5-Hydroxytryptamine 2A Receptor Antagonists As Potential Treatment For Psychiatric Disorders

Review
5-Hydroxytryptamine 2A receptor
antagonists as potential
treatment for psychiatric disorders
1.
Introduction
2.
Overview of the role of

5-HT2A-Rs in psychiatric
diseases and psychosis
associated with Alzheimers
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disease and Parkinsons disease

3.
5-HT2A-R antagonism as a
therapeutic target: overview
and appraisal of randomized
controlled studies
4.
Conclusion
5.
Expert opinion
Tiago A Mestre, Mateusz Zurowski & Susan H Fox
University of Toronto, Toronto Western Hospital and Division of Neurology,

Movement Disorders Centre, Toronto, Canada
Introduction: 5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are widely

expressed in the brain and have been implicated in mood and behavior. Based
on the use of atypical antipsychotics in schizophrenia, antagonism of 5-HT2A-Rs
initially emerged as a potential intervention capable of reducing the incidence
of extrapyramidal symptoms, while exerting an effective antipsychotic action.
More recently, highly selective 5-HT2A-R antagonists have been evaluated
in the treatment of a wide range of other psychiatric disorders.
Areas covered: The aim of the current review is to present important clinical
studies investigating the potential therapeutic effects of 5-HT2A-R antagonists in both primary psychiatric disorders, such as schizophrenia and mood
disorders, as well as in psychiatric manifestations of neurodegenerative
disorders. We present an overview of 5-HT2A-Rs in normal brain function
and the rationale for use in (neuro) psychiatric disease based on significant
findings from genetic association studies, neuroimaging data and postmortem studies. The majority of the studies relate to schizophrenia, depression,
anxiety, obsessive compulsive disorder and psychosis in Parkinsons disease
and Alzheimers disease. To date, there is sparse literature on 5-HT2A-Rs
in Gilles de la Tourette syndrome, attention deficit hyperactivity disorder,
eating disorders and autism spectrum disorders. The authors conclude by
reviewing recent clinical trials investigating highly selective 5-HT2A-R
antagonists in schizophrenia, psychosis in Parkinsons disease, insomnia
and generalized anxiety.
Expert opinion: Despite the potential, to date, 5-HT2A-R antagonists have not
made an impact in the management of psychiatric disorders and psychiatric
symptoms of neurodegenerative conditions.
Keywords: 5-HT2A receptors, Alzheimers disease, antagonist, CYR-10, depression,
eplivanserin, glemanserin, insomnia, nelotanserin, Parkinsons disease, partial agonist,
pimavanserin, pruvanserin, schizophrenia, serotonin, volinanserin
Expert Opin. Investig. Drugs (2013) 22(4):411-421
1.
Introduction
The neurotransmitter serotonin (5-HT) has been implicated in mediating mood

and behavior via a number of receptors within cortical, brainstem and basal ganglia regions. There are currently 14 subtypes of 5-HT receptors [1]. The 5-HT2A
receptor (5-HT2A-R) is a G protein-coupled receptor that exhibits functional
selectivity such that different ligands can differentially activate signaling pathways
via the same 5-HT2A-R [2]. This feature provides a multiplicity of intracellular
effects in cortical brain areas where it is expressed, most importantly, the
frontal lobes [3]. Nuclear imaging enables the in vivo assessment of 5-HT2A-R distribution and function in human brain disease. 11C-3-N-methyl-spiperone and
[18F]-setoperone were the initial radioligands with significant 5-HT2A-R binding
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411
T. A. Mestre et al.
Article highlights.
.
5-HT2A-Rs are widely distributed in the cerebral cortex,

notably frontal lobes, and basal ganglia; areas implicated
in mood and behavior.
Atypical antipsychotics, such as clozapine, are
characterized by a higher affinity to 5-HT2A-Rs, in
contrast to classical antipsychotic drugs, which argues
for a role of 5-HT2A-Rs in reduced incidence of
extrapyramidal side effects and possibly in
clinical efficacy.
5-HT2A-Rs has been implicated in the physiopathology
of schizophrenia, psychosis in PD and AD, insomnia,
depression, OCD, Gilles de la Tourette syndrome, ADHD,
eating disorders and autism spectrum disorders.
Highly selective 5-HT2A-Rs antagonists have been
studied in clinical trials in schizophrenia, generalized
anxiety, insomnia without success.
Currently, pimavanserin is the most promising 5-HT2A-R
antagonist being investigated for the treatment of
psychosis in PD.
This box summarizes key points contained in the article.
available for positron emission tomography (PET) imaging

