Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development.

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases.

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.

An item response analysis of the motor and behavioral subscales of the unified Huntington's disease rating scale in huntington disease gene expansion carriers.

Although the Unified Huntington's Disease Rating Scale (UHDRS) is widely used in the assessment of Huntington disease (HD), the ability of individual items to discriminate individual differences in motor or behavioral manifestations has not been extensively studied in HD gene expansion carriers without a motor-defined clinical diagnosis (ie, prodromal-HD or prHD). To elucidate the relationship between scores on individual motor and behavioral UHDRS items and total score for each subscale, a nonparametric item response analysis was performed on retrospective data from 2 multicenter longitudinal studies. Motor and behavioral assessments were supplied for 737 prHD individuals with data from 2114 visits (PREDICT-HD) and 686 HD individuals with data from 1482 visits (REGISTRY). Option characteristic curves were generated for UHDRS subscale items in relation to their subscale score. In prHD, overall severity of motor signs was low, and participants had scores of 2 or above on very few items. In HD, motor items that assessed ocular pursuit, saccade initiation, finger tapping, tandem walking, and to a lesser extent, saccade velocity, dysarthria, tongue protrusion, pronation/supination, Luria, bradykinesia, choreas, gait, and balance on the retropulsion test were found to discriminate individual differences across a broad range of motor severity. In prHD, depressed mood, anxiety, and irritable behavior demonstrated good discriminative properties. In HD, depressed mood demonstrated a good relationship with the overall behavioral score. These data suggest that at least some UHDRS items appear to have utility across a broad range of severity, although many items demonstrate problematic features.

Challenges assessing clinical endpoints in early Huntington disease.

The basic aim of this study was to evaluate the current accepted standard clinical endpoint for the earliest-studied HD participants likely to be recruited into clinical trials. As the advent of genetic testing for HD, it is possible to identify gene carriers before the diagnosis of disease, which opens up the possibility of clinical trials of disease-modifying treatments in clinically asymptomatic persons. Current accepted standard clinical endpoints were examined as part of a multinational, 32-site, longitudinal, observational study of 786 research participants currently in the HD prodrome (gene-positive but not clinically diagnosed). Clinical signs and symptoms were used to prospectively predict functional loss as assessed by current accepted standard endpoints over 8 years of follow-up. Functional capacity measures were not sensitive for HD in the prodrome; over 88% scored at ceiling. Prospective evaluation revealed that the first functional loss was in their accustomed work. In a survival analysis, motor, cognitive, and psychiatric measures were all predictors of job change. To our knowledge, this is the first prospective study ever conducted on the emergence of functional loss secondary to brain disease. We conclude that future clinical trials designed for very early disease will require the development of new and more sensitive measures of real-life function.

Population admixture modulates risk for alcohol dependence.

The admixture of different ancestral populations in America may have important implications for the risk for psychiatric disorders, as it appears to have for other medical disorders. The present study investigated the role of population admixture in risk for several psychiatric disorders in European-Americans (EAs) and African-Americans (AAs). This is a multisite study with 3,792 subjects recruited from across the United States, including 3,119 EAs and 673 AAs. These subjects included healthy controls and those with substance dependence (SD) [including alcohol dependence (AD), cocaine dependence, and opioid dependence], social phobia, affective disorders, and schizophrenia. In addition, DNA was included from 78 West Africans. The degree of admixture for each subject was estimated by analysis of a set of ancestry-informative genetic markers using the program STRUCTURE, and was compared between cases and controls. As noted previously, the degree of admixture in AAs was higher than EAs. In EAs, the degree of admixture (with African ancestry) was significantly lower in patients with SD (mainly AD) than controls (P = 0.009 for SD; P = 0.008 for AD). This finding suggests that population admixture may modulate risk for alcohol dependence. Population admixture might protect against alcohol dependence by increasing average heterozygosity and reducing the risk of deleterious recessive alleles. We cannot exclude the possibility that the results might have been influenced by selection bias due to the multisite nature of the study.

Longitudinal progression of negative symptoms in schizophrenia: a new look at an old problem.

