Marcinkowska2020 Article ManagementOfDementia-RelatedPs

CNS Drugs (2020) 34:243–268
https://doi.org/10.1007/s40263-020-00707-7
REVIEW ARTICLE
Management of Dementia‑Related Psychosis, Agitation

and Aggression: A Review of the Pharmacology and Clinical Effects
of Potential Drug Candidates
Monika Marcinkowska1 · Joanna Śniecikowska1,2 · Nikola Fajkis1 · Paweł Paśko1 · Weronika Franczyk1 ·
Marcin Kołaczkowski1,2
Published online: 12 February 2020

© The Author(s) 2020
Abstract
Along with cognitive decline, 90% of patients with dementia experience behavioral and psychological symptoms of dementia,
such as psychosis, aggression, agitation, and depression. Atypical antipsychotics are commonly prescribed off-label to man-
age certain symptoms, despite warnings from the regulatory agencies regarding the increased risk of mortality associated
with their use in elderly patients. Moreover, these compounds display a limited clinical efficacy, mostly owing to the fact
that they were developed to treat schizophrenia, a disease characterized by neurobiological deficits. Thus, to improve clinical
efficacy, it has been suggested that patients with dementia should be treated with exclusively designed and developed drugs
that interact with pharmacologically relevant targets. Within this context, numerous studies have suggested druggable tar-
gets that might achieve therapeutically acceptable pharmacological profiles. Based on this, several different drug candidates
have been proposed that are being investigated in clinical trials for behavioral and psychological symptoms of dementia. We
highlight the recent advances toward the development of therapeutic agents for dementia-related psychosis and agitation/
aggression and discuss the relationship between the relevant biological targets and their etiology. In addition, we review
the compounds that are in the early stage of development (discovery or preclinical phase) and those that are currently being
investigated in clinical trials for dementia-related psychosis and agitation/aggression. We also discuss the mechanism of
action of these compounds and their pharmacological utility in patients with dementia.
1 Introduction behavioral symptoms will manifest in almost all patients

with dementia in the course of their disease [4]. Behavioral
While describing the first case report of dementia, Alois and psychological symptoms of dementia can decrease the
Alzheimer indicated that along with memory impairment, quality of patients’ lives and are often cited as the main rea-
the patient demonstrated symptoms of psychosis [1, 2]. son for referring patients with dementia to nursing homes or
Currently, it is widely recognized that neuropsychiatric dis- similar institutions [5].
turbances constitute an inherent component of Alzheimer’s Currently, a specifically approved pharmacotherapy for
disease (AD) and its related dementias. These manifesta- BPSD remains elusive. The most troublesome psychiatric
tions are referred to in the literature as “behavioral and psy- events such as aggression and the remaining symptoms
chological symptoms of dementia” (BPSD), which include psychosis and agitation are addressed with atypical antip-
psychosis, agitation, aggression, irritability, depression, sychotics administered off-label [6]. However, the clinical
and anxiety [3]. It is estimated that at least one or more efficacy of these drugs is unsatisfactory because a large
percentage of patients do not respond or respond partially
to the drugs [7]. Moreover, atypical antipsychotics are not
* Monika Marcinkowska actually recommended for elderly patients because they pose
monika.marcinkowska@uj.edu.pl a risk of many side effects [8]. Elderly patients seem to be
1
Department of Medicinal Chemistry, Faculty of Pharmacy, particularly sensitive to severe adverse reactions induced by
Jagiellonian University Medical College, 9 Medyczna Street, atypical antipsychotics such as excessive sedation, orthos-
Kraków 30‑688, Poland tatic hypotension and related complications such as falls,
2
Adamed Pharma S.A., Czosnow, Poland extrapyramidal symptoms, cognitive slowing, cardiovascular
Vol.:(0123456789)

244 M. Marcinkowska et al.
deficits that are distinct from BPSD. Aging induces changes

Key Points in the quality and quantity of neurotransmitters, which may
account for the onset of behavioral symptoms in patients
Current pharmacotherapy of dementia-related psychosis with dementia [17, 18]. Consequently, fluctuations of neu-
and agitation/aggression relies on the off-label admin- rochemicals initiate changes in the expression of certain
istration of atypical antipsychotics, which have limited receptors that should be targeted with specific medications
clinical efficacy and induce various adverse reactions. [19]. Thus, patients with dementia might benefit from drugs
Genetic studies have suggested several druggable targets interacting with relevant molecular targets to maximize the
that correspond with the etiology of dementia-related clinical response.
psychosis and agitation/aggression: serotonin 5-HT2A In this regard, a plethora of experimental evidence has
and 5-HT1A receptors, serotonin transporter, alpha-1 recently highlighted several druggable targets that are
adrenoceptor, and dopamine D 1 and D3 receptors. believed to achieve therapeutically acceptable pharmaco-
logical profiles for BPSD. Several different drug candidates
Novel therapeutic approaches may benefit particularly are being investigated in clinical trials for BPSD, which
from targeting the serotoninergic system with serotonin hopefully will make the pharmacotherapy of BPSD a real-
5-HT2A and 5-HT1A ligands or serotonin transporter istic prospect. In this review, we present the drug candi-
inhibitors, which are currently being investigated in dates being currently investigated in clinical trials for BPSD.
phase III clinical trials. We focus on the most troublesome symptoms, aggression,
Preclinical and clinical studies have suggested other rel- agitation, and psychosis, which require pharmacological
evant molecular targets that may result in therapeutically intervention. We discuss their pharmacological profile in
acceptable efficacy: cannabinoid receptors, metabotropic terms of privileged biological targets, and assess how they
glutamate 2 receptors, muscarinic M1/M4 receptors, and correspond with the molecular mechanisms underlying
glutamate N-methyl-D-aspartate receptors. their pathology. We also provide information on the latest
investigational compounds at the early stage of development
Blockade of M1, alpha-2 adrenergic, and histamine H1 (discovery or preclinical phase). (For a review of the treat-
receptors and the human ether-a-go-go-related gene ment of depression in patients with dementia, the reader is
channel should be avoided because elderly patients are referred elsewhere [20]).
particularly sensitive to adverse reactions induced by the
drugs acting on these targets.
2 Overview of Potential Druggable Targets
for Pharmacological Treatment Matching
complications, and anticholinergic side effects [9]. Notably, the Etiology of Dementia‑Related
the use of currently available antipsychotics in patients Psychosis and Agitation/Aggression
with dementia has been associated with an increased risk of
death. Consequently, in April 2004, the US Food and Drug The etiology of dementia-related psychosis and agitation/
Administration (FDA) issued a black-box warning against aggression is very complex and is often a cluster of bio-
the use of atypical antipsychotics in elderly patients [10, logical factors (anatomical and neurochemical changes) as
11]. The American and British clinical guidelines [12–14] well as psychological and social aspects (responses to stress,
state that antipsychotics can be used only if the patient con- living arrangements [21]). Alzheimer’s disease is the most
stitutes a threat to self or others and should be administered common type of dementia, and the pathophysiology of this
after evaluating the benefit/risk ratio of the treatment [15]. particular disease is related to the loss of neurons. Depend-
If the physician decides to prescribe antipsychotics, clinical ing on the degree of neurodegeneration, the cerebral region
guidelines recommend the exclusive usage of the following involved, and consequently the extent of deficits in neuro-
drugs: risperidone, olanzapine, quetiapine, and aripiprazole transmitters, various psychiatric symptoms may appear [22].
[12]. Nevertheless, several reviews in this subject empha- For instance, psychosis has been associated with neurode-
sized that prior to treatment with antipsychotics, one should generation in the frontal and mesotemporal areas of the brain
always consider that these drugs exert detrimental effects [23], while depression has been linked to the degeneration
and provide limited efficacy [6, 7, 16]. of brainstem aminergic nuclei and a decrease in serotoner-
The main explanation for the poor clinical performance of gic neurotransmission [24]. Additionally, neuropathologi-
atypical antipsychotics in elderly patients is that these were cal changes that cause hypofunction of the cholinergic and
approved specifically for the treatment of schizophrenia, serotonergic systems and hyperfunction of dopaminergic
which affects mostly younger adults with neurobiological and noradrenergic transmission have been linked to agita-
tion manifested by patients with dementia [22]. Alterations
Dementia-Related Psychosis/Agitation/Aggression: A Review of Drug Candidates 245
in multiple neurotransmitter systems cause changes in the induces changes in the expression and function of metabo-
expression of specific receptors, which have a direct impact tropic glutamate receptors (mGluRs) and N-methyl-d-as-
on the regular functioning of the central nervous system partate (NMDA) receptors [40]. Disrupted glutamatergic
(CNS) [3, 18]. neurotransmission, in turn, is a well-recognized factor that
Numerous studies have revealed a close association contributes to the pathophysiology of neuropsychiatric dis-
between genetic polymorphisms and the onset of psychiatric orders [41, 42]. Studies in animal models revealed that the
symptoms in patients with dementia. Particularly, serotonin activation of metabotropic glutamate 2 receptor (mGlu2R)
5-HT2A receptors (5-HT2AR) are related to the etiopathology resulted in antipsychotic, memory-enhancing [43], and
of dementia-related psychosis and aggression. For instance, neuroprotective activity [44], while modulation of NMDA
in patients with dementia, 5-HT2AR binding is decreased receptors is crucial for neuroplasticity and also influences
[25]. Additionally, reduced density of 5-HT2AR in the pre- mood and behavior [40]. Therefore, while developing drugs
frontal cortex [26] and the polymorphism of 5-HT2AR have for dementia-related psychosis in the future, those targeting
been associated with an increased risk of hallucinations and mGluRs or NMDA receptors can be considered as poten-
aggression [26, 27]. Moreover, the type of hallucinations tial pharmacological targets. Furthermore, pharmacological
observed in patients with Lewy body dementia (mainly vis- activation of muscarinic receptors M1/M4 (M1R/M4R) may
ual) suggests the involvement of serotonin 5-HT2AR [28]. In represent a disease-modifying [45] and symptomatic treat-
fact, these resemble the hallucinations induced by 5-HT2AR ment [46]. Stimulation of M 1R/M4R mediates key effects
agonists lysergic acid diethylamide and mescaline rather on cognitive performance, protects neurons from beta-amy-
than those found in patients with schizophrenia, which tend loid toxicity [45], and promotes antipsychotic activity [46].
to be mainly auditory [29–31]. Therefore, compounds that In addition, mounting evidence shows that patients with
preferentially block 5-HT2AR might be used to treat demen- dementia may benefit from drugs targeting serotonin 5-HT6
tia-related psychosis or aggression. receptors (5-HT6R) [47]. Preclinical studies revealed that
Similarly, other molecular targets have been associated selective 5-HT6R antagonists display promising procogni-
with the manifestation of psychiatric symptoms in patients tive activity, as well as mood-modulating properties [48]. A
with dementia. A genetic study showed that the polymor- summary of the potential molecular targets for the treatment
phism of the serotonin transporter (SERT) promoter region of dementia-related psychosis and agitation/aggression is
(L/L genotype) is correlated with aggressive behavior in presented in Table 1.
patients with AD [32, 33]. Furthermore, decreased den-
sity of 5-HT1AR in the cortex has been directly linked with
the onset of aggressive behavior in patients with AD [34]. 3 New Drug Candidates on the Horizon
Furthermore, postmortem studies in patients with AD indi-
cated that neurodegeneration of noradrenergic neurons may 3.1 Identification of Compounds Investigated
account for the pathophysiology of agitation and aggression in Preclinical and Clinical Trials
related to AD [35]. In addition, polymorphisms in dopamine
D1 receptor (D1R) and D3 receptors (D3R) have been associ- To collect data regarding the compounds being investigated
ated with dementia-related psychosis and aggression [36]. In in clinical trials, we searched for trials registered by the US
summary, potential druggable targets that closely correspond National Institutes of Health (http://www.clinicaltrials.gov)
with the pathology of dementia-related psychosis, agitation, and EudraCT (https://eudract.ema.europa.eu) using the fol-
and aggression include serotonin 5-HT2AR and 5-HT1AR, lowing keywords: “dementia” or “Alzheimer’s disease” and/
SERT, alpha-1 adrenoceptors, and D1R and D3R. or “agitation,” and/or “aggression” and/or “psychosis.” We
Preclinical studies disclosed another palette of interesting restricted the search for trials from 2014 to present to obtain
molecular targets that may exhibit therapeutically relevant the most recent overview covering the last 5 years. Addi-
pharmacological profiles. For instance, an experimental tionally, we searched for literature data associated with the
study showed that knockout mice deficient in the cannabi- identified compounds, published from 2014 to the present,
noid CB1 receptor (CB1R) displayed aggressive behavior, using the compounds’ name and other keywords such as
which could be reduced by the short-term administration “Alzheimer’s disease” and “dementia” or “aggression” or
of a CB1R agonist [37]. Clinical evidence showed that the “psychosis.” We used PubMed, ScienceDirect, GlobalData,
cortical areas in patients with AD are characterized by and Google Scholar databases. If data regarding a com-
reduced expression and decreased availability of CB1R [38]. pound’s efficacy or the current status of its trial were not
Therefore, pharmacological modulation of C B1R deserves a published or posted on clinical trial registries, we searched
broadened evaluation to consider it as a potential molecular the websites of the pharmaceutical and biotech companies
target in the management of AD-related aggression [39]. responsible for that compound’s development. The search
Furthermore, many findings suggest that neurodegeneration was restricted to English.

Table 1 Summary of the potential druggable targets that might be suitable for pharmacological modulation of selected behavioral and psycho-
logical symptoms of dementia (BPSD): psychosis, aggression, and agitation
Matching with BPSD pathology Indicated by experimental studies
Target Pharmacological activity Target Pharmacological activity
Serotonin 5-HT2A receptors Antipsychotic, antiaggressive Muscarinic M1/M2 receptors Antipsychotic, procognitive
Serotonin 5-HT1A receptors Antiaggressive Cannabinoid receptor CB1 Antiaggressive
Serotonin transporter Antiaggressive Metabotrophic glutamate 2 recep- Antipsychotic
tor (mGlu2)
Dopamine D1, D2 receptors Antipsychotic, antiaggressive Serotonin 5-HT6 receptors Procognitive, anxiolytic
Alpha-1 adrenoreceptor Antiaggressive
The applied search resulted in the identification of several receptors [82]. Thus, it is believed that this compound does
drug candidates being investigated in clinical trials. Table 2 not induce adverse reactions that are characteristic of atypi-
summarizes the data extracted on the investigated drug can- cal antipsychotics. The unique pharmacological profile of
didates, which will be discussed in detail below (except for pimavanserin is characterized by high affinity and specific
lithium, which has been reviewed comprehensively else- functional activity at the 5-HT2AR. As an inverse agonist,
where [49, 50]). pimavanserin binds to the 5-HT2AR and not only blocks its
natural agonistic activity but also reduces its constitutive
activity. Importantly, pimavanserin does not bind to striatal
4 Drug Candidates for Dementia‑Related D2 receptors, which indicates a high margin of safety in
Psychosis and Agitation/Aggression terms of the extrapyramidal side effects [83].
in Clinical Trials Preclinical studies revealed that pimavanserin reduced
psychotic-like behavior in rodents [84, 85]. In clinical tri-
4.1 Drugs Affecting Serotonergic als, pimavanserin was found to be effective in the treatment
Neurotransmission of delusions and hallucinations associated with Parkinson’s
disease [86]. These promising results encouraged the evalua-
4.1.1 Serotonin 5‑HT2A Receptor Inverse Agonist: tion of the efficacy of this agent in other psychotic disorders,
Pimavanserin including AD-related psychosis. Recently, a phase II, ran-
domized, double-blind, placebo-controlled study evaluated
Among the various molecular targets considered as poten- the efficacy of pimavanserin in patients with AD-related
tial treatments of dementia-related psychosis or agitation/ psychosis (NCT02035553) [57, 58]. In the study, 181 sub-
aggression, serotonin receptors have come into the lime- jects with AD were enrolled and treated with pimavanserin
light. Age-related decline in serotonin function has been (17 mg twice daily) for 12 weeks (Table 3). Pimavanserin
linked with aggressive behavior in AD [77, 78]. Specifi- showed a statistically superior effect to placebo (change in
cally, a reduced density and polymorphism of 5-HT2AR have the psychosis score on Neuropsychiatric Inventory [NPI]-
been observed with the onset of aggression and psychosis Nursing Home Version scale) and an acceptable tolerability
in patients with dementia [77]. Therefore, modulation of profile with no undesirable side effects on cognition [58].
the activity of 5-HT2AR seems to be a promising therapeu- The sponsor (ACADIA Pharmaceuticals) is currently run-
tic strategy for reducing psychiatric symptoms that matches ning a phase III study, 52-week, open-label extension study
closely with the disease pathology. (registered in Europe:2017-004439-36) of pimavanserin in
A serotonin 5-HT2AR inverse agonist, pimavanserin, has the treatment of psychotic symptoms and agitation in 750
been proposed as a suitable agent for the treatment of demen- patients with dementia [65].
tia-related psychosis and agitation/aggression [79, 80]. As psychotic symptoms in patients with AD tend to remit
Pimavanserin was the first antipsychotic agent approved by and relapse [87], it has been suggested that it would be desir-
the FDA (in 2016) for the treatment of psychosis in patients able to further evaluate the efficacy of pimavanserin in pre-
with Parkinson’s disease. It is a nondopaminergic, highly venting psychotic symptoms in patients with AD. In this
selective 5-HT2A inverse agonist that acts predominantly on regard, a double-blind, placebo-controlled, phase III study
the 5-HT2AR and, to a lesser degree, on another serotonin (NCT03325556) is currently recruiting 356 participants to
receptor subtype 5-HT2C (Fig. 1) [81]. Pimavanserin displays evaluate the efficacy of pimavanserin (34 mg once daily)
no affinity to the other G protein-coupled receptors includ- in preventing the relapse of psychotic episodes in patients
ing dopaminergic, histaminergic, muscarinic, and adrenergic with dementia (primary outcome measure: time from
Table 2 Compounds investigated for the treatment of agitation, aggression, and psychosis associated with dementia of various types and their current status in clinical trials from 2014 to present
Compound Identifier Pharmacological action Indication Status Estimated completion date
Compounds investigated in phase I