in the 1990s. However, due to concomitant affinity to
dopamine D2 receptors, restricted to basal ganglia in the
case of [18F]-setoperone [4], more selective radioligands
[18F]-altanserin [5] and [11C]-MDL 100,907 [6] began to be
used. [123I]-5-I-R91150 has been used for single-photon
emission computed tomography (SPECT) [7]. In healthy
human subjects, PET studies using [18F]-altanserin have
shown widely distributed binding in the cerebral cortex,
notably frontal lobes, followed by putamen/pallidum, thalamus, and less in the amygdala/hippocampus [8]. The cerebellum has minimal binding potential for 5-HT2A-Rs [8].
Similar findings have been reported for [11C]-MDL
100,907 [6]. Of note, cortical 5-H2A-R binding decreases
with age, reflecting a loss of specific 5-HT2A-Rs [9]. This
could account for the onset of mood and anxiety
disorders as well as schizophrenia at an early age. Postmortem studies in human brain using autoradiographic binding
assays are consistent with in vivo human studies documenting higher levels of 5-HT2A-Rs in middle layer of the
cerebral cortex, followed by the striatum, and, to a lesser
extent, the substantia nigra [10,11].
2. Overview of the role of 5-HT2A-Rs in
psychiatric diseases and psychosis associated
with Alzheimers disease and Parkinsons
disease
In this section, we present an overview of the data regarding

5-HT2A-Rs in various psychiatric disorders, such as schizophrenia, depression, anxiety, obsessive compulsive disorder
(OCD), Gilles de la Tourette, attention deficit hyperactivity
disorder (ADHD), substance abuse, eating disorders and
412
autism spectrum disorders, as well as Parkinsons disease

(PD) and Alzheimers disease (AD)-associated psychosis.
The aim of this discussion is to provide data that justifies ongoing and future clinical studies of 5-HT2A-R antagonists in
psychiatry and psychiatric symptoms in neurodegenerative diseases.
Schizophrenia
Historically, the first clue as to a role for 5-HT2A-Rs in the
pathophysiology of hallucinations and psychosis (positive
symptoms) was provided by documenting activation of
5-HT2A-R in hallucinations secondary to lysergic acid diethylamide (LSD) and LSD-like hallucinogens [12,13]. Inayama et al.
first identified a positive association between the 5-HT2A
(HTR2A) gene and schizophrenia [14]. Subsequently, single
nucleotide polymorphisms (SNPs) (T102C, his452tyr,
-1438G/A) of the HTR2A gene have been implicated in
different aspects of schizophrenia including susceptibility
to the disease [15-17], family history, psycho-pathology [18]
and pharmacogenomics of antipsychotic medication regarding efficacy [19-22] and occurrence of tardive dyskinesia [23].
However, the overall results are conflicting [24] and metaanalyses of association studies with schizophrenia have either
reported no effect [25] or a minor effect with odds ratio (OR)
ranging from 1.07 to 1.18 [15,26].
In addition, a decreased 5-HT2A-R density has been
reported in the frontal cortex of subjects with schizophrenia
in postmortem studies [27-32]. The latter studies are limited
by the confounders of chronic antipsychotic medication
that can result in downregulation of 5-HT2A-Rs [33]. In addition, interpretation of changes in the 5-HT2A-R due to
psychosis is limited due to the inclusion of subjects with
end-stage disease and predominance of negative symptoms
rather than positive symptoms.
In vivo PET receptor binding studies using highly selective
5-HT2A-R ligands have suggested altered 5-HT2A-R function
in schizophrenia. Several studies using [18F]-setoperone report a
normal cortical 5-HT2A-R density in drug-nave or untreated
patients with schizophrenia [34-36], suggesting that changes in
5-HT2A-Rs in postmortem studies may be due to either medications or an effect of the advancing disease. Nevertheless,
inconsistencies still remain, and a recent study investigating cortical and subcortical 5-HT2A-R binding using [18F]-altanserin
in neuroleptic-nave first-episode schizophrenic patients reported a lower binding potential for 5-HT2A-R in the frontal
cortex when compared to control subjects. In addition, a significant negative correlation was found between 5-HT2A-R
binding potential in frontal cortex and psychotic symptoms [37].
Subjects at-risk of schizophrenia (positive family history) were
also reported as having decreased 5-HT2A-R density in the
prefrontal cortex [38].
The role of 5-HT2A-Rs has also been explored in the context of the pharmacological treatment of schizophrenia. First,
5-HT2A-Rs have been suggested to underlie the reduced frequency of undesired extrapyramidal side effects with atypical
antipsychotics in contrast to typical antipsychotics. This action
2.1
Expert Opin. Investig. Drugs (2013) 22(4)
5-Hydroxytryptamine 2A receptor antagonists as potential treatment for psychiatric disorders
may be due to a higher cortical 5-HT2A to striatal D1/

