13543784.2013

1. Introduction

2. Overview of the role of

5-HT2A-Rs in psychiatric

diseases and psychosis

associated with Alzheimers

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

Review

5-Hydroxytryptamine 2A receptorantagonists as potentialtreatment for psychiatric disordersTiago A Mestre, Mateusz Zurowski & Susan H FoxUniversity 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 antago-

nists 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 postmor-

tem 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 moodand behavior via a number of receptors within cortical, brainstem and basal gan-glia regions. There are currently 14 subtypes of 5-HT receptors [1]. The 5-HT2Areceptor (5-HT2A-R) is a G protein-coupled receptor that exhibits functionalselectivity such that different ligands can differentially activate signaling pathwaysvia the same 5-HT2A-R [2]. This feature provides a multiplicity of intracellulareffects in cortical brain areas where it is expressed, most importantly, thefrontal lobes [3]. Nuclear imaging enables the in vivo assessment of 5-HT2A-R dis-tribution and function in human brain disease. 11C-3-N-methyl-spiperone and[18F]-setoperone were the initial radioligands with significant 5-HT2A-R binding

10.1517/13543784.2013.769957 2013 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 411All rights reserved: reproduction in whole or in part not permitted

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available for positron emission tomography (PET) imagingin the 1990s. However, due to concomitant affinity todopamine D2 receptors, restricted to basal ganglia in thecase of [18F]-setoperone [4], more selective radioligands[18F]-altanserin [5] and [11C]-MDL 100,907 [6] began to beused. [123I]-5-I-R91150 has been used for single-photonemission computed tomography (SPECT) [7]. In healthyhuman subjects, PET studies using [18F]-altanserin haveshown widely distributed binding in the cerebral cortex,notably frontal lobes, followed by putamen/pallidum, thala-mus, and less in the amygdala/hippocampus [8]. The cere-bellum has minimal binding potential for 5-HT2A-Rs [8].Similar findings have been reported for [11C]-MDL100,907 [6]. Of note, cortical 5-H2A-R binding decreaseswith age, reflecting a loss of specific 5-HT2A-Rs [9]. Thiscould account for the onset of mood and anxietydisorders as well as schizophrenia at an early age. Postmor-tem studies in human brain using autoradiographic bindingassays are consistent with in vivo human studies docu-menting higher levels of 5-HT2A-Rs in middle layer of thecerebral cortex, followed by the striatum, and, to a lesserextent, the substantia nigra [10,11].

2. Overview of the role of 5-HT2A-Rs inpsychiatric diseases and psychosis associatedwith Alzheimers disease and Parkinsonsdisease

In this section, we present an overview of the data regarding5-HT2A-Rs in various psychiatric disorders, such as schizo-phrenia, depression, anxiety, obsessive compulsive disorder(OCD), Gilles de la Tourette, attention deficit hyperactivitydisorder (ADHD), substance abuse, eating disorders and

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 on-going and future clinical studies of 5-HT2A-R antagonists inpsychiatry and psychiatric symptoms in neurodegenerative diseases.

2.1 SchizophreniaHistorically, the first clue as to a role for 5-HT2A-Rs in thepathophysiology of hallucinations and psychosis (positivesymptoms) was provided by documenting activation of5-HT2A-R in hallucinations secondary to lysergic acid diethy-lamide (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, singlenucleotide polymorphisms (SNPs) (T102C, his452tyr,-1438G/A) of the HTR2A gene have been implicated indifferent aspects of schizophrenia including susceptibilityto the disease [15-17], family history, psycho-pathology [18]and pharmacogenomics of antipsychotic medication regar-ding efficacy [19-22] and occurrence of tardive dyskinesia [23].However, the overall results are conflicting [24] and meta-analyses of association studies with schizophrenia have eitherreported 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 beenreported in the frontal cortex of subjects with schizophreniain postmortem studies [27-32]. The latter studies are limitedby the confounders of chronic antipsychotic medicationthat can result in downregulation of 5-HT2A-Rs [33]. In addi-tion, interpretation of changes in the 5-HT2A-R due topsychosis is limited due to the inclusion of subjects withend-stage disease and predominance of negative symptomsrather than positive symptoms.

