of depression,

Ulrich et al. (2020) reported a significantly lower frequency of tremor, constipation
and blurred vision and a significantly higher frequency of insomnia with
tranylcypromine. Moclobemide has a relatively mild side effect profile, with weight
gain and sexual dysfunction uncommon, although nausea, insomnia, tremor and
light-headedness, fatigue, headache and nervousness may occur transiently (Moll
et al. 1994; Ricken et al. 2017). With the selegiline patch, there may be a reaction at
the site of application and headache, insomnia, diarrhea and dry mouth (Bodkin and
Amsterdam 2002).
Although concern about adverse effects has been a factor in the reduction of the
use of MAOIs over the past decades, the tolerability is manageable in many cases
(Grady and Stahl 2012; Gillman 2011a, 2018; Gillman et al. 2020). In a meta-
analysis, Meister et al. (2016) reported that MAOIs did not differ significantly from
selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake
inhibitors (SNRIs) in the likelihood of patients discontinuing antidepressant treat-
ment due to adverse effects.

Drug-Drug Interactions with MAOIs

The main drug-drug interactions of concern with MAOIs are those involved in
increased blood pressure caused by noradrenergic sympathomimetic drugs and
those that may cause serotonin syndrome (due to markedly increased serotonin
availability as a result of combining MAOIs with serotonin reuptake inhibitors).
With regard to noradrenergic drugs, product monographs indicate that the following
should be not be used in patients prescribed an MAOI: decongestants (phenyleph-
rine, pseudoephedrine), stimulants (amphetamine, methylphenidate, modafinil,
armodafinil), antidepressants that inhibit noradrenaline reuptake and some other
drugs including phentermine, local anaesthetics containing vasoconstrictors,
tramadol and tapentadol. However, in exceptional circumstances, some of these
drugs have been used cautiously in combination with MAOIs in treatment-resistant
depression (Grady and Stahl 2012; Israel 2015; Thomas et al. 2015), for example,
with some anaesthetics in situations in which surgeries are required and an MAOI
has been an essential antidepressant or in combination with certain antidepressants
when virtually all other antidepressant treatments have been unsuccessful. Patients
who are known abusers of cocaine, methamphetamine or other stimulants should not
be treated with MAOIs. With regard to opioids, there are no known direct interac-
tions between MAOIs and opioid mechanisms, but opioids with off-target effects
that influence the reuptake or release of serotonin such as meperidine, methadone,
tramadol and dextromethorphan or tapentadol which inhibits noradrenaline reuptake
are contraindicated. Other drugs that may cause serotonin syndrome in combination
with MAOIs include SSRIs, SNRIs, the tricyclics clomipramine and imipramine,
St. John’s wort, sumatriptan, chlorpheniramine and brompheniramine (Grady and
Stahl 2012). There is a wide range of symptoms in serotonin syndrome, the most
serious of these being hyperthermia, brain damage and even death (Grady and Stahl
Monoamine Oxidase Inhibitors in Depressive Disorders 1367

2012; Volpi-Abadie et al. 2013). The Hunter criteria used for diagnosis of serotonin
syndrome include clonus, agitation, diaphoresis, tremor and hyperreflexia (Dunkley
et al. 2003). For detailed discussions of serotonin syndrome/serotonin toxicity,
readers are referred to Gillman (2011b) and Buckley et al. (2014). Moclobemide
inhibits CYP2C19, CYP1A2 and CYP2D6 and may decrease catabolism of sub-
strates for those enzymes, although there have been relatively few reports of
clinically relevant drug interactions involving moclobemide (Bonnet 2003). Cimet-
idine has been reported to double plasma levels of moclobemide when the two drugs
are coadministered (Nair et al. 1993).
If discontinuation of a serotonin reuptake inhibitor is required in order to start a
patient on an MAOI, it may be necessary to wait for up to 2 weeks, depending on the
half-life of the serotonin reuptake inhibitor (but in the case of fluoxetine a 5-week
wait is required). If discontinuing an irreversible MAOI to switch to another drug, a
delay of 2 weeks is required to allow new MAO to be synthesized (Grady and Stahl
2012). In the case of the reversible MAOI moclobemide, the product monograph
typically recommends a washout period of 4–5 days. When switching from an
irreversible MAOI to another MAOI, a 2-week delay is also recommended, but it
is also acknowledged that the gap without antidepressant treatment may be associ-
ated with a worsening of symptoms in patients with severe depression, and there
have been reports of successful switches with much shorter delays (Szuba et al.
1997; Polnak et al. 2017), although such patients should be monitored closely.
A detailed table on switching based on the Maudsley Prescribing Guidelines is
available (Luft 2013). With regard to surgery on patients taking MAOIs, it has
generally been recommended that the use of MAOIs be discontinued prior to
surgery. However, such discontinuation may risk compromising the patient’s psy-
chiatric status, and there are reports indicating that discontinuation of the MAOI is
not always necessary (Van Haelst et al. 2012; Krings-Ernst et al. 2013).

Use of Drugs in Combination with MAOIs to Treat Depression

The product monographs for MAOIs consistently report that the addition of an
MAOI to a failed tricyclic antidepressant trial is dangerous because of the risk of a
possible hypertensive or serotonergic crisis. There is a dissenting view in the
literature reporting that the tricyclic (with the exception of clomipramine, which
must be avoided) plus MAOI combination is effective and well-tolerated (White and
Simpson 1981; Gillman 2007, 2019; Amsterdam and Kim 2019; Ulrich et al. 2020
and references therein). It has been proposed that the combination of tricyclic
antidepressants that are strong noradrenaline reuptake inhibitors with MAOIs
might even make the MAOIs safer since the tricyclic attenuates the pressor response
to tyramine (Gillman 2007, 2011a). When MAOIs and tricyclics have been proposed
as combinations, it has been indicated that the two drugs should be started together
or the tricyclic should be given before the MAOI (White and Simpson 1981; Ulrich
et al. 2020). There are cases in the literature where very serious adverse effects
occurred when the tricyclic is started after the MAOI, but there are fewer reports of
1368 J. H. Meyer et al.

serious adverse events when the MAOI is given after the TCA is started (White and
Simpson 1981). Gillman (2019) has published a comprehensive list of references to
studies on MAOI-tricyclic antidepressant combinations.
Other drugs that have been used in combination with MAOIs include trazodone,
bupropion, lithium, stimulants such as pemoline, amphetamine and methylpheni-
date, and atypical (second-generation) antipsychotics (Tariot et al. 1986; Fawcett
et al. 1991; Kok et al. 2007; Israel 2015; Thomas et al. 2015; Meyer et al. 2017;
Meyer 2018; Kiani 2020). Lithium augmentation has been used effectively with
tranylcypromine (Tariot et al. 1986) and phenelzine (Kok et al. 2007). However, it
should be noted that all of these, with the exception of lithium addition, are generally
contraindicated in combination with MAOIs in product monographs. It is reported
that the addition of low-dose trazodone to MAOIs appears to improve tolerability to
the MAOIs by counteracting insomnia (Nierenberg and Keck 1989). However,
trazodone has some serotonin reuptake-inhibiting ability and is listed in the June
2020 position statement of the Royal College of Psychiatrists in the United Kingdom
as one of the drugs that MAOIs should not be prescribed alongside because of the
risk of inducing serotonin syndrome (Chamberlain et al. 2020). Tranylcypromine
and bupropion in combination have been reported to improve symptoms in
treatment-refractory depression (Pierre and Gitlin 2000); however, Thomas et al.
(2015) have indicated that patients on this combination should be monitored closely
for hypertension and, as mentioned earlier, this is contraindicated in most product
monographs. Stimulants have been reported to be effective in combination with
MAOIs for treatment-refractory depression (Fawcett et al. 1991; Feinberg 2004).
The stimulants may help in normalizing blood pressure in those patients experienc-
ing hypotension when taking an MAOI, but patients taking this drug combination
must be monitored carefully (Thomas et al. 2015), and again, this is contraindicated
in most product monographs. Meyer et al. (2017) published a case report, accom-
panied by a literature review, in which a combination of phenelzine, aripiprazole and
quetiapine was effective in a treatment-resistant patient. The authors concluded that
the atypical antipsychotics are effective for augmenting MAOIs in patients who have
responded inadequately. They also stated that there may be a risk for orthostasis in
middle-aged and older patients with MAOI-atypical antipsychotic combinations but
that with the exception of ziprasidone, the combination does not carry the problem of
potential serotonin syndrome (Meyer et al. 2017).

Pharmacological and Neurochemical Actions of MAOIs

in Addition to Inhibition of MAO

In addition to being an inhibitor of MAO, phenelzine is an inhibitor of

γ-aminobutyric acid transaminase (GABA-T) and causes a marked, long-lasting
elevation of rat brain GABA after a single dose (Popov and Matthies 1969; Baker
et al. 1991). This may contribute to its anxiolytic actions and also to its
neuroprotective/neurorescue actions in an animal model of stroke (Song et al.
2013; Baker et al. 2019). The metabolite PEH has been proposed to make a major
Monoamine Oxidase Inhibitors in Depressive Disorders 1369

contribution to this GABA-elevating action (Paslawski et al. 2001). As primary

hydrazines, both phenelzine and PEH can sequester toxic reactive aldehydes such as
acrolein, 4-hydroxynonenal and formaldehyde (Wood et al. 2006; MacKenzie 2009;
Matveychuk et al. 2021), which may contribute to their effectiveness in attenuating
symptoms in animal models of multiple sclerosis (Benson et al. 2013), traumatic
brain injury (Singh et al. 2013) and spinal cord injury (Chen et al. 2016). Although
PEH is only a very weak inhibitor of MAO, like phenelzine, it is a relatively strong
inhibitor of primary amine oxidase (MacKenzie 2009; Song et al. 2013), the enzyme
responsible for catalyzing the metabolism of methylamine to the potentially toxic
reactive aldehyde formaldehyde (Lyles et al. 1990).
Tranylcypromine is a mixture of two enantiomers, the (
) enantiomer being an
inhibitor of noradrenaline reuptake and the (+) enantiomer responsible for the
inhibition of MAO (Hampson et al. 1986; Ulrich et al. 2017), and it is possible
that both effects contribute to its antidepressant actions (Schlessinger et al. 2011).
Long-term, but not short-term, administration of tranylcypromine to rats results in
increases in brain levels of brain-derived neurotrophic factor (BDNF), which may
also contribute to its antidepressant actions (Nibuya et al. 1995). It is well known that
selegiline has neuroprotective properties in a wide variety of models in vitro and
in vivo (Tatton et al. 2003; Youdim et al. 2006; Riederer and Muller 2017; Szoko
et al. 2018). It has been proposed that often these neuroprotective actions of
selegiline are not related directly to inhibition of MAO (Tatton et al. 2003; Riederer
and Muller 2017).

Target Matching of MAOIs in Major Depressive Disorder (MDD)

MDD is widely viewed as a heterogeneous disorder; however, some biological

differences during the illness are sufficiently common so as to be altered within
samples of major depressive episode (MDE) cases as compared to healthy controls.
[11C]-Harmine is a positron emission tomography (PET) radiotracer that binds to the
functional pocket of MAO-A, and [11C]-harmine PET identified a 30% elevation in
MAO-A binding in grey matter regions, including the prefrontal cortex (PFC) and
anterior cingulate cortex (ACC), in MDD patients as compared to healthy controls
(Meyer et al. 2006). This was replicated with the same PET technique in a separate
sample in a subsequent study, and a later postmortem study of the PFC reported
similar elevations in MAO-A density and activity in MDE as compared to controls
(Meyer et al. 2009; Johnson et al. 2011). Clinical symptoms of greater severity, as
well as hypersomnia, hyperphagia and weight gain, the last three symptoms which
are also associated with better response to MAOIs, are associated with the highest
MAO-A binding level in the PFC and ACC (Chiuccariello et al. 2014). More
recently, greater MAO-B binding of approximately 25% was also reported in the
PFC during MDEs, using [11C]-SL25.1188 PET imaging, raising the issue that this
may also be a target of interest, at least within subpopulations of MDD (Moriguchi
et al. 2019). Underlying mechanisms for the elevations in MAO-A and MAO-B
binding in MDE likely involve downstream and direct effects of glucocorticoids on
1370 J. H. Meyer et al.

MAO transcription, as well as intermediate transcription factors like TIEG-2 and

KLF-11 whose levels are altered in the PFC of MDE in a manner consistent with
increasing MAO-A and MAO-B transcription (Harris et al. 2014; Johnson et al. 2011).

Revitalization of Interest in MAOIs

There has been concern expressed for several years about the pricing and avail-
ability of MAOIs and the lack of adequate education of health care professionals
regarding the appropriate use of these drugs (Fiedorowicz and Swartz 2004;
Gillman 2011a; Grady and Stahl 2012; Shulman et al. 2013). Members of the
International MAOI Expert Group recently published a statement about MAOIs
enumerating these issues and making recommendations for improvements for the
future (Gillman et al. 2020).

Summary

The MAOIs represent a class of antidepressant drugs that are underutilized in the
treatment of depressive disorders, primarily because of concerns about their potential
adverse effects and the paucity of education about these drugs in academic curricula.
In this review, we discussed the five MAOIs currently available, namely, phenelzine,
tranylcypromine, isocarboxazid (irreversible, nonselective), moclobemide (revers-
ible, MAO-A selective) and selegiline (irreversible, MAO-B selective at low doses
but non-selective at higher doses; used as a patch in depression). Although it is
generally agreed that the MAOIs are useful in the treatment of atypical depression
and treatment-refractory depression, there are also numerous reports on their efficacy
in melancholic depression, dysthymic disorder, bipolar depression and various
anxiety disorders with or without accompanying depression. There are also numer-
ous reports in the literature suggesting that the MAOIs are multifaceted drugs with
neuroprotective effects, although these effects may in some cases be due, at least in
part, to actions other than inhibition of MAO. Concern over the “cheese effect” has
deterred many physicians from prescribing MAOIs, leading to underuse, even
though this effect can be avoided. As a result of underutilization, these drugs are
currently in short supply worldwide (Gillman et al. 2020).

Acknowledgments The authors are grateful to CIHR (GBB, AH, DM) and the Offices of the
Provost and the Vice President (Research) (GBB), the Faculty of Medicine & Dentistry and the
Department of Psychiatry, University of Alberta (GBB, DM, AH) for funding. The technical and
secretarial support of Ms. Tricia Kent is gratefully acknowledged.

Conflicts of Interest Dr. Meyer has patents to detect MAO in brain and blood in mood and
commonly associated disorders and is developing natural health products to counter temporary
elevation in MAO-A in the early postpartum. Dr. Baker is an advisor for NeuraWell Therapeutics
about MAOIs, but that company has had no input into the preparation of this manuscript. The other
authors have no conflicts to declare.
Monoamine Oxidase Inhibitors in Depressive Disorders 1371

References
Agnew PC, Baran ID, Klapman HJ, et al. A clinical evaluation of four antidepressant drugs (Nardil,
Tofranil, Marplan, and Deprol). Am J Psychiatry. 1961;118:160–2. https://doi.org/10.1176/ajp.
118.2.160.
Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline
transdermal system without dietary restrictions in patients with major depressive disorder. J Clin
Psychiatry. 2003;64(2):208–14. https://doi.org/10.4088/jcp.v64n0216.
Amsterdam JD, Kim TT. Relative effectiveness of monoamine oxidase inhibitor and tricyclic
antidepressant combination therapy for treatment-resistant depression. J Clin Psychopharmacol.
2019;39(6):649–52.
Amsterdam JD, Shults J. MAOI efficacy and safety in advanced stage treatment-resistant depres-
sion – a retrospective study. J Affect Disord. 2005;89:183–8.
Azzaro AJ, Ziemniak J, Kemper E, et al. Pharmacokinetics and absolute bioavailability of selegiline
following treatment of healthy subjects with the selegiline transdermal system (6 mg/24h): a
comparison with oral selegiline capsules. J Clin Pharmacol. 2007;47:1256–67.
Bach AW, Lan NC, Johnson DL, et al. cDNA cloning of human liver monoamine oxidase a and B:
molecular basis of differences in enzymatic properties. Proc Natl Acad Sci USA. 1988;85:4934–8.
Baker GB, Dewhurst WG. Biochemical theories of affective disorders. In: Dewhurst WG, Baker
GB, editors. Pharmacotherapy of affective disorders. Theory and practice. Beckenham: Croom
Helm Ltd.; 1985. p. 1–59.
Baker GB, Wong JT-F, Yeung JM, et al. Effects of the antidepressant phenelzine on brain levels of
γ-aminobutyric acid (GABA). J Affec Disorders. 1991;21:207–11.
Baker GB, Urichuk LJ, McKenna KF, et al. Metabolism of monoamine oxidase inhibitors. Cell Mol
Neurobiol. 1999;19:411–26.
Baker GB, Matveychuk D, MacKenzie EM, et al. Attenuation of the effects of oxidative stress by
the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine. Chem Biol Interact.
2019;304:139–47.
Bakish D, Bradwejn J, Nair N, McClure J, Remick R, Bulger L. A comparison of moclobemide,
amitriptyline and placebo in depression: a Canadian multicentre study. Psychopharmacology.
1992;106(Suppl):S98–S101. https://doi.org/10.1007/BF02246248.
Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety
disorders, post-traumatic stress disorder and obsessive compulsive disorder: a revision of the
2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol.
2014;28(5):403–9.
Bartholomew AA. An evaluation of tranylcypromine (“Parnate”) in the treatment of depression.
Med J Aust. 1962;49(1):655–62. https://doi.org/10.5694/j.1326-5377.1962.tb27021.x.
Baumhackl U, Biziere K, Fischbach R, et al. Efficacy and tolerability of moclobemide compared
with imipramine in depressive disorder (DSM-III): an Austrian double-blind, multicentre study.
Br J Psychiatry Suppl. 1989;6:78–83.
Benson CA, Wong G, Tenorio G, et al. The MAO inhibitor phenelzine can improve functional
outcomes in mice with established clinical signs in experimental autoimmune encephalomyelitis
(EAE). Behav Brain Res. 2013;252:302–11.
Binda C, Newton-Vinson P, Hubalek F, et al. Structure of human monoamine oxidase B, a drug
target for the treatment of neurological disorders. Nature Struct Biol. 2002;9(1):22–6.
Birkenhager TK, van den Broek WW, Mulder PG, et al. Efficacy and tolerability of tranylcypromine
versus phenelzine: a double-blind study in antidepressant-refractory depressed patients. J Clin
Psychiatry. 2004;65(11):1505–10.
Birkmayer W, Riederer P, Linauer W, et al. L-Deprenyl plus L-phenylalanine in the treatment of
depression. J Neural Transm. 1984;59:81–7.
Bodkin JA, Amsterdam J. Transdermal selegiline in major depression: a double-blind, placebo
controlled parallel-group study in outpatients. Am J Psychiatry. 2002;159(11):1869–75.
Bonnet U. Moclobemide: therapeutic use and clinical studies. CNS Drug Rev. 2003;9(1):97–140.
1372 J. H. Meyer et al.

British Medical Research Council. Clinical trial of the treatment of depressive illness. Report to the
Medical Research Council by its clinical Psychiatry committee. Br Med J. 1965;1(5439):881–6.
https://doi.org/10.1136/bmj.1.5439.881.
Buckley N, Isbister GK, Dawson AH. Serotonin syndrome. Br Med J. 2014;348:g1626.
Chamberlain SR, Metastasio A, Stokes PRA, et al. The use of monoamine oxidase inhibitors in
psychiatric practice. Royal College of Psychiatrists. 2020;PS03/20:1–20.
Chen Z, Park J, Butler B, et al. Mitigation of sensory and motor deficits by acrolein scavenger
phenelzine in a rat model of spinal cord contusive injury. J Neurochem. 2016;138(2):328–38.
Chiuccariello L, House S, Miler L, et al. Elevated monoamine oxidase A binding during major
depressive episodes is associated with greater severity and reversed neurovegetative symptoms.
Neuropsychopharmacology. 2014;39:973–80.
Chiuccariello L, Cooke RG, Miler L, et al. Monoamine oxidase-A occupancy by moclobemide and
phenelzine: implications for the development of monoamine oxidase inhibitors. Int J Neuropsy-
chopharmacol. 2016:1–9.
Chockalingam R, Gott BM, Conway CR. Tricyclic antidepressants and monoamine oxidase
inhibitors: are they too old for a new look? In: Macaluso M, Preskorn S, editors. Handbook
of experimental pharmacology: antidepressants, vol. 250. Heidelburg: Springer; 2018. p. 37–47.
Chouinard G, Saxena B, Nair NP, et al. Brofaromine in depression; a Canadian multicenter placebo
trial and a review of standard drug comparative studies. Clin Neuropharmacol. 1993;16(Suppl
2):551–4.
Cipriani A, Williams T, Nikolakopoulou A, et al. Comparative efficacy and acceptability of
pharmacological treatments for post-traumatic stress disorder in adults: a network meta-analysis.
Psychol Med. 2018;48(12):1975–84.
Classen W, Laux G. Psychometric alterations in treatment with the MAO-A-inhibitor moclobemide.
J Neural Transm. 1990;Suppl 32:185–8.
Clineschmidt BV, Horita A. The monoamine oxidase catalyzed degradation of phenelzine-1-14C,
an irreversible inhibitor of monoamine oxidase – I. Studies in vitro. Biochem Pharmacol.
1969;18(5):1011–20.
Danish University Antidepressant Group (DUAG). Moclobemide: a reversible MAO-A-inhibitor
showing weaker antidepressant effect than clomipramine in a controlled multicenter study.
J Affect Disord. 1993;28(2):105–16. https://doi.org/10.1016/0165-0327(93)90039-m.
Davidson JR, McLeod MN, Kurland AA, et al. Antidepressant drug therapy in psychotic depres-
sion. Br J Psychiatry. 1977;131:493–6. https://doi.org/10.1192/bjp.131.5.493.
Davidson JRT, Giller EL, Zisook S, et al. An efficacy study of isocarboxazid and placebo in
depression, and its relationship to depressive nosology. Arch Gen Psychiatry. 1988;45:120–7.
De Lima MS, Hotopf M. A comparison of active drugs for the treatment of dysthymia. Cochrane
Database Syst Rev. 2003;3:CD004047.
Dierick M, Cattiez P, Franck G, et al. Moclobemide versus clomipramine in the treatment of
depression: a double-blind multicentre study in Belgium. Acta Psychiatr Scand Suppl.
1990;360:50–1. https://doi.org/10.1111/j.1600-0447.1990.tb05328.x.
Dunkley EJC, Isbister GK, Sibbritt D, et al. The hunter serotonin toxicity criteria: simple and
accurate diagnostic decision rules for serotonin toxicity. QJ Med. 2003;96(9):635–42.
Entzeroth M, Ratty AK. Monoamine oxidase inhibitors – revisiting a therapeutic principle. Open
J Depress. 2017;6(2):31–68.
Evans L, George T, O’Sullivan B, Mitchell P, Johnson G, Adena M. An Australian multicentre
study of moclobemide versus amitriptyline in the treatment of depression. Aust N Z J Psychi-
atry. 1992;26(3):454–8. https://doi.org/10.3109/00048679209072070.
Fawcett J, Kravitz HM, Zajecka JM, et al. CNS stimulant potentiation of monoamine oxidase
inhibitors in treatment-refractory depression. J Clin Psychopharmacol. 1991;11(20):127–32.
Feiger AD, Rickels K, Rynn MA, et al. Selegiline transdermal system for the treatment of major
depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration trial.
J Clin Psychiatry. 2006;67(9):1354–61. https://doi.org/10.4088/jcp.v67n0905.
Monoamine Oxidase Inhibitors in Depressive Disorders 1373

Feinberg SS. Combining stimulants with monoamine oxidase inhibitors. A review of uses and one
possible additional indication. J Clin Psychiatry. 2004;65:1520–4.
Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric
practice. J Psychiatr Pract. 2004;10(4):239–48.
Fowler JS, Logan J, Volkow ND, et al. Evidence that formulations of the selective MAO-B
inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human
brain. Neuropsychopharmacology. 2015;40:650–7.
Fulton B, Benfield P. Moclobemide. An update of its pharmacological properties and therapeutic
use. Drugs. 1996;52(3):450–74.
Gachoud JP, Dick P, Kohler M. Comparison of the efficacy and tolerability of moclobemide and
maprotiline in depressed patients treated by general practitioners. Clin Neuropharmacol.
1994;17(Suppl 1):S29–37. https://doi.org/10.1097/00002826-199417001-00005.
Georgotas A, McCue RE, Hapworth W, et al. Comparative efficacy and safety of MAOIs versus
TCAs in treating depression in the elderly. Biol Psychiatry. 1986;21(12):1155–66. https://doi.
org/10.1016/0006-3223(86)90222-2.
Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J
Pharmacol. 2007;151:737–48.
Gillman PK. Advances pertaining to the pharmacology and interactions of irreversible nonselective
monoamine oxidase inhibitors. J Clin Psychopharmacol. 2011a;31(1):66–74.
Gillman PK. CNS toxicity involving methylene blue: the exemplar for understanding and predicting
drug interactions that precipitate serotonin toxicity. J Psychopharmacol. 2011b;25(3):429–36.
Gillman PK. A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired
old tyramine myths. J Neural Transm. 2018;125:1707–17.
Gillman PK. Overview: MAOI and TCA interactions. PsychoTropical Commen. 2019 (updated
Sept. 28, 2020). https://psychotropical.com/overview_maoi_and_tca_interactions/
Gillman PK, Feinberg SS, Fachtmann LJ. Revitalizing monoamine oxidase inhibitors: a call for
action. CNS Spectr. 2020;25:452–4.
Glick BS. Double-blind study of tranylcypromine and phenelzine in depression. Dis Nerv Syst.
1964;25:617–9.
Gottfries CG. Clinical trial with the monoamine oxidase inhibitor tranylcypromine on a psychiatric
clientele. Acta Psychiatr Scand. 1963;39(3):463–72. https://doi.org/10.1111/j.1600-0447.1963.
tb07476.x.
Grady MM, Stahl SM. Practical guide for prescribing MAOIs: debunking myths and removing
barriers. CNS Spectr. 2012;17:2–10.
Gram LF, Guentert TW, Grange S, et al. Moclobemide, a substrate of CYP2C19 and an inhibitor of
CYP2C19, CYP2D6 and CYP1A2: a panel study. Clin Pharmacol Therap. 1995;57(6):670–7.
Greenblatt M, Grosser GH, Wechsler H. Differential response of hospitalized depressed patients to
somatic therapy. Am J Psychiatry. 1964;120:935–43. https://doi.org/10.1176/ajp.120.10.935.
Guelfi JD, Payan C, Fermanian J, et al. Moclobemide versus clomipramine in endogenous depres-
sion. A double-blind randomised clinical trial. Br J Psychiatry. 1992;160:519–24. https://doi.
org/10.1192/bjp.160.4.519.
Hamilton M. The effect of treatment on the melancholias (depressions). Br J Psychiatry. 1982;140:
223–30. https://doi.org/10.1192/bjp.140.3.223.
Hampson DR, Baker GB, Coutts RT. A comparison of the neurochemical and pharmacological
properties of the stereoisomers of tranylcypromine. Cell Mol Biol. 1986;32:333–41.
Harris S, Johnson S, Duncan JW, et al. Evidence revealing deregulation of the KLF11-Mao A
pathway in association with chronic stress and depressive disorders. Neuropsychophar-
macology. 2014;40:1373–82.
Heinonen EH, Myllyla V, Sotaniemi K, et al. Pharmacokinetics and metabolism of selegiline. Acta
Neurol Scand Suppl. 1989;126:93–9.
Henkel V, Mergi R, Allgaier AK, et al. Treatment of depression with atypical features: a meta-
analytic approach. Psychiatry Res. 2006;141(1):89–101.
1374 J. H. Meyer et al.

Himmelhoch JM, Fuchs CZ, Symons BJ. A double-blind study of tranylcypromine treatment of
major anergic depression. J Nerv Ment Dis. 1982;170(10):628–34.
Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in
anergic bipolar depression. Am J Psychiatry. 1991;148(7):910–6. https://doi.org/10.1176/ajp.
148.7.910.
Imlah NW, Fahy PT, Harrington JA. A comparison of two antidepressant drugs. Psychophar-
macologia. 1964;6(6):472–4. https://doi.org/10.1007/BF00429573.
Ishizaki J, Mimura M. Dysthymia and apathy: diagnosis and treatment. Depress Res Treat.
2011;2011:893905.
Israel JA. Combining stimulants and monoamine oxidase inhibitors: a reexamination of the
literature and a report of a new treatment combination. Primary Care Companion CNS Disord.
2015;17(6) https://doi.org/10.4088/PCC.15br01836.
Jauch R, Griesser E, Oesterhelt G, et al. Biotransformation of moclobemide in humans. Acta
Psychiatr Scand Suppl. 1990;360:87–90.
Jessen L, Kovalick LJ, Azzaro AJ. The selegiline transdermal system (Emsam): a therapeutic option
for the treatment of major depressive disorder. Pharm Therap. 2008;33(4):212–46.
Johnson S, Stockmeier CA, Meyer JH, et al. The reduction of R1, a novel repressor protein for
monoamine oxidase A, in major depressive disorder. Neuropsychopharmacol. 2011;36:2139–48.
Johnston JP. Some observations upon a new inhibitor of monoamine oxidase in brain tissue.
Biochem Pharmacol. 1968;17(7):1285–97.
Jouvent R, Le Houezec J, Payan C, et al. Dimensional assessment of onset of action of antidepres-
sants: a comparative study of moclobemide vs. clomipramine in depressed patients with blunted
affect and psychomotor retardation. Psychiatry Res. 1998;79(3):267–75. https://doi.org/10.
1016/s0165-1781(98)00046-8.
Kallem RR, Jillela B, Ravula AR, et al. Highly sensitive LC-MS/MS-ESI method for determination
of phenelzine in human plasma and its application to a human pharmacokinetic study. J
Chromatogr B. 2016;1022:126–32.
Kay DW, Garside RF, Fahy TJ. A double-blind trial of phenelzine and amitriptyline in depressed
out-patients. A possible differential effect of the drugs on symptoms. Br J Psychiatry. 1973;123
(572):63–7. https://doi.org/10.1192/bjp.123.1.63.
Kayser A, Robinson DS, Nies A, Howard D. Response to phenelzine among depressed patients
with features of hysteroid dysphoria. Am J Psychiatry. 1985;142(4):486–8. https://doi.org/10.
1176/ajp.142.4.486.
Kayser A, Robinson DS, Yingling K, Howard DB, Corcella J, Laux D. The influence of panic
attacks on response to phenelzine and amitriptyline in depressed outpatients. J Clin
Psychopharmacol. 1988;8(4):246–53.
Kennedy SH, Holt A, Baker GB. Monoamine oxidase inhibitors. In: Sadock BJ, Sadock VA, Ruiz P,
editors. Kaplan & Sadock’s comprehensive textbook of psychiatry, 9th ed. Philadelphia: Wolters
Kluwer; 2009. pp. 3154–64.
Kiani C. Tranylcypromine: its pharmacology, safety and efficacy. Am J Psychiatry Residents’
J. 2020;15(4):3–5.
Kim T, Xu C, Amsterdam JD. Relative effectiveness of tricyclic antidepressant versus monoamine
oxidase inhibitor monotherapy for treatment-resistant depression. J Affect Disord. 2019;250:
199–203.
Knoll J, Magyar K. Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv
Biochem Psychopharmacol. 1972;5:393–408.
Kok RM, Vink D, Heeren DJ, et al. Lithium augmentation compared with phenelzine in treatment-
resistant depression in the elderly: an open, randomized, controlled trial. J Clin Psychiatry.
2007;68(8):1177–85.
Kragh-Sorensen P, Muller B, Andersen JV, et al. Moclobemide versus clomipramine in depressed
patients in general practice. A randomized, double-blind, parallel, multicenter study. J Clin
Psychopharmacol. 1995;15(4 Suppl 2):24S–30S. https://doi.org/10.1097/00004714-
199508001-00005.
Monoamine Oxidase Inhibitors in Depressive Disorders 1375

Krings-Ernst I, Ulrich A, Adli M. Antidepressant treatment with MAO-inhibitors during general and
regional anesthesia: a review and case report of spinal anesthesia for lower extremity surgery
without discontinuation of tranylcypromine. Int J Clin Pharmacol Therapeut. 2013;51(10):763–70.
Lapierre YD, Joffe R, McKenna K, et al. Moclobemide versus fluoxetine in the treatment of major
depressive disorder in adults. J Psychiatry Neurosci. 1997;22(2):118–26.
Larsen JK, Gjerris A, Holm P, et al. Moclobemide in depression: a randomized, multicentre trial
against isocarboxazid and clomipramine emphasizing atypical depression. Acta Psychiatr
Scand. 1991;84(6):564–70. https://doi.org/10.1111/j.1600-0447.1991.tb03196.x.
Larsen JK, Krogh-Neilsen L, Brosen K. The monoamine oxidase inhibitor isocarboxazid is a
relevant treatment option in treatment-resistant depression – experience-based strategies in
Danish psychiatry. Health Care Curr Rev. 2016;4:2.
Laux G, Beckmann H, Classen W, Becker T. Moclobemide and maprotiline in the treatment of
inpatients with major depressive disorder. J Neural Transm Suppl. 1989;28:45–52.
Laux G, Classen W, Sofic E, et al. Clinical, biochemical and psychometric findings with the new
MAO-A-inhibitors moclebemide and brofaromine in patients with major depressive disorder.
J Neural Transm Suppl. 1990;32:189–95.
Lecrubier Y, Guelfi JD. Efficacy of reversible inhibitors of monoamine oxidase-a in various forms
of depression. Acta Psychiatr Scand Suppl. 1990;360:18–23. https://doi.org/10.1111/j.1600-
0447.1990.tb05319.x.
Lecrubier Y, Pedarriosse AM, Payan C, et al. Moclobemide versus clomipramine in non-
melancholic, nonpsychotic major depression. A Study group. Acta Psychiatr Scand. 1995;92
(4):260–5. https://doi.org/10.1111/j.1600-0447.1995.tb09580.x.
Leitch A, Seager CP. A trial of four anti-depressant drugs. Psychopharmacologia. 1963;4:72–7.
https://doi.org/10.1007/BF00429366.
Liebowitz MR, Quitkin FM, Stewart JW, et al. Antidepressant specificity in atypical depression.
Arch Gen Psychiatry. 1988;45(2):129–37. https://doi.org/10.1001/archpsyc.1988.
01800260037004.
Lonnqvist J, Sintonen H, Syvalahti E, et al. Antidepressant efficacy and quality of life in depression:
a double-blind study with moclobemide and fluoxetine. Acta Psychiatr Scand. 1994;89(6):363–
9. https://doi.org/10.1111/j.1600-0447.1994.tb01530.x.
Lopez-Munoz F, Alamo C. Monoaminergic neurotransmission: the history of the discovery of
antidepressants from 1950s until today. Curr Pharm Des. 2009;15:1563–86.
Lotufo-Neto F, Trivedi M, Thase ME. Meta-analysis of the reversible inhibitors of monoamine
oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsycho-
pharmacology. 1999;20(3):226–47.
Luft B. Antidepressant switching strategies. Graylands Hospital Drug Bulletin. 2013;20(1):ISSN
1323-1251.
Lyles GA, Holt A, Marshall CM. Further studies on the metabolism of methylamine by
semicarbazide-senstive amine oxidase activities in human plasma, umbilical artery and rat
aorta. J Pharm Pharmacol. 1990;42(5):332–8.
MacKenzie EM. Neurochemical and neuroprotective aspects of phenelzine and it active metabolite
β-phentlethylidenehydrazine. PhD Thesis, University of Alberta, 2009.
Mallinger AG, Frank E, Thase ME, et al. Revisiting the effectiveness of standard antidepressants in
bipolar disorder: are monoamine oxidase inhibitors superior? Psychopharmacol Bull. 2009;42:
64–74.
Mann JJ, Aarons SF, Wilner PJ, et al. A controlled study of the antidepressant efficacy and side
effects of (-)-deprenyl. A selective monoamine oxidase inhibitor. Arch Gen Psychiatry. 1989;46:
45–50.
Martin ME. A Comparative trial of imipramine and phenelzine in the treatment of depression. Br J
Psychiatry. 1963;109(459):279–85. https://doi.org/10.1192/bjp.109.459.279.
Matveychuk D, MacKenzie EM, Kumpula D, et al. Overview of the neuroprotective effects of the
MAO-inhibiting antidepressant phenelzine. Cell Mol Neurobiol. 2021; https://doi.org/10.1007/
s10571-021-01078-3.
1376 J. H. Meyer et al.

McGrath PJ, Quitkin FM, Harrison W, et al. Treatment of melancholia with tranylcypromine. Am J
Psychiatry. 1984;141:288–9.
McGrath PJ, Stewart W, Harrison W, et al. Treatment of tricyclic refractory depression with a
monoamine oxidase inhibitor antidepressant. Psychopharmacol Bull. 1987;23:169–72.
McGrath PJ, Stewart JW, Nunes EV, et al. A double-blind crossover trial of imipramine and
phenelzine for outpatients with treatment-refractory depression. Am J Psychiatry. 1993;150
(1):118–23. https://doi.org/10.1176/ajp.150.1.118.
Meister R, von Wolff A, Mohr H, et al. Comparative safety of pharmacologic treatments for
persistent depressive disorder: a systematic review and network meta-analysis. PLoS One.
2016;11(5):e0153380.
Mendlewicz J, Youdim MBH. Anti-depressant potentiation of 5-hydroxytryptophan by L-deprenyl,
an MAO “type B” inhibitor. J Neural Transm. 1978;43:279–86.
Mendlewicz J, Youdim MBH. L-Deprenil, a selective monoamine oxidase type B inhibitor, in the
treatment of depression: a double blind evaluation. Br J Psychiatry. 1983;142:508–11.
Meyer JM. A concise guide to monoamine oxidase inhibitors. Curr Psychiatr Ther. 2017;16(12):
15–23.
Meyer JM. A concise guide to monoamine oxidase inhibitors: how to avoid drug interactions. Curr
Psychiatr Ther. 2018;17(1):22–33.
Meyer JM, Cummings MA, Proctor G. Augmentation of phenelzine with aripiprazole and
quetiapine in a treatment-resistant patient with psychotic unipolar depression: case report and
literature review. CNS Spectr. 2017;22:391–6.
Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase A levels in the brain: an
explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry. 2006;63
(11):1209–16.
Meyer JH, Wilson AA, Sagrati S, et al. Brain monoamine oxidase A binding in major depressive
disorder. Arch Gen Psychiatry. 2009;66(12):1304–12.
Moll E, Neumann N, Schmid-Burgk W, et al. Safety and efficacy during long-term treatment with
moclobemide. Clin Neuropharmacol. 1994;17(Suppl 1):S74–87.
Moriguchi S, Wilson AA, Miler L, et al. Monoamine oxidase B total distribution volume in the
prefrontal cortex of major depressive disorder. JAMA Psychiat. 2019;76(6):634–41.
Nair NP, Ahmed SK, Kin NM. Biochemistry and pharmacology of reversible inhibitors of MAO-A
agents: focus on moclobemide. J Psychiatry Neurosci. 1993;18(5):214–25.
Nair NP, Amin M, Holm P, et al. Moclobemide and nortriptyline in elderly depressed patients. A
randomized, multicentre trial against placebo. J Affect Disord. 1995;33(1):1–9. https://doi.org/
10.1016/0165-0327(94)00047-d.
Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic
ECS and antidepressant treatments. J Neurosci. 1995;15:7539–47.
Nierenberg AA, Keck PE. Management of monoamine oxidase inhibitor-associated insomnia with
trazodone. J Clin Psychopharmacol. 1989;9:42–5.
Nolen WA, van de Putte JJ, Dijken WA, et al. L-5HTP in depression resistant to re-uptake
inhibitors. An open comparative study with tranylcypromine. Br J Psychiatry. 1985;147:
16–22. https://doi.org/10.1192/bjp.147.1.16.
Nolen WA, van de Putte JJ, Dijken WA, et al. Treatment strategy in depression. II. MAO inhibitors
in depression resistant to cyclic antidepressants: two controlled crossover studies with
tranylcypromine versus L-5-hydroxytryptophan and nomifensine. Acta Psychiatr Scand.
1988;78(6):676–83. https://doi.org/10.1111/j.1600-0447.1988.tb06403.x.
O’Carroll AM, Fowler CJ, Phillips JP, et al. The deamination of dopamine by human brain
monoamine oxidase. Specificity for the two enzyme forms in seven brain regions. Naunyn
Schmiedeberg’s Arch Pharmacol. 1983;322(3):198–202.
Paslawski T, Knaus E, Iqbal N, et al. β-Phenylethylidenehydrazine, a novel inhibitor of GABA
transaminase. Drug Devel Res. 2001;54:35–9.
Philipp M, Kohnen R, Benkert O. A comparison study of moclobemide and doxepin in major
depression with special reference to effects on sexual dysfunction. Int Clin Psychopharmacol.
1993;7(3–4):149–53. https://doi.org/10.1097/00004850-199300730-00005.
Monoamine Oxidase Inhibitors in Depressive Disorders 1377

Pierre JM, Gitlin MJ. Bupropion-tranylcypromine combination in treatment-resistant depression.

J Clin Psychiatry. 2000;61:450–1.
Polnak JF, Finegan A, Ji H, et al. Monoamine oxidase inhibitor switching strategies: no adverse
events associated with outpatient cross-taper or inpatient rapid switch. J Clin Psychopharmacol.
2017;38(1):92–4.
Popov N, Matthies JW. Some effects of monoamine oxidase inhibitors on the metabolism of
gamma-aminobutyric acid in rat brain. J Neurochem. 1969;16(3):899–907.
Quitkin FM, Stewart JW, McGrath PJ, et al. Phenelzine versus imipramine in the treatment of
probable atypical depression: defining syndrome boundaries of selective MAOI responders. Am
J Psychiatry. 1988;145(3):306–11. https://doi.org/10.1176/ajp.145.3.306.
Quitkin FM, McGrath PJ, Stewart JW, et al. Phenelzine and imipramine in mood reactive depres-
sives. Further delineation of the syndrome of atypical depression. Arch Gen Psychiatry. 1989;46
(9):787–93. https://doi.org/10.1001/archpsyc.1989.01810090029005.
Quitkin FM, McGrath PJ, Stewart JW, et al. Atypical depression, panic attacks, and response to
imipramine and phenelzine. A replication. Arch Gen Psychiatry. 1990;47(10):935–41. https://
doi.org/10.1001/archpsyc.1990.01810220051006.
Quitkin FM, Harrison W, Stewart JW, et al. Response to phenelzine and imipramine in placebo
nonresponders with atypical depression. A new application of the crossover design. Arch Gen
Psychiatry. 1991;48(4):319–23. https://doi.org/10.1001/archpsyc.1991.01810280035005.
Quitkin FM, Stewart JW, McGrath PJ, et al. Columbia atypical depression: a subgroup of depres-
sives with better response to MAOI than to tricyclic antidepressants or placebo. Br J Psychiatry.
1993;21(Suppl):30–4.
Raskin A, Schulterbrandt JG, Reatig N, Crook TH, Odle D. Depression subtypes and response to
phenelzine, diazepam, and a placebo. Results of a nine hospital collaborative study. Arch Gen
Psychiatry. 1974;30(1):66–75. https://doi.org/10.1001/archpsyc.1974.01760070050008.
Ravaris CL, Nies A, Robinson DS, et al. A multiple-dose, controlled study of phenelzine in
depression-anxiety states. Arch Gen Psychiatry. 1976;33(3):347–50. https://doi.org/10.1001/
archpsyc.1976.01770030057008.
Ravaris CL, Robinson DS, Ives JO, et al. Phenelzine and amitriptyline in the treatment of
depression. A comparison of present and past studies. Arch Gen Psychiatry. 1980;37(9):
1075–80. https://doi.org/10.1001/archpsyc.1980.01780220113013.
Razani J, White KL, White J, et al. The safety and efficacy of combined amitriptyline and
tranylcypromine antidepressant treatment. A controlled trial. Arch Gen Psychiatry. 1983;40
(6):657–61. https://doi.org/10.1001/archpsyc.1983.04390010067008.
Rees L, Davies B. A controlled trial of phenelzine (“Nardil”) in the treatment of severe depressive
illness. J Ment Sci. 1961;107:560–6. https://doi.org/10.1192/bjp.107.448.560.
Reynaert C, Parent M, Mirel J, et al. Moclobemide versus fluoxetine for a major depressive episode.
Psychopharmacology. 1995;118(2):183–7. https://doi.org/10.1007/BF02245838.
Richmond PW, Roberts AH. A comparative trial of imipramine, amitriptyline, isocarboxazid and
tranylcypromine in out-patient depressive illness. Br J Psychiatry. 1964;110:846–50. https://doi.
org/10.1192/bjp.110.469.846.
Ricken R, Ulrich S, Schlattmann P, et al. Tranylcypromine in mind (Part II): review of clinical
pharmacology and meta-analysis of controlled studies in depression. Eur Neuropsycho-
pharmacol. 2017;27:714–31.
Riederer P, Muller T. Use of monoamine oxidase inhibitors in chronic neurodegeneration. Expert
Opin Drug Metab Toxicol. 2017;13(2):233–40.
Riederer P, Lachenmayer L, Laux G. Clinical applications of MAO-inhibitors. Curr Med Chem.
2004;11:2033–43.
Rimon R, Jaaskelainen J, Kaartinen P, et al. Moclobemide versus imipramine in depressed
out-patients: a double-blind multi-centre study. Int Clin Psychopharmacol. 1993;7
(3–4):141–7. https://doi.org/10.1097/00004850-199300730-00004.
Robinson DS, Nies A, Ravaris CL, Lamborn KR. The monoamine oxidase inhibitor, phenelzine, in
the treatment of depressive-anxiety states. A controlled clinical trial. Arch Gen Psychiatry.
1973;29(3):407–13. https://doi.org/10.1001/archpsyc.1973.04200030093015.
1378 J. H. Meyer et al.

Robinson D, Cooper TB, Jindal SP, et al. Metabolism and pharmacokinetics of phenelzine: lack of
evidence for acetylation pathway in humans. J Clin Psychopharmacol. 1985;5:337–57.
Rowan PR, Paykel ES, Parker RR. Phenelzine and amitriptyline: effects on symptoms of neurotic
depression. Br J Psychiatry. 1982;140:475–83. https://doi.org/10.1192/bjp.140.5.475.
Salonen JS, Nyman L, Boobis AR, et al. Comparative studies on the cytochrome P450 -associated
metabolism and interaction potential of selegiline between human liver-derived in vitro systems.
Drug Metab Dispos. 2003;31(9):1093–102.
Schildkraut JJ, Klerman GL, Hammond R, Friend DG. Excretion of 3-methoxy-4-hydroxymandelic
acid (VMA) in depressed patients treated with antidepressant drugs. J Psychiatr Res. 1964;2:
257–66. https://doi.org/10.1016/0022-3956(64)90012-3.
Schlessinger A, Geier E, Fan H, et al. Structure-based discovery of prescription drugs that interact
with the norepinephrine transporter, NET. Proc Natl Acad Sci USA. 2011;108:15810–5.
Sheehan DV, Ballenger J, Jacobsen G. Treatment of endogenous anxiety with phobic, hysterical,
and hypochondriacal symptoms. Arch Gen Psychiatry. 1980;37(1):51–9.
Shulman KI, Hermann N, Walker SE. Current place of monoamine oxidase inhibitors in the
treatment of depression. CNS Drugs. 2013;27:789–97.
Singh IN, Gilmer LK, Miller DM, et al. Phenelzine mitochondrial functional preservation and
neuroprotection after traumatic brain injury related to scavenging of the lipid-peroxidation
derived aldehyde 4-hydroxy-2-nonenal. J Cereb Blood Flow Metab. 2013;33(4):593–9.
Sogaard J, Lane R, Latimer P, et al. A 12-week study comparing moclobemide and sertraline in the
treatment of outpatients with atypical depression. J Psychopharmacol. 1999;13(4):406–14.
https://doi.org/10.1177/026988119901300412.
Song M-S, Matveychuk D, MacKenzie EM, et al. An update on amine oxidase inhibitors:
multifaceted drugs. Progr Neuropsychopharmacol Biol Psychiatry. 2013;44:118–24.
Spear FG, Hall P, Stirland JD. A comparison of subjective responses to imipramine and
tranylcypromine. Br J Psychiatry. 1964;110:53–5. https://doi.org/10.1192/bjp.110.464.53.
Stein DJ, Cameron A, Amrein R, et al. Moclobemide is effective and well tolerated in the long-term
pharmacotherapy of social anxiety disorder with or without comorbid anxiety disorder. Int Clin
Psychopharmacol. 2002;17(4):161–70.
Szoko E, Tabi T, Riederer P, et al. Pharmacological aspects of the neuroprotective effects of
irreversible MAO-B inhibitors, selegiline and rasagaline, in Parkinson’s disease. J Neural
Transm. 2018;125:1735–49.
Szuba MP, Hornig-Rohan M, Amsterdam JD. Rapid conversion from one monoamine oxidase
inhibitor to another. Expert Opin Drug Metab Toxicol. 1997;58(7):307–10.
Tabi T, Vecsel L, Youdim MB, et al. Selegiline: a molecule with innovative potential. J Neural
Transm. 2020;127:831–42.
Tariot PN, Murphy DL, Sunderland T, et al. Rapid antidepressant effect of addition of lithium to
tranylcypromine. J Clin Psychopharmacol. 1986;6(3):165–7.
Tatton W, Chalmers-Redman R, Tatton N. Neuroprotection by deprenyl and other propargylamines:
glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase-B. J Neural
Transm. 2003;110:509–15.
Thase ME, Mallinger AG, McKnight D, Himmelhoch JM. Treatment of imipramine-resistant
recurrent depression, IV: a double-blind crossover study of tranylcypromine for anergic bipolar
depression. Am J Psychiatry. 1992;149(2):195–8. https://doi.org/10.1176/ajp.149.2.195.
Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsy-
chopharmacology. 1995;12(3):185–219. https://doi.org/10.1016/0893-133X(94)00058-8.
Thomas SJ, Shin M, Mcinnis MG, et al. Combination therapy with monoamine oxidase inhibitors
and other antidepressants or stimulants: strategies for the management of treatment-resistant
depression. Pharmacotherapy. 2015;35(4):433–49.
Tipton KF, Spires IP. Oxidation of 2-phenylethylhydrazine by monoamine oxidase. Biochem
Pharmacol. 1972;21(2):268–70.
UK Moclobemide Study Group. A multicentre comparative trial of moclobemide, imipramine and
placebo in major depressive disorder. Int Clin Psychopharmacol. 1994;9(2):109–13. https://doi.
org/10.1097/00004850-199400920-00007.
Monoamine Oxidase Inhibitors in Depressive Disorders 1379

Ulrich S, Ricken R, Adli M. Tranylcypromine in mind (Part I): review of pharmacology. Eur
Neuropsychopharmacol. 2017;27:697–713.
Ulrich S, Ricken R, Buspanavich P, et al. Efficacy and adverse effects of tranylcypromine and tricyclic
antidepressants in the treatment of depression. J Clin Psychopharmacol. 2020;40:63–74.
Van Haelst IMM, van Klei WA, Doodeman HJ, et al. Antidepressive treatment with monoamine
oxidase inhibitors and the occurrence of intraoperative hemodynamic events: a retrospective
observational cohort study. J Clin Psychiatry. 2012;73(8):1103–9.
Vazquez GH, Tondo L, Undurraga J, et al. Overview of antidepressant treatment of bipolar
depression. Int J Neuropsychopharmacol. 2013;16:1673–85.
Versiani M, Oggero U, Alterwain P, et al. A double-blind comparative trial of moclobemide
v. imipramine and placebo in major depressive episodes. Br J Psychiatry. 1989;155(Suppl
6):72–7.
Versiani M, Nardi AE, Mundim FD, et al. The long-term treatment of social phobia with
moclobemide. Int Clin Psychopharmacol. 1996;11(Suppl 3):83–8.
Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13(4):533–40.
Volz H-P, Gleiter CH, Waldmeier PC, et al. Brofaromine – a review of its pharmacological
properties and therapeutic use. J Neural Transm. 1996;103:217–45.
Waldmeier P, Amrein R, Schmid-Burgk W. Pharmacology and pharmacokinetics of brofaromine
and moclobemide in animals and humans. In: Kennedy SH, editor. Clinical advances in
monoamine oxidase inhibitor therapies. Washington, DC: American Psychiatric Press; 1994.
p. 33–59.
White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a reevaluation. J Clin
Psychopharmacol. 1981;1:264–82.
White K, Razani J, Cadow B, et al. Tranylcypromine vs nortriptyline vs placebo in depressed
outpatients: a controlled trial. Psychopharmacology. 1984;82(3):258–62. https://doi.org/10.
1007/BF00427786.
Williams R, Edwards RA, Newburn GM, Mullen R, Menkes DB, Segkar C. A double-blind
comparison of moclobemide and fluoxetine in the treatment of depressive disorders. Int Clin
Psychopharmacol. 1993;7(3–4):155–8. https://doi.org/10.1097/00004850-199300730-00006.
Williams T, McCaul M, Schwarzer G, et al. Pharmacological treatments for social anxiety disorder
in adults: a systematic review and network meta-analysis. Acta Neuropsychiatr. 2020;32(4):
169–76.
Wood PL, Khan MA, Moskal JR, et al. Aldehyde load in ischemia-reperfusion brain injury:
neuroprotection by neutralization of reactive aldehydes with phenelzine. Brain Res.
2006;1122(1):184–90.
Youdim MBH, Collins GGS, Sandler M, et al. Human brain monoamine oxidase, multiple forms
and selective inhibitors. Nature. 1972;236:225–8.
Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors.
Nat Rev Neurosci. 2006;7:295–309.
Zhang W, Davidson JR. Post-traumatic stress disorder: an evaluation of existing pharmacotherapies
and new strategies. Expert Opin Pharmacother. 2007;8(12):1861–187.
Agomelatine and Depressions

Gerd Laux

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1382
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1382
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1382
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1382
Indications (of Marketed Products) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383
Depressive Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383
Sleep Disorders, Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383
Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383
Long-Term Studies, Relapse Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1388
Side Effects, Adverse Reactions, and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1388
Combination Therapy – Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1389
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1389
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1389

Abstract
Agomelatine is an antidepressant drug acting as melatonergic MT1- and MT2-
receptor agonist and selective serotonergic 5-HT2C-antagonist. The efficacy in
treatment of major depressive disorder was established in randomized, double-
blind, placebo controlled studies and a maintenance study in adult in- and out-
patients. Positive effects on sleep parameters have been reported. Side effects are
rare; weight gain, sexual dysfunction, or discontinuation syndromes are missing;

G. Laux (*)
Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich,
Germany
e-mail: ipm@ipm-laux.de

© Springer Nature Switzerland AG 2022 1381

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_31
1382 G. Laux

Fig. 1 Chemical formula

agomelatine

increase of hepatic transaminases values must be monitored, however; and

agomelatine is contraindicated in patients with liver impairment.