D2 binding ratio that differentiates these atypical neuroleptics
from classical agents [39]. Thus, reduced antagonism of nigrostriatal dopamine D2 receptors will reduce the incidence of parkinsonism and tardive dyskinesia. Nevertheless, it is important
to recognize that atypical antipsychotics have a broad extradopaminergic action and bind to muscarinic, adrenergic and
histaminic receptors, which may also contribute to their lower
propensity for inducing extrapyramidal side effects.
Second, atypical antipsychotic drugs have higher affinity
to 5-HT2A-Rs, compared to typical antipsychotics [40].
Whether this action at 5-HT2A-Rs may contribute to the
therapeutic action of atypical antipsychotics in both positive
and negative symptoms is still a source of debate. 5-HT2AR affinity was shown to be unrelated to clinical improvement
following treatment with risperidone and clozapine in
schizophrenia [41]. In contrast, a 6-month longitudinal study
with neuroleptic-nave first-episode schizophrenic patients
treated with quetiapine did report an association between
specific 5-HT2A-R occupancy levels and treatment effect [42],
although an attrition rate of 50% limits the interpretation of
the findings. A prospective study of schizophrenic patients
starting an atypical antipsychotic in the prior 6 months
reported that, at 18 months, chronic treatment of an
atypical antipsychotic with a high affinity to 5-HT2A-Rs
was associated with a worse cognitive performance
compared with atypical antipsychotics with a low affinity
to 5-HT2A-Rs [43]. Thus, although genetic, PET and
postmortem as well as pharmacological studies suggest
some association between 5-HT2A-Rs and psychosis; a role
for 5-HT2A-R antagonism in the reduction of psychotic
symptoms in schizophrenia remains unclear at present.
2.2
Psychosis in AD and PD
Alzheimers disease
2.2.1
Several studies have implicated 5-HT2A-Rs in cognitive function. Postmortem studies [44] have shown a reduction in
5-HT2A-Rs in the neocortex of AD patients compared with
normal controls. Similarly, patients with mild cognitive
impairment of the amnestic type have a reduced 5-HT2A-R
binding in most neocortical areas [45], but not in subcortical
areas [46], a feature that remains unchanged even for those
patients progressing to probable AD [47]. Genetic association
studies of the T102C polymorphism of the HTR2A gene have
reported positive findings with hallucinations [48], delusions [49],
psychosis [50,51] and depression [52] in AD subjects. Nevertheless,
these results should be interpreted with caution. Although a
meta-analysis of genetic association studies of psychosis in AD
reported the C allele of T102C polymorphism as a significant
risk factor for psychosis of AD (OR = 5.143 for a homozygotic
state) [53], other studies have documented no association [54-56].
Parkinsons disease
As noted above, atypical antipsychotic drugs, such as clozapine, have a lower propensity to induce parkinsonism in
2.2.2
schizophrenia. As a result, clozapine has been used to successfully treat PD psychosis (visual hallucinations and paranoid
delusions) without worsening PD motor symptoms [57,58].
The dose required in PD is usually 10-fold lower than that
needed in schizophrenia. At these low doses, clozapine binds
to 5HT2A-Rs rather than dopamine D2 [59]; hence, one
suggestion is that clozapine may be exerting an antipsychotic
effect in PD via an action in 5-HT2A-Rs rather than dopamine D2. A PET study using [18F]-setoperone provided preliminary in vivo evidence of increased 5-HT2A-R binding in
the ventral visual pathway in non-demented PD patients [60].
A single genetic study investigating T102C polymorphism of
the 5-HT2A-R, however, did not show significant differences
in distribution between PD patients with psychosis, without
psychosis and a healthy control group [61].
Mood disorders
A meta-analysis of 10 genetic studies in depression and 21
studies in bipolar mood disorder found no association with
polymorphisms of the HTR2A gene [62]. In contrast, more
recently, the tyrosine variant of the His452Tyr polymorphism in the HTR2A gene was reported to be a susceptibility
factor for bipolar disorder [63]. To date, there have been limited in vivo binding studies of 5-HT2A-Rs in depression and
it remains unclear whether changes are due to the underlying
pathophysiology or due to chronic use of antidepressant medications. Two PET studies reported a reduced 5-HT2A-R
binding in the hippocampus in depressed patients compared
to normal age-matched controls [64,65]. In one of the studies,
5-HT2A-R binding in the hippocampus was higher in treated
depressed patients compared with untreated ones [65],
suggesting an upregulation of 5-HT2A-R secondary to the
use of antidepressant. Other studies have attempted
to document the potential therapeutic value of 5-HT2A-R
antagonism by determining genetic polymorphisms of the
HTR2A gene associated with a positive response to
antidepressants [66-69] or using in vivo binding studies to
establish changes in binding potential associated with a clinical response to antidepressants [70,71]. Binding studies consistently report an increase in 5-HT2A-R binding potential with
improvement of depression and a decrease in subjects with
major depression who are taking or recently stopped antidepressant medication. In addition, neuroticism, which is a personality trait known to be a risk factor for major depression,
has been positively correlated to 5-HT2A-R in PET binding
studies [71].
2.3
Suicide
Postmortem studies in suicide completers suggest an increase
in 5-HT2A-Rs in the prefrontal cortex [72-74]. However, in
patients with a non-completed suicide and nave for serotonergic medications, reduced frontal binding of 5-HT2A-Rs
was found using [123I]-5-I-R91150 SPECT imaging [75].
These changes were greater in deliberate self-injury patients
than in self-poisoning patients [75]. The discordances described
2.4
413
T. A. Mestre et al.
above illustrate the complexity of suicide as behavior with