In vivo PET receptor binding studies using highly selective5-HT2A-R ligands have suggested altered 5-HT2A-R functionin schizophrenia. Several studies using [18F]-setoperone report anormal cortical 5-HT2A-R density in drug-nave or untreatedpatients with schizophrenia [34-36], suggesting that changes in5-HT2A-Rs in postmortem studies may be due to either medi-cations or an effect of the advancing disease. Nevertheless,inconsistencies still remain, and a recent study investigating cor-tical and subcortical 5-HT2A-R binding using [18F]-altanserinin neuroleptic-nave first-episode schizophrenic patients re-ported a lower binding potential for 5-HT2A-R in the frontalcortex when compared to control subjects. In addition, a signi-ficant negative correlation was found between 5-HT2A-Rbinding potential in frontal cortex and psychotic symptoms [37].Subjects at-risk of schizophrenia (positive family history) werealso reported as having decreased 5-HT2A-R density in theprefrontal cortex [38].

The role of 5-HT2A-Rs has also been explored in the con-text of the pharmacological treatment of schizophrenia. First,5-HT2A-Rs have been suggested to underlie the reduced fre-quency of undesired extrapyramidal side effects with atypicalantipsychotics in contrast to typical antipsychotics. This action

Article highlights.

. 5-HT2A-Rs are widely distributed in the cerebral cortex,notably frontal lobes, and basal ganglia; areas implicatedin mood and behavior.

. Atypical antipsychotics, such as clozapine, arecharacterized by a higher affinity to 5-HT2A-Rs, incontrast to classical antipsychotic drugs, which arguesfor a role of 5-HT2A-Rs in reduced incidence ofextrapyramidal side effects and possibly inclinical efficacy.

. 5-HT2A-Rs has been implicated in the physiopathologyof 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 beenstudied in clinical trials in schizophrenia, generalizedanxiety, insomnia without success.

. Currently, pimavanserin is the most promising 5-HT2A-Rantagonist being investigated for the treatment ofpsychosis in PD.

This box summarizes key points contained in the article.

T. A. Mestre et al.

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

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may be due to a higher cortical 5-HT2A to striatal D1/D2 binding ratio that differentiates these atypical neurolepticsfrom classical agents [39]. Thus, reduced antagonism of nigros-triatal dopamine D2 receptors will reduce the incidence of par-kinsonism and tardive dyskinesia. Nevertheless, it is importantto recognize that atypical antipsychotics have a broad extra-dopaminergic action and bind to muscarinic, adrenergic andhistaminic receptors, which may also contribute to their lowerpropensity for inducing extrapyramidal side effects.

Second, atypical antipsychotic drugs have higher affinityto 5-HT2A-Rs, compared to typical antipsychotics [40].Whether this action at 5-HT2A-Rs may contribute to thetherapeutic action of atypical antipsychotics in both positiveand negative symptoms is still a source of debate. 5-HT2A-R affinity was shown to be unrelated to clinical improvementfollowing treatment with risperidone and clozapine inschizophrenia [41]. In contrast, a 6-month longitudinal studywith neuroleptic-nave first-episode schizophrenic patientstreated with quetiapine did report an association betweenspecific 5-HT2A-R occupancy levels and treatment effect [42],although an attrition rate of 50% limits the interpretation ofthe findings. A prospective study of schizophrenic patientsstarting an atypical antipsychotic in the prior 6 monthsreported that, at 18 months, chronic treatment of anatypical antipsychotic with a high affinity to 5-HT2A-Rswas associated with a worse cognitive performancecompared with atypical antipsychotics with a low affinityto 5-HT2A-Rs [43]. Thus, although genetic, PET andpostmortem as well as pharmacological studies suggestsome association between 5-HT2A-Rs and psychosis; a rolefor 5-HT2A-R antagonism in the reduction of psychoticsymptoms in schizophrenia remains unclear at present.