Chemistry, Developmental History

The chemical structure of agomelatine is very similar to that of melatonin (Fig. 1).
Agomelatine was discovered and developed by Servier; it received approval from
the European Medicines Agency (EMA) in 2009 and 2010 in Australia.

Pharmacology

Agomelatine is a melatonergic MT1- and MT2-receptor agonist and selective sero-

tonergic 5-HT2C-antagonist (Millan et al. 2003). In experimental models of depres-
sion as well as in humans, it has been shown that the substance resynchronizes
disturbed circadian rhythms by antagonizing 5-HT2C (Racagni et al. 2011).
Agomelatine has no anticholinergic or antihistaminergic properties.

Pharmacokinetics

Agomelatine is metabolized in the liver, mainly by the cytochrome P450 CYP1A2-

Isoenzyme. The presence of renal impairment did not affect the apparent clearance.
The mean terminal half-life is around 2 hours only (Hiemke et al. 2018).

Mechanism of Action

The psychotropic effects of agomelatine are due to the synergy between its melatonergic
and 5-HT (hydroxytryptaminergic) effects. Agomelatine dose-dependently inhibits the
firing of cells in the SCN (the endogeneous master clock), synchronizes the circadian
rhythm to 24 h by phase advancing circadian rhythms, and resynchronizes circadian
rhythms (Lemoine et al. 2007; Kasper and Hamon 2009; Kasper et al. 2010; Dridi et al.
2013). Agomelatine affects transcriptional-translational molecular circadian clock,
neurogenesis, synaptic remodeling, and glutamate signaling.
Agomelatine and Depressions 1383

Indications (of Marketed Products)

Agomelatine is approved and released for the treatment of major depressive

disorder (MDD). Off-label use of anxiety and sleep disorders is undertaken in
practice.
Recommended dose is 25 mg in the evening; dose can be increased to 50 mg/day.

Clinical Studies

Reviews of clinical studies are given by Kennedy and Rizvi (2010), Howland 2011,
Guaiana et al. (2013), and Norman and Olver 2019.

Depressive Disorders

Antidepressive treatment with agomelatine has shown significant efficacy versus

placebo. Difference to placebo increased with severity of depression (Montgomery
and Kasper 2007). Overall it is as effective as other antidepressants (see Table 1).

Sleep Disorders, Insomnia

Agomelatine is also studied for its effects on sleep regulation. Studies report various
improvements in general quality of sleep metrics, as well as benefits in circadian
rhythm disorders (Dridi et al. 2013).
Outpatients with DSM-IV-TR-defined MDD received either agomelatine 25 to
50 mg (n ¼ 154) or sertraline 50 to 100 mg (n ¼ 159) during a 6-week, randomized,
double-blind treatment. Sleep latency and sleep efficiency improved significantly
more with agomelatine than with sertraline as did anxiety symptoms. Sleep-wake
cycle at week 1 reflected early improvement in sleep and daytime functioning
(Kasper et al. 2010).
In depressed patients, agomelatine increased slow wave sleep without modifica-
tion of rapid eye movement (REM) sleep amount or REM latency. From the first
week of treatment, onset of sleep and the quality of sleep were significantly
improved without daytime clumsiness as assessed by patients (Quera Salva et al.
2007).

Other Studies

It has been found more effective than placebo in the treatment of generalized anxiety
disorder (De Berardis et al. 2013). A 12-week international RCT of agomelatine
(N ¼ 139) vs. escitalopram (N ¼ 142) vs placebo (N ¼ 131) showed response rates
of 64%, 66.2%, and 36.6%, respectively. Remission rates were 36.7%, 31.7%, and
19.9%, respectively. Agomelatine was well tolerated with no more adverse events
 1384

Table 1 Survey controlled clinical studies with agomelatine (A) in Major Depressive Disorder (MDD)
N, patients, Study arms, comparators,
Study duration placebo (Pl) Results Drop-out rates Relevant side effects
Lemoine N ¼ 332 Venlafaxine (V) 75–150 mg/day A ¼V A 4.2% Nausea, dizziness, tremor
et al. V >A
(2007)
RCT 6 weeks R: A 76%, V 71% V 13.2%
A > V sleep
parameters
Quera- N ¼ 138 Escitalopram (E) A¼E Nausea E > A
Salva et al.
(2011)
RCT 24 weeks 10–20 mg/day R:A 77%, E 74%
RR:A 48%, E 42%
A > in nighttime
sleep and daytime
condition
Laux et al. N ¼ 9283 R: 78.7% 5.3% headache, nausea
(2017)
Pooled 12 weeks RR: 34.5% 0.5% transaminase elevations
analysis of 52 weeks R: 75.9%
4 NIS RR: 47.5%
G. Laux
Laux N ¼ 3317 R 65.8% (>50% 25.8% (13.5% patient’s 1.7% headache, nausea 1.4%,
(2012) decrease in request, 9.1% insufficient dizziness 0.9%, 0.6% increase
svMADRS) efficacy, 5.2% transaminase levels (0.2%
NIS 12 weeks RR 54.8% intolerability) >3ULN)
(svMADRS < 12)
Kasper N ¼ 154 A Sertraline (S) 50–100 mg/day R: A 70%, 61.5% S A 2.6% Fatigue 5.9%, A > S, diarrhea
et al. and hyperhidrosis S > A
(2010)
RCT N ¼ 159 S RR: 32.7% A, S 11.3%
Agomelatine and Depressions

28.8% S
6 weeks A > S sleep wake
cycle, sleep
efficiency
Martinotti N ¼ 30 A Venlafaxine (V) 75–150 mg/day A greater efficacy on A 3.2% A 3.2%, V 39.2%
et al. anhedonia
(2012)
RCT N ¼ 30 V V 17.8%
8 weeks
Olie and N ¼ 238 Pl A > Pl A 14.4%, Pl 15.0%, due to Headache 5%Fatigue A > Pl,
Kasper side effects A 3.4%, Pl Headache Pl > A
(2007) 5.8%
RCT 6 weeks Effect size 0.41
R: A 54.3%, Pl 4% nausea, dizziness, n.s.
35.3%
Hale et al. N ¼ 515 N ¼ 252 A A>F A 11.9% A¼F
(2010)
RCT 8 weeks N ¼ 263 Fluoxetine (F) R: A 71.7% F 18.6% Liver enzyme elevations A
Severe MDD F 63.8% 4, F 1
(HAMD > 25)
(continued)
1385
 1386

Table 1 (continued)
N, patients, Study arms, comparators,
Study duration placebo (Pl) Results Drop-out rates Relevant side effects
Heun et al. N ¼ 222 Pl A > Pl
(2013) 8 weeks N ¼ 151 A R: A 59.5%
Age > 65 years N ¼ 71 Pl Pl 38.6%
Guaiana N ¼ 4495 SSRIs, Venlafaxine R and RR A lower than venlafaxine A fewer side effects
et al.
(2013)
Review A ¼ SSRIs,
13 studies Venlafaxine
Singh et al. N ¼ 3661 N ¼ 1963 Pl A > Pl Effect size
(2012) 0.26
Meta- N ¼ 1698 SSRIs A vs. Comparators
analysis Effect size 0.11
Corruble N ¼ 324 N ¼ 164 A R: A 82.6% A 11.0%, E 18.1%
et al.
(2013)
RCT 24 weeks N ¼ 160 Escitalopram (E) E 81.3%
RR: A 69.5%
E 63.1%
Sleep A > E
G. Laux
Kasper N ¼ 1997 N ¼ 1001 A A > SSRIs/SNRI
et al.
(2013)
Pool N ¼ 996 Sertraline, fluoxetine, R: A 71%
analysis venlafaxine, escitalopram, SSRIs/SNRI 66%
paroxetine
Taylor et al. N ¼ 7460 N ¼ 3951 Pl A > Pl Effect size A 18% NA
(2014) 0.24
Meta- N ¼ 4559 Sertraline (S), A > S, A ¼ F, E, V Pl 19%
Agomelatine and Depressions

analysis paroxetine (P), fluoxetine (F), A(<) P Comp. 19%

20 studies escitalopram (E), venlafaxine (V) Due to side effects: A 4%,
Pl 5%, Comp. 8%
Papakostas N ¼ 493 V 10–20 mg/d V >A V 21% Rare side effects
et al. SSRI/SNRI A 25–50 mg/d A 26% A >V
(2018) nonresponders
EU multicenter
12 weeks
> ¼ significant better, NA ¼ not applicable, NIS ¼ noninterventional study, R ¼ Response rate, RR ¼ Remission rate
1387
1388 G. Laux

than placebo, and escitalopram was accompanied by a higher incidence of side

effects (Stein et al. 2014).
Regarding treatment of seasonal affective disorder 37 acutely depressed SAD
patients had good response with agomelatine over 14 weeks (response rate 75.7%)
with good tolerability (Pjrek et al. 2007).
A 2019 review suggested no recommendations of agomelatine in support of, or
against, its use to treat individuals with seasonal affective disorder, however
(Nussbaumer-Streit et al. 2019).

Long-Term Studies, Relapse Prevention

In a meta-analytic, pooled analysis of four published 24-week studies, the final

HAM-D-17 score was significantly lower in patients treated with agomelatine than
in patients treated with selective serotonin reuptake inhibitors (SSRIs). HAM-D
response rates were significantly higher in patients treated with agomelatine than
in patients treated with SSRIs. Treatment discontinuation was 9.4% in patients
treated with SSRIs and 6.6% in patients treated with agomelatine (Demyttenaere
et al. 2013).
A 24-week relapse prevention study of agomelatine in depression showed a
significant advantage for agomelatine over placebo – relapse rate agomelatine
23.9%, placebo 50% (Goodwin et al. 2009).
A meta-analysis including unpublished relapse prevention studies, however,
suggested no advantage for agomelatine over placebo. None of the negative trials
were published and conflicting results between published and unpublished studies
were observed (Koesters et al. 2013).
A 2018 network meta-analysis of 522 trials comprising 116,477 patients com-
paring 21 antidepressants found agomelatine effective with lowest drop-out rate
(Cipriani et al. 2018).

Side Effects, Adverse Reactions, and Toxicology

Agomelatine has a low incidence of nausea and dizziness and seems not to affect
sexual function, hematologic parameters, QTc interval, and weight. In studies,
agomelatine was well tolerated with no more adverse events than placebo (Stein
et al. 2014).
Data of the drug surveillance program in German-speaking countries of 184234
psychiatric inpatients revealed incidence rates of drug-induced liver injury for
agomelatine 0.33%, mianserine 0.36%, clomipramine 0.23%, and escitalopram
0.01% (Friedrich et al. 2016).
An observational cohort study 6-month evolution of 8453 depressed patients
(female: 67.7%; mean age: 49.1 years) reported cutaneous events in 1.7% of the
patients and increased hepatic transaminases values in 0.9% of the patients
(Gorwood et al. 2021). Hepatotoxic reactions like acute liver injury are an identified
Agomelatine and Depressions 1389

risk in the European risk management plan for agomelatine. Formal required are
liver function testing at baseline and 3, 6, 12, and 24 weeks. This monitoring is
mandated because of a low but important incidence of raised liver enzyme activity
and the risk of nonfatal “toxic hepatitis.” Summarizing agomelatine increased ALAT
and ASAT (liver enzymes) in 1.1% of patients (vs. 0.7% in placebo groups) (Laux
et al. 2017). On the other hand, a case-control study using data sources in Denmark,
Germany, Spain, and Sweden evaluated 3,238,495 new antidepressant and 74,440
agomelatine users. Agomelatine was not associated with an increased risk of ALI
hospitalization (Pladevall-Vila et al. 2019).
Agomelatine is contraindicated in patients with liver impairment, no
co-medication with strong CYP1A2 inhibitors like fluvoxamine or ciprofloxacine.
Clinical worsening, (hypo-) mania, and suicide risk must be monitored by all
antidepressants.

Pregnancy: Use of agomelatine is not recommended.

Discontinuation: Discontinuation symptoms are not reported with agomelatine
(Montgomery et al. 2004).

Combination Therapy – Interactions

Agomelatine is a substrate of CYP1A2 mainly. Inhibitors of these enzymes, for

example, the SSRI antidepressant fluvoxamine, reduce its clearance and can there-
fore lead to an increase in agomelatine plasma levels.

Cross-References

▶ Antidepressants: Course and Duration of Therapy, Withdrawal Syndromes, and

Resistance to Therapy
▶ Antidepressants: Definition, Classification, Guidelines
▶ Antidepressants: Indications, Contraindications, Interactions, and Side Effects
▶ Antidepressants: Pharmacology and Biochemistry
▶ Combination Therapies and Switching of Agents in Depression and Bipolar
Disorders
▶ Psychopharmacotherapy of depressive disorders

References
Cipriani A, Furukawa TA, Salanti G, Chaimani A, et al. Comparative efficacy and acceptability of
21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a
systematic review and network meta-analysis. Lancet. 2018;391:1357–66.
Corruble E, de Bodinat C, Belaidi C, Goodwin G. Efficacy of agomelatine and escitalopram on
depression, subjective sleep and emotional experiences in patients with major depressive
1390 G. Laux

disorder: a 24-wk randomized, controlled, double-blind trial. Int J Neuropsychopharmacol.

2013;16:2219–34.
De Berardis D, Conti CM, Marini S, Ferri F, et al. Is there a role for agomelatine in the treatment of
anxiety disorders? A review of published data. Int J Immunopath Pharmacol. 2013;26:299–304.
Demyttenaere K, Corruble E, Hale A, Quera-Salva MA, Picarel-Blanchot F, Kapser S. A pooled
analysis of six month comparative efficacy and tolerability in four randomized clinical trials:
agomelatine versus escitalopram, fluoxetine, and sertraline. CNS Spectr. 2013;18:163–70.
Dridi D, Zouiten A, Mansour HB. Depression: chronophysiology and chronotherapy. Biol Rhythm
Res. 2013;45:77–91.
Friedrich ME, Akimova E, Huf W, Konstantinidis A, et al. Drug-induced liver injury during
antidepressant treatment: results of AMSP, a drug surveillance program. Int J Neuropsycho-
pharmacol. 2016;19:pyv126.
Goodwin G, Emsley R, Rembry S, Rouillon F, et al. Agomelatine prevents relapse in patients with
major depressive disorder, without evidence of a discontinuation syndrome. J Clin Psychiatry.
2009;70:1128–37.
Gorwood P, Benichou J, Moore N, Martínez EA, et al. The safety of agomelatine in standard
medical practice in depressed patients: a 26-week international multicentre cohort study. Hum
Psychopharmacol. 2021;36:e2759.
Guaiana G, Gupta S, Chiodo D, Davies SJ, Haederle K, Koesters M. Agomelatine versus other
antidepressive agents for major depression. Cochrane Database Syst Rev. 2013;12:CD008851.
Hale A, Corral R, Mencacci O, Saiz Ruiz J, Albarran SC. Superior antidepressant efficacy results of
agomelatine versus fluoxetine in severe MDD patients: a randomised, double-blind study. Int
Clin Psychopharmacol. 2010;25:305–14.
Heun R, Ahokas A, Boyer P, et al. The efficacy of agomelatine in elderly patients with recurrent
major depressive disorder. A placebo-controlled study. J Clin Psychiatry. 2013;74:587–94.
Hiemke C, Bergemann N, Clement HW, Conca A, et al. Consensus guidelines for therapeutic drug
monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Howland RH. A benefit-risk assessment of agomelatine in the treatment of major depression. Drug
Saf. 2011;34:709–31.
Kasper S, Hamon M. Beyond the monoaminergic hypothesis: agomelatine, a new antidepressant
with an innovative mechanism of action. World J Biol Psychiatry. 2009;10:117–26.
Kasper S, Hajak G, Wulff K, Hoogendijk WJ, et al. Efficacy of the novel antidepressant
agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients
with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin
Psychiatry. 2010;71:109–20.
Kasper S, Corruble E, Hale A, Lemoine P, et al. Antidepressant efficacy of agomelatine versus
SSRI/SNRI: results from a pooled analysis of head-to-head studies without a placebo control.
Int Clin Psychopharmacol. 2013;28:12–9.
Kennedy SH, Rizvi SJ. Agomelatine in the treatment of major depressive disorder. CNS Drugs.
2010;24:479–99.
Koesters M, Guaiana G, Cipriani A, Becker T, Barbui C. Agomelatine efficacy and acceptability
revisited: systematic review and meta-analysis of published and unpublished randomised trials.
Br J Psychiatry. 2013;203:179–87.
Laux G. The antidepressant agomelatine in daily practice: results of the non-interventional study
VIVALDI. Pharmacopsychiatry. 2012;45:284–29.
Laux G, Barthel B, Hajak G, et al. Pooled analysis of four non-interventional studies: Effectiveness
and tolerability of the antidepressant agomelatine in daily practice. Adv Ther. 2017;34:895–914.
Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive
disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with
venlafaxine. J Clin Psychiatry. 2007;68:1723–32.
Martinotti G, Sepede G, Gambi F, Di Iorio G, et al. Agomelatine versus venlafaxine XR in the
treatment of anhedonia in major depressive disorder: a pilot study. J Clin Psychopharmacol.
2012;32:487–91.
Agomelatine and Depressions 1391

Millan MJ, Gobert A, Lejeune F, et al. The novel melatonin agonist agomelatine (S20098) is an
antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of
frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther. 2003;306:954–64.
Montgomery SA, Kasper S. Severe depression and antidepressants: focus on a pooled analysis of
placebo-controlled studies on agomelatine. Int Clin Psychopharmacol. 2007;22:283–91.
Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux, et al. Absence of discontinuation symp-
toms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a ran-
domized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol.
2004;19:271–80.
Norman TR, Olver JS. Agomelatine for depression: expanding the horizons? Expert Opin
Pharmacother. 2019;20:647–56.
Nussbaumer-Streit B, Greenblatt A, Kaminski-Hartenthaler A, et al. Melatonin and agomelatine for
preventing seasonal affective disorder. Cochrane Database Syst Rev. 2019;6:CD011271.
Olie JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic
properties, in major depressive disorder. Int J Neuropsychopharmacol. 2007;10:661–73.
Papakostas GI, Nielsen RZ, Dragheim M, Tonnoir B. Efficacy and tolerability of vortioxetine
versus agomelatine, categorized by previous treatment, in patients with major depressive
disorder switched after an inadequate response. J Psychiatr Res. 2018;101:72–9.
Pjrek E, Winkler D, Konstantinidis A, Willeit M, et al. Agomelatine in the treatment of seasonal
affective disorder. Psychopharmacology (Berl). 2007;190:575–9.
Pladevall-Vila M, Pottegård A, Schink T, Reutfors J, et al. Risk of acute liver injury in agomelatine
and other antidepressant users in four European countries: a cohort and nested case–control
study using automated health data sources. CNS Drugs. 2019;33:383–95.
Quera Salva MA, Vanier B, Laredo J, et al. Major depressive disorder, sleep EEG and agomelatine:
an open-label study. Int J Neuropsychopharmacol. 2007;10:691–6.
Quera-Salva MA, Hajak G, Philip P, Montplaisir J, et al. Comparison of agomelatine and
escitalopram on nighttime sleep and daytime condition and efficacy in major depressive disorder
patients. Int Clin Psychopharmacol. 2011;26:252–62.
Racagni G, Riva MA, Molteni R, Musazzi L, et al. Mode of action of agomelatine: synergy between
melatonergic and 5-HT(2C) receptors. World J Biol Psychiatry. 2011;12:574–87.
Singh SP, Singh V, Kar N. Efficacy of agomelatine in major depressive disorder: meta-analysis and
appraisal. Int J Neuropsychopharmacol. 2012;15:417–28.
Stein DJ, Ahokas A, Marquez MS, Höschl C, et al. Agomelatine in generalized anxiety disorder: an
active comparator and placebo-controlled study. J Clin Psychiatry. 2014;75:362–8.
Taylor D, Sparshatt A, Varma S, et al. Antidepressant efficacy of agomelatine: meta-analysis of
published and unpublished studies. BMJ. 2014;348:g1888.
Hypericum and Depression

Hans-Peter Volz

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395
Side Effects/Adverse Effects and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1396
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1398
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1399
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1399

Abstract
St. John’s wort (also known as hypericum extract, HE) is a long used phythophar-
maceutical compound, showing, besides others, antidepressive properties. The
antidepressive activity of HE seems to be closely linked to only a few of the more
than 150 constituents, mainly hypericin and hyperforin. In several studies an
inhibitory effect on the mitochondrial monoamineoxidase (MAO) A and B could
be shown; also interactions with the GABAA- and GABAB-receptor were dem-
onstrated. Hyperforin also acts as a reuptake inhibitor of serotonin, dopamine,
noradrenaline, GABA, and L-glutamate. In animal studies, the antidepressive
effect of HE could be demonstrated. In several clinical trials, HE was more
effective compared to placebo and as effective as synthetical antidepressants in
mild to moderate depression. These single trials have been included in several
meta-analyses confirming the overall efficacy. The subjective tolerability is
excellent with placebo-level frequencies of adverse events, results being present

H.-P. Volz (*)

Krankenhaus für Psychiatrie, Psychotherapie und Psychosomatische Medizin Schloss Werneck,
Werneck, Germany
e-mail: hans-peter.volz@kh-schloss-werneck.de

© Springer Nature Switzerland AG 2022 1393

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_93
1394 H.-P. Volz

in single trials and also in several meta-analyses. Since HE might induce certain
CYP 450 isoenzymes and p-glycoprotein, pharmacokinetic interactions are
possible.

Chemistry, Developmental History

Hypericum perforatum (more known as St. John’s wort) is a herbaceous plant

commonly found in Europe and Asia. Most often, hypericum extracts (HE) are
used as antidepressants; however, wound-healing effects, antimicrobial properties
against a number of bacterial and fungal strains, and also antiviral properties are
described (Russo et al. 2014). The herbal extracts contain various concentrations of
constituents with documented biological activity such as flavonol glycosides,
phloroglucinols, naphthodianthrones, etc. (Crupi et al. 2013). For a survey, see
Table 1. The standardization of HE is normally based on the content of hyperforin
(3.0%) and hypericin (0.3–0.5%) (Zirak et al. 2018). These active compounds have
been reported to be mainly responsible for the pharmacological effect of HE. The
chemical structure of four major components of HE is shown in Fig. 1.

Pharmacology

The antidepressive activity of HE seems to be closely linked to only a few of the

more than 150 constituents, mainly hypericin and hyperforin. In several studies an
inhibitory effect on the mitochondrial monoamineoxidase (MAO) A and B could be
shown; also interactions with the GABAA- and GABAB-receptor were demon-
strated. Hyperforin also acts as a reuptake inhibitor of serotonin, dopamine, nor-
adrenaline, GABA, and L-glutamate. In a series of animal models for antidepressive
activity (the forced swimming test, the open field test, the tail suspension test, or a
model of stress-impaired memory) HE or single constituents showed results com-
parable to synthetic antidepressants (Barnes et al. 2001; Müller 2003; Hirano et al.

Table 1 Constituents of Group Constituents Plant parts

Hypericum perforatum and
Flavonoids Rutin Leaves
the plant parts from which
Hyperoside Stalk
they are derived
Isoquercitrin Buds
Miquelianin
Quercetin
Quercetin
Biflavonoids I2,II8-Biapigenin Flowers
Amentoflavone
Naphthodianthrones Hypericin Flowers
Pseudohypericin Buds
Phloroglucinols Hyperforin Flowers
Adhyperforin Buds
According to Crupi et al. (2013)
Hypericum and Depression 1395

Fig. 1 Chemical structure of four major constituents of HE. (According to Zirak et al. 2018)

2004; De Marchis et al. 2006; Grundmann et al. 2010; Crupi et al. 2011; Schmidt
und Butterweck 2015). In a cell-modell (transfected rat C6 glioblastoma cells) it
could be shown that hyperforin and hyperoside, both compounds of HE, lead to a
postsynaptic β-down-regulation (Jakobs et al. 2013).
Pharmacokinetic parameters are dependent on the extract used in such pharma-
cokinetic trials. Just to give one example, the results of Schulz et al. (2005) using
STW-3612 mg dry extract in 18 male patients in a single and multiple design is given
(means + standard deviation): After single administration, the AUC(0
1) [h∙ng/ml]
was 75.96  23.52 for hypericin, 93.03  29.40 for pseudohypericin,
1009.0  203.4 for hyperforin, and 318.70  130.82 for quercetin. Cmax [ng/ml]
was 3.14  1.57, 8.50  4.35, 83.5  27.8 resp. 47.7  22.5, tmax [h] was 8.1  1.8,
3.0  1.4, 3.0  1.4 resp. 1.17  0.52, and t1/2 [h] was 23.76  5.46, 25.39  10.18,
19.64  6.35 resp. 4.16  2.97.

Clinical Studies

Most of the randomized clinical trials (RCT) were performed in mild to moderate
depressed patients, with only some exceptions (Vorbach et al. 1997; Szegedi et al.
2005) investigating also severely depressed patients. In the meantime several meta-
analyses have been published, the most important will be summarized.
Linde et al. (2008) included a total of 29 trials (5.489 patients). Eighteen comparisons
versus placebo and 17 comparisons versus synthetic antidepressant compounds were
performed. Regarding the placebo comparisons, the combined response rate ratio was
for nine larger trials 1.28 (95% confidence interval [95% CI]: 1.10–1.49) and for nine
smaller trials 1.87 (95% CI: 1.22–2.87). This separation into larger and smaller trials
1396 H.-P. Volz

was done since the efficacy results of the placebo-HE comparisons were statistically
heterogeneous. The results of the trials comparing HE and standard antidepressants
were statistically homogeneous. Regarding the comparison with tri- or tetracyclic
antidepressants, the response rate ratios were 1.02 (95% CI: 0.90–1.15; 5 trials),
regarding the comparison with SSRIs, the response rate ratios were 1.00 (95% CI:
0.90–1.11; 12 trials). The authors state that trails from German-speaking countries
showed more favorable results for HE than trials from non-German-speaking countries.
Recently Ng et al. (2017) published another meta-analysis comprising 27 RCTs
comparing HE with SSRIs with a total of 3.808 patients. They found a comparable
response (pooled response rate ratio 0.983 [95% CI: 0.924–1.042, p < 0.001]) and
remission (pooled remission rate ratio 1.013 [95% CI: 0.892–1.134, p < 0.001]) rate
compared to standard SSRIs. The pooled standardized mean differences (SMD) from
baseline Hamilton Depression Rating Scale-scores (pooled SMD -0.068 [95% CI:

0.127–0.021, p < 0.001]) also support the significant clinical efficacy of HE.
Further reviews and meta-analyses were published by Apaydin et al. (2016),
Forsdike and Pirotta (2017), Zirak et al. (2018), Sarris et al. (2013) and Cui and
Zheng (2016) (see also Table 2).
Regarding long-term efficacy, one trial evaluated in a double-blind manner
moderately to severe depressed patients after the acute treatment phase of 6 weeks
(results reported by Szegedi et al. 2005) for another 16 weeks comparing the HE WS
5570 to paroxetine (Anghelescu et al. 2006) and found no differences between the
groups; however, the design was not suited to detect equal efficacy. In a placebo-
controlled long-term trial (Kasper et al. 2008), a state-of-the art design to show
efficacy (and tolerability) in the continuation and prophylactic (maintenance) phase
of long-term treatment was used. After an initial open treatment phase with WS 5570
for 6 weeks, responders were randomized to WS 5570 (3X300 mg/day) or placebo
and treated in a double-blind manner for an additional 26 weeks (continuation
phase), stable patients on WS 5570 were then again randomized to WS 5570 resp.
placebo, stable patients who have been already in the placebo group continued with
placebo for another 52 weeks (prophylaxis/maintenance phase). WS 5570 was very
efficacious (time to relapse, relapse rates) in the continuation phase, but in the
prophylaxis phase this superiority was only present initially in severely ill patients.
Regarding efficacy, it is noteworthy that – since the constituents of HE differ
considerably between the individual manufacturers – the efficacy cannot be extrap-
olated from one extract to another. As Kasper et al. (2010a) showed, WS 5572, LI
160, WS 5570, and ZE 117 are significantly more efficacious than placebo and at
least as efficacious with better tolerability than synthetic antidepressants, which is
also the case for STW3/-VI (Uebelhack et al. 2004; Gastpar et al. 2005, 2006).

Side Effects/Adverse Effects and Toxicology

HE show a similar adverse event (AE) frequency as placebo-treated patients. In the

two big meta-analyses already mentioned, this favorable side effect profile was
confirmed: Thus, Linde et al. (2008), report that patients given HE dropped out of
Hypericum and Depression 1397

Table 2 Reviews and meta-analyses mentioned in the text with the most important details
regarding methods and results
Author Type Method Result
Linde Meta-analysis A total of 29 studies with 5,489 HE showed superior efficacy
et al. patients have been included compared to placebo and equal
(2008) efficacy compared to
synthetical antidepressants.
Tolerability of HE was
superior to synthetical
antidepressants
Ng et al. Meta-analysis A total of 35 studies with 6,993 HE showed superior efficacy
(2017) patients have been included compared to placebo and equal
efficacy comped to SSRI.
Tolerability of HE was better
compared to SSRI
Forsdike Scoping 13 studies including 5,183 With the exception of
and review about physicians/care providers and Germany St. John’s wort was
Pirotta attitudes and a total population of 1,903,649 seldomly used due to little
(2017) experiences knowledge about efficacy data
of the single extracts
Zirak Narrative Available data of in vitro, HE may exert potent
et al. review in vivo, and clinical evidence antidepressant effects. It seems
(2018) to be also safe
Sarris Narrative Outlines the current evidence Evidence supports the use of
(2013) review of the efficacy of HE in HE for mild to moderate
common psychiatric disorders, depression and somatization
not only in depression, but also disorder, but not in other
in other disorders. Mechanisms psychiatric disorders.
of action, including emerging Differences in the quality and
pharmacogenetic data, safety, safety of HE need to be
and clinical considerations are addressed in recommending
also detailed extracts to the patients.
Potential interactions should
be kept in mind
Cui and Meta-analysis 27 studies with a total of 3,126 Equal efficacy of HE compared
Zheng patients have been included to SSRI and superior
(2016) tolerability
Abbr.: HE hypericum extract, SSRI serotonin reuptake inhibitor

trials due to adverse effects less frequently than those given older antidepressants
(odds ratio [OR]: 0.24 [95% CI: 0.13–0.46]) or SSRIs (OR: 0.53 [95% CI: 0.34–
0.83]). Similar results were found by Ng et al. (2017) who showed significantly
lower discontinuation/dropout rates compared to standard SSRIs (pooled OR 0.587
[95% CI: 0.478–0.697], p < 0.001).
The differential side effect profile in comparison to SSRIs was analyzed by
Kasper et al. (2010b), based on four RCTs (with a total of 1.661 outpatients
included). The HE WS 5570 (dose between 600 and 1.800 mg/day) was compared
to 20–40 mg/day paroxetine resp. to placebo. Across the four trials the percentage of
patients with an adverse event (AE) under HE was comparable to placebo (risk ratio
1398 H.-P. Volz

Table 3 Symptom clusters of adverse events (%) of patients affected and risk ratio with 95%
confidence interval (95& CI)
Placebo
WS 5570 Placebo Paroxetine vs. WS Paroxetine
(n ¼ 1.264) (n ¼ 271) (n ¼ 126) 5570 vs. WS 5570
Symptom
clusters N (%) N (%) N (%) RR (95% CI)
Sedationa 20 (1.6) 1 (0.4) 26 (20.6) 0.23 (0.04– 13.04 (7.51–
1.35) 22.44)
Anticholinergic 11 (0.9) 4 (1.5) 42 (33.3) 1.70 (0.57– 38.30 (20.42–
reactionsb 4.99) 71.72)
Typical SSRI 63 (5.0) 20/7.4) 52 (41.3) 1.48 (0.91– 8.26 (5.99–
symptomsc 2.38) 11.31)
Sexual 0 (0.0) 0 (0.0) 3 (2.4) – (7.84–)
dysfunctiond
Heart rhythme 2 (0.2) 0 (0.0) 2 (1.6) 0.00 (0.00– 10.03 (1.77–
8.92) 56.32)
Hypotension/ 11 (0.9) 3 (1.1) 28 (22.2) 1.27 (0.38– 25.54 (13.15–
vertigof 4.19) 49.37)
According to Kasper et al. (2010b)
a
Fatigue, somnolence, insomnia, flat affect
b
Constipation, constipation aggravated, dry mouth
c
Headache, migraine, headache aggravated, diarrhea, nausea, vomiting, insomnia, initial insomnia,
agitation, restlessness, irritability, nervousness
d
Libido decreased, loss of libido, ejaculation disorders
e
Bradycardia, palpitation
f
Hypotension, hypotension postural, dizziness, dizziness (ex vertigo), vertigo

[RR]: 1.1 [95% CI: 0.9–1.3]) and significantly lower than for paroxetine (RR: 2.4
[95% CI: 2.1–2.8]). For further details, see Table 3.
Regarding single AEs of HE, rare cases of gastro-intestinal disorders, allergic
skin reactions, tiredness, and restlessness are reported (Russo et al. 2014). Photo-
sensitivity seems only to occur after very high doses of HE and/or intense sun light
(Schulz et al. 2006).

Combination Therapy: Interactions

Hypericum is a substrate of hepatic cytochrome isoenzymes (CYP) and phospho-

glycoprotein (P-gp). Hypericum also induces several CYP isoenzymes (before all
CYP3A4, but also CYP2E1, CYP2C19) thereby increasing the metabolism of
different drugs (leading to lower plasma levels and to a potential reduction of
efficacy) (Russo et al. 2014). Hypericum induces also the synthesis of P-gp in the
intestines thus drug absorption can be reduced (Russo et al. 2014). Due to these
mechanisms close monitoring of coagulation parameters is required when HE is
co-administered with coumarin-type anticoagulants (phenprocoumon, warfarin)
(Schwabe 2014). A reduction in contraceptive action or oral contraceptives has
Hypericum and Depression 1399

been discussed. Indeed, clinical studies have demonstrated a higher incidence of

intracyclic bleeding when HE and oral contraceptives were administered together;
however, post-marketing data do not show an increase of this rate when HE are
co-administered to oral contraceptives (Russo et al. 2014; Berry-Bibee et al. 2016).
A decrease in the efficacy of digoxin, amitriptyline, nortriptyline, midazolam, and
theophylline can occur when HE is co-administered, hence no combination treat-
ment with cyclosporine, tacrolimus, indinavir and other protease inhibitors,
irinotecan, imatinib, and other cytostatic agents should be initiated (Schwabe 2014).

Cross-References

▶ Antidepressants: Definition, Classification, Guidelines

▶ TCM Substances in Neuropsychopharmacotherapy
▶ TCM Substances in Neuropsychopharmacotherapy: Basic Aspects with a Focus
on Depression

References
Anghelescu IG, Kohnen R, Szegedi A, Klement S, Kieser M. Comparison of Hypericum extract
WS 5570 and paroxetine in ongoing treatment after recovery from an episode of moderate to
severe depression: results from a randomized multicenter study. Pharmacopsychiatry.
2006;39:213–9.
Apaydin EA, Maher AR, Shanman R, Booth MS, Miles JN, Sorbero ME, Hempel S. A systematic
review of St. John’s wort for major depressive disorder. Syst Rev. 2016;5:148.
Barnes J, Anderson LA, Phillipson JD. St John’s wort (Hypericum perforatum L.): a review of its
chemistry, pharmacology and clinical properties. J Pharm Pharmacol. 2001;53:583–600.
Berry-Bibee EN, Kim MJ, Tepper NK, Riley HE, Curtis KM. Co-administration of St. John’s wort
and hormonal contraceptives: a systematic review. Contraception. 2016;94:668–77.
Crupi R, Mazzon E, Marino A, La Spada G, Bramanti P, Battaglia F, Cuzzocrea S, Spina
E. Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress
model in mice. BMC Complement Altern Med. 2011;11:7.
Crupi R, Abusamra YA, Spina E, Calapai G. Preclinical data supporting/refuting the use of
Hypericum perforatum in the treatment of depression. CNS Neurol Disord Drug Targets.
2013;12:474–86.
Cui YH, Zheng Y. A meta-analysis on the efficacy and safety of St John’s wort extract in depression
therapy in comparison with selective serotonin reuptake inhibitors in adults. Neuropsychiatr Dis
Treat. 2016;12:1715–23.
De Marchis GM, Bürgi S, Kientsch U, Honegger UE. Vitamin E reduces antidepressant-related
beta-adrenoceptor down-regulation in cultured cells. Comparable effects on St. John’s wort and
tricyclic antidepressant treatment. Planta Med. 2006;72:1436–7.
Forsdike K, Pirotta M. St John’s wort for depression: scoping review about perceptions and use by
general practitioners in clinical practice. J Pharm Pharmacol. 2017;71:117–28.
Gastpar M, Singer A, Zeller K. Efficacy and tolerability of hypericum extract STW3 in long-term
treatment with a once-daily dosage in comparison with sertraline. Pharmacopsychiatry.
2005;38:78–86.
Gastpar M, Singer A, Zeller K. Comparative efficacy and safety of a once-daily dosage of
hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-
blind, randomized, multicentre, placebo-controlled study. Pharmacopsychiatry. 2006;39:66–75.
1400 H.-P. Volz

Grundmann O, Lv Y, Kelber O, Butterweck V. Mechanism of St. John’s wort extract (STW3-VI)

during chronic restraint stress is mediated by the interrelationship of the immune, oxidative
defense, and neuroendocrine system. Neuropharmacology. 2010;58:767–73.
Hirano K, Kato Y, Uchida S, Sugimoto Y, Yamada J, Umegaki K, Yamada S. Effects of oral
administration of extracts of Hypericum perforatum (St John’s wort) on brain serotonin trans-
porter, serotonin uptake and behaviour in mice. J Pharm Pharmacol. 2004;56:1589–95.
Jakobs D, Hage-Hülsmann A, Prenner L, Kolb C, Weiser D, Häberlein H. Downregulation of β1
-adrenergic receptors in rat C6 glioblastoma cells by hyperforin and hyperoside from St John’s
wort. J Pharm Pharmacol. 2013;65:907–15.
Kasper S, Volz HP, Möller HJ, Dienel A, Kieser M. Continuation and long-term maintenance
treatment with Hypericum extract WS 5570 after recovery from an acute episode of moderate
depression–a double-blind, randomized, placebo controlled long-term trial. Eur Neuropsycho-
pharmacol. 2008;18:803–13.
Kasper S, Caraci F, Forti B, Drago F, Aguglia E. Efficacy and tolerability of Hypericum extract for
the treatment of mild to moderate depression. Eur Neuropsychopharmacol. 2010a;20:747–65.
Kasper S, Gastpar M, Möller HJ, Müller WE, Volz HP, Dienel A, Kieser M. Better tolerability of
St. John’s wort extract WS 5570 compared to treatment with SSRIs: a reanalysis of data from
controlled clinical trials in acute major depression. Int Clin Psychopharmacol. 2010b;25:204–13.
Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev.
2008;(4):CD000448.
Müller WE. Current St John’s wort research from mode of action to clinical efficacy. Pharmacol
Res. 2003;47:101–9.
Ng QX, Venkatanarayanan N, Ho CY. Clinical use of Hypericum perforatum (St John’s wort) in
depression: a meta-analysis. J Affect Disord. 2017;210:211–21.
Russo E, Scicchitano F, Whalley BJ, Mazzitello C, Ciriaco M, Esposito S, Patanè M, Upton R,
Pugliese M, Chimirri S, Mammì M, Palleria C, De Sarro G. Hypericum perforatum: pharma-
cokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytother Res.
2014;28:643–55.
Sarris JS. John’s Wort for the treatment of psychiatric disoders. Psychiatr Clin N Am. 2013;36:65–72.
Schmidt M, Butterweck V. The mechanisms of action of St. John’s wort: an update. Wien Med
Wochenschr. 2015;165:229–35.
Schulz HU, Schürer M, Bässler D, Weiser D. Investigation of the bioavailability of hypericin,
pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin following single and
multiple oral dosing of a hypericum extract containing tablet. Arzneimittelforschung.
2005;55:15–22.
Schulz HU, Schürer M, Bässler D, Weiser D. Investigation of the effect on photosensitivity
following multiple oral dosing of two different hypericum extracts in healthy men. Arzneimit-
telforschung. 2006;56:212–21.
Schwabe. Product Monograph Neuroplant ®. 2014.
Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with
hypericum extract WS 5570 (St John’s wort): randomised controlled double blind
non-inferiority trial versus paroxetine. BMJ. 2005;330(7490):503.
Uebelhack R, Gruenwald J, Graubaum HJ, Busch R. Efficacy and tolerability of Hypericum extract
STW3-VI in patients with moderate depression: a double-blind, randomized, Plazebo-controlled
clinical trial. Adv Ther. 2004;21:265–75.
Vorbach EU, Arnoldt KH, Hübner WD. Efficacy and tolerability of St. John’s wort extract LI
160 versus imipramine in patients with severe depressive episodes according to ICD-10.
Pharmacopsychiatry. 1997;30(Suppl 2):81–5.
Zirak N, Shafiee M, Soltani G, Mirzaei M, Sahebkar A. Hypericum perforatum in the treatment of
psychiatric and neurodegenerative disorders: current evidence and potential mechanisms of
action. J Cell Physiol. 2018;234:8496–508.
Ginseng and Ginsenosides in Depression

Makoto Naoi, Wakako Maruyama, and Masayo Shamoto Nagai

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1402
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1403
Constituents of Ginseng and Phytochemical Classification of Ginsenoside . . . . . . . . . . . . . . 1403
Pharmacological Activities in the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1404
Antidepressant Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1406
Pharmacokinetics of Ginseng and Ginsenosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1410
Side Effects/Adverse Reactions and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1410
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1414
Financial and Competitive Interests Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415

Abstract
Panax ginseng Meyer is a well-known traditional Chinese medicine and has been
proposed to heal any disease. Ginseng and the major ingredient saponins
(ginsenosides) have multiple pharmacological activities, such as antioxidant, anti-
aging, anti-inflammatory, and immunomodulatory activity and are used as anti-
depressive, anti-stress, anti-fatigue, and anxiolytic agents in depressive state. The
antidepressant-like functions have been proved in animal models of depression
prepared by physical and psychological stress. Antidepressant function of ginseng
is mainly due to modulation of the hypothalamic–pituitary–adrenal axis and
immune system and anti-inflammation rather than modulation of monoamine
transmitter systems, brain-derived neurotrophic factor expression, and hippocampal
neurogenesis in contrast to other phytochemicals. The clinical trials of ginseng have

M. Naoi (*) · W. Maruyama · M. S. Nagai

Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin
University, Nisshin, Aichi, Japan
e-mail: mnaoi@dpc.agu.ac.jp; maruyama@dpc.agu.ac.jp; nagaim@dpc.agu.ac.jp

© Springer Nature Switzerland AG 2022 1401

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_92
1402 M. Naoi et al.

been reported mainly in depressive state of postmenopausal women by the estro-

gen-like function and subjects suffered from fatigue and anxiety, but scarcely
reported in major depressive disorder and dipolar depression. Ginseng ingredients
are poorly absorbed in human body and rapidly metabolized and only limited
amounts can cross the blood–brain barrier into the brain. Discrepancy of therapeu-
tic efficacy of ginseng between preclinical and clinical results suggests necessity to
increase the bioavailability and stability for clinical application. The benefits and
limits of antidepressant functions of ginseng and ginsenosides are discussed in
comparison with other phytochemicals.

Introduction

Ginseng (Panax ginseng) is a popular traditional Chinese medicine (TCM) capable

of promoting the health of the aged, and Korean ginseng products are used for more
than five thousand years in China, Korea, and Japan (Choi 2008). “Panax” means
“all-healing” in Greek and “ginseng” arises from the Chinese character “renshen”
(人参) meaning “essence of men.” Ginseng has been believed to improve the
pathological condition, adjust the balance of the human body, and heal any kind of
disease and promote longevity. In the TCM theory depression is a class of disease
and symptoms caused by emotional impairment and dysfunction of “Qi” (気). “Qi”
is a specific substance essential for survival and also the general name of the
functional activities of human organs. Ginseng activates human organs, restores
Qi, and calms the mood. However, Qi is a holistic perspective, which modern
science is difficult to define.
Ginseng is the root and rhizome of the Aaraliaceae plant and includes three major
commercial sorts, Korean (Panax ginseng C.A. Meyer), Chinese (Panax
notoginseng), and American ginseng (Panax quinquefolius L.). Red and white
ginseng are prepared by different processing methods of the same plant origins.
The fresh root, dried form, tonic drinks and wines, extract, G115 (standardized
extract), HYFPG™ (fermented ginseng extract), KGC05P0 (non-saponin fraction),
and the isolated ingredients, such as GINST15 ® [compound K (C-K)], are currently
used. Ginseng is one of the most popular natural products in the United States, and is
used up by to 30% of the population.
The basic pharmacology of ginseng is upregulation of nonspecific resistance to
various pathological factors and recovery to normal physiological function. In
randomized control trials, effects of ginseng have been reported on physical and
psychomotor performance, cognition, immunomodulation, diabetes mellitus, car-
diovascular risk factors, and quality of life. Ginseng and ginsenosides the major
saponin ingredients have diverse functions in the brain: antioxidant, antiaging,
neuroprotection, anxiolytic, and anti-fatigue activities and stimulation of brain
functions, learning and memory. However, pharmacological properties reported
in clinical studies on depression have been contradictory and the mechanisms have
been not fully clarified from modern medical, biochemical, and pharmacological
aspects (Yu et al. 2019).
Ginseng and Ginsenosides in Depression 1403

Pharmacology

Constituents of Ginseng and Phytochemical Classification of

Ginsenoside

Functional constituents of ginseng include ginseng saponins (called ginsenosides),

polyacetylenes, phenolic components, sesquiterpenes, alkaloids, polysaccharides,
and oligopeptides (Lee et al. 2015). Ginseng root contains 2–3% ginsenosides,
which have a common triterpenoid dammarane structure of four-ring, steroid-like
configuration conjugated with sugar. The chemical structures of most common
ginsenosides are shown in Fig. 1. Ginsenosides are classified into protopanaxadiols

Fig. 1 Chemical structure of major ginsenosides and the metabolism pathway. (a) Structure of PPD
and PPT. (b) Related derivatives. (c) Metabolic pathway of ginsenosides by intestinal microflora.
Rg3 and Rg1 have potent antidepressant activity and Rb1 anxiolytic activity. Glc, β-D-
glucopyranose; Ara(p), α-L-arabinose (pyranose); Ara(f), α-L-arabiose (fucose); Rha, α-L-
rhambopyranose; Xyl, β-D-xylopyranose
1404 M. Naoi et al.

(PPDs), protopanaxatriols (PPTs), and oleanolic acid (ginsenoside Ro). PPDs have
the sugar moieties attached to the 3-position of tripeptide, and include ginsenoside
Rb1, Rb2, Rb3, Rc, Rd., Rg3, Rg5, Rh2, and C-K, and notoginsenoside R1, whereas
PPTs have sugar moieties at the 6-position and include ginsenoside Re, Rg1, Rg2,
and Rf. Among 150 different types of ginsenosides, PPDs constitute more than 90%
of the total ginsenosides in Panax ginseng. Major bioactive ginsenosides include
Rb1, Rb2, Rb3, and notoginsenoside Fc and contain three to five sugars, whereas
minor ones are Rg3, Rh2, C-K, and 20-protopanaxaiol (20-PPD). The bioactivity
depends on the glycosylation patterns; the type, position, and number of sugar
moieties attached to the glycosidic bond at C-3 and C-6. Each ginsenoside has
different action mechanisms and tissue-specific effects, and exerts multiple func-
tions. Ginsenoside contents vary according to Panax species, the age and parts of
ginseng, season of harvest, and preservation and extraction methods.
Other constituents of ginseng also show pharmacological activities. Acidic poly-
saccharides, pectin combined with galacturonic acid, glucuronic acid, and mannuronic
acid, have antioxidant, anti-fatigue, immune-modulating, and antiproliferative effects
and show neuroprotection by activation of ERK/MAPK signaling pathway in cultured
neuronal cells. Polyacetylenes are unsaturated triple-bonded polyalcohols, including
panaxynol (heptadeca-1,9-diene-4,6-dine-3-ol), panaxydol (heptadeca-1-ene-9,10-
epoxy-4,6-dinye-3-ol), panaxytriol, panacacol, and panaxylene epoxide, and have
antioxidant and anticancer effects. Gintonin, a ginseng glycolipoprotein complex,
contains lysophosphatidic acids, linoleic acid, and lysophosphatidyl-inositol. Gintonin
binds to the lysophosphatidic acid (LPA) receptors, the G-protein coupled receptors
(GPCRs), GPR40 and GPR55; activates phosphatidylinostol-3-kinase (PI3K)/AKT
signaling pathway; exerts neuroprotection; and ameliorates cognition impairment in
Alzheimer’s, Parkinson’s, and Huntington’s diseases.

Pharmacological Activities in the Brain

Ginseng and ginsenosides stimulate or inhibit the brain functions and protect
neurons in neurodegeneration and ischemia. They have anti-inflammatory and
immunomodulatory functions, promotion of neurotrophic factors (NTFs) expression
and neurogenesis, phytoestrogen-like activities, and modulation of neurotransmitter
systems [serotonin (5-hydroxytryptamine, 5-HT), noradrenalin (NA), dopamine
(DA), GABA, glutamate, acetylcholine] in animal models. They also affect cardio-
vascular, antineoplastic, and aphrodisiac effects, which will not be discussed here. In
general, PPD derivatives have neuroprotective function, whereas PPT derivatives
antidepressant activities. Rb3 compromises over 15% of Panax notoginseng and has
antidepressant effects in animal models. Rb1 and its metabolite C-K are associated
with the most pharmacological activities in cardiovascular, endocrine, and immune
system and neurodegenerative diseases. Rb1 is an active anxiolytic compound. Rb2
has anticancer, anti-adipocytic, antidiabetic, and antioxidant functions in animal
models. Rg3 is enriched in Korean red ginseng and has neuromodulatory, cognition
enhancing, anti-inflammatory, antioxidant, antiangiogenic, and anticancer activities.
Ginseng and Ginsenosides in Depression 1405

The 20(S)-epimer of Rg3 more easily dissolves in water than the 20(R)-, and has
proapoptotic and anticancer activity. Rg1 is the primary ingredient, induces NTFs,
promotes neurogenesis, and has sex hormone-like activities to exert potent antide-
pressant function. Rh3, Rc, Rg1, Rg2, and Rh1 have antiaging, memory promoting,
and neuroprotective activities in animal models, but clinical trials have presented
only insufficient evidences for the effectiveness.
Pharmacological function of ginseng is characterized by the intracellular signal
transduction mediated by non-selective receptors or channels without any intracellular
signal transduction pathway (Nah 2014). Ginsenosides inhibit cation influx, stimulate
anion influx, and decrease the excitability of neuronal cells (Fig. 2). Ginsenosides
modulate voltage-gated ion channel. Rg3 and Rh2 affect Na+ channel, and ginseng,
Rb1, and Rg1 L-type voltage-gated Ca2+ channel (VGCC) and show neuroprotection.

Fig. 2 Ion channels, receptors, and intracellular signal transduction of ginsenosides for antide-
pressant function. Ginsenosides regulate voltage-gated ion channel, such as voltage-gated calcium
channel (VGCC) and voltage-gated sodium (Na+) channel (VGNC), and also ligand-gated ion
channel, such as GABAA and glycine receptor, NMDA, and nicotinic acetylcholine receptor.
Gintonin binds to G-protein-coupled LPA receptors and activates p38/MAPK pathway. Signaling
pathways activate transcription and enhance BDNF expression, or suppress the expression of
cytokines to exert anti-inflammation. ERα and ERβ, estrogen receptors; RXRα-PPARγ, retinoid
X receptor α-peroxisome-proliferating receptor γ; PGC-1α, proliferator-activated receptor γ
coactivator-1a
1406 M. Naoi et al.

