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O P L
OX F O R D PSYCH IATRY LIB RARY
Depression
O P L
OX F O RD P S YC HIATRY LIB RARY
Depression
THIRD EDITION
Raymond W. Lam
Professor and BC Leadership Chair in Depression Research
Department of Psychiatry, University of British Columbia
Vancouver, British Columbia, Canada
1
1
Great Clarendon Street, Oxford, OX2 6DP,
United Kingdom
Oxford University Press is a department of the University of Oxford.
It furthers the University’s objective of excellence in research, scholarship,
and education by publishing worldwide. Oxford is a registered trade mark of
Oxford University Press in the UK and in certain other countries
© Oxford University Press 208
First Edition published in 2008
Second Edition published in 202
The moral rights of the author have been asserted
Impression:
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a retrieval system, or transmitted, in any form or by any means, without the
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Published in the United States of America by Oxford University Press
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ISBN 978–0–9–88044–7
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Oxford University Press makes no representation, express or implied, that the
drug dosages in this book are correct. Readers must therefore always check
the product information and clinical procedures with the most up-to-date
published product information and data sheets provided by the manufacturers
and the most recent codes of conduct and safety regulations. The authors and
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contained in any third party website referenced in this work.
Preface to the Third Edition
Despite some initial controversy, DSM-5 (Diagnostic and Statistical Manual of
Mental Disorders, 5th edn) has been accepted and adopted by most clinicians as
an incremental advance for the field. This new edition now incorporates DSM-5
as well as recent revisions in treatment guidelines for depression. The CANMAT
206 Clinical Guidelines for the Management of Adults with Major Depressive
Disorder were published as a theme issue in the Canadian Journal of Psychiatry,
and are available for free download at http://www.canmat.org, accessed
October 207. The CANMAT guidelines provide much of the reference material
used to summarize new evidence and recommendations for the dizzying array
of available treatments for depression, ranging from mindfulness-based psycho-
therapies to novel antidepressant medications, to neurostimulation and exercise.
All the key references in this edition have been updated to reflect the latest evi-
dence. I want to thank, again, my CANMAT colleagues (nearly 50 strong) for their
dedicated leadership in producing these internationally used guidelines, especially
my guidelines’ co-lead, Dr Sidney Kennedy. Their efforts contribute to making this
book clinically useful.
Progress usually advances incrementally, but medicine is at the tipping point
for the next great revolution—a digital personalized one. The emergence of
data science with ‘big data’ artificial intelligence and machine learning algorithms
heralds a real promise of precision medicine. Biomarker studies have given way
to biosignature research incorporating panels of integrated clinical, neuroimag-
ing, and molecular markers. Predicting individual response to treatment using
crowdsourced EEG (electroencephalographic) and clinical information; personal-
ized alerts for relapse with apps that analyze voice modulation, text messages,
and geographic location patterns; reprogramming neural circuits with individual-
ized brain games; adapting the lighting at home to optimize sleep and circadian
rhythms—these possibilities are no longer science fiction even if, for now, they
are not yet ready for prime-time clinical use. I have no doubt that this innova-
tive research will soon transform the diagnosis, management, and treatment of
depression. I look forward to incorporating these discoveries in a major rewrite
for the next edition of this book.
. Introduction 1
2. Epidemiology and burden 3
3. Pathogenesis 11
4. Clinical features and diagnosis 23
5. Associated clinical features 35
6. Clinical management 45
7. Psychological treatments 53
8. Pharmacological treatments 63
9. Somatic treatments 85
0. Special populations 95
xii • abbreviations
SAM-e S-adenosylmethionine
SCID Structured Clinical Interview for DSM-IV-TR
SERT serotonin transporter
SGA second-generation antipsychotic
SIGMA structured interview guide for the Montgomery–Åsberg Depression
Rating Scale
SNRI serotonin and noradrenaline reuptake inhibitor
SRI serotonin reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
STAR*D Sequenced Treatment Alternatives to Relieve Depression (study)
SWA slow-wave activity
SWS slow-wave sleep
TADS Treatment for Adolescents with Depression Study
TCA tricyclic antidepressant
TRD treatment-resistant depression
TSD total sleep deprivation
VNS vagus nerve stimulation
WHO World Health Organization
Chapter 1
Introduction
Key points
• Depression is a common and disabling psychiatric condition that must be
recognized by all physicians and health professionals.