HTL0016878 NCT03244228 Muscarinic M4 agonist Compound developed for: neurobe- Completed September 2019 [51]
havioral symptoms in AD
Compounds investigated in phase II
Eltoprazine H.134.5012 [52] Serotonin 5-HT1A/5-HT1B partial agonist Aggression associated with AD Completed December 2015 [52]
GDCT0252614a
Lithium NCT02129348 Complex Psychosis, agitation in AD Recruiting January 2020 [50]
LY2979165 (MP-101) NCT03044249 mGluR2 agonist Psychosis, aggression, and agitation in Recruiting August 2020 [53]
dementia
Prazosin NCT03710642 Alpha-1 adrenoceptor antagonist [54] Agitation in AD Recruiting December 2022 [55]
Pimavanserin NCT03118947 Serotonin 5-HT2AR inverse agonist Agitation and aggression in AD Completed February 2019 [56]
Pimavanserin NCT02035553 Serotonin 5-HT2AR inverse agonist Psychosis in AD Completed October 2016 [57, 58]
SND-51 GDC30016463a DAAO inhibitor Dementia and psychosis Ongoing Date has not been disclosed
GDCT0310097a
Compounds investigated in phase III
Nabilone NCT02351882 Cannabinoid receptor (CB1) Agitation in AD Completed March 2019 [59–61]
AXS-05 (dextromethorphan/ NCT03226522 Multi-receptor Agitation in AD Recruiting June 2020 [62, 63]
bupropion)
Pimavanserin NCT03325556 Dementia-related psychosis Recruiting March 2020 [64]
Dementia-Related Psychosis/Agitation/Aggression: A Review of Drug Candidates
Serotonin 5-HT2AR inverse agonist

Pimavanserin 2017-004439-36 Serotonin 5-HT2AR inverse agonist Neuropsychiatric symptoms related to Ongoing Date has not been disclosed
neurodegenerative disease [65]
Pimavanserin 2017-002227-13 Serotonin 5-HT2AR inverse agonist Dementia-related psychosis Ongoing Date has not been disclosed
[66]
Escitalopram NCT03108846 SERT inhibitor Agitation in AD Recruiting August 2022 [67]
Brexpiprazole NCT03724942 Partial agonistic activity at dopamine D2 and Agitation in AD Recruiting May 2021 [69]
serotonin 5-HT1AR, and antagonism of sero-
tonin 5-HT2AR [68]
Brexpiprazole 2017-003940-19 Partial agonistic activity at dopamine D 2 and Agitation in AD Ongoing Date has not been disclosed
serotonin 5-HT1AR, and antagonism of sero- [70]
tonin 5-HT2AR [68]
Brexpiprazole 2018-002783-88 Partial agonistic activity at dopamine D 2 and Agitation in AD Ongoing Date has not been disclosed
serotonin 5-HT1AR, and antagonism of sero- [71]
tonin 5-HT2AR [68]
Lumateperone NCT02817906 Antagonistic activity at the serotonin 5-HT2A Agitation in dementia, including AD Terminated December 2018 [73]
receptor, partial agonistic activity at the
presynaptic dopamine D 2 receptor, antago-
nistic activity at the postsynaptic dopamine
D2 receptor [72], and SERT blockade
247

Estimated completion date
June 2022 [74]
March 2022
July 2020
[75]
[76]
Fig. 1 Structure and receptor profile of pimavanserin [81]

Recruiting
Recruiting
Recruiting
Status
randomization to relapse in the double-blind period, up to

26 weeks) [62]. In parallel, the sponsor is running a phase III
Night-time agitation and sleep distur-
study registered in Europe (2017-002227-13), which evalu-

ates the efficacy of pimavanserin in relapse prevention of
psychotic symptoms in 212 patients with dementia [66]. In
addition, a phase II open-label study (NCT03118947) [64]
AD Alzheimer’s disease, DAAO D-amino acid oxidase, mGluR2 metabotropic glutamate 2 receptor, SERT serotonin transporter
has been completed recently. The study evaluated the safety

Agitation in dementia
bance in dementia
and tolerability of pimavanserin (10 or 17 mg twice daily,

Agitation in AD
primary outcome measure: treatment-emergent adverse

events [Table 3]). The results have not been revealed yet.
Indication
4.1.2 Serotonin 5‑HT1A/1B Receptor Agonist: Eltoprazine

Noradrenergic and specific serotonergic anti-
Previous findings revealed that aggressive behaviors in

patients with AD directly correlate with a reduced density
of 5-HT1AR in the CNS [34]. Several clinical reports dis-
closed a significant reduction in agitation and aggression
in patients with dementia after the administration of drugs
acting via 5-HT1AR: tandospirone [88] and buspirone [89].
Calcium channel inhibitor
Pharmacological action
Therefore, it has been suggested that modulation of the

activity of 5-HT1AR might be considered as a promising
therapeutic strategy for the treatment of dementia-related
Multi-receptor
depressant
agitation/aggression.
Eltoprazine was developed as an anti-aggressive agent
[90–92]. It was reported that eltoprazine potently suppressed
aggressive behavior in animal models without causing seda-
tion [93, 94]. Eltoprazine is a 5-HT1A/5-HT1B partial ago-
nist but also acts as a full agonist at 5-HT2CR (Fig. 2) [96].
AVP-923 (dextromethorphan/ NCT02446132
NCT03031184
NCT03082755
GDCT trial identifier provided by GlobalData
Its anti-aggressive properties most probably result from the

Identifier
reduction in serotonin release due to the activation of pre-

Compounds investigated in phase IV
synaptic 5-HT1A and 5-HT1B autoreceptors [97, 98]. Moreo-

ver, mixed 5-HT1A/5-HT1B partial agonism of eltoprazine is
responsible for its highly effective inhibition of aggressive
behavior [98].
In phase I of clinical trials, eltoprazine was found to be
Table 2 (continued)
safe and well tolerated [97]. In a phase II study on the treat-

ment of AD-related aggression, eltoprazine showed prom-
Mirtazapine
quinidine)
Gabapentin
Compound
ising results [52]. This double-blind, randomized, placebo-

controlled study found that eltoprazine (10 mg once daily
for 4 weeks) significantly reduced aggressive behavior
a
Table 3 Summary of completed clinical trials evaluating drug candidates in psychosis, aggression, and agitation associated with dementia and Alzheimer’s disease (AD)
Drug/indication Trial identifier Study design Results
Participants Dosing paradigm Study design Primary outcome meas-
ure
Pimavanserin/psychosis NCT02035553 [57] 181 patients with AD 34 mg/day for 12 weeks Phase II, single-center, Change from baseline to Statistically superior effect
in AD double-blind, placebo- week 6 in the NPI-NH of pimavanserin com-
controlled psychosis score pared with placebo at the
primary endpoint (week
6), with an acceptable
tolerability profile and no
negative effect on cogni-
tion (week 12) [58]
Pimavanserin/agitation NCT03118947 [56] 79 patients with AD 20 mg/day or 34 mg/day Phase II, open-label, TEAEs, safety and toler- Results not available yet
and aggression in AD for 52 weeks single-group ability of pimavanserin
after 52 weeks of
treatment
Eltoprazine/aggression H.134.5012 [52] 29 patients with SDAT 5–10 mg/day for 4 weeks Phase II, multi-center, Social Dysfunction and Significant improvement
in AD GDCT0252614a or mixed SDAT/multi- double-blind, ran- Aggression Scale and of aggressive behavior
infarct dementia domized, placebo- the Staff Observation within the eltoprazine-
controlled Scale after 4 weeks treated group compared
with the placebo group
[52]
Citalopram/agitation in NCT00898807 [191] 186 patients with AD 10–30 mg/day Phase III, randomized, Evaluated by NBRS-A Clinically meaningful
AD for > 3 weeks (based on multi-center, placebo- and mADCS-CGIC at reduction in the AD-
response and toler- controlled, double- week 9 associated agitation com-
ability) blind pared with placebo. [103]
Cognitive and cardiac
adverse effects associated
with citalopram treatment
Escitalopram/psychotic NCT 01119638 [109] 40 patients with AD Escitalopram/risperi- Phase IV, randomized, Change in the total score Escitalopram and risperi-
symptoms and agitation done 5–10 mg/day and double-blind, single- on NPI (week 6) done were equally effec-
in AD 0.5–1.0 mg/day for center, pilot tive in reducing psychotic
6 weeks symptoms and agitation
[110]
Mirtazapine/agitation Pilot study [176] 16 patients with AD 15–30 mg/day for Open-label, prospective Changes in behavior were Significant reduction in
in AD 12 weeks assessed using CMAI- CMAI-SF and CGI-S
SF (2, 8, and 12 weeks) between pre- and post-
treatment with mirtazap-
ine [176]. No significant
side effect and cognitive
deterioration
249

250

ure
Prazosin/agitation and Pilot study [151] 22 patients with AD Mean dose: 5.7 mg/day Double-blind, placebo- Improvement on BPRS Significant improvements
aggression in AD for 8 weeks controlled, randomized and NPI at weeks 1, 2, in the NPI and BPRS
4, 6, and 8 within the prazosin-
treated group compared
with the placebo group
[151]
Brexpiprazole/agitation NCT01862640 [192] 433 patients with AD 1 and 2 mg/day for Phase III, randomized, Change in the CMAI total The improvements in the
in AD 12 weeks double-blind, placebo- score (baseline to week primary endpoint of
controlled, multi-center 12). The secondary CMAI for brexpiprazole
outcome is the change 2 mg were statistically
in the CGI-S score better than placebo and
appeared more robust
than the improvements
on the key secondary
endpoint of CGI-S [114]
Brexpiprazole/agitation NCT01922258 [193] 270 patients with AD A flexible dose range: Phase III, randomized, Change in the CMAI total The improvements in the
in AD 0.5 mg/day, 1 mg/ double-blind, placebo- score (baseline to week primary endpoint of
day, or 2 mg/day for controlled, multi-center 12). The secondary CMAI appeared less
12 weeks outcome is the change robust than the improve-
in the CGI-S score ments on the key second-
ary endpoint of CGI-S
[114]
Lumateperone/agitation NCT02817906 [119] 177 patients with AD 9 mg/day for 4 weeks Phase III, randomized, CMAI-C (week 4) Terminated (pre-specified
in AD double-blind, placebo- interim analysis indicated
controlled, multi-center futility) [119]
THC/dementia-related NCT01608217 [194] 50 patients diagnosed 4.5 mg/day for 3 weeks Phase II, randomized, NPI assessed at baseline No significant difference in
neuropsychiatric with AD, vascular double-blind, placebo- and after 14 and reduction from baseline
symptoms (agitation, dementia, or mixed controlled study, multi- 21 days between THC and pla-
aggression, or aberrant dementia center cebo [163]
motor behavior)
THC/dementia-related NCT01302340 [195] 22 patients with AD, Period A: 1.5 mg/day for Phase II, repeated Change in NPI score (at No benefit of THC treat-
neuropsychiatric vascular dementia, or 6 weeks crossover, randomized, day 3 and 10 during ment (0.75 mg and
symptoms with at least mixed dementia Period B: 3 mg/dayb for double-blind, placebo- treatment blocks and 1.5 mg twice daily) on
agitation or aggression 6 weeks controlled, multi-center after 1 month) neuropsychiatric symp-
toms in
dementia [164]
Dronabiol/dementia- Retrospective study 40 patients with dementia 7.03 mg daily for 16 days Retrospective PAS (at day 7) Total PAS score decreased
related behavioral dis- significantly during dron-
turbances (aggression, abinol treatment [165]
agitation)
M. Marcinkowska et al.
ure
Dronabiol/night-time Open-label pilot study 6 patients diagnosed with 2.5 mg daily for 2 weeks Open-label pilot NPI, Actiwatch (at day 5) Dronabinol led to a reduc-
agitation in dementia late-stage dementia (5 tion in nocturnal motor
with AD, 1 with vascu- activity [167]
lar dementia)
Nabilone/agitation in AD NCT02351882 [59] 39 patients with AD 1–2 mg for 14 weeksc Phase II/III, pilot, rand- Change in agitation; Significant reduction in
omized, double-blind, CMAI (after 14 weeks) agitation over 6 weeks
crossover in the nabilone group.
[60, 61]
Sedation occurred during
treatment with nabilone
AVP-923 (dextrometho- NCT01584440 [196] 220 patients with AD Dextromethorphan/ Phase II randomized, Change from baseline in Significant improvement
rphan/quinidine)/agita- quinidine at doses of multi-center, double- NPI Agitation/Aggres- on NPI, Agitation/
tion in AD 20 mg/10 mg once blind, placebo-con- sion domain score Aggression score com-
daily to 30 mg/10 mg trolled (10 weeks) pared with placebo [128]
twice daily for
10 weeks
BPRS Brief Psychiatric Rating Scale, CGI-S Clinical Global Impression-Severity of Illness, CMAI Cohen-Mansfield Agitation Inventory, CMAI-C Cohen-Mansfield Agitation Inventory-Com-
munity, CMAI-SF Cohen-Mansfield Agitation Inventory-Short Form, mADCS-CGIC modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change, NBRS-A Neurobe-
havioral Rating Scale Agitation subscale, NPI Neuropsychiatric Inventory, NPI-NH Neuropsychiatric Inventory Nursing Home Version scale, PAS Pittsburgh Agitation Scale, SDAT senile
dementia of Alzheimer’s type, TEAEs treatment-emergent adverse events, THC Δ-9-tetrahydrocannabinol
a
GDCT trial identifier provided by GlobalData
b
Period A (6 weeks): 0.75 mg of THC twice daily for 3 successive days, separated by a 4-day washout. Period B: 1.5 mg of THC twice daily for 3 successive days, separated by a 4-day washout
period
c
14-week, randomized, double-blind, crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases
251