contribution from depression, psychiatric medication, substance abuse and personality disorders, which are potential
confounders in the studies of suicide.
It has been suggested that 5-HT2A-R function is related to
violent behavior in suicide [76] or to suicidal ideation [77]. In
regard to suicide in depression, a meta-analysis of 12 association studies concluded that there was no association between
known HTR2A polymorphisms and suicidal behavior in
depressed patients [78].
Anxiety
Serotonin is a core neurotransmitter in the physiopathology of
anxiety disorders and selective serotonin reuptake inhibitors are
the first-line treatment [79]. There are few studies on the specific role of 5-HT2A-Rs in anxiety disorders. A genetic study
found a significant association between symptom severity in
panic disorder and the 1438A/G and T102C HTR2A polymorphisms, although there was no significant difference in
the prevalence of the above polymorphisms between patients
with panic disorder and normal controls [80]. Another association study using SNPs reported an increased frequency of some
SNPs in panic disorder as well as in the personality trait reward
dependence [81]. As in schizophrenia, pharmacogenomic
studies have found the rs7997012 HTR2A gene polymorphism to be a predictor of response to venlafaxine in
generalized anxiety disorder [82,83].
2.5
2.6
Obsessive compulsive disorder
Serotonergic medications are the mainstay of treatment for

OCD. Genetic association studies of HTR2A gene polymorphisms are scarce for OCD and lack robust findings [84,85].
A pharmacogenomic study reported an association between
responses to paroxetine in OCD patients with the 1438A/G
polymorphism in the 5-HT2A-R [86]. Two PET studies with
the 5-HT2A-R ligand [C-11]MDL 100907 conducted in
untreated OCD patients reported reduced binding potential
in frontal dorsolateral, medial frontal, parietal and temporal
association cortices [87] and caudate nuclei [88] of patients.
A correlation between 5-HT2A-R availability in orbitofrontal
and dorsolateral frontal cortex and clinical severity has also
been reported [87].
Eating disorders
Serotonin is one of the neurotransmitters known to regulate
satiety and appetite (for a review, see Ref. [89]). In vivo imaging studies have consistently shown reduced 5-HT2A-R
binding in the cingulate, parietal and occipital cortices in
patients diagnosed with anorexia nervosa and/or bulimia
nervosa [90], and in the mesial temporal region in anorexia
nervosa [91]. It is postulated that reduced binding of
5-HT2A-Rs underlies some features of anorexia nervosa,
including harm avoidance [92] and body image distortions
(for review, see Ref. [93]). In contrast, a higher cerebral cortex
5-HT2A-R binding potential has been positively correlated
2.7
414
with obesity in a [18F]-altanserin PET study. The authors postulate a compensatory upregulation of cerebral 5-HT2A-R
density due to a primary decrease of brain serotonin levels
that leads to increased food intake [94]. Genetic association
studies have not shown an association of HTR2A gene
polymorphism with anorexia nervosa (for meta-analyses, see
Refs [95-97]).
Other disorders
In Gilles de la Tourette syndrome, [18F]-altanserin PET
studies have documented increased 5-HT2A-R binding in
the anterior cingulate and orbitofrontal cortices, and of other
cortical areas [98]. In ADHD, a meta-analysis concluded that
there was no association between childhood ADHD and the
HTR2A gene polymorphisms His452Tyr and rs6313 [99]. In
the field of autism spectrum disorders, high functioning
autistic patients show decreased [18F]-setoperone binding in
the thalamus and demonstrate a negative association of
thalamic binding with a history of language impairment [100].
More recently, a PET study with [C-11]-MDL100907 did
not show any abnormality in patients with Aspergers
disease [101].
2.8
5-HT2A-R antagonism as a therapeutic

target: overview and appraisal of
randomized controlled studies
3.
To date, no purely selective 5-HT2A-R antagonists are available in clinical practice. Evidence of a role for 5-HT2A-R
antagonists in psychiatric disease has come from the come
from the use of old drugs with mixed pharmacology, but
including 5-HT2-R antagonism, such as the atypical neuroleptic clozapine and the antidepressants mirtazapine and
mianserin. In major depression and OCD, the complementary use of these medications with selective serotonin reuptake
inhibitors has been shown to enhance therapeutic efficacy [79].
In PD, clozapine is used for the treatment of delusions and
hallucinations due to its low propensity to worsen parkinsonian motor symptoms compared to other antipsychotic
drugs [102]. Trazodone is an antidepressant with 5-HT2A/C
receptor antagonism but is often used for insomnia and
behavioral disorders in dementia (for review, see Ref. [103]).
Nefazodone is another example of a 5-HT2A/C receptor
antagonist with a potential use in depression, and dysthymic
disorder, but it has been discontinued in some countries due
to the risk, albeit rare, of liver failure requiring transplantation [104]. Ketanserin, another 5-HT2A/2C receptor antagonist can have a potential benefit for tics in the pediatric
population [105].
We undertook a literature search for 5-HT2A-R antagonists
using search parameters: 5-HT2A, serotonin, antagonis*,
inverse agonis* in the medical database PubMed (start date:
1965) and clinical trials.gov up to October 2012. We were
able to identify the following compounds tested in clinical
studies for their highly selective 5-HT2A-R activity:
Table 1. Summary of highly selective 5-HT2A-R antagonists tested in randomized controlled studies.
5-HT2A-R antagonists
Indication
Results/comments
Pimavanserin
Schizophrenia [107,108]
Eplivanserin
Psychosis in PD [109]
Schizophrenia [115]
Nelotanserin
Volinanserin
Chronic primary insomnia [116]

Fibromyalgia-related insomnia [117]
Schizophrenia [108]
Pruvanserin
CYR-101
Chronic primary insomnia and depression [124]