• The principles of care for major depressive disorder include: thorough
assessment and diagnosis, selection of appropriate and evidence-based
treatments, and careful follow up using measurement-based care.
A 36 year old janitor who has insomnia and is fatigued all the time. A 24 year old
with diabetes who has stopped taking her insulin. A 40 year old homemaker who
cries and cannot cope at home. A 69 year old seen in the emergency room with
his second heart attack within 3 months. A 32 year old executive who is procras-
tinating about making decisions at work. A 7 year old high-school student who
cannot stop thinking about ending her life. What do all these various people have
in common? They are all suffering from depression, one of the most common of
all medical conditions, yet one of the most difficult to recognize.
Depression is ubiquitous, but the number and range of physical and cognitive
symptoms associated with major depressive disorder (MDD) means that many
people do not present with emotional symptoms. Although one in seven people
will suffer psychosocial impairment from MDD, many will not be diagnosed des-
pite repeated healthcare visits. And, it is not only family physicians, psychiatrists
and mental health clinicians that need to diagnose depression. The high preva-
lence of MDD with other medical illnesses means that other health profession-
als and physicians, whether internists or oncologists or surgeons or cardiologists
or neurologists or any other specialist, must also recognize and manage clinical
depression in their patients. After all, as some authors have noted, there is ‘no
health without mental health’.
Governments and healthcare payers are now finally appreciating the hidden
socioeconomic burden that results from MDD. Depression is a huge drain on
the economy, with exceedingly high rates of disability and reduced productivity.
The World Health Organization announced in 207 that depression had become
the leading medical cause of functional disability worldwide. The concentration,
memory, and decision-making problems associated with depression are particu-
larly damaging to workforces in knowledge-based industries, a major issue for
many countries trying to convert from resource-based economies.
chapter 1
2 • introduction
But, recognizing depression is not enough. The good news is that there are very
effective treatments for depression. Evidence-based psychotherapies abound,
there are many effective antidepressant medications, and several non-invasive
somatic treatments also are available. With appropriate treatment, most patients
are able to promptly recover from a depressive episode and return to their usual
functioning. And, there is an explosion of new research and new methodolo-
gies to expand our understanding of the pathophysiology of depression, with the
promise of new, more effective, and better tolerated treatments to come.
The bad news, however, is that many patients with depression are still not able
to access these treatments, whether psychotherapy or new medications or new
technologies. Even when available, the current systems of health care often do
not achieve best practices for treating MDD, so that the ‘usual care’ of depression
is not good enough. For those patients whose depression can be regarded as a
chronic or persistent condition, collaborative disease management programmes
that include a focus on self-management and functional improvement, instead of
symptom resolution, will further engage patients and clinicians to optimize care.
Mobile and internet technologies also herald promise in terms of access to both
educational information and evidence-based treatments. And, we are getting
closer to identifying clinically useful biomarkers to personalize treatment recom-
mendations for patients with MDD.
This book seeks to succinctly address the diagnostic and treatment issues
that clinicians will encounter when dealing with patients with MDD. The princi-
ples of care for depression can be quite simple. Attention to early recognition,
careful assessment, selection of appropriate evidence-based treatments, and
measurement-based follow up will help our patients get the best care possible.
Further Reading
Lam RW, Kennedy SH, Parikh SV, et al. (206) Canadian Network for Mood and Anxiety
Treatments (CANMAT) 206 Clinical Guidelines for the Management of Adults with
Major Depressive Disorder: Introduction and methods. Can J Psychiatry 61: 506–9.
