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Herbert Y Meltzer - One of the best experts on this subject based on the ideXlab platform.
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identification of a serotonin 2a receptor subtype of schizophrenia spectrum disorders with Pimavanserin the sub sero proof of concept trial protocol
Frontiers in Pharmacology, 2020Co-Authors: Olga B Baltzersen, Herbert Y Meltzer, Vibe G Frokjaer, Jayachandra Mitta Raghava, Lone Baandrup, Birgitte Fagerlund, Henrik Larsson, Christian H Fibiger, Birte Glenthoj, Gitte M KnudsenAbstract:Background: All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naive patients will respond to serotonin 2A receptor (2AR) blockade. Aims: This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, Pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Materials and Equipment: Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective serotonin 2AR antagonist (Pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. Outcome Measures: The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of Pimavanserin response. Anticipated Results: Clinically, we expect Pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect Pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of Pimavanserin will be explored. Perspectives: Sub-Sero will provide unique information about the role serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. Clinical Trial Registration: ClinicalTrials, identifier NCT03994965.
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Identification of a Serotonin 2A Receptor Subtype of Schizophrenia Spectrum Disorders With Pimavanserin: The Sub-Sero Proof-of-Concept Trial Protocol
Frontiers in Pharmacology, 2020Co-Authors: Olga B Baltzersen, Herbert Y Meltzer, Vibe G Frokjaer, Jayachandra Mitta Raghava, Lone Baandrup, Birgitte Fagerlund, Henrik Larsson, Birte Glenthoj, H. Christian Fibiger, Gitte M KnudsenAbstract:All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naïve patients will respond to serotonin 2A receptor (2AR) blockade. This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, Pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective serotonin 2AR antagonist (Pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of Pimavanserin response. Clinically, we expect Pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect Pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of Pimavanserin will be explored. Sub-Sero will provide unique information about the role serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. ClinicalTrials, identifier NCT03994965. Copyright © 2020 Baltzersen, Meltzer, Frokjaer, Raghava, Baandrup, Fagerlund, Larsson, Fibiger, Glenthøj, Knudsen and Ebdrup.
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Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT_1A Partial Agonist
Neuropsychopharmacology, 2012Co-Authors: Masakuni Horiguchi, Kayleen E Hannaway, Adesewa E Adelekun, Karu Jayathilake, Herbert Y MeltzerAbstract:Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N -methyl- D -aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)_2A/dopamine D_2 antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT_1A partial agonist properties, tandospirone, a selective 5-HT_1A partial agonist, haloperidol, a D_2 antagonist, and Pimavanserin, a 5-HT_2A inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), Pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1–7), followed by a 7-day washout (day8–14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not Pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT_1A antagonists, further evidence for the importance of 5-HT_1A receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.
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Pimavanserin, a Serotonin_2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis
Neuropsychopharmacology, 2010Co-Authors: Herbert Y Meltzer, Roger Mills, Hilde Williams, Stephen Revell, Ann Johnson, Daun Bahr, Joseph H FriedmanAbstract:Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD). Clozapine and quetiapine, two atypical antipsychotic drugs, at doses markedly lower than those effective in schizophrenia, which, nevertheless, still cause sedation, hypotension, and other side effects, are widely used to treat psychotic symptoms in patients with PD psychosis (PDP), although quetiapine has never been shown to be effective in a placebo-controlled study. The demonstrated efficacy of clozapine in PDP has been attributed to serotonin (5-HT_2A) receptor blockade. We postulated that Pimavanserin (ACP-103), a highly selective 5-HT_2A inverse agonist, would attenuate psychosis in patients with PDP, but avoid motoric worsening and non-motoric side effects. In this double-blind, randomized multicenter 28-day study, the tolerability and efficacy of Pimavanserin was compared with placebo in 60 patients with L -DOPA or dopamine (DA) agonist-induced PDP. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. Antipsychotic efficacy was evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS) and a UPDRS Part I psychosis-relevant item. Pimavanserin did not differentiate from placebo with regard to motor impairment, sedation, hypotension, or other side effects. The principal measures of efficacy of antipsychotic response to Pimavanserin, the SAPS total domain score, only showed a trend. However, the Pimavanserin-treated patients showed significantly greater improvement in some but not all measures of psychosis, including SAPS global measures of hallucinations and delusions, persecutory delusions, and the UPDRS measure of delusions and hallucinations. Pimavanserin showed significantly greater improvement in psychosis in patients with PDP at a dose which did not impair motor function, or cause sedation or hypotension Thus, Pimavanserin may represent a novel treatment for PDP. Furthermore, these results support the hypothesis that attenuation of psychosis secondary to DA receptor stimulation in PDP may be achieved through selective 5-HT_2A receptor antagonism.