OBJECTIVE: Longitudinal analysis is crucial in determining the ability of new interventions to successfully reduce negative symptoms in schizophrenia. However, there are still conflicting reports as to whether there are significant treatment effects on these symptoms and the extent of these effects. We examine the possible effects of analysis method on these questions. METHODS: We use generalized linear mixed models (GLMM) to assess the change in specific negative symptom items following treatment changes in two separate cohorts of schizophrenia patients, one chronic and one first episode. RESULTS: Both data sets indicate that examining the change in prevalence of moderate to severe symptoms provides a useful estimate of the effect size associated with changes in treatment that often differs from that given using analysis of means. CONCLUSIONS: The use of categorical longitudinal methods may be critical to determining the responsiveness of negative symptoms to treatment as well as determining the stability of these symptoms over time.

Semantic memory in schizophrenia: association with cell membrane essential fatty acids.

INTRODUCTION: Semantic memory and language deficits are associated with schizophrenia. Understanding how these systems operate in this disorder will likely require a multi-factorial model that explains their linkages with cognition and modulation by dopamine. A biological factor that may provide causal convergence for these connections is cell membrane composition and dynamics. METHODS: N400 is an electrophysiological measure of semantic memory and language that is sensitive to deficits in schizophrenia. Relationships among N400, cognition, dopamine, and cell membrane polyunsaturated fatty acids (PUFAs) were examined for patients tested under medicated (haloperidol only) and unmedicated (placebo) conditions. Relationships between these factors and clinical symptoms were also evaluated. The sample included 37 male schizophrenia inpatients and 34 male normal controls. The N400 priming effect was measured from visual event-related potentials recorded during a semantic priming-lexical decision task, in which semantic association (related versus unrelated words) and presentation rate (Stimulus Onset Asynchrony/SOAs: 350 and 950 ms) were varied. RESULTS: N400 was associated with cognition (speed, visuoperception, attention) in patients and controls. These relationships were influenced by SOA in both groups, and by pharmacological condition in patients. Levels of total PUFAs and arachidonic acid were associated with N400 in unmedicated patients. Clinical symptoms (paranoia, thought disturbance) were associated with N400, but not with cognition or PUFAs. CONCLUSIONS: Results suggest cell membrane fatty acids are associated with semantic memory and language in schizophrenia. Findings also suggest a series of linkages that are modulated by dopamine: cell membrane fatty acids are associated with N400 semantic priming; N400 semantic priming is associated with clinical symptoms.

Clinical Management of Neuropsychiatric Symptoms of Huntington Disease: Expert-Based Consensus Guidelines on Agitation, Anxiety, Apathy, Psychosis and Sleep Disorders.

BACKGROUND: In clinical practice, several strategies and pharmacological options are available to treat neuropsychiatric symptoms of Huntington disease (HD). However, there is currently insufficient data for evidence-based guidelines on the management of these common symptoms. OBJECTIVE: We aimed to develop expert-based recommendations regarding the management of agitation, anxiety, apathy, psychosis, and sleep disorders. METHODS: Guideline development was based on a modified Institute of Medicine guideline process that accounted for a lack of evidence base. An international committee of 11 multidisciplinary experts proposed a series of statements regarding the description and management of each symptom. Statement assessment and validation was performed using a web-based survey tool and 84 international HD experts (neurologists and psychiatrists) who assessed the statements and indicated their level of agreement. RESULTS: High-level agreement (≥85% experts strongly agreed or agreed) was reached for 107 of the 110 statements that have been incorporated into the expert-based clinical recommendations presented herein. CONCLUSIONS: Clinical statements to guide the routine management of agitation, anxiety, apathy, psychosis, and sleep disorders in HD have been developed. Although not specifically tested in the HD population, clinical experience has shown that most of the neuropsychiatric symptoms discussed, when considered in isolation are treatable using pharmacologic and non-pharmacologic strategies developed for use in other populations. However, the management of neuropsychiatric symptoms in HD can be complex because neuropsychiatric symptoms often co-exist and treatment decisions should be adapted to cover all symptoms while limiting polypharmacy.

Factor analytic support for social cognition as a separable cognitive domain in schizophrenia.