Schizophrenia [108]
Glemanserin
Generalized anxiety disorder [120]
pimavanserin, eplivanserin, nelotanserin, volinanserin, pruvanserin, CYR-101 and glemanserin. When required, we
consulted the websites of the pharmaceutical companies responsible for the development of the above compounds. Only
randomized controlled clinical trials were included in this
review. The results are presented grouped by compound and
include the following conditions: schizophrenia, insomnia,
psychosis in PD and generalized anxiety (Table 1).
Pimavanserin (ACP-103)
Pimavanserin is a highly selective 5-HT2A-R inverse agonist
with lower affinity to 5-HT2C receptors and no functional
activity at 5-HT2B, D2 and other human monoaminergic
receptors [106]. Pimavanserin has been studied as adjunctive
therapy in the treatment of schizophrenia and for psychosis
in PD. In schizophrenia, the efficacy of pimavanserin as an
adjunctive medication in the treatment of acutely hospitalized
patients was investigated in a multicenter, randomized,
double--blind, placebo-controlled study with 423 patients.
Patients were allocated to five different arms: i) pimavanserin
20 mg/day plus risperidone 2 mg/day; ii) risperidone 2 mg/
day plus placebo; iii) risperidone 6 mg/day plus placebo;
iv) pimavanserin 20 mg/day plus haloperidol 2 mg/day; and
v) placebo plus haloperidol. Pimavanserin 20 mg/day with a
low-dose of risperidone (2 mg/day) was significantly different
from placebo for both positive and negative symptoms, using
the Positive and Negative Syndrome Scale (PANSS). The
results were identical to the 6 mg/day risperidone arm, though
high doses of risperidone were associated with greater weight
gain, higher glucose and plasma prolactin levels, and higher
incidence of akathisia [107]. In two other Phase II studies
involving a total of 18 healthy volunteers and 34 patients
with schizophrenia or schizoaffective disorder, pimavanserin
(60 -- 100 mg/day) reduced haloperidol-induced akathisia
measured by the Barnes Subjective-Distress Rating Scale [108].
The assessment of pimavanserin for the treatment of psychosis in PD is ongoing and six trials were identified. An
3.1
Greater efficacy than placebo, but less than

conventional antipsychotics.
Phase III results are expected.
conventional antipsychotics. No further studies.
Nonclinically significant reduction of insomnia (~ 10 min).
Improvement in quality of sleep not different from placebo.
Nonclinically significant reduction of insomnia (~ 10 min).
conventional antipsychotics.
Negative efficacy results.
Discontinued development.
Nonsignificant finding in Phase IIa study.
No Phase III has been initiated.
No significant anxiolytic effects. Well tolerated.
initial dose-escalation 8-week trial (pimavanserin 20, 40 and