Rh2, Rg3, C-K, PPT, and Rd. inhibit cation-gated N-methyl-D-aspartate (NMDA)
receptors and neuronal Na+ channels and stimulate anion-gated GABAA receptors and
glycine receptors to show anxiolytic effects. Rg3 regulates also ligand-gated ion
channels, 5-HT, nicotine acetylcholine, and NMDA receptors; affects nuclear retinoid
X receptor α-peroxisome-proliferating receptor γ (RXRα-PPARγ); activates PPAR
signaling; and has anti-inflammation activity. Ginsenosides bind also to estrogen
receptor (ER), glucocorticoid receptor (GR), and insulin-like growth factor-1 (IGF-1)
receptors and activate tyrosine kinase, PI3K/Akt and ERK1/2, p38 kinases. PPD
derivatives (Rh2, C-K) have higher affinity to GR than the PPT (Re, Rg1), whereas
Rh1 and Rg3 function as ER ligands. Gintonin binds to G protein-coupled LPA
receptors and activates MAPK, PI3K, PKC, and Rho kinases through cytosolic
calcium as a second messenger. Ginsenosides activate these receptors, induce brain-
derived neurotrophic factor (BDNF), promote hippocampal neurogenesis, and have
anti-inflammation and anti-fatigue activity. On the other hand, bioactive polyphenols,
such as flavonoids, bind to tyrosine kinase B (TrkB), the BDNF receptor, and other
receptors coupled with downstream mediators to have trophic effects, including the
formation, stabilization, and potentiation of neuronal architecture.

Antidepressant Functions

Depressive disorders are heterogeneous diseases, including major depressive dis-

order (MDD), bipolar disease (BD), reactive psychotic, and atypical depression.
Epidemiological, clinical, and basic studies reveal a complex interplay between
genetic and environmental factors in development of depression. At present,
available antidepressants, such as selective serotonin reuptake inhibitor (SSRI)
and serotonin-noradrenalin reuptake inhibitors (SARI), have efficiency of only 28–
63% and remission rate of about 30% and induce side effects, such as delayed
onset of action, extrapyramidal symptoms, drug-drug and diet interactions, sexual
dysfunction, and cardiac toxicity. For treatment of drug-resistant depression,
complementary and alternative medicine (CAM) is proposed by use of natural
products, herbs, dietary supplements, and physical activities. In animal models of
depression, CAM has been proved to modulate the etiopathogenic factors of
depression. Main pathogenic factors of depression include deficit of 5-HT, NA
and DA, enhanced activity and expression of type A monoamine oxidase (MAO-
A), decreased BDNF level and impaired adult neurogenesis in the hippocampus,
stress-induced hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and
deregulation of neuroendocrine and neuroimmune. A large number of preclinical
studies of ginseng have demonstrated therapeutic efficacy in depressive state,
insomnia, anxiety, and neurasthenia (Jin et al. 2019). Ginseng total saponins,
G115, and ginsenosides ameliorate the depression-like behaviors (immobility,
decreased locomotor activity, and sucrose preference index) in rodent models of
depression. Table 1 summarizes the pathogenic factors of depression targeted by
ginseng ingredients. Among PPDs, Rg3 exerted the highest antidepressant effects,
followed by Rb2 and C-K in mouse model of despair (Zhang et al. 2016).
Ginseng and Ginsenosides in Depression 1407

Table 1 Pathogenic factors of depression targeted by ginseng composition

Pathogenic factors Effects of ginseng, ginsenosides, and other ingredients
Deficit of 5-HT, NA, DA/ Increases 5-HT, NA, DA, 5-HT2A (ginseng, Rb1, Rg3,
Hyperactive MAO-A Rb3, C-K, Rg2)
Activates TRH (Rb1, Rg3 C-K, Rg1, Rh) and TH (Re)
Activates 5-HT2A, 3, NA, DA receptors (Rb1, Rb3, C-K,
Rg2, Rg3, 20-PPD)
Promotes monoamine release (Rb1)
Inhibits 5-HT reuptake (20-PPD)
Inhibits IDO (Rb1, Rg3)
Releases 5-HT from astrocytes (gintonin)
Inhibits MAO (Rb1)
Deregulated HPA and HPG axis/ Enhances hippocampal GR expression, decreases serum
Neuroendocrine system CORT (ginseng, Rb1, Rh1, Rg1, Rg2, Eg3)
Estrogen-like effects, increases ERs (ginseng, Rb1, Rg1,
Rh1)
Functions as ligands of ERs (Rh1, Rg3), or of GRs (Rh2,
C-K)
Impaired immune system/ Suppresses IL-1β, IL-6, TNF-α, iNOS, COX-2 (ginseng,
Neuroinflammation Rb1, C-K, Rg1, Rg3, Rh2)
Prevents microglia activation (Rg3, Rg1)
Increases antioxidative, protective Nrf2, HO-1 (ginseng,
Rh3)
Decreased BDNF/ Enhances BDNF expression (ginseng, G115, Rg3, Rg5,
Impaired adult neurogenesis Rb3, Rb2, Rg1, Rg2, 20-PPD, Re)
Promotes neurogenesis (Rb1)
Anxiolytic effects Binds to GABAA receptor (Rg3, Rb1, Re, Rh1, PPD)
Antagonizes GABA/benzodiazepine receptor (Rg3, Rh2)

Monoamine (Serotonin) and Type a Monoamine Oxidase Hypotheses

Conventional antidepressants have been developed to compensate monoamine deficit
by inhibition of the reuptake and MAO-A activity. Herbs [Hypericum perforatum
(St John’s wort) Peganum harmala (Zygophyllacease), Lepidium meyenii] (maca)]
and flavonoids (kaempferol, luteolin, quercetin) inhibit MAO-A, increase mono-
amines, and ameliorate depressive state. On the other hand, ginsenosides do not inhibit
MAO, but increase monoamine biosynthesis and affect 5-HT receptors and trans-
porters. Pretreatment of ginseng fruit saponin significantly increased 5-HT levels in the
serum and platelets, but could not reverse the 5-HT decline in the brain of the rat
depression and myocardial model. In mouse model, Rb3, Rg3, and C-K significantly
increased NA levels in the brain, but did not effect 5-HT and DA levels. Rb1 enhanced
5-HT synthesis and transmission by the estrogen-like effects, increased significantly
5-HT, 5-hydroxyindoleacetic acid (5-HIAA) a major 5-HT metabolite, NA and DA
levels in the prefrontal cortex and hippocampus of rodents exposed to chronic
unpredictable mild stress, and attenuated depression-like behaviors. Rg3, Rb1, and
Re activated cAMP-dependent protein kinase (PKA)/ERK 1/2 pathway, increased
activities of tryptophan hydroxylase (TRH) and tyrosine hydroxylase (TH), rate-
limiting enzymes in 5-HT and DA/NA biosynthesis in ovariectomized mice and rat
fatigue model. Rb1 induced expression of receptors for 5-HT, NA, DA, GABA, and
1408 M. Naoi et al.

glutamate in mouse hippocampus and prefrontal cortex. 20(S)-PPD inhibited 5-HT

and NA reuptake in the hippocampus and cortex of rat olfactory bulbectomy depres-
sion model. Gintonin released glutamate, 5-HT, and ATP from astrocytes in mouse
model of despair. These results suggest that antidepressant function of ginseng
derivatives might primarily be due to modulation of NA system.

Effects on the HPA Axis

Neuroendocrine dysfunction is another pathogenic factor of depression. In depres-
sion, GR decrease induces loss of feedback regulation of the HPA axis and hyper-
activity of the hippocampus and prefrontal cortex and stress response, and increases
corticosterone (CORT), resulting in atrophy or apoptosis of neurons in the hippo-
campus and amygdala, impaired neurogenesis, and reduced hippocampal volumes.
In patients with MDD, a linear increase of CORT and inflammatory markers
[C-reactive protein (CRP), interleukin (IL)-6] was present. In male patients with
depressive disorders the hypothalamic–pituitary–gonadal (HPG) axis is also
deregulated, and estradiol significantly increases, whereas testosterone decreases.
Ginseng ameliorates hyperactivity of the HPA axis in stress-related depression
and anxiety. R1, Rg2, and Rg3 decreased serum CORT, upregulated GR protein in
the prefrontal cortex and hippocampus, prevented decrease in hippocampal cortico-
tropin releasing hormone (CRH), CORT, and ACTH, and ameliorated depressive
behaviors (anhedonia, hopelessness) in rodent models of depression and post-trau-
matic stress disorder (PTSD). Rh1, Rg3, and Rg3, modulate the HPA axis by
interacting with ERs, whereas Rh2, C-K, Rg1, and Rg2 the HPG axis via GRs.
Rg1 had androgen-like effects, increased GRs, and androgen receptors in the
prefrontal cortex and hippocampus, and decreased serum CORT levels in the
gonadectomized model. Anxiolytic activities of Rg3 were reported to be mainly
associated with modulation of the HPA axis.

Effects on Deregulated Immune System

In individuals with MDD, particularly in treatment-resistant patients, levels of periph-
eral inflammatory cytokines, including IL-1α, IL-1β, IL-6, and tumor necrosis factor-α
(TNF-α), increased. Enhanced neuronal activity induces neuroinflammation, increases
the cytokine, activates the HPA-glucocorticoid signaling, and exacerbates stress
responses to affect mood and behaviors. Increased cytokines activate NMDA receptor,
perturb neurotransmission, and induce stress-induced depression and cognitive impair-
ment. In chronic inflammatory condition, IL-γ triggered ROS production in macro-
phages, destroys 5,6,7,8-tetrahydrobiopterin (BH4), the cofactor of TH and TRH,
decreased synthesis of 5-HT, DA, and NA, and deregulated neuronal function and
behavioral control. Inflammation enhances the activity of indole 2,3-dioxygenase
(IDO), which oxidizes the pyrrole moiety of L-tryptophan and turns it into kynuramine
(KYN) pathway instead of 5-HT pathway. In MDD patients, IDO and the L-trypto-
phan-KYN pathway produce neurotoxic tryptophan catabolites (TRYCATs), such as
kynurenic acid, 3-hydroxykynurenic acid, and quinolinic acid, in macrophages and
microglia, resulting in immune challenges, neuroinflammation, and decrease of the
hippocampal subfield volumes.
Ginseng and Ginsenosides in Depression 1409

Ginseng and ginsenosides maintain immune homeostasis and function. Panax

ginseng extract decreased serum ACTH and CORT levels and increased anti-
oxidative nuclear factor erythrocyte 2 related factor 2 (Nrf2) and cytoprotective
heme oxygenase-1 (HO-1) in the amygdala in mouse depression models. Rb1, C-K,
Rg1, Rg3, Rh1, and sulfated Rh2 suppressed production of proinflammatory IL-1β,
IL-6, TNF-α, downregulated inducible nitric oxide synthase (iNOS) and cyclooxy-
genase-2 (COX-2), and prevented the activation of MAPK, NF-κB, IL-6 receptor-
associated kinase (IRAK)-1, and activator protein-1 in Akt/mTOR (mammalian
target of rapamycin) signal pathways and alleviated depression-like behaviors in
rodent depression models. Rg3 and Rg1 activated PPAR signal pathway, modulated
NF-κB pathway, prevented microglia activation, and had anti-inflammatory and
antidepressant activities. Rg1 suppressed ionized calcium binding adaptor molecule
1(Iba-1), modulated NF-κB/ERK1/2/MAPK pathway and iNOS activation in the
hippocampus, and inhibited lipopolysaccharide (LPS)-induced microglial activation
in mice. Rh1 increased anti-inflammatory IL-10 and HO-1 expression, suppressed
microglia activation, and inhibited iNOS and ROS production through inhibition of
LPS-activated MAPL/NF-κB signal pathway. Rh3 enhanced phosphorylation of
PKA, regulated sirtin 1 (SIRT1) and Nrf2 DNA binding activities and exerted
anti-inflammatory effects in microglia. Peripheral anti-inflammatory functions of
ginsenosides may explain the paradox of significant antidepressant effects in spite of
their poor distribution in the brain.
Proinflammatory status links with occurrence of chronic disease-related fatigue.
Ginseng has been shown to treat fatigue in cancer, schizophrenia, and HIV/AIDS
(Arring et al. 2018). Ginseng saponin and 20(S)-PPT significantly showed anti-
fatigue effects in mice, but ginseng water-extract or 20(S)-PPD did not. Red ginseng
alleviated psychological fatigue more effectively than physical fatigue in mice. Rb1
suppressed inflammation and modulated cytokine-NMDA receptor pathway in the
hippocampus, and exerted anti-fatigue activity in rat model of postoperative fatigue
syndrome. Rg3 increased superoxide dismutase (SOD), peroxisome proliferator-
activated receptor γ coactivator-1α (PGC1-α and phosphoenolpyruvate carboxylase
(PEPCK), activated SIRT1, downregulated p53 transcriptional activity, and signif-
icantly increased fatigue resistance in a rat model of postoperative fatigue syndrome.

Effects on BDNF and Adult Neurogenesis in the Hippocampus

BDNF deceases in the brain and serum of depressed patients. Peripheral BDNF has
been proposed as a biomarker of depression and an indicator of the efficacy of
antidepressants. BDNF deficit increased glucocorticoids, deregulated serotonergic
system, downregulated prenatal neurogenesis, and increased vulnerable sensitivity
to early life stress in depressive patients. Impaired adult neurogenesis in the dentate
gyrus causes structural changes and decreased volume in the hippocampus and the
gray matter in patients with MDD. Maturation of newly generated neurons in the
dentate gyrus is proposed to be relevant with the delayed onset of therapeutic effects
of antidepressants.
Panax ginseng extract and the total saponins, Rg1 and 20-PPD derivatives
activated ERK/MAPK/CREB (cAMP response element-binding protein) pathway
1410 M. Naoi et al.

by interfering with glycogen synthase kinase (GSK)-3β and induced BDNF expres-
sion in the prefrontal cortex and hippocampus of rodent depression models. G115
and ginsenosides (Rg1, Rg2, Rb1, Rb3, Rg3, Rg5) also increase BDNF and exert
antidepressant effects by activation of the BDNF/TrkB-CREB pathway. Rg1
increased BDNF expression and reversed decrease in hippocampal neurogenesis
and dendritic spine density in depression mouse models (Jiang et al. 2012).
Sesquiterpenoids from Panax ginseng root showed antidepressant effects by activa-
tion of BDNF/TrkB/NF-κB signal pathway, in addition to modulation of DA,
GABA, and glutamine systems.

Pharmacokinetics of Ginseng and Ginsenosides

Bioavailability of ginseng is decreased by the poor membrane permeability, insta-

bility in the gastrointestinal tract and extreme metabolism in the body, and oral
bioavailability of ginsenosides is less than 10%. Ginsenosides are highly hydrophilc
and orally administered ginsenosides cannot be easily absorbed by the intestine, and
are digested by microbiota in the gastrointestinal tract. β-Glucosidases of microflora,
Bacteroides sp., Fusobacterium sp., Bifidobacterium bifidum, breve, Lactobacillus
delbueckii, and Leuconostoc mesenteroides deglycosylate ginsenosides into hydro-
phobic compounds. PPD-type ginsenosides are finally transformed into C-K, and
PPT-type ones to Rh1 and PPT, and they are absorbed from gastrointestinal tract into
the circulation and have long elimination half-lives, longer than 30 h. These
deglycosylated ginsenosides play important roles in anticancer, antidiabetic, antiox-
idant, and antiaging functions. Rb1, Rb2, Rc, Rd., Rg3, C-K, PPD, and PPT were
detected in human plasma of healthy volunteers after oral administration of red
ginseng extract. When Rg1 was administered intravenously in rats, the highest level
was detected in liver, followed by lung, spleen, and kidney. After oral administration
of ginseng saponin in rats, only Rg1 was detected in the brain, mainly in vascular
endotheliocytes and astrocytes and in few neurons, indicating low permeability of
ginsenosides across the blood–brain barrier (BBB) (Zhao et al. 2018). Gintonin
increased junction spaces and enhanced the BBB permeability in the primary human
brain microvascular endothelial cells.

Side Effects/Adverse Reactions and Toxicology

In general, ginseng is safe and the root of Panax ginseng appears nontoxic in human
when ginseng consumption is limited under 1–2 g ginseng containing 4–5%
ginsenosides per day. However, ginseng is stimulant and may cause nervousness
or insomnia, if taken at high doses. “Ginseng-abuse syndrome” was described in 14
of 133 long-term ginseng users (3 g/day Panax ginseng root material), presenting
side effects of hypertension, restlessness, and skin rash. In a 15 g/day ginseng user,
confusion, depression, or depersonalization was observed (Siegel 1979). There were
five cases (two females, three males) of ginseng-associated mania, and the reported
Ginseng and Ginsenosides in Depression 1411

daily doses of ginseng were quite higher than recommended doses. Two cases of
new onset of manic psychosis without any prior psychiatric history were reported
after daily ginseng use and manic symptoms remitted within days by discontinuation
of ginseng (Norelli and Xu 2015). These results suggest that ginseng ingredients
might be psychotropic and affect mood function especially in BD. Other adverse
effects are related to the estrogen-like activity, such as vaginal bleeding, and
ginsenosides may effect particularly pregnant or breastfeeding women.

Drug-Drug Interactions

Drug transporters, such as protein organic anion transporter (OAT) and multiple drug
resistance (MDR), and drug metabolizing enzymes, cytochrome P450s (CYPs) and
P-glycoprotein (P-gp), play a vital role in modification of pharmacokinetics and dug-
drug interaction. Ginseng and ginsenosides are weak inhibitors of CYPs and trans-
porters, and severe harmful drug-ginseng interaction has never been reported in
clinical studies. During the use of ginseng, serotonin syndrome was detected in
patients treated with SSRI or SNRI (escitalopram, fluoxetine, paroxetine) and
ventricular arrhythmias in patients with haloperidol (Woron and Siwek 2018).
Adverse effects of ginseng and ginsenosides on chemotherapeutic, antiplatelet,
anticoagulant, and antidiabetic drugs have been never presented. For treatment of
fatigue in adjuvant chemotherapy, ginseng improved fatigue-related syndrome with-
out causing critical adverse events, but did not change survival rates and tumor
markers. Panax ginseng was reported to induce CYP3A activity in liver and
gastrointestinal tract, suggesting the interaction with CYP3A or P-gp substrates. In
rats, the co-administration of ginsenosides (Rg1, Re, Rd., Rf, Rb1, Rc, Rb2) and
warfarin the most common anticoagulant increased 7-hydroxywarfarin, a metabolite
by CYP2C9 and CYP3A4, in liver and attenuated anticoagulation. But, the clinical
data on the interaction of ginsenosides with warfarin were not consistent.
Deglycosylated ginsenosides increase bioavailability and elimination half-lives
and their interaction with drugs should be further investigated.

Clinical Studies

Clinical trials of ginseng and ginsenosides have been scarcely reported in depression
(Table 2). Siberian ginseng (Eleutherococcus senticosus), whose active constituents
are different from Panax ginseng, showed antidepressant activities in patients with
BD (Weng et al. 2007). Ginseng adjunctive administration to lithium improved 17-
Item-Hamilton Depression Rating Scale (HAMD-17) score, but the difference was
not statistically significant from lithium group. Korean red ginseng significantly
improved depressive state in women with residual symptoms of MDD (Jeong et al.
2015). Estrogen-like activity of Korean red ginseng is associated with improvement
of severe climacteric syndromes, including fatigue, insomnia, and depression in
postmenopausal subjects (Tode et al. 1999), but later trials with fermented red
Table 2 Representative clinical trials of ginseng and ginsenosides in patients with depressive diseases and chronic fatigue
1412

Adverse
Study Subjects. Sample size Aim and design Results Dropout rate effects
PCT 12 PM women with climacteric KRG (6 g/d
30 days) Improved CMI, STAI-A score
Tode et al. syndrome
(1999) (Control; 8 without syndrome)
Japan
DBRPCT 30 PM women Ginsosana No significant effects on HAD 11/30
Hartley et (Placebo, 27) (320 mg/d
12 weeks)
al. (2004) UK
DBRPCT BD patients Adjunct effects to lithium, Improved HAMD-17 Nausea,
Weng et al. 37 (Li + SG; f/m ¼ 21/16), 39 compared with fluoxetine rash
(2007) (Li + fluorexetine; f/m ¼ 24/15) Siberian ginseng
China (750 mg/d
6 weeks)
DBRPCT Healthy young adults G115 Improved working memory
Reay et al. 30 volunteers (200, 400 mg
8 days) Increased calmness
(2010) (f/m ¼ 15/15)
UK
Direct 35 MDD women with residual Effects as adjunct of SSRI, Improved DRSS, MADRS, CGI- 4 /35 GI
evaluation syndrome SNRI S scores syndromes
Jeong et al. South Korea KRG (3 g/d
4 weeks) Headache,
(2015) insomnia
DBRPCT Post-stress KRG No improved mood 4/32
Baek et al. 32 (f/m ¼ 15/17) (2 g/d
6 weeks) (4/31)
(2019) Control; 31 (f/m ¼ 16/15)
South Korea
DBRPT Idiopathic chronic fatigue KG extract Improved VAS score In 2 g/d Ginseng 1 g/d *AR
Kim et al. Ginseng 1 g 30 (1, 2 g/d
4 weeks) group group, 1/30
(2013) Ginseng 2 g 30 Improved NRS score in 1, 2 g/d Ginseng 2 g/d
Placebo 30 groups group, 1*/30
South Korea Placebo, 0/30
M. Naoi et al.
 DBRPT Cancer-related fatigue Wisconsin ginsengb Improved MFSI-SF score Ginseng, 38/ 16 AR
Barton et Ginseng 171 (2000 mg/d
8 weeks) 171 13 AR
al. (2013) Placebo 170 Placebo 42/170
USA
DBRPT Volunteers 180 KRG Improved fatigue self-assessment Placebo, 4/60 1 AR
Zhang et Placebo 60 (f/m ¼ 30/21) (1.8 g, 3.6 g/d
4 weeks) score 1.8 g/d, 0/60 1 common
al. (2019) KRG 1.8 g 60 (f/m ¼ 43/19) 3.6 g/d, 2*/60 cold
KRG 3.6 g (f/m ¼ 43/17)
China
DBRPCT 15, Patients with chronic fatigues Fatigue No effects on VAS, BDI scales 1/25
Sung et al. (15 Placebo) KRG (3 g/d
6 weeks) Improved only in aged (Placebo, 2/25)
(2020) South Korea (>50 years) with moderate
fatigue
a
Ginseng and Ginsenosides in Depression

Combined 120 mg Ginkgo biloba and 200 mg Panax ginseng

b
Panax quinoquefolius
AR, Allergic response; BDI, Beck Depression Index; CGI-S, Clinical Global Impressions Scale for Severity; CMI, Cornell Medical Index; DBRPCT, double-
blind, randomized, placebo-controlled trial; DRSS, Depression Residual Syndrome Scale; f/m, female/male; GI, gastro-intestinal; FAD, Hospital Anxiety and
Depression; HAMD-17, 17-Item Hamilton Depression Rating Scale; KRG, Korean red ginseng; MADRS, Montogomery-Asberg Depression Rating Scale;
MFSI-SF, Multidimentional Fatigue Symptom Inventory-NRS, numerical self rating scale; PCT, placebo-control trial; PM, postmenopausal; STAI-A, State-
Trait Anxiety Inventory as anxiety state; VAS, visual analogue scale
1413
1414 M. Naoi et al.

ginseng containing high C-K could not approve the beneficial effects. A Panax
ginseng and Ginkgo biloba combination (gincosan) therapy improved physiological
and cognition function in humans, but the synergy could not be confirmed. Effects of
Korean red ginseng were investigated in individuals exposed to high stress, but
beneficial effects could not be confirmed (Baek et al. 2019). Wisconsin ginseng
(Panax quinquefolius), Korean red ginseng, and ginsenosides improved chronic
fatigue-related symptoms, including quality of life and mood, but did not increase
physical activities (Sung et al. 2020). Meta-analyses of reported clinical results of
ginsenosides have not presented conclusive evidences for the effects in depression
and mental and physical fatigue.

Discussion

Ginseng the most popular TCM is still enigmatic medicine and the pharmacological
characteristics are hard to clarify from aspect of modern medicine. Clinical results on
antidepressant potency of ginseng and ginsenosides in MDD and BD should be
tempered because of small sample size and brief intervention duration, and the
benefit has been not fully approved. Ginseng and ginsenosides could improve
stress-induced depressive state in postmenopausal women and individual with
chronic fatigues, cancer, and frailty, which might be caused by the decline of “Qi”
according to the term of the TCM. Ginseng contains various multifunctional active
components, and they may afford ginseng the synergistic pharmacological effects.
The effects on “Qi” have been commonly evaluated by the holistic TCM criteria
based on symptomatic observation of patients, and not by reductionism- and evi-
dence-based modern medicine. Clinical studies of ginseng and ginsenosides should
be further continued by use of the consistent and quality-controlled samples and
more objective quantitative determination of the effects in more systematically
designed trials. The structure-activity relationship of ginsenosides should be further
investigated in order to develop new antidepressant agents.
The very poor bioavailability of ginsenosides in the brain may reduce the
antidepressant activity of ginsenosides. Co-administration of Ginkgo biloba extract
increased the permeability of ginsenoside (Rg1, Re, Rd., and Rb1) across the BBB
and improved the uptake in the brain. Ginkgo biloba extract activated A1 adenosine
receptor signal pathway, phosphorylated the BBB tight junction-relate proteins
(ezrin/radixin/moesin, myosin light chain), and increased the BBB permeability.
Modification of ginsenoside properties has been tried to increase bioavailability.
Highly hydrophilic properties of Rb1 inhibited direct absorbance in human body and
the cleavage of the four glycosides of 3-O-Glc-Glc- and 20-O-Glic-Glc- substitutes
by enzymatic and chemical reactions increased the bioavailability and activity. Rb1
was modified by hydrogenation, acetylation, and epoxidation, which enhanced the
potency to promote cell proliferation in ARPR-19 cells. Chemical sulfation of Rh2
increased water solubility and anti-inflammatory activities. The 3-hydroxy group of
PPD was modified with fatty acids and diacids, and the esters increased anticancer
activity. At present, it has not been reported whether such modification can promote
Ginseng and Ginsenosides in Depression 1415

the antidepressant or anxiolytic functions of ginsenosides. In order to improve

ginsenoside stability, the micro- and nano-sized delivery system is proposed. Micro-
emulsion, macro- and nano-particles, and liposome systems increase the intestinal
absorption of ginsenosides, and further the availability in the brain. Rg1 nano-
particles targeting transferrin receptor could penetrate the BBB and reduce the
cerebral infarction volume and enhance neuronal recovery in diabetic rats. Nasal
delivery of microemulsion containing Rg1, Rb1, and Rg3 increased the uptake into
the brain, increased the residence time and anti-fatigue and immune-boosting effects.

Financial and Competitive Interests Disclosure

The authors’ research of food-derived bioactive compounds is supported by the

Grants-in-Aids for Scientific Research, No. 18Kk07430 (W.M.). The authors have
no other relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from that disclosed.

Cross-References

▶ Antidepressants: Molecular Aspects of SSRIs

▶ Hypericum and Depression

References
Arring NM, Millstine D, Marks LA, Nal LM. Ginseng as treatment for fatigue: a systematic review.
J Altern Complement Med. 2018;24(7):624–33.
Baek JH, Heo JY, Fava M, Mischoulaon D, Choi KW, Na EJ, Cho H, Jeon HJ. Effect of Korean red
ginseng in individuals exposed to high stress levels: a 6-week, double-blind, randomized,
placebo-controlled trial. J Ginseng Res. 2019;43(3):402–7.
Barton DL, Liu H, Dakhi SR, et al. Wisconsin ginseng (Panax quinquefolius) to improve cancer-
related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105(16):
1230–8.
Choi K. Botanical characteristics, pharmacological effects and medical components of Korean
Panax ginseng C A Meyer. Acta Pharmacol Sin. 2008;29(9):1109–18.
Hartley DE, Elsabagh S, File SE. Ginsosan (a combination of Ginkgo biloba and Panax ginseng):
the effects on mood and cognition of 6 and 12 weeks’ treatment in post-menopausal women.
Nutr Neurosci. 2004;7(5–6):325–33.
Jeong HG, Ko YH, Oh SY, Han C, Kim T, Joe SH. Effect of Korean red ginseng as an adjunct
treatment for women with residual symptoms of major depression. Asia Pac Psychiatry. 2015;
7(3):330–6.
Jiang B, Xiong Z, Yang J, Wang W, Wang Y, Hu ZL, Wang F, Chen JG. Anti-depressant-like effects
of ginsenoside Rg1 are due to activation of BDNA signalling pathway in the hippocampus. Br J
Pharmacol. 2012;166(6):1872–87.
Jin Y, Cui R, Zhao L, Fan J, Li B. Mechanisms of Panax ginseng action as an antidepressant. Cell
Prolif. 2019;52(6):e12606.
1416 M. Naoi et al.

Kim HG, Cho JH, Yoo AR, Lee JS, Han JM, Lee NH, Ahn YC, Son CG. Antifatigue effects of
Panax ginseng C.A. Mayer: a randomised, double-blind, placebo-controlled trial. PLoS One.
2013;8(4):e61271.
Lee SM, BAE B, Park H, Ahn N, Cho B, Cho Y, Kwak Y. Characterization of Korean red ginseng
(Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res.
2015;39(4):384–91.
Nah SY. Ginseng ginsenoside pharmacology in the nervous system: involvement in the regulation
of ion channels and receptors. Front Physiol. 2014;5:98.
Norelli LJ, Xu C. Manic psychosis associated with ginseng: a report of two cases and discussion of
the literature. J Diet Suppl. 2015;12(2):119–25.
Reay JL, Scholey AB, Kennedy DO. Panax finseng (G115) improves aspect of working memory
performance and subjective rating of calmness in healthy young adult. Hum Psychopharmacol
Clin Exp. 2010;2596:462–71.
Siegel RK. Ginseng abuse syndrome. Problems with the panacea. JAMA. 1979;241(15):1614–5.
Sung WS, Kang HR, Jung CY, Park SS, Lee SH, Kim EJ. Efficacy of Korean red ginseng (Panax
ginseng) for middle-aged and moderate level of chronic fatigue patients: a randomized, double-
blind, placebo-controlled trial. Complement Ther Med. 2020;48:102246.
Tode T, Kikuchi Y, Hirata J, Kita T, Nakata H, Nagata I. Effect of Korean red ginseng on
psychological functions in patients with severe climacteric syndromes. Int J Glynecol Obstet.
1999;67(3):169–74.
Weng S, Tang J, Wang G, Wang X, Wang H. Comparison of the addition of Siberian ginseng
(Acanthopanax senticosus) versus fluoxetine to lithium for the treatment of bipolar disorder in
adolescents: a randomized, double-blind trial. Curr Ther Res Clin Exp. 2007;68(4):280–90.
Woron J, Siwek M. Unwanted effects of psychotropic drug interactions with medicinal products and
diet supplements containing plant extracts. Psychiatr Pol. 2018;52(6):983–96.
Yu SE, Mwesige B, Yi Y, Yoo BC. Ginsenosides: the need to move forward from bench to clinical
trials. J Ginseng Res. 2019;43(3):361–7.
Zhang H, Li Z, Zhou Z, Yang H, Zhong Z, Lou C. Antidepressant-like effects of ginsenosides: a
comparison of ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K
and 20(S)-protopanaxadiol in mice model of despair. Pharmacol Biochem Behav. 2016;140:17–26.
Zhang L, Chen X, Cheng Y, et al. Safety and antifatigue effect of Korean red ginseng: a randomized,
double-blind, and placebo-controlled clinical trial. J Ginseng RE. 2019;43(4):676–83.
Zhao YN, Shao X, Ouyang LF, Chen L, Gu L. Quantitative detection of ginsenosides in brain
tissues after oral administration of high purity ginseng total saponins by using polyclonal
antibody against ginsenosides. Chin J Nat Med. 2018;16(3):175–83.
Vortioxetine and Depressions

Gerd Laux

Contents
Chemistry, Developmental History (Fig. 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1418
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1418
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1418
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1419
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1419
Side Effects, Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421
Combination Therapy: Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1422

Abstract
Vortioxetine is a multimodal antidepressant acting on serotonin (5-HT) receptors
in several ways: as an antagonist on 5-HT3, 5-HT7, and 5-HT1D receptors, as a
partial agonist on 5-HT1B receptors, and as an agonist on 5-HT1A receptors;
furthermore, it inhibits the 5-HT transporter. The efficacy in treatment of major
depressive disorder was established in randomized, double-blind, placebo-con-
trolled studies and a maintenance study in adult in- and outpatients. In preclinical
animal studies as well as clinical studies, vortioxetine showed positive effects on
learning and memory. Dose-related nausea was the most common adverse
reaction.

G. Laux (*)
Institute of Psychological Medicine (IPM), Soyen, Germany
MVZ Waldkraiburg, Center of Neuropsychiatry, Waldkraiburg, Germany
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich,
Germany
e-mail: ipm@ipm-laux.de

© Springer Nature Switzerland AG 2022 1417

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_114
1418 G. Laux

Chemistry, Developmental History (Fig. 1)

Vortioxetine has been developed adding further mechanisms of action to the

established serotonin transporter effect. First publications came in 2011, and it has
been approved, released, and introduced in the year 2013 in the USA and Europe.
Now the substance is approved in Chile, China, Mexico, Argentina, South Korea,
Turkey, Australia, and South Africa, since 2019 also in Japan.

Pharmacology

Pharmacokinetics

The pharmacokinetics of vortioxetine are linear and dose-proportional. Pharmaco-

logical activity is due to the parent drug. The maximal plasma concentration is
reached within 7 to 11 hours post dose. Absolute bioavailability is 75%. The plasma
protein binding is 98%. Vortioxetine is extensively metabolized primarily through
oxidation via cytochrome P450 isoenzymes CYP2D6, CYP3A4, CYP2C9, and
CYP2A6. CYP2D6 is the primary enzyme catalyzing the metabolism. The presence
of hepatic (mild to moderate) or renal impairment did not affect the apparent
clearance of vortioxetine. The mean terminal half-life is approximately 66 hours
(Areberg et al. 2012).

Mechanism of Action

Vortioxetine is a multimodal antidepressant acting on serotonin (5-HT) receptors in

several ways: as an antagonist on 5-HT3, 5-HT7, and 5-HT1D receptors, as a partial
agonist on 5-HT1B receptors, and as an agonist on 5-HT1A receptors; furthermore, it
inhibits the 5-HT transporter (Mørk et al. 2012; Meeker et al. 2015) (Fig. 2).

Fig. 1 Chemical formula of

vortioxetine
Vortioxetine and Depressions 1419

Fig. 2 Modulation of serotonin (5-HT) receptors on glutamatergic and GABAergic neurotrans-

mission and effects of vortioxetine. [Mod. from Mork et al. 2012]

Indications

Vortioxetine is indicated for the treatment of major depressive disorder (MDD).

Recommended starting dose is 10 mg orally once daily. The dose should then be
increased to 20 mg/day.

Clinical Studies

The efficacy in treatment for MDD was established in 11 6- to 8-week randomized,

double-blind, placebo-controlled fixed dose studies including 1824 pts. treated with
placebo, 3304 with vortioxetine (Thase et al. 2016), 1 maintenance study (Jacobsen
et al. 2015a, b), and 1 relapse prevention study (Boulenger et al. 2012).
Studies vs active comparators are summarized in Table 1 (Fig. 3).
In elderly depressed patients, vortioxetine was effective and well tolerated;
dosage should be reduced to 5 mg/d (Nomikos et al. 2017). Meta-analyses have
been published by Baldwin et al. (2016) and Berhan & Barker (2014).
Network meta-analysis of 24 RCTs and controlled observational studies includ-
ing adult outpatients with MDD indicated similar efficacy among levomilnacipran,
vilazodone, or vortioxetine and other second-generation antidepressants. Rates of
adverse events and discontinuation were similar (Wagner et al. 2018).
Some studies showed meaningful clinical efficacy in the improvement of cogni-
tive functioning in working patients with MDD independent of improvement in
Table 1 Survey review
1420

Study arms,
comparators, Dropout
Study N, Patients placebo Results rates Relevant side effects
Alvarez et al. 429 pts. Pl, venlafaxine Response rate V 68%, venla 72%, Pl 4%, vort Nausea, hyperhidrosis,
2012 EU, Asia, Canada XR 225 mg/d Pl 45% 10%, venla dry mouth
RCT 14%
Baldwin et al. 766 pts. Pl, duloxetine V > pl Pl 8%, vort Nausea, dizziness, dry
2012 EU, Asia, Canada 60 mg/d V ¼ duloxetine 9%, dulox mouth
RCT 12%
Katona et al. 2012 452 elderly pts. (mean age 70 years) Pl, duloxetine V response rate 53%, pl 35%, Pl 3%, Nausea (22%), dulox
RCT 60 mg/d dulox 63% dulox 10%, nausea, constipation,
V > Pl in cognition tests of speed vort 6% dry mouth, somnolence
of processing, verbal learning, and
memory
Mahableshwarkar 614 pts Pl, duloxetine V > Pl in MADRS and cognitive Nausea, diarrhea
et al. 2015a, b US multicenter 60 mg/d tests
RCT
McIntyre et al. Pl, duloxetine V improved cognition
2016 independent of depressive
Meta-analysis 3 symptoms
RCTs
Citrome 2016 8 studies for duloxetine, 3 for escitalopram, 5 V ¼ comparison drugs Overall tolerability
Indirect for levomilnacipran, 1 for sertraline, 4 for NNTs for response vs placebo (NNHs
comparison venlafaxine, 2 for vilazodone, 11 for 6–10 V > comparators
vortioxetine
Vieta et al. 2018 N ¼ 101 Escitalopram V favored for improvements of Nausea
RCT Nonresponders 10–20 mg/d cognition, functioning, and mood
symptoms
Papakostas et al. N ¼ 493 V 10–20 mg/d V > Agomelatine V 21% Rare side effects,
2018 SSRI/SNRI nonresponders Agomelatine Ago 26% Agomel > V
EU multicenter 25–50 mg/d
G. Laux
Vortioxetine and Depressions 1421

Fig. 3 shows the results of a pivotal study comparing vortioxetine with venlafaxine regarding
MADRS difference scores (Alvarez et al. 2012)

depressive symptoms (Al-Sukhri et al. 2015, McIntyre et al. 2016). Data of one
study are summarized in Fig. 4 (Herrera-Guzman et al. 2009).
In systematic reviews’ perspective, Cochrane Database concluded the place of
vortioxetine in the treatment of acute depression to be unclear; in comparison to
SNRIs no advantage has been found; major limitation is the lack of comparisons
with the first-line treatment SSRIs (Koesters et al. 2017).

Side Effects, Adverse Reactions

The most common adverse reactions (incidence >5% and at least twice the rate of
placebo) are nausea, constipation, and vomiting. Table 2 shows the side effect (SE)
profile compared to venlafaxine and placebo (Alvarez et al. 2012).
Clinical worsening, (hypo-) mania, and suicide risk must be monitored by all
antidepressants.
Sexual dysfunction is common with SSRIs, vortioxetine showed benefits com-
pared to escitalopram, and rates were not significantly different from placebo in
short-term clinical trials (Jacobsen et al. 2015a, b, 2016).

Combination Therapy: Interactions

Use of MAOIs is contraindicated because of an increased risk of serotonin syndrome.

Concomitant use of serotonergic drugs like triptans, tramadol, and buspirone must be
monitored, and dose must be reduced by half when strong inhibitors of CYP2D6 are
1422 G. Laux

Fig. 4 Improvement of cognition in elderly depressed patients

Table 2 Side effects of vortioxetine compared to placebo and venlafaxine XR 225 mg ( 5%

during 6-week treatment % patients). [Mod. according to Alvarez et al. 2012]
Placebo Vortioxetine Vortioxetine Venlafaxine XR
(n ¼ 105) 5 mg (n ¼ 108) 10 mg (n ¼ 100) 225 mg (n ¼ 113)
Patients with 61,0 67,6 74,0 75,2
1 SE
Nausea 9,5 29,6*** 38,0*** 33,6***
Headache 24,8 21,3 25,0 28,3
Hyperhidrosis 1,9 2,8 10,0* 15,0***
Vomiting 1,0 1,9 9,0** 3,5
Constipation 1,0 0,9 3,0 9,7**
Anorgasmia 0 0 0 6,2*
Erection 0 0 0 7,8
disturbed
(Men)
*p < 0,05; **p < 0,01; ***p < 0,001 vs. Placebo

coadministered. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs

(NSAIDs), and anticoagulants can result in gastrointestinal and other bleeding.

References
Alvarez E, Perez V, Dragheim M, Loft H, Artigas F. A double-blind, randomized, placebo-
controlled, active reference study of Lu AA21004 in patients with major depressive disorder.
Int J Neuropsychopharmacol. 2012;15:589–600.
Vortioxetine and Depressions 1423

Al-Sukhri M, Maruschak NA, McIntyre RS. Vortioxetine: a review of efficacy, safety and tolera-
bility with a focus on cognitive symptoms in major depressive disorder. Expert Opin Drug Saf
2015;14:1291–304.
Areberg J, Sogaard B, Hojer AM. The clinical pharmacokinetics of LuAA21004 and its major
metabolite in healthy young volunteers. Basic Clin Pharmacol Toxicol. 2012;111:198–205.
Baldwin DS, Loft H, Dragheim M. A randomised, double-blind, placebo controlled, duloxetine-
referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major
depressive disorder (MDD). Eur Neuropsychopharmacol. 2012;22:482–91.
Baldwin DS, Florea I, Jacobsen PL, Zhong W, Nomikos GG. A meta-analysis of the efficacy of
vortioxetine in patients with major depressive disorder (MDD) and high levels of anxiety
symptoms. J Affect Disord. 2016;206:140–50.
Berhan A, Barker A. Vortioxetine in the treatment of adult patients with major depressive disorder: a
meta-analysis of randomized double-blind controlled trials. BMC Psychiatry. 2014;27:276.
Boulenger JP, Loft H, Florea I. A randomized clinical study of Lu AA21004 in the prevention of
relapse in patients with major depressive disorder. J Psychopharmacol. 2012;26:1408–16.
Citrome L. Vortioxetine for major depressive disorder: an indirect comparison with duloxetine,
escitalopram, levomilnacipran, sertraline, venlafaxine, and vilazodone, using number needed to
treat, number needed to harm, and likelihood to be helped or harmed. J Affect Disord. 2016;196:
225–33.
Connolly KR, Thase ME. Vortioxetine: a new treatment for major depressive disorder. Expert Opin
Pharmacother. 2016;17:421–31.
Herrera-Guzman I, Gudayol-Ferre E, Herrera-Guzman D, et al. Effects of selective serotonin
reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental
processing speed in patients with major depressive disorder. J Psychiatr Res. 2009;43:855–63.
Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, Clayton AH. Effect of Vortioxetine vs.
Escitalopram on sexual functioning in adults with well-treated major depressive disorder
experiencing SSRI-induced sexual dysfunction. J Sex Med. 2015a;12:2036–48.
Jacobsen PL, Harper L, Chrones L, Chan S, Mahableshwarkar AR. Safety and tolerability of
vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-
label, flexible-dose, 52-week extension study. Int Clin Psychopharmacol. 2015b;30:255–64.
Jacobsen PL, Mahableshwarkar AR, Palo WA, Chen Y, Dragheim M, Clayton AH. Treatment-
emergent sexual dysfunction in randomized trials of vortioxetine for major depressive disorder
or generalized anxiety disorder: a pooled analysis. CNS Spectr. 2016;21:367–78.
Katona C, Hansen T, Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-
referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly
patients with major depressive disorder. Int Clin Psychopharmacol. 2012;27:215–23.
Koesters M, Ostuzzi G, Guaiana G, Breilmann J, Barbui C. Vortioxetine for depression in adults.
Cochrane Database Syst Rev. 2017;5(7):CD011520. https://doi.org/10.1002/14651858.
CD011520.pub2.
Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A randomized, placebo-controlled,
active-reference, double-blind, flexible-dose study of the efficacy of Vortioxetine on cognitive
function in major depressive disorder. Neuropsychopharmacology. 2015a;40:2025–37.
Mahableshwarkar AR, Jacobsen PL, Chen Y, Serenko M, Trivedi MH. A randomized, double-blind,
duloxetine-referenced study comparing efficacy and tolerability of 2 fixed doses of vortioxetine
in the acute treatment of adults with MDD. Psychopharmacology. 2015b;232:2061–70.
Meeker AS, Herink MC, Haxby DG, Hartung DM. The safety and efficacy of vortioxetine for acute
treatment of major depressive disorder: a systematic review and meta-analysis. Syst Rev.
2015;4:21.
McIntyre RS, Harrison J, Loft H, Jacobson W, Olsen CK. The effects of vortioxetine on cognitive
function in patients with major depressive disorder(MDD): a meta-analysis of three randomized
controlled trials. Int J Neuropsychopharmacol 2016;19:pyw055.
Mørk A, Pehrson A, Brennum LT, Nielsen SM, Zhong H, Lassen AB, Miller S, Westrich L, Boyle
NJ, Sánchez C, Fischer CW, Liebenberg N, Wegener G, Bundgaard C, Hogg S, Bang-Andersen
B, Stensbøl TB. Pharmacological effects of Lu AA21004: a novel multimodal compound for the
treatment of major depressive disorder. J Pharmacol Exp Ther. 2012;340:666–75.
1424 G. Laux

Nomikos GG, Tomori D, Zhong W, Affinito J, Palo W. Efficacy, safety, and tolerability of
vortioxetine for the treatment of major depressive disorder in patients aged 55 years or older.
CNS Spectr. 2017;22:348–62.
Papakostas GI, Nielsen R, Dragheim M, Tonnoir B. Efficacy and tolerability of vortioxetine versus
agomelatine, categorized by previous treatment, in patients with major depressive disorder
switched after an inadequate response. J Psychiatr Res 2018;101:72–79.
Thase ME, Mahableshwarkar AR, Dragheim M, Loft H, Vieta E. A meta-analysis of randomized,
placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in adults.
Eur Neuropsychopharmacol. 2016;26:979–93.
Thase ME, Danchenko N, Brignone M, Florea I, Diamand F, Jacobsen PL, Vieta E. Comparative
evaluation of vortioxetine as a switch therapy in patients with major depressive disorder. Eur
Neuropsychopharmacol. 2017;27:773–81.
Vieta E, Sluth LB, Olsen CK. The effects of vortioxetine on cognitive dysfunction in patients with
inadequate response to current antidepressants in major depressive disorder: a short-term,
randomized, double-blind, exploratory study versus escitalopram. J Affect Disord. 2018;227:
803–9.
Wagner G, Schultes MT, Titscher V, Teufer B, Klerings I, Gartlehner G. Efficacy and safety of
levomilnacipran, vilazodone and vortioxetine compared with other second-generation antide-
pressants for major depressive disorder in adults: a systematic review and network meta-
analysis. J Affect Disord. 2018;228:1–12.
 Part IV
Mood Stabilizers

Andreas Menke
Mood Stabilizer: Definition

Andreas Menke

Contents
Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1427
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428

Abstract
The term mood stabilizer is commonly used in the context of the treatment of
bipolar disorder. However, there is no consensus on the exact definition among
researchers or clinicians. A widely accepted agreement recommends that a mood
stabilizer should have at least two of the four properties: antimanic, antidepres-
sant, preventing relapse of depression, and preventing relapse of mania, without
increasing the risk for a switch in the opposite episode. While lithium still remains
the gold standard, also anti-convulsants and atypical antipsychotics are used for
maintenance treatment of bipolar disorder.

Description

The term mood stabilizer is commonly used in the context of the treatment of bipolar
disorder. However, there is no consensus on the exact definition among researchers
or clinicians (Ketter 2018). Roughly, there are mood-stabilizing agents treating from
above, ameliorating manic symptoms, or treating from below, thus improving
depressive symptoms. A possible agreement that is widely accepted recommends
that a drug should have at least two of the four properties: antimanic, antidepressant,
preventing relapse of depression, and preventing relapse of mania, without

A. Menke (*)
Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg,
Würzburg, Germany
e-mail: menke_a@ukw.de

© Springer Nature Switzerland AG 2022 1427

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_35
1428 A. Menke

increasing the risk for a switch in the opposite episode (Bauer and Mitchner 2004).
Lithium has been shown to be clearly one of the most effective drugs for preventing
both manic and depressive episodes and thus remains the gold standard (Kessing
et al. 2018; Miura et al. 2014). Randomized placebo-controlled clinical trials in
bipolar disorder have further proved the efficacy in the maintenance treatment of
anti-convulsants such as valproate and lamotrigine (Miura et al. 2014), as well as
atypical antipsychotics such as quetiapine, olanzapine, and aripiprazole (Lindstrom
et al. 2017). In addition, there is limited evidence that mood stabilizers are also
effective in schizoaffective disorder (Vieta 2010), a disorder on a spectrum between
bipolar disorder and schizophrenia, and borderline personality disorder (Belli et al.
2012). There is an emerging approach to categorize drugs using the Neuroscience-
based Nomenclature for Psychotropic Medications (NbN, www.ecnp.eu/nomencla
ture), that is based on the mechanisms of the drugs. However, due to insufficient
understanding of mechanisms of the mood-stabilizing agents, it is challenging to
apply this taxonomy on this heterogeneous class (Ketter 2018). In the following
chapters, we will address the classification and indications of mood stabilizers, the
pharmacology and biochemistry, and the course of the therapy including adverse
events, and we will review the mood-stabilizing agents such as lithium, valproate,
lamotrigine, carbamazepine, risperidone, olanzapine, quetiapine, and asenapine.

References
Bauer MS, Mitchner L. What is a “mood stabilizer”? An evidence-based response. Am J Psychiatry.
2004;161:3–18.
Belli H, Ural C, Akbudak M. Borderline personality disorder: bipolarity, mood stabilizers and
atypical antipsychotics in treatment. J Clin Med Res. 2012;4:301–8.
Kessing LV, Bauer M, Nolen WA, Severus E, Goodwin GM, Geddes J. Effectiveness of mainte-
nance therapy of lithium vs other mood stabilizers in monotherapy and in combinations:
a systematic review of evidence from observational studies. Bipolar Disord. 2018. PMID:
29441712. https://doi.org/10.1111/bdi.12623
Ketter TA. Definition of the term “mood stabilizer”. Bipolar Disord. 2018;20:74–5.
Lindstrom L, Lindstrom E, Nilsson M, Hoistad M. Maintenance therapy with second generation
antipsychotics for bipolar disorder – a systematic review and meta-analysis. J Affect Disord.
2017;213:138–50.
Miura T, Noma H, Furukawa TA, Mitsuyasu H, Tanaka S, Stockton S, Salanti G, Motomura K,
Shimano-Katsuki S, Leucht S, Cipriani A, Geddes JR, Kanba S. Comparative efficacy and
tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a
systematic review and network meta-analysis. Lancet Psychiatry. 2014;1:351–9.
Vieta E. Developing an individualized treatment plan for patients with schizoaffective disorder:
from pharmacotherapy to psychoeducation. J Clin Psychiatry. 2010;71(Suppl 2):14–9.
Mood Stabilizers: Classification, Indications
and Differential Indications

Andreas Menke

Contents
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430
Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430
Anti-convulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430
Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1431
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1431
Differential Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1432
Unipolar Depression/Major Depressive Disorder (MDD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1432
Schizoaffective Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1432
Borderline Personality Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1432
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1433
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1433

Abstract
Pharmacological long-term maintenance treatment of bipolar disorder usually con-
sists of mood stabilizing agents. While there is no consensus on the exact definition
of mood stabilizer, it is widely accepted that a mood stabilizing agent should have at
least two of the four properties: anti-manic, anti-depressant, preventing relapse of
depression, and preventing relapse of mania. Thus, mood stabilizing agents belong
to a heterogeneous class of drugs acting through many different mechanisms.
Lithium still remains the gold standard in the maintenance treatment of bipolar
disorder. In addition, anti-convulsants such as valproate and lamotrigine and atypical

A. Menke (*)
Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg,
Würzburg, Germany
e-mail: Menke_A@ukw.de

© Springer Nature Switzerland AG 2022 1429

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_36
1430 A. Menke

antipsychotics such as quetiapine, olanzapine, aripiprazole, and risperidone exert

mood stabilizing properties. In addition, mood stabilizers may be also used for
several differential indications, such as treatment-resistant unipolar depression,
schizoaffective disorder, and borderline personality disorder. This chapter is meant
to give an overview; the detailed mechanisms of the several drugs and the indica-
tions/differential indications are discussed in the respective chapters.

Classification

Due to the recurrent and chronic nature of bipolar disorder, a long-term maintenance
treatment is essential. This long-term management usually consists of pharmacolog-
ical treatments, psychological therapies, and lifestyle approaches (Vieta et al. 2018).
The pharmacological approach typically comprises the mood stabilizers, a hetero-
geneous class of drugs acting through many different mechanisms (Baldessarini
et al. 2018).

Lithium

Lithium still remains the first-line maintenance treatment for bipolar disorder, for
example, a network meta-analysis observed a risk ratio of 0.62 (95% credible
interval 0.53–0.72) for the risk of recurrence or relapse compared with placebo
(Miura et al. 2014). Despite the many decades of research and clinical use, the
mechanisms of lithium have been only partially understood. There is some evidence
that lithium restores electrolyte balance, but newer research shows that lithium
affects multiple steps in cellular signaling. Key nodes of these regulatory networks
are CREB (cAMP response element-binding protein), GSK3 (glycogen synthase
kinase 3), and Na+-K+ ATPase (Alda 2015). In addition, lithium exerts also chrono-
biological effects (Alda 2015).