Fig. 2 Structure and receptor H non-cardiotoxic antidepressants should be evaluated in clini-

profile of eltoprazine N
cal trials [105].
N
An (S)-stereoisomer of citalopram (Fig. 3), escitalopram,
O seems to be safer, as the magnitude of QT prolongation
observed with this compound is lower compared with cit-
O alopram and the effect is dose dependent [106–108]. A rand-
omized, double-blind, pilot study evaluated the effectiveness
Eltoprazine of escitalopram (5–10 mg/day) in reducing psychotic symp-
5-HT1A Ki = 40 nM toms and agitation in 40 patients with AD in a 6-week treat-
5-HT1B Ki = 52 nM
5-HT2C Ki = 81 nM
ment period (primary outcome measure: change in the total
score on NPI), in comparison to the antipsychotic risperi-
done (0.5–1.0 mg/day) [109]. This study found that escitalo-
(evaluated by the Social Dysfunction and Aggression Scale pram and risperidone were equally effective (Table 3) [110].
and the Staff Observation Scale) in 29 subjects (Table 3). The authors did not observe any adverse event in the escital-
These encouraging results suggest that further phase III opram group. This pilot study justified the need for a larger,
clinical studies should be conducted on this indication. more comprehensive study. Currently, a phase III, double-
blind, randomized, placebo-controlled trial (NCT03108846)
4.1.3 Selective Serotonin Reuptake Inhibitors [67] is recruiting patients with AD-related dementia and
clinically significant agitation (392 participants) to evalu-
Genetic studies revealed that certain forms of the SERT have ate the safety and effectiveness of escitalopram at a dose
been linked with the onset of dementia-related psychosis of 5–15 mg/day in reducing agitation in patients with AD
and aggressive behavior [32, 33]. In addition, administra- during 12 weeks (primary outcome measure: change in the
tion of the selective serotonin reuptake inhibitor citalopram modified Alzheimer’s Disease Cooperative Study-Clinical
resulted in a significant decrease in the pathological levels of Global Impression of Change score after 12 weeks) [67].
amyloid-β in patients with AD [99]. Preclinical studies have
shown that citalopram blocked the growth of pre-existing 4.2 Drugs Acting on Several Biological Targets
amyloid-β plaques and reduced the formation of new plaques
by 78% [100]. Moreover, selective serotonin reuptake inhibi- 4.2.1 Novel Atypical Antipsychotics
tors increase the levels of serotonin and thus may stimulate
hippocampal neurogenesis [101]. Therefore, administration Recently, two novel atypical antipsychotic agents have
of the drugs acting on SERT to mitigate behavioral symp- been investigated in phase III clinical trials for AD-related
toms in patients with dementia is a rational intervention. agitation and psychosis: brexpiprazole and lumateperone.
One of the first studies showed the effectiveness of cit- These agents target primarily the serotonin 5-HT2ARs while
alopram in a short-term in-hospital management program of maintaining a relatively weaker interaction with D 2R, which
dementia-related aggression and agitation in patients with makes them less likely to induce unfavorable extrapyrami-
dementia [102]. These preliminary data have been confirmed dal side effects. Elderly patients are particularly sensitive to
in a larger randomized, placebo-controlled, double-blind extrapyramidal symptoms [111] owing to an aging-related
study (NCT00898807) that enrolled 186 patients with AD impairment of dopamine function [112]; therefore, the inter-
[103] (Table 3). The study showed that long-term adminis- action of these agents with the D 2R should be retained at the
tration of citalopram (10–30 mg/day for 3 weeks) led to a lowest level.
clinically meaningful reduction in the AD-associated agi-
tation compared with placebo (primary outcome measured
by the Neurobehavioral Rating Scale Agitation subscale).
However, treatment with citalopram has been associated
with mild cognitive decline and cardiac side effects (QT
interval prolongation), which hampers its long-term clinical
application. In fact, in August 2011, the FDA announced a
safety warning recommending to limit the maximum dose of
citalopram to 20 mg/day in elderly patients aged > 60 years
because of the possible occurrence of QT prolongation
[104]. Therefore, it has been suggested that lower doses
(< 30 mg/day) of citalopram [103] or alternatively other Fig. 3 Chemical structure and binding profile of citalopram and escit-
alopram [107]. SERT serotonin transporter
Fig. 4 Chemical structures and

receptor profiles of brexpipra-
zole and lumateperone [68, 72].
SERT serotonin transporter
Brexpiprazole is a novel atypical antipsychotic approved to induce extrapyramidal side effects. Lumateperone has a
by the FDA in 2015 for the treatment of schizophrenia and unique mechanism of action, modulating synergistically
major depressive disorder as an add-on therapy [113]. Its multiple neurotransmitter systems, and has been suggested
mechanism of action is mediated via the antagonism of as a potential treatment for a range of neuropsychiatric dis-
5-HT2AR and partial agonism of D2R and 5-HT1AR (Fig. 4) orders [73]. A recently completed phase III, randomized,
[68]. Partial agonistic activity at the D2 receptor accounts double-blind, placebo-controlled, multi-center study
for the reduced occurrence of extrapyramidal side effects. (NCT02817906) has investigated the efficacy and safety
Lately, two phase III clinical trials have evaluated the of lumateperone (9 mg/day for 4 weeks; primary outcome
safety and efficacy of brexpiprazole in AD-related agita- measured using CMAI-Community Version) in 177 patients
tion (NCT01862640 investigated two-fixed doses of 1 and with dementia with clinically significant agitation (Table 3).
2 mg/day and NCT01922258 investigated the flexible dosing The sponsor announced that the study was unlikely to meet
of 0.5, 1.0, or 2.0 mg/day during the 12-week treatment). its primary endpoint upon completion [119], and therefore,
These randomized, double-blind, placebo-controlled, multi- it has been terminated.
center studies enrolled 433 and 270 participants, respectively
(Table 3). The sponsor announced that brexpiprazole signifi- 4.2.2 Dextromethorphan Formulations
cantly ameliorated the symptoms of agitation in compari-
son to placebo (evaluated by a change from baseline in the Preclinical data revealed that a sigma-1 receptor agonist,
Cohen-Mansfield Agitation Inventory [CMAI] total score) dextromethorphan, exerts promising mood-modulating
[114, 115]. A corresponding trial (phase III, 12-week, multi- properties [121] For instance, dextromethorphan showed
center, randomized, double-blind, placebo-controlled, two- anti-stress activity by reducing fear stress in conditioned
arm, fixed-dose: 0.5 mg and 1 mg, 225 patients) registered mice, which was suggested to involve a sigma-1-depend-
in Europe (2017-003940-19) has not been accomplished yet ent stimulation of the dopaminergic system [121]. Further
[70]. In addition, a phase III, multi-center, active-treatment- studies in rodents revealed that dextromethorphan displayed
extension trial (NCT03724942) is recruiting 250 patients to anti-depressive-like activity and exerted neuroprotective and
evaluate the safety and tolerability of brexpiprazole (2–3 mg/ antioxidant effects [122, 123]. Dextromethorphan is an FDA-
day for 12 weeks) in patients with AD-associated agitation approved antitussive drug that acts in the CNS [124, 125].
(primary outcome data will include adverse events elic- Dextromethorphan exhibits high affinity to several biological
ited from participants) [116]. A corresponding European targets: sigma-1 receptor, SERT, norepinephrine transporter,
active-treatment extension trial (a phase III, 12-week, multi- NMDA receptor, alpha-2 adrenoceptor, histamine H 1 recep-
center study, 225 patients with dementia) is ongoing (2018- tor (H1R), and nicotinic α3β4 receptor (Fig. 5) [124].
002783-88 [70]). The specific receptor profile of dextromethorphan con-
Lumateperone is another atypical antipsychotic drug with tributes to its complex pharmacological activities, which
a mechanism of action based on the antagonistic activity at prompted scientists to investigate its therapeutic potential
the 5-HT2AR, partial agonistic activity at the presynaptic in dementia-related agitation. However, dextromethorphan
D2 receptors, and antagonistic activity at the postsynaptic showed an unfavorable pharmacokinetic profile in humans,
D2R [72, 117], as well as SERT blockade (Fig. 4). Clinical related to its rapid hepatic metabolism, which hampered
studies in healthy volunteers using positron emission tomog- the attainment of therapeutic concentrations in the brain.
raphy revealed that lumateperone displayed high occupancy To reduce the first-pass effect and improve its pharmacoki-
of the 5-HT2AR in the cortex and negligible occupancy of netics, dextromethorphan was combined with a cytochrome
the D2 striatal receptors [118], suggesting that it is less likely P450 2D6 inhibitor, quinidine (formulation known as

Fig. 5 Chemical structure of deuterated (d6) dextromethorphan/quinidine (AVP-786) and dextromethorphan/bupropion (AXS-05). NET
noradrenaline transporter, NMDA N-methyl-d-aspartate, SERT serotonin transporter
AVP-923). Quinidine is an anti-arrhythmic agent used in first FDA-approved deuterated compound for the treatment
clinical practice (200–300 mg) to treat cardiac arrhythmias of dementia-related agitation [126]. However, it should
[124, 126]. It reversibly inhibits cytochrome P450 2D6, and be emphasized that the first dextromethorphan/quinidine
has been added to formulations at subclinical doses (10 mg) formulation (AVP-923, Neudexta) label carries a warning
to inhibit cytochrome P450 2D6 and prolong the plasma regarding cardiac safety [127], suggesting that this com-
half-life of dextromethorphan [124]. AVP-923 (Neudexta) pound should be avoided in patients with congenital long-
has been approved by the FDA for the treatment of pseudob- QT syndrome and the QTc interval should be evaluated in
ulbar affect [127]. the patients at risk of QTc prolongation [126, 127].
The first clinical study, a phase II, randomized, Another combination formula that includes dextrometho-
multi-center, double-blind, placebo-controlled trial rphan is AXS-05, which contains low doses of bupropion.
(NCT01584440), evaluated the efficacy of AVP-923 (dex- Bupropion inhibits the reuptake of norepinephrine and
tromethorphan/quinidine at the doses of 20/10 mg once daily dopamine and antagonizes nicotinic receptors. As a potent
to 30/10 mg twice daily for 10 weeks) in reducing agitation cytochrome P450 2D6 inhibitor, bupropion was added to the
in 220 patients with dementia, and revealed that AVP-923 formulation to increase the plasma concentrations of dex-
exerted statistically significant effects on agitation compared tromethorphan [130]. AXS-05 received a fast-track desig-
with placebo (primary outcome measure was the change from nation from the FDA for the evaluation of its efficacy in the
baseline in the NPI Agitation/Aggression domain score) treatment of AD-related agitation [131]. Currently, a phase
[128] (Table 3). Meanwhile, another formulation had been II/III clinical trial (NCT03226522) [62] is evaluating the
developed, containing a subclinical dose of quinidine and safety and efficacy of AXS-05 (one tablet daily for 5 weeks)
deuterated dextromethorphan (AVP-786). Dextrometho- for its use in the management of AD-related agitation (pri-
rphan (Fig. 5) was deuterated to additionally improve its mary outcome measured using CMAI). This randomized,
pharmacokinetic profile and reduce its first-pass metabolism double-blind, placebo-controlled study enrolled 435 subjects
in the liver [126]. Using the data generated for AVP-923, the with AD. Recently, the sponsor has announced the positive
FDA agreed to initiate a follow-up, phase III clinical trial outcome of the interim analysis of the study and received
(NCT02446132), an extension study, to evaluate the long- recommendation for further continuation [63].
term safety and efficacy of AVP-786 (three various doses
administered twice a day over 52 weeks) in the management 4.3 Drugs Affecting Glutamatergic
of dementia-associated agitation [129]. The primary outcome Neurotransmission
measure includes, inter alia, the number of participants with
any treatment-emergent serious adverse event, the Mini-Men- 4.3.1 Metabotropic Glutamate 2 Receptor Agonist:
tal State Examination score, and the Alzheimer’s Disease LY2812223
Assessment Scale-Cognitive Subscale score [74].
Based on the promising results of previous studies, In the early 1990s, it was first proposed that dysfunction
experts strongly believe that AVP-786 may become the in glutamatergic neurotransmission could be implicated in
mental disorders [132]. Therefore, it was postulated that availability of d-serine, an endogenous agonist of the NMDA
modulation of glutamatergic activity may constitute a novel receptor. N-methyl-D-aspartate dysfunction in turn has been
nondopaminergic strategy for the treatment of psychosis associated with schizophrenia and AD [141]. D-amino acid
[133–135]. Additionally, previous studies highlighted the oxidase inhibitors were found to exert antipsychotic activ-
activation of glutamate receptors exerts neuroprotective and ity and improve cognitive function in AD [142, 143]. Cur-
memory-enhancing effects in animal models, which might rently, SyneuRx International Corp. is developing a com-
be particularly beneficial to patients with dementia [42]. petitive antagonist of DAAO, compound SND-51, for the
Eli Lilly and Company discovered LY2812223 (Fig. 6), a treatment of dementia and psychosis. SND-51 is botanic
mGluR2 agonist [136, 137]. LY2812223 was found active in origin (chemical structure has not been disclosed), and
in an animal model of psychosis, sensitive to mGluR2 in animal models, it elicited antipsychotic and anxiolytic
[95, 137]. Unfortunately, in the pharmacokinetic studies, activity and improved spatial memory [144]. SND-51 has
LY2812223 showed a poor oral bioavailability (~ 4%). now progressed to phase II clinical trials, and its efficacy in
However, this did not limit the further development of the the treatment of dementia and psychosis is being evaluated
mGluR2 agonist for the treatment of mental disorders. Low [145].
bioavailability of LY2812223 was overcome by design-
ing its alanine prodrug MP-101 (LY2979165). MP-101 is 4.4 Drugs Affecting Cholinergic Neurotransmission
administered orally and absorbed in the gastrointestinal tract
through active transport and then, it is rapidly hydrolyzed to 4.4.1 Selective Muscarinic M4 Receptor Agonist:
LY281223 (Fig. 6) [95, 138]. HTL0016878
MP-101 is under development for the treatment of
dementia-related psychosis and/or agitation and aggres- Another promising example of compounds being developed
sion (NCT03044249) [139]. This randomized, placebo- for treating dementia-related psychosis and agitation/aggres-
controlled, phase II clinical trial will assess the efficacy sion is the selective muscarinic M 4R agonist HTL0016878
(measured as the change from baseline in the NPI-Psycho- (chemical structure has not been disclosed). The muscarinic
sis subscale score), safety, and pharmacokinetic profile of receptors are abundantly expressed in the cortex and hip-
MP-101 (20–60 mg/day for 10 weeks), compared to placebo. pocampus, the areas involved in cognitive and neurobehav-
LY2979165 was previously evaluated in healthy subjects, ioral functions [146]. In animal models, nonselective M 1R/
in whom it was overall well tolerated and showed a linear M4R agonists improved psychotic behaviors and cognitive
pharmacokinetic profile [53, 137]. performance [46]. These findings have been confirmed in
muscarinic M4R-knockout mice, and thus, it has been sug-
4.3.2 Inhibitors of D‑Amino Acid Oxidase gested that M 4R agonists represent an attractive molecular
target for the development of novel antipsychotic agents
An interesting approach for indirectly controlling the glu- [120]. A first-in-class selective M4R agonist, HTL0016878,
tamatergic neurotransmission is to inhibit the activity of developed by Sosei Heptares for the treatment of neurobe-
D-amino acid oxidase (DAAO). D-amino acid oxidase havioral symptoms in patients with AD, has advanced to
regulates the brain levels of D-amino acids, and in several phase I clinical trials (NCT03244228). This randomized,
psychiatric conditions, the activity and expression of DAAO double-blind, placebo-controlled study evaluated the safety,
are enhanced [140]. Overactivation of DAAO decreases the pharmacokinetics, and pharmacodynamics of this compound
in 106 healthy young volunteers as well as in elderly patients
[51]. The results have not been revealed yet.
O OH
O OH
N H
H OH enzymatic
H OH
4.5 Drugs Affecting Noradrenergic
transformation
N
N
O N
N H Neurotransmission
S NH O
H H2N N S NH2
H
O 4.5.1 Alpha‑1 Adrenoceptor Inhibitor: Prazosin
MP-101 (LY2979165) LY2812223
Several findings indicated the robust association between
hmGluR2 Ki = 144 noradrenergic depletion and AD [35, 147, 148]. Postmor-
hmGluR2 EC50 = 5.6 nM, tem studies revealed that the prefrontal cortex in patients
Emax = 99% (cAMP assay)
with AD was characterized by a significant reduction in
noradrenergic neurons [148], which may be associated
Fig. 6 Chemical structure and metabolic activation of MP-101, a
prodrug of LY281223. cAMP cyclic adenosine monophosphate, with a poor cognitive performance as well as the onset of
hmGluR2 human metabotropic glutamate receptor type 2 aggression [147]. Postmortem studies also showed that the