60 mg/day) [109] reported no significant improvement in
psychosis using the Scale for Assessment of Positive Symptoms (SAPS) total score (pimavanserin vs placebo = -4.6;
p = 0.089) and subscores of hallucinations (pimavanserin vs
placebo = -2.8, p = 0.164) and delusions (pimavanserin vs placebo = -2.3, p = 0.059). Nevertheless, there was a significant
improvement in the Unified Parkinsons Disease Rating Scale
(UPDRS) Part I (the subjective measure of the presence of psychosis using the PD specific rating scale) (p = 0.048). Pimavanserin was well tolerated and did not worsen parkinsonism as
measured by UPDRS Part III. In the first multicenter randomized controlled Phase III study (NCT00477672) with
298 non-demented PD patients with moderate-to-severe psychotic symptoms, pimavanserin 10 and 40 mg/day did not
show a significant change (5.8 and 6.7 points with 10 and
40 mg/day, respectively) from placebo (5.9 points with placebo) after 6 weeks of treatment using the hallucinations and
delusions subscores of the SAPS. However, the secondary endpoint has prompted further study of pimavanserin 40 mg/day,
in spite of failing to show efficacy for the selected primary outcomes. One issue was the presence of a high placebo response,
more frequently observed in centers outside the United States
and in patients with less severe psychosis at baseline. An
ongoing Phase III study (NCT01174004) enrolled
200 patients and adapted the design to a high placebo
response [110]. Positive preliminary results released in
November 2012 have demonstrated a greater reduction of
3 points in the SAPS-PD, after 6 weeks of pimavanserin
versus placebo, without a deterioration in motor function
measured by the UPDRS [111].
The use of pimavanserin for psychosis in AD has also been
evaluated in preclinical models with positive findings [112].
Preclinical data and early human studies in healthy volunteers
point toward the potential study of pimavanserin for
other indications, such as insomnia [113], parkinsonism and
L-DOPA-induced dyskinesia in PD [114].
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T. A. Mestre et al.
Eplivanserin (SR-46349)
Eplivanserin is a highly selective 5-HT2A-R antagonist and has
been studied in schizophrenia and chronic insomnia. One randomized study comparing eplivanserin with placebo and haloperidol in schizophrenic subjects [115] reported a significant
reduction in the mean PANSS (-10.2 18.4; p = 0.04) and
Brief Psychiatric Rating Scale (BPRS) (-6.8 11.4; p = 0.04)
total scores compared to placebo, though not in a clinicianrated Clinical Global Impression of severity of illness scale
(-0.6 1.0; p = 0.08) or in the score of the BPRS psychosis
cluster (-2.8 4.6; p = 0.20). Eplivanserin was well tolerated
with a 3% incidence of extrapyramidal effects compared with
18% in the haloperidol group [115]. To the best of our knowledge, no other studies of eplivanserin in schizophrenia exist
and drug development was directed to chronic insomnia,
with a total of six identified studies conducted in adult populations and one in a pediatric population. Four of these studies
were randomized, double-blind, placebo-controlled Phase III
trials: EPLILONG (NCT00253903; n = 1145, 12 weeks)
and GEMS (NCT00253968; n = 962, 12 weeks), EPOCH
(NCT00308503; n = 608, 6 weeks) and ECLIPSE
(NCT00805350; n = 600, 6 weeks), in which participated 3,