Social cognition has received increasing attention in schizophrenia due to its theoretical relevance to core features of the disorder as well as the marked deficits in social functioning exhibited by these patients. However, there remains a need to develop and validate measures of social cognitive abilities and to demonstrate that they are constructs that are separable from non-social neurocognitive processes. In the current study, the Wechsler Adult Intelligence Scale-Revised (WAIS-R) was administered to 169 males with schizophrenia, and test results were subjected to confirmatory factor analysis (CFA) to determine if those WAIS-R subtests containing social content would form a distinct Social Cognition (SC) factor. CFA was used to evaluate various models that hypothesized an SC factor, and for comparison purposes the same models were evaluated in the WAIS-R standardization sample. Results confirmed the presence of a four-factor model that included an SC factor, as well as the more commonly reported Verbal Comprehension, Perceptual Organization, and Working Memory factors. The SC factor consisted of the Picture Arrangement and Picture Completion subtests, and demonstrated small but significant correlations with disorganization and negative symptoms, as well as with an index of social functioning. Results provide support for the validity of the SC factor as a measure of social cognition in schizophrenia, and demonstrate that at least some aspects of social cognition represent separable cognitive domains in schizophrenia.

Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers.

The pharmacokinetics, safety, and tolerability of ACP-103, a selective serotonin 5-HT(2A) receptor inverse agonist, were evaluated in 2 double-blind, placebo-controlled, dose escalation studies in healthy male volunteers. Pharmacokinetic sampling was measured up to 216 hours after single oral/nasogastric doses of ACP-103 and after the last dose of once-daily oral administration of ACP-103 for 14 days. Single doses of ACP-103 (20-300 mg) resulted in dose-proportionate mean C(max) values (9-152 ng/mL) and AUC(0-infinity) (706-10 798 h x ng/mL), and multiple doses (50-150 mg) resulted in dose-proportionate mean C(max,ss) (93-248 ng/mL) and AUC(0-infinity,ss) (1839-4680 h x ng/mL). The half-life of ACP-103 was approximately 55 hours, with a t(max) at 6 hours. ACP-103 was well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily for 14 days.

Differential patterns of premorbid academic and social deterioration in patients with schizophrenia.

Schizophrenia is a neurodevelopmental disorder that is characterized by a number of behavioral abnormalities that are present prior to onset. These premorbid abnormalities may serve as unique markers for the disorder. The current study examines academic and social functioning prior to schizophrenia onset in a group of 58 males diagnosed with schizophrenia. The pattern of deterioration for social and academic functioning was examined across three age periods including childhood, early adolescence, and late adolescence, using the retrospective Premorbid Adjustment Scale (PAS). Results indicated that while increasing deterioration was present for both social and academic adjustment across age periods, there was a significant difference in deterioration between academic and social functioning (p<.05) during late adolescence, with greater deterioration in academic functioning. Results of the current study suggest that premorbid academic functioning is particularly susceptible to deterioration during late adolescence, with accelerating deterioration as schizophrenia onset becomes imminent. When considered together with results from other studies, the present findings suggest that deterioration in premorbid academic functioning from early to late adolescence may be a unique premorbid marker for schizophrenia.

The effects of antipsychotic medication on factor and cluster structure of neurologic examination abnormalities in schizophrenia.

This study extends a previous study of the factor structure of the neurologic examination in unmedicated schizophrenia, utilizing cluster analysis and adding a medicated condition. We administered a modified version of the Neurologic Evaluation Scale (NES) on two occasions to 80 patients with schizophrenia or schizoaffective disorder, once while on antipsychotic medications and once while off medication. Data were distilled by combining right- and left-side scores, and by excluding rarely abnormal and unreliable items from the analysis. Principal components analysis yielded an intuitive four-factor solution in the unmedicated condition, but an inscrutable five-factor solution during medication. Cluster analysis revealed three groups: normal, cognitively impaired, and diffusely impaired. These results were also less interpretable with data from the medicated condition. Neurologic performance was better in the medicated than in the unmedicated condition. As is the case with other domains of symptoms and performance in schizophrenia, relationships among neurologic exam variables are altered by the presence of antipsychotic medication.