Prince M, Patel V, Saxena S, et al. (2007) No health without mental health. Lancet
370: 859–77.
Summergrad P (206) Investing in global mental health: the time for action is now. Lancet
Psychiatry 3: 390–.
World Health Organization (207) Depression and Other Common Mental Disorders.
Geneva: WHO Document Production Services.
chapter 1
Chapter 2
2.1 Prevalence
2.. Current trends
Depressive disorders are very common conditions as the lifetime risk for expe-
riencing major depressive disorder (MDD) is approximately 5% (Table 2.).
Depression also contributes significantly to disability, with estimates that depres-
sion accounts for .3–4.4% of all disability and premature deaths worldwide. Two
major epidemiological trends are occurring with respect to depressive disorders.
First, the lifetime risk of developing depression in those born after the Second
World War is increasing, although some studies suggest this increase began as far
back as 925. Second, in both women and men, the age of onset for depression
is becoming increasingly younger, which corresponds to the rise in psychiatric
hospitalizations amongst adolescents.
2..2 Sex
The lifetime prevalence of MDD is .6–3. times more common in women than
men, with a greater disparity found in the USA and Western Europe. The dispar-
ity begins at the age of puberty and it is common to find worsening of depressive
symptoms in women coinciding with the onset of menses. Other hypothesized
causes of increased depressive episodes in women include hormonal differences,
psychosocial stressors, and childbirth. The disparity between the sexes appears
to be narrowing in studies involving younger cohorts, and the gap also decreases
after the age of 50–55 years as women enter menopause.
chapter 2
4 • epidemiology and burden
2..3 Age
In worldwide population samples aged 8–64 years, the average age for the
onset of depression varies from 24 to 35 years, with a mean age of 27 years.
There is currently a trend of an increasingly younger age of depression onset. For
example, 40% of depressed individuals have their first depressive episode prior
to the age of 20, 50% have their first episode between the ages of 20–50, and the
remaining 0% after 50 years of age.
Depressive symptoms also vary with age. Childhood depression tends to involve
more somatic complaints combined with irritability and social withdrawal, and ado-
lescents experience more ‘atypical’ features of depression (e.g. overeating, hyper-
somnia), while elderly depressed patients are most likely to have depressive features
of melancholia (e.g. loss of interest or pleasure, lack of reactivity, insomnia).
chapter 2
epidemiology and burden • 5
symptoms, which can be present for weeks to years prior to diagnosis, include
anxiety and other mild depressive symptoms. The length of an untreated depres-
sive episode varies from 4 to 30 weeks for a mild–moderate depression, while
severe episodes have an average length of 6–8 months. Nearly 25% of individuals
with severe depressive episodes will endure symptoms for more than 2 months.
Treated depressive episodes last on average 3 months; however, stopping anti-
depressants prior to 3 full months of use almost always results in the return of
symptoms.
2.2.2 Prognosis
For many patients, MDD can be a chronic, relapsing illness. Relapse within the
first 6 months of recovery occurs in 25% of patients, 58% will relapse within the
first 5 years, and 85% will relapse within 5 years of initial recovery. Moreover,
those individuals that have had two previous depressive episodes have a 70%
probability of a third, and having three previous depressive episodes incurs a 90%
likelihood of relapse. As the disease progresses, the interval between depressive
episodes becomes shorter and the severity of each episode becomes greater.
Over a 20-year span, depressive recurrences occur on average five to six times.
A significant proportion of depressed individuals remain chronically ill with
varying levels of symptoms. About two-thirds of patients with a major depressive
episode will fully recover, while one-third of depressed patients will either only
partially recover or remain chronically ill. In a study of patients at year post-
MDD diagnosis, 40% had recovered with no symptoms of depression, 20% con-
tinued to have residual symptoms but did not meet the criteria for MDD, while
40% remained in a major depressive episode. Those individuals that continue to
have residual depressive symptoms are at a high risk of relapse, suicide, poor
psychosocial functioning, and higher mortality from other medical conditions.