2.2 Psychosis in AD and PD2.2.1 Alzheimers diseaseSeveral studies have implicated 5-HT2A-Rs in cognitive func-tion. Postmortem studies [44] have shown a reduction in5-HT2A-Rs in the neocortex of AD patients compared withnormal controls. Similarly, patients with mild cognitiveimpairment of the amnestic type have a reduced 5-HT2A-Rbinding in most neocortical areas [45], but not in subcorticalareas [46], a feature that remains unchanged even for thosepatients progressing to probable AD [47]. Genetic associationstudies of the T102C polymorphism of the HTR2A gene havereported 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 ameta-analysis of genetic association studies of psychosis in ADreported the C allele of T102C polymorphism as a significantrisk factor for psychosis of AD (OR = 5.143 for a homozygoticstate) [53], other studies have documented no association [54-56].

2.2.2 Parkinsons diseaseAs noted above, atypical antipsychotic drugs, such as cloza-pine, have a lower propensity to induce parkinsonism in

schizophrenia. As a result, clozapine has been used to success-fully treat PD psychosis (visual hallucinations and paranoiddelusions) without worsening PD motor symptoms [57,58].The dose required in PD is usually 10-fold lower than thatneeded in schizophrenia. At these low doses, clozapine bindsto 5HT2A-Rs rather than dopamine D2 [59]; hence, onesuggestion is that clozapine may be exerting an antipsychoticeffect in PD via an action in 5-HT2A-Rs rather than dopa-mine D2. A PET study using [18F]-setoperone provided pre-liminary in vivo evidence of increased 5-HT2A-R binding inthe ventral visual pathway in non-demented PD patients [60].A single genetic study investigating T102C polymorphism ofthe 5-HT2A-R, however, did not show significant differencesin distribution between PD patients with psychosis, withoutpsychosis and a healthy control group [61].

2.3 Mood disordersA meta-analysis of 10 genetic studies in depression and 21studies in bipolar mood disorder found no association withpolymorphisms of the HTR2A gene [62]. In contrast, morerecently, the tyrosine variant of the His452Tyr polymor-phism in the HTR2A gene was reported to be a susceptibilityfactor for bipolar disorder [63]. To date, there have been limi-ted in vivo binding studies of 5-HT2A-Rs in depression andit remains unclear whether changes are due to the underlyingpathophysiology or due to chronic use of antidepressant med-ications. Two PET studies reported a reduced 5-HT2A-Rbinding in the hippocampus in depressed patients comparedto normal age-matched controls [64,65]. In one of the studies,5-HT2A-R binding in the hippocampus was higher in treateddepressed patients compared with untreated ones [65],suggesting an upregulation of 5-HT2A-R secondary to theuse of antidepressant. Other studies have attemptedto document the potential therapeutic value of 5-HT2A-Rantagonism by determining genetic polymorphisms of theHTR2A gene associated with a positive response toantidepressants [66-69] or using in vivo binding studies toestablish changes in binding potential associated with a clini-cal response to antidepressants [70,71]. Binding studies consis-tently report an increase in 5-HT2A-R binding potential withimprovement of depression and a decrease in subjects withmajor depression who are taking or recently stopped antide-pressant medication. In addition, neuroticism, which is a per-sonality trait known to be a risk factor for major depression,has been positively correlated to 5-HT2A-R in PET bindingstudies [71].

2.4 SuicidePostmortem studies in suicide completers suggest an increasein 5-HT2A-Rs in the prefrontal cortex [72-74]. However, inpatients with a non-completed suicide and nave for seroto-nergic medications, reduced frontal binding of 5-HT2A-Rswas found using [123I]-5-I-R91150 SPECT imaging [75].These changes were greater in deliberate self-injury patientsthan in self-poisoning patients [75]. The discordances described

5-Hydroxytryptamine 2A receptor antagonists as potential treatment for psychiatric disorders

Expert Opin. Investig. Drugs (2013) 22(4) 413

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above illustrate the complexity of suicide as behavior withcontribution from depression, psychiatric medication, sub-stance abuse and personality disorders, which are potentialconfounders 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]. Inregard to suicide in depression, a meta-analysis of 12 associa-tion studies concluded that there was no association betweenknown HTR2A polymorphisms and suicidal behavior indepressed patients [78].