Elevated cerebrospinal fluid SNAP-25 in schizophrenia.

BACKGROUND: Research suggests an association between abnormal exocytosis and schizophrenia. We previously demonstrated increased synaptosomal associated protein, 25 kDa (SNAP-25), a member of the exocytotic mechanism, in the cerebrospinal fluid (CSF) of schizophrenia subjects. In this study, we explored SNAP-25 level and clinical variables in a new group of subjects. METHODS: Twenty-five haloperidol-treated subjects with chronic schizophrenia and twenty-five healthy control subjects participated in the study. Subjects received haloperidol treatment for at least 3 months and then had a lumbar puncture (n = 19). Medication was replaced by placebo, and the lumbar puncture was repeated (n = 25) after 6 weeks or sooner if limited psychotic symptoms occurred. We measured the level of SNAP-25 in the CSF and symptoms with the Brief Psychiatric Rating Scale (BPRS). RESULTS: In both haloperidol (p =.001) and placebo (p =.001) treatment conditions, SNAP-25 was elevated. There was no significant difference in SNAP-25 level between conditions. We identified significant positive correlations among SNAP-25 and the BPRS total score and psychosis and thinking disturbance subscales in subjects on haloperidol. CONCLUSIONS: These observations confirm our previous report of elevated CSF SNAP-25 and suggest that synaptic pathology may be linked with the pathophysiology of schizophrenia.

Automatic activation of the semantic network in schizophrenia: evidence from event-related brain potentials.

BACKGROUND: Language disorder associated with schizophrenia might be due to disturbances in both automatic activation and mechanisms of controlled attention. The contribution of each process to semantic memory dysfunction has not been determined for schizophrenia, and the semantic priming paradigm is well-suited for addressing this question. In the present report, event-related potentials (ERPs) elicited under conditions assumed to reveal automatic activation (short prime-target interval and low proportion of related words) are compared directly with ERPs elicited under conditions associated with controlled processing (long prime-target interval and high proportion of related words). METHODS: Visual ERPs were recorded during a lexical decision task, in which semantic relationship (associated and unassociated words), expectancy (relatedness proportions), and prime-target interval (250- and 850-msec inter-stimulus intervals [ISIs]) were varied. Diagnosis and expectancy were between-subjects factors; semantic relationship and ISI were repeated measures. The N400 priming effect (enhanced negativity to unassociated words) was compared between 34 male normal control subjects tested once and 37 male schizophrenia inpatients evaluated during their participation in a double-blind haloperidol maintenance therapy and placebo replacement protocol. RESULTS: The N400 priming effect for patients was significantly reduced during both pharmacologic phases, compared with controls. During haloperidol treatment, however, patients showed a significant N400 priming effect over the anterior scalp region and additionally under the automatic activation condition. The N400 priming effect was enhanced under the controlled processing condition for control subjects; this effect was not observed for patients. N400 amplitude elicited under the rapid presentation rate (250-msec ISI) differed between medicated patients and controls; groups did not differ for the 850-msec ISI. CONCLUSIONS: Findings suggest that automatic activation and mechanisms of controlled attention are both disrupted during semantic memory access for schizophrenia patients. Pharmacologic agents, such as haloperidol, might enhance automatic activation of the semantic network in this patient population, as indexed by the N400 component of the ERP.

NOTCH4 gene haplotype is associated with schizophrenia in African Americans.

BACKGROUND: The goal of this study was to investigate the relationship between the NOTCH4 gene and schizophrenia in African American (AA) and European American (EA) subjects. METHODS: Two single nucleotide polymorphisms (SNPs) at the NOTCH4 locus were genotyped in 123 AA schizophrenia patients, 223 EA schizophrenia patients, 85 AA healthy control subjects, and 211 EA healthy control subjects. The specific markers studied were -1725T/G and -25T/C. Comparisons of allele and haplotype frequencies between patients and control subjects were performed with the chi-square test, the Fisher's Exact Test, and CLUMP software. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. RESULTS: The haplotype -1725G/-25T associates to schizophrenia in AA subjects (p =.0008), but not in EA subjects. Alleles -1725G and allele -25T are in positive LD both in AAs and EAs. Allele and haplotype frequencies differ significantly between AAs and EAs. CONCLUSIONS: The haplotype -1725G/-25T at the NOTCH4 locus, which results from SNPs of NOTCH4 that are in LD, may increase susceptibility to schizophrenia in AAs. Any effect of this locus on risk for schizophrenia is population-specific.