NH2 cannabinoid receptor agonists may serve as a potential treat-

O ment for managing AD-related aggression.
N
Among the various cannabinoid receptor agonists, Δ-9-
O N N tetrahydrocannabinol (THC), dronabinol, and nabilone
N (Fig. 8) [synthetic analogs of THC] have been the most
O
widely investigated in clinical trials [156]. A randomized,
O double-blind, placebo-controlled study that investigated the
effect of THC (1.5 mg administered three times daily for
Prazosin 3 weeks) in 50 patients with dementia agitation or aggres-
sion found no significant differences between the treatment
alpha 1A Ki = 0.01 nM group and the placebo group (primary outcome measured
using the NPI) [163]. Similarly, another trial showed no
Fig. 7 Chemical structure and binding profile of prazosin [154, 155] efficacy for THC in reducing agitation or aggression [164]
(Table 3).
In contrast, a synthetic analog of THC, dronabinol, was
compensatory upregulation of postsynaptic alpha-1 adreno- found to be effective in reducing agitation in patients with
ceptor is linked with AD-related aggression [149, 150]. dementia [156]. A retrospective study conducted on 40
Therefore, it has been proposed that reducing the activity of acutely hospitalized patients with severe dementia showed
the overstimulated postsynaptic alpha-1 adrenoceptors may that dronabinol (7 mg/day for 2 weeks) significantly reduced
alleviate the aggressive behavior [151, 152]. motor agitation and aggressiveness (a significant decrease in
Among dugs acting on the alpha-1 adrenoceptors, prazo- all domains of the Pittsburgh Agitation Scale) [165]. How-
sin remains the only centrally acting agent that can readily ever, some authors reported the occurrence of adverse effects
pass the blood–brain barrier and block the alpha-1 adreno- associated with dronabinol use, with a particular emphasis
ceptors in the CNS (Fig. 7) [153]. The first pilot study that on sedation [165, 166]. Other studies found that dronabi-
evaluated the effectiveness of prazosin in suppressing the nol reduced night-time agitation [165, 167–169] in patients
dementia-related aggression and agitation was a double- with dementia. An open-label pilot study of six patients with
blind placebo-controlled study that enrolled 22 patients with dementia with night-time agitation treated with dronabinol
AD [151] (Table 3). Administration of prazosin (mean dose: (2.5 mg/day for 2 weeks) reported a significant reduction in
5.7 mg/day, 8 weeks) led to a significant reduction in aggres- nocturnal motor activity [167] (assessed using the NPI scale)
sion/agitation (improvement on the Brief Psychiatric Rat- (Table 3). These encouraging results led to further interest
ing Scale and the NPI score) compared with placebo [151]. in this class of compounds and the initiation of a clinical
Side effects and blood pressure fluctuations were compa- investigation of another synthetic cannabinoid, nabilone.
rable between the prazosin group and the placebo group. First, the efficacy of nabilone has been only described in two
These data provided further support to initiate a larger phase case reports, which described the improvement of behavio-
II study (NCT03710642) enrolling 186 patients with AD ral disturbances (agitation and psychosis) in patients with
with agitation [55]. This double-blind, placebo-controlled, dementia after treatment with nabilone [170, 171]. Further, a
randomized study will evaluate the effectiveness of prazo-
sin (4–6 mg/day) in reducing agitation in patients with AD
during 12 weeks (primary outcome measured using Clinical O
Global Impression of Change in Agitation) [55]. OH OH

H
4.6 Drugs Targeting the Endocannabinoid System H

O O
Targeting cannabinoid receptors has acquired paramount
importance as it offers a perspective to treat the symptoma-
tology and pathology of AD [156]. Activation of cannabi-
noid receptors by agonists at non-psychoactive doses induces Dronabinol Nabilone
neuroprotective effects [157, 158] and can influence mood
CB1 Ki = 40 nM CB1 Ki = 2.2 nM
and behavior [156]. Preclinical studies have shown that can-
nabinoid receptor agonists decrease amyloid-β levels and CB2 Ki = 36 nM CB2 Ki = 1.8 nM
reduce neuroinflammation [159, 160]. Further preclinical
studies showed that a cannabinoid receptor agonist reduced Fig. 8 Chemical structure and receptor affinity of dronabinol and
aggressive behaviors [37, 161, 162]. These data suggest that nabilone [160, 161]. CB cannabinoid
Fig. 9 Chemical structure and but also helps to improve sleep quality [178]. The first pilot
binding profile of mirtazapine N
study evaluating the effect of mirtazapine (15–30 mg/day) on
[180]
N AD-related agitation was a 12-week open-label, prospective
N
study that included 16 patients who had clinically significant
agitation [176] (Table 3). The authors observed a significant
reduction in agitation in the patients treated with mirtazap-
ine compared with pre-treatment with mirtazapine (changes
Mirtazapine
in behavior were assessed using CMAI-Short Form) [176].
5-HT2A Ki = 6.3 nM These encouraging data prompted the initiation of a larger
5-HT3 Ki = 2900 nM phase III, pragmatic, multi-center, double-blind, placebo-
alpha 2A Ki = 20 nM controlled, randomized study (NCT03031184), which is
alpha 2B Ki = 88 nM
alpha 2C Ki = 18 nM currently recruiting 222 patients to evaluate the safety and
H1 Ki = 1.6 nM effectiveness of mirtazapine (15–30 mg/day for 12 weeks) in
reducing AD-related agitation (primary outcome measure:
CMAI score at 12 weeks) [75].
randomized, double-blind, placebo-controlled cross-over trial
(NCT02351882) [59] evaluated the safety and effectiveness 4.8 α2δ Subunit‑Containing Voltage‑Dependent
of nabilone (1–2 mg) for 14 weeks (6-week treatment with a Calcium Channel Blocker: Gabapentin
1-week washout between phases) in the management of agita-
tion in 39 patients with AD (primary outcome measured using In a large percentage of patients with dementia, agitation
CMAI) (Table 3). The authors reported a statistically signifi- and wandering manifest during the night-time [173]. The
cant reduction in agitation within the nabilone group [60, nocturnal episodes of behavioral disturbances have a nega-
61]. During the treatment, the patients treated with nabilone tive influence on daily functioning and additionally induce
experienced sedation. The authors concluded that nabilone aggression during the day [173]. This vicious circle might
may constitute a promising treatment for agitation associated be broken by treatment with a sedative agent that can help
with AD; however, the obtained data should be confirmed in to decrease agitation and improve sleep quality during the
a longer and larger study and side effects such as sedation and night.
possibly cognitive decline should be monitored [61]. Never- In 2011, a case report described the effectiveness of
theless, nabilone seems to have a greater effect in reducing gabapentin in reducing the dementia-associated noctur-
agitation, compared with other cannabinoids such as THC nal agitation [181]. Gabapentin is an FDA-approved drug
and dronabinol [61] and offered the most favorable pharma- for the treatment of epilepsy [182]. Gabapentin blocks
cokinetic profile among all the studied cannabinoids [172]. the α2δ subunit-containing voltage-dependent calcium
Further clinical studies are warranted to confirm its efficacy. channels (Fig. 10), which are associated with the release
of neurotransmitters [183, 184]. Gabapentin displays a
4.7 Drugs Improving Sleep Quality Displaying versatile pharmacological profile, including anticonvul-
Various Mechanisms of Action sant, sedating, and anxiolytic activities [185]. In addition,
the positive effects of gabapentin on the sleep quality and
4.7.1 Noradrenergic and Specific Serotonergic architecture have been well documented [186]. A series of
Antidepressant: Mirtazapine case reports have described the treatment of patients with
dementia with agitation using gabapentin and showed that
Nocturnal sleep quality may contribute to the onset of the patients responded to the treatment favorably [187, 188].
behavioral problems in patients with dementia [173]. Clini- Currently, gabapentin is being investigated in a phase IV
cal observations suggested that agitative behavior in patients study (NCT03082755) to test its effect (300–600 mg/day) on
with dementia might be caused by sleep disturbances [174, night-time agitation (primary outcome measure: night-time
175]. In this regard, it has been proposed that both condi- agitation measured using CMAI) [119]. During the 8-week
tions could be effectively addressed by a drug that displays treatment, this double-blind, placebo-controlled, randomized
anxiolytic as well as sleep-promoting activity [176]. clinical trial will enroll 136 participants [76]. The remain-
Mirtazapine is an antidepressant with sedative properties ing options available for the treatment of sleep disturbances
and an ability to promote sleep [177, 178]. It interacts with and nocturnal agitation such as benzodiazepines are not rec-
several types and subtypes of receptors including seroto- ommended in vulnerable elderly individuals because these
nin 5-HT2AR and 5-HT3R, alpha-2 adrenoceptors, and H 1R agents are well documented to cause harmful effects such
(Fig. 9) [179]. The unique pattern of receptor modulation as cognitive worsening and increase the risk of fall-related
by mirtazapine not only ameliorates psychiatric symptoms injuries [189].

Fig. 10 Chemical structure and NH2 eight antipsychotic drugs tested in the same experimental
binding profile of gabapentin O setting [199].
[190]. VDCC voltage-dependent
calcium channel OH
Similarly, a series of multi-modal ligands exhibiting high
affinity to SERT, D 2R, 5-HT1AR, 5-HT6R, and 5-HT7R have
Gabapentin been identified (Fig. 11). It has been shown that tetrahy-
dropyridin-4-yl‐1H‐indole is a privileged scaffold, which
α2δ VDCC Ki = 0.05 µM
accounts for an interaction with SERT, D 2R and 5-HT1AR,
and its combination with the aryl sulfonamide moiety pro-
5 Compounds in the Early Stage vides additional interaction with 5-HT6R and 5-HT7R. The
of Development (Discovery or Preclinical selected compound 2 was tested in vivo and found to exhibit
Phase) antipsychotic and antidepressant activity, as well as exert
memory-enhancing effects [200].
We additionally searched for literature data associated with Another notable approach of identifying novel MTLDs
the identified compounds in the early stage of development relies on combining D2R partial agonism with 5-HT 6R
(discovery or preclinical phase), published from 2014 to the antagonism. The partial D2 agonism concept is based on
present day to obtain the most recent overview covering the the modulation of dopaminergic neurotransmission at a low
last 5 years, using the compounds’ name and other keywords sufficient level that simultaneously prevents the occurrence
such as “Alzheimer’s disease” and “dementia” or “aggres- of extrapyramidal side effects by preventing excessive D 2R
sion” or “psychosis.” We used PubMed, ScienceDirect, blockade in the striatum [201]. This strategy resulted in the
GlobalData, and Google Scholar databases for our search development of a series of hybrid molecules, combining
(papers written in English). If data regarding the identified the 5-HT6 and D2 pharmacophores (Fig. 11). The selected
compounds were not published, we searched the websites of molecule 3 displayed antidepressant and anxiolytic activity
pharmaceutical and biotech companies responsible for the in aged animals, as well as promising procognitive effects
compounds’ development. Several molecules that matched [201]. The abovementioned compounds (2 and 3) are cur-
the selection criteria were identified, which are described rently at an early stage of development by Adamed Pharma
in detail below. [202, 203].
5.1 Multi‑Target‑Directed Ligand Concept 5.1.2 Molecules Targeting Muscarinic M1 and M4 Receptors
It has been suggested that parallel modulation of several Modulation of muscarinic receptors activity may improve
molecular targets may result in a balanced, and thus supe- both cognitive and psychosis-related symptoms. Targeting
rior, pharmacological action, compared to a selectively the centrally located M 1R and M4R proved to enhance the
acting drug. Considering this, a novel approach in drug memory function and reduce psychosis both in animal mod-
discovery involves designing a single chemical entity that els and in clinics [204, 205]. Additionally, stimulation of
can simultaneously modulate the activity of several biologi- muscarinic receptors controls the increase of amyloid-β lev-
cal targets. Such compounds are described in the literature els and prevents memory impairments [206]. This evidence
as “multi-target-directed ligands” [197]. The multi-target- encouraged the development of dual ligands acting on M1R/
directed ligand concept intended to design “clean” ligands M4R. Sosei Heptares, jointly with Allergan, is developing a
that bind to selected molecular targets while sparing off series of dual M1/M4 agonists for the treatment of memory
targets, and thus reduce the risk of side effects [198]. The deficits and comorbid psychosis in patients with AD. The
multi-target-directed ligand concept is relatively new; how- joint project has progressed to an advanced preclinical devel-
ever, it has recently been widely explored in the literature opment stage [207]. Further data have not been revealed.
and several experimental compounds have emerged from
this strategy. 5.1.3 Cholinesterase and Monoamine Oxidase Inhibitor:
Ladostigil
5.1.1 Ligands Targeting Several Monoaminergic Receptors
Degeneration of cholinergic cortical neurons is considered
A combination of chemical scaffolds responsible for inter- as a key pathology that accounts for the cognitive deficit in
action with 5-HT6R/5-HT7R and 5-HT2AR/D2R yielded a patients with AD. Drugs that act by inhibiting cholinester-
hybrid molecule 1, which elicited favorable psychotropic ase, and as a result, increasing cholinergic transmission in
effects (Fig. 11). In pharmacological studies, the selected the affected cortical areas are expected to improve memory
multi-modal ligand 1 showed antidepressant and antipsy- function. Interestingly, a cholinesterase inhibitor rasagiline
chotic activity and did not affect cognition, in contrast to the reduced aggression and delusions in patients with AD [208].
Fig. 11 Examples of multi-target-directed ligands obtained by combining the scaffolds responsible for interactions with 5-HT6R, 5-HT7R,
5-HT2AR, and D2R (discovery stage). SERT serotonin transporter
In a dual-acting drug, ladostigil, the carbamate fragment of relationship with the pathology of dementia-related psycho-
rivastigmine, which accounts for the inhibition of cholinest- sis (see Sect. 2). Therefore, merging 5-HT2AR and 5-HT6R
erases, was merged with the N-(prop-2-yn-1-yl)-2,3-dihy- into a single chemical entity, having the pharmacological
dro-1H-inden-1-amine fragment of rasagiline, which blocks activities of both the receptors, may be beneficial in the
the activity of monoamine oxidases A and B (Fig. 12) [209]. treatment of dementia-related psychosis. Small molecules
Ladostigil is a multi-modal agent developed by Avraham targeting 5-HT6R and 5-HT2AR are currently under devel-
Pharmaceuticals to treat patients with mild cognitive impair- opment (discovery phase/advanced preclinical development
ment with concomitant behavioral symptoms. Preclinical stage) for the treatment of dementia-related psychosis by
studies showed that ladostigil improves memory deficits and Adamed Pharma [213]. The chemical structure and preclini-
exerts anxiolytic and antidepressant-like activity [210, 211]. cal data have not been disclosed.
Therefore, ladostigil has been suggested for use in patients
with dementia with comorbid depression; however, no clini-
cal data are available so far [210]. 6 Safety Issues Regarding Pharmacotherapy
of Dementia‑Related Psychosis
5.1.4 Ligands Targeting Serotonin 5‑HT6 and 5‑HT2A and Agitation/Aggression: Summary
Receptors of Off Targets
Serotonin 5-HT6 receptors are localized in the cortical Previous studies indicated that patients with dementia were
and limbic areas, and ligands modulating the activity of found to be particularly sensitive to side effects induced by
5-HT6 receptors exert memory-enhancing, anxiolytic, and atypical antipsychotics [214]. Patients with dementia seem
antidepressant effects [47, 48]. Importantly, several selec- to be at a greater risk of developing antipsychotic-associated
tive 5-HT6 antagonists entered clinical trials and have been stroke events [215]. It should be emphasized that atypical
regarded as potential drug candidates for the treatment of antipsychotics used so far in clinical settings (risperidone,
cognitive impairment associated with AD [48, 212]. olanzapine, quetiapine, and aripiprazole) interact with mul-
Similarly, serotonin 5-HT2A receptor has emerged as a tiple receptors, including “off targets,” which induce seri-
promising target for the treatment of AD, owing to its strong ous side effects (Table 4). For instance, similar to the first