Anti-convulsants

Only some anti-convulsants have mood stabilizing effects, while others that exert
similar pharmacodynamics effects lack the mood stabilizing properties (Baldessarini
et al. 2018). Currently, valproate, lamotrigine, and carbamazepine are clinically used
for long-term maintenance treatment of bipolar disorder (Baldessarini et al. 2018).
Of note, valproate is not recommended for the treatment of women of childbearing
age, because this agent has teratogenic effects and increases, for example, the risks of
spina bifida and low IQ in off-spring (Yatham et al. 2018). While the exact mech-
anisms of action are still not fully understood, there are various hypotheses:
inhibiting voltage-sensitive sodium channels, boosting the actions of GABA, reduc-
ing excitatory glutamate neurotransmission, and the regulation of downstream signal
transduction cascades (Landmark 2007).
Mood Stabilizers: Classification, Indications and Differential Indications 1431

Antipsychotics

Second-generation antipsychotics, or atypical antipsychotics, have meanwhile been

established for the maintenance treatment of bipolar disorder. Antipsychotics with
mood stabilizing effects are quetiapine, olanzapine, risperidone, paliperidone,
aripiprazole, and asenapine. The main mechanisms of quetiapine, olanzapine,
paliperidone, and asenapine are antagonizing D2 and 5-HT2A receptors. Aripiprazole
is a D2 and D3 partial agonist (Morsel et al. 2018; Vieta et al. 2018). Most recently,
cariprazine, also a D2 and D3 partial agonist, is under investigation for maintenance
treatment; it is approved already by the United States Food and Drug Administration
(FDA) for acute mania and mixed episodes within bipolar disorder (Mazza et al.
2018).

Indications

Generally mood stabilizing agents are indicated for the maintenance treatment of
bipolar disorder, i.e., preventing a relapse of depression and/or mania. However, the
mood stabilizer should be selected with respect of the patient’s predominant polarity,
that is, defined as the condition the patient experiences at least twice as often as the
other conditions (Vieta et al. 2018). The polarity index is a metric tool that classifies
the maintenance treatment as predominant antidepressive or as predominant anti-
manic (Carvalho et al. 2014). For example, patients who experience more depressive
episodes may benefit from lamotrigine, while patients who experience more manic
episodes may improve with atypical antipsychotics such as risperidone (see Fig. 1)
(Baldessarini et al. 2012; Grande et al. 2012). Of note, Lithium and quetiapine have a
polarity index around 1, thus these agents are equally suitable for the prevention of
depressive and manic episodes (Vieta et al. 2018).

Fig. 1 Polarity index: The polarity index of drugs used for the maintenance treatment of patients
with bipolar disorders is the ratio of the number of patients needed to treat for prevention of
depression to the number of patients needed to treat for prevention of mania on the basis of results of
randomized placebo-controlled trials 173. This index classifies therapies as those with an antimanic
prophylactic effect and those with an antidepressant prophylactic effect. A polarity index of
1 reflects an equal efficacy in preventing manic and depressive episodes. (Reprinted by permission
from Springer Nature: Nature Reviews Disease Primers (Bipolar disorders, Eduard Vieta, Michael
Berk, Thomas G. Schulze, André F. Carvalho, Trisha Suppes et al.), (2018))
1432 A. Menke

Large multicenter randomized, placebo-controlled studies observed efficacy of

the mood stabilizing agents lamotrigine and quetiapine also for treatment of bipolar
depression (Geddes et al. 2009; Weisler et al. 2008). Smaller trials also showed
efficacy for valproate (Bond et al. 2010).
A large number of randomized trials revealed antipsychotics and valproate as
first-line options for the treatment of acute episodes of mania and mixed states
(Yildiz et al. 2011). Just recently, the atypical antipsychotic agent Cariprazine has
been FDA approved for bipolar mania and mixed states (Mazza et al. 2018).

Differential Indications

Unipolar Depression/Major Depressive Disorder (MDD)

The risk of recurrence of major MDD is substantially increased by each subsequent

episode, by the severity of the acute episode or by residual symptoms after remission
of the acute episode (Angst et al. 2003; Nierenberg et al. 2010; Solomon et al. 2000).
Thus, a maintenance treatment is recommended warranted for many patients. Plenty
of evidence shows that antidepressants can prevent relapse or recurrence (Geddes
et al. 2003; Hansen et al. 2008), but also mood stabilizing agents such as Lithium
reduce this risk (Fawcett 2003). In addition, mood stabilizing agents have also been
observed to be effective as antidepressant augmentation in treatment resistant
depression. A meta-analysis on randomized controlled trials found that augmenta-
tion with the atypical antipsychotics olanzapine, quetiapine, aripiprazole, and ris-
peridone was significantly more effective than placebo (Nelson and Papakostas
2009). A meta-analysis of lithium augmentation also suggested that lithium is an
effective augmentation strategy (Crossley and Bauer 2007). In addition, meta-
analysis in patients with recurrent MDD clearly observed antisuicidal effects of
lithium with 88.5% lower risk for suicide or attempt in patients taking lithium versus
those without lithium (Guzzetta et al. 2007).

Schizoaffective Disorder

Schizoaffective disorders fall on a spectrum between schizophrenia and bipolar

disorder. Hence, the treatment has to address both psychotic as well as affective
symptoms (Vieta 2010). Treatment regimes usually include atypical antipsychotics,
and there is also evidence for beneficial effects augmentations with valproate or
lithium (Ventriglio et al. 2011; Vieta 2010; Vincenzi et al. 2016).

Borderline Personality Disorder

There is a common phenomenology of borderline personality disorder with bipolar

disorder having several common symptoms, particularly mood instability. In fact,
Mood Stabilizers: Classification, Indications and Differential Indications 1433

several studies observed beneficial effects of mood stabilizing agents on borderline

personality disorder (Gunderson and Choi-Kain 2018; Paolini et al. 2017). For
example, there is supportive evidence for the use or quetiapine, olanzapine, and
aripiprazole (Canadian Agency for Drugs and Technologies in Health 2017). In
addition, “classical” mood stabilizing agents such as valproate, lithium, and
lamotrigine showed also clinical efficacy (Belli et al. 2012). However, a double-
blind, placebo-controlled randomized trial comparing lamotrigine with placebo in
borderline personality disorder did not show a significant improvement (Crawford
et al. 2018).

Cross-References

▶ Guidelines on Mood Stabilizers

▶ Mood Stabilizer: Definition
▶ Mood Stabilizers: Lamotrigine
▶ Mood Stabilizers: Lithium
▶ Mood Stabilizers: Valproate
▶ Mood Stabilizers: Quetiapine
▶ Mood Stabilizers: Side Effects, Contraindications, and Interactions

References
Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol
Psychiatry. 2015;20:661–70.
Angst J, Gamma A, Sellaro R, Lavori PW, Zhang H. Recurrence of bipolar disorders and major
depression. A life-long perspective. Eur Arch Psychiatry Clin Neurosci. 2003;253:236–40.
Baldessarini RJ, Undurraga J, Vazquez GH, Tondo L, Salvatore P, Ha K, Khalsa HM, Lepri B, Ha
TH, Chang JS, Tohen M, Vieta E. Predominant recurrence polarity among 928 adult interna-
tional bipolar I disorder patients. Acta Psychiatr Scand. 2012;125:293–302.
Baldessarini RJ, Tondo L, Vazquez GH. Pharmacological treatment of adult bipolar disorder. Mol
Psychiatry. 2018;24:198.
Belli H, Ural C, Akbudak M. Borderline personality disorder: bipolarity, mood stabilizers and
atypical antipsychotics in treatment. J Clin Med Res. 2012;4:301–8.
Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute bipolar
depression: a systematic review and meta-analysis. J Affect Disord. 2010;124:228–34.
Canadian Agency for Drugs and Technologies in Health (CADTH). Aripiprazole for borderline
personality disorder: a review of the clinical effectiveness. In: Aripiprazole for borderline
personality disorder: a review of the clinical effectiveness. Ottawa: Canadian Agency for Drugs
and Technologies in Health; 2017.
Carvalho AF, Quevedo J, McIntyre RS, Soeiro-de-Souza MG, Fountoulakis KN, Berk M,
Hyphantis TN, Vieta E. Treatment implications of predominant polarity and the polarity
index: a comprehensive review. Int J Neuropsychopharmacol. 2014;18(2):1–11.
Crawford MJ, Sanatinia R, Barrett B, Cunningham G, Dale O, Ganguli P, Lawrence-Smith G,
Leeson V, Lemonsky F, Lykomitrou G, Montgomery AA, Morriss R, Munjiza J, Paton C,
Skorodzien I, Singh V, Tan W, Tyrer P, Reilly JG, LABILE Study Team. The clinical effective-
ness and cost-effectiveness of lamotrigine in borderline personality disorder: a randomized
placebo-controlled trial. Am J Psychiatry. 2018;175:756–64.
1434 A. Menke

Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depres-
sive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry.
2007;68:935–40.
Fawcett JA. Lithium combinations in acute and maintenance treatment of unipolar and bipolar
depression. J Clin Psychiatry. 2003;64(Suppl 5):32–7.
Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, Goodwin GM. Relapse
prevention with antidepressant drug treatment in depressive disorders: a systematic review.
Lancet. 2003;361:653–61.
Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: inde-
pendent meta-analysis and meta-regression of individual patient data from five randomised
trials. Br J Psychiatry. 2009;194:4–9.
Grande I, Balanza-Martinez V, Jimenez-Arriero M, Iglesias Lorenzo FG, Franch Valverde JI, de
Arce R, Zaragoza S, Cobaleda S, Vieta E, SIN-DEPRES Group. Clinical factors leading to
lamotrigine prescription in bipolar outpatients: subanalysis of the SIN-DEPRES study. J Affect
Disord. 2012;143:102–8.
Gunderson JG, Choi-Kain LW. Medication management for patients with borderline personality
disorder. Am J Psychiatry. 2018;175:709–11.
Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ. Lithium treatment reduces suicide risk in
recurrent major depressive disorder. J Clin Psychiatry. 2007;68:380–3.
Hansen R, Gaynes B, Thieda P, Gartlehner G, Deveaugh-Geiss A, Krebs E, Lohr K. Meta-analysis
of major depressive disorder relapse and recurrence with second-generation antidepressants.
Psychiatr Serv. 2008;59:1121–30.
Landmark CJ. Targets for antiepileptic drugs in the synapse. Med Sci Monit. 2007;13:RA1–7.
Mazza M, Marano G, Traversi G, Carocci V, Romano B, Janiri L. Cariprazine in bipolar depression
and mania: state of the art. CNS Neurol Disord Drug Targets. 2018;17:723.
Miura T, Noma H, Furukawa TA, Mitsuyasu H, Tanaka S, Stockton S, Salanti G, Motomura K,
Shimano-Katsuki S, Leucht S, Cipriani A, Geddes JR, Kanba S. Comparative efficacy and
tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a
systematic review and network meta-analysis. Lancet Psychiatry. 2014;1:351–9.
Morsel AM, Morrens M, Sabbe B. An overview of pharmacotherapy for bipolar I disorder. Expert
Opin Pharmacother. 2018;19:203–22.
Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a
meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980–91.
Nierenberg AA, Husain MM, Trivedi MH, Fava M, Warden D, Wisniewski SR, Miyahara S, Rush
AJ. Residual symptoms after remission of major depressive disorder with citalopram and risk of
relapse: a STARD report. Psychol Med. 2010;40:41–50.
Paolini E, Mezzetti FA, Pierri F, Moretti P. Pharmacological treatment of borderline personality
disorder: a retrospective observational study at inpatient unit in Italy. Int J Psychiatry Clin Pract.
2017;21:75–9.
Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW, Shea MT, Coryell W, Warshaw M,
Turvey C, Maser JD, Endicott J. Multiple recurrences of major depressive disorder. Am J
Psychiatry. 2000;157:229–33.
Ventriglio A, Vincenti A, Centorrino F, Talamo A, Fitzmaurice G, Baldessarini RJ. Use of mood
stabilizers for hospitalized psychotic and bipolar disorder patients. Int Clin Psychopharmacol.
2011;26:88–95.
Vieta E. Developing an individualized treatment plan for patients with schizoaffective disorder:
from pharmacotherapy to psychoeducation. J Clin Psychiatry. 2010;71(Suppl 2):14–9.
Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, Gao K, Miskowiak KW,
Grande I. Bipolar disorders. Nat Rev Dis Primers. 2018;4:18008. https://doi.org/10.1038/
nrdp.2018.8.
Vincenzi B, Greene CM, Ulloa M, Parnarouskis L, Jackson JW, Henderson DC. Lithium or
valproate adjunctive therapy to second-generation antipsychotics and metabolic variables in
patients with schizophrenia or schizoaffective disorder. J Psychiatr Pract. 2016;22:175–82.
Mood Stabilizers: Classification, Indications and Differential Indications 1435

Weisler RH, Calabrese JR, Thase ME, Arvekvist R, Stening G, Paulsson B, Suppes T. Efficacy of
quetiapine monotherapy for the treatment of depressive episodes in bipolar I disorder: a post hoc
analysis of combined results from 2 double-blind, randomized, placebo-controlled studies. J
Clin Psychiatry. 2008;69:769–82.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, Sharma V, Goldstein BI,
Rej S, Beaulieu S, Alda M, MacQueen G, Milev RV, Ravindran A, O’Donovan C, McIntosh D,
Lam RW, Vazquez G, Kapczinski F, McIntyre RS, Kozicky J, Kanba S, Lafer B, Suppes T,
Calabrese JR, Vieta E, Malhi G, Post RM, Berk M. Canadian Network for Mood and Anxiety
Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines
for the management of patients with bipolar disorder. Bipolar Disord. 2018;20:97–170.
Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of
randomized, controlled trials. Neuropsychopharmacology. 2011;36:375–89.
Mood Stabilizers: Pharmacology
and Biochemistry

Leif Hommers

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1438
Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1438
Anti-convulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1440
Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1442
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445

Abstract
Drugs successfully applied in the treatment of bipolar disorder have been termed
mood stabilizers and include different pharmacological classes: antipsychotic
agents, anti-convulsants, and lithium.
Contrary to the development of antipsychotic and antidepressive drugs, no
drug has been developed on biological models or hypotheses of bipolar disorder.
The most commonly applied drug lithium has been introduced based on findings
by serendipity, and no unique pharmacological mechanism of mood stabilization
was identified so far. However, several mood stabilizers share a modulation of
inositol- and GSK-3β-mediated pathways leading to neuroprotection and
increased neuronal plasticity.
Future hypothesis-driven drug development is presently limited since
(I) bipolar disorder results from a large spectrum of molecular mechanisms also
associated and shared with other psychiatric morbidities and (II) animal models
allow to address only neurobiological aspects well conserved across species.

L. Hommers (*)
Zentrum für Psychische Gesundheit, Universitätsklinikum Würzburg, Würzburg, Germany
e-mail: L.Hommers@ihp-labor.de

© Springer Nature Switzerland AG 2022 1437

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_37
1438 L. Hommers

Introduction

Drugs successfully applied in the treatment of bipolar disorder have been termed
mood stabilizers and include different pharmacological classes: lithium, antipsy-
chotic agents, and anti-convulsants. Lithium has been in medical use to treat
different conditions since the early nineteenth century. However, its effect on bipolar
disorder was only recognized in the late 1940s, and it represents the first mood
stabilizer established and still commonly used today (Cade 1949). Later on, it was
noted that anti-convulsants show not only activity against epileptic seizures. Mood-
stabilizing effect of carbamazepine has been recognized since the 1970s, of valproic
acid since the 1980s, and of lamotrigine since the 1990s. While the effect of
antipsychotic drugs in treating acute mania has been recognized for a long time,
research was focusing on mood stabilizing of antipsychotic agents only recently, and
the typical drugs applied are asenapine, olanzapine, quetiapine, and risperidone class
(López-Muñoz et al. 2018). This chapter reviews the molecular pharmacology of
drugs proposed to be mood stabilizers.

Lithium

Lithium (Li+) is the smallest alkali metal sharing some chemical characteristics with
sodium and potassium, but without any identified physiological role. Li+ is com-
monly applied as lithium carbonate, lithium citrate, or lithium sulfate. It becomes
almost completely absorbed from the gastrointestinal tract with peak plasma con-
centrations at about 4 h after intake of commonly applied slow-release lithium
carbonate. There is no relevant protein binding, and lithium is evenly distributed
in extracellular compartments. However, concentrations in organs may vary, and Li+
concentrations in liquor were reported to reach only about 50% of serum concen-
trations with a slow equilibration between liquor and serum due to a slow passage of
the blood-brain barrier, as it was also noted for intracellular Li+ concentrations in
erythrocytes. Lithium is eliminated by renal excretion at about 95% of a single dose.
While it is freely filtered in the nephron, the majority of filtered Li+ becomes
reabsorbed resulting in a Li+ clearance of only 20% of that of creatinine. The
elimination half-time is about 24 h, and excretion upon discontinuation follows
two phases with 6–12 h of rapid excretion and 10–14 days of slow excretion. Li+
has a narrow therapeutic window. The concentration-response relationship points
toward serum levels to be maintained between 0.5 and 1.2 mmol/l in order to balance
therapeutic and unwanted side effects (Hiemke et al. 2018). Depending on single or
twice daily dosing schemes, peak and trough levels are expected to show a greater or
smaller variation. There is no consensus whether single or twice daily dosing leads to
better tolerability with equivalent efficacy. Moreover, there is no consensus, whether
therapeutic drug monitoring of Li+ serum levels should be generally conducted 12 h
after the last dose or at trough conditions, in case of single dosing 24 h after the
last dose.
Mood Stabilizers: Pharmacology and Biochemistry 1439

Contrary to most drugs, no specific pharmacological target of lithium has been

identified so far. Multiple molecular mechanisms of Li+ at different stages of
molecular signaling and cellular processes have been reported, and Li+ appears to
modulate key regulatory networks involved in the pathogenesis of bipolar disorder at
several points simultaneously. Some mechanisms are shared with other mood-
stabilizing drugs such as valproic acid, and these mechanisms may be of higher
relevance for the mood-stabilizing effects of Li+ as well as the pathogenesis of
bipolar disorder. This heterogeneity in molecular mechanisms may also be reflected
by the heterogeneity in treatment response to Li+ (Alda 2015).
On the level of electrolytes, early studies suggested that Li+ may lead to an
alteration of intra- and extracellular ionic composition (Coppen and Shaw 1967). It
was recognized that Li+ modulates the electrophysiological properties of neurons, e.g.,
by reducing the resting membrane potential as well as neuronal excitability (Schou
1957). However, Li+ is not distributed evenly across and within organs such as the
brain (Spirtes 1976). Since Li+ develops only a small electrochemical transmembrane
gradient compared to other ions such as Na+, K+, and Ca2+, interference of Li+ with
signal transduction on the level of ion currents has been considered to be of minor
relevance. However, interactions between sodium and lithium in the context of diuretic
therapy, sweating, or febrile as well as diarrheal illness should be noted: high serum
concentrations of Na+ induce renal excretion of Li+, and low serum concentrations of
Na+ result in Li+ retention (Oruch et al. 2014). This mechanism may lead to clinically
relevant lithium retention and intoxication upon sodium loss.
Studies focusing on molecular effects of Li+ on intracellular signaling mediated
by second messengers identified the following mechanisms: (I) depletion of inositol
due to interference with phosphatidylinositol pathways upon inhibition of inositol
monophosphatase and inositol polyphosphate-1-phosphatase (Berridge et al. 1989),
(II) inhibition of protein kinase A and adenylate cyclase of G protein-coupled
receptor pathways resulting in altered neurotransmitter and hormone release as
well as tyrosine hydroxylase activity (Manji and Lenox 2000), and (III) inhibition
of GSK-3β leading to increased hippocampal (Wnt)/β-catenin signaling (Jope 2003).
Li+ was also reported (I) to enhance serotoninergic signaling due to increasing
synthesis and increased release of serotonin, resulting from antagonistic effects at
presynaptic 5-HT1 receptors, (II) to increase glutamate reuptake at steady-state
therapeutic levels, and (III) to stabilize the inactive conformation of heterotrimeric
Gi and Gs proteins. Further mechanisms may involve modulation of β-arrestin
2, Akt, and protein phosphates 2A (Beaulieu et al. 2008) as well as guanylate cyclase
and nitric oxide signaling (Ghasemi and Dehpour 2011).
Taken together, it has recently been suggested that the molecular pharmacological
action of lithium results from the ability of Li+ to interfere with Mg2+, which has a
similar ion radius. In enzymes relying on Mg2+ as a cofactor, such as inositol
monophosphatase, adenylate cyclase, GSK-3β, or G proteins, it may be a false
substitute (Alda 2015). On the level of gene expression, these mechanisms will
lead to neuroprotection, including neurotrophic and angiogenic effects, modulating
apoptotic signaling as well as cell survival signaling, oxidative stress pathways, and
protein quality control mechanism (Chiu et al. 2013).
1440 L. Hommers

Anti-convulsants

Anti-convulsants have been developed for the treatment of epileptic seizures. They
represent a diverse class of drugs with different molecular pharmacological mech-
anisms. The anti-seizure activity of these drugs is primarily related to mechanisms
enhancing inhibitory neuronal activity (e.g., GABA-mediated signaling) as well as
mechanisms inhibiting excitatory neuronal activity (e.g., Na+ and Ca2+ currents).
However, these mechanisms may be involved in, but are not considered to be
primarily responsible for, the mood-stabilizing effects of valproic acid, carbamaze-
pine, and lamotrigine. It has been hypothesized that mechanisms induced resembling
molecular actions of lithium are responsible for mood-stabilizing effects and most
data has been accumulated for valproic acid.
Valproic acid. Valproic acid is a simple branched-chain carboxylic acid. It is
absorbed completely after oral administration within 1–4 h. Extended release for-
mulations lead to a delay for up to several hours. 78% to 94% of valproic acid are
bound to plasma proteins. Valproic acid undergoes complex hepatic metabolism.
The major pathways are glucuronidation by UGT enzymes and β-oxidation in the
mitochondria. Valproic acid may also be hydroxylated by CYP2C9 and CYP2C19
and to a minor extent by CYP2A6 and CYP2B6. Valproic acid weakly inhibits
CYP2A6, CYP2C9, CYP2C19, CYP3A4/5, and UGT enzymes; however, it is a
strong inhibitor of UGT1A4, important for the inhibition of lamotrigine metabolism
by valproic acid. Complex drug-drug pharmacokinetic interactions have frequently
been observed for valproic putatively due to inhibition of drug oxidation, suggesting
to apply therapeutic drug monitoring when valproic acid is administered. The
therapeutic range when applied as an anti-seizure or mood stabilizer is small and
ranges from 50 μg/l to 100 μg/l (Hiemke et al. 2018).
The antiepileptic properties of valproic acid were discovered by serendipity when
it was used as a vehicle for compounds being screened. A number of molecular
pharmacological mechanisms have been identified. Valproic acid potentiates the
inhibitory effects of GABA. It inhibits GABA transaminase, succinic semialdehyde
dehydrogenase, and alpha-ketoglutarate dehydrogenase, resulting in increased
GABA levels during initiation of treatment. It suppresses glutamatergic neurotrans-
mission and NMDA receptor activity, and this mechanism may also be important for
the efficacy when treating mania. However, the underlying processes are presently
not fully understood. In rodent models, administration of valproic acid leads to an
increase in norepinephrine, dopamine, and serotonin brain levels, and the link
between GABAergic and serotonergic neurotransmission via presynaptic serotonin-
ergic 5-HT1 receptors may also be of high relevance for its mood-stabilizing
properties. Moreover, valproic acid inhibits high-frequency firing of neurons in
models of epileptic seizures. However, direct inhibition of voltage-gated Na+ chan-
nels, as well as T-type Ca2+ channels, appears to be only relevant at higher concen-
trations of valproic acid in vivo, suggesting that impairment of neuronal ATP
production due to inhibitory effects on cerebral glucose metabolism resulting from
the inhibition of alpha-ketoglutarate dehydrogenase may equally be relevant
(Johannessen and Johannessen 2003). Valproic acid inhibits HDACs at therapeutic
Mood Stabilizers: Pharmacology and Biochemistry 1441

serum concentrations, thereby promoting a more transcriptionally active chromatin

structure. The epigenetic control of genes through modification of histones and
resultant remodeling of chromatin has been shown to affect important aspects of
neuronal cellular processes including development, synaptic plasticity, learning, and
circadian rhythm (Chiu et al. 2013).
It has long been noticed that lithium and valproic acid share pharmacological
targets. Both (I) regulate protein kinase C signaling pathway in a similar manner
(Manji and Zarate 2002); (II) decrease inositol biosynthesis, increase the phosphor-
ylation of GSK-3β activity, activate MAPK pathways, as well as increase the
expression of the antiapoptotic gene bcl-2(Gurvich and Klein 2002); (III) increase
levels of BDNF and bcl-2-associated athanogene (BAG-1 – a cochaperone protein
inhibiting glucocorticoid receptor activation) (Schloesser et al. 2012); and
(IV) modulate the methylation signature (Pisanu et al. 2018). These mechanisms
ultimately lead to modulation of gene expression involved in synaptic plasticity and
cytoskeleton remodeling.
Carbamazepine. Carbamazepine is an iminostilbene in medical use since the
1960s and chemically related to tricyclic antidepressants. It is absorbed slowly
from the gastrointestinal tract with delayed peak plasma concentrations at least
4–8 h after oral ingestion. Seventy-five percent of carbamazepine binds to plasma
proteins. Carbamazepine is metabolized primarily by CYP3A4/5 to its pharmaco-
logically active epoxide metabolite, with CYP2C8 and CYP2B6 playing a minor
role. The epoxide becomes glucuronidated or is metabolized by the epoxide hydro-
lase 1. Carbamazepine strongly induces drug-metabolizing enzymes due to activa-
tion of the pregnane X receptor and the constitutive androstane receptor. This results
in high increased expression of CYP3A4, UGT enzymes, and MDRD1
(P-glycoprotein), as well as CYP2B6 and CYP2C. This may affect not only the
metabolism of drugs from different classes but also endogenous substrates such as
vitamin D (Hiemke et al. 2018).
On the molecular level, carbamazepine inhibits voltage-gated Na+ channels. It
limits the repetitive firing of action potentials as believed to occur during spread of
seizure activity, without affecting ordinary ongoing neural activity. Carbamazepine
shows preferred binding to the inactive conformation of voltage-gated Na+ channels.
At hyperpolarized membrane potentials, clinically relevant concentrations of carba-
mazepine block channels only weakly. Upon depolarization a marked increase in the
degree of inhibition, showing a strong accumulation with prolonged or repetitive
channel activation (“use-dependent” block), is observed. Consequently, protection
against seizures without causing a generalized impairment of brain function may be
achieved. While carbamazepine does not directly alter excitatory or inhibitory
synaptic responses, the effect on action potentials translates into reduced transmitter
output at synapses, and glutamate release might be inhibited more strongly than
other neurotransmitters, including GABA. Concerning its mood-stabilizing effects,
there is only limited knowledge available. Carbamazepine has been linked to inositol
depletion, as has been lithium and valproic acid. However, no comparable effect on
GSK-3β has been noted, but carbamazepine may induce similar functional effects
upstream of GSK-3β (Rogawski and Löscher 2004b). Carbamazepine has also been
1442 L. Hommers

shown to increase growth cone area, presumably unrelated to GSK-3β and HDAC
(Williams et al. 2002). Due to its structural relation, carbamazepine may inhibit the
serotonin transporter weakly at therapeutic concentrations (Sarker et al. 2010).
Recently, carbamazepine was related to increasing global methylation levels, resem-
bling lithium and valproic acid (Pisanu et al. 2018).
Lamotrigine. Lamotrigine is a phenyltriazine derivative and becomes completely
absorbed within 1–4 h from the gastrointestinal tract upon oral intake. It is metab-
olized primarily by glucuronidation, predominantly by UGT1A4 with a plasma half-
life of about 24 h. The half-time may largely vary on the UGT1A4 genotype. About
50% are bound to plasma proteins (Hiemke et al. 2018).
Lamotrigine was initially developed as an antifolate agent, but its established
pharmacological mechanism is use- and voltage-dependent inhibition of Na+ chan-
nels comparable to carbamazepine. Since lamotrigine appears to be effective in a
broader range of epileptic syndromes, it has been speculated that other mechanisms
than those shared with carbamazepine may be involved in its mood-stabilizing
effects, e.g., lamotrigine was reported to weakly inhibit voltage-gated Ca2+ channels
and to show antiglutamatergic activity, as well as a weak inhibition of the serotonin
transporter, but direct interference with monoaminergic, NMDA, or GABA recep-
tors is not known. Neuroprotective effects have been observed in translational
models, but no unique mechanism was identified so far (Ketter et al. 2003). There
is conflicting data concerning the activation of the Akt/GSK-3β (Rogawski and
Löscher 2004a; Aubry et al. 2009).

Antipsychotics

Antipsychotic drugs have been discovered serendipitously. They effectively

decrease psychotic symptoms of delirium, mania, and schizophrenia. Some drugs
may also alleviate negative symptoms of schizophrenia in long-term treatment, and
some drugs are effective in the treatment of depression as well as bipolar disorder.
Inhibition of dopaminergic neurotransmission is a major mechanism of the thera-
peutic effects of antipsychotic drugs, and treatment response is related to
counteracting increased dopaminergic signaling (Davis et al. 1991). It is presently
unknown whether mood-stabilizing effects of antipsychotic drugs are mediated by
mechanisms different from pharmacological targets presumed to be relevant in the
treatment of schizophrenia. Most antipsychotic drugs exhibit antagonistic or inverse
agonistic effects at various G protein-coupled receptors, and some drugs also show
partial agonistic and rarely agonistic effects at specific receptors. These effects are
related to the fact that “receptor activity” leading to activation of intracellular
downstream signaling is a spectrum of “active” receptor conformations, ranging
from intrinsic/constitutive activity of a receptor to conformations only stabilized
upon binding of the physiological ligand or an agonist. Antagonistic drugs prevent
binding of the physiological ligand (e.g., dopamine) to the receptor. They do not
affect the intrinsic activity. Inverse agonists prevent binding of the physiological
ligand and lower the intrinsic activity of the receptor. Partial agonists prevent
Mood Stabilizers: Pharmacology and Biochemistry 1443

binding of the physiological ligand and increase the activity of the receptor. In the
presence of high levels of physiological ligand, a partial agonist may therefore lead
to physiologically inhibitory effects on a signaling pathway (Kenakin 2002).
Dopaminergic D2 and serotoninergic 5-HT2A receptors are considered to be the
most important molecular targets of antipsychotic drugs mediating antipsychotic
effects. Drug-specific inhibition of histaminergic, adrenergic, and muscarinergic
receptors is commonly related to several side effects of antipsychotic drugs, but
depending on the class and exact agent. Among dopaminergic and serotoninergic
receptors, several lines of evidence suggest that agonistic effects at D1, 5-HT1A,
5-HT2C, and 5-HT4 as well as antagonistic effects at D3, D4, 5-HT3, 5-HT6, and
5-HT7 may additionally contribute to antipsychotic, anxiolytic, and antidepressive
effects of antipsychotic drugs. It has also been suggested that not only the affinity
toward a given receptor but also the rates of association to and dissociation from the
receptor of each drug modulate their pharmacological profile. This hypothesis was
used to explain the prevalence of hyperprolactinemia and parkinsonism for different
antipsychotic agents upon comparable dopamine D2 receptor binding in vivo when
reaching therapeutic steady-state serum concentrations (Kapur and Seeman 2001).
Additionally, allosteric activation of NMDA as well as AMPA receptors, inhibition
of glycine transporters, activation of metabotropic glutamate receptors, and (partial)
activation of cholinergic as well as muscarinergic receptors among many other
putative mechanisms may contribute to the pharmacological effects of antipsychotic
drugs. Agonism at metabotropic glutamate receptors has specifically been related to
the mood-stabilizing effects of some antipsychotic drugs (Miyamoto et al. 2012). In
the synaptic cleft, G protein-coupled receptors may not only act as independent
monomers, as in several in vitro experiments, but also form oligomeric homo- and
heteromers (Ferré et al. 2014). This may then result in various modulatory effects on
receptor-mediated intracellular signaling upon binding of ligand. Allosteric modu-
lation and biased agonism at heteromers represent important mechanisms: while a
homomer may only activate canonically one class of G proteins, any ligand may now
have distinctive effects on the activation of different receptors and intracellular
signaling cascades, depending on the composition of the heteromer. This may
range from allosteric activation of the secondary receptor to antagonistic effects on
one canonical pathway (e.g., inhibition of G protein activation) but (partial) agonistic
effects on a second pathway (e.g., β-arrestin signaling) (Kenakin 2009). These
phenomena have been reported in molecular studies of antipsychotic agents (Masri
et al. 2008), and it has been suggested that antipsychotic drugs counteract psychotic
symptoms related to neuronal dysbalance of Gi- and Gq-dependent signaling by
binding to a heteromeric 5-HT2A:mGluR2-receptor complex, thereby re-balancing
Gi- and Gq-dependent signaling (Fribourg et al. 2011). Downstream, signaling may
then be modulated and converge on the level of Akt/GSK-3β (Beaulieu and
Gainetdinov 2011). However, the importance toward treatment response and side
effects has not been ultimately established so far.
Asenapine. Asenapine is a tetracyclic dibenzooxepinpyrrole derivative with some
structural resemblance toward the antidepressants mianserine and mirtazapine. It is
rapidly absorbed when applied sublingually and undergoes extensive first-pass
1444 L. Hommers

metabolism to about 65% of a single dose. Upon ingestion, the bioavailability is only
minimal. It is bound to plasma proteins to a large extent. It becomes directly
glucuronidated by UGT1A4 and metabolized by CYP1A2 as well as to a smaller
extent by CYP2D6 and CYP3A4. The half-life is about 24 h. Asenapine is a strong
antagonist at 5-HT2A/C, 5-HT7, and D2 and D3 receptors but also at H1 and α1/2
receptors. It is a partial agonist at 5-HT1A receptors. No significant interaction with
muscarinergic receptors has been identified (Hiemke et al. 2018; Aringhieri et al.
2018).
Olanzapine. Olanzapine is a thiobenzodiazepine derivative structurally resem-
bling clozapine. It is well absorbed within 4–6 h after ingestion, and about 40% of
a single dose undergo first-pass metabolism. It is bound to plasma protein to a
large extent. It becomes metabolized by CYP1A2 and to a smaller extent by
CYP2A6, CYP2C8, and CYP2D6 or becomes directly glucuronidated. The half-
life is between 33 and 52 h and increases with age. Olanzapine is an inverse
agonist predominantly at 5-HT2A/C and H1 receptors. It is an antagonist at D2, D3,
5-HT7, M1, M2, and M4 receptors as well as adrenergic α1/2 receptors. The
affinity for the 5-HT2A receptor is considerably higher than for the D2 receptor.
Inhibitory effects at BDNF receptors have been reported (Hiemke et al. 2018;
Aringhieri et al. 2018).
Quetiapine. Quetiapine is a dibenzothiazepine structurally resembling clozapine.
It is well absorbed within 2 h after ingestion. It is bound to plasma protein to a large
extent. It becomes metabolized by CYP3A4 and to a smaller extent by CYP2D6. The
half-life is about 8 h. Quetiapine is a strong antagonist at H1 receptors. To a lesser
extent, it is an antagonist at α1/2, 5-HT2A/C, 5-HT7, and D2/3 receptors as well and a
partial agonist at 5-HT1A receptors. Minor antagonistic effects have been reported at
muscarinergic as well as BDNF receptors. Its metabolite norquetiapine additionally
inhibits the norepinephrine transporter and shows antagonistic properties at
muscarinergic receptors (Hiemke et al. 2018; Aringhieri et al. 2018).
Risperidone. Risperidone is a benzisoxazole derivative. It is rapidly absorbed
within 1 h after ingestion, and about 90% are bound to plasma proteins. It becomes
rapidly metabolized by CYP2D6 and to a smaller extent by CYP3A4 within less
than 12 h into its active metabolite 9-hydroxyrisperidone. 9-Hydroxyrisperidone
becomes predominantly excreted renally unchanged, with the remainder being
metabolized by at least four different pathways, leading to a terminal half-life of
about 24 h. Both are substrates of MDRD1. 9-Hydroxyrisperidone is also available
as paliperidone. Risperidone is an antagonist at D2 and 5-HT7 receptors as well as
an inverse agonist at 5-HT2, α2C, and D3 receptors. Like olanzapine, its affinity for
the 5-HT2A receptor is larger than for the D2 receptor. Only minimal antagonism at
H1 as well as BDNF receptors has been identified, and no significant interaction
with muscarinergic receptors has been noted so far. While it must be noted that due
to its longer half-life 9-hydroxyrisperidone is primarily mediating the pharmaco-
logical effects of risperidone, only minor differences concerning the receptor
binding profile of both agents have been identified (Hiemke et al. 2018; Aringhieri
et al. 2018).
Mood Stabilizers: Pharmacology and Biochemistry 1445

References
Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol
Psychiatry. 2015;20(6):661–70.
Aringhieri S, et al. Molecular targets of atypical antipsychotics: from mechanism of action to
clinical differences. Pharmacol Ther. 2018;192:20. Ahead of print
Aubry J-M, et al. Early effects of mood stabilizers on the Akt/GSK-3beta signaling pathway and on
cell survival and proliferation. Psychopharmacology. 2009;205(3):419–29.
Beaulieu J-M, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine recep-
tors. Pharmacol Rev. 2011;63(1):182–217.
Beaulieu J-M, et al. A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell.
2008;132(1):125–36.
Berridge MJ, Downes CP, Hanley MR. Neural and developmental actions of lithium: a unifying
hypothesis. Cell. 1989;59(3):411–9.
Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2(10):349–52.
Chiu C-T, et al. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar
disorder. Pharmacol Rev. 2013;65(1):105–42.
Coppen A, Shaw DM. The distribution of electrolytes and water in patients after taking lithium
carbonate. Lancet. 1967;2(7520):805–6.
Davis KL, et al. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry.
1991;148(11):1474–86.
Ferré S, et al. G protein-coupled receptor oligomerization revisited: functional and pharmacological
perspectives. Pharmacol Rev. 2014;66(2):413–34.
Fribourg M, et al. Decoding the signaling of a GPCR heteromeric complex reveals a unifying
mechanism of action of antipsychotic drugs. Cell. 2011;147(5):1011–23.
Ghasemi M, Dehpour AR. The NMDA receptor/nitric oxide pathway: a target for the therapeutic
and toxic effects of lithium. Trends Pharmacol Sci. 2011;32(7):420–34.
Gurvich N, Klein PS. Lithium and valproic acid: parallels and contrasts in diverse signaling
contexts. Pharmacol Ther. 2002;96(1):45–66.
Hiemke C, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychophar-
macology: update 2017. Pharmacopsychiatry. 2018;51(1–02):9–62.
Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev. 2003;9
(2):199–216.
Jope RS. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends
Pharmacol Sci. 2003;24(9):441–3.
Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of
atypical antipsychotics? A new hypothesis. Am J Psychiatry. 2001;158(3):360–9.
Kenakin T. Efficacy at G-protein-coupled receptors. Nat Rev Drug Discov. 2002;1(2):103–10.
Kenakin TP. Cellular assays as portals to seven-transmembrane receptor-based drug discovery. Nat
Rev Drug Discov. 2009;8(8):617–26.
Ketter TA, Manji HK, Post RM. Potential mechanisms of action of lamotrigine in the treatment of
bipolar disorders. J Clin Psychopharmacol. 2003;23(5):484–95.
López-Muñoz F, et al. A history of the pharmacological treatment of bipolar disorder. Int J Mol Sci.
2018;19(7):2143.
Manji HK, Lenox RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol
Psychiatry. 2000;48(6):518–30.
Manji HK, Zarate CA. Molecular and cellular mechanisms underlying mood stabilization in bipolar
disorder: implications for the development of improved therapeutics. Mol Psychiatry. 2002;7
Suppl 1(S1):S1–7.
Masri B, et al. Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common
property of clinically effective antipsychotics. Proc Natl Acad Sci U S A. 2008;105
(36):13656–61.
1446 L. Hommers

Miyamoto S, et al. Pharmacological treatment of schizophrenia: a critical review of the pharma-

cology and clinical effects of current and future therapeutic agents. Mol Psychiatry. 2012;17
(12):1206–27.
Oruch R, et al. Lithium: a review of pharmacology, clinical uses, and toxicity. Eur J Pharmacol.
2014;740(C):464–73.
Pisanu C, et al. Understanding the molecular mechanisms underlying mood stabilizer treatments in
bipolar disorder: potential involvement of epigenetics. Neurosci Lett. 2018;669:24–31.
Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of non-
epileptic conditions. Nat Med. 2004a;10(7):685–92.
Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004b;5
(7):553–64.
Sarker S, et al. The high-affinity binding site for tricyclic antidepressants resides in the outer
vestibule of the serotonin transporter. Mol Pharmacol. 2010;78(6):1026–35.
Schloesser RJ, Martinowich K, Manji HK. Mood-stabilizing drugs: mechanisms of action. Trends
Neurosci. 2012;35(1):36–46.
Schou M. Biology and pharmacology of the lithium ion. Pharmacol Rev. 1957;9(1):17–58.
Spirtes MA. Lithium levels in monkey and human brain after chronic, therapeutic, oral dosage.
Pharmacol Biochem Behav. 1976;5(2):143–7.
Williams RSB, et al. A common mechanism of action for three mood-stabilizing drugs. Nature.
2002;417(6886):292–5.
Mood Stabilizers: Side Effects,
Contraindications, and Interactions

Hubertus Himmerich and Amy Hamilton

Contents
Preliminary Pathophysiological Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1448
Important Generic Side Effects of Mood Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453
Specific Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1456
Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1459
Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1460
Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1464
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1465
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1465

Abstract
The key mood stabilizers used in clinical practice are a heterogeneous group of
medications with multiple disparities. Included among this group are lithium,
certain antiepileptic drugs such as carbamazepine, lamotrigine, and valproate, as
well as certain atypical antipsychotics such as asenapine, olanzapine, quetiapine,
and risperidone. The side effect profile is varied, but these medications can have
an impact on the central nervous system as well as the cardiac, gastrointestinal,
endocrine, renal, and the hematopoietic systems. Sexual and allergic side effects
are also of significant importance. Among the mood stabilizers, valproate treat-
ment seemingly carries the highest risk for birth defects. Other specific side
effects of clinical importance include lithium toxicity which can lead to ataxia,
rigor, cerebral seizures, and shock; decreased bone marrow function under
carbamazepine treatment; and Stevens-Johnson syndrome and Lyell’s syndrome

H. Himmerich (*)
Department of Psychological Medicine, King’s College London, London, UK
e-mail: hubertus.himmerich@kcl.ac.uk
A. Hamilton
Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust, London, UK
e-mail: Amy.Hamilton@slam.nhs.uk

© Springer Nature Switzerland AG 2022 1447

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_40
1448 H. Himmerich and A. Hamilton

induced by carbamazepine or lamotrigine. In addition to this, it is important to be

aware of the risk of liver failure and pancreatic damage caused by valproate and
weight gain and metabolic disturbances associated with atypical antipsychotics
such as olanzapine and quetiapine.
Having a pre-existing condition which affects any of the organs listed above
puts the patient at higher risk of developing these side effects. Hence, this would
be one of the major contraindications. Conditions involving the organs which
metabolize the medication in question can also present as a contraindication, for
example, if the condition involves the liver or kidneys.
In order to gauge potential interactions, one must take into account
the metabolization and elimination of the medication, together with the medica-
tion’s potential to induce or inhibit cytochrome P450 isoenzymes and
glucuronosyltransferases.

Preliminary Pathophysiological Remarks

General considerations: “Mood stabilizer” is the term given to a group of various

medications currently comprised of lithium salts, certain antiepileptic drugs such as
carbamazepine, lamotrigine, and valproate, as well as a couple of antipsychotics such
as asenapine, olanzapine, quetiapine, and risperidone. This chapter will explain the
broad range of side effects, contraindications, and interactions of mood stabilizers and
will focus only on those medications listed above, although it is worth mentioning that
this is not an exhaustive list and there are others which have not been included.
Mood stabilizers are not only chemically heterogeneous but also differ substan-
tially with respect to their molecular effects, metabolization, and elimination. They
also vary with regard to the ways in which they influence the metabolization of other
drugs. Their mechanisms of action, the way they are metabolized in the body, and the
mode in which they influence the action and metabolism of other drugs can lead to
a multitude of potential side effects, interactions, and contraindications.
Despite the wide range of heterogeneity between different mood stabilizers, their
broad range of effects and side effects, and the variety of bodily systems they affect,
this book chapter aims to explore these in a systematic fashion with a logical
structure that encompasses the most clinically relevant side effects. The first sections
refer to the prescribing information of the respective medications; two psychophar-
macological textbooks (Taylor et al. 2018; Benkert and Hippius 2019) and the
“Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychophar-
macology: Update 2017” (Hiemke et al. 2018) are referenced as the most important
sources. In the last section on future directions of research in this area, more specific
reference will be made to recently published journal articles.
The information presented and discussed in this chapter is briefly summarized
in Table 1. For more detailed information on the side effects, contraindications,
and interactions of a specific mood stabilizer, we refer to the chapters ▶ “Mood
Stabilizers: Asenapine,” ▶ “Mood Stabilizers: Carbamazepine,” ▶ “Mood Stabilizers:
Lamotrigine,” ▶ “Mood Stabilizers: Lithium,” ▶ “Mood Stabilizers: Olanzapin,”
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1449

Table 1 Important side effects, contraindications, interactions, and clinical management of

selected mood stabilizers. Even though not mentioned in the table as specific aspects of clinical
management, regular history taking and clinical examination for side effects, monitoring of clinical
routine laboratory parameters, and ECG measurements are necessary during the treatment with all
mood stabilizers. For references, see main text of this chapter
Implications
Mood for clinical
stabilizer Side effects Contraindications Interactions management
Lithium
Lithium Tremor Severe Eliminated renally Renal function
carbonate Cognitive problems electrolyte without previous to be tested
Lithium Increased thirst disturbances metabolization before lithium
aspartate Impaired renal Severe kidney Various therapy
Lithium sulfate function dysfunction medications can Regular
Polyuria, polydipsia Addison’s increase lithium determination
Hypothyroidism disease levels of lithium
Hyperparathyroidism Severe Lithium levels to levels:
Weight gain cardiovascular be measured symptoms of
Worsening of disease regularly when intoxication
psoriasis Pregnancy combining lithium occur at
Intoxication: with other concentrations
somnolence, medications above
dysarthria, ataxia, 1.2 mmol/l
cerebral seizures, Patient to be
shock educated about
warning signs
of toxicity
Antiepileptics
Carbamazepine Sedation, History of bone Metabolized Low starting
somnolence marrow problems hepatically by dose, slow dose
Ataxia Severe hepatic CYP3A4 increase
Liver enzyme dysfunction Induces the Patient to be
elevations Severe renal CYP3A4, informed about
Blood count changes dysfunction CYP2B6, UGTs the possibility
Bone marrow Acute Accelerated of life-
toxicity intermittent degradation of threatening
Stevens-Johnson porphyria drugs that are skin reactions
syndrome Pregnancy substrates of Stevens-
Lyell’s syndrome Treatment with CYP3A4 Johnson
Sexual dysfunction clozapine CYP3A4 inhibitors syndrome and
Weight gain increase in Lyell’s
carbamazepine syndrome:
levels carbamazepine
Caution: to be stopped
combination with immediately
sedating Caution:
medications history of
Carbamazepine allergic skin
must not be reactions
combined with
other bone
marrow-toxic
substances
(continued)
1450 H. Himmerich and A. Hamilton

Table 1 (continued)
Implications
Mood for clinical
stabilizer Side effects Contraindications Interactions management
Lamotrigine Headache Severe hepatic Metabolized by Low starting
Somnolence dysfunction UGTs dose, slow dose
Aggressiveness Severe renal No combination increase
Nausea, vomiting dysfunction with sertraline Patient to be
Stevens-Johnson No combination informed about
syndrome with ethinyl the possibility
Lyell’s syndrome estradiol of life-
Quincke’s edema Caution: threatening
combination with skin reactions.
sedating Stevens-
medications Johnson
Combination with syndrome and
valproate: Lyell’s
lamotrigine levels syndrome:
to be measured lamotrigine to
regularly be stopped
immediately
Caution:
history of
allergic skin
reactions
Valproate Drowsiness Severe hepatic Metabolized by Pregnancy to
Nausea, vomiting dysfunction UGTs, CYP2A6, be excluded
Tremor Severe renal CYP2B6, before start of
Paresthesia dysfunction CYP2C9, treatment
Birth defects: spina Coagulation CYP2C19 Caution:
bifida, valproate disorder Combination with history of
syndrome Pancreatitis CYP2A6-, allergic skin
Acute CYP2B6-, reactions
intermittent CYP2C9-, or
porphyria CYP2C19-
Pregnancy inducing
substances:
valproate levels to
be measured
regularly
Combinations with
anticoagulants or
TCAs to be
avoided
Caution:
combination with
sedating
medications
Antipsychotics
Asenapine Somnolence Long QT Metabolized via Attention to be
Anxiety syndrome CYP1A2, UGTs paid to weight
EPS Severe hepatic Caution when gain
(continued)
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1451

Table 1 (continued)
Implications
Mood for clinical
stabilizer Side effects Contraindications Interactions management
Weight gain dysfunction combined with
Prolonged QTc Severe renal CYP1A2 inhibitors
Malignant dysfunction Smokers may need
neuroleptic Hyperthyroidism higher doses
syndromea History of Caution:
malignant combination with
neuroleptic sedating
syndrome medications
People > 65 y.o. Caution:
combination with
QTc-prolonging
medications
Olanzapine Drowsiness Narrow-angle Metabolized by Attention to be
EPS glaucoma CYP1A2, paid to weight
Orthostatic Prostatic CYP2D6 gain,
hypotension hyperplasia Caution when dyslipidemia,
Weight gain Diabetes combined with and diabetes
Disturbances of Long QT CYP1A2 inhibitors
glucose and lipid syndrome Smokers may need
metabolism Severe hepatic higher doses
Prolonged QTc dysfunction Caution:
Sexual dysfunction Severe renal combination with
Blood count changes dysfunction sedating
Malignant History of medications
neuroleptic malignant Caution:
syndrome neuroleptic combination with
Postinjection syndrome QTc-prolonging
syndrome medications
(IM administration)
Quetiapine EPS Long QT Metabolized by Attention to be
Prolonged QTc syndrome CYP3A4 paid to weight
Weight gain Severe hepatic Pharmacologically gain
Disturbances of dysfunction active metabolite: Attention to be
glucose and lipid Severe renal norquetiapine paid to thyroid
metabolism dysfunction Not to be hormones
Decrease in the History of combined with
thyroid hormones malignant CYP3A4 inhibitors
Cardiomyopathya neuroleptic Combination with
Epilepsy syndrome CYP3A4 inducers:
Malignant loss of the
neuroleptic therapeutic effect
syndrome Caution:
combination with
sedating
medications
Caution:
combination with
QTc-prolonging
medications
(continued)
1452 H. Himmerich and A. Hamilton

Table 1 (continued)
Implications
Mood for clinical
stabilizer Side effects Contraindications Interactions management
Risperidone Headache Long QT Metabolized via Attention to be
Somnolence syndrome CYP2D6, paid to
EPS Parkinson’s CYP3A4 prolactin levels
Prolonged QTc disease Active metabolite:
Prolactin elevation Prolactin- paliperidone
Respiratory tract dependent tumors CYP3A4 inducers:
infections Severe hepatic loss of therapeutic
Gastrointestinal dysfunction effect
disturbances Severe renal CYP2D6
Malignant dysfunction inhibitors: reduced
neuroleptic Epilepsy tolerability
syndrome History of Caution:
malignant combination with
neuroleptic sedating
syndrome medications
Caution:
combination with
QTc-prolonging
medications
Abbreviations: TCA tricyclic antidepressant, EPS extrapyramidal motor symptoms, UGT
glucuronosyltransferase, CYP cytochrome P450 isoenzyme
a
Only sporadic cases reported

▶ “Mood Stabilizers: Quetiapine,” ▶ “Mood Stabilizers: Risperidone for Treating

Bipolar Disorders in Adults,” and ▶ “Mood Stabilizers: Valproate” of this book.
Lithium: Lithium has been reported to modulate the neurotransmitter signaling of
norepinephrine, serotonin, glutamate, gamma-aminobutyric acid (GABA), and nitric
oxide. It also functions to influence intracellular second messenger and enzyme
systems such as G proteins, cyclic adenosine monophosphate, inositol mono-
phosphate, phosphoadenosine phosphate phosphatase, and the complexes I and
II of the mitochondrial electron transport chain (Can et al. 2014). Depending on its
tissue and plasma concentration, it can exert neuroprotective or neurotoxic effects
(Rybakowski 2016). It is exclusively renally excreted and does not undergo
prior metabolism (Jinhua et al. 2019; Hiemke et al. 2018; Paulzen et al. 2019; Taylor
et al. 2018).
Antiepileptic drugs: Most antiepileptic drugs influence ion channels and thus the
formation and development of electrical impulses and conduction. Carbamazepine,
valproate, and lamotrigine, for example, are blockers of voltage-gated sodium
channels and thus stabilize neuronal membranes which explain their antiepileptic
effect (Stahl 2004). Carbamazepine has also been reported to influence serotonin
release and reuptake (Dailey et al. 1998). It has been proposed that valproate works
through modulating GABA signaling and inhibiting histone deacetylases, which is
a form of epigenetic regulation (Ren et al. 2004). Lamotrigine has been hypothesized
to suppress the release of glutamate and aspartate and to influence GABA signaling
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1453

(Choi and Morrell 2003). Carbamazepine is predominantly metabolized hepatically

by the cytochrome P450 isoenzymes (CYP) 3A4. It induces the CYP3A4 and
CYP2B6, glucuronosyltransferases (UGT), and epoxide hydrolases. Lamotrigine is
metabolized in the liver by glucuronide conjugation via UGTs, and valproate
is mainly hepatically metabolized by glucuronosyltransferases, CYP2A6,
CYP2B6, CYP2C9, CYP2C19, and β-oxidation (Hiemke et al. 2018; Paulzen
et al. 2019; Taylor et al. 2018).
Antipsychotic drugs: Asenapine, olanzapine, quetiapine, and risperidone are
antipsychotic drugs which influence neurotransmitter signaling, whereby the dopa-
minergic, serotonergic, and histaminergic signal transduction has been shown to
play a decisive role for their therapeutic and side effects (Citrome 2014; Weber
and McCormack 2009; Sümegi 2008; Chopko and Lindsley 2018). They are all
metabolized in the liver: asenapine via CYP1A2 and UGTs, and to a lesser
extent, via CYP3A4 and CYP2D6; olanzapine via conjugation and oxidation by
N-glucuronosyltransferase, flavin monooxygenase, CYP1A2, and slightly CYP2D6;
quetiapine via CYP3A4 thus leading to further pharmacologically active metabolites
such as norquetiapine; and risperidone via CYP2D6 and CYP3A4 which leads to its
active metabolite 9-hydroxy risperidone also known as paliperidone (Hiemke et al.
2018; Müller and Benkert 2019; Taylor et al. 2018).
In summary, mood stabilizers influence neurotransmitter signaling. Furthermore,
lithium specifically influences intracellular second messenger systems, while anti-
epileptic drugs have an impact on ion channels, and the antipsychotics used as mood
stabilizers have a well-established affinity to dopamine, serotonin, and histamine
receptors. Their metabolization can induce liver enzymes or produce further active
substances. The elimination of lithium via the kidneys and that of antiepileptics and
antipsychotics via the liver and the kidneys can interact with the elimination of other
drugs.