Topiramate normalizes hippocampal NPY-LI in flinders sensitive line 'depressed' rats and upregulates NPY, galanin, and CRH-LI in the hypothalamus: implications for mood-stabilizing and weight loss-inducing effects.

Topiramate is currently used in the treatment of epilepsy, but this anticonvulsant drug has also been reported to exert mood-stabilizing effects and induce weight loss in patients. Neuropeptide Y (NPY) is abundantly and widely distributed in the mammalian central nervous system and centrally administered NPY markedly reduces pharmacologically induced seizures and induces antidepressant-like activity as well as feeding behavior. Two other peptides, galanin and corticotropin-releasing hormone (CRH), have also been proposed to play a modulatory role in mood, appetite, and seizure regulation. Consequently, we investigated the effects of single and repeated topiramate (10 days, once daily: 40 mg/kg i.p.) or vehicle treatment in 'depressed' flinders sensitive line (FSL) and control Flinders resistant line (FRL) rats on brain regional peptide concentrations of NPY, galanin, and CRH. The handling associated with repeated injections reduced hippocampal levels of NPY- and galanin-like immunoreactivities (LI) while NPY- and CRH-LI levels were increased in the hypothalamus, regardless of strain or treatment. In the hippocampus, concentrations of NPY-LI, galanin-LI, and CRH-LI were lower in FSL than FRL animals. Repeated topiramate treatment selectively normalized NPY-LI in this region in the FSL animals. In the hypothalamus, galanin-LI was reduced in FSL compared to FRL animals. Topiramate elevated the hypothalamic concentrations of NPY-LI, CRH-LI, and galanin-LI in both strains. Furthermore, topiramate elevated serum leptin but not corticosterone levels. The present findings show that topiramate has distinct effects on abnormal hippocampal levels of NPY, with possible implications for its anticonvulsant and mood-stabilizing effects. Furthermore, stimulating hypothalamic NPY-LI, CRH-LI and galanin-LI as well as serum leptin levels may be associated with the weight loss-inducing effects of topiramate.

Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report.

BACKGROUND: The hypothesis that exposure to traumatic events may sensitize or kindle limbic nuclei has led to efforts to treat posttraumatic stress disorder (PTSD) with anticonvulsants. Based on the kindling hypothesis of PTSD, this open-label study assesses clinical response to topiramate as a potential treatment for DSM-IV PTSD. METHOD: A naturalistic data review was conducted of medical records of all adult outpatients (9 men. 26 women symptomatic for a mean +/- SD of 18 +/- 15 years with DSM-IV chronic civilian PTSD) treated with topiramate, 12.5 to 500 mg/day, as add-on (N = 28) or monotherapy (N = 7). The last 17 patients completed the PTSD Checklist-Civilian Version (PCL-C) before treatment and at week 4. Dosage titration started at 12.5 to 25 mg/day and increased in 25- to 50-mg increments every 3 to 4 days until a therapeutic response was achieved or the drug was no longer tolerated. The mean duration of treatment was 33 weeks (range, 1-119 weeks). RESULTS: Topiramate decreased nightmares in 79% (19/24) and flashbacks in 86% (30/35) of patients, with full suppression of nightmares in 50% and of intrusions in 54% of patients with these symptoms. Nightmares or intrusions partially improved in a median of 4 days (mean = 11 +/- 13 days) and were fully absent in a median of 8 days (mean = 35 +/- 49 days). Response was seen in 95% of partial responders at a dosage of 75 mg/day or less, and in 91% of full responders at a dosage of 100 mg/day or less. Mean reductions in PCL-C score from baseline to week 4 were highly significant (baseline score = 60 vs. week 4 score = 39, p < .001), with similar reductions in reexperiencing, avoidance, and hyperarousal criteria symptoms. Thirteen patients discontinued for various reasons during the > 2-year study period. Except for a single instance of acute secondary narrow-angle glaucoma, there were no serious side effects. CONCLUSION: Topiramate appeared effective as add-on or monotherapy for chronic PTSD. It demonstrated a rapid onset of action and minimally serious, dose-related side effects without the development of tolerance. Double-blind studies are indicated.