Fig. 12 Chemical structure
of ladostigil. Ladostigil is
composed of two fragments: the
carbamate moiety of rivastig-
mine, which accounts for the
inhibition of cholinesterases,
merged with the N-(prop-2-yn-
1-yl)-2,3-dihydro-1H-inden-1-
amine fragment of rasagiline,
which blocks the monoamine
oxidases (MAO) A and B [209]
generation of antihistamines, antipsychotic agents tend to the potential inhibitory effects on the hERG channel should
induce excessive daytime sleepiness owing to their high become an obligatory safety practice in the early stages of
affinity to H1R present in the brain [216]. Interaction with drug discovery for dementia-related psychosis and agitation/
alpha-adrenoceptors (risperidone and quetiapine) causes aggression [219, 220].
orthostatic hypotension, and as a result, may increase the Considering the safety issues regarding elderly patients
risk of falls and hip fractures [217]. Moreover, a large clini- and their particular sensitiveness to adverse reactions, future
cal study found a correlation between the increased risk of therapeutic agents designed for dementia-related psychosis
stroke and treatment with antipsychotics that exhibit high and agitation/aggression should not antagonize the mus-
binding affinity to alpha-2 adrenoceptor and M1R. A pos- carinic, adrenergic, and histaminergic receptors or the hERG
sible mechanism underlying this relationship is that block- channel [112].
ade of alpha-2 adrenoceptor and M1 may induce orthos-
tatic hypotension and tachycardia, which prompts unstable
hemodynamic conditions and increases the risk of stroke 7 Conclusions and Future Perspectives
[214, 215]. In addition, blockade of the muscarinic recep-
tors intensifies the cholinergic deficit and worsens cogni- Treatments currently used for dementia-related psychosis
tive functioning in patients with dementia, who already and agitation/aggression pose a great challenge to clinicians,
have memory impairment. Blockade of M 1R may induce and specifically targeted pharmacotherapies are lacking.
additional uncomfortable symptoms, such as severe con- Despite known harms and modest clinical efficacy, antipsy-
stipation and urine retention [218]. Furthermore, previous chotics still are often administered off-label to control some
studies showed that inhibition of hERG (human ether-a- symptoms [221]. Several clinical experts have agreed that to
go–go-related gene) potassium channel has been considered optimize the clinical response, patients with dementia should
as the most common mechanism of drug-induced cardiotox- be treated with specifically developed medications that inter-
icity (prolongation of QT interval). Therefore, evaluation of act with pharmacologically relevant targets [16, 222, 223].
Within this context, preclinical and clinical studies have
pointed out various biological targets that might constitute
Table 4 Simplified representation of an off-target receptor profile potential therapeutics for dementia-related psychosis and
Receptor Pharmacological activity agitation/aggression.
Considering that the polymorphism of serotonin 5-HT2AR
Side-effect receptor action and its disrupted functioning has been associated with the
5-HT2C Weight gain onset of psychosis and aggression in AD, it seems justifi-
Alpha-2 Orthostatic hypotension able that the ligands modulating the activity of 5-HT2AR
H1 Excessive sedation, weight gain could be attractive therapeutic agents for dementia-related
M1 Memory deficits, anticholinergic side psychosis and aggression [26, 27, 82]. A selective inverse
effect
agonist of 5-HT2AR (pimavanserin) and novel atypical antip-
hERG channel QT prolongation, arrhythmia
sychotics acting as 5-HT2A antagonists (lumateperone, brex-
hERG human ether-a-go–go-related gene piprazole) have advanced to phase III clinical trials after
showing promising efficacy in phase II studies in the man- pathology of dementia-related psychosis and agitation/
agement of dementia-related psychosis and agitation [58, aggression, their promising pharmacological profile suggests
73, 114]. A phase III study has reported promising results their potential therapeutic utility. Favorable pharmacological
for brexpiprazole, which significantly reduced agitation in properties have been reported for mGluR2, CB1, NMDA,
patients with dementia, and its long-term efficacy will be M4, and M 1/M4 agonists. A C B1R agonist, nabilone, showed
further evaluated in a treatment-extension study [114]. In efficacy in reducing aggression in patients with dementia in
contrast, a phase III clinical trial that investigated the effi- a recently completed phase II/III clinical trial. An mGluR2
cacy of lumateperone in reducing dementia-related agita- agonist, LY2979165, has advanced to phase II clinical trials
tion has been terminated because of a lack of efficacy [119]. that will investigate its safety and efficacy in the treatment
Moreover, several compounds targeting 5-HT2AR are in the of dementia-related psychosis and agitation/aggression.
early stage of the drug discovery process [199, 213]. In addi- Similarly, an indirect NMDA agonist compound SND-51
tion, the role of 5-HT1AR is well elucidated in the onset has advanced to phase II clinical trials that will evaluate
of neuropsychiatric symptoms [34]. A 5-HT1AR/5-HT1BR its efficacy in the treatment of dementia and psychosis. A
agonist eltoprazine has also completed phase II clinical selective M4 receptor agonist, HTL0016878, has progressed
trials, showing positive results in suppressing AD-related to phase I clinical trials. In addition, various compounds
aggression. Similarly, pathological changes in the function acting on the pharmacologically relevant targets (5-HT6R
of alpha-1 adrenoceptor have been linked with the onset of and M1R/M4R) have progressed to an advanced preclini-
aggressive behavior in patients with AD [148]. A centrally cal development stage. To sum up, future drugs targeting
acting alpha-1 adrenergic antagonist prazosin is currently mGluR, NMDA receptors, CB1R, M1/M4R, and 5-HT6R also
being investigated in a phase II study in the treatment of offer the possibility to tackle dementia-related psychosis and
dementia-related aggression. agitation/aggression.
Several groups of patients with dementia with comorbid Additionally, the key success of a clinically effective
conditions may require specific adjusted pharmacological agent will likely depend on its safety and lack of harmful
treatment. The episodes of nocturnal agitation in patients side effects [8, 9, 11]. Considering that previous clinical
with dementia seem to require an agent displaying sedative observations have shown that patients with dementia are
properties and adjunctive sleep-promoting activity [174]. at a higher risk of stroke [112], future drug candidates for
Within this context, two generic drugs, mirtazapine and patients with dementia should consistently avoid interactions
gabapentin, are currently being investigated in phase III and and further blockade of alpha-2 adrenoceptors, M 1R, H1R,
phase IV trials, respectively. Both agents exhibit sedative and the hERG channel to avoid cardiotoxicity, stroke, exces-
properties and the ability to improve sleep quality, which sive sedation, and memory impairments.
may be suitable for this subgroup of patients. Nevertheless, the future pharmacotherapy of dementia-
Molecules acting via the inhibition of SERT appear to related psychosis, agitation/aggression will likely depend on
constitute another class of promising therapeutics [32, 33]. the successful compilation of phase III clinical trials and fur-
Polymorphism of the SERT has been associated with AD- ther approvals. So far, the most promising results have been
related aggression. Significant clinical efficacy of a selec- observed for compounds modulating serotoninergic signal-
tive SERT inhibitor, citalopram, has been observed in a ing. Another set of molecules displaying favorable pharma-
phase III clinical trial. However, citalopram induced cardiac cological activity are at an early stage of development.
side effects, and therefore, its long-term clinical applica-
tion remains dubious. Currently, a phase III clinical trial is Compliance with Ethical Standards
recruiting patients to evaluate the safety and efficacy of the
S-enantiomer of citalopram, escitalopram, in reducing AD- Funding This work was supported by the National Science Center of
Poland (Grant DEC-2014/15/D/NZ7/01789) and National Center for
related aggression. Escitalopram seems to be a safer alter-
Research and Development (Grant POIR.01.01.01-00-0108/17). The
native and does not tend to induce risky cardiac reactions open access has been sponsored by Jagiellonian University, Kraków,
[106]. It is worth nothing that dextromethorphan displays Poland.
high affinity to SERT, which further supports the evalua-
tion of its combined formulations (AVP-786 and AXS-05) in Conflict of interest Marcin Kołaczkowski and Joanna Śniecikowska
clinical trials. Both formulations are currently being inves- are employees of Adamed Pharma S.A. Monika Marcinkowska, Niko-
la Fajkis, Paweł Paśko, and Weronika Franczyk have no other relevant
tigated in ongoing phase III studies. The interim analysis affiliations or financial involvement with any organization or entity
of the study with AXS-05 showed promising outcomes and with a financial interest in or financial conflict with the subject matter
reported no safety issues [63]. or materials discussed in this article apart from those disclosed. No
Although certain drug candidates presented here act on writing assistance was utilized in the production of this article.
the molecular targets that do not meticulously match the