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Pimavanserin a serotonin 2a receptor inverse agonist for the treatment of parkinson s disease psychosis
Neuropsychopharmacology, 2010Co-Authors: Herbert Y Meltzer, Roger Mills, Hilde Williams, Stephen Revell, Ann Johnson, Daun Bahr, Joseph H FriedmanAbstract:Pimavanserin, a Serotonin 2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis
Gitte M Knudsen - One of the best experts on this subject based on the ideXlab platform.
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identification of a serotonin 2a receptor subtype of schizophrenia spectrum disorders with Pimavanserin the sub sero proof of concept trial protocol
Frontiers in Pharmacology, 2020Co-Authors: Olga B Baltzersen, Herbert Y Meltzer, Vibe G Frokjaer, Jayachandra Mitta Raghava, Lone Baandrup, Birgitte Fagerlund, Henrik Larsson, Christian H Fibiger, Birte Glenthoj, Gitte M KnudsenAbstract:Background: All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naive patients will respond to serotonin 2A receptor (2AR) blockade. Aims: This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, Pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Materials and Equipment: Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective serotonin 2AR antagonist (Pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. Outcome Measures: The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of Pimavanserin response. Anticipated Results: Clinically, we expect Pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect Pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of Pimavanserin will be explored. Perspectives: Sub-Sero will provide unique information about the role serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. Clinical Trial Registration: ClinicalTrials, identifier NCT03994965.
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Identification of a Serotonin 2A Receptor Subtype of Schizophrenia Spectrum Disorders With Pimavanserin: The Sub-Sero Proof-of-Concept Trial Protocol
Frontiers in Pharmacology, 2020Co-Authors: Olga B Baltzersen, Herbert Y Meltzer, Vibe G Frokjaer, Jayachandra Mitta Raghava, Lone Baandrup, Birgitte Fagerlund, Henrik Larsson, Birte Glenthoj, H. Christian Fibiger, Gitte M KnudsenAbstract:All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naïve patients will respond to serotonin 2A receptor (2AR) blockade. This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, Pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective serotonin 2AR antagonist (Pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of Pimavanserin response. Clinically, we expect Pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect Pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of Pimavanserin will be explored. Sub-Sero will provide unique information about the role serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. ClinicalTrials, identifier NCT03994965. Copyright © 2020 Baltzersen, Meltzer, Frokjaer, Raghava, Baandrup, Fagerlund, Larsson, Fibiger, Glenthøj, Knudsen and Ebdrup.
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11c labeling and preliminary evaluation of Pimavanserin as a 5 ht2a receptor pet radioligand
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Valdemar L Andersen, Gitte M Knudsen, Hanne D Hansen, Matthias M Herth, Agnete Dyssegaard, Jesper L KristensenAbstract:Abstract Pimavanserin is a selective serotonin 2A receptor (5-HT2AR) inverse agonist that has shown promise for treatment of psychotic symptoms in patients with Parkinson’s disease. Here, we detail the 11C-labeling and subsequently evaluate Pimavanserin as a PET-radioligand in pigs. [11C]Pimavanserin was obtained by N-methylation of an appropriate precursor using [11C]MeOTf in acetone at 60 °C giving radiochemical yields in the range of 1–1.7 GBq (n = 4). In Danish Landrace pigs the radio ligand readily entered the brain and displayed binding in the cortex in accordance with the distribution of 5-HT2ARs. However, this binding could not be blocked by either ketanserin or Pimavanserin itself, indicating high nonspecific binding. The lack of displacement by the 5-HT2R antagonist and binding in the thalamus suggests that [11C]Pimavanserin is not selective for the 5-HT2AR in pigs.
Hilde Williams - One of the best experts on this subject based on the ideXlab platform.