2.5 AnxietySerotonin is a core neurotransmitter in the physiopathology ofanxiety disorders and selective serotonin reuptake inhibitors arethe first-line treatment [79]. There are few studies on the spe-cific role of 5-HT2A-Rs in anxiety disorders. A genetic studyfound a significant association between symptom severity inpanic disorder and the 1438A/G and T102C HTR2A poly-morphisms, although there was no significant difference inthe prevalence of the above polymorphisms between patientswith panic disorder and normal controls [80]. Another associa-tion study using SNPs reported an increased frequency of someSNPs in panic disorder as well as in the personality trait rewarddependence [81]. As in schizophrenia, pharmacogenomicstudies have found the rs7997012 HTR2A gene poly-morphism to be a predictor of response to venlafaxine ingeneralized anxiety disorder [82,83].

2.6 Obsessive compulsive disorderSerotonergic medications are the mainstay of treatment forOCD. Genetic association studies of HTR2A gene polymor-phisms are scarce for OCD and lack robust findings [84,85].A pharmacogenomic study reported an association betweenresponses to paroxetine in OCD patients with the 1438A/Gpolymorphism in the 5-HT2A-R [86]. Two PET studies withthe 5-HT2A-R ligand [C-11]MDL 100907 conducted inuntreated OCD patients reported reduced binding potentialin frontal dorsolateral, medial frontal, parietal and temporalassociation cortices [87] and caudate nuclei [88] of patients.A correlation between 5-HT2A-R availability in orbitofrontaland dorsolateral frontal cortex and clinical severity has alsobeen reported [87].

2.7 Eating disordersSerotonin is one of the neurotransmitters known to regulatesatiety and appetite (for a review, see Ref. [89]). In vivo imag-ing studies have consistently shown reduced 5-HT2A-Rbinding in the cingulate, parietal and occipital cortices inpatients diagnosed with anorexia nervosa and/or bulimianervosa [90], and in the mesial temporal region in anorexianervosa [91]. It is postulated that reduced binding of5-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 cortex5-HT2A-R binding potential has been positively correlated

with obesity in a [18F]-altanserin PET study. The authors pos-tulate a compensatory upregulation of cerebral 5-HT2A-Rdensity due to a primary decrease of brain serotonin levelsthat leads to increased food intake [94]. Genetic associationstudies have not shown an association of HTR2A genepolymorphism with anorexia nervosa (for meta-analyses, seeRefs [95-97]).

2.8 Other disordersIn Gilles de la Tourette syndrome, [18F]-altanserin PETstudies have documented increased 5-HT2A-R binding inthe anterior cingulate and orbitofrontal cortices, and of othercortical areas [98]. In ADHD, a meta-analysis concluded thatthere was no association between childhood ADHD and theHTR2A gene polymorphisms His452Tyr and rs6313 [99]. Inthe field of autism spectrum disorders, high functioningautistic patients show decreased [18F]-setoperone binding inthe thalamus and demonstrate a negative association ofthalamic binding with a history of language impairment [100].More recently, a PET study with [C-11]-MDL100907 didnot show any abnormality in patients with Aspergersdisease [101].

3. 5-HT2A-R antagonism as a therapeutictarget: overview and appraisal ofrandomized controlled studies

To date, no purely selective 5-HT2A-R antagonists are avail-able in clinical practice. Evidence of a role for 5-HT2A-Rantagonists in psychiatric disease has come from the comefrom the use of old drugs with mixed pharmacology, butincluding 5-HT2-R antagonism, such as the atypical neuro-leptic clozapine and the antidepressants mirtazapine andmianserin. In major depression and OCD, the complemen-tary use of these medications with selective serotonin reuptakeinhibitors has been shown to enhance therapeutic efficacy [79].In PD, clozapine is used for the treatment of delusions andhallucinations due to its low propensity to worsen parkinso-nian motor symptoms compared to other antipsychoticdrugs [102]. Trazodone is an antidepressant with 5-HT2A/Creceptor antagonism but is often used for insomnia andbehavioral disorders in dementia (for review, see Ref. [103]).Nefazodone is another example of a 5-HT2A/C receptorantagonist with a potential use in depression, and dysthymicdisorder, but it has been discontinued in some countries dueto the risk, albeit rare, of liver failure requiring transplan-tation [104]. Ketanserin, another 5-HT2A/2C receptor antago-nist can have a potential benefit for tics in the pediatricpopulation [105].