Open Access This article is licensed under a Creative Commons Attri- recommendations and treatment practice. Z Gerontol Geriatr.
bution-NonCommercial 4.0 International License, which permits any 2017;50:106–14.
non-commercial use, sharing, adaptation, distribution and reproduction 16. Kales HC, Lyketsos CG, Miller EM, Ballard C. Management of
in any medium or format, as long as you give appropriate credit to the behavioral and psychological symptoms in people with Alzhei-
original author(s) and the source, provide a link to the Creative Com- mer’s disease: an international Delphi consensus. Int Psychogeri-
mons licence, and indicate if changes were made. The images or other atr. 2019;31:83–90.
third party material in this article are included in the article’s Creative 17. VanGuilder HD, Yan H, Farley JA, Sonntag WE, Freeman WM.
Commons licence, unless indicated otherwise in a credit line to the Aging alters the expression of neurotransmission-regulating
material. If material is not included in the article’s Creative Commons proteins in the hippocampal synaptoproteome. J Neurochem.
licence and your intended use is not permitted by statutory regula- 2010;113:1577–88.
tion or exceeds the permitted use, you will need to obtain permission 18. Choudhury A, Sahu T, Ramanujam PL, Banerjee AK,
directly from the copyright holder.To view a copy of this licence, visit Chakraborty I, Kumar AR, et al. Neurochemicals, behaviours
http://creativecommons.org/licenses/by-nc/4.0/. and psychiatric perspectives of neurological diseases. Neuropsy-
chiatry. 2018;8:395–424.
19. Vogt I, Prinz J, Campillos M. Molecularly and clinically related
drugs and diseases are enriched in phenotypically similar drug-
References disease pairs. Genome Med. 2014;6:52.
20. Ford AH, Almeida OP. Management of depression in patients
1. Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related with dementia: is pharmacological treatment justified? Drugs
dementias: diagnostic criteria for a distinct syndrome. Am J Geri- Aging. 2017;34:89–95.
atr Psychiatry. 2000;8:29–34. 21. Hersch EC, Falzgraf S. Management of the behavioral and
2. Alzforum. https: //www.alzfor um.org/papers /uber-eine-eigena rtig psychological symptoms of dementia. Clin Interv Aging.
e-erkrankung-der-hirnrinde/en. Accessed 16 Dec 2019. 2007;2:611–21.
3. Müller-Spahn F. Behavioral disturbances in dementia. Dialog 22. Murley AG, Rowe JB. Neurotransmitter deficits from frontotem-
Clin Neurosci. 2003;5:49–59. poral lobar degeneration. Brain. 2018;141:1263–85.
4. Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and 23. Bondareff W. Neuropathology of psychotic symptoms in Alz-
psychological symptoms of dementia. Front Neurol. 2012;3:73. heimer’s disease. Int Psychogeriatr. 1996;8(Suppl. 3):233–7
5. Toot S, Swinson T, Devine M, Challis D, Orrell M. Causes (discussion 269–72).
of nursing home placement for older people with demen- 24. Zubenko GS. Clinicopathologic and neurochemical correlates of
tia: a systematic review and meta-analysis. Int Psychogeriatr. major depression and psychosis in primary dementia. Int Psycho-
2017;29:195–208. geriatr. 1996;83:219–23.
6. Gerlach LB, Kales HC. Managing behavioral and psycho- 25. Meltzer CC, Smith G, DeKosky ST, Pollock BG, Mathis CA,
logical symptoms of dementia. Psychiatr Clin North Am. Moore RY, et al. Serotonin in aging, late-life depression, and
2018;41:127–39. Alzheimer’s disease: the emerging role of functional imaging.
7. Tampi RR, Tampi DJ, Balachandran S, Srinivasan S. Antipsy- Neuropsychopharmacology. 1998;18:407–30.
chotic use in dementia: a systematic review of benefits and risks 26. Lorke DE, Lu G, Cho E, Yew DT. Serotonin 5-HT2A and 5-HT6
from meta-analyses. Ther Adv Chronic Dis. 2016;7:229–45. receptors in the prefrontal cortex of Alzheimer and normal aging
8. Farlow MR, Shamliyan TA. Benefits and harms of atypical antip- patients. BMC Neurosci. 2006;7:36.
sychotics for agitation in adults with dementia. Eur Neuropsy- 27. Holmes C, Arranz MJ, Powell JF, Collier DA, Lovestone S.
chopharmacol. 2017;27:217–31. 5-HT2A and 5-HT2C receptor polymorphisms and psycho-
9. Parker C, Coupland C, Hippisley-Cox J. Antipsychotic drugs pathology in late onset Alzheimer’s disease. Hum Mol Genet.
and risk of venous thromboembolism: nested case-control study. 1998;7:1507–9.
BMJ. 2010;341:42–5. 28. Gomperts SN. Lewy body dementias: dementia with Lewy bod-
10. FDA Public Health Advisory. Deaths with antipsychotics in ies and Parkinson disease dementia. Contin Minneap Minn.
elderly patients with behavioral disturbances. http://psychright 2016;22:435–63.
s.org/drugs/FDAantipsychotics4elderlywarning.htm. Accessed 29. Tsuang D, Larson EB, Bolen E, Thompson ML, Peskind E,
16 Dec 2019. Bowen J, et al. Visual hallucinations in dementia: a prospective
11. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical community-based study with autopsy. Am J Geriatr Psychiatry.
antipsychotic drug treatment for dementia: meta-analysis of ran- 2009;17:317–23.
domized placebo-controlled trials. JAMA. 2005;294:1934–43. 30. Sinforiani E, Terzaghi M, Pasotti C, Zucchella C, Zambrelli E,
12. Reus VI, Fochtmann LJ, Eyler AE, Hilty DM, Horvitz-Lennon Manni R. Hallucinations and sleep-wake cycle in Alzheimer’s
M, Jibson MD, et al. The American Psychiatric Association disease: a questionnaire-based study in 218 patients. Neurol Sci.
practice guideline on the use of antipsychotics to treat agita- 2007;28:96–9.
tion or psychosis in patients with dementia. Am J Psychiatry. 31. Brodaty H, Ames D, Snowdon J, Woodward M, Kirwan J, Clar-
2016;173:543–6. nette R, et al. Risperidone for psychosis of Alzheimer’s disease
13. Dupuis DS, Mannoury la Cour C, Chaput C, Verrièle L, and mixed dementia: results of a double-blind, placebo-con-
Lavielle G, Millan MJ. Actions of novel agonists, antagonists trolled trial. Int J Geriatr Psychiatry. 2005;20:1153–7.
and antipsychotic agents at recombinant rat 5-HT6 receptors: 32. Sukonick DL, Pollock BG, Sweet RA, Mulsant BH, Rosen
a comparative study of coupling to G alpha s. Eur J Pharmacol. J, Klunk WE, et al. The 5-HTTPR*S/*L polymorphism and
2008;588:170–7. aggressive behavior in Alzheimer disease. Arch Neurol.
14. NICE. Dementia: supporting people with dementia and their car- 2001;58:1425–8.
ers in health and social care. https://www.nice.org.uk/guidance/ 33. Sweet RA, Pollock BG, Sukonick DL, Mulsant BH, Rosen J,
cg42. Accessed 16 Dec 2019. Klunk WE, et al. The 5-HTTPR polymorphism confers liability
15. Hewer W, Thomas C. Treatment with psychotropic agents in to a combined phenotype of psychotic and aggressive behavior
patients with dementia and delirium: gap between guideline in Alzheimer disease. Int Psychogeriatr. 2001;13:401–9.
34. Lai MKP, Tsang SWY, Francis PT, Esiri MM, Keene J, Hope T, 53. ClinicalTrials.gov. A study of MP-101 in dementia-related psy-
et al. Reduced serotonin 5-HT1A receptor binding in the tem- chosis and/or agitation and aggression. https://clinicaltrials.gov/
poral cortex correlates with aggressive behavior in Alzheimer ct2/show/NCT03044249. Accessed 20 Aug 2019.
disease. Brain Res. 2003;974:82–7. 54. Davey MJ. The pharmacology of prazosin, an alpha 1-adrenocep-
35. Gannon M, Che P, Chen Y, Jiao K, Roberson ED, Wang Q. tor antagonist and the basis for its use in the treatment of essen-
Noradrenergic dysfunction in Alzheimer’s disease. Front Neu- tial hypertension. Clin Exp Hypertens A. 1982;4(1–2):47–59.
rosci. 2015;9:220. 55. ClinicalTrials.gov. Prazosin for agitation in Alzheimer’s disease.
36. Sweet RA, Nimgaonkar VL, Kamboh MI, Lopez OL, Zhang https://clinicaltrials.gov/ct2/show/NCT03710642. Accessed 20
F, DeKosky ST. Dopamine receptor genetic variation, psy- Aug 2019.
chosis, and aggression in Alzheimer disease. Arch Neurol. 56. ClinicalTrials.gov. A study of pimavanserin for the treatment of
1998;55:1335–40. agitation and aggression in subjects with Alzheimer’s disease.
37. Rodriguez-Arias M, Navarrete F, Daza-Losada M, Navarro D, https://clinicaltrials.gov/ct2/show/NCT03118947. Accessed 20
Aguilar MA, Berbel P, et al. CB1 cannabinoid receptor-mediated Aug 2019.
aggressive behavior. Neuropharmacology. 2013;75:172–80. 57. ClinicalTrials.gov. A study of the safety and efficacy of pimavan-
38. Ahmad R, Goffin K, Van den Stock J, De Winter F-L, Cleeren serin in patients with Alzheimer’s disease psychosis. https://clini
E, Bormans G, et al. In vivo type 1 cannabinoid receptor avail- caltrials.gov/ct2/show/NCT02035553. Accessed 20 Aug 2019.
ability in Alzheimer’s disease. Eur Neuropsychopharmacol. 58. Ballard C, Banister C, Khan Z, Cummings J, Demos G, Coate
2014;24:242–50. B, et al. Evaluation of the safety, tolerability, and efficacy of
39. Mulder J, Zilberter M, Pasquaré SJ, Alpár A, Schulte G, Ferreira pimavanserin versus placebo in patients with Alzheimer’s disease
SG, et al. Molecular reorganization of endocannabinoid signal- psychosis: a phase 2, randomised, placebo-controlled, double-
ling in Alzheimer’s disease. Brain J Neurol. 2011;134:1041–60. blind study. Lancet Neurol. 2018;17:213–22.
40. Wang R, Reddy PH. Role of glutamate and NMDA receptors in 59. ClinicalTrials.gov. Safety and efficacy of nabilone in Alzhei-
Alzheimer’s disease. J Alzheimers Dis. 2017;57:1041–8. mer’s disease. https://clinicaltrials.gov/ct2/show/NCT0235188
41. Niciu MJ, Kelmendi B, Sanacora G. Overview of glutamatergic 2. Accessed 20 Aug 2019.
neurotransmission in the nervous system. Pharmacol Biochem 60. Lanctot KL, Ruthirakuhan M, Gallagher D, Sherman C, Abra-
Behav. 2012;100:656–64. ham EH, Verhoeff NPLG, et al. Nabilone significantly improves
42. Crupi R, Impellizzeri D, Cuzzocrea S. Role of metabotropic glu- agitation/adression in patients with moderate-to-severe AD: pre-
tamate receptors in neurological disorders. Front Mol Neurosci. liminary results of a placebo-controlled, double-blind, cross-over
2019;12:20. trial. Alzheimers Dement. 2018;14:1385.
43. Hovelsø N, Sotty F, Montezinho LP, Pinheiro PS, Herrik KF, 61. Herrmann N, Ruthirakuhan M, Gallagher D, Verhoeff NPLG,
Mørk A. Therapeutic potential of metabotropic glutamate recep- Kiss A, Black SE, et al. Randomized placebo-controlled trial
tor modulators. Curr Neuropharmacol. 2012;10:12–48. of nabilone for agitation in Alzheimer’s disease. Am J Geriatr
44. Bratek E, Ziembowicz A, Bronisz A, Salinska E. The activation Psychiatry. 2019;27(11):1161–73.
of group II metabotropic glutamate receptors protects neonatal 62. ClinicalTrials.gov. Addressing dementia via agitation-centered
rat brains from oxidative stress injury after hypoxia-ischemia. evaluation. https://clinicaltr ials.gov/ct2/show/NCT03226522.
PLoS One. 2018;13(7). Accessed 20 Aug 2019.
45. Farías GG, Godoy JA, Hernández F, Avila J, Fisher A, Inestrosa 63. Axsome Therapeutics, Inc. Axsome Therapeutics announces pos-
NC. M1 muscarinic receptor activation protects neurons from itive outcome of interim analysis of ADVANCE-1 phase 2/3 trial
beta-amyloid toxicity: a role for Wnt signaling pathway. Neuro- of AXS-05 in Alzheimer’s disease agitation. GlobeNewswire
biol Dis. 2004;17:337–48. News Room. 2018. http://www.globenewswire.com/news-relea
46. Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsy- se/2018/12/10/1664251/0/en/Axsome-Therapeutics-Announces-
chotic potential of muscarinic receptor subtype selective ago- Positive-Outcome-of-Interim-Analysis-of-ADVANCE-1-Phase
nists. CNS Drug Rev. 2003;9:159–86. -2-3-Trial-of-AXS-05-in-Alzheimer-s-Disease-Agitation.html.
47. Ferrero H, Solas M, Francis PT, Ramirez MJ. Serotonin 5-HT6 Accessed 20 Aug 2019.
receptor antagonists in Alzheimer’s disease: therapeutic rationale 64. ClinicalTrials.gov. Relapse prevention study of pimavanserin in
and current development status. CNS Drugs. 2017;31:19–32. dementia-related psychosis. https://clinicaltrials.gov/ct2/show/
48. Marcos B, Gil-Bea FJ, Hirst WD, García-Alloza M, Ramírez NCT03325556. Accessed 20 Aug 2019.
MJ. Lack of localization of 5-HT6 receptors on cholinergic 65. Clinical Trials Register. Search for 2017-004439-36. https://
neurons: implication of multiple neurotransmitter systems in www.clinicaltr ialsregister.eu/ctr-search/search?query=2017-
5-HT6 receptor-mediated acetylcholine release. Eur J Neurosci. 004439-36. Accessed 16 Dec 2019.
2006;24:1299–306. 66. Clinical Trials Register. Search for 2017-002227-13. https://
49. Cummings J, Lee G, Ritter A, Zhong K. Alzheimer’s disease www.clinicaltr ialsregister.eu/ctr-search/search?query=2017-
drug development pipeline: 2018. Alzheimers Dement Transl 002227-13. Accessed 16 Dec 2019.
Res Clin Interv. 2018;4:195–214. 67. ClinicalTrials.gov. Escitalopram for agitation in Alzheimer’s dis-
50. Devanand DP, Strickler JG, Huey ED, Crocco E, Forester BP, ease. https: //clinic altri als.gov/ct2/show/NCT031 08846 . Accessed
Husain MM, et al. Lithium treatment for agitation in Alzheimer’s 20 Aug 2019.
disease (Lit-AD): clinical rationale and study design. Contemp 68. Maeda K, Sugino H, Akazawa H, Amada N, Shimada J, Futa-
Clin Trials. 2018;71:33–9. mura T, et al. Brexpiprazole I: in vitro and in vivo characteriza-
51. ClinicalTrials.gov. A two part study to assess safety, PK, PD, tion of a novel serotonin-dopamine activity modulator. J Phar-
and food effect of oral HTL0016878. https://clinicaltrials.gov/ macol Exp Ther. 2014;350:589–604.
ct2/show/NCT03244228. Accessed 20 Aug 2019. 69. ClinicalTrials.gov. Brexpiprazole for the long-term treatment of
52. Amarantus announces positive phase 2 data for eltoprazine in patients with agitation associated with dementia of the Alzhei-
Alzheimer’s aggression. Available from: https: //www.amaran tus. mer’s type. https://clinicaltrials.gov/ct2/show/NCT03724942.
com/news/press- releas es/detail /2033/amaran tus-announ ces-posit Accessed 20 Aug 2019.
ive-phase-2-data-for-eltoprazine. Accessed 20 Aug 2019.