In addition to depression, 5–0% of individuals who have experienced a major
depressive episode will subsequently have a manic or mixed episode indicative
of bipolar disorder.
Numerous studies have focused on prognostic indicators which have a pre-
dictive value in terms of the recovery rate and relapse probability in depressed
individuals (Box 2.).
chapter 2
6 • epidemiology and burden
Similarly, depressed patients have almost two times greater overall mortality risk
than the general population owing to direct causes (e.g. suicide) and indirect causes
(e.g. medical illness). The risk of death by suicide increases 26-fold in depressed
individuals. However, the lifetime prevalence of suicide for depressed individuals
is 2.2% and suicide represents only % of reported deaths related to depression.
Depressed patients are at a .8 times greater risk of developing a medical
illness year post-diagnosis. In particular, hospitalized depressed patients with
comorbid cardiovascular disease are at a significantly increased risk for myocar-
dial infarct and death for 0 years post-hospitalization. For example, depressed
patients with unstable angina are at a three times greater risk of death than non-
depressed individuals. The increased risk of cardiovascular death likely is due to
both direct physiological effects (e.g. reduced heart rate variability, increased
platelet aggregation) and indirect effects (e.g. poor compliance with medications,
drug and alcohol abuse, etc.) of depression (see Chapter 0).
chapter 2
epidemiology and burden • 7
Major
depression
Iron deficiency
anaemia
Neck pain
Hearing loss
0 20 40 60 80
Mean years lived with disability (x1,000,000)
Figure 2. The Global Burden of Disease Study. In 203, depression ranked second
in total health-related disability worldwide.
treating depression. Studies have also found that employers, on the whole, have
negative beliefs about mental illness and are less likely to hire depressed individu-
als based on expectations of sub-standard work performance. In fact, depressed
individuals have a perceived increase in self-rated productivity when they experi-
ence fewer and less severe depressive symptoms, suggesting that early treatment
of depression would economically benefit employers.
The astounding economic costs of depression are due to a combination of dir-
ect treatment of depression, premature mortality (e.g. by suicide), and reduced
productivity and absenteeism. The total annual costs of depression in the United
States are estimated at US$44 billion: US$2.4 billion in direct costs of treat-
ment (hospitals, medications, doctors’ fees), US$8 billion in premature death,
and US$24 billion in absenteeism and reduced productivity in the workplace. In
Canada, the indirect costs of depression (premature mortality and reduced prod-
uctivity) are estimated at C$5 billion, and represent 58% of the overall economic
cost of depression. These approximations, however, underestimate the overall
cost of depression because they do not include out-of-pocket family expenses,
and costs of minor and untreated depression, excessive hospitalization, general
medical services, and diagnostic tests.
chapter 2
8 • epidemiology and burden
suicide more often than MDD-diagnosed patients. In a U.S. study, patients diag-
nosed with depression recovering from surgery stay on average 0 days longer in
hospital than non-depressed patients. However, those individuals with untreated
depressive symptoms stayed 26 days longer than non-depressed patients. In fact,
individuals with untreated depression account for the majority of ‘high utilizers’
of general medical services. Thus, diagnosing and treating these individuals should
lessen the burden on the medical system.
100
Perceived need for treatment Received any treatment Received adequate treatment
90
80
70
% of people with MDD
60
50
40
30
20
10
0
USA France Germany Spain Brazil* Mexico Bulgaria Iraq China* Columbia Peru
6.7% 5.6% 3.1% 3.8% 10.1% 3.7% 3.0% 3.9% 2.0% 5.3% 2.7%
* Data from individual city surveys for Brazil (Sao Pâulo) and China (Beijing/Shanghai).
Percentages below country label indicate the 12-month prevalence rate of MDD.