The language system in schizophrenia: effects of capacity and linguistic structure.

Dysfunction in receptive language processes has been reliably observed in individuals diagnosed with schizophrenia and their first degree family members. The present study addressed the unresolved issue of whether receptive syntax is intact in schizophrenia. The principal question concerned whether comprehension dysfunction in schizophrenia involves a disturbance in the processing of syntactic structure, a susceptibility to demands placed on temporal auditory processing, or some combination of these two general factors. Comprehension accuracy was compared between 32 males diagnosed with schizophrenia and 22 males with no lifetime diagnosis of psychiatric disorder. Accuracy was examined for responses to Who questions ("Who did X?" and "Who was done X?") about information in the sentential clauses (main vs. relative) of two types of relative sentences (subject-relatives vs. object-relatives) that were presented aurally at conversational and accelerated rates. The relationship between cognitive functions and comprehension accuracy was also tested. Results showed highly significant effects of diagnosis, syntactic structure, and temporal demand. Patients were characterized by reduced overall comprehension accuracy compared to controls. More important, patients and controls differed in their patterns of accuracy across the different types of syntactic structure. Finally, cognitive functions predicted but did not completely account for comprehension accuracy. Findings suggest the hypothesis that receptive syntax is disrupted in schizophrenia, and this dysfunction may not be entirely explained by compromised general cognitive ability.

Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day.

Most atypical antipsychotic drugs (APDs), e.g. risperidone (RIS), produce more extensive blockade of brain serotonin (5-HT)(2A) than dopamine (DA) D(2) receptors. This distinguishes them from typical APDs, e.g. haloperidol (HAL). Our objective was to test the hypothesis that augmentation of low doses of RIS or HAL (2mg/day) with pimavanserin (PIM), a selective 5-HT(2A) inverse agonist, to enhance 5-HT(2A) receptor blockade, can achieve efficacy comparable to RIS, 6mg/day, but with lesser side effects. In a multi-center, randomized, double-blind, 6week trial, 423 patients with chronic schizophrenia experiencing a recent exacerbation of psychotic symptoms were randomized to RIS2mg+placebo (RIS2PBO), RIS2mg+PIM20mg (RIS2PIM), RIS6mg+PBO (RIS6PBO), HAL2mg+PBO (HAL2PBO), or HAL2mg+PIM20mg (HAL2PIM). Improvement in psychopathology was measured by the PANSS and CGI-S. The reduction in PANSS Total Score with RIS2PIM at endpoint was significantly greater than RIS2PBO: -23.0 vs. -16.3 (p=0.007), and not significantly different from the RIS6PBO group: -23.2 points. The percentage of patients with ≥20% improvement at day 15 in the RIS2PIM group was 62.3%, significantly greater than the RIS6PBO (42.1%; p=0.01) and the RIS2PBO groups (37.7%; p=0.002). Weight gain and hyperprolactinemia were greater in the RIS6PBO group than the RIS2PIM group but there was no difference in extrapyramidal side effects (EPS). HAL2PBO and HAL2PIM were not significantly different from each other in efficacy but HAL2PIM had less EPS at end point. Both HAL groups and RIS6PBO showed equal improvement in psychopathology at endpoint, indicating HAL 2mg/day is effective to treat an acute exacerbation in chronic schizophrenia patients. In conclusion, a sub-effective RIS dose combined with PIM to enhance 5-HT(2A) receptor blockade provided faster onset of action, and at endpoint, equal efficacy and better safety, compared to standard dose RIS. These results support the conclusion that 5-HT(2A) receptor blockade is a key component of the action of some atypical APDs and can reduce EPS due to a typical APD.