Important Generic Side Effects of Mood Stabilizers

Side effects of the central nervous system: Central nervous system (CNS) effects are
among the most frequent side effects associated with mood stabilizers. Lithium, for
example, can elicit tremor, cognitive problems, tiredness, shakiness of the hands, and
increased thirst. Intoxication with lithium can lead to nausea, somnolence, psycho-
motor retardation, dysarthria, ataxia, rigor, cerebral seizures, and shock. Potential
CNS side effects of antiepileptic drugs include dizziness, somnolence, aggressive-
ness, confusion, ataxia, and double or blurred vision (Jinhua et al. 2019). The most
important adverse effects of antipsychotics like olanzapine, quetiapine, and risper-
idone on the brain are extrapyramidal motor symptoms (EPS) like parkinsonism and
an increase in appetite and weight, most probably elicited by their antihistaminergic
effects (Divac et al. 2014). Atypical antipsychotics such as olanzapine can also have
unfavorable effects on glucose and lipid metabolism (Himmerich et al. 2015).
However, mood stabilizers like carbamazepine and lithium which do not have
antihistaminergic properties are also capable of inducing weight gain (Himmerich
1454 H. Himmerich and A. Hamilton

et al. 2005). Mood stabilizers often cause disturbances of sleep and sleep-wake
regulation such as tiredness, somnolence, nightmares, somnambulism, or sleepless-
ness (Rumble et al. 2015).
Cardiac side effects: As mood stabilizers modulate ion currents at cell membranes
and thus the formation and development of electrical impulses and conduction, they
bear a risk for eliciting disturbances in the conduction system of the heart. Such side
effects could present in the form of bradycardic arrhythmias, sinus node dysfunc-
tions, delays in conduction, atrioventricular blocks, or bundle branch blocks. The
electrocardiogram (ECG) may show an increase in QTc time trigger or torsade de
pointes. This highlights the importance of regular ECG monitoring. When com-
mencing mood stabilizers or considering a dose increase, extra vigilance and caution
should be taken regarding the risk associated with concomitant use of additional
medications that prolong QTc interval. The presence of other risk factors for torsade
de pointes must also be considered (Wu et al. 2015; Mehta and Vannozzi 2017;
Zaccara et al. 2017).
Gastrointestinal side effects: As with any psychiatric and somatic medication,
mood stabilizers can lead to a variety of gastrointestinal symptoms including
anticholinergic effects such as dry mouth and constipation but also diarrhea, nausea,
feelings of fullness and loss of appetite and weight, and other gastrointestinal
complaints. The liver or pancreas may be affected as reflected by liver enzyme
elevation, pancreatic enzyme elevation, dyspepsia, or pain (Jinhua et al. 2019;
Severance et al. 2015).
Hormonal and renal side effects: Lithium treatment can alter the function of the
thyroid gland and the kidneys, for example, it reduces the urine-concentrating ability
and leads to hypothyroidism, hyperparathyroidism, and weight gain. Very high
lithium doses and serum concentrations are particularly associated with impaired
renal function, hypothyroidism, and hypercalcemia. Overall, the findings on long-
term renal effects of lithium treatment remain inconsistent (Dineen et al. 2017).
The antidopaminergic effects of antipsychotic drugs in the tuberoinfundibular sys-
tem mediate their neuroendocrinological side effects such as prolactin increase
(Bostwick et al. 2009).
Allergic side effects: Mood stabilizers can have various effects on the skin; this is
particularly true with antiepileptic drugs like carbamazepine and lamotrigine. These
effects can range from general skin lesions to Stevens-Johnson syndrome or toxic
epidermal necrolysis. There is data suggesting that the major histocompatibility
complex (MHC) class IA gene, also known as human leukocyte antigen (HLA)-A
gene, conveys a risk for allergic side effects of the skin in certain populations
(Błaszczyk et al. 2015).
Hematopoietic disorders: Disorders of the hematopoietic system including eosin-
ophilia, neutropenia, leucopenia, thrombocytopenia, and agranulocytosis can arise
during treatment with various different mood stabilizers such as lithium, antiepilep-
tics like carbamazepine and valproate, or antipsychotics such as olanzapine (Curtis
2014).
Sexual dysfunction: Sexual dysfunction is common in patients with bipolar
disorder. However, the risk of this is further increased in treatment with some
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1455

mood stabilizers. Lithium treatment carries some risk of sexual dysfunction (Elnazer
et al. 2015); however, carbamazepine treatment is associated with a high-risk for the
development of various sexual side effects. This is because carbamazepine has been
reported to alter the protein binding of testosterone in the serum by reducing free
testosterone (Calabrò and Bramanti 2013). Libido and orgasmic disorders were
specifically reported in women with bipolar disorder during valproate treatment
(Verrotti et al. 2016). During treatment with antipsychotics, sexual dysfunction
may be a result of their antidopaminergic effect which leads to an increase in
prolactin release (Montejo et al. 2015).
Birth defects: Birth defects are particularly prevalent in treatment with valproate;
exposure during pregnancy is associated with about three times as many major
abnormalities as usual, mainly spina bifida. More rarely, a “valproate syndrome” is
seen, which has specific characteristics including facial features that tend to evolve
with age, a triangle-shaped forehead, tall forehead with bifrontal narrowing,
epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root,
anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick
lower lip, and small downturned mouth. Children of mothers taking valproate during
pregnancy are at risk of lower intelligence quotients and have a higher probability of
autism. Women who intend to become pregnant should therefore switch to a
different medication or decrease their dose of valproate (Wiedemann et al. 2017).
Women who take lithium during the first trimester are also more likely to have a baby
with a birth defect, compared to pregnant women who have a mental disorder but do
not take lithium (Patorno et al. 2017).
Suicide risk: Several years ago, the “Food and Drug Administration” (FDA) had
issued a warning that anti-convulsant treatment was linked to a higher risk of suicidal
ideation and suicidal behavior. However, a meta-analysis of 5,130,795 patients
showed that there was in fact a decrease in the risk of suicide among people
with epilepsy or bipolar disorder treated with anti-convulsants (Arana et al. 2010).
However, even though the risk was relativized by meta-analyses, the warnings were
included in anti-convulsant patient information leaflets as stipulated by the FDA.
In an observational longitudinal study with 199 patients, the use of carbamazepine,
lamotrigine, and valproate showed no increased suicide rate in patients with bipolar
disorder (Leon et al. 2012). However, irrespective of the contradictory data, when
using anti-convulsants and other mood stabilizers, clinicians must carefully pay due
attention to the risk of suicidal ideation, suicide attempts, and suicide. Such caution
arises from the fact that bipolar disorder is associated with an increased risk of
suicide. It is estimated that 25% to 50% of patients with bipolar disorder will attempt
suicide at least once over their lifetime and that between 8% and 19% will complete
suicide. However, it appears that the introduction of lithium treatment was the most
important breakthrough in the prevention of suicide in bipolar disorder (Latalova
et al. 2014).
Risk populations: Certain populations fall into a higher risk category where mood
stabilizers are concerned. It is important to be aware of the specific patient groups
where these risks are elevated. One such group is those with cardiovascular system
defects and cardiac disease such as orthostatic dysregulation, heart failure, cardiac
1456 H. Himmerich and A. Hamilton

arrythmias, or QTc prolongation. People with kidney or liver problems are also at
risk, because mood stabilizers are metabolized and eliminated through these organs.
Almost all mood stabilizers have the potential to affect the hematopoietic system;
therefore, having abnormalities in the blood count should be recognized as a severe
risk factor for further complications where a mood stabilizer is being considered.
Considering all of this, it is paramount that we carry out a full physical examination;
obtain the necessary blood tests, including electrolytes, liver function tests, and
pancreatic enzymes and full blood count; and perform an ECG before commencing
mood stabilizers (Benkert and Hippius 2019; Mehta and Vannozzi 2017; Zaccara
et al. 2017).
As these problems frequently occur in elderly patients, this age group must be
deemed a specific risk population. In this regard, it is worth mentioning that
risperidone is the only currently approved atypical antipsychotic for patients with
dementia and pronounced psychotic or behavioral disorders.

Specific Side Effects

Lithium: Many patients take lithium on a long-term basis without any unwanted
effects. Side effects often occur at the beginning of lithium treatment but disappear
spontaneously. Initial side effects should, therefore, not necessarily lead to discon-
tinuation of treatment. Thus, it is of importance to inform the patient about these
potentially transient side effects and provide some reassurance that they may even-
tually settle down but should be monitored closely.
Lithium can have a number of psychiatric and neurological side effects such as
tremor, cognitive problems, tiredness, and muscle weakness; renal side effects such
as polyuria and polydipsia, renal impairment and dysfunction, and glomerulonephri-
tis; endocrine adverse effects such as goiter, hypothyroidism, hyperparathyroidism,
and weight gain; and cardiovascular side effects such as repolarization disturbances
and arrythmias. It may also lead to unwanted effects regarding fluid and electrolyte
balance such as facial or ankle edema, the hematopoietic system like leukocytosis,
the skin such as alopecia, folliculitis, pruritus, or exacerbations of psoriasis; and the
gut like diarrhea, nausea, feelings of fullness, and loss of appetite. The most common
side effects include increased urination, shakiness of the hands, and increased thirst.
If used during pregnancy, lithium can cause birth defects. It appears to be safe to use
while breastfeeding. For further information on specific side effects of lithium, see
chapter ▶ “Mood Stabilizers: Lithium.”
Special note: As lithium is eliminated renally, renal function should be tested
before initiating lithium therapy. Symptoms of lithium toxicity can occur at concen-
trations above 1.2 mmol/l, in some cases even at lower lithium plasma concentra-
tions. Signs of lithium toxicity include nausea, vomiting, diarrhea, hand tremor,
fatigue, psychomotor slowdown, vigilance reduction, dizziness, dysarthria, ataxia,
rigor, hyperreflexia, fasciculations, cerebral seizures, and shock. In extreme
cases, lithium toxicity can lead to loss of consciousness, coma, and cardiac arrest
(Paulzen et al. 2019).
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1457

Carbamazepine: Many side effects of carbamazepine occur in a dose-dependent

manner, especially at the start of treatment. They may disappear after 2 weeks or
after temporary dose reduction. Therefore, daily dose of carbamazepine should
up-titrated gradually. Very common unwanted effects include dizziness, somno-
lence, sedation, ataxia, changes of liver enzyme levels, and leukopenia. Further
frequent side effects are headache, double vision, allergic skin reactions with or
without fever, eosinophilia, thrombocytopenia, hyponatremia and edema, an
increase or loss of appetite, weight gain, and sexual dysfunction. Leukocytosis,
decreased bone marrow function with agranulocytosis, cardiac arrhythmia, liver
failure, or a diminished bone density emerge very rarely, but these conditions are
of high clinical relevance. For further information on specific side effects of carba-
mazepine, see chapter ▶ “Mood Stabilizers: Carbamazepine.”
Carbamazepine should not be used in those with a history of bone marrow
problems. Its use during pregnancy may cause harm to the baby; its use during
breastfeeding is not recommended. Care should be taken in those with either kidney
or liver problems.
Special note: Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s
syndrome) are life-threatening conditions which can arise during treatment with
carbamazepine. Carbamazepine must be stopped immediately. Carbamazepine must
not be combined with other potentially bone marrow-toxic substances such as
clozapine (Paulzen et al. 2019).
Lamotrigine: Very common side effects of lamotrigine include headache, som-
nolence, aggressiveness, nausea, vomiting, rash, and double or blurred vision.
Fatigue, insomnia, dizziness, nystagmus, irritability, tremor, ataxia, arthralgia,
pain, and gastrointestinal complaints are further frequent side effects. At the start
of therapy with lamotrigine, skin reactions occur relatively frequently which means
in about 10% of patients. Prescribing a high initial dose or increasing the dose too
fast can lead to an increase in frequency of skin reactions. When combined with
valproate, the lamotrigine starting dose must be particularly low, and the dose
increase should happen very slowly. The patient must be informed about the
possibility of potentially life-threatening skin reactions. Stevens-Johnson and
Lyell’s syndrome, nystagmus and conjunctivitis, confusion, hallucinations, as
well as neutropenia, leukopenia, and agranulocytosis occur relatively rarely during
lamotrigine treatment. For further information on specific side effects of
lamotrigine, see chapter ▶ “Mood Stabilizers: Lamotrigine.” Many studies have
found no association between lamotrigine exposure in utero and birth defects.
Systematic reviews indicate that overall rates of congenital malformations in
infants exposed to lamotrigine in utero are similar to the rate of malformations in
the general population. Breastfeeding is not recommended during treatment with
lamotrigine.
Special note: Quincke’s edema, Stevens-Johnson syndrome, and Lyell’s syn-
drome can be fatal. The patient should therefore be informed about early symptoms
before starting lamotrigine treatment. Treatment should start with a very low dose
and be up-titrated slowly. Skin reactions are rare with slow and careful dose
increases (Paulzen et al. 2019).
1458 H. Himmerich and A. Hamilton

Valproate: Common side effects of the central nervous system include drowsiness,
nausea, vomiting, tremor, and paresthesia. Occasionally, headache, irritability, hyper-
activity, confusion, stupor, spasticity, or ataxia may occur. Another frequent side effect
is hyperammonemia. Hypersalivation, weight gain or weight loss, diarrhea, and
hepatic problems including liver failure, pancreatitis, and pancreas damage are uncom-
mon but possible and serious adverse events. Rare events under valproate treatment
comprise peripheral edema, bleeding, and impaired bone marrow function including
aplasia, agranulocytosis, macrocytic anemia or macrocytosis, lupus erythematosus,
and erythema multiforme. Further possible but rare adverse drug effects include
disorders of the sexual organs such as dysmenorrhea or polycystic ovaries, temporary
hair loss, as well as Stevens-Johnson syndrome, Lyell’s syndrome, and reversible
hypothermia in isolated cases. In some studies, diminished bone density has been
detected after long-term administration of valproate. For further information on
specific side effects of valproate, see chapter ▶ “Mood Stabilizers: Valproate.”
Special note: When valproate is taken together with anticoagulants or anti-
aggregants, this may increase the risk of bleeding. Therefore, in these cases, it is
recommended to regularly monitor blood clotting. In high-risk patients who are
immobilized over long periods without sun exposure or low calcium intake, Vitamin
D substitution should be considered. Due to the risk of birth defects, pregnancy
should be excluded before starting treatment with valproate (Paulzen et al. 2019).
Asenapine: Very frequent side effects of asenapine are anxiety and somnolence.
Frequent side effects include appetite and weight gain, akathisia, dystonia, muscle
rigidity, dyskinesia, parkinsonism, sedation, fatigue, dizziness, taste disorders, oral
hypesthesia, and liver enzyme elevation. Occasionally, hyperglycemia, syncope,
dysarthria, seizures, prolonged QTc time, bundle branch block, hypotension, ortho-
stasis, swollen tongue, sexual dysfunction, amenorrhea, EPS, sinus bradycardia and
tachycardia, dysphagia, glossodynia, and oral paresthesia are seen. In rare cases,
neutropenia, accommodation disorders, malignant neuroleptic syndrome, rhabdo-
myolysis, pulmonary embolism, gynecomastia, galactorrhea, and sleepwalking have
been described (Müller and Benkert 2019). For further information on specific side
effects of asenapine, see chapter ▶ “Mood Stabilizers: Asenapine.”
Olanzapine: The risk of weight gain and metabolic syndrome is very high with
olanzapine treatment. However, beneficial psychotherapeutic, behavioral, and phar-
macological measures for the prevention and reduction of weight gain associated
with olanzapine have meanwhile been tested successfully.
Very frequent side effects of olanzapine include drowsiness, increased appetite
and weight gain, hyperprolactinemia, and orthostatic hypotension. Further adverse
effects frequently encountered are fatigue, asthenia, dizziness, akathisia, parkinson-
ism, dyskinesia, eosinophilia, leukopenia, neutropenia, increased glucose, triglycer-
ide, and cholesterol levels, glucosuria, transient elevation of liver enzymes, transient
anticholinergic effects such as constipation and dry mouth, rash, arthralgia, edema,
erectile dysfunction, decreased libido, and fever. Rare side effects are bradycardia,
QTc time prolongation, malignant neuroleptic syndrome, hepatitis including hepa-
tocellular or cholestatic liver damage, development or worsening of diabetes plus
accompanying ketoacidosis or coma, thrombocytopenia, hypothermia, pancreatitis,
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1459

ventricular tachycardia, rhabdomyolysis, priapism, and sleepwalking. For further

information on specific side effects of olanzapine, see chapter ▶ “Mood Stabilizers:
Olanzapin.”
When given parenterally, in about 2% of patients, postinjection syndrome can occur
with symptoms of olanzapine overdose, including severe sedation, coma or delirium,
confusion, disorientation, agitation, anxiety, other cognitive impairments, EPS, speech
disorders, ataxia, aggression, dizziness, weakness, hypertension, and seizures.
Special note: Attention must be paid to potential weight gain, dyslipidemia, and
diabetes (Himmerich et al. 2015; Müller and Benkert 2019).
Quetiapine: Very common side effects associated with quetiapine treatment are
dizziness, headache, somnolence, weight gain, dry mouth, increase in triglycerides
and LDL cholesterol, decrease in HDL cholesterol, decrease in hemoglobin, and
EPS. Frequent adverse effects include asthenia, irritability, nightmares, suicidal
thoughts and suicidal behavior, orthostatic hypotension, tachycardia, palpitations,
leukopenia, neutropenia, eosinophilia, liver enzyme elevations, hyperprolactinemia,
hyperglycemia, increased appetite, constipation, dyspepsia, blurred vision, edema,
hypothyroidism with a decrease in thyroid hormones T3 and T4, increase in TSH,
dysarthria, dyspnea, vomiting, and pyrexia. Occasionally, seizures, malignant neu-
roleptic syndrome, QTc time extension, diabetes mellitus, restless legs syndrome and
sexual dysfunctions, somnambulism and related conditions such as sleep talking and
sleep-related eating disorders, pancreatitis, rhabdomyolysis, menstrual disorders,
and hypothermia were reported. For further information on specific side effects of
quetiapine, see chapter ▶ “Mood Stabilizers: Quetiapine.”
Special note: Single cases of cardiomyopathy have recently been described.
Typical symptoms of cardiomyopathy are shortness of breath and peripheral
edema (Müller and Benkert 2019).
Risperidone: Very common side effects of risperidone are headache, insomnia,
sedation or somnolence, and EPS. Further frequent adverse effects include dizziness,
asthenia, agitation, tremor, dyskinesia, dystonia, arthralgia, increased prolactin,
increased or decreased appetite, gastrointestinal disturbances, abdominal pain,
diarrhea, constipation, dyspepsia, weight gain, dry mouth, tachycardia, fever, pneu-
monia, bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections,
conjunctivitis, ear infections, influenza, dyspnea, cough, constipation, blurred vision,
pharyngolaryngeal pain, chest pain, back pain, erythema, edema, akathisia, epistaxis,
rash, anxiety, sleep disorders, depression, fatigue, pain, hypertension, vomiting, nau-
sea, musculoskeletal pain, muscle spasms, urinary incontinence, and pyrexia (Müller
and Benkert 2019). For further information on specific side effects of risperidone, see
chapter ▶ “Mood Stabilizers: Risperidone for Treating Bipolar Disorders in Adults.”

Contraindications

General contraindications: When it comes to treatment with mood stabilizers

including lithium and antiepileptic and antipsychotic drugs, there are several impor-
tant general contraindications to be aware of. A known hypersensitivity to the
1460 H. Himmerich and A. Hamilton

corresponding chemical substance or ingredients used in the medication is one such

contraindication. Further contraindications are acute alcohol intoxication, sleeping
pills, analgesics, or other psychopharmacological agents, as well as severe distur-
bance of consciousness (Taylor et al. 2018; Benkert and Hippius 2019).
Lithium: Severe electrolyte disturbances, severe kidney dysfunction, disturbances
of the glomerular filtration, Addison’s disease, and severe cardiovascular diseases
are specific contraindications for lithium (Paulzen et al. 2019).
Antiepileptic drugs: Pre-existing bone marrow damage excludes treatment with
carbamazepine. As carbamazepine carries a risk of bone marrow toxicity, it must not
be combined with clozapine. There is also a certain risk of bone marrow toxicity with
valproate. In the case of coagulation disorders, extra care must be taken in those
patients undergoing treatment with valproate. Severe liver damage is a contraindi-
cation for treatment with carbamazepine and valproate, and lamotrigine should be
used with caution. Valproate must not be given to patients with pancreatitis or acute
intermittent porphyria, and this is also a contraindication for carbamazepine.
In treatment with antiepileptic drugs, caution is recommended in people with a
history of allergic skin reactions (Paulzen et al. 2019).
Antipsychotics: There are several principal contraindications and some clinical
conditions to be vigilant of when using antipsychotic medication. These contraindi-
cations and hazardous conditions include diseases of the hematopoietic system,
urination problems, narrow angle glaucoma, prostatic hyperplasia, myasthenia
gravis, pheochromocytoma, prolactin-dependent tumors, Parkinson’s disease, other
common ganglia diseases, epilepsy, organic brain damage, severe hepatic and renal
dysfunction, cardiac problems and disturbances of the cardiac rhythm including
long QT syndrome, and a history of malignant neuroleptic syndrome (Müller and
Benkert 2019).
On top of these contraindications and relative contraindications for antipsychotics
as a group, hyperthyroidism is a specific relative contraindication to asenapine.
Important further relative contraindications for olanzapine are diabetes or risk factors
for the development of diabetes, treatment with potentially hepatotoxic substances,
and orthostatic hypotension. Regarding quetiapine, extra care needs to be taken
when treating patients with known cardiovascular or cerebrovascular diseases and
disorders prone to hypotension. Risperidone should not be used as mood stabilizer in
people with Parkinson’s disease or prolactin-dependent tumors (Taylor et al. 2018;
Benkert and Hippius 2019).

Interactions

General considerations: Sedation is a common side effect of all mood stabilizers.

Therefore, they should all be used with caution when combined with other sedating
medications including antidepressants, antipsychotics, benzodiazepines, and in com-
bination with alcohol. This is especially true for the antipsychotic mood stabilizers
such as asenapine, olanzapine, quetiapine, and risperidone which can lead to QTc
time prolongation and possibly torsade de pointes; therefore, extra care should be
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1461

taken when combining those mood stabilizers with other medications that prolong
QTc time. If arterial hypotension occurs during treatment with the antipsychotics
olanzapine, quetiapine, or risperidone, it should not be treated with epinephrine but
norepinephrine, because of the risk of a further drop in blood pressure due to
a reverse epinephrine response. The effect of dopamine agonists such as bromocrip-
tine or L-dopa will be weakened under treatment with antidopaminergic medication
like the antipsychotic mood stabilizers.
Lithium: Lithium has interactions with other psychopharmacological agents but
also with drugs used for the treatment of physical diseases.
It has been discussed in the literature that monoamine oxidase inhibitors (MAOIs)
may potentially increase lithium plasma levels. Selective serotonin and norepineph-
rine reuptake inhibitors (SSNRIs), duloxetine and venlafaxine, have been reported to
possibly increase lithium-induced neurotoxicity. A severe and serious side effect
of such a combination is central serotonin syndrome. Tricyclic antidepressants
(TCA) can increase tremor. However, lithium has been reported to improve the
antidepressant efficacy of SSNRIs, duloxetine, venlafaxine, and TCAs, when used to
augment their antidepressant effect. According to the scientific literature, there is no
indication of a specific interaction between lithium and mirtazapine.
Lithium has been shown to increase side effects of antipsychotics including EPS
and sometimes neurotoxicity leading to electroencephalographic (EEG) abnormali-
ties, delirium, and convulsions. It also possibly increases the risk of malignant
neuroleptic syndrome. In very rare cases, irreversible movement disorders with
persistent EEG changes have been described. Lithium also increases the risk for
severe side effects including neurotoxicity of carbamazepine and phenytoin.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor
blockers (ARBs) amplify the side effects of lithium while having the potential to
increase its plasma concentration and thus increasing the risk of nephrotoxicity;
therefore, weekly lithium plasma concentration measurements are recommended in
the first 8 weeks of such combinations. Further drugs associated with an increase
of lithium plasma concentrations and thus lithium-induced side effects or toxicity
include antibiotics like ampicillin, tetracyclines, aminoglycosides, and metronida-
zole as well as certain nonsteroidal anti-inflammatory drugs (NSAIDs) such as
cyclooxygenase (COX)-2 inhibitors, calcium channel blockers, ketamine, and
methyl-dopamine. This is why it is recommended to measure lithium plasma levels
frequently. Lithium may attenuate the hypotensive effect of clonidine. If lithium is
delivered together with digoxin, the risk of arrhythmias is reinforced, but the
antimanic effect of lithium may be weakened. Diuretics such as thiazide diuretics
like hydrochlorothiazide, potassium-sparing diuretics like amiloride and triamterene,
as well as loop diuretics like furosemide decrease lithium renal clearance, posing the
risk of lithium toxicity. Acetazolamide, sodium bicarbonate, and methylxanthines
such as theophylline and caffeine lead to an increased lithium excretion with
decreased lithium plasma concentrations. Potassium iodide increases lithium’s
thyrostatic action. When used together with muscle relaxants such as pancuronium
and suxamethonium, lithium can lead to a prolonged neuromuscular blockade.
Lithium can mitigate the hypertensive effect of sympathomimetics. The use
1462 H. Himmerich and A. Hamilton

of alcohol alongside lithium treatment leads to increased cognitive impairment,

psychomotor retardation, and impaired responsiveness.
Carbamazepine: Carbamazepine must not be used in combination with poten-
tially bone marrow-toxic substances such as clozapine and TCAs, with MAOIs or
with voriconazole. Co-administration of SSRIs may lead to central serotonin syn-
drome. Caution is indicated in the combination of drugs which induce hyponatremia
such as SSRIs, venlafaxine, and diuretics because of the risk of the syndrome of
inappropriate antidiuretic hormone secretion (SIADH). Extra care should be taken
when combining carbamazepine with centrally attenuating psychotropic drugs or
when alcohol is simultaneously consumed due to decreased motor coordination and
impaired reactivity and responsiveness. Co-administration of levetiracetam may
increase the toxicity of carbamazepine.
The CYP3A4-inducing effect of carbamazepine is of importance. It can lead to
accelerated degradation of drugs that are substrates of CYP3A4, e.g., quetiapine,
midazolam, aripiprazole, and cyclosporine, which means these drugs exert a weaker
effect. After discontinuation of carbamazepine, plasma concentrations of these sub-
strates of CYP3A4 may increase which can lead to increased side effects and toxicity
of these medications. Caution is advised when carbamazepine is combined with
CYP3A4 inhibitors, such as erythromycin or ritonavir, as this can potentially
increase carbamazepine plasma concentration. Carbamazepine may decrease the
levels of paliperidone, risperidone, and methadone. Grapefruit juice raises
the bioavailability of carbamazepine by inhibiting CYP3A4.
Lamotrigine: The metabolism of lamotrigine is accelerated when used in combi-
nation with carbamazepine, ethinyl estradiol, phenobarbital, phenytoin, primidone,
or rifampicin. Therefore, these combinations should only be prescribed if plasma
levels can be monitored closely. Plasma levels of lamotrigine should also be regu-
larly measured if combined with valproate because valproate reduces the breakdown
of lamotrigine. Sertraline inhibits the key enzyme of the glucuronidation
of lamotrigine to lamotrigine 2-N-glucuronide, thereby potentially altering the
metabolic pathways used for its degradation. This process can lead to the formation
of the toxic intermediate aryl epoxide, which increases the risk of skin reactions.
A combination of lamotrigine and sertraline should therefore be avoided.
Contraceptives containing ethinyl estradiol should not be used, because ethinyl
estradiol induces a glucuronosyltransferase making the effective levels of
lamotrigine fall, and higher maintenance doses of lamotrigine may be required.
During the pill-free week, lamotrigine levels may increase drastically. If oral con-
traceptives containing ethinyl estradiol cannot be avoided, a continuous intake
without a pill-free week and with adjustment of the lamotrigine dose according to
plasma level is recommended to ensure a stable lamotrigine plasma level. A mono-
therapeutic contraception with a progestogen such as levonorgestrel, norethisterone,
or etonogestrel should be preferred. Women who need contraceptive protection
should avoid lamotrigine because of the complex pharmacokinetic interactions.
Valproate: The risk of seizures and other TCA side effects are increased when
using a combination of valproate with amitriptyline, desipramine, or nortriptyline.
This is because valproate influences the metabolism of TCAs via CYP2C9 and
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1463

CYP2C19 by increasing the drug levels of TCAs in the plasma. Concomitant use of
valproate and anticoagulants or antiaggregants like acetylsalicylic acid leads to an
increased bleeding tendency, which is why regular checks of blood coagulation
markers are recommended. Valproate inhibits the glucuronidation and thus the
degradation of lamotrigine. Lamotrigine, in turn, induces glucuronosyltransferases
and thus accelerates the metabolism of valproate. When combined with olanzapine,
it can cause both a drop and an increase in the plasma concentration of olanzapine
since valproate inhibits glucuronosyltransferases (UGTs) in the short term but
induces UGTs and CYP1A2 in the long term. When combined with enzyme-
inducing substances such as carbamazepine, imipenem, mefloquine, meropenem,
panipenem, phenytoin, primidone, or rifampicin, plasma levels of valproate should
be controlled regularly, as the levels may fall.
Asenapine: Asenapine is metabolized via CYP1A2. Therefore, when
co-administered with CYP1A2 inhibitors like fluvoxamine and ciprofloxacin, the
dose should be reduced. Smokers may need to have their dose increased, because of
induction of CYP1A2.
Olanzapine: When combined with valproate, treatment with olanzapine is asso-
ciated with an increased risk of thrombo-, leuko-, or neutrocytopenia. This combi-
nation with valproate can cause both a drop and an increase of the plasma
concentration of olanzapine, since valproate inhibits UGTs short term but induces
and UGTs and CYP1A2 long term. The combination should therefore only be used
with repeated measurements of plasma concentrations of olanzapine and valproate.
Extra care should be taken when combining olanzapine with inhibitors of CYP1A2,
e.g., fluvoxamine; this will lead to slowed down degradation and thus increase in
olanzapine plasma level. Smokers have on average 30% lower plasma concentra-
tions than non-smokers, and an increase in plasma concentration can be observed
during the week after termination of smoking.
Quetiapine: Beware of combinations with other medications that prolong the QTc
time or can lead to hypokalemia such as amiodarone, quinidine, chlorpromazine,
gatifloxacin, pentamidine, procainamide, methadone, moxifloxacin, thioridazine, or
ziprasidone. Quetiapine should not be combined with CYP3A4 inhibitors such as
clarithromycin and erythromycin, because this may lead to a five- to eightfold
increase in plasma concentrations of quetiapine. CYP3A4 inducers like carbamaz-
epine, phenytoin, or St. John’s wort lower the plasma level and lead to a possible loss
of the effect of quetiapine. Lamotrigine lowers quetiapine plasma levels most
probably by induction of glucuronidation. Therefore, in this combination, measure-
ment of quetiapine plasma levels and, if necessary, dose adjustments are necessary, if
lamotrigine is discontinued.
Risperidone: As risperidone is metabolized by CYP3A4 and CYP2D6, combi-
nation with carbamazepine or St. John’s wort preparations should happen alongside
close monitoring and control of plasma concentrations, because both substances
induce CYP3A4. When combined with CYP2D6 inhibitors like paroxetine or
terbinafine, an increase in risperidone plasma concentration and reduction in risper-
idone tolerability can be expected. Risperidone may enhance the effects
of antihypertensives.
1464 H. Himmerich and A. Hamilton

For further information and guidance related to drug interactions of mood

stabilizers, see the “Consensus Guidelines for Therapeutic Drug Monitoring in
Neuropsychopharmacology: Update 2017” (Hiemke et al. 2018), the Prescribing
Guidelines in Psychiatry (Taylor et al. 2018), and the Kompendium der
Psychiatrischen Pharmakotherapie (Benkert and Hippius 2019) which have also
been the main sources for this section.

Future Perspectives

Pharmacogenetic testing: Until recently, psychiatrists had little choice but to pre-
scribe medications without knowing in advance how their patients might genetically
respond. Pharmacogenetic testing, while not yet widely implemented in clinical
psychiatry, offers promising and exciting prospects for the future. It is assumed
that this technology can be implemented soon to predict therapeutic effects, potential
side effects, and drug interactions during therapy with psychopharmacological
agents such as mood stabilizers in an individual patient. One of the biggest barriers
to implementing this is the current lack of translation of evidence-based recommen-
dations and standardization of genetic testing panels. However, minimum gene and
allele sets for pharmacogenetic testing in psychiatry have been proposed. These sets
include cytochrome P450 enzymes as well as MHC genes like HLA-A (Bousman
et al. 2019).
Psychopharmacology of the gut-brain axis: Our knowledge about how the human
gut microbiome is involved in the development and regulation of physiological
systems is increasing, and evidence has accumulated to suggest a role for the gut
microbiome in drug response to psychopharmacological agents and the side effects
of psychiatric drug treatment (Kanji et al. 2018). However, the complex relationships
between the enteric nervous system, the gut microbiota, and the central nervous
system during psychiatric conditions and the mechanisms how the relations between
these systems are influenced by psychopharmacological agents are currently far from
being understood.
Inflammation and mood stabilizers: There is growing evidence that bipolar and
unipolar affective disorders are linked to changes within the immune system (Mao
et al. 2018). Additionally, mood stabilizers have been shown to modulate cytokine
signaling, for example, the interleukin (IL)-1β, IL-2, and IL-22 and tumor necrosis
factor (TNF)-α signaling pathways (Himmerich et al. 2013). Therefore, it seems
promising to abandon the relatively narrow pharmacological perspective that
predominantly looks at how neurotransmitter signaling is involved in the pathophys-
iology of psychiatric disorders and their therapy but to broaden the view to include
the signaling pathways of immune cells within the brain and the body such as
astrocytes, microglia, dendritic cells, macrophages, and T helper cells. This will
potentially help to explain side effects such as bone marrow toxicity with carbamaz-
epine; Stevens-Johnson syndrome and Lyell’s syndrome associated with
lamotrigine; liver failure or pancreatitis caused by valproate; swollen tongue from
asenapine; rhabdomyolysis caused by olanzapine; jaundice, angioedema, and
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1465

anaphylactic reactions with quetiapine; and an elevated risk of fever, pneumonia,

bronchitis, upper respiratory tract infections, sinusitis, and urinary tract infections
seen with risperidone treatment. All these inflammatory side effects of mood stabi-
lizers cannot be sufficiently explained by their potential to influence synaptic
monoaminergic neurotransmission or their neurophysiological properties.

Cross-References

▶ Mood Stabilizers: Asenapine

▶ Mood Stabilizers: Carbamazepine
▶ Mood Stabilizers: Lamotrigine
▶ Mood Stabilizers: Lithium
▶ Mood Stabilizers: Olanzapin
▶ Mood Stabilizers: Quetiapine
▶ Mood Stabilizers: Risperidone for Treating Bipolar Disorders in Adults
▶ Mood Stabilizers: Valproate

References
Arana A, Wentworth CE, Ayuso-Mateos JL, Arellano FM. Suicide-related events in patients treated
with antiepileptic drugs. N Engl J Med. 2010;363:542–51.
Benkert O, Hippius H. Kompendium der Psychiatrischen Pharmakotherapie. 12th ed. Heidelberg/
Berlin: Springer; 2019.
Błaszczyk B, Lasoń W, Czuczwar SJ. Antiepileptic drugs and adverse skin reactions: an update.
Pharmacol Rep. 2015;67:426–34.
Bostwick JR, Guthrie SK, Ellingrod VL. Antipsychotic-induced hyperprolactinemia.
Pharmacotherapy. 2009;29:64–73.
Bousman C, Maruf AA, Müller DJ. Towards the integration of pharmacogenetics in psychiatry:
a minimum, evidence-based genetic testing panel. Curr Opin Psychiatry. 2019;32:7–15.
Calabrò RS, Bramanti P. Carbamazepine-related sexual disorders: beyond hormonal changes! J Sex
Med. 2013;10:1440.
Can A, Schulze TG, Gould TD. Molecular actions and clinical pharmacogenetics of lithium therapy.
Pharmacol Biochem Behav. 2014;123:3–16.
Choi H, Morrell MJ. Review of lamotrigine and its clinical applications in epilepsy. Expert Opin
Pharmacother. 2003;4:243–51.
Chopko TC, Lindsley CW. Classics in chemical neuroscience: risperidone. ACS Chem Nerosci.
2018;9:1520–9.
Citrome L. Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and
metabolism. Expert Opin Drug Metab Toxicol. 2014;10:893–903.
Curtis BR. Drug-induced immune neutropenia/agranulocytosis. Immunohematology.
2014;30:95–101.
Dailey JW, Reith ME, Steidley KR, Milbrandt JC, Jobe PC. Carbamazepine-induced release of
serotonin from rat hippocampus in vitro. Epilepsia. 1998;39:1054–63.
Dineen R, Bogdanet D, Thompson D, Thompson CJ, Behan LA, McKay AP, Boran G, Wall C,
Gibney J, O’Keane V, Sherlock M. Endocrinopathies and renal outcomes in lithium therapy:
impact of lithium toxicity. QJM. 2017;110:821–7.
1466 H. Himmerich and A. Hamilton

Divac N, Prostran M, Jakovcevski I, Cerovac N. Second-generation antipsychotics and extrapyra-

midal adverse effects. Biomed Res Int. 2014;2014:656370.
Elnazer HY, Sampson A, Baldwin D. Lithium and sexual dysfunction: an under-researched area.
Hum Psychopharmacol. 2015;30:66–9.
Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G,
Egberts K, Gerlach M, Greiner C, Gründer G, Haen E, Havemann-Reinecke U, Hefner G,
Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T, Mössner R, Müller MJ, Paulzen M,
Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS,
Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G,
Zurek G, Baumann P. Consensus guidelines for therapeutic drug monitoring in neuropsycho-
pharmacology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Himmerich H, Koethe D, Schuld A, Yassouridis A, Pollmächer T. Plasma levels of leptin and
endogenous immune modulators during treatment with carbamazepine or lithium. Psychophar-
macology (Berl). 2005;179:447–51.
Himmerich H, Bartsch S, Hamer H, Mergl R, Schönherr J, Petersein C, Munzer A, Kirkby KC,
Bauer K, Sack U. Impact of mood stabilizers and antiepileptic drugs on cytokine production
in-vitro. J Psychiatr Res. 2013;47:1751–9.
Himmerich H, Minkwitz J, Kirkby KC. Weight gain and metabolic changes during treatment with
antipsychotics and antidepressants. Endocr Metab Immune Disord Drug Targets.
2015;15:252–60.
Jinhua W, Sawmiller D, Wheeldon B, Jun T. A review for lithium: pharmacokinetics, drug design
and toxicity. CNS Neurol Disord Drug Targets. 2019;18:769–78.
Kanji S, Fonseka TM, Marshe VS, Sriretnakumar V, Hahn MK, Müller DJ. The microbiome-gut-
brain axis: implications for schizophrenia and antipsychotic induced weight gain. Eur Arch
Psychiatry Clin Neurosci. 2018;268:3–15.
Latalova K, Kamaradova D, Prasko J. Suicide in bipolar disorder: a review. Psychiatr Danub.
2014;26:108–14.
Leon AC, Solomon DA, Li C, Fiedorowicz JG, Coryell WH, Endicott J, Keller MB. Antiepileptic
drugs for bipolar disorder and the risk of suicidal behavior: a 30-year observational study. Am J
Psychiatry. 2012;169:285–91.
Mao R, Zhang C, Chen J, Zhao G, Zhou R, Wang F, Xu J, Yang T, Su Y, Huang J, Wu Z, Cao L,
Wang Y, Hu Y, Yuan C, Yi Z, Hong W, Wang Z, Peng D, Fang Y. Different levels of pro- and
anti-inflammatory cytokines in patients with unipolar and bipolar depression. J Affect Disord.
2018;237:65–72.
Mehta N, Vannozzi R. Lithium-induced electrocardiographic changes: a complete review. Clin
Cardiol. 2017;40:1363–7.
Montejo AL, Montejo L, Navarro-Cremades F. Sexual side-effects of antidepressant and antipsy-
chotic drugs. Curr Opin Psychiatry. 2015;28:418–23.
Müller MJ, Benkert O. Antipsychotika. In: Benkert O, Hippius H, editors. Kompendium der
Psychiatrischen Pharmakotherapie. 12th ed. Heidelberg/Berlin: Springer; 2019. p. 284–504.
Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-
Diaz S. Lithium use in pregnancy and the risk of cardiac malformations. N Engl J Med.
2017;376:2245–54.
Paulzen M, Gründer G, Benkert O. Medikamente zur Behandlung bipolarer Störungen. In:
Benkert O, Hippius H, editors. Kompendium der Psychiatrischen Pharmakotherapie. 12th
ed. Heidelberg/Berlin: Springer; 2019. p. 209–83.
Ren M, Leng Y, Jeong M, Leeds PR, Chuang DM. Valproic acid reduces brain damage induced by
transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat
shock protein induction. J Neurochem. 2004;89:1358–67.
Rumble ME, White KH, Benca RM. Sleep disturbances in mood disorders. Psychiatr Clin North
Am. 2015;38:743–59.
Rybakowski JK. Effect of lithium on neurocognitive functioning. Curr Alzheimer Res.
2016;13:887–93.
Mood Stabilizers: Side Effects, Contraindications, and Interactions 1467

Severance EG, Prandovszky E, Castiglione J, Yolken RH. Gastroenterology issues in schizophre-

nia: why the gut matters. Curr Psychiatry Rep. 2015;17:27.
Stahl SM. Anticonvulsants as mood stabilizers and adjuncts to antipsychotics: valproate,
lamotrigine, carbamazepine, and oxcarbazepine and actions at voltage-gated sodium channels.
J Clin Psychiatry. 2004;65:738–9.
Sümegi A. Quetiapin in bipolar disorders. Neuropsychopharmacol Hung. 2008;10:281–91.
Taylor DM, Barnes TRE, Young AH. The Maudsley prescribing guidelines in psychiatry.
13th ed. Hoboken: Wiley; 2018.
Verrotti A, Mencaroni E, Cofini M, Castagnino M, Leo A, Russo E, Belcastro V. Valproic acid
metabolism and its consequences on sexual functions. Curr Drug Metab. 2016;17:573–81.
Weber J, McCormack PL. Asenapine. CNS Drugs. 2009;23:781–92.
Wiedemann K, Stüber T, Rehn M, Frieauff E. Fetal valproate syndrome – still a problem today!
Z Geburtshilfe Neonatol. 2017;221:243–6.
Wu CS, Tsai YT, Tsai HJ. Antipsychotic drugs and the risk of ventricular arrhythmia and/or sudden
cardiac death: a nation-wide case-crossover study. J Am Heart Assoc. 2015;4:e001568.
Zaccara G, Giovannelli F, Giorgi FS, Franco V, Gasparini S, Benedetto U. Tolerability of new
antiepileptic drugs: a network meta-analysis. Eur J Clin Pharmacol. 2017;73:811–7.
Mood Stabilizers: Course and Duration of
Therapy, Withdrawal Syndromes, and
Resistance to Therapy

Georgios Schoretsanitis and Michael Paulzen

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1471
Anti-convulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1471
Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1472
Antipsychotics (AP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473
Course and Duration of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475
Acute Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475
Mood Stabilizers for Manic Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1476
Mood Stabilizers for Depressive Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1477
Mood Stabilizers for Mixed Symptoms/Mixed Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1478
Mood Stabilizers for Agitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1479
Maintenance Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1480
Withdrawal Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1482
Anti-convulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483
Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483
Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1484
Resistance to Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1484
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1486

G. Schoretsanitis (*)
Psychiatry Research, The Zucker Hillside Hospital, New York, USA
e-mail: george.schor@gmail.com
M. Paulzen
Department of Psychiatry, Psychotherapy and Psychosomatics and JARA – Translational Brain
Medicine, RWTH Aachen University, Aachen, Germany
Alexianer Hospital Aachen, Aachen, Germany
e-mail: m.paulzen@alexianer.de

© Springer Nature Switzerland AG 2022 1469

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_39
1470 G. Schoretsanitis and M. Paulzen

Abstract
Despite different available pharmacological frameworks, mood stabilizers are
widely acknowledged as a group of agents prescribed in the treatment of bipolar
disorders. In this chapter we use an indication-based approach to describe acute and
maintenance treatment with mood stabilizers encompassing lithium, anti-convul-
sants, and antipsychotics in adult patients. Primary and secondary clinical evidence
as well established guidelines are reviewed focusing on the included agents.
Further, we elaborate on clinical manifestations related to the discontinuation of
mood stabilizers, although these drugs do not typically possess the potential for
withdrawal syndromes. Lastly, therapeutic options for treatment-refractory forms of
bipolar disorders including pharmacological and non-pharmacological interven-
tions are discussed. Summing up, the armamentarium of mood stabilizers has not
been essentially revised during the past decades; older agents still comprise a core
part of routine pharmacotherapy in bipolar disorders. However, prescription of
mood stabilizers remains a tricky business, and clinicians need to develop a
comprehensive understanding of profiles of action and adverse drug reactions in
order to enhance efficacy and safety.

Abbreviations
5-HT Serotonin
ADR Adverse drug-induced reaction
AP Antipsychotic treatment
BP-I Bipolar I disorder
CANMAT Canadian Network for Mood and Anxiety Treatments
CYP Cytochrome P450
ECT Electroconvulsive therapy
EMA European Medicines Agency
ER Extended-release
FDA US Food and Drug Administration
FGA First-generation antipsychotics
GABA Gamma-aminobutyric acid
GSK-3 Glycogen synthase kinase 3
HDAC Histone deacetylase
IR Immediate-release
ISBD International Society for Bipolar Disorders
LAI Long-acting injectable
P-gp P-Glycoprotein
PKC Protein kinase C
RAI Rapid-acting injectable
SGA Second-generation antipsychotics
TMS Transcranial magnetic stimulation
UGT Uridine 50 -diphospho-glucuronosyltransferase
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1471

Introduction

There is no unanimously accepted definition for mood stabilizers, and the clinical
utility of this category or classification may be disputed (Malhi et al. 2018). In fact,
there is not a distinct pattern of common properties for the agents we may refer to as
mood stabilizers other than their application in the treatment of bipolar disorders.
This approach reproduces a clear indication-based nomenclature (Zohar et al. 2015).
In fact, the group of mood stabilizers encompasses medications of strikingly hetero-
geneous pharmacologic profiles, originally introduced for utterly different indica-
tions. By trying to narrow the definition of mood stabilizers, groups or classes of
drugs, such as antidepressants, that have been included in guidelines over the years
(Nierenberg et al. 2006) are no longer suggested for the treatment of bipolar
disorders without a concomitantly applied mood stabilizer. Another corollary of
this issue is that mood stabilizers are not exclusively prescribed for bipolar disorders
but may be used in terms of off-label therapeutic regimens in other psychiatric
diseases as well (Fond et al. 2018; Crawford et al. 2018; Rajaratnam et al. 2017).
The scope of this chapter is to review evidence for compounds that are used in the
treatment of bipolar disorders in adults foregoing a rigorous definition of mood
stabilizers. We focus on medications holding approval from the US Food and Drug
Administration, FDA, or the European Medicines Agency, EMA, for the treatment
of bipolar disorders. Agents with approval for bipolar disorders in children or
adolescents will not be discussed in this chapter.
An established classification of mood stabilizers follows the pharmacological class of
these drugs: (1) a subset of anti-convulsants, (2) lithium, and (3) antipsychotics (AP).
Following an alternative perspective, we may classify these agents based on the polarity
index (Popovic et al. 2012); this newly introduced concept is based on antimanic and/or
antidepressant preventive properties of mood stabilizers prescribed in maintenance
treatment of bipolar disorders. According to this classification, at one pole of the polarity
index, the anti-convulsant lamotrigine is the unique agent with relapse-preventing
properties in bipolar disorders with predominantly depressive episodes, whereas on
the other side, risperidone long-acting injectable (LAI) and aripiprazole display pro-
nounced antimanic properties. Another conceptualization framework is integrating
knowledge about distinct properties of different drugs targeting acute symptoms or
addressing prophylactic properties (Malhi et al. 2018). This elaborate four-domain
model (antimanic vs. antidepressant and acute vs. maintenance) aims to assist clinicians
during the decision-making process by considering additional treatment aspects.

Anti-convulsants

Anti-convulsants with an FDA approval for bipolar disorders include valproate or

valproic acid, lamotrigine, and carbamazepine. Originally introduced as an anti-
convulsant, valproate affects the GABA metabolism (Chateauvieux et al. 2010),
while additional pathways of action may include inhibition of PKC, GSK-3, and
1472 G. Schoretsanitis and M. Paulzen

HDAC. Nevertheless, the precise mechanisms of action remain only partially under-
stood, and current knowledge predominantly derives from in vitro models. Compa-
rably undiscovered is the pharmacokinetics of valproate, which is mainly
metabolized via UGT1A3, UGT1A6, and UGT2B7, but also via CYP2A6,
CYP2B6, CYP2C9, CYP2C19, and by β-oxidation. Furthermore, valproate slightly
inhibits cytochrome P450 (CYP) 2C9 as well as other isoenzymes with clinical
effects remaining unclear. Valproate is particularly efficacious for acute mania
(Bowden et al. 1994), for which it holds an approval from FDA in both available
forms, valproic acid and divalproex (a stable coordination compound comprised of
sodium valproate and valproic acid). The latter is the enteric-coated counterpart of
the first and may be better tolerable (Schwartz et al. 2000).
Lamotrigine is a second-generation anti-convulsant presumably acting on sodium
channels. Its main metabolic pathway is a glucuronidation catalyzed by uridine
diphosphate-glucuronosyltransferase 1A4 (UGT1A4) leading to its major metabolite,
lamotrigine-2-N-glucuronide (Paulzen et al. 2018). Lamotrigine shows antidepressant
properties in the treatment of major depressive disorder; however, its approval is only
in maintenance treatment for the prophylaxis of depressive episodes in bipolar disorder
when depressive episodes are predominant. Since lamotrigine was reported to be of
low teratogenic risk, there has been a shift in prescription patterns of anti-convulsants
in pregnant women with lamotrigine now being the most commonly prescribed anti-
convulsant or mood-stabilizing drug (Petersen et al. 2016).
The third anti-convulsant approved for patients with bipolar disorders is carba-
mazepine. Its primarily CYP3A4/5- and CYP2C8-based metabolic pathway (Hata et
al. 2008) leads to carbamazepine 10,11-epoxide, which also possesses anti-convul-
sant activity. Like other mood stabilizers, carbamazepine acts at sodium channels in
terms of its anti-convulsant action, whereas its mood-stabilizing properties may be
based on inositol-signaling mechanisms. Its extended-release (ER) form holds
approval for the treatment of acute mania. The prescription of carbamazepine usually
introduces a challenge for clinicians due to its high potential for pharmacokinetic
interactions, with carbamazepine acting as a strong inductor mainly on CYP3A4 and
P-glycoprotein (P-gp) (Schoretsanitis et al. 2016).
In the course of the past decades, some other anti-convulsant agents have also
been prescribed as mood stabilizers: levetiracetam, topiramate, tiagabine,
gabapentin, zonisamide, and oxcarbazepine have received considerable attention.
Notwithstanding, the evidence displaying a considerable effect for these drugs is still
lacking, and therefore, these therapeutic regimens remain off-label.

Lithium

Introduced in psychiatry almost 70 years ago (Cade 1949), lithium is probably the
mood stabilizer with the longest clinical application and still the reference drug in the
treatment of bipolar disorders. The mechanisms of action for this prototypical mood
stabilizer have been investigated better than any other agent from this group. Lithium
seems to share common pathways with valproate (Harwood and Agam 2003); modes
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1473

of action include neuroprotective properties based on BDNF as well as an inhibition

of PKC and GSK-3. Moreover, the effects of lithium on second messenger systems
have also received attention, and the so-called inositol depletion hypothesis explains
at least partially some of its effects on free inositol and calcium mobilization
intracellularly (Williams et al. 2002). As lithium is excreted unmetabolized via the
kidneys, a sufficient renal function is highly required under a treatment with lithium.
Lithium holds approval for manic episodes as well as for the maintenance treatment
and is the only substance with antisuicidal properties.