Figure 2.2 Proportion of people with MDD who perceived a need for treatment,
received any treatment, and received adequate treatment in the WHO World
Mental Health Survey.
Source data from The WHO World Mental Health Surveys: Global Perspectives on the Epidemiology of
Mental Disorders, Kessler R.C and Ustun T.B (eds.), 2008.
chapter 2
epidemiology and burden • 9
scaling up treatment services for depression are considerable, with a global study
estimating a US$5 return on investment for every US$ spent.
Further Reading
Bromet E, Andrade LH, Hwang I, et al. (20) Cross-national epidemiology of DSM-IV
major depressive episode. BMC Medicine 9: 90.
Chesney E, Goodwin GM, Fazel S (204) Risks of all-cause and suicide mortality in mental
disorders: a meta-review. World Psychiatry Rep 13: 53–60.
Chisolm D, Sweeny K, Sheehan P, et al (206) Scaling-up treatment of depression and
anxiety: a global return on investment analysis. Lancet Psychiatry 3: 45–24.
Coventry PA, Hudson JL, Kontopantelis E, et al. (204) Characteristics of effective
collaborative care for treatment of depression: a systematic review and meta-regression
of 74 randomised controlled trials. PLoS One 9: e084.
Donohue JM, Pincus HA (2007) Reducing the societal burden of depression: a review of
economic costs, quality of care and effects of treatment. Pharmacoeconomics 25: 7–24.
Global Burden of Disease Study 203 Collaborators (205) Global, regional, and national
incidence, prevalence, and years lived with disability for 30 acute and chronic diseases
and injuries in 88 countries, 990–203: a systematic analysis for the Global Burden of
Disease Study 203. Lancet 386: 743–800.
Kessler RC (202) The costs of depression. Psychiatr Clin North Am 35: –4.
Lam RW, McIntosh D, Wang JL, et al. (206) Canadian Network for Mood and Anxiety
Treatments (CANMAT) 206 Clinical Guidelines for the Management of Adults with
Major Depressive Disorder: Section . Disease burden and principles of care. Can J
Psychiatry 61: 50–23.
Thornicroft G, Chatterji S, Evans-Lacko S, et al. (207) Undertreatment of people with
major depressive disorder in 2 countries. Br J Psychiatry 210: 9–24.
World Health Organization (207) Depression and Other Common Mental Disorders.
Geneva: WHO Document Production Services.
chapter 2
Chapter 3
Pathogenesis
Key points
• There are likely multiple processes to explain the aetiology and pathophysiology
of depression, with involvement of biological, psychological, and social factors.
• Circadian rhythmicity, stressful life events, and stress reactivity can modify
genetic and biological processes (gene–environment interactions) to contribute
to depression.
• Endophenotypes, or genetic expressions of neural systems involved in
depression, are important in the study of the pathogenesis of depression and
the development of novel treatments.
3.1 Introduction
The exact pathophysiology of major depressive disorder (MDD) remains
unknown, but the aetiology has always been presumed to be heterogeneous
since the diagnosis of MDD is only descriptive and likely consists of a number
of syndromes with related symptoms. Biological, psychological, and social factors
all influence MDD, and each has reciprocal relationships with the others (Figure
3.). New research in genetics, neuroimaging, and molecular biology has clarified
some of the relationships between these broad forces, particularly in the modu-
lation of stress and life events on genetic and neurobiological processes. There is
increasing emphasis on endophenotypes, defined as endogenous phenotypes that
are not evident to the unaided eye that fill the gap between genes and a complex
disease, to advance our classification of depressive disorders and to guide treat-
ment selection (Figures 3.2 and 3.3). This chapter will highlight some of these
recent advances.