70. Clinical Trials Register. Search for 2017-003940-19. https:// psychological symptoms associated with dementia. Int J Neu-
www.clinicaltr ialsregister.eu/ctr-search/search?query=2017- ropsychopharmacol. 2007;10:281–3.
003940-19. Accessed 16 Dec 2019. 89. Cantillon M, Brunswick R, Molina D, Bahro M. Buspirone vs.
71. Clinical Trials Register. https://www.clinicaltrialsregister.eu/ctr- haloperidol: a double-blind trial for agitation in a nursing home
search/trial/2018-002783-88/BG. Accessed 16 Dec 2019. population with Alzheimer’s disease. Am J Geriatr Psychiatry.
72. Zhang L, Hendrick JP. The presynaptic D2 partial agonist 1996;4:263–7.
lumateperone acts as a postsynaptic D2 antagonist. Matters. 90. Tiihonen J, Hakola P, Paanila J, Turtiainen M. Eltoprazine for
2018;4:201712000006. aggression in schizophrenia and mental retardation. Lancet.
73. Kumar B, Kuhad A, Kuhad A. Lumateperone: a new treatment 1993;341:307.
approach for neuropsychiatric disorders. Drugs Today Barc 91. Amarantus BioScience Holdings, Inc. (AMBS). Eltoprazine.
Spain. 1998;2018(54):713–9. https://www.amarantus.com/therapeutics-pipeline/therapeutics/
74. ClinicalTrials.gov. Long term, extension study of the safety and eltoprazine. Accessed 20 Aug 2019.
efficacy of AVP-786 for the treatment of agitation in patients 92. ClinicalTrials.gov. A study of efficacy and safety of eltoprazine
with dementia of the Alzheimer’s type. https://clinicaltr ials.gov/ HCl for treating levodopa-induced dyskinesia in Parkinson’s dis-
ct2/show/NCT02446132. Accessed 20 Aug 2019. ease patients. https://clinicaltrials.gov/ct2/show/NCT024 39125.
75. ClinicalTrials.gov. Study of mirtazapine for agitation in demen- Accessed 20 Aug 2019.
tia. https://clinicaltrials.gov/ct2/show/NCT03031184. Accessed 93. Raghoebar M, Mak M, Cournot A, et al. Pharmacokinet-
20 Aug 2019. ics of eltoprazine inhealthy male subjects after single dose
76. ClinicalTrials.gov. Nighttime agitation and restless legs syn- oral and intravenous administration. Br J Clin Pharmacol.
drome in people with Alzheimer’s disease. https://clinicaltrials. 1990;30:879–83.
gov/ct2/show/NCT03082755. Accessed 20 Aug 2019. 94. Mos J, Olivier B, Poth M, van Aken H. The effects of intra-
77. Serretti A, Drago A, De Ronchi D. HTR2A gene variants and ventricular administration of eltoprazine, 1-(3-trifluorometh-
psychiatric disorders: a review of current literature and selection ylphenyl)piperazine hydrochloride and 8-hydroxy-2-(di-n-pro-
of SNPs for future studies. Curr Med Chem. 2007;14:2053–69. pylamino)tetralin on resident intruder aggression in the rat. Eur
78. Fidalgo S, Ivanov DK, Wood SH. Serotonin: from top to bottom. J Pharmacol. 1992;212(2–3):295–8.
Biogerontology. 2013;14(1):21–45. 95. Monn J, Prieto L, Taboada Martinez L, Montero Salgado C,
79. ACADIA Pharmaceuticals announces positive top-line results Shaw BW. Mglu2 agonists. Patent WO2011084437, 2011.
from phase II study of pimavanserin for Alzheimer’s disease psy- 96. Mos J, Olivier B, Poth M, van Aken H. The effects of intra-
chosis. 2016. https://www.businesswire.com/news/home/20161 ventricular administration of eltoprazine, 1-(3-trifluorometh-
220005379/en/ACADIA-Pharmaceuticals-Announces-Positive- ylphenyl)piperazine hydrochloride and 8-hydroxy-2-(di-n-pro-
Top-Line-Results-Phase. Accessed 16 Dec 2019. pylamino)tetralin on resident intruder aggression in the rat. Eur
80. Business Wire. ACADIA Pharmaceuticals initiates phase III J Pharmacol. 1992;212:295–8.
study of pimavanserin in dementia-related psychosis. https 97. Svenningsson P, Rosenblad C, Af Edholm Arvidsson K, Wic-
://www.busine sswire.com/news/home/201710 04006 297/en/ torin K, Keywood C, Shankar B, et al. Eltoprazine counteracts
ACADIA -Pharma ceuti cals- Initia tes-Phase- III-Study- Pimava nser l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-
in. Accessed 16 Dec 2019. finding study. Brain J Neurol. 2015;138:963–73.
81. Hacksell U, Burstein ES, McFarland K, Mills RG, Williams H. 98. Schipper J, Tulp MT, Sijbesma H. Neurochemical profile of elto-
On the discovery and development of pimavanserin: a novel prazine. Drug Metabol Drug Interact. 1990;8:85–114.
drug candidate for Parkinson’s psychosis. Neurochem Res. 99. Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD,
2014;39:2008–17. Sathyan A, et al. Serotonin signaling is associated with lower
82. Weiner DM, Burstein ES, Nash N, Croston GE, Currier EA, Van- amyloid-β levels and plaques in transgenic mice and humans.
over KE, et al. 5-Hydroxytryptamine2A receptor inverse agonists Proc Natl Acad Sci USA. 2011;108:14968–73.
as antipsychotics. J Pharmacol Exp Ther. 2001;299:268–76. 100. Sheline YI, West T, Yarasheski K, Swarm R, Jasielec MS, Fisher
83. Nordstrom AL, Mansson M, Jovanovic H, Karlsson P, Halldin JR, et al. An antidepressant decreases CSF Aβ production in
C, et al. PET analysis of the 5-HT2A receptor inverse ago- healthy individuals and in transgenic AD mice. Sci Transl Med.
nist ACP-103 in human brain. Int J Neuropsychopharmacol. 2014;6:236–44.
2008;11(2):163–71. 101. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S,
84. Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, et al. Requirement of hippocampal neurogenesis for the behav-
Lameh J, et al. Pharmacological and behavioral profile of N- ioral effects of antidepressants. Science. 2003;301:805–9.
(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2- 102. Pollock BG, Mulsant BH, Rosen J, Sweet RA, Mazumdar S,
methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxyb- Bharucha A, et al. Comparison of citalopram, perphenazine, and
utanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) placebo for the acute treatment of psychosis and behavioral dis-
receptor inverse agonist. J Pharmacol Exp Ther. 2006;317:910–8. turbances in hospitalized, demented patients. Am J Psychiatry.
85. Price DL, Bonhaus DW, McFarland K. Pimavanserin, a 5-HT2A 2002;159:460–5.
receptor inverse agonist, reverses psychosis-like behaviors 103. Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Franga-
in a rodent model of Alzheimer’s disease. Behav Pharmacol. kis C, Ismail Z, et al. Effect of citalopram on agitation in Alz-
2012;23:426–33. heimer disease: the CitAD randomized clinical trial. JAMA.
86. Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, 2014;311:682–91.
Corbett A, et al. Pimavanserin for patients with Parkinson’s dis- 104. US FDA. FDA drug safety communication: abnormal heart
ease psychosis: a randomised, placebo-controlled phase 3 trial. rhythms associated with high doses of Celexa (citalopram hydro-
Lancet. 2014;383:533–40. bromide). 2018. http://www.fda.gov/drugs/ drug-safety -and-avail
87. Ballard CG, Saad K, Patel A, Gahir M, Solis M, Coope B, et al. ability/fda-drug-safety-communication-abnor mal-heart-rhyth
The prevalence and phenomenology of psychotic symptoms in ms-associated-high-doses-celexa-citalopram. Accessed 20 Aug
dementia sufferers. Int J Geriatr Psychiatry. 1995;10:477–85. 2019.
88. Sato S, Mizukami K, Asada T. A preliminary open-label study 105. McCarrell JL, Bailey TA, Duncan NA, Covington LP, Clifford
of 5-HT1A partial agonist tandospirone for behavioural and KM, Hall RG, et al. A review of citalopram dose restrictions in
the treatment of neuropsychiatric disorders in older adults. Ment 122. Nguyen L, Robson MJ, Healy JR, Scandinaro AL, Matsumoto
Health Clin. 2019;9:280–6. RR. Involvement of sigma-1 receptors in the antidepressant-like
106. Hasnain M, Howland RH, Vieweg WVR. Escitalopram and QTc effects of dextromethorphan. PLoS One. 2014;9:89985.
prolongation. J Psychiatry Neurosci. 2013;38:E11. 123. Shin E-J, Bach J-H, Lee SY, Kim JM, Lee J, Hong J-S, et al. Neu-
107. Sanchez C, Reines EH, Montgomery SA. A comparative review ropsychotoxic and neuroprotective potentials of dextromethor-
of escitalopram, paroxetine, and sertraline: are they all alike? Int phan and its analogs. J Pharmacol Sci. 2011;116:137–48.
Clin Psychopharmacol. 2014;29:185–96. 124. Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR.
108. Qirjazi E, McArthur E, Nash DM, Dixon SN, Weir MA, Vasudev Pharmacology of dextromethorphan: Relevance to dextrometho-
A, et al. Risk of ventricular arrhythmia with citalopram and esci- rphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther.
talopram: a population-based study. PloS One. 2016;11. 2016;164:170–82.
109. ClinicalTrials.gov. Escitalopram treatment for BPSD in Alzhei- 125. Morris H, Wallach J. From PCP to MXE: a comprehensive
mer’s disease in comparison to risperidone. https://clinicaltrials. review of the non-medical use of dissociative drugs. Drug Test
gov/ct2/show/NCT01119638. Accessed 20 Aug 2019. Anal. 2014;6(7–8):614–32.
110. Barak Y, Plopski I, Tadger S, Paleacu D. Escitalopram versus ris- 126. Garay RP, Grossberg GT. AVP-786 for the treatment of agitation
peridone for the treatment of behavioral and psychotic symptoms in dementia of the Alzheimer’s type. Expert Opin Investig Drugs.
associated with Alzheimer’s disease: a randomized double-blind 2017;26:121–32.
pilot study. Int Psychogeriatr. 2011;23:1515–9. 127. Drugs@FDA. FDA-approved drugs. https: //www.access data. fda.
111. Berry AS, Shah VD, Baker SL, Vogel JW, O’Neil JP, Janabi M, gov/scripts/cder/daf/index.cfm?event=overview.process&varAp
et al. Aging affects dopaminergic neural mechanisms of cognitive plNo=021879. Accessed 16 Dec 2019.
flexibility. J Neurosci. 2016;36:12559–69. 128. Cummings JL, Lyketsos CG, Peskind ER, Porsteinsson AP, Mint-
112. Berry AS, Shah VD, Baker SL, et al. Aging affects dopamin- zer JE, Scharre DW, et al. Effect of dextromethorphan-quinidine
ergic neural mechanisms of cognitive flexibility. J Neurosci. on agitation in patients with Alzheimer disease dementia: a ran-
2016;36(50):12559–69. domized clinical trial. JAMA. 2015;314:1242–54.
113. US FDA. Novel drug approvals for 2015. http://www.fda.gov/ 129. Avanir Pharmaceuticals Inc. Avanir Pharmaceuticals announces
drugs/new-drugs-fda-cders-new-molecular-entities-and-new- accelerated development path for AVP-786 following success-
therapeutic-biological-products/novel-drug-approvals-2015. ful pre-IND meeting with FDA. https://www.avanir.com/press
Accessed 27 Aug 2019. /avanir-pharmaceuticals-announces-accelerated-developmen
114. Lundbeck H. Otsuka and Lundbeck announce improvement of t-path-avp-786-following-successful. Accessed 16 Dec 2019.
agitation symptoms related to Alzheimer’s-type dementia follow- 130. Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT. Review
ing treatment with brexpiprazole relative to placebo. 2017. https of the pharmacology and clinical profile of bupropion, an anti-
://investor.lundbeck.com/news-releases/news-release-details/ depressant and tobacco use cessation agent. CNS Drug Rev.
otsuka-and-lundbeck-announce-improvement-agitation-sympt 2006;12:178–207.
oms/ 131. Axsome Therapeutics. About AXS-05. https://axsome.com/axs-
115. Das S, Barmwal P, Winston AB, Mondal S, Saha I. Brexpipra- pipeline/about-axs-05/. Accessed 16 Dec 2019.
zole: so far so good. 2016;6(1):39–54. 132. Javitt DC. Glutamate and schizophrenia: phencyclidine,
116. ClinicalTrials.gov. A 12-week extension trial to evaluate the N-methyl-d-aspartate receptors, and dopamine-glutamate inter-
safety and tolerability of brexpiprazole in the treatment of sub- actions. Int Rev Neurobiol. 2007;78:69–108.
jects with agitation associated with dementia of the Alzheimer’s 133. Mehta MA, Schmechtig A, Kotoula V, McColm J, Jackson K,
type. https: //clinic altri als.gov/ct2/show/NCT035 94123 . Accessed Brittain C, et al. Group II metabotropic glutamate receptor ago-
24 Aug 2019. nist prodrugs LY2979165 and LY2140023 attenuate the func-
117. Davis R, Dmitrienko A, Glass S, Kozauer S, Saillard J, Weingart tional imaging response to ketamine in healthy subjects. Psy-
M, et al. F46. Lumateperone (ITI-007): favorable safety profile chopharmacology. 2018;235:1875–86.
in an open label safety switching study from standard-of-care 134. Kinon BJ, Millen BA, Zhang L, McKinzie DL. Exploratory anal-
antispychotic therapy in patients with schizophrenia. Schizophr ysis for a targeted patient population responsive to the metabo-
Bull. 2018;44:S236–7. tropic glutamate 2/3 receptor agonist pomaglumetad methionil
118. Davis RE, Vanover KE, Zhou Y, Brašić JR, Guevara M, Bisuna in schizophrenia. Biol Psychiatry. 2015;78:754–62.
B, et al. ITI-007 demonstrates brain occupancy at serotonin 135. Mechri A, Saoud M, Khiari G, d’Amato T, Dalery J, Gaha L.
5-HT2A and dopamine D2 receptors and serotonin transporters Glutaminergic hypothesis of schizophrenia: clinical research
using positron emission tomography in healthy volunteers. Psy- studies with ketamine. L’Encephale. 2001;27:53–9.
chopharmacology. 2015;232:2863–72. 136. Felder CC, Schober DA, Tu Y, Quets A, Xiao H, Watt M, et al.
119. Intra-Cellular Therapies Inc. Intra-Cellular Therapies announces Translational pharmacology of the metabotropic glutamate 2
update on ITI-007-201 clinical trial for treatment of agitation in receptor-preferring agonist LY2812223 in the animal and human
patients with probable Alzheimer’s disease. https://ir.intracellu brain. J Pharmacol Exp Ther. 2017;361:190–7.
lartherapies.com/news-releases/news-release-details/intra-cellu 137. McColm J, Brittain C, Suriyapperuma S, Swanson S, Tauscher-
lar-therapies-announces-update-iti-007-201-clinical. Accessed Wisniewski S, Foster J, et al. Evaluation of single and multiple
24 Aug 2019. doses of a novel mGlu2 agonist, a potential antipsychotic therapy,
120. Tzavara ET, Bymaster FP, Davis RJ, Wade MR, Perry KW, in healthy subjects. Br J Clin Pharmacol. 2017;83:1654–67.
Wess J, et al. M4 muscarinic receptors regulate the dynamics of 138. Célanire S, Duvey G, Poli S, Rocher J-P. mGluR2 activators and
cholinergic and dopaminergic neurotransmission: relevance to mGluR5 blockers advancing in the clinic for major CNS disor-
the pathophysiology and treatment of related CNS pathologies. ders. Annu Rep Med Chem. 2012;47:71–88.
FASEB J. 2004;18:1410–2. 139. TVM Life Science Ventures VII announces investment in Mediti
121. Kamei H, Kameyama T, Nabeshima T. (+)-SKF-10,047 and dex- Pharma Inc. for the development of a novel treatment for Alz-
tromethorphan ameliorate conditioned fear stress via dopamin- heimer’s disease psychosis. 2016. https://www.tvm-lifescienc
ergic systems linked to phenytoin-regulated sigma 1 sites. Eur J e.com/tvm-life-science-ventures-vii-announces-investment-in-
Pharmacol. 1996;309:149–58. mediti-pharma-inc-for-the-development-of-a-novel-treatment-
for-alzheimers-disease-psychosis/. Accessed 16 Dec 2019.