Antipsychotics (AP)

According to recent pharmacoepidemiological data, the prescription of antipsychotics,

in particular second-generation antipsychotics (SGA), for patients with bipolar disor-
ders massively increased in the past years (Kessing et al. 2016; Hayes et al. 2011). In
these terms, the concept of mood stabilizers may include drugs out of the class of SGA
as well. FDA approval for the treatment of bipolar disorder is held by the following
antipsychotics (in alphabetical order) – aripiprazole, asenapine, cariprazine, chlor-
promazine, haloperidol, loxapine, lurasidone, olanzapine, quetiapine, risperidone,
and ziprasidone – although more agents from this pharmacological class may be
prescribed off-label in patients with bipolar disorders.
Unlike the majority of antipsychotics, aripiprazole offers a particular pharmaco-
dynamic profile with partial dopamine D2-receptor agonism (GrÜnder et al. 2003).
The CYP2D6- and CYP3A4-mediated metabolism of aripiprazole leads to various
metabolites with the major metabolite, dehydroaripiprazole, being pharmacologi-
cally active. FDA indications include acute mania as well as maintenance treatment.
The long-acting injectable form of aripiprazole (once monthly) also holds approval
for maintenance treatment of BP-I since 2017. Moreover, there is a rapid-acting
intramuscular injectable form of aripiprazole with the indication of agitation associ-
ated with bipolar mania (Citrome 2007).
Asenapine shows particular affinity for serotoninergic antagonism apart from its
antidopaminergic effects. Fast-dissolving sublingual tablets enable an oral mucosal
absorption, overcoming absorption limitations due to extensive first-pass metabo-
lism of asenapine (Citrome 2011).
The most recently released drug of this class is cariprazine, which got approved
for bipolar disorders in 2015. It shares the profile of a partial dopamine agonist with
aripiprazole, with particularly high affinity for dopamine D3-receptors. Cariprazine
undergoes hepatic metabolism mediated by CYP3A4 and CYP2D6 with active
metabolites possessing clinically relevant properties (Mauri et al. 2018). A special
characteristic of cariprazine refers to its strikingly long half-life, the longest across
oral antipsychotics (Hiemke et al. 2018), which may be of profit for patients with
compliance issues. Its indication is acute mania.
On the other hand, chlorpromazine, a first-generation antipsychotic (FGA) with
FDA approval for the treatment of bipolar disorders and, in particular, manic
episodes, has been instrumental in the development of psychopharmacological
1474 G. Schoretsanitis and M. Paulzen

research in the past decades. After almost 70 years, it is still prescribed, though in
smaller numbers than in the past. It possesses affinity for a large group of receptors, but
its primary effect is considered the dopaminergic antagonism. Its main metabolic
pathway comprises a 7-hydroxylation catalyzed by CYP2D6 and partially by
CYP1A2 (Yoshii et al. 2000). Another FGA, probably the most widely prescribed,
haloperidol, is approved by the EMA, but not the FDA for acute mania. Haloperidol is a
high-affinity D2-receptor antagonist and has various metabolic pathways involving
CYP2D6 and CYP3A4 as well as UGT. The most usual adverse effect related to
haloperidol treatment is extrapyramidal symptoms. Across the agents described in this
section, loxapine is the only drug that is delivered in an inhalable application form and
holds approval for agitation in schizophrenia or bipolar disorder. Although being
originally classified as an FGA, it has been debated that it mainly acts as a SGA with
moderate affinity for D1- and D2-dopamine as well as 5-HT2-receptors (Glazer 1999).
The application device of the drug leads to rapid absorption via inhalation of the agent,
which is then hepatically metabolized through CYP1A2, CYP3A4, and CYP2D6.
Slightly deviating from the principle of dopaminergic antagonism for antipsy-
chotics, lurasidone has a high affinity for D2-receptors, but does not bind to D4-
receptors, which has been suggested as contributing to procognitive effects (Murai et
al. 2014). The hepatic metabolism of lurasidone involves CYP3A4 with metabolites
lacking clinical relevance. Due to its reasonable safety profile, lurasidone may
qualify as a reliable option in treatment of older patients (Vasudev et al. 2018).
Also noteworthy is that its indications are depressive episodes.
One of the first SGAs entering the market was olanzapine, which is approved for
bipolar disorders as monotherapy or augmentation to lithium or valproate. It has
been also approved in the treatment of bipolar disorders in combination with
fluoxetine, although this product has been available only limited to several countries.
Mainly metabolized by CYP1A2, olanzapine acts on the dopaminergic system, but
also displays a considerable affinity for histaminic receptors. This affinity may
explain the propensity of olanzapine to cause metabolic abnormalities, which in
turn is the major complication of olanzapine-based maintenance treatment
(Schoretsanitis et al. 2018b). The rapid-acting injectable form of olanzapine holds
approval for acute agitation in bipolar disorders.
Very similar to olanzapine is quetiapine in terms of its chemical structure.
Quetiapine is marketed in two pharmacokinetically distinct forms, as an immediate-
and as an extended-release formulation, and is metabolized by CYP3A4 leading to
multiple metabolites, which barely contribute to psychotropic effects (Mauri et al.
2018). Its action might rather relate to serotonergic antagonism, whereas
quetiapine’s affinity for D2-receptors is low. Quetiapine holds indication for acute
treatment of manic episodes as monotherapy or as an adjunctive treatment to lithium
or valproate, acute treatment of depressive episodes, and maintenance treatment (as
monotherapy or combined with lithium or valproate).
Risperidone is a benzisoxazole derivative acting on both serotonergic and dopa-
minergic neurotransmitter systems. Its metabolic pathways include CYP2D6 and
CYP3A4, and the active metabolite, 9-hydroxyrisperidone, displays approximately
70% of the pharmacological activity of the parent compound. For risperidone, the
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1475

LAI formulation has been also approved as monotherapy or adjunctive therapy for
maintenance treatment of bipolar I disorder (BP-I).
Lastly, ziprasidone is a SGA with approval for acute manic or mixed episodes of
bipolar disorders. It antagonizes D2- and 5-HT2A-receptors and is highly metabo-
lized following multiple oxidations. Patients under ziprasidone-based treatment may
be at risk for QTc prolongation, and therefore, monitoring is suggested.
Apart from the FDA-approved antipsychotics for the treatment of bipolar disor-
ders, there is pharmacoepidemiological data for other antipsychotics as well
(LÄhteenvuo et al. 2018). Although off-label, pharmacological interventions may
be very effective; as these agents do not hold approval for bipolar disorders,
clinicians need to proceed with caution.

Course and Duration of Treatment

The indications for mood stabilizers include acute and maintenance treatment of
bipolar disorders. It is plausible that these two types of treatment options introduce
quintessentially different challenges for clinicians, as they differ in terms of goal,
course, and duration. The propensity of bipolar episode to changes regarding the
polarity and the severity of the symptoms introduces additional challenges for
clinicians. A typical pitfall in the management of bipolar episodes is the prescription
of agents, which may effectively treat depressive symptoms at the expense of
inducing manic symptoms (Salvadore et al. 2010). In fact, the heterogeneity of the
action profiles for the various mood stabilizers furthermore sets obstacles for pre-
scribers. For instance, some of these medications are starkly efficacious in amelio-
rating acute mania, but do not possess antidepressant properties, whereas other
agents reduce the risk of reoccurrence of mood symptoms, but are ineffective in
the treatment of acute episodes. Therefore, clinicians need to be highly aware of the
risk for rapid changes in psychopathology, while a more comprehensive understand-
ing of treatment options will facilitate improvement of treatment outcomes.

Acute Treatment

Clinicians would claim that the most characteristic acute bipolar presentation referred
for treatment is manic states, but symptom clusters may also include hypomanic,
depressive, or mixed states (Table 1).
The following agents hold FDA approval for acute treatment: aripiprazole (oral
and rapid-acting injection), asenapine (as monotherapy or adjunctive to lithium or
valproate), carbamazepine, cariprazine, chlorpromazine, lithium, olanzapine (oral as
monotherapy, adjunctive to fluoxetine, lithium or valproate and rapid-acting injec-
tion), quetiapine (as monotherapy or adjunctive to lithium or valproate), risperidone
(oral as monotherapy or adjunctive to lithium or valproate and long-acting),
valproate, and ziprasidone. Haloperidol is approved for the indication of mania by
the EMA, but not the FDA.
1476 G. Schoretsanitis and M. Paulzen

Table 1 Medications with FDA indication for acute treatment of bipolar disorders
Drugs Mania Mixed Depression
Aripiprazole √ √ x
Asenapine √ √ x
Asenapine + lithium/valproate √ √ x
Carbamazepine ER √ √ x
Cariprazine √ √ x
Chlorpromazine √ x x
Divalproex sodium √ √ x
Haloperidol √a x x
Lithium (ER and IR) √ x x
Lurasidone x x √
Lurasidone + lithium/valproate x x √
Olanzapine √ √ x
Olanzapine + fluoxetine x x √
Olanzapine + lithium/valproate √ √ x
Quetiapine IR √ x √
Quetiapine IR + lithium/valproate √ x x
Quetiapine ER √ √ √
Quetiapine ER + lithium/valproate √ √ x
Risperidone √ √ x
Risperidone + lithium/valproate √ √ x
Valproic acid √ √ x
Ziprasidone √ √ x
FDA US Food and Drug Administration, EMA European Medicines Agency, ER extended-release,
IR immediate-release
a
Approved by the EMA, but not the FDA

Mood Stabilizers for Manic Symptoms

Lithium remains the most intensively studied agent in the treatment of bipolar
disorders over the last years. It is the only mood stabilizer with antisuicidal effects
and is widely embraced as the mainstay of treatment for patients with suicidal
ideation. Therapeutic drug monitoring of lithium concentrations is an inherent part
of a treatment with lithium. Measuring blood concentrations enables clinicians to
minimize toxicity and enhance treatment efficacy, even for drugs with narrow
therapeutic windows. For patients with acute manic episodes, lithium concentrations
ranging between 0.6 and 1.0 mmol/l are suggested (Malhi et al. 2016). Early partial
response to lithium may predict remission of manic symptoms (Machado-Vieira et
al. 2013). For patients not responding to lithium, anti-convulsants, i.e., valproate and
carbamazepine, may offer efficacious treatment alternatives (Grunze et al. 2009). In
particular, patients with psychotic features or rapid cycling may profit from
lamotrigine or valproate (Lieberman and Tasman 2006). These patients may also
respond to carbamazepine when not responding to lithium. As valproate and
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1477

carbamazepine seem to share a profile of action, clinicians may consider profiles of

related ADRs in order to decide between them. Clinical evidence highlights the role
of antipsychotics in the treatment of manic episodes. Olanzapine and risperidone do
not only effectively ameliorate mania; both drugs are also very well tolerable
compared to other mood stabilizers (Cipriani et al. 2011). Cipriani and colleagues
furthermore reported pronounced antimanic effects for haloperidol in the same
network meta-analysis. The mean duration for the analyzed pharmacological inter-
ventions was 3.4 weeks.
In fact, time to remission/or response presents another valuable aspect when
addressing acute mania. The speed of onset for effects may differ between antipsy-
chotics and other mood stabilizers (Ogawa et al. 2014): a comparative analysis of
olanzapine vs. valproate yielded a median time to remission of 14 days for
olanzapine over 62 days for valproate (Zhu et al. 2005). When assessing time to
response, meta-analytical data highlighted a faster onset for haloperidol compared to
SGAs (Goikolea et al. 2013). Newer primary evidence reported a rapid onset of
antimanic action for asenapine as well (Buoli et al. 2017).
The joint CANMAT and ISBD Bipolar Treatment Guidelines suggest asenapine,
aripiprazole, cariprazine, divalproex, lithium, paliperidone, quetiapine, and risperi-
done as first-line monotherapy for acute mania (Yatham et al. 2018). This hierarchy
is based on both efficacy and tolerability profiles of mood stabilizers. Response rates
are estimated around 50% of patients within a month of antimanic treatment. This
implies that a considerable percentage of patients will not respond; after 2 weeks of
lacking response, clinicians may need to switch or add other mood stabilizers to an
ongoing treatment. Combined therapeutic regimens including aripiprazole,
asenapine, valproate/divalproex, lithium, quetiapine, and risperidone are particularly
indicated for patients with more severe symptoms. In fact, comparative trials dem-
onstrate superior efficacy for a combination of anti-convulsants/lithium with SGA
over monotherapy (Ogawa et al. 2014). Nevertheless, augmentation strategies may
be also more burdensome, and clinicians need to be aware of ADRs (Galling et al.
2015). In fact, some of these strategies remain off-label. Therefore, it may be
beneficial to keep in mind the FDA-approved therapeutic regimens.

Mood Stabilizers for Depressive Symptoms

Clinicians have been barely aware of the clinical and neurobiological differences
between unipolar and bipolar depression, and the treatment of depressive presentations
either as unipolar depressive episodes or as bipolar depression has been less extensively
investigated compared to acute mania. The FDA has provided approval only for three
agents, i.e., quetiapine, lurasidone, and the combination of olanzapine and fluoxetine
for acute depressive episodes. The antidepressant effect of quetiapine is dose-indepen-
dent, at least over 300 mg daily (Yatham et al. 2018). For lurasidone, clinicians may
consider its reasonable safety profile and, therefore, a valuable role in the treatment of
acute depression in older patients (Sajatovic et al. 2016). Although evidence for
olanzapine as monotherapy in acute bipolar depression is equivocal, the combination
1478 G. Schoretsanitis and M. Paulzen

of olanzapine and fluoxetine holds FDA approval. The prescription of this therapeutic
regimen may be limited through tolerability issues (Silva et al. 2013), as fluoxetine does
not seem to reverse the metabolic effects of olanzapine (Bustillo et al. 2003).
Apart from the approved agents, there is robust evidence for some more com-
pounds in terms of off-label therapies. As previously mentioned, lithium is a first-
line medication for patients with suicidal ideations. When prescribed for depressive
patients, lithium concentrations in the patient’s blood are suggested to be in a range
between 0.4 and 0.8 mmol/l (Malhi et al. 2016). Valproate may be also considered
when first-line agents fail to be effective (Yatham et al. 2018). Furthermore, a recent
meta-analysis implies a potential benefit for a subset of antidepressants as an add-on
therapy in the short term, whereas long-term prescription contributes to the risk of
treatment emergent affective switches into mania or hypomania (Mcgirr et al. 2016).
The criterion of early response, i.e., response to an agent within 2 weeks, applies in
the treatment of acute depression as well.

Mood Stabilizers for Mixed Symptoms/Mixed Features

Apart from the unipolar or pure forms of mood symptom clusters such as manic or
depressive episodes, clinicians may also encounter mixed states related to bipolar
disorders. According to the nomenclature of the Diagnostic and Statistical Manual of
Mental Disorders, 5th revision, DSM-5, the former description of “mixed symptoms”
has been changed into “with mixed features.” Presentations of mixed features are
frequently trickier to recognize and even more complicated to efficiently treat. Mixed
features may be frequently misclassified as manic or depressive presentations and often
receive less recognition as a distinct clinical pattern. However, reservations need to be
made, as the clinical practice and wisdom from the other two bipolar presentations
cannot be carried to mixed states. Nevertheless, it is no surprise that the armamentarium
of approved mood stabilizers with effects on mixed states looks very similar to the
group of agents approved for manic symptoms; exceptions regard chlorpromazine,
lithium, and the immediate-release form of quetiapine (as monotherapy or adjunctive),
which only hold approval for manic symptoms, but not for mixed states.
The reasons underlying these exceptions may relate to marketing issues. How-
ever, for lithium, it is of particular interest that it is, indeed, considered less
efficacious for patients with mixed features (Swann et al. 1997). Notwithstanding,
as patients with mixed features may display an enhanced propensity to switch from
depressive to manic symptoms and back (Fornaro et al. 2018), lithium may be
considered, though in combination with other mood stabilizers. The WFSBP Guide-
lines primarily suggest olanzapine as monotherapy or in combination for the treat-
ment of manic syndromes with mixed features, with aripiprazole monotherapy as a
second-line option (Grunze et al. 2018). The role of SGAs for mixed features is also
highlighted by the CANMAT guidelines (Yatham et al. 2018). These guidelines do
not only include approved agents but also antipsychotics that are prescribed off-label
such as paliperidone, which is suggested as first-line monotherapy for manic symp-
toms in acute episodes with mixed features.
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1479

In terms of the decision-making process, clinicians also need to take additional

clinical aspects into account; for example, comorbidities such as substance disorders,
to which patients with mixed states may be more prone. Further, for more severe
presentations, combinations of SGAs with lithium or valproate may have superior
effects over monotherapy (Verdolini et al. 2018). Nevertheless, clinicians need to
proceed with caution, particularly in highly vulnerable patients, given the burden of
combinations of mood stabilizers.

Mood Stabilizers for Agitation

In bipolar disorders, acute agitation can be gauged grounded on the psychopatholog-

ical basis of manic phases, although it can also occur in depressive presentations.
There are several aspects that highlight the unique challenges for the management of
acute agitation, also referred to as rapid tranquillization. Medications licensed for
agitation related to bipolar disorders include aripiprazole, loxapine, and olanzapine.
Although two of these agents for acute agitation are available in intramuscular
formulations (aripiprazole and olanzapine), they should be only applied in terms of
escalation protocols, which begin with proposing oral medications (Gonzalez et al.
2013). These pharmacotherapies cannot be strictly referred to as mood stabilizers as
they are unspecifically prescribed, i.e., for diagnosis-independent rapid tranquil-
lization. In other words, these agents are also used for agitation related to schizophre-
nia. Moreover, they do not hold approval for any other bipolar presentation. Thus,
someone would easily argue against the attempt to include these drugs into the group
of mood stabilizers. In the same direction, analyses addressing efficacy of pharmaco-
logical interventions for agitation may pool data for patients with schizophrenia and
bipolar disorders (Dundar et al. 2016; San et al. 2018), and specific evidence for
agitation in patients with bipolar disorders is quantitatively and qualitatively limited.
Contrastingly, the pharmacotherapy for other bipolar presentations, e.g., the
treatment of acute agitation, refers to a very short time frame because agitation
reflects even more severe manifestations and is directly linked to risks for a patient
himself/herself and/or others. The time to respond, i.e., time to reduce agitation,
ranges from minutes to a maximum of an hour following the application of the
medication (Table 2).

Table 2 Medications with FDA indication for acute agitation

Drugs Application route t1/2
Aripiprazole RAI Intramuscular 75
Haloperidola Intramuscular 21
Loxapine Inhalation 6–8
Olanzapine RAI Intramuscular 30
Half-life provided in hours. FDA US Food and Drug Administration, RAI rapid-acting injectable, t1/2
half-life
a
Approved by the EMA, but not the FDA
1480 G. Schoretsanitis and M. Paulzen

Across the licensed agents, loxapine offers a less invasive alternative to injectable
medications, because it is applied as an inhalation powder. The therapeutic outcome
may be dose-dependent, and 10 mg loxapine may counter agitation symptoms more
successfully than 5 mg (Dundar et al. 2016). A recent study directly compared up to
two doses of 9.1 mg inhaled loxapine with a single intramuscular aripiprazole
injection for agitation in a mixed sample of patients with schizophrenia or bipolar
disorders (San et al. 2018). The comparison favored loxapine for all assessments
during 24 h after drug administration. Lastly, rapid-acting intramuscular injectable
olanzapine is also approved for agitation in bipolar disorders. Comparative analyses
highlighted the superiority of olanzapine in reducing agitation symptoms 1 h after
application (Dundar et al. 2016).
Apart from the approved agents, there is also data that supports the application of
some additional psychotropic drugs. For instance, intramuscular lorazepam has been
reported as equally efficacious as olanzapine (Meehan et al. 2001) and is also
suggested as first-line treatment for the management of agitation by the CANMAT
(Yatham et al. 2018). The same guidelines include across second-line options
asenapine, haloperidol (as monotherapy or in combination), risperidone, and
ziprasidone, for which previous primary data has provided support (Baldacara et
al. 2011). Data analyzing different agents than asenapine may be less easy to
interpret as they mainly derive from samples with mixed diagnoses. Nevertheless,
asenapine and risperidone offer oral treatment options, which may be preferred over
intramuscular routes for milder forms of agitation (Garriga et al. 2016).

Maintenance Treatment

The prescription of mood stabilizers in the long-term or maintenance treatment

differs from the acute phase treatment. In the phase following recovery from acute
episodes, mood stabilizers should ideally demonstrate prophylactic properties, that
is, the extension of euthymic periods and an ongoing reduction of symptoms of acute
episodes. Maintenance treatment for bipolar disorders may frequently be a lifelong
treatment and, thus, presents multifaceted pitfalls and challenges for treating physi-
cians. These complexities relate to the course of the bipolar disorder over the years
on the one hand and the potentially occurring long-term adverse effects of the
prescribed agents on the other hand. Nevertheless, available data from randomized
clinical trials do not extend over 2 years. Furthermore, a major limitation refers to a
considerable selection bias reported in many maintenance treatment trials, as study
participants are usually already stabilized patients and the challenge of transition
from acute to maintenance treatment remains unaddressed.
Medications holding FDA approval for maintenance treatment of bipolar disor-
ders include aripiprazole (oral and LAI), asenapine, lamotrigine, lithium, olanzapine,
quetiapine in adjunction to lithium or valproate, risperidone LAI (as monotherapy or
adjunctive to lithium or valproate), and ziprasidone in combination with lithium or
valproate. Lithium is considered the first-line maintenance option and long-term
naturalistic data highlight its superior efficacy (Goodwin et al. 2016; LÄhteenvuo et
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1481

Table 3 Medications with FDA indication for maintenance treatment

Drugs
Oral LAI
Aripiprazole Aripiprazole ER LAI
Asenapine Risperidone LAI
Lamotrigine Risperidone LAI + lithium/valproate
Lithium (IR and ER)
Olanzapine
Quetiapine (IR and ER) + lithium/valproate
Ziprasidone + lithium/valproate
ER extended-release, FDA US Food and Drug Administration, IR immediate-release, LAI long-
acting injectable

al. 2018). Nevertheless, lithium may be less efficacious in patients with a history of
substance abuse (Maj 2003), probably because these patients are more likely to
relapse into depression (Kemp et al. 2009). Combinations of agents may be consid-
ered for patients that did not benefit from monotherapy (Table 3).
When choosing across the various psychotropic agents, clinicians also need to
take into account the patient’s risk for depressive or manic episodes. For instance,
lamotrigine and quetiapine may be more efficacious in preventing depressive epi-
sodes on the one hand (Popovic et al. 2012; Grunze et al. 2013). On the other hand,
risperidone LAI, aripiprazole, lithium, and ziprasidone are more successful in
preventing manic episodes (Yatham et al. 2018; Li et al. 2017). Data for olanzapine
is rather equivocal (Pan et al. 2014; Popovic et al. 2012). Apart from the number (or
severity) of new episodes, time to recurrence of mood episodes presents an addi-
tional valuable measure for clinicians when assessing efficacy of mood stabilizers in
maintenance treatment. For instance, time to recurrence in olanzapine-medicated
patients was longer than in risperidone LAI-medicated patients, while it was longer
for quetiapine compared to lithium (Grunze et al. 2013). Although more comparative
trials have been conducted, differences between mood stabilizers have been fre-
quently nonsignificant. Perhaps, this is due to pooling of depressive and manic
episodes when investigating time to recurrence for mood stabilizers.
In the literature, there is also some support for a few off-label treatments. Various
international guidelines encompass valproate across first-line pharmacotherapies
(Yatham et al. 2018; Goodwin et al. 2016). The marketer company has pursued
approval of valproate in the European Union, but has been rejected due to lack of
placebo-controlled studies (EMA 2011). Moreover, there may be some place for
other LAI agents apart from risperidone and aripiprazole; in a large naturalistic trial
long-acting injections were associated with lower risk of psychiatric hospitalizations
(LÄhteenvuo et al. 2018). The effects of perphenazine and haloperidol LAI essen-
tially contributed to these findings. The evidence for LAI agents indirectly highlights
the role of compliance in recurrence of mood episodes. Further, there is a single trial
reporting prophylactic properties for manic episodes for oral paliperidone
(Berwaerts et al. 2012), while a naturalistic small cohort study reported encouraging
1482 G. Schoretsanitis and M. Paulzen

results for patients stabilized and continued on the middle-term with lurasidone
(Schaffer et al. 2016). Last, the BAP guidelines describe carbamazepine across
long-term treatments particularly for patients not responding to lithium (Goodwin
et al. 2016).
The prescription of mood stabilizers for long periods confers lifelong vulnera-
bility for adverse mood stabilizer-induced drug reactions. There is a variety of
ADRs depending on the individual safety profile of the prescribed agent, although
combinations of mood stabilizers are in general more burdensome (Galling et al.
2015). Chronic treatment with lithium poses a potential risk of acute or chronic
nephrotoxicity, so that regular monitor schedules are necessary, although data
about potentially toxic effects of lithium on renal function remain inconsistent.
For long-term lithium treatment, recommended plasma levels range between 0.6
and 0.8 mmol/l (Malhi et al. 2016). Many of the mood stabilizers and in particular
antipsychotics are linked to metabolic abnormalities in a dose- and treatment
duration-independent way (Bak et al. 2014). For patients at high risk for a
metabolic syndrome, agents such as aripiprazole and ziprasidone may be treatment
of choice in using antipsychotics, whereas olanzapine and quetiapine should only
be considered, when all other options are excluded. As women may be at higher
risk for the hyperprolactinemia sequelae, they may be good candidates for partial
dopamine agonists, when AP treatment is considered; aripiprazole (and in Europe
off-label cariprazine) may be less prone in inducing hyperprolactinemia compared
to other AP. For the majority of the mood stabilizers, data for teratogenic risk is
barely available. However, there is an increasing consensus regarding the terato-
genic potential of valproate, so that it should be avoided in women of reproductive
age or pregnant patients (Patel et al. 2018). Valproate may be also not the first-line
treatment for patients with hepatic deficits. In this subgroup of patients, long-acting
agents may be indicated as they display a limited first-pass metabolism
(Schoretsanitis et al. 2018a). Another particularly vulnerable patient subgroup
includes elderly patients. There is a dearth of evidence for the safety and efficacy
issues in these individuals. However, post hoc data support off-label prescription
of lurasidone in elderly patients, while open-label data support asenapine and
aripiprazole as well (Vasudev et al. 2018).

Withdrawal Syndromes

Withdrawal syndromes in the treatment with mood stabilizers invariably refer to

bipolar rebound phenomena after discontinuation or dose reduction. They may occur
in a prolonged time frame over months compared to the traditional definition of
withdrawal symptoms, although rapid bipolar recurrence has also been reported for
lithium. For lithium monotherapy, there is a plethora of available data, as this
syndrome was firstly observed and investigated for lithium. Data regarding other
mood stabilizers is very limited.
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1483

Anti-convulsants

Reports of withdrawal syndromes after anti-convulsant discontinuation describe

enhanced recurrence rates of mood episodes for valproate and lamotrigine in small
cohorts (Newport et al. 2008; Sharma et al. 2014). In some cases, the interpretation of
clinical data may be hampered by polypharmacy (Franks et al. 2008). For instance, in a
cohort of pregnant patients, discontinuation of anti-convulsants was a common strat-
egy (Viguera et al. 2007); however, as patients were mainly treated with more than one
psychotropic agent, withdrawal effects were less easy to evaluate. In particular,
valproate withdrawal was not accompanied by rebound phenomena in a trial where
patients were co-medicated with lithium (Kemp et al. 2009).
Discontinuation of carbamazepine has been less frequently reported leading to the
recurrence of mood episodes. However, carbamazepine withdrawal introduces differ-
ent types of challenges. These complications result from the inducing properties of
carbamazepine on the activity of CYP1A2 and CYP3A4, which catalyze the metab-
olism of numerous psychotropic agents including mood stabilizers (Schoretsanitis et
al. 2016). Once carbamazepine is discontinued, the blood levels of co-prescribed
agents will considerably increase, as loss of enzymatic induction takes place in the
following 3 weeks. Loss of induction may take shorter for CYP3A4 than CYP1A2
substrates (De Leon 2012). Expected symptoms depend on the co-prescribed agents
and are likely to be more severe in patients with polypharmacy.

Lithium

Lithium is the prototypic substance for which bipolar rebound phenomena have been
described and investigated during the past decades. Research has addressed short-
and long-term effects of the discontinuation of lithium monotherapy. Researchers
have also acknowledged recurrence due to the natural course of bipolar disorders,
which poses difficulties in disentangling the inherent relapse risk of bipolar disorders
from lithium discontinuation effects.
Lithium discontinuation may at first support the remission of lithium-induced
adverse reactions (Christodoulou and Lykouras 1982), but has also been linked to
early recurrence of bipolar episodes with an enhanced risk within the first weeks
after discontinuation (Verdoux and Bourgeois 1993). In fact, the frequency of mood
episodes in patients with discontinued treatment was comparable to the frequency in
unmedicated patients. Abrupt versus gradual discontinuation of lithium may
enhance the risk of early recurrence (Suppes et al. 1993). There have also been
reports of psychotic states following lithium withdrawal (Klein et al. 1981). Patients
relapsing during discontinuation are less responsive to lithium in case of a
reintroduction of lithium (Cakir et al. 2017). Actually, this is an old notion postu-
lating that patients who discontinued lithium more than once develop a lithium-
refractoriness. However, it is uneasy to clarify if this effect is tolerance effect
1484 G. Schoretsanitis and M. Paulzen

reported in patients with uninterrupted lithium treatment as well or relates to lithium

discontinuation and the debate is still ongoing (De Vries et al. 2013). Although not
strictly classified as withdrawal symptom, one has to note that lithium discontinua-
tion is also related to an increased mortality with implicated mechanisms potentially
involving suicidality (Dunner 1998). Summing up, lithium discontinuation is widely
accepted nowadays to precipitate bipolar rebound recurrences.

Antipsychotics

Discontinuation symptoms have been mainly described for antipsychotics in samples of

patients with schizophrenia. They include supersensitivity rebound psychosis and
various mixed symptoms (Chouinard and Chouinard 2008), while reports of movement
disorders are also available. Data regarding withdrawal symptoms after discontinuation
of antipsychotics in bipolar disorders are less robust with only few exceptions. More-
over, polypharmacy and co-medication with other mood stabilizers in many samples
raise plausible concerns for interpretation (Franks et al. 2008). Across licensed agents,
patients with aripiprazole LAI monotherapy discontinuing treatment suffered from
higher rates of reoccurring mood episodes compared to patients that were consistently
under aripiprazole LAI (Calabrese et al. 2017). There is also a rare case report of oral
low-dose aripiprazole treatment in an elderly patient with a dysthymic disorder, the
experience of which may be extrapolated to bipolar disorders (Sansone and Sawyer
2013); despite the long half-life of aripiprazole, this patient developed depressive
symptoms within 2 days post-discontinuation. In a small cohort of AP-treated patients,
one patient receiving oral risperidone and lithium showed psychotic symptoms after
risperidone withdrawal (Saksa et al. 2004). Furthermore, a retrospective review of
patients receiving olanzapine plus lithium or anti-convulsants gradually discontinuing
olanzapine reported a mean time of 1.9 months to relapse following olanzapine with-
drawal (ARORA and Praharaj 2014). This time interval may be more likely to be
attributed to the olanzapine discontinuation than the course of the bipolar disorder. No
rebound phenomena have been described for discontinuation of the FGAs perphenazine
and haloperidol (Saksa et al. 2004). In fact, the prescription of perphenazine was
associated with a shorter time to relapse in patients receiving simultaneously anti-
convulsants or lithium (Zarate and Tohen 2004). Contrasting to this data, in another
small cohort of patients medicated with FGAs, patients relapsed into depression after
FGA discontinuation (Hendrick et al. 1994). However, these agents do not hold
approval for maintenance treatment for bipolar disorders and patients stabilized under
FGAs are consequently moved to mood stabilizers on the middle and long term.

Resistance to Therapy

Resistance to therapy with mood stabilizers reflects a very serious problem with a
high burden given its strikingly high prevalence (Geddes and Miklowitz 2013).
When mood stabilizers do not work, clinicians may extrapolate their clinical
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1485

experience from refractory major depression; this strategy may be of success, but
also hides considerable traps. Before activating their knowledge for treatment-
resistant major depression, prescribers need to exhaust evidence-based options for
bipolar disorders (Goodwin et al. 2016). In fact, adherence has to be assessed,
because it is a common problem in these patients (LECLERC et al. 2013). In
treatment-refractory bipolar depression, clinicians may consider lamotrigine,
which might have positive effects on depressive symptoms (Nierenberg et al.
2006). In principle, combinations of agents are more likely to be effective than
monotherapies (Galling et al. 2015). Therefore, for patients not responding to a
mood stabilizer treatment, augmenting with a second mood stabilizer offers a
reasonable second step. Nevertheless, the decision-making algorithm is restricted
to an offering of additionally reliable options for patients not responding to a
combination of mood stabilizers.
There are two treatment options that have consistently received attention by the
majority of established guidelines, whereas there may be some space for novel
therapies as well. First, modern guidelines place electroconvulsive therapy (ECT)
across options when patients do not respond to first- or second-line therapies
(Fountoulakis et al. 2017; Goodwin et al. 2016; Yatham et al. 2018). However, a
randomized clinical trial for ECT in treatment-refractory was not available till
recently; Schoeyen and colleagues reported larger reduction in depressive symptoms
and higher response rates for patients receiving ECT for 6 weeks compared to
patients allocated to algorithm-based pharmacological treatment (Schoeyen et al.
2015). Older data had previously implied that continuation as well as maintenance
ECT may accelerate treatment response (Sikdar et al. 1994). Second, based on the
superiority of clozapine over every other pharmacotherapy in schizophrenia,
research has expanded on its application in affective disorders with encouraging
results. Nevertheless, a controlled trial for treatment-refractory bipolar disorder is yet
to be conducted. Guidelines consider clozapine as monotherapy or adjunctive for
patients not responding to mood stabilizers (Yatham et al. 2018; Goodwin et al.
2016; Grunze et al. 2009). When prescribed in patients with bipolar disorders,
clozapine may need to be titrated slower than in other patients (Calabrese et al.
1996). Clinical improvement is likely to be observed within 2 months from cloza-
pine initiation (Green et al. 2000), and the presence of psychotic features did not
predict treatment outcome (Suppes et al. 1999).
Literature provides some evidence for additional options in treatment-refractory
bipolar disorders. These encompass pharmacological and non-pharmacological inter-
ventions. Data for agents such as pramipexole, memantine, and pregabalin show
efficacy in small samples, but need further support by studies with larger groups of
patients (Goodwin et al. 2016; Hui Poon et al. 2015). Antidepressants also introduce a
plausible approach, specifically for treatment-resistant bipolar depressive episodes.
Furthermore, the enormous excitement for ketamine has pushed researchers and
clinicians to use it for treatment-resistant bipolar disorder. Meta-analytical data report
drastic short-term reduction of depressive symptoms and suicidal ideation after a
single-dose of intravenous ketamine (Parsaik et al. 2015); however, as in unipolar
depression, these effects are limited through their short duration. Lastly, there may be a
1486 G. Schoretsanitis and M. Paulzen

role for thyroid replacement therapies for these patients. A recent trial investigating
patients with rapid cycling bipolar disorder reinvigorated the interest for the link
between bipolar disorders and thyroid economy (Walshaw et al. 2018).
Research has also addressed the effects of non-pharmacological treatments such
as stimulation-modulation therapies. Repetitive transcranial magnetic stimulation
(TMS) for depressive episodes has received considerable interest, although data
often derive from mixed samples (unipolar and bipolar depression). Trials have
failed to highlight its role as add-on to pharmacotherapy (Hu et al. 2016; Fitzgerald
et al. 2016). However, a particular modality of TMS, known as deep TMS, applying
a different type of coil was recently shown to be efficacious for treatment-resistant
bipolar depression with treatment response being twofold higher than in placebo
(Tavares et al. 2017). Data for vagal nerve stimulation has not been encouraging.
Future research activity needs to address many questions regarding standardization
of these processes, before they enter clinical routine.

References
Arora M, Praharaj SK. Olanzapine discontinuation emergent recurrence in bipolar disorder. Indian J
Psychol Med. 2014;36:170–3.
Bak M, Fransen A, Janssen J, Van Os J, Drukker M. Almost all antipsychotics result in weight gain:
a meta-analysis. PLoS One. 2014;9:e94112.
Baldacara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in
emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus
promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr.
2011;33:30–9.
Berwaerts J, Melkote R, Nuamah I, Lim P. A randomized, placebo- and active-controlled study of
paliperidone extended-release as maintenance treatment in patients with bipolar I disorder after
an acute manic or mixed episode. J Affect Disord. 2012;138:247–58.
Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis JM,
Rush AJ, Small JG, Al E. Efficacy of divalproex vs lithium and placebo in the treatment of
mania. The Depakote Mania Study Group. JAMA. 1994;271:918–24.
Buoli M, Esposito CM, Godio M, Caldiroli A, Serati M, Altamura AC. Have antipsychotics a
different speed of action in the acute treatment of mania? A single-blind comparative study.
J Psychopharmacol. 2017;31:1537–43.
Bustillo JR, Lauriello J, Parker K, Hammond R, Rowland L, Bogenschutz M, Keith S. Treatment of
weight gain with fluoxetine in olanzapine-treated schizophrenic outpatients. Neuropsychophar-
macology. 2003;28:527–9.
Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2:349–52.
Cakir S, Yazici O, Post RM. Decreased responsiveness following lithium discontinuation in bipolar
disorder: a naturalistic observation study. Psychiatry Res. 2017;247:305–9.
Calabrese JR, Kimmel SE, Woyshville MJ, Rapport DJ, Faust CJ, Thompson PA, Meltzer HY.
Clozapine for treatment-refractory mania. Am J Psychiatry. 1996;153:759–64.
Calabrese JR, Sanchez R, Jin N, Amatniek J, Cox K, Johnson B, Perry P, Hertel P, Such P, Salzman
PM, Mcquade RD, Nyilas M, Carson WH. Efficacy and safety of Aripiprazole once-monthly in
the maintenance treatment of bipolar I disorder: a double-blind, placebo-controlled, 52-week
randomized withdrawal study. J Clin Psychiatry. 2017;78:324–31.
Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and
toxicity of valproic acid. J Biomed Biotechnol. 2010;2010. https://doi.org/10.1155/2010/
479364.
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1487

Chouinard G, Chouinard VA. Atypical antipsychotics: CATIE study, drug-induced movement

disorder and resulting iatrogenic psychiatric-like symptoms, supersensitivity rebound psychosis
and withdrawal discontinuation syndromes. Psychother Psychosom. 2008;77:69–77.
Christodoulou GN, Lykouras EP. Abrupt lithium discontinuation in manic-depressive patients. Acta
Psychiatr Scand. 1982;65:310–4.
Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin
GM, Geddes JR. Comparative efficacy and acceptability of antimanic drugs in acute mania: a
multiple-treatments meta-analysis. Lancet. 2011;378:1306–15.
Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a
quantitative review of efficacy and safety. J Clin Psychiatry. 2007;68:1876–85.
Citrome L. Role of sublingual asenapine in treatment of schizophrenia. Neuropsychiatr Dis Treat.
2011;7:325–39.
Crawford MJ, Sanatinia R, Barrett B, Cunningham G, Dale O, Ganguli P, Lawrence-Smith G,
Leeson V, Lemonsky F, Lykomitrou G, Montgomery AA, Morriss R, Munjiza J, Paton C,
Skorodzien I, Singh V, Tan W, Tyrer P, Reilly JG, Team LS. The clinical effectiveness and cost-
effectiveness of lamotrigine in borderline personality disorder: a randomized placebo-controlled
trial. Am J Psychiatry. 2018;175:756–64.
De Leon J. A practitioner’s guide to prescribing carbamazepine for adults with intellectual disabil-
ities. In: De Leon J, editor. A practitioner’s guide to prescribing antiepileptics and mood
stabilizers for adults with intellectual disabilities. New York/Dordrecht/Heidelberg/London:
Springer; 2012.
De Vries C, Van Bergen A, Regeer EJ, Benthem E, Kupka RW, Boks MP. The effectiveness of
restarted lithium treatment after discontinuation: reviewing the evidence for discontinuation-
induced refractoriness. Bipolar Disord. 2013;15:645–9.
Dundar Y, Greenhalgh J, Richardson M, Dwan K. Pharmacological treatment of acute agitation
associated with psychotic and bipolar disorder: a systematic review and meta-analysis. Hum
Psychopharmacol. 2016;31:268–85.
Dunner DL. Lithium carbonate: maintenance studies and consequences of withdrawal. J Clin
Psychiatry. 1998;59(Suppl 6):48–55; discussion 56.
EMA. Questions and answers on the review of medicines containing valproate for use in bipolar
disorder. 2011. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/refer
rals/Valproate/human_referral_000187.jsp. Accessed 16 Sept 2018.
Fitzgerald PB, Hoy KE, Elliot D, McQueen S, Wambeek LE, Daskalakis ZJ. A negative double-
blind controlled trial of sequential bilateral rTMS in the treatment of bipolar depression. J Affect
Disord. 2016;198:158–62.
Fond G, Tinland A, Boucekine M, Girard V, Loubiere S, Auquier P, Boyer L, French Housing First
Study G. Prescription of potentially inappropriate psychotropic drugs in homeless people with
schizophrenia and bipolar disorders. Results from the French Housing First (FHF) program.
Prog Neuropsychopharmacol Biol Psychiatry. 2018;89:84–9.
Fornaro M, Anastasia A, Monaco F, Novello S, Fusco A, Iasevoli F, De Berardis D, Veronese N,
Solmi M, De Bartolomeis A. Clinical and psychopathological features associated with treat-
ment-emergent mania in bipolar-II depressed outpatients exposed to antidepressants. J Affect
Disord. 2018;234:131–8.
Fountoulakis KN, Yatham L, Grunze H, Vieta E, Young A, Blier P, Kasper S, Moeller HJ. The
International College of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar
disorder in adults (CINP-BD-2017), part 2: review, grading of the evidence and a precise
algorithm. Int J Neuropsychopharmacol. 2017;20:121–79.
Franks M, Macritchie KA, Mahmood T, Young AH. Bouncing back: is the bipolar rebound
phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol.
2008;22:452–6.
Galling B, Garcia MA, Osuchukwu U, Hagi K, Correll CU. Safety and tolerability of antipsychotic-
mood stabilizer co-treatment in the management of acute bipolar disorder: results from a
systematic review and exploratory meta-analysis. Expert Opin Drug Saf. 2015;14:1181–99.
1488 G. Schoretsanitis and M. Paulzen

Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, Baldacara L, San L,
McAllister-Williams RH, Fountoulakis KN, Courtet P, Naber D, Chan EW, Fagiolini A, Moller
HJ, Grunze H, Llorca PM, Jaffe RL, Yatham LN, Hidalgo-Mazzei D, Passamar M, Messer T,
Bernardo M, Vieta E. Assessment and management of agitation in psychiatry: expert consensus.
World J Biol Psychiatry. 2016;17:86–128.
Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381:1672–82.
Glazer WM. Does loxapine have “atypical” properties? Clinical evidence. J Clin Psychiatry.
1999;60(Suppl 10):42–6.
Goikolea JM, Colom F, Capapey J, Torres I, Valenti M, Grande I, Undurraga J, Vieta E. Faster onset of
antimanic action with haloperidol compared to second-generation antipsychotics. A meta-analysis
of randomized clinical trials in acute mania. Eur Neuropsychopharmacol. 2013;23:305–16.
Gonzalez D, Bienroth M, Curtis V, Debenham M, Jones S, Pitsi D, George M. Consensus statement
on the use of intramuscular aripiprazole for the rapid control of agitation in bipolar mania and
schizophrenia. Curr Med Res Opin. 2013;29:241–50.
Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, Coghill DR, Fazel S,
Geddes JR, Grunze H, Holmes EA, Howes O, Hudson S, Hunt N, Jones I, Macmillan IC,
McAllister-Williams H, Miklowitz DR, Morriss R, Munafo M, Paton C, Saharkian BJ, Saunders
K, Sinclair J, Taylor D, Vieta E, Young AH. Evidence-based guidelines for treating bipolar
disorder: revised third edition recommendations from the British Association for Psychophar-
macology. J Psychopharmacol. 2016;30:495–553.
Green AI, Tohen M, Patel JK, Banov M, Durand C, Berman I, Chang H, Zarate C Jr, Posener J, Lee
H, Dawson R, Richards C, Cole JO, Schatzberg AF. Clozapine in the treatment of refractory
psychotic mania. Am J Psychiatry. 2000;157:982–6.
GrÜnder G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not
just antagonism. Arch Gen Psychiatry. 2003;60:974–7.
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Azorin JM, Yatham L, Mosolov S, Moller
HJ, Kasper S, Members of the WFSBP Task Force on Bipolar Affective Disorders Working on
this topic. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for
the Biological Treatment of Bipolar Disorders: acute and long-term treatment of mixed states in
bipolar disorder. World J Biol Psychiatry. 2018;19:2–58.
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, Kasper S. The World
Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treat-
ment of bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry.
2009;10:85–116.
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, Kasper S, Disorders
WTFOTGFB. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines
for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of
bipolar disorder. World J Biol Psychiatry. 2013;14:154–219.
Harwood AJ, Agam G. Search for a common mechanism of mood stabilizers. Biochem Pharmacol.
2003;66:179–89.
Hata M, Tanaka Y, Kyoda N, Osakabe T, Yuki H, Ishii I, Kitada M, Neya S, Hoshino T. An
epoxidation mechanism of carbamazepine by CYP3A4. Bioorg Med Chem. 2008;16:5134–48.
Hayes J, Prah P, Nazareth I, King M, Walters K, Petersen I, Osborn D. Prescribing trends in bipolar
disorder: cohort study in the United Kingdom THIN primary care database 1995-2009. PLoS
One. 2011;6:e28725.
Hendrick V, Altshuler LL, Szuba MP. Is there a role for neuroleptics in bipolar depression? J Clin
Psychiatry. 1994;55:533–5.
Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts
K, Gerlach M, Greiner C, GrÜnder G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R,
Janssen G, Jaquenoud E, Laux G, Messer T, Mossner R, Muller MJ, Paulzen M, Pfuhlmann B,
Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B,
Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G,
Baumann P. Consensus guidelines for therapeutic drug monitoring in neuropsychophar-
macology: update 2017. Pharmacopsychiatry. 2018;51:9–62.
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1489

Hu SH, Lai JB, Xu DR, Qi HL, Peterson BS, Bao AM, Hu CC, Huang ML, Chen JK, Wei N, Hu JB,
Li SL, Zhou WH, Xu WJ, Xu Y. Efficacy of repetitive transcranial magnetic stimulation with
quetiapine in treating bipolar II depression: a randomized, double-blinded, control study. Sci
Rep. 2016;6:30537.
Hui Poon S, Sim K, Baldessarini RJ. Pharmacological approaches for treatment-resistant bipolar
disorder. Curr Neuropharmacol. 2015;13:592–604.
Kemp DE, Gao K, Ganocy SJ, Elhaj O, Bilali SR, Conroy C, Findling RL, Calabrese JR. A 6-
month, double-blind, maintenance trial of lithium monotherapy versus the combination of
lithium and divalproex for rapid-cycling bipolar disorder and co-occurring substance abuse or
dependence. J Clin Psychiatry. 2009;70:113–21.
Kessing LV, Vradi E, Andersen PK. Nationwide and population-based prescription patterns in
bipolar disorder. Bipolar Disord. 2016;18:174–82.
Klein HE, Broucek B, Greil W. Lithium withdrawal triggers psychotic states. Br J Psychiatry.
1981;139:255–6.
LÄhteenvuo M, Tanskanen A, Taipale H, Hoti F, Vattulainen P, Vieta E, Tiihonen J. Real-world
effectiveness of pharmacologic treatments for the prevention of rehospitalization in a Finnish
nationwide cohort of patients with bipolar disorder. JAMA Psychiatry. 2018;75:347–55.
LECLERC E, Mansur RB, Brietzke E. Determinants of adherence to treatment in bipolar disorder: a
comprehensive review. J Affect Disord. 2013;149:247–52.
Li DJ, Tseng PT, Stubbs B, Chu CS, Chang HY, Vieta E, Fornaro M, Carvalho AF, Solmi M,
Veronese N, Chen TY, Chen YW, Lin PY, Chow PC. Efficacy, safety and tolerability of
aripiprazole in bipolar disorder: an updated systematic review and meta-analysis of randomized
controlled trials. Prog Neuro-Psychopharmacol Biol Psychiatry. 2017;79:289–301.
Lieberman JA, Tasman A. Handbook of psychiatric drugs. West Sussex: Wiley; 2006.
Machado-Vieira R, Luckenbaugh DA, Soeiro-De-Souza MG, Marca G, Henter ID, Busnello JV,
Gattaz WF, Zarate CA Jr. Early improvement with lithium in classic mania and its association
with later response. J Affect Disord. 2013;144:160–4.
Maj M. The effect of lithium in bipolar disorder: a review of recent research evidence. Bipolar
Disord. 2003;5:180–8.
Malhi GS, Gershon S, Outhred T. Lithiumeter: version 2.0. Bipolar Disord. 2016;18:631–41.
Malhi GS, Porter R, Irwin L, Hamilton A, Morris G, Bassett D, Baune BT, Boyce P, Hopwood MJ,
Mulder R, Parker G, Mannie Z, Outhred T, Das P, Singh AB. Defining a mood stabiliser: novel
framework for research and clinical practice. BJPsych Open. 2018;4:278–81.
Mauri MC, Paletta S, Di Pace C, Reggiori A, Cirnigliaro G, Valli I, Altamura AC. Clinical
pharmacokinetics of atypical antipsychotics: an update. Clin Pharmacokinet. 2018;58(9):1217–8.
Mcgirr A, Vohringer PA, Ghaemi SN, Lam RW, Yatham LN. Safety and efficacy of adjunctive
second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in
acute bipolar depression: a systematic review and meta-analysis of randomised placebo-con-
trolled trials. Lancet Psychiatry. 2016;3:1138–46.
Meehan K, Zhang F, David S, Tohen M, Janicak P, Small J, Koch M, Rizk R, Walker D, Tran P,
Breier A. A double-blind, randomized comparison of the efficacy and safety of intramuscular
injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed
with bipolar mania. J Clin Psychopharmacol. 2001;21:389–97.
Murai T, Nakako T, Ikeda K, Ikejiri M, Ishiyama T, Taiji M. Lack of dopamine D4 receptor affinity
contributes to the procognitive effect of lurasidone. Behav Brain Res. 2014;261:26–30.
Newport DJ, Stowe ZN, Viguera AC, Calamaras MR, Juric S, Knight B, Pennell PB, Baldessarini
RJ. Lamotrigine in bipolar disorder: efficacy during pregnancy. Bipolar Disord. 2008;10:432–6.
Nierenberg AA, Ostacher MJ, Calabrese JR, Ketter TA, Marangell LB, Miklowitz DJ, Miyahara S,
Bauer MS, Thase ME, Wisniewski SR, Sachs GS. Treatment-resistant bipolar depression: a
STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with
lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163:210–6.
Ogawa Y, Tajika A, Takeshima N, Hayasaka Y, Furukawa TA. Mood stabilizers and antipsychotics
for acute mania: a systematic review and meta-analysis of combination/augmentation therapy
versus monotherapy. CNS Drugs. 2014;28:989–1003.
1490 G. Schoretsanitis and M. Paulzen