We undertook a literature search for 5-HT2A-R antagonistsusing 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 wereable to identify the following compounds tested in clinicalstudies for their highly selective 5-HT2A-R activity:

T. A. Mestre et al.


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pimavanserin, eplivanserin, nelotanserin, volinanserin, pru-vanserin, CYR-101 and glemanserin. When required, weconsulted the websites of the pharmaceutical companies res-ponsible for the development of the above compounds. Onlyrandomized controlled clinical trials were included in thisreview. The results are presented grouped by compound andinclude the following conditions: schizophrenia, insomnia,psychosis in PD and generalized anxiety (Table 1).

3.1 Pimavanserin (ACP-103)Pimavanserin is a highly selective 5-HT2A-R inverse agonistwith lower affinity to 5-HT2C receptors and no functionalactivity at 5-HT2B, D2 and other human monoaminergicreceptors [106]. Pimavanserin has been studied as adjunctivetherapy in the treatment of schizophrenia and for psychosisin PD. In schizophrenia, the efficacy of pimavanserin as anadjunctive medication in the treatment of acutely hospitalizedpatients was investigated in a multicenter, randomized,double--blind, placebo-controlled study with 423 patients.Patients were allocated to five different arms: i) pimavanserin20 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; andv) placebo plus haloperidol. Pimavanserin 20 mg/day with alow-dose of risperidone (2 mg/day) was significantly differentfrom placebo for both positive and negative symptoms, usingthe Positive and Negative Syndrome Scale (PANSS). Theresults were identical to the 6 mg/day risperidone arm, thoughhigh doses of risperidone were associated with greater weightgain, higher glucose and plasma prolactin levels, and higherincidence of akathisia [107]. In two other Phase II studiesinvolving a total of 18 healthy volunteers and 34 patientswith schizophrenia or schizoaffective disorder, pimavanserin(60 -- 100 mg/day) reduced haloperidol-induced akathisiameasured by the Barnes Subjective-Distress Rating Scale [108].

The assessment of pimavanserin for the treatment of psy-chosis in PD is ongoing and six trials were identified. An

initial dose-escalation 8-week trial (pimavanserin 20, 40 and60 mg/day) [109] reported no significant improvement inpsychosis using the Scale for Assessment of Positive Symp-toms (SAPS) total score (pimavanserin vs placebo = -4.6;p = 0.089) and subscores of hallucinations (pimavanserin vsplacebo = -2.8, p = 0.164) and delusions (pimavanserin vs pla-cebo = -2.3, p = 0.059). Nevertheless, there was a significantimprovement in the Unified Parkinsons Disease Rating Scale(UPDRS) Part I (the subjective measure of the presence of psy-chosis using the PD specific rating scale) (p = 0.048). Pimavan-serin was well tolerated and did not worsen parkinsonism asmeasured by UPDRS Part III. In the first multicenter random-ized controlled Phase III study (NCT00477672) with298 non-demented PD patients with moderate-to-severe psy-chotic symptoms, pimavanserin 10 and 40 mg/day did notshow a significant change (5.8 and 6.7 points with 10 and40 mg/day, respectively) from placebo (5.9 points with pla-cebo) after 6 weeks of treatment using the hallucinations anddelusions subscores of the SAPS. However, the secondary end-point has prompted further study of pimavanserin 40 mg/day,in spite of failing to show efficacy for the selected primary out-comes. One issue was the presence of a high placebo response,more frequently observed in centers outside the United Statesand in patients with less severe psychosis at baseline. Anongoing Phase III study (NCT01174004) enrolled200 patients and adapted the design to a high placeboresponse [110]. Positive preliminary results released inNovember 2012 have demonstrated a greater reduction of3 points in the SAPS-PD, after 6 weeks of pimavanserinversus placebo, without a deterioration in motor functionmeasured by the UPDRS [111].

The use of pimavanserin for psychosis in AD has also beenevaluated in preclinical models with positive findings [112].Preclinical data and early human studies in healthy volunteerspoint toward the potential study of pimavanserin forother indications, such as insomnia [113], parkinsonism andL-DOPA-induced dyskinesia in PD [114].

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] Greater efficacy than placebo, but less thanconventional antipsychotics.