315 adults with sleep maintenance problems and a diagnosis
of primary insomnia (according to DSM-IV-TR criteria). In
all studies, the primary outcome measure was the change
from baseline of wake time after sleep onset (WASO).
The measurement tool varied between polysomnography
(EPOCH and ECLIPSE) and patient-report (EPLILONG
and GEMS). The EPOCH (least-square [LS] mean difference
of = -3:37 min:s; p > 0.05) and ECLIPSE (LS mean difference
of -2:30 min:s, p = 0.41) studies could not establish a statistical
significant difference to placebo [116]. The other two studies
reported a small effect in the reduction of WASO after
12 weeks: the LS mean difference was -13:31 min:s;
95% CI: -19:19 to -7:43; p < 0.0001 in the EPLILONG study
and -11:32 min:s; 95% CI: -17:03 to -6.02; p < 0.0001 in the
GEMS study. An additional study (NCT00313885) [116,117]
has been conducted in patients with the diagnosis of fibromyalgia and did not demonstrate a statistically significant improvement in quality of sleep -- the primary outcome measure [115].
The pharmaceutical company conducting the clinical development of eplivanserin decided to withdraw market authorization
applications from both United States and European regulatory
agencies, after a complete response letter issued by the Food
and Drug Administration, USA [118].
3.2
Nelotanserin (APD-125)
Nelotanserin is a highly selective 5-HT2A-R inverse agonist
developed primarily for the treatment of chronic insomnia.
Nelotanserin (APD-125) was first studied in a multicenter, randomized, double-blind, placebo-controlled study (NCT00452179).
The effect on the reduction of WASO defined by polysomnographic criteria was small with a reduction of 51.73.4 minutes
compared with 44.03.8 minutes in the placebo group
(p = 0.01). The development of nelotanserin was discontinued
3.3
416
following negative results of a Phase IIb clinical trial

(NCT00664664) that differed from the prior study by the
use of number of awakenings as primary outcome [119].
Other highly selective 5-HT2A-R antagonists
The first highly selective 5-HT2A-R antagonist to be developed was glemanserin, and it was initially studied for generalized anxiety disorder without success [120]. Volinanserin
(MDL-100,907) was the second highly selective 5-HT2A-R
antagonist to be used in clinical research but the first one to
be used for schizophrenia. However, it was discontinued after
two Phase III trials showed greater efficacy than placebo, but
less than haloperidol [108]. Volinanserin was also studied for
the treatment of insomnia and depression without documented efficacy [121]. The drug is currently widely used for
clinical research in in vivo binding studies of quantification
and visualization of 5-HT2A-Rs [122]. Pruvanserin
(EMD-281,014, LY-2,422,347) [123] is another 5-HT2A-R
inverse agonist/antagonist studied for the treatment of insomnia that has been discontinued. CYR-101 (previously
MT-210) is a 5-HT2A-R antagonist studied for the treatment
of schizophrenia. Its development has been most likely
suspended, after the report of a nonsignificant reduction in
the PANSS total score and subscores in an initial Phase IIa
study [108]. No registry of a Phase III study was found in
clincaltrials.gov [121] (last accessed 19 November 2012).
3.4
4.
Conclusion
In the current review, we present data derived from clinical