Pan PY, Lee MS, Lo MC, Yang EL, Yeh CB. Olanzapine is superior to lamotrigine in the prevention
of bipolar depression: a naturalistic observational study. BMC Psychiatry. 2014;14:145.
Parsaik AK, Singh B, Khosh-Chashm D, Mascarenhas SS. Efficacy of ketamine in bipolar
depression: systematic review and meta-analysis. J Psychiatr Pract. 2015;21:427–35.
Patel N, Viguera AC, Baldessarini RJ. Mood-stabilizing anticonvulsants, spina bifida, and folate
supplementation: commentary. J Clin Psychopharmacol. 2018;38:7–10.
Paulzen M, Stingl J, Augustin M, Saßmannshausen H, Franz C, GrÜnder G, Schoretsanitis G.
Comprehensive measurements of intrauterine and postnatal exposure to lamotrigine. Clin
Pharmacokinet. 2018;58(4):535–43.
Petersen I, McCrea RL, Sammon CJ, Osborn DP, Evans SJ, Cowen PJ, Freemantle N, Nazareth I.
Risks and benefits of psychotropic medication in pregnancy: cohort studies based on UK
electronic primary care health records. Health Technol Assess. 2016;20:1–176.
Popovic D, Reinares M, Goikolea JM, Bonnin CM, Gonzalez-Pinto A, Vieta E. Polarity index of
pharmacological agents used for maintenance treatment of bipolar disorder. Eur Neuropsycho-
pharmacol. 2012;22:339–46.
Rajaratnam K, Xiang YT, Tripathi A, Chiu HF, Si TM, Chee KY, Avasthi A, Grover S, Chong MY,
Kuga H, Kanba S, He YL, Lee MS, Yang SY, Udomratn P, Kallivayalil RA, Tanra AJ, Maramis
MM, Shen WW, Sartorius N, Kua EH, Tan CH, Mahendran R, Shinfuku N, Sum MY,
Baldessarini RJ, Sim K. Clinical use of mood stabilizers with antidepressants in Asia: report
from the research on Asian psychotropic prescription patterns for antidepressants (REAP-AD)
projects in 2004 and 2013. J Clin Psychopharmacol. 2017;37:255–9.
Sajatovic M, Forester BP, Tsai J, Kroger H, Pikalov A, Cucchiaro J, Loebel A. Efficacy of
Lurasidone in adults aged 55 years and older with bipolar depression: post hoc analysis of 2
double-blind, placebo-controlled studies. J Clin Psychiatry. 2016;77:e1324–31.
Saksa JR, Baker CB, Woods SW. Mood-stabilizer-maintained, remitted bipolar patients: taper and
discontinuation of adjunctive antipsychotic medication. Gen Hosp Psychiatry. 2004;26:233–6.
Salvadore G, Quiroz JA, Machado-Vieira R, Henter ID, Manji HK, Zarate CA Jr. The neurobiology
of the switch process in bipolar disorder: a review. J Clin Psychiatry. 2010;71:1488–501.
San L, Estrada G, Oudovenko N, Montanes F, Dobrovolskaya N, Bukhanovskaya O, Popov M,
Vieta E. Placid study: a randomized trial comparing the efficacy and safety of inhaled loxapine
versus intramuscular aripiprazole in acutely agitated patients with schizophrenia or bipolar
disorder. Eur Neuropsychopharmacol. 2018;28:710–8.
Sansone RA, Sawyer RJ. Aripiprazole withdrawal: a case report. Innov Clin Neurosci.
2013;10:10–2.
Schaffer CB, Schaffer LC, Nordahl TE, Stark NM, Gohring CE. An open trial of Lurasidone as an
acute and maintenance adjunctive treatment for outpatients with treatment-resistant bipolar
disorder. J Clin Psychopharmacol. 2016;36:88–9.
Schoeyen HK, Kessler U, Andreassen OA, Auestad BH, Bergsholm P, Malt UF, Morken G,
Oedegaard KJ, Vaaler A. Treatment-resistant bipolar depression: a randomized controlled trial
of electroconvulsive therapy versus algorithm-based pharmacological treatment. Am J Psychi-
atry. 2015;172:41–51.
Schoretsanitis G, De Leon J, Haen E, Stegmann B, Hiemke C, Grunder G, Paulzen M. Pharmaco-
kinetics of risperidone in different application forms – comparing long-acting injectable and oral
formulations. Eur Neuropsychopharmacol. 2018a;28:130–7.
Schoretsanitis G, Haen E, Grunder G, Stegmann B, Schruers KR, Hiemke C, Lammertz SE, Paulzen
M. Pharmacokinetic drug-drug interactions of mood stabilizers and Risperidone in patients
under combined treatment. J Clin Psychopharmacol. 2016;36:554–61.
Schoretsanitis G, Paulzen M, Unterecker S, Schwarz M, Conca A, Zernig G, Grunder G, Haen E,
Baumann P, Bergemann N, Clement HW, Domschke K, Eckermann G, Egberts K, Gerlach M,
Greiner C, Havemann-Reinecke U, Hefner G, Helmer R, Janssen G, Jaquenoud-Sirot E, Laux
G, Messer T, Mossner R, Muller MJ, Pfuhlmann B, Riederer P, Saria A, Schoppek B, Silva
Gracia M, Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Waschgler R, Zurek G, Hiemke
C. Tdm in psychiatry and neurology: a comprehensive summary of the consensus guidelines for
therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians.
World J Biol Psychiatry. 2018b;19:162–74.
Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and. . . 1491

Schwartz TL, Massa JL, Gupta S, Al-Samarrai S, Devitt P, Masand PS. Divalproex sodium versus
valproic acid in hospital treatment of psychotic disorders. Prim Care Companion J Clin
Psychiatry. 2000;2:45–8.
Sharma PS, Kongasseri S, Praharaj SK. Outcome of mood stabilizer discontinuation in bipolar
disorder after 5 years of euthymia. J Clin Psychopharmacol. 2014;34:504–7.
Sikdar S, Kulhara P, Avasthi A, Singh H. Combined chlorpromazine and electroconvulsive therapy
in mania. Br J Psychiatry. 1994;164:806–10.
Silva MT, Zimmermann IR, Galvao TF, Pereira MG. Olanzapine plus fluoxetine for bipolar
disorder: a systematic review and meta-analysis. J Affect Disord. 2013;146:310–8.
Suppes T, Baldessarini RJ, Faedda GL, Tondo L, Tohen M. Discontinuation of maintenance
treatment in bipolar disorder: risks and implications. Harv Rev Psychiatry. 1993;1:131–44.
Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomized 1-
year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a
history of mania. Am J Psychiatry. 1999;156:1164–9.
Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, Dilsaver SC, Davis JM.
Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry.
1997;54:37–42.
Tavares DF, Myczkowski ML, Alberto RL, Valiengo L, Rios RM, Gordon P, De Sampaio-Junior B,
Klein I, Mansur CG, Marcolin MA, Lafer B, Moreno RA, Gattaz W, Daskalakis ZJ, Brunoni
AR. Treatment of bipolar depression with deep TMS: results from a double-blind, randomized,
parallel group, sham-controlled clinical trial. Neuropsychopharmacology. 2017;42:2593–601.
Vasudev A, Chaudhari S, Sethi R, Fu R, Sandieson RM, Forester BP. A review of the pharmaco-
logical and clinical profile of newer atypical antipsychotics as treatments for bipolar disorder:
considerations for use in older patients. Drugs Aging. 2018;35(10):887–95.
Verdolini N, Hidalgo-Mazzei D, Murru A, Pacchiarotti I, Samalin L, Young AH, Vieta E, Carvalho
AF. Mixed states in bipolar and major depressive disorders: systematic review and quality
appraisal of guidelines. Acta Psychiatr Scand. 2018;138(3):196–222.
Verdoux H, Bourgeois M. Short-term sequelae of lithium discontinuation. Encéphale.
1993;19:645–50.
Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z, Reminick A, Zurick A, Cohen LS.
Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood
stabilizer discontinuation. Am J Psychiatry. 2007;164:1817–24; quiz 1923.
Walshaw PD, Gyulai L, Bauer M, Bauer MS, Calimlim B, Sugar CA, Whybrow PC. Adjunctive
thyroid hormone treatment in rapid cycling bipolar disorder: a double-blind placebo-controlled
trial of levothyroxine (L-T4) and triiodothyronine (T3). Bipolar Disord. 2018;20(7):594–603.
Williams RS, Cheng L, Mudge AW, Harwood AJ. A common mechanism of action for three mood-
stabilizing drugs. Nature. 2002;417:292–5.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, Sharma V, Goldstein BI, Rej
S, Beaulieu S, Alda M, Macqueen G, Milev RV, Ravindran A, O'donovan C, McIntosh D, Lam
RW, Vazquez G, Kapczinski F, McIntyre RS, Kozicky J, Kanba S, Lafer B, Suppes T, Calabrese
JR, Vieta E, Malhi G, Post RM, Berk M. Canadian Network for Mood and Anxiety Treatments
(CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the
management of patients with bipolar disorder. Bipolar Disord. 2018;20:97–170.
Yoshii K, Kobayashi K, Tsumuji M, Tani M, Shimada N, Chiba K. Identification of human
cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver
microsomes. Life Sci. 2000;67:175–84.
Zarate CA Jr, Tohen M. Double-blind comparison of the continued use of antipsychotic treatment
versus its discontinuation in remitted manic patients. Am J Psychiatry. 2004;161:169–71.
Zhu B, Tunis SL, Zhao Z, Baker RW, Lage MJ, Shi L, Tohen M. Service utilization and costs of
olanzapine versus divalproex treatment for acute mania: results from a randomized, 47-week
clinical trial. Curr Med Res Opin. 2005;21:555–64.
Zohar J, Stahl S, Moller HJ, Blier P, Kupfer D, Yamawaki S, Uchida H, Spedding M, Goodwin GM,
Nutt D. A review of the current nomenclature for psychotropic agents and an introduction to the
neuroscience-based nomenclature. Eur Neuropsychopharmacol. 2015;25:2318–25.
Mood Stabilizers: Lithium

Janusz K. Rybakowski

Contents
Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1494
Chemical Formula: Graphics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1496
Physicochemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1496
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1496
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1496
Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1497
Clinical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1499
Mood Stabilization in Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1499
Comparison of Lithium with Other Mood-Stabilizing Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1501
Excellent Lithium Responders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1502
Genetic Studies of Lithium Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1503
Lithium in the Treatment of Acute Episodes of Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 1504
Anti-suicidal Action in Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1504
Antiviral and Immunomodulatory Action in Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505
Neuroprotective Action in Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1506
Lithium in Dementia and Neurodegenerative Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1507
Side Effects/Adverse Reactions and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1509
The Long-Term Effects of Lithium on Kidney, Thyroid, and Parathyroid Function . . . . . . 1510
Effect of Lithium on Neurocognitive Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1511
Lithium in Pregnancy and the Postpartum Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1513
Lithium Intoxication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1513
Lithium Interaction with Other Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1514
Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1516
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1516
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1516

J. K. Rybakowski (*)
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
e-mail: janusz.rybakowski@gmail.com

© Springer Nature Switzerland AG 2022 1493

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_45
1494 J. K. Rybakowski

Abstract
The developmental history of lithium and its physicochemical properties, phar-
macokinetics, and mechanisms of action are presented. Among the latter, the
effect on the phosphatidylinositol (PI) system and the inhibition of the glycogen
synthase kinase 3beta (GSK-3β) activity are the most important. Lithium makes a
prototype of the mood-stabilizing drug, is regarded as the drug of the first choice
for the prophylaxis of bipolar disorders, and, as a monotherapy, surpasses all
other mood stabilizers. The drug can also be used in the treatment of acute
episodes of mood disorders, especially for the augmentation of antidepressants
in treatment-resistant depression. Lithium possesses significant anti-suicidal
properties, the strongest among all mood stabilizers. The drug exerts antiviral,
especially against herpes infection, and immunomodulatory influence. The evi-
dence has also been accumulated for the neurotrophic and neuroprotective effects
of lithium. Neuroimaging studies in bipolar subjects showed an increase in the
volume of some brain structures during lithium administration. Lithium therapy is
associated with numerous side effects, most of them can be successfully man-
aged. Given lithium superiority for the prophylaxis of mood disorders, together
with its anti-suicidal, immunomodulatory, and neuroprotective effects, the drug is
currently greatly underprescribed, and its therapeutic potential in patients with
bipolar disorder is not sufficiently utilized.
Recently, epidemiological data suggest an association between lithium intake
and dementia risk reduction. In experimental models of neurodegenerative dis-
orders, lithium exhibits significant therapeutic activity. Promising results have
also been obtained in some clinical studies.

Developmental History

Lithium history goes back to as early as the beginning of the world since lithium
appeared as one of the first elements after the Big Bang. This was mentioned by
recently deceased, the prominent English theoretical physicist and mathematician,
Stephen Hawking (1942–2018), in his book A Brief History of Time published
30 years ago (Hawking 1988). In the second century A.D., the outstanding Roman
physician, Soranus of Ephesus (98–138 A.D.), recommended that people with
nervous disorders should drink alkaline mineral waters with, as it transpired later,
a significant content of lithium ions (Gerdtz 1994).
The existence of lithium as a chemical element has been known for 200 years as it
was discovered in 1817 thanks to the research of a Swedish chemist, Johann August
Arfwedson (1792–1841), working in the Stockholm laboratory of famous chemistry
and pharmacy professor, Jons Jacob Berzelius (1779–1848). Arfwedson obtained
lithium carbonate from the mineral petalite that occurs on the Swedish island Utő
(Arfwedson 1818). In the middle of the nineteenth century, chemists found that the
salt lithium urate was among the most soluble urates. This prompted to introduce
lithium salts to treat gout and other rheumatic diseases in which an excess of
Mood Stabilizers: Lithium 1495

urate deposits was suspected. Such treatment was initiated by the English physician,
Alfred Baring Garrod (1819–1907) (Garrod 1859).
The first to use lithium for the treatment of acute mania was American physician,
William Alexander Hammond, in New York, and it was the bromide salt of lithium
(Hammond 1871). However, the real credit for introducing lithium for the treatment
of mood disorders should be given to the Danish doctor and scholar, Carl Lange
(1834–1900), also known as the co-author of the first neurobiological concept of the
emotions (the James-Lange theory). In 1886, Carl Lange published in Denmark his
treatise on the periodic depressive states “Om Periodiske Depressionstilstande og
deres Patogenese” (Lange 1886). This was produced 9 years later in the German
language as “Periodische Depressionzustände und ihre Pathogenesis auf dem Boden
der harnsauren Diathese” (On periodical depressions and their pathogenesis in the
context of uric acid abnormality) (Lange 1895). The important issue in this mono-
graph was a pathogenic concept of depression as a condition connected with an
excess of uric acid, something like a “gout of the brain.” This prompted Lange to
administer lithium as lithium carbonate to eliminate a possible uric acid excess by
forming the lithium urate in depressive patients. To this aim, he also used the dose
recommended by Garrod, i.e., around 25 mmol lithium (equalling about 1000 mg of
lithium carbonate) per day. According to Felber (1987), he might treat with lithium
as much as 2000 patients. While Carl Lange was giving lithium to ambulatory
patients in his private practice, this treatment was taken up by his brother, Fritz
Lange, the superintendent of Middelfart psychiatric hospital who administered it to
psychiatric inpatients.
Half a century after Carl Lange’s endeavors of lithium treatment, the Australian
psychiatrist John F. Cade (1912–1980) working in Melbourne researched on bio-
logical causes of mental disorders, using guinea pigs as experimental animals. Cade
found that the urine of patients in a manic state showed particular toxicity for guinea
pigs and reached the conclusion that such patients had probably an excess of urates.
He observed that after administering lithium urate, a significant decrease of toxic
symptoms and calming down of the animals occurred. However, a similar effect was
also obtained after giving lithium carbonate, indicating the primary effect of lithium
ions. Cade carried out a clinical self-experiment by taking himself lithium carbonate.
When it turned out that this did not lead to poisoning, he decided to give lithium
carbonate to ten patients with acute and chronic manic states. The results were
spectacular. Even though it was not possible to exclude spontaneous remission
among some patients with acute symptoms of mania, the significant improvements
observed in patients among whom manic symptoms had lasted for many months
were remarkable. Cade even hypothesized: “The effect on patients with pure psy-
chotic excitement – that is, true manic attacks – is so specific that it inevitably leads
to speculation as to the possible etiological significance of a deficiency in the body of
lithium ions in the genesis of this disorder” (Cade 1949).
Cade’s publication in the Medical Journal of Australia in 1949, in which he
described the antimanic effect of lithium, may be acknowledged as the evidence of
the introduction of lithium to modern psychiatric therapy. This publication could
also mark the beginning of modern clinical psychopharmacology because it
1496 J. K. Rybakowski

preceded by 3 years the first French publication on a neuroleptic (antipsychotic)

drug, chlorpromazine (Delay et al. 1952).

Chemical Formula: Graphics

Physicochemical Properties

Lithium (from Greek word “lithos,” meaning “stone”) is a chemical element with
symbol Li and atomic number 3, the lightest metal, and the first member of the
family of alkali metals. Its atomic structure is simple: the nucleus comprising three or
four neutrons and three protons, and there are three electrons on two valence orbitals.
Naturally occurring lithium (3Li) is composed of two stable isotopes, lithium-6 and
lithium-7, where lithium-7 makes about 92.5% of the atoms (Fig. 1).
Lithium resembles sodium and potassium as the elements of the same group 1A
of the periodic table and is interacting with these ions in the mechanisms of
membrane transport. Moreover, lithium exhibits a similarity to magnesium, belong-
ing to the group IIA, to which it bears a diagonal relationship in the periodic table. It
has been supposed that many lithium biological effects may involve an interaction or
competition between lithium and magnesium ions.

Pharmacology

Pharmacokinetics

After oral administration lithium is absorbed completely from the gastrointestinal

system within 6–8 h, with peak plasma levels between 1 and 3 h after ingestion. It
can be taken during or after meals as food is not interfering with its absorption. Slow-

Fig. 1 The picture of Li7 Energy Levels (Orbits) (2)

isotope’s atom

+ Protons (3)
N – Nucleons (7)
+N
– Neutrons (4)
N+ + e N
N – – Electrons (3)
e

Nuclide (Nucleus)

Atomic Structure (Lithium Atom - 73 Li)

Mood Stabilizers: Lithium 1497

release preparations result in the peak about 12 h after ingestion. Lithium is distrib-
uted quickly throughout the body. The balance between blood (extracellular) and
tissue (intracellular) concentration is maintained by several transport mechanisms.
The concentrations of lithium in cells (e.g., erythrocytes) and in the brain are lower
than the plasma concentration. However, there is a significant correlation between
these parameters. Lithium is eliminated in 97% via the kidneys, and a negligible
amount is excreted in sweat and feces. The elimination half-life of lithium ranges
from 10 to 42 h (average 20 h) which means that lithium can be administered in one
daily dose (Alda 2006).
The lithium ion is filtered freely through the glomerular membrane and is in 80%
reabsorbed in the proximal tubule, proportionally to the reabsorption of sodium and,
generally, not reabsorbed in the distal nephron. Lithium clearance is usually
8–40 ml/min, on the average 20–30% of the glomerular filtration rate (GFR), and
can be calculated as the daily dosage of mmol lithium, divided by 1.44 and next by
the serum lithium concentration in mmol/l. Lithium concentration in serum after a
given dose is depending on lithium clearance. The changes in lithium clearance can
be due to the changes in the GFR, the variations of antinatriuretic and natriuretic
mechanisms, and the activation of lithium reabsorption in the distal nephron.
Lithium clearance is decreased in older age what makes a necessity to adjust the
dose of lithium, accordingly, in such patients. On the other hand, lithium clearance is
increased in pregnancy. Therefore, the dose of lithium can be increased during
pregnancy to achieve a desirable level and decreased after delivery when the
clearance declines. Most pharmacokinetic interactions of lithium are connected
with an effect on renal lithium clearance (Schou and Kampf 2006).
For prophylaxis of affective recurrences, lithium concentrations of 0.6–0.8 mmol/
l are recommended, and higher concentration can be attained for the treatment of
mania. However, the concentrations above 1.2 should be avoided as they may lead to
lithium intoxication. The measurement of lithium concentration in serum should be
performed 10–12 h after the last dose.

Mechanisms of Action

The mechanisms of lithium in mood disorders made the topic of several reviews
(Pasquali et al. 2010; Quiroz et al. 2010; Alda 2015; Malhi and Outhred 2016). The
authors concluded that among a variety of biological systems, the most important
mechanisms of lithium action are connected with intracellular signaling, especially
with the effect of lithium on the phosphatidylinositol (PI) system and with the
inhibition by lithium of the glycogen synthase kinase-3beta (GSK-3β). Also, a
neurotrophic and neuroprotective effect of lithium has been highlighted as an
important element of its therapeutic action in mood disorders but also in making
lithium a therapeutic candidate to be used in neurodegenerative disorders.
Lithium is acting on several stages of the phosphatidylinositol (PI) system, and
this activity has been thought of as important for its therapeutic action in mood
disorders. The inositol depletion hypothesis of bipolar mood disorder formulated
1498 J. K. Rybakowski

nearly 30 years ago by Berridge et al. (1989) proposes that lithium attenuates PI
signaling. Lithium inhibits inositol monophosphatase-1 which ameliorates inositol
depletion-related mitochondrial dysfunction. Changes in IP signaling measured as a
spread of growth cones were postulated to make a common effect of the first
generation mood stabilizers (lithium, valproates, and carbamazepine) (Williams et
al. 2004). Another part of intracellular signaling which has long been implicated in
the mechanism of lithium action is the system of adenylyl cyclases which converts
ATP into cyclic adenosine monophosphate (cAMP). Mann et al. (2009) suggest that
the inhibition of adenylyl cyclase isoforms by lithium and carbamazepine may be
related to their antidepressant effect. The important element of this system is also the
cAMP response element-binding protein (CREB), the regulator of gene expression.
The third component of the lithium mechanism connected with intracellular signal-
ing is inhibition by lithium of protein kinase C (PKC). New findings show that
lithium acts to inhibit PKC through a myristoylated alanine-rich C kinase substrate
(MARCKS) pathway. This mechanism of lithium is shared with another mood-
stabilizing drug, valproate, and was a basis to introduce PKC inhibitor, tamoxifen,
to the treatment of mania.
The evidence has been accumulating using various experimental models showing
that lithium inhibits glycogen synthase kinase-3beta (GSK-3β) activity. GSK-3β is a
serine/threonine kinase that regulates gene transcription, synaptic plasticity, apopto-
sis, cellular structure and resilience, and the circadian cycle, all of which are
implicated in the pathophysiology of mood disorders. Therefore, the GSK-3β inhi-
bition by lithium can make the main mechanism of therapeutic action in mood
disorders (Jope 2011). GSK-3β is also a key enzyme in the metabolism of amyloid
precursor protein and in the phosphorylation of the tau protein, playing the main
pathogenetic role in Alzheimer’s disease (AD). Due to the inhibition of GSK-3β,
lithium arrests the development of neurofibrillary tangles in mutant tau transgenic
mice with advanced neurofibrillary pathology (Leroy et al. 2010), and, in the
Drosophila fly, adult-onset model of the AD ameliorates amyloid-beta pathology
(Sofola et al. 2010).
Lithium exerts a stimulatory action on the brain-derived neurotrophic factor
(BDNF), the most important member of the neurotrophin family, necessary for the
survival and function of neurons. BDNF modulates the activity of such neurotrans-
mitters like glutamate, gamma-aminobutyric acid, dopamine and serotonin.
Transcription of the BDNF gene is activated by CREB. In experimental studies, it
was demonstrated that lithium activates CREB and increases BDNF expression. In
clinical studies, lithium treatment increases the blood level of BDNF.
Lithium treatment results in an increase of B-cell leukemia 2 (Bcl-2) in the brain
of experimental animals. Bcl-2 is an important protein for cellular resilience and
plasticity, exerting mostly anti-apoptotic effects. The expression of Bcl-2 is activated
by CREB. Lithium also increases the expression of Bcl-2-associated athanogene
(bag-1) which is known to attenuate glucocorticoid receptor nuclear translocation,
thus potentiating the anti-apoptotic effect.
Lithium is a monovalent cation, similar to sodium and potassium, and the first
theories of the mechanisms of lithium action were connected with electrolytes and
Mood Stabilizers: Lithium 1499

membrane transport. The early studies pointed to increased residual sodium during
acute episodes (depression or mania) and its normalization in the course of lithium
treatment. In the 1970s, the lithium-sodium countertransport system was discovered
as the main mechanism of lithium transport out of the cells. This system was
supposed to be deficient in bipolar disorder, reflected by an increased erythrocyte/
plasma lithium ratio in such patients. It was also found that lithium can enhance the
activity of the sodium-potassium adenosine triphosphatase (ATPase) which can be
decreased in mood disorders.
The interest in the pathogenetic role of altered neurotransmission in mood
disorder resulted in identifying meaningful effects of lithium on several neurotrans-
mitters. In experimental studies, it was demonstrated that lithium increases serotonin
transmission through multiple mechanisms and inhibits increased dopaminergic
activity. It was also found that lithium can reduce the glutamate-induced
excitotoxicity and also reverses and repair oxidative stress connected with
excitotoxicity.
Disturbances of circadian rhythm belong to the high-order modulatory biological
systems implicated in mood disorders. Many experimental and clinical studies
demonstrated that lithium could ameliorate and rectify circadian rhythm due to its
effect on the GSK-3β and PI system and by modulating the expression of certain
clock genes. In our molecular genetic study, we found an association between the
prophylactic effect of lithium and polymorphisms in the biological clock genes
(Rybakowski et al. 2014).
Recently, Pisanu et al. (2018) suggest that the epigenome might be also a target of
lithium and other mood stabilizers, as they can favorably interfere with the epige-
netic mechanisms such as DNA methylation and histone deacetylase activity.

Clinical Indications

Mood Stabilization in Bipolar Disorder

Lithium is the prototypic “mood stabilizer” showing therapeutic and prophylactic

action in both psychopathological poles of bipolar mood disorder (Bauer and
Mitchner 2004). Current definition of mood stabilizer (MS) involves reducing or
ameliorating manic and/or depressive symptoms during an acute episode; prevention
of manic and/or depressive recurrences during long-term administration, when a
drug is given as monotherapy for a duration of at least 1 year; and not inducing or
worsening either manic or depressive episodes or mixed states. On the basis of their
chronology of introducing into psychiatric armamentarium, a division of MSs
was proposed into first-generation mood stabilizers, introduced in the 1960s and
1970s (lithium, valproates, and carbamazepine), and second-generation mood stabi-
lizers, introduced since the second half of the 1990s, which include atypical anti-
psychotics (clozapine, olanzapine, quetiapine, aripiprazole, and risperidone) and
lamotrigine (Rybakowski 2007, 2018).
1500 J. K. Rybakowski

The first paper showing a possibility of mood-stabilizing action by lithium, i.e.,

prophylaxis of the recurrences of mood disorders, was that of the British psychiatrist,
Geoffrey Hartigan, published in the British Journal of Psychiatry 55 years ago. The
administration of lithium for 3 years to seven patients with bipolar disorder and eight
with recurrent depression resulted in a vanishing of illness’ recurrences in six bipolar
and six depressive patients (Hartigan 1963). A year later, similar observations were
made by the Danish psychiatrist Paul Christian Baastrup (Baastrup 1964). And
4 years later, the paper of the Danish psychiatrists appeared, summing up the
experiences of lithium administration for an average duration of 6 years to 88
patients with the unipolar and bipolar mood disorder. The authors showed that,
while the average duration of mood disorders within a year preceding lithium use
was 13 weeks, it decreased on lithium to 2 weeks, arguing that lithium may exert a
favorable prophylactic effect on the course of mood disorders (prophylactic or
mood-stabilizing effect) (Baastrup and Schou 1967). However, next year, a backlash
on the concept of lithium prophylaxis appeared in Lancet where British researchers
described prophylactic lithium as “another therapeutic myth” (Blackwell and
Shepherd 1968).
Publication of the results of eight controlled studies including the use of placebo
performed in Europe (in Denmark and the UK) and the USA, researching the
prophylactic effectiveness of lithium, took place in 1970–1973. All patients studied
had, in the period of the preceding 2 years, at least two recurrences of illness.
Analysis of all research showed that the percentage of patients in whom recurrences
of depression or mania occurred was on average 30% while receiving lithium and on
average 70% while taking a placebo (Schou and Thompsen 1976). Following these
publications, the use of lithium for prophylaxis of mood disorders had been
flourishing, reaching its peak on 1980–1990.
In 1988, an initiative of Mogens Schou of Denmark, Paul Grof from Canada, and
Bruno Müller-Oerlinghausen from Germany resulted in the formation of the Inter-
national Group of Study for Lithium-Treated Patients (IGSLI). Collaborative IGSLI
studies demonstrated an influence of lithium on mortality and suicide prevention
(Müller-Oerlinghausen et al. 1992) as well as the neuroprotective effect of this ion
(Hajek et al. 2014). In 1990, the international journal Lithium was launched, aiming
to integrate research on the significance of this ion, particularly in bipolar disorders.
However, this happened in a period of a relative decline of interest in lithium and
intense promotion of antidepressants and other mood-stabilizing drugs, including
atypical antipsychotics with mood-stabilizing properties, as alternatives to lithium.
Despite new and interesting properties of lithium being discovered in this time, such
as anti-suicidal and antiviral effects, the Lithium journal ceased to exist after 5 years.
Also, lithium therapy during this time was described in the autobiographies of
eminent people. Salvador Luria (1912–1991), the Nobel prize winner for medicine
in 1969 for pioneering research on bacteriophages, described his lithium treatment in
the book A Slot Machine, a Broken Test Tube: An Autobiography (Luria 1984). Patty
Duke, the American film actress, the youngest ever (at the age of 16) Oscar winner,
for her role in the film Miracle Worker, did this in her two autobiographies: Call Me
Anna (Duke and Turan 1987) and A Brilliant Madness: Living with Manic-
Mood Stabilizers: Lithium 1501

Depressive Illness (Duke and Hochman 1992). However, the most influential about
treating the illness with lithium was the autobiography An Unquiet Mind, written by
a professional, Kay Redfield Jamison, the co-author (together with Frederick
Goodwin) of the fundamental textbook Manic-Depressive Illness (Jamison 1996).
Another backlash on lithium therapy emerged in the second part of 1990
containing allegations that there has been inadequate methodological evidence that
lithium has a beneficial effect and that it is ineffective in the long-term treatment of
bipolar disorder and may be associated with various form of harm, being “old but
flourishing blunder” (Moncrieff 1997). However, three meta-analyses of the twenty-
first century have amply confirmed the prophylactic effectiveness of lithium in
bipolar disorder. The first analysis performed by Geddes et al. (2004) including 5
randomized controlled trials with 770 patients showed that lithium was significantly
more effective than a placebo in preventing all affective relapses, being slightly
better against manic than against depressive recurrences. In the second study, Nivoli
et al. (2010) analyzed long-term controlled trials lasting at least half a year, with
1,561 patients, of whom 534 were receiving lithium. They noticed that earlier
research had suggested the nearly equal effectiveness of lithium against both
mania and depression; however, nowadays, lithium prophylaxis is regarded as
more effective against manic than against depressive relapses. The most recent
meta-analysis has been performed by Severus et al. (2014). Including seven trials
(1,580 patients) comparing lithium with placebo, the authors concluded that lithium
was significantly superior to placebo in preventing any mood episodes and manic
episodes. In some analyses, lithium was also better than a placebo in preventing
depressive episodes.
Nowadays, lithium is regarded as the drug of the first choice for long-term
prevention of mood recurrences in bipolar disorders. In a proportion of patients, it
is administered in combination with other mood stabilizers.
Lithium can be also of use for long-term prevention of depressive recurrences in
unipolar depression. A recent meta-analysis showed that lithium monotherapy is
significantly more effective for prevention of depressive recurrences than placebo
and is better, albeit nonsignificantly that antidepressant monotherapy and combina-
tion of lithium with an antidepressant is superior to an antidepressant alone in this
respect (Undurraga et al. 2019).

Comparison of Lithium with Other Mood-Stabilizing Drugs

The studies comparing lithium with other first-generation mood stabilizers (carba-
mazepine and valproates) were the MAP (Multicenter study of long-term treatment
of Affective and schizoaffective Psychoses) and the BALANCE (Bipolar Affective
disorder Lithium/ANti-Convulsant Evaluation). In the MAP study, lasting 2.5 years,
lithium was better than carbamazepine in patients with bipolar I disorder, and both
drugs had similar efficacy in bipolar II illness. In subjects experiencing mood-
incongruent delusions and psychiatric comorbidity, a better effect of carbamazepine
was observed (Kleindienst and Greil 2000). In the BALANCE study, bipolar patients
1502 J. K. Rybakowski

randomized to lithium (n = 110) or valproate (n = 110) monotherapy, or both drugs

in combination (n = 110) were followed-up for 2 years. Fifty-four percent of
subjects from the combined lithium-valproate group, 59% from the lithium mono-
therapy, and 69% from the valproate monotherapy experienced a recurrence of
a manic or depressive episode, showing the prophylactic superiority of lithium
(Geddes et al. 2010).
Goodwin et al. (2004) comparing the prophylactic efficacy of lithium versus
lamotrigine found that both drugs were better than placebo where time to occur-
rence of any affective episode was taken into account. However, lithium was
better than a placebo for the prevention of mania, and lamotrigine performed
better for the prevention of depression. In Severus et al. (2014) meta-analysis,
comparing lithium with anti-convulsants (valproate, carbamazepine, lamotrigine),
including 1,305 participants, it was found that lithium was better prophylaxis
for manic episodes but not better than anti-convulsants for prevention of
depression.
A comparison between lithium and another second-generation mood stabilizer,
quetiapine, was performed in the framework of the Bipolar CHOICE (the Clinical
and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder)
project. The 6-month study did not reveal differences in the efficacy between these
drugs. In their review paper, Ketter et al. (2016) suggest a comparable efficacy of
lithium and quetiapine in the treatment of acute episodes of bipolar disorder and its
prophylaxis and significantly better effectiveness of combination therapy than either
agent alone.
Recently, Kessing et al. (2018) analyzed observational studies comparing mono-
therapy with lithium and monotherapy with other mood stabilizers. They found that
prophylactic lithium monotherapy was more effective compared to monotherapy
with such mood stabilizers as valproate, lamotrigine, olanzapine, and quetiapine.
The authors concluded that, in real life, prophylactic lithium monotherapy is superior
to such monotherapy with other most frequently used mood stabilizers.

Excellent Lithium Responders

The term “excellent lithium responders” (ER) was introduced by the Canadian
psychiatrist, Paul Grof (1999), for patients which on monotherapy with lithium
experienced a dramatic change in their life as their mood episodes were fully
prevented. We followed-up for 10 years 60 patients who started lithium prophylaxis
in the 1970s and 49 patients beginning this procedure in the 1980s. Those without
mood episodes during this period (ER) made 35% of the first group and 27% of the
second one, roughly one-third of bipolar subjects treated longitudinally with lithium
(Rybakowski et al. 2001). Grof (2010) suggests that lithium responders can be
characterized by distinct mood episodes, with full remissions between them, the
absence of other psychiatric morbidity, and frequent history of bipolar illness in their
families, reminding the aspects of the illness, defined by Emil Kraepelin (1899) as
“manisch-depressives Irresein.”
Mood Stabilizers: Lithium 1503

Successful lithium therapy may favorably influence clinical, neurobiological, and

neurocognitive components of the progression of the illness. Such an effect is especially
evident in the group of ER where, due to complete prevention of affective relapses, the
progress of the illness is halted. As a decrease in serum BDNF has been postulated as a
marker of the later stage of bipolar disorder, we have found that ER with a mean of
21 years of lithium treatment have normal serum BDNF levels (Rybakowski and
Suwalska 2010). We have also demonstrated that in lithium-treated patients experienc-
ing a long-term euthymic status, the inflammatory cytokine concentrations did not differ
from those observed in healthy persons (Remlinger-Molenda et al. 2012).
Recently, we described five patients (two men and three women, aged 64–79 years)
with a good response to the ultra-long-term lithium treatment (40–45 years). Serum
lithium in them was in the range of 0.60–0.65 mmol/l, except for one male, having
0.7–0.8 mmol/l. Both males had impaired renal function with no progression in the last
5 years. One female suffered from Hashimoto’s disease and was treated with
levothyroxine. In all patients, the cognition and professional activity were at the
level of healthy subjects with comparable age and education’s years. Their functioning
in family and social roles was good. The beginning of lithium prophylaxis usually has
been made within the first 3 years of the illness. Thus, in patients with favorable
response to lithium, such a longitudinal administration of the drug can produce a
satisfactory performance in vocational and psychosocial areas, and the management of
potential adverse effects can be adequate (Permoda-Osip et al. 2016).

Genetic Studies of Lithium Response

The quality of prophylactic lithium response makes a good topic for molecular
genetic studies. A review of genetic influences on the efficacy of lithium prophylaxis
was made by the author of this chapter (Rybakowski 2013). The genes studied for
their association with lithium response have been those connected with neurotrans-
mitters (serotonin, dopamine, and glutamate); second messengers, phosphatidy-
linositol (PI), cyclic adenosine monophosphate (cAMP) and protein kinase C
(PKC) pathways); and glycogen synthase kinase 3-β (GSK-3β), substances involved
in neuroprotection (brain-derived neurotrophic factor (BDNF)), in circadian
rhythms, and a number of other miscellaneous genes.
In 2009, an initiative of the National Institutes of Mental Health and the Interna-
tional Group for the Study of Lithium-Treated Patients (IGSLI) resulted in the
formation of the International Consortium on Lithium Genetics (ConLiGen), aiming
for the first genome-wide association study (GWAS) of lithium response (Schulze et
al. 2010). In 2013, the first report of the key phenotypic measures of the “Retro-
spective Criteria of Long-Term Treatment Response in Research Subjects with
Bipolar Disorder” scale, known as the Alda’s scale, used by ConLiGen was pre-
sented (Manchia et al. 2013). The first GWAS of lithium response was published in
2016, in which 2563 patients were included coming from 22 participating sites of the
ConLiGen. A single locus of four-linked single nucleotide polymorphisms (SNPs)
on chromosome 21 met genome-wide significance criteria for association with
1504 J. K. Rybakowski

lithium response. This region contains two genes for long, noncoding RNAs
(lncRNAs) which are important regulators of gene expression in the central nervous
system (Hou et al. 2016).
A recent study of the ConLiGen suggests some specificity of lithium for bipolar
disorder as patients with a higher polygenic score for schizophrenia had a worse
response to prophylactic lithium administration (International Consortium on
Lithium Genetics 2018).

Lithium in the Treatment of Acute Episodes of Mood Disorders

The most important study of lithium in mania after Cade’s report (Cade 1949) was
that of Danish psychiatrist Mogens Schou (1918–2005). He and his colleagues
studied the effectiveness of lithium among 38 patients in a manic state. In the
study, for the first time, a placebo was used. A spectacular improvement was noted
in 12 patients, improvement in 15, and a lack of effect in 3 of them (Schou et al.
1954). Since then lithium has been widely and successfully used in the treatment of
mania both as monotherapy and combined with other drugs. A meta-analysis shows
a significant therapeutic effect of lithium in moderate and severe manic episodes
(Storosum et al. 2007). However, recent comparative analyses suggest superiority of
antipsychotic drugs over lithium in severe manic episodes (Cipriani et al. 2011).
Since the 1970s, the reports showing a possibility of the therapeutic effect of
lithium in a depressive episode have been published and in some American guidelines
of 1980–1990 lithium were recommended to treat a depressive episode in the course of
bipolar disorder. In 1981, Canadian psychiatrists showed that adding lithium to
antidepressant drugs among people whose therapy does not bring satisfying results
brings a substantial, and sometimes very quick, improvement of mood (De Montigny
et al. 1981). Since then evidence has been systematically gathered that lithium causes
potentiation of the effectiveness of antidepressant drugs. Rybakowski and Matkowski
(1992) showed that the augmenting effect of lithium is better in depression in the
course of bipolar disorder than in unipolar disorder. A review on this subject, in
particular, research comparing the effect of lithium with a placebo by the German
psychiatrists, demonstrates that lithium is an effective remedy augmenting the effect of
antidepressant drugs in treatment-resistant depression both bipolar and unipolar and a
successful effect may be expected in at least 50% of patients (Crossley and Bauer
2007; Bauer et al. 2014). In most current therapeutic standards, the strategy of
potentiation of antidepressant drugs by lithium is recommended in the first place.

Anti-suicidal Action in Mood Disorders

The evidence that long-term lithium treatment can decrease mortality, primarily by
preventing suicide, has been accumulated since the early 1990s. Coppen et al. (1991)
observing 103 patients attending lithium clinic for 11 years concluded that lithium
Mood Stabilizers: Lithium 1505

reverses the excess mortality associated with mood disorders, mainly by preventing
suicide. The researchers assembled in the IGSLI group analyzing 827 patients with
bipolar and schizoaffective disorder given lithium treatment for more than 6 months
observed that the mortality of these patients did not differ significantly from that of
the general population (Müller-Oerlinghausen et al. 1992). Fifteen years later, a
meta-analysis from Harvard University group, including 45 papers containing data
on suicides committed while taking lithium (on average for 1.5 years) and 34 papers
registered suicides of persons not receiving lithium, showed that the risk of com-
mitting suicide was five times lower among patients taking lithium than those
subjected to other forms of treatment (Baldessarini et al. 2006). A recent meta-
analysis performed by Cipriani et al. (2013) with 6,674 patients concluded that
lithium was significantly better than a placebo in reducing the number of suicides
and deaths from any cause both in bipolar disorder and recurrent depression and
superior to other mood stabilizers or antidepressants.
Currently, the anti-suicidal effect of lithium in mood disorders is well
documented, and, in many comparative papers, it has been shown that it is signif-
icantly greater than other mood-stabilizing drugs. For example, a recent meta-
analysis did not show an effect of valproates on suicide risk in bipolar disorder
(Chen et al. 2019)
While being on lithium prevents suicide, its discontinuation significantly
increases this risk. The anti-suicidal effect is not significantly correlated with the
quality of prevention of mood recurrences by lithium, which points to the specificity
of such an effect exerted by lithium (Lewitzka et al. 2015)
In recent years, the anti-suicidal effect of lithium has been also demonstrated with
trace levels of this drug. In studies performed in Japan, Austria, and the USA, a
negative correlation between suicides and lithium concentrations in drinking water
was demonstrated (Ohgami et al. 2009; Kapusta et al. 2011; Blüml et al. 2013).
These results may reactivate Cade’s speculation he made when administered lithium
to manic patients, suggesting that lithium can be a trace element for mood disorders.

Antiviral and Immunomodulatory Action in Mood Disorders

Researchers from the University of Birmingham showed that lithium in 5–30 mmol/l
concentration inhibits replication of the herpes simplex virus (Skinner et al. 1980).
The mechanism of action here probably involves blockage of synthesis of the virus’s
DNA by lithium or competition with magnesium ions catalyzing enzymatic reac-
tions of the virus. At that time also descriptions of cases of labial herpes remissions
while using lithium appeared. Labial herpes is caused by an infection of herpes
simplex virus type 1 (HSV-1) and occurs in approximately 1/3 of the population, and
its course is characterized by frequent recurrences.
Retrospective research of labial herpes occurrence in patients receiving lithium
for prophylactic purposes was carried out within a collaborative study of the
Department of Adult Psychiatry, Poznan University of Medical Sciences, and the
Department of Psychiatry of the University of Pennsylvania. In the Polish population
1506 J. K. Rybakowski

of 28 persons with recurrent labial herpes, during lithium therapy, the full cessation
of recurrence of herpes occurred in 13 patients, among 7 the frequency of recur-
rences decreased, among 6 it remained at the same level, and among 2 increased. The
general decrease in recurrence frequency was 64%. A better effect was observed in
patients in whom lithium concentration in the serum was higher than 0.65 mmol/l
and erythrocyte concentration exceeded 0.35 mmol/l. The American population
comprised two groups, 52 persons in each, matched with sex, age, and the duration
of systematic pharmacological treatment. In the first group, including mainly
patients with bipolar disorder treated with lithium, the frequency of labial herpes
recurrences in comparison with the 5-year period before the treatment decreased by
73%. In the second group, including patients with recurrent depression receiving
antidepressant drugs, no significant difference was observed (Rybakowski and
Amsterdam 1991).
Lithium can profoundly influence hematological and immunological system. An
increase of leukocytes by lithium treatment was observed nearly 70 years ago
(Radomski et al. 1950) and subsequently confirmed in many studies. Such a property
of lithium made some therapeutic uses also beyond psychiatry (e.g., in oncology). In
recent two decades, it was also found that lithium can mitigate the immune-endo-
crine component of the pathogenesis of the bipolar disorder, such as the acute-phase
reaction, production of pro-inflammatory cytokines, and excessive activation of the
hypothalamic-pituitary-adrenal axis (Rybakowski 2000). The anti-inflammatory
effect of lithium was the subject of a review 4 years ago (Nassar and Azab 2014).
Recently, we examined the impact of long-term lithium administration on very small
embryonic-like stem cells (VSELs) and the mRNA expression of pluripotency and
glial markers, in peripheral blood, showing that lithium can alleviate excessive
regenerative and inflammatory processes in bipolar disorder (Ferensztajn-
Rochowiak et al. 2018).

Neuroprotective Action in Mood Disorders

Lithium induces neurotrophic and neuroprotective effects in a wide range of pre-

clinical and translational models. Lithium’s neurotrophic effects are related to the
enhancement of cellular proliferation, differentiation, growth, and regeneration,
whereas its neuroprotective effects limit the progression of neuronal atrophy or
cell death (Machado-Vieira 2018).
The neuroprotective effect of lithium in bipolar patients can be reflected in
neuroimaging studies. Following a research letter to the Lancet submitted by
Moore et al. (2000), suggesting a lithium-induced increase in human brain grey
matter, the results of several confirmatory studies have been reported and recently
reviewed by Hajek and Weiner (2016). The brain structures influenced by either
short-term or long-term lithium treatment were the prefrontal cortex, anterior cingu-
late, and hippocampus. The most frequently reported pattern was larger grey matter
volumes in patients currently treated with lithium compared to those currently not on
lithium. The association between lithium treatment and higher grey matter volume
Mood Stabilizers: Lithium 1507

was reported regardless of mood state and diagnostic subtype. In the IGSLI study,
bipolar patients receiving lithium had larger hippocampal volumes compared to non-
lithium patients and similar to healthy controls (Hajek et al. 2014). Two studies
compared the effects of lithium with those of anti-convulsants and antipsychotics,
possessing mood-stabilizing properties. Lyoo et al. (2010) found that lithium caused
an increase in gray matter volume, peaking at weeks 10–12, and maintained through
16 weeks of treatment and that this increase was associated with positive clinical
response. By contrast, valproate-treated patients did not show grey matter volume
changes over time. Germana et al. (2010) found that the volume of gray matter in the
subgenual anterior cingulate gyrus on the right and the postcentral gyrus, the
hippocampus/amygdala complex, and the insula on the left was greater in patients
on lithium treatment compared to all other treatments. Thus, there is considerable
evidence for lithium causing an increase in cerebral grey matter volume both in
healthy subjects and in patients with bipolar disorders which may be associated with
its neuroprotective effect at a clinical level. Such a replicated and consistent evidence
for this has not been demonstrated for any other mood-stabilizing drugs.

Lithium in Dementia and Neurodegenerative Disorders

The results of population studies reviewed by Donix and Bauer (2016) suggest an
association between lithium treatment and dementia risk reduction or reduced
dementia severity. In two papers from the Danish University of Copenhagen in
which the nationwide register of lithium prescriptions was used, it was found that in
patients who continued to take lithium, the rate of dementia decreased to the same
level as the rate for the general population. However, in persons treated with anti-
convulsant drugs, the risk of dementia increased with the duration of treatment
(Kessing et al. 2008). Continued treatment with lithium was also associated with a
reduced rate of dementia in patients with bipolar disorder, in contrast to
continued treatment with anti-convulsants, antidepressants, or antipsychotics
(Kessing et al. 2010).
Three studies concerning lithium treatment of AD or mild cognitive impairment
(MCI) were meta-analyzed by Matsunaga et al. (2015), suggesting some benefit
from lithium treatment. Of interest, one of these studies (Nunes et al. 2013) evaluated
the effect of a microdose of 300 μg lithium, administered to AD patients once daily
for 15 months. The treated group showed no decreased performance in the mini-
mental state examination test, in opposition to the lower scores observed for the
control group during this time. A possible effect of trace doses of lithium has been
recently suggested in a Danish study of Kessing et al. (2017) showing a negative
association between the incidence of dementia and lithium concentration in drinking
water. Concurring with this was a recent American study demonstrating that changes
in Alzheimer’s dementia mortality were negatively correlated with trace lithium in
drinking water (Fajardo et al. 2018). Taking into account the association between
suicidality and lithium in drinking water mentioned earlier, again, speculation on a
possible role of lithium as a trace element for mental health may be reasonable.
1508 J. K. Rybakowski

Table 1 Major meta-analyses and reviews on lithium therapeutic efficacy in the last decade
Subject of
study Authors Design Main results
Prevention of Nivoli et al. Six randomized controlled High effectiveness of
episodes in (2010) trials lasting at least half a year: lithium against mania and
bipolar 1,561 bipolar I and II patients, slightly less against
disorder randomizing 534 to lithium depression
Prophylaxis against mania:
lithium = valproate <
olanzapine
Prophylaxis against
depression:
lithium<lamotrigine
Prevention of Severus et Lithium versus placebo: seven Lithium more effective than
episodes in al. (2014) trials (1,580 participants) placebo in preventing:
bipolar overall mood episodes
disorder (RR 0.66)
manic episodes (RR 0.52)
depressive episodes
(RR 0.78)
Lithium versus anti- Preventing manic episodes:
convulsants: seven trials (1,305 lithium > anti-convulsants
participants) No difference in preventing
overall and depressive
episodes
Augmentation Bauer et al. 10 placebo controlled trials Mean response rate
of (2014) 30 open trials Lithium 41.2%; placebo
antidepressants 14.4%
Good efficacy of lithium
augmentation of TCA and
SSRI
No comparator superior to
lithium augmentation
Prevention of Undurraga Long-term lithium treatment: Lithium monotherapy >
episodes in et al. 21 trials (846 participants) placebo (7 trials)
unipolar (2019) Lithium monotherapy =
disorder antidepressant
Augmentation monotherapy (5 trials)
of Lithium + antidepressant >
antidepressants antidepressant
monotherapy (9 trials)
Augmentation of Lithium > placebo (OR
antidepressants 12 trials (541 2.34)
participants)
Treatment of Matsunaga Three clinical trials (232 Lithium > placebo in
Alzheimer’s et al. participants) decreasing cognitive
disease (2015) decline
Standardized mean
difference 0.41
Mood Stabilizers: Lithium 1509

There were also attempts to use lithium in other neurodegenerative disorders,

based on promising experimental findings on the animal models. However, the
results of clinical studies were not significant (Rybakowski et al. 2018).
In Table 1, major meta-analyses and reviews of lithium therapeutic efficacy in
mood disorders and dementia performed in the last decade are shown.

Side Effects/Adverse Reactions and Toxicology

The issues of lithium side effects and toxicity as well as their prevalence and
management strategies were recently reviewed by Gitlin (2016). In many cases,
adverse reactions to lithium present a significant burden and may play a role in non-
adherence and also in lithium discontinuation. These effects may appear already at
the initial stage of lithium therapy but also after several years of such treatment.
However, in most cases, they can be manageable. The adverse effects of lithium
perceived as posing a significant challenge for its long-term administration include
mostly kidney and thyroid effects.
Gastrointestinal side effects, such as nausea and diarrhea, occur in about 10–20% of
lithium-treated patients early in the treatment and tend to decrease during long-term
therapy. They may be connected with serum lithium concentration and with a type of
preparation (regular or slow-release). Both vomiting and diarrhea appear during lithium
intoxication. Weight gain is pretty common during lithium treatment although its
prevalence differs in various studies, pertaining, on the average, to 25% of patients.
This abnormality is sometimes bothersome, and, in some patients, it can result in lithium
discontinuation. Therapeutic options for lithium-induced weight gain include dietary
control and physical activity, adjunctive treatment with topiramate, and, in severe and
resistant cases, switching to another mood stabilizer (Rybakowski and Suwalska 2006).
Polyuria and polydipsia may occur within several weeks of lithium treatment. The
main reason is a decrease in renal concentrating capacity caused by lithium. This
side-effect can alleviate after reducing lithium dose. Therefore the optimal manage-
ment when these symptoms appear is keeping lithium levels as low as possible. If the
effect of lithium is favorable, severe polyuria can be treated with amiloride. Polyuria
normally disappears after lithium discontinuation. Some decrease of lithium-induced
renal concentrating capacity may persist for many years during long-term lithium
administration (Rybakowski et al. 2012).
The tremor, occurring in about 20% of lithium-treated patients, is a fine tremor of
the upper limbs occurring as postural or action tremor. It looks like an exaggeration
of physiologic tremor with a similar frequency range between 8 and 13 Hz, differing
from resting Parkinsonian tremor, which has a frequency of 4–6 Hz. Predisposing
factors include high lithium level; older age; and concomitant treatment with the
antidepressant, anti-convulsant, or antipsychotic drugs. Lithium-induced tremor is
usually mild and often disappears after dose reduction. However, if a reduction of
lithium dosage is not possible and if the tremor is considered clinically relevant (i.e.,
1510 J. K. Rybakowski

interfering with the patients’ daily activities), administration of low-dose beta-

blockers, e.g., propranolol at 30–80 mg/day, can be used with good results.
Other than tremor, neurological adverse effects of lithium are infrequent and
comprise extrapyramidal and oculomotor symptoms. Sometimes they may occur
even with lithium concentration within the therapeutic range. Predisposing factors
are similar to tremor. Any pre-existing cerebral abnormalities may also constitute a
risk factor. Extrapyramidal symptoms may include Parkinsonism, akathisia, or
tardive dyskinesia and occur mostly in patients who receive co-treatment with
antipsychotic drugs. These symptoms do not favorably respond to anti-Parkinsonian
medications. Lithium-induced nystagmus is usually reversible under a reduction of
lithium dose or lithium discontinuation (Rybakowski 2015).
Among the dermatological effects of lithium, the exacerbation of acne and
psoriasis, as well as induction of new cases of these conditions, should be noticed.
Moderate to severe psoriasis can present a relative contraindication to lithium
therapy. Dermatological effects of lithium may be related to lithium concentration;
thus, lowering the lithium dose can be considered. Also, usual dermatologic reme-
dies for these conditions should be tried if the effect of lithium is favorable. Only in
very severe cases, there is a necessity of replacing lithium with another mood
stabilizer.
The most common lithium’s cardiovascular side effects include non-specific
alterations of the repolarization period in the electrocardiogram (ECG) without
concomitant symptoms of clinical importance. However, several cases of arrhythmia
were observed, the most frequent being the sinus node bradyarrhythmia. In severe
cases of arrhythmia, if lithium therapy seems indispensable, cardiological manage-
ment should be introduced (Bierbrauer et al. 2006).