140. Burnet P, Eastwood S, Bristow G, Godlewska B, Sikka P, Walker of neurodegeneration in Alzheimer’s disease. J Alzheimers Dis.
M, et al. D-amino acid oxidase (DAO) activity and expression are 2015;43:1115–36.
increased in schizophrenia. Mol Psychiatry. 2008;13:658–60. 159. Aso E, Juvés S, Maldonado R, Ferrer I. CB2 cannabinoid recep-
141. Zhou Q, Sheng M. NMDA receptors in nervous system diseases. tor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1
Neuropharmacology. 2013;74:69–75. mice. J Alzheimers Dis. 2013;35:847–58.
142. Sershen H, Hashim A, Dunlop DS, Seckow RF, Cooper TB, et al. 160. Cassano T, Calcagnini S, Pace L, De Marco F, Romano A,
Modulating NMDA receptor function with D-amino acid oxi- Gaetani S. Cannabinoid receptor 2 signaling in neurodegenera-
dase inhibitors: understanding functional activity in PCP-treated tive disorders: from pathogenesis to a promising therapeutic tar-
mouse model. Neurochem Res. 2016;41(1–2):398–408. get. Front Neurosci. 2017;11:30.
143. Lin C-H, Chen P-K, Chang Y-C, Chuo L-J, Chen Y-S, Tsai GE, 161. Vilela FC, Giusti-Paiva A. Cannabinoid receptor agonist disrupts
et al. Benzoate, a D-amino acid oxidase inhibitor, for the treat- behavioral and neuroendocrine responses during lactation. Behav
ment of early-phase Alzheimer disease: a randomized, double- Brain Res. 2014;263:190–7.
blind, placebo-controlled trial. Biol Psychiatry. 2014;75:678–85. 162. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology
144. Chen Q, Xiao EY, Goldman AL, Bharadwaj R, Healy K, et al. of three plant cannabinoids: delta9-tetrahydrocannabinol, can-
Poster session III Wednesday, December 9, 2015. Neuropsychop- nabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol.
harmacology. 2015;40(1):443–611. 2008;153:199–215.
145. Pipeline—SyneuRx. http://www.syneur x.com/en/pipeli ne/. 163. Van den Elsen GAH, Ahmed AIA, Verkes R-J, Kramers C, Feuth
Accessed 16 Dec 2019. T, et al. Tetrahydrocannabinol for neuropsychiatric symptoms in
146. Volpicelli LA, Levey AI. Muscarinic acetylcholine receptor dementia. Neurology. 2015;84(23):2338–46.
subtypes in cerebral cortex and hippocampus. Prog Brain Res. 164. van den Elsen GAH, Ahmed AIA, Verkes R-J, Feuth T, van
2004;145:59–66. der Marck MA, Olde Rikkert MGM. Tetrahydrocannabinol in
147. Leanza G, Gulino R, Zorec R. Noradrenergic hypothesis linking behavioral disturbances in dementia: a crossover randomized
neurodegeneration-based cognitive decline and astroglia. Front controlled trial. Am J Geriatr Psychiatry. 2015;23:1214–24.
Mol Neurosci. 2018;11:254. 165. Woodward MR, Harper DG, Stolyar A, Forester BP, Ellison
148. Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Ras- JM. Dronabinol for the treatment of agitation and aggressive
kind MA. Changes in adrenoreceptors in the prefrontal cortex behavior in acutely hospitalized severely demented patients with
of subjects with dementia: evidence of compensatory changes. noncognitive behavioral symptoms. Am J Geriatr Psychiatry.
Neuroscience. 2007;146:471–80. 2014;22:415–9.
149. Sharp SI, Ballard CG, Chen CPL-H, Francis PT. Aggres- 166. Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects
sive behavior and neuroleptic medication are associated with of dronabinol on anorexia and disturbed behavior in patients with
increased number of alpha1-adrenoceptors in patients with Alz- Alzheimer’s disease. Int J Geriatr Psychiatry. 1997;12:913–9.
heimer disease. Am J Geriatr Psychiatry. 2007;15:435–7. 167. Walther S, Mahlberg R, Eichmann U, Kunz D. Delta-9-tetrahy-
150. Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Ras- drocannabinol for nighttime agitation in severe dementia. Psy-
kind MA. Compensatory changes in the noradrenergic nervous chopharmacology. 2006;185(4):524–8.
system in the locus ceruleus and hippocampus of postmortem 168. Mahlberg R, Walther S. Actigraphy in agitated patients with
subjects with Alzheimer’s disease and dementia with Lewy bod- dementia: monitoring treatment outcomes. Z Gerontol Geriatr.
ies. J Neurosci. 2006;26:467–78. 2007;40:178–84.
151. Wang LY, Shofer JB, Rohde K, Hart KL, Hoff DJ, McFall YH, 169. Walther S, Schüpbach B, Seifritz E, Homan P, Strik W. Ran-
et al. Prazosin for the treatment of behavioral symptoms in domized, controlled crossover trial of dronabinol, 2.5 mg, for
patients with Alzheimer disease with agitation and aggression. agitation in 2 patients with dementia. J Clin Psychopharmacol.
Am J Geriatr Psychiatry. 2009;17:744–51. 2011;31:256–8.
152. Greve MJ, DesJarlais D, Ahmed I. Successful treatment of agi- 170. Nikas SP, Alapafuja SO, Papanastasiou I, Paronis CA, Shukla
tation and aggression with prazosin in an elderly patient with VG. Novel 1′,1′-chain substituted hexahydrocannabinols:
dementia and comorbid heart disease. J Clin Gerontol Geriatr. 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol
2016;7:109–11. (AM2389) a highly potent cannabinoid receptor 1 (CB1) agonist.
153. van Zwieten PA. Antihypertensive drugs interacting with alpha- J Med Chem. 2010;52(19):6996–7010.
and beta-adrenoceptors: a review of basic pharmacology. Drugs. 171. Amanullah S, MacDougall K, Sweeney N, Coffin J, Cole J. Syn-
1988;35(Suppl. 6):6–19. thetic cannabinoids in dementia with agitation: case studies and
154. The Binding Database. Compounds in cluster. http://www.bindi literature review. Clin Neuropsychiatry. 2013;10:142–7.
ngdb.org/bind/searchby_monomerids.jsp?monomerids=29568 172. Kogan NM, Mechoulam R. Cannabinoids in health and disease.
,50063906,50403647,50403649,50408679,50411350,50411 Dialog Clin Neurosci. 2007;9:413–30.
351,50411352,50411353,50411354&title=10+similar+compo 173. Blytt KM, Bjorvatn B, Husebo B, Flo E. Clinically significant
unds+to+monomer+50122826. Accessed 24 Aug 2019. discrepancies between sleep problems assessed by standard clini-
155. Jones SB, Smith JM, Jones AW, Bylund DB. Alpha-1 adrenergic cal tools and actigraphy. BMC Geriatr. 2017;17:253.
receptor binding in aortas from rat and dog: comparison of [3H] 174. Cho HJ, Lavretsky H, Olmstead R, Levin MJ, Oxman MN, Irwin
prazosin and beta-iodo-[125I]-4-hydroxyphenyl-ethyl-aminome- MR. Sleep disturbance and depression recurrence in commu-
thyl-tetralone. J Pharmacol Exp Ther. 1987;241:875–81. nity-dwelling older adults: a prospective study. Am J Psychiatry.
156. Liu CS, Chau SA, Ruthirakuhan M, Lanctôt KL, Herrmann N. 2008;165:1543–50.
Cannabinoids for the treatment of agitation and aggression in 175. Cohen-Mansfield J, Garfinkel D, Lipson S. Melatonin for treat-
Alzheimer’s disease. CNS Drugs. 2015;29:615–23. ment of sundowning in elderly persons with dementia: a prelimi-
157. Rossi S, Motta C, Musella A, Centonze D. The interplay between nary study. Arch Gerontol Geriatr. 2000;31:65–76.
inflammatory cytokines and the endocannabinoid system in 176. Cakir S, Kulaksizoglu IB. The efficacy of mirtazapine in agitated
the regulation of synaptic transmission. Neuropharmacology. patients with Alzheimer’s disease: a 12-week open-label pilot
2015;96:105–12. study. Neuropsychiatr Dis Treat. 2008;4:963–6.
158. Bedse G, Romano A, Lavecchia AM, Cassano T, Gaetani S. The
role of endocannabinoid signaling in the molecular mechanisms
177. Dolder CR, Nelson MH, Iler CA. The effects of mirtazapine on 198. Morphy R, Kay C, Rankovic Z. From magic bullets to designed
sleep in patients with major depressive disorder. Ann Clin Psy- multiple ligands. Drug Discov Today. 2004;9(15):641–51.
chiatry. 2012;24:215–24. 199. Kołaczkowski M, Marcinkowska M, Bucki A, Pawłowski M,
178. Schmid DA, Wichniak A, Uhr M, Ising M, Brunner H, Held Mitka K, Jaśkowska J, et al. Novel arylsulfonamide deriva-
K, et al. Changes of sleep architecture, spectral composition of tives with 5-HT6/5-HT7 receptor antagonism targeting behav-
sleep EEG, the nocturnal secretion of cortisol, ACTH, GH, pro- ioral and psychological symptoms of dementia. J Med Chem.
lactin, melatonin, ghrelin, and leptin, and the DEX-CRH test in 2014;57:4543–57.
depressed patients during treatment with mirtazapine. Neuropsy- 200. Bucki A, Marcinkowska M, Śniecikowska J, Więckowski K,
chopharmacology. 2006;31:832–44. Pawłowski M, Głuch-Lutwin M, et al. Novel 3-(1,2,3,6-tetrahy-
179. Anttila SA, Leinonen EV. A review of the pharmacological and dropyridin-4-yl)-1H-indole-based multifunctional ligands with
clinical profile of mirtazapine. CNS Drug Rev. 2001;7:249–64. antipsychotic-like, mood-modulating, and procognitive activity.
180. Van der Mey M, Windhorst AD, Klok RP, Herscheid JDM, Ken- J Med Chem. 2017;60:7483–501.
nis LE, Bischoff F, et al. Synthesis and biodistribution of [11C] 201. Kołaczkowski M, Marcinkowska M, Bucki A, Śniecikowska J,
R107474, a new radiolabeled alpha2-adrenoceptor antagonist. Pawłowski M, Kazek G, et al. Novel 5-HT6 receptor antagonists/
Bioorg Med Chem. 2006;14:4526–34. D2 receptor partial agonists targeting behavioral and psychologi-
181. Buskova J, Busek P, Nevsimalova S. Gabapentin in the treat- cal symptoms of dementia. Eur J Med Chem. 2015;92:221–35.
ment of dementia-associated nocturnal agitation. Med Sci Monit. 202. Kołaczkowski M, Marcinkowska M, Bucki A, Pawłowski M,
2011;17:CS149–51. Krukowski A, Rusiecki R, et al. Sulphonamide derivatives of
182. Reddy DS. An enigmatic role of tonic inhibition in gabapentin alicyclic amines for the treatment of central nervous system dis-
therapy. EBioMedicine. 2019;42:14–5. eases. Patent WO2013001505, 2013.
183. Dolphin AC. Voltage-gated calcium channels and their auxiliary 203. Kołaczkowski M, Marcinkowska M, Bucki A, Pawłowski
subunits: physiology and pathophysiology and pharmacology. J M, Kazek G, Bednarski M, et al. Indoleamine derivatives
Physiol. 2016;594:5369–90. for the treatment of central nervous system diseases. Patent
184. Taylor CP. Emerging perspectives on the mechanism of action of WO2013001499, 2013.
gabapentin. Neurology. 1994;44(6):10–6. 204. Foster DJ, Choi DL, Conn PJ, Rook JM. Activation of M1
185. Chouinard G, Beauclair L, Belanger MC. Gabapentin: long- and M4 muscarinic receptors as potential treatments for Alz-
term antianxiety and hypnotic effects in psychiatric patients heimer’s disease and schizophrenia. Neuropsychiatr Dis Treat.
with comorbid anxiety-related disorders. Can J Psychiatry. 2014;10:183–91.
1998;43(3):305. 205. Bubser M, Bridges TM, Dencker D, Gould RW, Grannan M,
186. Sammaritano M, Sherwin A. Effect of anticonvulsants on sleep. Noetzel MJ, et al. Selective activation of M4 muscarinic acetyl-
Neurology. 2000;54(5):16–24. choline receptors reverses MK-801-induced behavioral impair-
187. Roane DM, Deinberg TE, Meckler L, Miner CR, Scicutella A. ments and enhances associative learning in rodents. ACS Chem
Treatment of dementia-associated agitation with gabapentin. J Neurosci. 2014;5:920–42.
Neuropsychiatry Clin Neurosci. 2000;12(1):40–3. 206. Lebois EP, Schroeder JP, Esparza TJ, Bridges TM, Lindsley CW,
188. Kim Y, Wilkins KM, Tampl RR. Use of gabapentin in the treat- et al. Disease-modifying effects of M1 muscarinic acetylcholine
ment of behavioural and psychological symptoms of dementia. receptor activation in an Alzheimer’s disease mouse model. ACS
Drugs Aging. 2008;25(3):187–96. Chem Neurosci. 2017;8(6):1177–87.
189. Rochon PA, Vozoris N, Gill SS. The harms of benzodiazepines 207. Partnered Programs—Sosei Heptares. https: //soseih eptar es.com/
for patients with dementia. CMAJ. 2017;189:517–8. our-pipeline/rd-pipeline/partnered-programs.html. Accessed 16
190. Zvejniece L, Vavers E, Svalbe B, Veinberg G, Rizhanova K, Dec 2019.
Liepins V, et al. R-phenibut binds to the α2-δ subunit of volt- 208. Rösler M. The efficacy of cholinesterase inhibitors in treating
age-dependent calcium channels and exerts gabapentin-like anti- the behavioural symptoms of dementia. Int J Clin Pract Suppl.
nociceptive effects. Pharmacol Biochem Behav. 2015;137:23–9. 2002;127:20–36.
191. ClinicalTrials.gov. Citalopram for agitation in Alzheimer’s dis- 209. Weinreb O, Amit T, Bar-Am O, Youdim MB. A novel anti-Alz-
ease. https: //clinic altri als.gov/ct2/show/NCT008 98807 . Accessed heimer’s disease drug, ladostigil neuroprotective, multimodal
16 Dec 2019. brain-selective monoamine oxidase and cholinesterase inhibitor.
192. ClinicalTrials.gov. Safety and tolerability study of two fixed- Int Rev Neurobiol. 2011;100:191–215.
doses of brexpiprazole in the treatment of subjects with agitation 210. Weinreb O, Amit T, Bar-Am O, Youdim MBH. Ladostigil: a
associated with dementia of the Alzheimer’s type. .https://clini novel multimodal neuroprotective drug with cholinesterase and
caltrials.gov/ct2/show/NCT01862640. Accessed 16 Dec 2019. brain-selective monoamine oxidase inhibitory activities for Alz-
193. ClinicalTrials.gov. Safety and tolerability study of flexible dos- heimer’s disease treatment. Curr Drug Targets. 2012;13:483–94.
ing of brexpiprazole in the treatment of subjects with agitation 211. Weinstock M, Poltyrev T, Bejar C, Youdim MB. Effect of
associated with dementia of the Alzheimer’s type. https://clini TV3326, a novel monoamine-oxidase cholinesterase inhibitor,
caltr i als.gov/ct2/show/NCT01 9 2225 8 ?term=NCT01 9 2225 in rat models of anxiety and depression. Psychopharmacology.
8&draw=2&rank=1. Accessed 16 Dec 2019. 2002;160(3):318–24.
194. ClinicalTrials.gov. Delta-THC in dementia. https://clinicaltrials. 212. Calhoun A, Ko J, Grossberg GT. Emerging chemical therapies
gov/ct2/show/NCT01608217. Accessed 16 Dec 2019. targeting 5-hydroxytryptamine in the treatment of Alzheimer’s
195. ClinicalTrials.gov. Delta-THC in behavioral disturbances in disease. Expert Opin Emerg Drugs. 2017;22:101–5.
dementia. https://clinicaltr ials.gov/ct2/show/NCT01302340. 213. R&D Department. Adamed. https://adamed.com.pl/en/rd-depar
Accessed 16 Dec 2019. tment. Accessed 16 Dec 2019.
196. ClinicalTrials.gov. Efficacy, safety and tolerability study of AVP- 214. Wu C-S, Wang S-C, Gau SS-F, Tsai H-J, Cheng Y-C. Association
923 (dextromethorphan/quinidine) for treatment of symptoms of of stroke with the receptor-binding profiles of antipsychotics-a
agitation in Alzheimer’s patients. https://clinicaltrials.gov/ct2/ case-crossover study. Biol Psychiatry. 2013;73:414–21.
show/NCT01584440. Accessed 16 Dec 2019. 215. Douglas IJ, Smeeth L. Exposure to antipsychotics and risk of
197. Morphy R, Rankovic Z. Designed multiple ligands: an emerging stroke: self controlled case series study. BMJ. 2008;337:1227.
drug discovery paradigm. J Med Chem. 2005;48:6523–43.

216. Paśko P, Rodacki T, Domagała-Rodacka R, Palimonka K, Mar- 220. Fenichel RR, Malik M, Antzelevitch C, Sanguinetti M, Roden
cinkowska M, Owczarek D. Second generation H1—antihista- DM, Priori SG, et al. Drug-induced torsades de pointes and
mines interaction with food and alcohol: a systematic review. implications for drug development. J Cardiovasc Electrophysiol.
Biomed Pharmacother. 2017;93:27–39. 2004;15:475–95.
217. Aftab A, Shah AA. Behavioral emergencies: special considera- 221. Üçok A, Gaebel W. Side effects of atypical antipsychotics: a brief
tions in the geriatric psychiatric patient. Psychiatr Clin North overview. World Psychiatry. 2008;7:58–62.
Am. 2017;40:449–62. 222. Garay RP, Citrome L, Grossberg GT, Cavero I, Llorca P-M.
218. Pfister B, Jonsson J, Gustafsson M. Drug-related problems and Investigational drugs for treating agitation in persons with
medication reviews among old people with dementia. BMC Phar- dementia. Expert Opin Investig Drugs. 2016;25:973–83.
macol Toxicol. 2017;18:52. 223. Magierski R, Sobow T. Serotonergic drugs for the treatment of
219. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT inter- neuropsychiatric symptoms in dementia. Expert Rev Neurother.
val prolongation: mechanisms and clinical management. Ther 2016;16:375–87.
Adv Drug Saf. 2012;3:241–53.

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CNS Drugs (2020) 34:243–268

Management of Dementia‑Related Psychosis, Agitation

Published online: 12 February 2020

1 Introduction behavioral symptoms will manifest in almost all patients

deficits that are distinct from BPSD. Aging induces changes

Compounds investigated in phase I

Serotonin 5-HT2AR inverse agonist

Estimated completion date

June 2022 [74]

Fig. 1 Structure and receptor profile of pimavanserin [81]

randomization to relapse in the double-blind period, up to

study registered in Europe (2017-002227-13), which evalu-

has been completed recently. The study evaluated the safety

and tolerability of pimavanserin (10 or 17 mg twice daily,

primary outcome measure: treatment-emergent adverse

4.1.2 Serotonin 5‑HT1A/1B Receptor Agonist: Eltoprazine

Previous findings revealed that aggressive behaviors in

Therefore, it has been suggested that modulation of the

GDCT trial identifier provided by GlobalData

Its anti-aggressive properties most probably result from the

reduction in serotonin release due to the activation of pre-

synaptic 5-HT1A and 5-HT1B autoreceptors [97, 98]. Moreo-

safe and well tolerated [97]. In a phase II study on the treat-

ising results [52]. This double-blind, randomized, placebo-

Drug/indication Trial identifier Study design Results

Fig. 2 Structure and receptor H non-cardiotoxic antidepressants should be evaluated in clini-

Fig. 4 Chemical structures and

NH2 cannabinoid receptor agonists may serve as a potential treat-

Global Impression of Change in Agitation) [55]. OH OH

4.6 Drugs Targeting the Endocannabinoid System H

5.1 Multi‑Target‑Directed Ligand Concept 5.1.2 Molecules Targeting Muscarinic ­M1 and ­M4 Receptors

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Fig. 1 Structure and receptor profile of pimavanserin [81]

4.1.2 Serotonin 5‑HT1A/1B Receptor Agonist: Eltoprazine

Fig. 2 Structure and receptor H non-cardiotoxic antidepressants should be evaluated in clini-

Fig. 4 Chemical structures and

4.6 Drugs Targeting the Endocannabinoid System H

5.1 Multi‑Target‑Directed Ligand Concept 5.1.2 Molecules Targeting Muscarinic M1 and M4 Receptors