Psychosis in PD [109] Phase III results are expected.Eplivanserin Schizophrenia [115] Greater efficacy than placebo, but less than

conventional antipsychotics. No further studies.Chronic primary insomnia [116] Nonclinically significant reduction of insomnia (~ 10 min).Fibromyalgia-related insomnia [117] Improvement in quality of sleep not different from placebo.

Nelotanserin Chronic primary insomnia [119] Nonclinically significant reduction of insomnia (~ 10 min).Volinanserin Schizophrenia [108] Greater efficacy than placebo, but less than

conventional antipsychotics.Chronic primary insomnia and depression [124] Negative efficacy results.

Pruvanserin Chronic primary insomnia [123] Discontinued development.CYR-101 Schizophrenia [108] Nonsignificant finding in Phase IIa study.

No Phase III has been initiated.Glemanserin Generalized anxiety disorder [120] No significant anxiolytic effects. Well tolerated.



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3.2 Eplivanserin (SR-46349)Eplivanserin is a highly selective 5-HT2A-R antagonist and hasbeen studied in schizophrenia and chronic insomnia. One ran-domized study comparing eplivanserin with placebo and halo-peridol in schizophrenic subjects [115] reported a significantreduction in the mean PANSS (-10.2 18.4; p = 0.04) andBrief Psychiatric Rating Scale (BPRS) (-6.8 11.4; p = 0.04)total scores compared to placebo, though not in a clinician-rated Clinical Global Impression of severity of illness scale(-0.6 1.0; p = 0.08) or in the score of the BPRS psychosiscluster (-2.8 4.6; p = 0.20). Eplivanserin was well toleratedwith a 3% incidence of extrapyramidal effects compared with18% in the haloperidol group [115]. To the best of our knowl-edge, no other studies of eplivanserin in schizophrenia existand drug development was directed to chronic insomnia,with a total of six identified studies conducted in adult popula-tions and one in a pediatric population. Four of these studieswere randomized, double-blind, placebo-controlled Phase IIItrials: 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 diagnosisof primary insomnia (according to DSM-IV-TR criteria). Inall studies, the primary outcome measure was the changefrom baseline of wake time after sleep onset (WASO).The measurement tool varied between polysomnography(EPOCH and ECLIPSE) and patient-report (EPLILONGand GEMS). The EPOCH (least-square [LS] mean differenceof = -3:37 min:s; p > 0.05) and ECLIPSE (LS mean differenceof -2:30 min:s, p = 0.41) studies could not establish a statisticalsignificant difference to placebo [116]. The other two studiesreported a small effect in the reduction of WASO after12 weeks: the LS mean difference was -13:31 min:s;95% CI: -19:19 to -7:43; p < 0.0001 in the EPLILONG studyand -11:32 min:s; 95% CI: -17:03 to -6.02; p < 0.0001 in theGEMS study. An additional study (NCT00313885) [116,117]has been conducted in patients with the diagnosis of fibromyal-gia and did not demonstrate a statistically significant improve-ment in quality of sleep -- the primary outcome measure [115].The pharmaceutical company conducting the clinical develop-ment of eplivanserin decided to withdraw market authorizationapplications from both United States and European regulatoryagencies, after a complete response letter issued by the Foodand Drug Administration, USA [118].

3.3 Nelotanserin (APD-125)Nelotanserin is a highly selective 5-HT2A-R inverse agonistdeveloped primarily for the treatment of chronic insomnia.Nelotanserin (APD-125) was first studied in amulticenter, random-ized, double-blind, placebo-controlled study (NCT00452179).The effect on the reduction of WASO defined by polysomno-graphic criteria was small with a reduction of 51.73.4 minutescompared with 44.03.8 minutes in the placebo group(p = 0.01). The development of nelotanserin was discontinued

following negative results of a Phase IIb clinical trial(NCT00664664) that differed from the prior study by theuse of number of awakenings as primary outcome [119].