research that supports the ongoing study of 5-HT2A-R antagonism as a potential therapeutic strategy for a variety of psychiatric symptoms and diseases. Postmortem studies and
in vivo binding studies have generated data revealing changes
in 5-HT2A-R function in psychiatric diseases but also as a
result of their treatment. Genetic association studies show
less compelling results. The most comprehensive human
research was conducted in schizophrenia, depression and suicide. Anxiety, OCD, Gilles de la Tourette syndrome, ADHD
and eating disorders are additional examples of psychiatric
conditions where 5-HT2A-R may play a potential role. In
addition, the study of 5-HT2A-R function in psychosis of
AD and PD adds new potential indication for clinical studies
of 5-HT2A-R antagonists.
In contrast, interventional studies using 5-HT2A-R antagonists have been disappointing to date, as demonstrated by
the results of placebo-controlled studies. None of the drugs
in these studies have been shown to be superior to standard
of care or have they obtained approval for the studied indication(s). As exemplified in the review, studies of 5-HT2A-R
antagonists in schizophrenia were better than placebo but
inferior to currently available antipsychotics. Overall,
5-HT2A-R antagonists are clinically less effective, although
perhaps better tolerated with less extrapyramidal side effects.
The potential for a better safety profile with a combination
therapy must be better assessed. The therapeutic effects in

PD-associated psychosis may be greater and the detailed
results of the clinical study of pimavanserin in this patient
population are awaited. In insomnia, the benefit provided
for sleep represented a decrease in about 10 min of WASO,
which cannot be considered as clinically significant.
5.
Expert opinion
The history of the development of 5-HT2A-R antagonists as

potential therapies in psychiatric disease is an important
lesson for the future development of therapeutic strategies in
psychiatry. The lack of efficacy of 5-HT2A-R antagonism
for any of the studied conditions most likely reflects the complex biology that underlies psychiatric disease. Consequently,
the therapeutic potential of a single therapeutic agent or
combination of agents has to be determined by the profile
of action in different neurotransmitter receptors, instead of
specific action in a single neurotransmitter system. As exemplified in the review, in schizophrenia 5-HT2A-R antagonists
were better than placebo but inferior to currently available
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Faseb J 2004;18(12):1410-12
Affiliation
Tiago A Mestre1 MD MSc,
Mateusz Zurowski2 FRCP &
Susan H Fox3 MRCP PhD
Author for correspondence

1
Clinical Fellow of Movement Disorders,
University of Toronto, Toronto Western
Hospital and Division of Neurology,
Movement Disorders Centre,
Toronto, Canada
2
Assistant Professor of Psychiatry,
University of Toronto,
Toronto Western Hospital,
Department of Psychiatry,
Toronto, Canada
3
Associate Professor of Neurology,
University of Toronto, Toronto Western
Hospital and Division of Neurology,
Movement Disorders Centre,
399 Bathurst Street, MCL7-421,
Toronto, Canada
Tel: +416 603 6422; Fax: +416 603 5004;
E-mail: sfox@uhnresearch.ca
421

5-Hydroxytryptamine 2A Receptor Antagonists As Potential Treatment For Psychiatric Disorders

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5-Hydroxytryptamine 2A Receptor Antagonists As Potential Treatment For Psychiatric Disorders

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Review

Overview of the role of

disease and Parkinsons disease

Tiago A Mestre, Mateusz Zurowski & Susan H Fox

University of Toronto, Toronto Western Hospital and Division of Neurology,

Introduction: 5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are widely

The neurotransmitter serotonin (5-HT) has been implicated in mediating mood

5-HT2A-Rs are widely distributed in the cerebral cortex,

This box summarizes key points contained in the article.

available for positron emission tomography (PET) imaging

In this section, we present an overview of the data regarding

autism spectrum disorders, as well as Parkinsons disease

Expert Opin. Investig. Drugs (2013) 22(4)