The Long-Term Effects of Lithium on Kidney, Thyroid, and

Parathyroid Function

The most serious concern connected with long-term lithium use is the possibility of
lithium-induced interstitial nephropathy. This complication can develop after
10–20 years of treatment and leads to increased creatinine concentration and a
decreased glomerular filtration rate (GFR) (Rybakowski et al. 2012). In a recent
IGSLI study, Tondo et al. (2017) analyzed data from 312 patients with bipolar
disorder, coming from 12 participating centers, receiving lithium carbonate for
8–48 (mean 18) years. The lowering of GFR amounted to 0.71% with each year of
age and 0.92% with each year of lithium administration. Nearly 1/3 of subjects had
the value of GFR <60 mL/min/1.73 m2 more than once, more frequently after
15 years of lithium administration and after 55 years of age, and 18.1% of patients
had that value more than twice. However, no case of an end-stage renal failure was
detected.
In a small fraction of patients receiving long-term lithium administration, pro-
gressive renal damage may occur. Such a situation frequently fosters discontinuation
of lithium and replacing with other mood stabilizer. However, a decision about
Mood Stabilizers: Lithium 1511

stopping lithium should be taken with caution, especially in good responders, since
other mood stabilizers may not be equally efficacious. This may result in a high risk
of relapse of the illness and a further treatment-resistant course (Rybakowski et al.
2012). In patients with lithium-induced nephropathy, kidney function should be
closely and frequently monitored, and some guidelines for managing such patients
were recently published (Severus and Bauer 2013).
The influence of lithium on the thyroid gland is one of the key side effects in long-
term therapy with this drug. Lithium is accumulated in the thyroid gland at three- to
fourfold higher concentrations as compared to its plasma levels. Its administration
results in a reduced production with release inhibition of thyroid hormones, altering
the immune processes of this gland. Fifty years ago, Schou et al. (1968) were the first
to report the incidence of goiter in lithium-treated patients. According to the current
knowledge, the most common thyroid side effects associated with long-term lithium
treatment are goiter and hypothyroidism. Hyperthyroidism is a rare complication.
Lithium may also interfere with thyroid immunity (Kraszewska et al. 2014).
In bipolar disorder, the thyroid function should be examined in the context of the
role of the thyroid gland, the hypothalamic-pituitary-thyroid axis, and the thyroid
autoimmunity in the pathophysiology of this illness. Recently we studied 98 bipolar
subjects receiving lithium for mean 19 years and 39 subjects, matched for gender and
duration of the illness, never receiving lithium. The concentration of the thyroid-
stimulating hormone (TSH) and the volume of the thyroid gland were significantly
higher in patients receiving lithium. However, the frequency of hypothyroidism in
the course of the illness was similar in both groups (24% vs. 18%), higher in women
than in men (32% vs. 7% and 22% vs. 8%, respectively). In lithium-treated subjects,
hypothyroidism usually developed in the first years of lithium therapy, and all
hypothyroid patients were successfully treated with levothyroxine. No difference
in thyroid autoantibodies was found between the two groups (Kraszewska et al
2019a, b). In another study, we showed that patients who have been taking lithium
for 10–20 years had similar indexes of thyroid function as the patients in which the
drug was given for 20 years or more (Kraszewska et al. 2015).
Lithium increases renal calcium reabsorption and stimulates the release of the
parathyroid hormone. Long-term lithium administration causes a 10% increase of
serum calcium, and the cases of hyperparathyroidism have also been described. In
asymptomatic patients, monitoring of calcium level is recommended. In case of
serious hyperparathyroidism, the condition should be treated similarly as primary
cases.

Effect of Lithium on Neurocognitive Functions

Moderate cognitive impairment is perceived by clinicians as connected with lithium

treatment. However, since patients with bipolar disorder present cognitive problems
of mild intensity across mood states, worsening during manic or depressive epi-
sodes, and sometimes also persisting during euthymia, this should be taken into
account when assessing lithium effect. The biggest meta-analysis in this respect
1512 J. K. Rybakowski

performed by Wingo et al. (2009) including 276 lithium-treated and 263 similar
subjects lithium-free showed that lithium treatment of mood disorder patients was
associated with a small, but significant, impairment in immediate verbal learning and
memory and longer duration of treatment – with impairment of psychomotor
performance. On the other hand, the results of animal research point to lithium
exerting a favorable effect on cognitive function as demonstrated in various models.
Lithium treatment protects irradiated hippocampal neurons from apoptosis and
improves cognitive performance in irradiated mice. Such a pro-cognitive effect of
lithium was associated with the inhibition of GSK-3beta and an increase in Bcl-2
protein expression (Yazlovitskaya et al. 2006). In another study, using three different
positive reinforcement spatial cognitive tasks in rats, it was demonstrated that
lithium magnifies learning in all three tasks which may be associated with enhancing
hippocampal synaptic plasticity (Nocjar et al. 2007).
Clinical studies assessing the effect of lithium on cognitive functions were
recently reviewed (Rybakowski 2016). It seems that lithium treatment may
not negatively affect previously impaired cognitive functions in bipolar patients.
Spanish researchers (Lopez-Jaramillo et al. 2010) found a lower performance on
episodic verbal and visual-verbal memory tests of bipolar patients, compared to the
healthy subjects but no differences between lithium-treated and bipolar patients with
no medication intake and concluded that lithium therapy had no deleterious effect on
cognition. We have attempted to correlate cognitive functions in lithium-treated
patients with a quality of lithium prophylactic effect. We found that non-responders
to lithium had significantly worse performance on many domains of the Wisconsin
Card Sorting Test, compared to excellent and partial responders (Rybakowski et al.
2009). In another study, using neuropsychological tests from a CANTAB battery
which measured spatial working memory and sustained attention, we demonstrated
that bipolar patients who are excellent lithium responders have cognitive functions
comparable to those of matched control subjects, thereby probably constituting a
specific subgroup of bipolar patients in which long-term lithium administration can
produce complete normality in this respect (Rybakowski and Suwalska 2010).
Out of possible mechanisms mitigating the negative effect of lithium on cognitive
functions, the most important could be related to the prevention by lithium of
affective recurrences. Studies performed on bipolar patients have shown a correla-
tion between existing neuropsychological deficits, a greater number of affective
episodes, and a more severe course of the illness. The neurobiological components
mitigating a negative effect of lithium on cognitive functions could mostly be due to
its neurotrophic and neuroprotective effects. The most important neurobiological
processes in this respect are the stimulation of the BDNF system and inhibition of
GSK-3β. An antiviral effect of lithium, especially against herpes viruses, may also be
taken into account. Dickerson et al. (2004) demonstrated that infection with herpes
simplex virus type 1 was an independent predictor of decreased cognitive function-
ing (mostly immediate verbal memory) in bipolar patients, while a study of
Rybakowski and Amsterdam (2001) showed that lithium treatment exerted a signif-
icant anti-herpes activity. Finally, using lithium in the lowest possible dose could
also be a protective factor against possible cognitive problems.
Mood Stabilizers: Lithium 1513

Lithium in Pregnancy and the Postpartum Period

In women with bipolar disorder, there is an increased risk for a recurrence of illness
during pregnancy. Therefore it is agreed upon that women with the previous
favorable effect of lithium should continue using lithium during pregnancy. Gener-
ally, such a procedure is thought to be relatively safe; however, in each case, the cost-
benefit ratio should be considered between the effectiveness of lithium at reducing
relapse and increased risk of potential complications with lithium use. A recent meta-
analysis included data from pregnant women and their children from 6 international
cohorts based in the community (Denmark, Sweden, and Canada) and clinics (the
Netherlands, UK, and the USA), identifying 727 lithium-exposed out of 22,124
eligible pregnancies. Lithium exposure was not associated with any of the predefined
pregnancy complications or delivery outcomes. Such an exposure during the first
trimester was associated with a 1.7-fold increased risk of major malformations, but
for major cardiac malformations, the difference was not significant. A 1.6-fold
increased risk for neonatal readmission within 28 days of birth was also seen in
the lithium-exposed group (Munk-Olsen et al. 2018). Women using lithium should
remember that during pregnancy lithium clearance increases. Therefore, starting
with the second trimester, there is a necessity to increase the lithium dose. Also,
there is a need to reduce the dose of lithium or temporarily stop its use for 1 or 2 days
before expected delivery.
Lithium is excreted in breast milk. In infants, the plasma levels of lithium may
reach 30–50% of the mother. Therefore, there is a need for the mother to reconsider
breastfeeding or to reduce lithium dose and monitor closely the infant for any signs
of toxicity.

Lithium Intoxication

Lithium intoxication can be caused by intentional or accidental overdose and by

disrupting salt and water balance due to several factors (e.g., dehydration, infection
with fever, adding new medication). The symptoms can appear at a lithium concen-
tration of 1.2 mmol/l or higher. In mild lithium intoxication, symptoms include
weakness, worsening tremor, mild ataxia, poor concentration, and diarrhea. In severe
intoxication, vomiting and increase of neurological disturbances such as cerebellar
signs (tremor, nystagmus, dysarthria, vertigo, ataxia), extrapyramidal Parkinsonian,
or choreoathetotic motor symptoms occur. This may lead to a loss of consciousness,
occasionally with the occurrence of convulsions.
Treatment of lithium intoxication includes supportive care and enhancement of
lithium elimination with intravenous saline. Hemodialysis is the method of choice
for treating patients with severe intoxication and high lithium levels (>2 mmol/l). In
some patients, persisting neurological and cognitive deficits following lithium intox-
ication such as short-term memory disturbances and cerebellar dysfunctions (espe-
cially ataxia) can ensue, named the syndrome of irreversible lithium-effectuated
neurotoxicity (SILENT) (Adityanjee et al. 2005).
1514 J. K. Rybakowski

Lithium Interaction with Other Drugs

The review of lithium interaction with other drugs was recently made by Finley
(2016). Pharmacokinetic interactions with lithium are mainly connected with the
effect of other drugs on renal lithium clearance. A decrease of lithium clearance
can be due to stimulation on proximal tubular sodium reabsorption with concom-
itant reabsorption of lithium. This makes a mechanism of decreasing lithium
clearance by thiazides, amiloride, and spironolactone. Furosemide exerts only
minimal effect in this respect. Drugs that are lowering blood pressure such as
angiotensin-converting enzyme (ACE) inhibitors, beta-blocking agents, or calcium
entry blocker, verapamil, can decrease lithium clearance by reducing renal perfu-
sion pressure. However, other calcium entry blockers such as nifedipine or
isradipine can cause an increase in lithium clearance by producing afferent arteri-
olar vasodilatation. The same mechanism pertains to xanthines, such as aminoph-
ylline, theophylline, and caffeine. Patients who abruptly stop excessive drinking of
coffee or tea may be at risk of decreasing lithium clearance which may even result
in intoxication. On the other hand, a decrease of lithium clearance using nonste-
roidal anti-inflammatory drugs (NSAIDs) is due to inducing by these drugs the
reabsorption of lithium in the distal neuron. Aspirin does not seem to have such an
effect. Accelerating lithium elimination can be also obtained through decreasing
lithium reabsorption in the proximal tubule by osmotic diuresis (e.g., mannitol),
carbonic anhydrase inhibitor, acetazolamide, and sodium bicarbonate (Schou and
Kampf 2006).
Pharmacodynamic drug interactions of lithium are mostly connected with
neural transmission. Since lithium can attenuate dopaminergic transmission and
enhance serotonergic one, this may be significant for the interaction of lithium with
antipsychotic and antidepressant drugs. Concomitant use of lithium with typical
antipsychotic drugs, with strong antidopaminergic activity, such as haloperidol,
can result in an increase of neurotoxicity, e.g., exaggeration of extrapyramidal
symptoms, disturbances of consciousness, and a higher risk of the neuroleptic
malignant syndrome. Such effects are dose-dependent. Conversely, lithium may
attenuate the effect of dopaminergic substances such as cocaine or amphetamine.
The use of lithium with serotonergic antidepressant drugs (tricyclic drug clomip-
ramine and all selective serotonin reuptake inhibitors – SSRI) may increase the risk
for serotonin syndrome. Using lithium with any tricyclic antidepressant may cause
an intensification of the muscular tremor. Concomitant use of lithium and anti-
convulsants, especially in higher concentrations may increase the neurotoxicity. It
can also be noticed that carbamazepine used with lithium can decrease lithium-
induced polyuria and lithium can prevent carbamazepine-induced leukopenia.
Lithium can cause a prolongation of action of a neuromuscular blocker,
suxamethonium, by interfering with the cholinergic system. Therefore, lithium
withdrawal has been recommended before the course of electroconvulsive therapy,
where suxamethonium is used.
The significant main interactions of lithium with other drugs are shown in Table 2.
Mood Stabilizers: Lithium 1515

Table 2 Pharmacokinetic and pharmacodynamic interactions between lithium and other drugs
Pharmacokinetic interactions (the effect via renal lithium clearance)
Drugs decreasing lithium clearance (the increase of lithium concentration and toxicity)
Diuretics: thiazides, amiloride (furosemide – minimal effect)
Angiotensin-converting enzyme (ACA) inhibitors: captopril, enalapril
Non-steroidal anti-inflammatory drugs (NSAID): indomethacin, diclofenac, piroxicam, ibuprofen
(aspirin – minimal effect)
Drug increasing lithium clearance (accelerating lithium elimination)
Xanthines: aminophylline, caffeine, theophylline
Osmotic diuretics: glucose, mannitol
Carbonic anhydrase inhibitors: acetazolamide
Sodium bicarbonate
Pharmacodynamic interactions (the effect via neural transmission)
Typical antipsychotic drugs, e.g., haloperidol: increase of neurotoxicity – an exaggeration of
extrapyramidal symptoms, disturbances of consciousness, higher risk of the neuroleptic malignant
syndrome
Psychostimulant drugs (cocaine, amphetamine) – attenuation of euphoriant action
Serotonergic antidepressant drugs, e.g., clomipramine, selective serotonin reuptake inhibitors
(SSRI): higher risk of the serotonin syndrome
Tricyclic antidepressant drugs: intensification of muscular tremor
Anti-convulsant drugs: increase of neurotoxicity (carbamazepine may decrease lithium-induced
polyuria)
Neuromuscular blockers (suxamethonium) – prolonged duration of action

Combination Therapy

For prophylaxis of mood recurrences, monotherapy with lithium is fully effective in

about 30% of the subjects (excellent lithium responders). It is conceivable that such a
percentage of good response may apply to monotherapy with any other mood
stabilizer, although clinical characteristics of responding patients can be different.
Therefore, it is widely accepted that in at least half of bipolar patients, the effective
prophylaxis can be attained by a targeted combination of two mood stabilizers. The
use of lithium as a part of the treatment in combination with other mood stabilizers is
justified by research showing that the use of lithium together with olanzapine,
quetiapine, or aripiprazole shows significantly greater prophylactic efficacy that
uses of each of these drugs individually (Katagiri et al. 2012; Suppes et al. 2013;
Marcus et al. 2011). Also in the BALANCE study, the combination of lithium with
valproate was more prophylactically effective than lithium alone (Geddes et al.
2010). Such combinations with lithium are usually well tolerated.
Lithium can also be used in combination therapy with another mood stabilizer
during an acute phase of severe mania. The combination therapy of lithium with
antidepressants can serve as an augmentation of antidepressant drugs in treatment-
resistant depression.
1516 J. K. Rybakowski

Conclusions

The recent, most comprehensive textbook on lithium, titled Lithium in Neuropsy-

chiatry: The Comprehensive Guide was published 12 years ago (Bauer et al. 2006).
Therefore, in this chapter, an attention has been paid to the main developments
connected with lithium that took place in the last decade. It seems that two such most
important issues can be delineated. First, molecular genetic studies assessed a
genetic underpinning of the quality of lithium response, and the biggest development
in this area was the first GWAS of lithium prophylaxis. Second, the accumulation of
data pointing at the neurotrophic and neuroprotective properties of lithium gave rise
to attempts of its use in dementia and neurodegenerative disorders.
As to bipolar mood disorder, lithium remains the drug of the first choice.
However, despite its clinical efficacy surpassing other mood-stabilizing drugs, and
powerful anti-suicidal, immunomodulatory, and neuroprotective effects, the drug
nowadays is greatly underprescribed, and its therapeutic potential in bipolar disorder
is not fully utilized.

Cross-References

▶ Guidelines on Mood Stabilizers

▶ Mood Stabilizers: Carbamazepine
▶ Mood Stabilizers: Course and Duration of Therapy, Withdrawal Syndromes, and
Resistance to Therapy
▶ Mood Stabilizers: Lamotrigine
▶ Mood Stabilizers: Pharmacology and Biochemistry
▶ Mood Stabilizers: Side Effects, Contraindications, and Interactions
▶ Mood Stabilizers: Valproate

References
Adityanjee, Munshi KR, Thampy A. The syndrome of irreversible lithium-effectuated neurotoxic-
ity. Clin Neuropharmacol. 2005;28:38–48.
Alda M. Pharmacokinetics of lithium. In: Bauer M, Grof P, Müller-Oerlinghausen B, editors.
Lithium in neuropsychiatry. The comprehensive guide. Boca Raton: Taylor & Francis; 2006.
p. 321–8.
Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol
Psychiatry. 2015;20:661–70.
Arfwedson A. Untersuchungen einiger bei der Eisen Grube von Utö vorkommenden Fossilien und
von einem darin gefundenen neuen feuerfesten Alkali. Schweiggers Journal für Chemie und
Physik. 1818;22:93–120.
Baastrup PC. The use of lithium in manic-depressive psychoses. Compr Psychiatry.
1964;5:396–408.
Baastrup PC, Schou M. Lithium as a prophylactic agent. Its effect against recurrent depression and
manic-depressive psychosis. Arch Gen Psychiatry. 1967;16:162–72.
Mood Stabilizers: Lithium 1517

Bauer MS, Mitchner L. What is a “mood stabilizer”? An evidence-based response. Am J Psychiatry.

2004;161:3–18.
Bauer M, Grof P, Müller-Oerlinghausen B. Lithium in neuropsychiatry. The comprehensive guide.
Boca Raton: Taylor & Francis; 2006.
Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the
management of major depressive disorder. CNS Drugs. 2014;28:331–42.
Berridge MJ, Downes CP, Hanley MR. Neural and developmental actions of lithium: a unifying
hypothesis. Cell. 1989;59:411–9.
Bierbrauer J, Albrecht J, Müller-Oerlinhausen B. Lithium and its cardiovascular effects. In: Bauer
M, Grof P, Müller-Oerlinghausen B, editors. Lithium in neuropsychiatry. The comprehensive
guide. Boca Raton: Taylor & Francis; 2006. p. 295–301.
Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J. Decreased risk of suicides and
attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord. 2006;8:625–39.
Blackwell B, Shepherd M. Prophylactic lithium: another therapeutic myth? An examination of the
evidence to date. Lancet. 1968;291:968–71.
Blüml V, Regier MD, Hlavin G, Rockett IR, König F, Vyssoki B, et al. Lithium in the public water
supply and suicide mortality in Texas. J Psychiatr Res. 2013;47:407–11.
Cade JFK. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;36:349–52.
Chen TY, Kamali M, Chu CS, Yeh CB, Huang SY, Mao WC, et al. Divalproex and its effect on
suicide risk in bipolar disorder: a systematic review and meta-analysis of multinational obser-
vational studies. J Affect Disord. 2019;245:812–8.
Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al. Comparative efficacy and
acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet.
2011;378:1306–15.
Coppen A, Standish-Barry H, Bailey J, Houston G, Silcocks P, Hermon C. Does lithium reduce the
mortality of recurrent mood disorders? J Affect Disord. 1991;23:1–7.
Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depres-
sive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry.
2007;68:935–40.
Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood
disorders: updated systematic review and meta-analysis. Br Med J. 2013;346:f3646.
De Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in
tricyclic antidepressant nonresponders. Br J Psychiatry. 1981;138:262–56.
Delay J, Deniker P, Harl J-M. Utilisation en thérapeutique psychiatrique d’une phénothiazine
d’action centrale elective. Ann Méd-Psychol. 1952;110:112–31.
Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Cole S, Krivogorsky B, et al. Infection with
herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder. Biol
Psychiatry. 2004;55:588–93.
Donix M, Bauer M. Population studies of association between lithium and risk of neurodegener-
ative disorders. Curr Alzheimer Res. 2016;13:873–8.
Duke P, Hochman G. A brilliant madness; living with manic-depressive illness. New York:
Bantam Books; 1992.
Duke P, Turan K. Call me Anna: the autobiography of Patty Duke. New York: Bantam Books; 1987.
Fajardo VA, Fajardo VA, LeBlanc PJ, MacPherson REK. Examining the relationship between trace
lithium in drinking water and the rising rates of age-adjusted Alzheimer’s disease mortality in
Texas. J Alzheimers Dis. 2018;61:425–34.
Felber W. Die Lithiumprophylaxe der Depression vor 100 Jahren – ein genialem Irrtum. Fortschr
Neurol Psychiatr. 1987;55:141–4.
Ferensztajn-Rochowiak E, Kucharska-Mazur J, Tarnowski M, Samochowiec J, Ratajczak MZ,
Rybakowski JK. Stem cells, pluripotency and glial cell markers in peripheral blood of bipolar
patients on long-term lithium treatment. Prog Neuro-Psychopharmacol Biol Psychiatry.
2018;80:28–33.
Finley PR. Drug interactions with lithium: an update. Clin Pharmacokinet. 2016;55:925–41.
1518 J. K. Rybakowski

Garrod AB. Gout and rheumatic gout. London: Walton and Maberly; 1859.
Geddes JR, Burgess S, Kawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar
disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry.
2004;161:217–22.
Gerdtz J. Mental illness and the Roman physician: the legacy of Soranus of Ephesus. Hosp
Community Psychiatry. 1994;45:485–7.
Geddes JR, Goodwin GM, Rendell J Azorin J-M, Cipriani A, Ostacher MJ, et al. Lithium plus
valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder
(BALANCE): a randomized open-label trial. Lancet. 2010;375:385–95.
Germana C, Kempton MJ, Sarnicola A, Christodoulou T, Haldane M, Hadjulis M, et al. The effects
of lithium and anticonvulsants on brain structure in bipolar disorder. Acta Psychiatr Scand.
2010;122:481–7.
Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar
Disord. 2016;4:27.
Goodwin GM, Bowden CL, Calabrese JR, Grunze H, Kasper S, White R, et al. A pooled analysis of
2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I
disorder. J Clin Psychiatry. 2004;65:432–41.
Grof P. Excellent lithium responders: people whose lives have been changed by lithium prophy-
laxis. In: Birch NJ, Gallicchio VS, Becker RW, editors. Lithium: 50 years of psychopharma-
cology, new perspectives in biomedical and clinical research. Cheshire: Weidner Publishing
Group; 1999. p 36–51.
Grof P. Sixty years of lithium responders. Neuropsychobiology. 2010;62:27–35.
Hajek T, Weiner MW. Neuroprotective effects of lithium in human brain? Food for thought. Curr
Alzeimer Res. 2016;13:862–72.
Hajek T, Bauer M, Simhandl C, Rybakowski J, O’Donovan C, Pfennig A, et al. Neuroprotective
effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treat-
ment response. Psychol Med. 2014;44:507–17.
Hammond WA. Treatise on diseases of the nervous system. New York: Appleton; 1871.
Hartigan GP. The use of lithium salts in affective disorders. Br J Psychiatry. 1963;109:810–4.
Hawking S. A brief history of time. From the Big Bang to back holes. New York: Bantam Books;
1988.
Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, et al. Genetic variants
associated with response to lithium treatment in bipolar disorder: a genome-wide association
study. Lancet. 2016;387:1085–93.
International Consortium on Lithium Genetics (ConLi+Gen), Amare AT, Schubert KO, Hou L,
Clark SR, Papiol S, et al. Association of polygenic score for schizophrenia and HLA antigen and
inflammation genes with response to lithium in bipolar affective disorder: a genome-wide
association study. JAMA Psychiat. 2018;75:65–74.
Jamison KR. An unquiet mind. A memoir of moods and madness. New York: Alfred A. Knopf;
1996.
Jope RS. Glycogen synthase kinase-3 in the etiology and treatment of mood disorders. Front Mol
Neurosci. 2011;4:16.
Kapusta ND, Mossaheb N, Etzersdorfer E, Hlavin G, Thau K, Willeit M, et al. Lithium in drinking
water and suicide mortality. Br J Psychiatry. 2011;198:346–50.
Katagiri H, Takita Y, Tohen M, Higuchi T, Kanba S, Takahashi M. Safety and efficacy of olanzapine
monotherapy and olanzapine with a mood stabilizer in 18-week treatment of manic/mixed
episodes for Japanese patients with bipolar I disorder. Curr Med Res Opin. 2012;28:701–13.
Kessing LV, Sondergard L, Forman JL, Andersen PK. Lithium treatment and the risk of dementia.
Arch Gen Psychiatry. 2008;65:1331–5.
Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia ? Bipolar Disord.
2010;12:97–4.
Kessing LV, Gerds TA, Knudsen NN, Jørgensen LF, Kristiansen SM, Voutchkova D, et al.
Association of lithium in drinking water with the incidence of dementia. JAMA Psychiat.
2017;74:1005–10.
Mood Stabilizers: Lithium 1519

Kessing LV, Bauer M, Nolen WA, Severus E, Goodwin GM, Geddes J. Effectiveness of mainte-
nance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: a
systematic review of evidence from observational studies. Bipolar Disord. 2018; https://doi.org/
10.1111/bdi.12623.. [Epub ahead of print]
Ketter TA, Miller S, Dell’Osso B, Wang PW. Treatment of bipolar disorder: review of evidence
regarding quetiapine and lithium. J Affect Disord. 2016;191:256–73.
Kraszewska A, Ziemnicka K, Jończyk-Potoczna K, Sowiński J, Rybakowski JK. Thyroid structure
and function in long-term lithium-treated and lithium-naïve bipolar patients. Hum
Psychopharmacol. 2019a;34:e2708.
Kraszewska A, Ziemnicka K, Sowiński J, Ferensztajn-Rochowiak E, Rybakowski JK. No connec-
tion between long-term lithium treatment and antithyroid antibodies. Pharmacopsychiatry.
2019b;52:232–6.
Kleindienst N, Greil W. Differential efficacy of lithium and carbamazepine in the prophylaxis of
bipolar disorder: results of the MAP study. Neuropsychobiology. 2000;42(suppl 1):2–10.
Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. 6th ed. Leipzig: Barth; 1899.
Kraszewska A, Abramowicz M, Chłopocka-Woźniak M, Sowiński J, Rybakowski J. The effect of
lithium on thyroid function in patients with bipolar disorder. Psychiatr Pol. 2014;48:417–28.
Kraszewska A, Chlopocka-Wozniak M, Abramowicz M, Sowinski J, Rybakowski JK. A cross-
sectional study of thyroid function in 66 patients with bipolar disorder receiving lithium for
10–44 years. Bipolar Disord. 2015;17:375–80.
Lange C. Om Periodiske Depressionstilstande og deres Patogenese. Lund: Copenhagen; 1886.
Lange C. Periodische Depressionzustände und ihre Pathogenesis auf dem Boden der harnsäuren
Diathese. Hamburg/Leipzig: Verlag von Leopold Voss; 1895.
Leroy K, Ando K, Heraud C, Yilmaz Z, Authelet M, Boeynaems JM, et al. Lithium treatment arrests
the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neuro-
fibrillary pathology. J Alzheimers Dis. 2010;19:705–19.
Lewitzka U, Severus E, Bauer R, Ritter P, Müller-Oerlinghausen B, Bauer M. The suicide
prevention effect of lithium: more than 20 years of evidence-a narrative review. Int J Bipolar
Disord. 2015;3:32.
Lopez-Jaramillo C, Lopera-Vasquez J, Ospina Duque J, et al. Lithium treatment effects on the
neuropsychological functioning of patients with bipolar I disorder. J Clin Psychiatry.
2010;71:1055–60.
Luria SE. A slot machine, a broken test tube: an autobiography. New York: Harper and Row; 1984.
Lyoo K, Dager SR, Kim JE, Yoon SJ, Friedman SD, Dunner DL, et al. Lithium-induced grey matter
volume increase as a neural correlate of treatment response in bipolar disorder. A longitudinal
brain imaging study. Neuropsychopharmacology. 2010;35:1743–50.
Machado-Vieira R. Lithium, stress, and resilience in bipolar disorder: deciphering this key homeo-
static synaptic plasticity regulator. J Affect Disord. 2018;233:92–9.
Malhi GS, Outhred T. Therapeutic mechanisms of lithium in bipolar disorder: recent advances and
current understanding. CNS Drugs. 2016;30:931–49.
Manchia M, Adli M, Akula N, Ardau R, Aubry JM, Backlund L, et al. Assessment of response to
lithium maintenance treatment in bipolar disorder: a Consortium on Lithium Genetics
(ConLiGen) report. PLoS One. 2013;8:e65636.
Mann L, Heldman E, Bersudsky Y, Vatner SF, Ishikawa Y, Almog O, et al. Inhibition of specific
adenylyl cyclase isoforms by lithium and carbamazepine, but not valproate, may be related to
their antidepressant effect. Bipolar Disord. 2009;11:885–96.
Marcus R, Khan A, Rollin L, Morris B, Timko K, Carson W. Efficacy of aripiprazole adjunctive to
lithium or valproate in the long-term treatment of patients with bipolar I disorder with an
inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, random-
ized study. Bipolar Disord. 2011;13:133–44.
Matsunaga S, Kishi T, Annas P, Basun H, Hampel H, Iwata N. Lithium as a treatment for
Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2015;48:403–10.
Moncrieff J. Lithium: evidence rconsidered. Br J Psychiatry. 1997;171:113–9.
1520 J. K. Rybakowski

Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK. Lithium-induced increase in human brain
grey matter. Lancet. 2000;356:1241–2.
Müller-Oerlinghausen B, Ahrens B, Grof E, Grof P, Lenz G, Schou M, et al. The effect of long-term
lithium treatment on the mortality of patients with manic-depressive and schizoaffective illness.
Acta Psychiatr Scand. 1992;86:218–22.
Munk-Olsen T, Liu X, Viktorin A, Brown HK, Di Florio A, D’Onofrio BM, et al. Maternal and
infant outcomes associated with lithium use in pregnancy: an international collaborative meta-
analysis of six cohort studies. Lancet Psychiatry. 2018;5:644–52.
Nassar A, Azab AN. Effects of lithium on inflammation. ACS Chem Neurosci. 2014;5:451–8.
Nivoli AMA, Murru A, Vieta E. Lithium: still a cornerstone in the long-term treatment in bipolar
disorder? Neuropsychobiology. 2010;62:27–35.
Nocjar C, Hammonds MD, Shim SS. Chronic lithium treatment magnifies learning in rats.
Neuroscience. 2007;150:774–88.
Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in
patients with Alzheimer’s disease. Curr Alzheimer Res. 2013;10:104–7.
Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N. Lithium levels in drinking water and risk of
suicide. Br J Psychiatry. 2009;195:464–5.
Pasquali L, Busceti CL, Fulceri F, Paparelli A, Fornai F. Intracellular pathways underlying the
effects of lithium. Behav Pharmacol. 2010;21:473–92.
Permoda-Osip A, Abramowicz M, Kraszewska A, Suwalska A, Chłopocka-Woźniak M,
Rybakowski JK. Kidney, thyroid and other organ functions after 40 years or more of lithium
therapy: a case series of five patients. Ther Adv Psychopharmacol. 2016;6:277–82.
Pisanu C, Papadima EM, Del Zompo M, Squassina A. Understanding the molecular mechanisms
underlying mood stabilizer treatments in bipolar disorder: potential involvement of epigenetics.
Neurosci Lett. 2018;669:24–31.
Quiroz JA, Machado-Vieira R, Zarate CA, Manji HK. Novel insights into lithium’s mechanism of
action: neurotrophic and neuroprotective effects. Neuropsychobiology. 2010;62:50–60.
Radomski J, Fuyat HN, Nelson AA, Smith PK. The toxic effects, excretion and distribution of
lithium chloride. J Pharmacol Exp Ther. 1950;100:429–40.
Remlinger-Molenda A, Wojciak P, Michalak M, Karczewski J, Rybakowski JK. Selected cytokine
profiles during remission in bipolar patients. Neuropsychobiology. 2012;66:193–8.
Rybakowski JK. Antiviral and immunomodulatory effect of lithium. Pharmacopsychiatry.
2000;33:159–64.
Rybakowski JK. Two generations of mood stabilizers. Int J Neuropsychopharmacol.
2007;10:709–11.
Rybakowski JK. Genetic influences on response to mood stabilizers in bipolar disorder: current
status of knowledge. CNS Drugs. 2013;27:165–73.
Rybakowski JK. Neurological, cognitive and neuroprotective effects of treatment used in bipolar
disorder. In: Yildiz A, Ruiz P, Nemeroff CB, editors. The bipolar book. History, neurobiology
and treatment. New York: Oxford University Press; 2015. p. 403–15.
Rybakowski JK. Effect of lithium on neurocognitive functioning. Curr Alzheimer Res.
2016;13:887–93.
Rybakowski JK. Meaningful aspects of the term ‘mood stabilizer’. Bipolar Disord. 2018;20:391–2.
Rybakowski JK, Amsterdam JD. Lithium prophylaxis and recurrent labial herpes infections.
Lithium. 1991;2:43–7.
Rybakowski J, Matkowski K. Adding lithium to antidepressant therapy: factors related to thera-
peutic potentiation. Eur Neuropsychopharmacol. 1992;2:161–5.
Rybakowski JK, Chłopocka-Woźniak M, Suwalska A. The prophylactic effect of long-term lithium
administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disord
2001;3:63–67.
Rybakowski JK, Suwalska A. Gastrointestinal, metabolic and body weight changes during treat-
ment with lithium. In: Bauer M, Grof P, Müller-Oerlinghausen B, editors. Lithium in neuro-
psychiatry. The comprehensive guide. Boca Raton: Taylor & Francis; 2006. p. 283–94.
Mood Stabilizers: Lithium 1521

Rybakowski JK, Permoda-Osip A, Borkowska A. Response to prophylactic lithium in bipolar

disorder may be associated with a preservation of executive cognitive functions. Eur Neuropsy-
chopharmacol. 2009;19:791–5.
Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and
plasma BDNF levels. Int J Neuropsychopharmacol. 2010;13:617–22.
Rybakowski J, Drogowska J, Abramowicz M, Chłopocka-Woźniak M, Czekalski S. The effect of
long-term lithium treatment on kidney function. Psychiatr Pol. 2012;46:627–36.
Rybakowski JK, Dmitrzak-Weglarz M, Kliwicki S, Hauser J. Polymorphism of circadian clock
genes and prophylactic lithium response. Bipolar Disord. 2014;16:151–8.
Rybakowski JK, Suwalska A, Hajek T. Clinical perspectives of lithium’s neuroprotective effect.
Pharmacopsychiatry. 2018;51:194–9.
Schou M, Juel-Nielsen N, Stromgren E, Voldby H. The treatment of manic psychoses by the
administration of lithium salts. J Neurol Neurosurg Psychiatry. 1954;17:250–60.
Schou M, Kampf D. Lithium and the kidneys. In: Bauer M, Grof P, Müller-Oerlinghausen B,
editors. Lithium in neuropsychiatry. The comprehensive guide. Boca Raton: Taylor & Francis;
2006. p. 251–8.
Schou M, Thompsen K. Lithium prophylaxis of recurrent endogenous affective disorders.
In: Johnson FN, editor. Lithium research and therapy. London: Academic; 1976. p. 63–84.
Schou M, Amdisen A, Eskjaer Jensen S, Olsen T. Occurrence of goitre during lithium treatment.
Br Med J. 1968;3:710–3.
Schulze TG, Alda M, Adli M, Akula N, Ardau R, Bui ET, et al. The International Consortium on
Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis
of response to lithium treatment. Neuropsychobiology. 2010;62:72–8.
Severus E, Bauer M. Managing the risk of lithium-induced nephropathy in the long-term treatment
of patients with recurrent affective disorders. BMC Med. 2013;11:34.
Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M, et al. Lithium for prevention of mood
episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord.
2014;2:15.
Skinner GRB, Hartley C, Buchan A, Harper L, Gallimore P. The effect of lithium chloride on the
replication of herpes simplex virus. Med Microbiol Immunol. 1980;168:258–65.
Sofola O, Kerr F, Rogers I, Killick R, Augustin H, Gandy C. Inhibition of GSK-3 ameliorates Abeta
pathology in an adult-onset Drosophila model of Alzheimer’s disease. PLoS Genet. 2010;6:pii:
e1001087.
Storosum JG, Wohlfarth T, Schene A, Elferink A, van Zwieten BJ, van den Brink W. Magnitude of
effect of lithium in short-term efficacy studies of moderate to severe manic episode. Bipolar
Disord. 2007;9:793–8.
Suppes T, Vieta E, Gustafsson U, Ekholm B. Maintenance treatment with quetiapine when
combined with either lithium or divalproex in bipolar I disorder: analysis of two large random-
ized, placebo-controlled trials. Depress Anxiety. 2013;30:1089–98.
Tondo L, Abramowicz M, Alda M, Bauer M, Bocchetta A, Bolzani L, et al. Long-term lithium
treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parame-
ters. Int J Bipolar Disord. 2017;5:27.
Undurraga J, Sim K, Tondo L, Gorodischer A, Azua E, Tay KH, et al. Lithium treatment for
unipolar major depressive disorder: systematic review. J Psychopharmacol. 2019;33:167–76.
Williams R, Ryves WJ, Dalton EC, Eickholt B, Shaltiel G, Agam G, et al. A molecular cell biology
of lithium. Biochem Soc Trans. 2004;32(Pt 5):799–802.
Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effect of lithium on cognitive performance: a
meta-analysis. J Clin Psychiatry. 2009;70:1588–97.
Yazlovitskaya EM, Edwards E, Thotala D, Fu A, Osusky KL, Whetsell WO Jr, et al. Lithium
treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res.
2006;66:11179–86.
Mood Stabilizers: Carbamazepine

Johannes M. Hennings

Contents
Chemistry, Developmental History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1524
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1525
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1525
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1525
Chemically Related Drugs: Oxcarbazepine and Eslicarbazepine . . . . . . . . . . . . . . . . . . . . . . . . . . 1526
Indications (of Marketed Products) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1526
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1527
Side Effects/Adverse Reactions and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1527
Dose-Related Effects Related to Drug Mechanism of Action, and Toxic Effects . . . . . . . . . 1532
Not Necessarily Dose-Related Effects, Cutaneous Adverse Reactions . . . . . . . . . . . . . . . . . . . . 1532
Teratogenic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1533
Combination Therapy – Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1533
Summary for Clinical Use in Psychiatric Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1534
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1534
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1534

Abstract
Carbamazepine is an antiepileptic drug that is chemically related to tricyclic
antidepressants. In psychiatric indications, it has been first used as an antimanic
treatment in bipolar disorder in the 1970s. Carbamazepine is now approved as
second-line treatment in bipolar disorder with best evidence in the treatment of
acute manic episodes. Carbamazepine is also effective in the management of
alcohol and benzodiazepine withdrawal syndromes. It was somehow useful in
various other psychiatric indications, including aggressive and impulsive behav-
ior, suicidality, and as an add-on in refractory schizophrenia. However, these
approaches are poorly supported by data. The clinical use of carbamazepine, on

J. M. Hennings (*)
kbo Isar-Amper-Klinikum Munich, Haar/Munich, Bavaria, Germany
e-mail: Johannes.hennings@kbo.de

© Springer Nature Switzerland AG 2022 1523

P. Riederer et al. (eds.), NeuroPsychopharmacotherapy,
https://doi.org/10.1007/978-3-030-62059-2_44
1524 J. M. Hennings

the other hand, is limited by its potential to interact with various other drugs,
some important side effects, especially in risk populations, and the presence of
somehow better alternatives in most indications. The carbamazepine-related
drugs oxcarbazepine and eslicarbazepine may have a more favorable side effect
and drug-interaction profile compared to its mother compound, but data are still
limited for the use in psychiatric indications.

Chemistry, Developmental History

Carbamazepine is a derivate of dibenzazepine (iminostilbene) and chemically related

to tricyclic antidepressants (TCA). The compound has been developed in the
laboratories of Geigy in Switzerland and first synthesized 1961 by Schindler
(López-Muñoz et al. 2018). The carbamyl group moiety at the position five is
regarded as essential for antiseizure affects. Historically, it has been used since the
1960s for the treatment of trigeminal neuralgia and as an antiepileptic drug (AED). It
is now approved by the Food and Drug Administration (FDA) for the treatment of
epilepsy, trigeminal neuralgia, tic douloureux, as well as acute manic and mixed
affective episodes in bipolar disorder. Specifically, it is considered to be a primary
drug for partial seizures with complex symptomatology (psychomotor, temporal
lobe), generalized tonic seizures (grand mal), and mixed seizure patterns. First
studies observed antimanic and mood stabilizing effects in the 1970s (López-
Muñoz et al. 2018) (Fig. 1).

Fig. 1 Chemical structure of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and

eslicarbazepine (obtained from Wikimedia Commons on 12/03/2018). The prodrug oxcarbazepine
is metabolized to (S)-licarbazepine (eslicarbazepine) and (R)-licarbazepine in a 4:1 ratio.
Eslicarbazepine acetate undergoes a quick and near complete first-pass hydrolysis to
eslicarbazepine primarily in the liver (Fricke-Galindo et al. 2018)
Mood Stabilizers: Carbamazepine 1525

Pharmacology

Pharmacokinetics

Carbamazepine itself is poorly soluble in water and its absorption is slow and
erratical after oral administration (McNamara 2001). Peak concentrations occur
after 4–8 h after oral ingestion. Carbamazepine distributes rapidly into all tissues,
but most of the drug will remain to plasma protein due to its high protein binding
property (about 75%). It is almost entirely metabolized in the liver by epoxidation
and hydroxylation. The elimination half-life is approximately 35 h, but it has been
reported to be lower in children (about 10 h) and higher in elderly patients
(30–50 h). The active metabolite carbamazepine-10,11-epoxide which may reach
50% of the parent compound plasma concentration, emerge from hepatic oxidation
via CYP3A4 and to a lesser extent CYP3A5 and CYP2C8 (Thorn et al. 2011).
The 10,11-epoxide is further metabolized and excreted partly as inactive glucuro-
nides in the urine. Carbamazepine upregulates transcription of CYP3A4 and other
enzymes, thus inducing its own metabolism. Subsequently increased clearance
may require dose adjustments after 2 or 3 week of treatment (Fricke-Galindo
et al. 2018).
Therapeutic drug concentrations in plasma are indicated between 4 and 12 μg/ml,
corresponding to 600–1200 mg/day. Nevertheless, there is no simple relationship
between the dose of carbamazepine and plasma concentrations, and dosing was not
specifically optimized for bipolar disorder (Baldessarini et al. 2019; Fountoulakis
et al. 2017).

Mechanism of Action

Carbamazepine blocks voltage-sensitive sodium channels (VSSCs) in a voltage-

dependent and frequency-dependent manner at clinically relevant concentrations.
Besides its action on the VSSC, carbamazepine perhaps also interferes with other ion
channels for calcium and potassium (Stahl 2013). In addition, carbamazepine
enhances the inhibitory effect of GABA and decreases the excitatory effect of
glutamate (Thorn et al. 2011).
Although these pharmacodynamic properties of carbamazepine are well
described, especially its action on voltage-sensitive sodium channels, it is not
entirely clear which specific pharmacological action is linked to which specific
clinical effect or side effect (Stahl 2013), particularly not for the psychiatric effects.
Some recent analyses point to an additional action on epigenetic mechanisms of
mood stabilizers including carbamazepine that still need to be further elucidated
(Pisanu et al. 2018). Substantial clinical efficacy has been demonstrated as an
antiepileptic, antimanic, mood-stabilizing (in terms of prophylaxis of hypomanic
or manic states), and as a neuropathic analgesic drug. Carbamazepine has less
antidepressive properties, prevents less from upcoming depressive episodes, and
has less analgesic effect in fibromyalgia.
1526 J. M. Hennings

Chemically Related Drugs: Oxcarbazepine and Eslicarbazepine

The prodrug oxcarbazepine and its active 10-hydroxy derivate eslicarbazepine are
structurally related to carbamazepine and presumably act also via binding to the
open channel conformation of the VSSC. Eslicarbazepine acetate is a once daily
antiepileptic drug that has been approved in 2009 by the European Medicines
Agency and in 2013 by the FDA and Health Canada as an adjunctive AED. After
oral administration, eslicarbazepine acetate undergoes extensive first pass hydrolysis
to its major active metabolite eslicarbazepine that represents about 95% of circulat-
ing active moieties (Soares-da-Silva et al. 2015). Compared to carbamazepine and
oxcarbazepine, eslicarbazepine has a higher affinity to the inactivated state of
the VSSC, resulting in a greater inhibitory effect on rapidly firing neurons.
Eslicarbazepine is further much more selective for the epileptogenic Cav3.2 calcium
channels (Soares-da-Silva et al. 2015).
While similar clinical effects as an antiepileptic agent has been described
compared to carbamazepine, the mood stabilizing properties of oxcarbazepine
seem to be less pronounced. Nevertheless, compared to carbamazepine,
oxcarbazepine seems to be less sedating, be less bone marrow toxic, and to
have fewer CYP3A4 interactions (Stahl 2013). Compared to carbamazepine,
eslicarbazepine is not metabolized to carbamazepine-10,11-epoxide, which is
accused to be related to enzymatic CYP450 induction and side effects
(Fricke-Galindo et al. 2018; McNamara 2001). Eslicarbazepine has shown an
improved tolerability, a better drug availability (once-daily administration) and
fewer drug-interactions compared to carbamazepine in the treatment focal
seizures (Fricke-Galindo et al. 2018) and, potentially, also in refractory bipolar
disorder. However, clinical efficacy in bipolar disorder, including acute
mania, has not yet been proven in a recent phase II clinical study (Grunze et al.
2018).

Indications (of Marketed Products)

Carbamazepine is used for the treatment of epilepsy and neuropathic pain.

It is used as a second-line treatment for bipolar disorder and off-label in combi-
nation with an antipsychotic in some cases of schizophrenia and schizoaffective
disorder when treatment with a conventional antipsychotic alone has failed. In the
United States, it is FDA-approved for epilepsy, trigeminal neuralgia, and manic
and mixed episodes of bipolar disorder. According to the American Psychiatric
Association (APA) (Hirschfeld 2002), carbamazepine or oxcarbazepine can
be used as an alternative medication in lieu of lithium or valproate for the
treatment of acute manic or mixed episodes. For maintenance treatment,
carbamazepine and oxcarbamazepine can be an alternative to first-line treatment
with lithium and valproate. Nevertheless, the use of oxcarbazepine or
eslicarbazepine in bipolar disorder is not yet unambiguously proven (Baldessarini
et al. 2019).
Mood Stabilizers: Carbamazepine 1527

Clinical Studies

In the 1970s, first clinical studies demonstrated mood stabilizing and antimanic proper-
ties of carbamazepine (López-Muñoz et al. 2018). Despite its wide clinical use in
various psychiatric indications, the evidence based on randomized placebo-controlled
trials (RCT) is limited, even for the treatment of bipolar disorder (Baldessarini et al.
2019). Acute antimanic effects have been shown in two randomized placebo-controlled
trials with 427 subjects in total (Baldessarini et al. 2019). Carbamazepine was not
significantly different to placebo in one long-term trial (up to 12 months), and carba-
mazepine was inferior compared to lithium in two long-term trials. The evidence for the
use in bipolar depression is limited to one RCT (Baldessarini et al. 2019).
According to recent guidelines of the World Federation of Societies of Biological
Psychiatry (Grunze et al. 2018), carbamazepine and oxcarbazepine remain second-
line treatments in bipolar disorder. There is a grade 2 (fair research-based evidence)
recommendation of the International College Neuropsychopharmacology (CINP)
for carbamazepine for the acute treatment, while grades for oxcarbazepine and
eslicarbazepine are 3 (some evidence from comparative studies without placebo
arm or from post-hoc analyses) and 5 (negative data), respectively (Fountoulakis
et al. 2017). In acute mixed episodes, there is a grade 3 recommendation for
depressive and manic symptomatology, mirroring that the evidence is limited due
to only few available studies and syndromal overlap of this entity with other
conditions such as borderline personality disorder (BPD). Maintenance treatment
for manic or depressive episode prevention with carbamazepine has a level 4
recommendation (inconclusive data or poor quality of RCTs). There is no recom-
mendation of neither carbamazepine, oxcarbazepine, or eslicarbazepine in the NICE
guidelines (National Collaborating Centre for Mental Health (UK) 2018).
In contrast to some former reports of its potential use in refractory cases of
schizophrenia and schizoaffective disorder, carbamazepine cannot be recommended
as a routine use in the treatment of schizophrenia, even not if augmented to an
existing antipsychotic medication according to a recent meta-analysis (Leucht et al.
2014). Some smaller studies further suggests effectivity for behavioral control in
BPD as well as agitation, aggression, and impulsive behavior with or without
dementia (Belli et al. 2012; Gallagher and Herrmann 2014; Jones et al. 2011).
Carbamazepine and oxcarbazepine has shown mood-stabilizing properties in atten-
tion-deficit hyperactivity disorder (ADHD) (Davids et al. 2006; Silva et al. 1996).
Recommendations for carbamazepine’s various psychiatric indications are summa-
rized in Table 1, illustrating its wide use in off-label indications with limited
evidence from controlled clinical studies (Perucca and Gilliam 2012).

Side Effects/Adverse Reactions and Toxicology

Nearly, 50–70% of patients receiving carbamazepine experience side effects (Fricke-

Galindo et al. 2018; Hirschfeld 2002). An overview of carbamazepine’s adverse
drug reactions (ADR), its clinical presentation, prevention, and management is given
in Table 2.
1528 J. M. Hennings

Table 1 Psychiatric indications of carbamazepine

Approved Dose
Psychiatric indication rangea Summary of
indication (FDA) (mg/die) recommendation Reference(s)
Acute mania Yes 600–1200 Second-line treatment Fountoulakis
(bipolarIdisorder) (grade 2 recommendation et al. (2017),
according to CINP) Grunze et al.
(2018),
Hirschfeld (2002)
Bipolar No 450 Some evidence in small Grunze et al.
depression (mean) trials, no general (2018), Shim
recommendation et al. (2017)
Acute mixed Yes 600–1200 Second-line treatment Fountoulakis
episodes (bipolar (grade 3 recommendation et al. (2017),
I disorder) according to CINP) Grunze et al.
(2018),
Hirschfeld (2002)
Bipolar No 600–1200 Possible second-line Fountoulakis
maintenance: treatment, combination et al. (2017),
Prevention of with lithium, inconclusive Grunze et al.
depressive data (2018),
episodes Hirschfeld (2002)
Bipolar No 600–1200 Possible second-line Fountoulakis
maintenance: treatment, combination et al. (2017),
Prevention of with lithium, inconclusive Grunze et al.
manic episodes data (2018),
Hirschfeld (2002)
Aggression, No 100–300 Among AEDs, best Gallagher and
agitation, evidence for the treatment Herrmann (2014)
impulsive of agitation and
behavior aggression in dementia,
but limited use due to
tolerability.
450 Among AEDs and Jones et al.
(mean) lithium, best evidence for (2011)
carbamazepine/
oxcarbazepine in placebo-
controlled trials in patients
without diagnosis of
intellectual disability,
organic brain injury, and
psychosis. Dose range for
oxcarbazepine is
1200–2400 mg/die.
800 Off-label use for Belli et al. (2012)
(mean) behavioral control in
BPD, similar observations
for oxcarbazepine.
(continued)
Mood Stabilizers: Carbamazepine 1529

Table 1 (continued)
Approved Dose
Psychiatric indication rangea Summary of
indication (FDA) (mg/die) recommendation Reference(s)
N/A Possible mood-stabilizing Davids et al.
effect in adult ADHD for (2006), Silva
oxcarbazepine et al. (1996),
(300–1500 mg/die). Some Gorman et al.
preliminary evidence for (2015)
carbamazepine in child
and adolescent ADHD,
but recommendation
against use in child and
adolescent conduct
disorder due to ADRs and
limited behavioral effects.
Schizophrenia No 600–1200 Off-label use for Leucht et al.
refractory schizophrenia (2014)
and schizoaffective
disorder. According to a
recent meta-analysis, no
evidence for superiority
over placebo, even not in
combination with an
antipsychotic.
Suicidality No N/A Some effect in mood Chen et al.
disorders that cannot (2019), Tondo
clearly separated from and Baldessarini
primary anti-aggressive (2016)
effects, but less
pronounced than reported
for lithium. Negative
results in a recent meta-
analysis.
Substance use No 600–1200 Treatment of alcohol Welsh et al.
withdrawal symptoms, (2018), Fond et
but inconclusive evidence al. (2019), Soyka
in withdrawal seizure et al. (2017)
prevention compared to
benzodiazepines.
Reducing withdrawal in
benzodiazepine taper.
a
Note that dose recommendations derive from studies using occasionally various dosages, and
dosages may further be beyond this range in individual cases (e.g., in case of drug interactions).
Therefore, the dosage may be primarily adjusted according to the plasma concentration range
recommended for the treatment of epilepsia or bipolar disorder, i.e., 4 (6) to 12 μg/ml (Benkert
and Hippius 2019; Fountoulakis et al. 2017). Lower dosages (100–300 mg/die) have been used
throughout in child, adolescent and geriatric indications. N/A: not available (e.g., doses not
evaluated in studies). CINP: International College Neuropsychopharmacology, AED: antiepileptic
drug, BPD: Borderline personality disorder, ADHD: attention deficit hyperactivity disorder.
Table 2 Adverse drug reactions, clinical presentation, and recommendations
1530

Type of ADR, characteristics Clinical presentation Prevention Management

Related to the mechanism of Neurological symptoms (dizziness, diplopia, Careful dosing in elderly, check for Adjust dose, if necessary,
action, dose-related, common blurred vision, fatigue, nausea, and ataxia), drug-interactions discontinue.
(1–10%) or very common hyponatremia (antidiuretic effect) In case of intoxication,
(>10%), predictable and additional symptomatic
reversible treatment, gastric lavage, and
hemoperfusion may be required.
Related to immunological or • MPE (3–14 days after drug exposure onset): Genetic testing in Asians for HLA-B15:02 Instant drug discontinuation;
genetic susceptibility, Maculopapular skin lesions on the trunk and allele before initiation of treatment symptomatic treatment,
uncommon (0,1–1%) or rare chest (may further distribute to extremities and Risk allele carriers should not be treated intensive or intermediate care
(<0,1%), non-dose-related, mucosa)