3.4 Other highly selective 5-HT2A-R antagonistsThe first highly selective 5-HT2A-R antagonist to be devel-oped was glemanserin, and it was initially studied for general-ized anxiety disorder without success [120]. Volinanserin(MDL-100,907) was the second highly selective 5-HT2A-Rantagonist to be used in clinical research but the first one tobe used for schizophrenia. However, it was discontinued aftertwo Phase III trials showed greater efficacy than placebo, butless than haloperidol [108]. Volinanserin was also studied forthe treatment of insomnia and depression without docu-mented efficacy [121]. The drug is currently widely used forclinical research in in vivo binding studies of quantificationand visualization of 5-HT2A-Rs [122]. Pruvanserin(EMD-281,014, LY-2,422,347) [123] is another 5-HT2A-Rinverse agonist/antagonist studied for the treatment of insom-nia that has been discontinued. CYR-101 (previouslyMT-210) is a 5-HT2A-R antagonist studied for the treatmentof schizophrenia. Its development has been most likelysuspended, after the report of a nonsignificant reduction inthe PANSS total score and subscores in an initial Phase IIastudy [108]. No registry of a Phase III study was found inclincaltrials.gov [121] (last accessed 19 November 2012).

4. Conclusion

In the current review, we present data derived from clinicalresearch that supports the ongoing study of 5-HT2A-R antag-onism as a potential therapeutic strategy for a variety of psy-chiatric symptoms and diseases. Postmortem studies andin vivo binding studies have generated data revealing changesin 5-HT2A-R function in psychiatric diseases but also as aresult of their treatment. Genetic association studies showless compelling results. The most comprehensive humanresearch was conducted in schizophrenia, depression and sui-cide. Anxiety, OCD, Gilles de la Tourette syndrome, ADHDand eating disorders are additional examples of psychiatricconditions where 5-HT2A-R may play a potential role. Inaddition, the study of 5-HT2A-R function in psychosis ofAD and PD adds new potential indication for clinical studiesof 5-HT2A-R antagonists.

In contrast, interventional studies using 5-HT2A-R antag-onists have been disappointing to date, as demonstrated bythe results of placebo-controlled studies. None of the drugsin these studies have been shown to be superior to standardof care or have they obtained approval for the studied indica-tion(s). As exemplified in the review, studies of 5-HT2A-Rantagonists in schizophrenia were better than placebo butinferior to currently available antipsychotics. Overall,5-HT2A-R antagonists are clinically less effective, althoughperhaps better tolerated with less extrapyramidal side effects.The potential for a better safety profile with a combination

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therapy must be better assessed. The therapeutic effects inPD-associated psychosis may be greater and the detailedresults of the clinical study of pimavanserin in this patientpopulation are awaited. In insomnia, the benefit providedfor 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 aspotential therapies in psychiatric disease is an importantlesson for the future development of therapeutic strategies inpsychiatry. The lack of efficacy of 5-HT2A-R antagonismfor any of the studied conditions most likely reflects the com-plex biology that underlies psychiatric disease. Consequently,the therapeutic potential of a single therapeutic agent orcombination of agents has to be determined by the profileof action in different neurotransmitter receptors, instead ofspecific action in a single neurotransmitter system. As exem-plified in the review, in schizophrenia 5-HT2A-R antagonistswere better than placebo but inferior to currently available

antipsychotics, which suggests that the primary modulationof the dopamine system is required for a clinical significantantipsychotic effect and a different binding profile toother neurotransmitter receptors determines tolerability,rather than efficacy.

To our knowledge, current therapeutic research efforts arelimited to pimavanserin in PD psychosis. From the currentreview, it remains unclear why 5-HT2A-R antagonism has notbeen further explored in other psychiatric conditions, suchanxiety, OCD and, to a lesser extent, depression. A lack of effi-cacy from seminal interventional studies is the likely explanationfor anxiety disorders. Nevertheless, further studies in mooddisorders could be considered, as serotonin is a key neurotrans-mitter in the pathophysiology of mood disorders, and drugswith an antagonism for 5-HT2A-Rs, such as trazodone,mirtazapine and mianserin, are used in clinical practice.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

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Faseb J 2004;18(12):1410-12

AffiliationTiago A Mestre1 MD MSc,

Mateusz Zurowski2 FRCP &

Susan H Fox3 MRCP PhDAuthor for correspondence1Clinical Fellow of Movement Disorders,

University of Toronto, Toronto Western

Hospital and Division of Neurology,

Movement Disorders Centre,

Toronto, Canada2Assistant Professor of Psychiatry,

University of Toronto,

Toronto Western Hospital,

Department of Psychiatry,

Toronto, Canada3Associate 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: [email protected]



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