3.2 Genetics
3.2. Family, twin, and adoption studies
Family studies indicate at least two or three times increased relative risk (5–25%)
for MDD in first-degree relatives of MDD probands, with early age of onset
and recurrent depression conferring greater risk. Adoption studies, most from
Scandinavia, found that biological relatives of depressed adoptees were much
more likely to have depression than the adoptive relatives. Twin studies, by
comparing monozygotic to dizygotic twins, allow the dissection of genetic from
chapter 3
12 • pathogenesis
Relationships,
Genetics Personality
Work/Leisure
Circadian
Rhythms
Neurohormones,
Neurochemicals,
Person
with depression
Neuroinflammation
Figure 3. Relationships between biological, psychological, and social factors in the
pathophysiology of depression.
chapter 3
pathogenesis • 13
Major depression
Increased stress
Depressed mood sensitivity (Gender
(Mood bias toward specific)
negative emotions)
Anhedonia
Impaired learning
(Impaired reward
and memory
Stress function)
Stress
Increased amygdala
activity/decreased Reduced Reduced Decreased
amygdala volume hippocampal ACC subgenual PFC
volume volume activity
CREB
events, suggesting that this transporter gene modifies stress reactivity rather
than causing MDD, per se. Other candidate genes being investigated in MDD
include tryptophan hydroxylase-2, brain-derived neurotrophic factor (BDNF),
cAMP-responsive element-binding protein (CREB)-, and genes involved in the
circadian clock.
3.3 Neurobiology
3.3. Monoamines
The monoamine hypothesis has been the foundation of neurobiological theories
for depression for the past half century. Initially based upon observations of the
mechanism of action of antidepressants, this hypothesis postulates that depres-
sion results from deficits in key brain areas in serotonin (5-HT) or noradrenaline
synaptic neurotransmission. Antidepressants were thought to act by blocking the
chapter 3
14 • pathogenesis
chapter 3
pathogenesis • 15
chapter 3
16 • pathogenesis
Figure 3.5 Mechanisms for cellular plasticity and neurogenesis and therapeutic effects
of standard and novel antidepressants. Abbreviations: α2AR, α2 adrenergic recep-
tor; 5-HT, serotonin; AC, adenyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptor; Bcl-2, B-cell lymphoma 2 protein; BDNF,
brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CREB,
cAMP response element binding; CRH, corticotropin-releasing hormone; GC, gluco-
corticoids; Glu, glutamate; GR, glucocorticoid receptor; HPA, hypothalamic pituit-
ary adrenal; MAPK, mitogen-activated protein kinase; NE, norepinephrine; NMDAR,
N-methyl-D-aspartate (NMDA) receptor; PKA, protein kinase A; TrkB, receptor
tyrosine kinase B.
This figure depicts the multiple targets by which neuroplasticity and cellular resilience can be increased in
mood disorders. (a) Phosphodiesterase inhibitors increase the levels of pCREB; (b) MAP kinase modula-
tors increase the expression of the major neurotrophic protein Bcl-2; (c) mGluR II/III agonists modu-
late the release of excessive levels of glutamate; (d) drugs such as lamotrigine and riluzole act on Na+
channels to attenuate glutamate release; (e) AMPA potentiators upregulate the expression of BDNF;
(f ) NMDA antagonists like ketamine and memantine enhance plasticity and cell survival; (g) novel drugs
to enhance glial release of trophic factors and clear excessive glutamate may have utility for the treatment
of depressive disorders; (h) CRF antagonists and (i) glucocorticoid antagonists attenuate the deleterious
effects of hypercortisolemia, and CRF antagonists may exert other beneficial effects in the treatment of
depression via non-HPA mechanisms; (j) agents which upregulate Bcl-2 (e.g., pramipexole, shown to be
effective in bipolar depression). These distinct pathways have convergent effects on cellular processes
such as bioenergetics (energy metabolism), neuroplasticity, neurogenesis, resilience, and survival.
Adapted from: Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood
disorders. Neuropsychopharmacology 2008; 33:2080–2092.
chapter 3
Exploring the Variety of Random
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