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decreased burden among caregivers of patients with parkinson s disease psychosis pdp treated with Pimavanserin a selective 5 ht2a inverse agonist p6 044
Neurology, 2015Co-Authors: Dag Aarsland, Kathy Chiburris, Roger Mills, Hilde Williams, Michaela Karistedt, Clive BallardAbstract:OBJECTIVE: To determine the effect of Pimavanserin, a selective 5-HT2A inverse-agonist, on caregiver burden. BACKGROUND: Parkinson9s Disease Psychosis (PDP) is associated with functional and cognitive decline, morbidity/mortality, and increased caregiver burden often leading to early institutionalization. Pimavanserin is a potent 5-HT2A inverse-agonist being developed for PDP. Unlike current antipsychotics, it has no dopaminergic, histaminergic, adrenergic or muscarinic activity. Pimavanserin 40mg demonstrated improvements in psychosis, nighttime sleep and daytime wakefulness in randomized controlled trials (RCTs) in PDP. RCT completers could roll into a long-term open-label study (OLS). A consented caregiver had to attend all RCT and OLS visits and complete the Zarit 22-item caregiver burden scale (CBS). METHOD: In an integrated analysis of the 6-week RCTs, CBS scores were evaluated among caregivers of 268 PDP patients in N.America who received Pimavanserin 40mg or placebo. Most caregivers were spouses or other family. Continued effect was assessed in the OLS. RESULTS: Mean baseline (pretreatment) CBS scores were 30.6 for placebo (N=133) and 28.8 for Pimavanserin 40mg (N=135). Significant improvement in burden was observed for the Pimavanserin group (-4.8 points) over placebo (-1.1 points) at 6 weeks (p=0.0009). These results did not strongly correlate with psychosis or sleep improvements, suggesting broader benefits of Pimavanserin not captured by other study measures. More caregiver benefit was observed for patients with less dementia and less co-morbid disease. In the OLS, CBS scores remained generally stable (+1-point difference) for up to 9 months.CONCLUSIONS: Improvements on caregiver burden among Pimavanserin-treated people with PDP, provide important context around the benefit-risk profile of this selective 5-HT2A inverse-agonist that has shown significant benefit on psychosis and sleep and a well-tolerated safety profile. Disclosure: Dr. Aarsland has nothing to disclose. Dr. Mills has received personal compensation for activities with Acadia Pharmaceuticals, Inc. as an employee. Dr. Williams has received personal compensation for activities with ACADIA Pharmaceuticals Inc. as an employee. Dr. Chi-Burris has nothing to disclose. Dr. Karistedt has nothing to disclose. Dr. Ballard has received personal compensation for activities with Novartis, Eisai, ACADIA Pharmaceuticals, and Lundbeck Research USA, Inc. as a consultant.
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Decreased burden among caregivers of patients with Parkinson’s disease psychosis (PDP) treated with Pimavanserin, a selective 5-HT2A inverse agonist (P6.044)
Neurology, 2015Co-Authors: Dag Aarsland, Roger Mills, Hilde Williams, Michaela Karistedt, Kathy Chi-burris, Clive BallardAbstract:OBJECTIVE: To determine the effect of Pimavanserin, a selective 5-HT2A inverse-agonist, on caregiver burden. BACKGROUND: Parkinson9s Disease Psychosis (PDP) is associated with functional and cognitive decline, morbidity/mortality, and increased caregiver burden often leading to early institutionalization. Pimavanserin is a potent 5-HT2A inverse-agonist being developed for PDP. Unlike current antipsychotics, it has no dopaminergic, histaminergic, adrenergic or muscarinic activity. Pimavanserin 40mg demonstrated improvements in psychosis, nighttime sleep and daytime wakefulness in randomized controlled trials (RCTs) in PDP. RCT completers could roll into a long-term open-label study (OLS). A consented caregiver had to attend all RCT and OLS visits and complete the Zarit 22-item caregiver burden scale (CBS). METHOD: In an integrated analysis of the 6-week RCTs, CBS scores were evaluated among caregivers of 268 PDP patients in N.America who received Pimavanserin 40mg or placebo. Most caregivers were spouses or other family. Continued effect was assessed in the OLS. RESULTS: Mean baseline (pretreatment) CBS scores were 30.6 for placebo (N=133) and 28.8 for Pimavanserin 40mg (N=135). Significant improvement in burden was observed for the Pimavanserin group (-4.8 points) over placebo (-1.1 points) at 6 weeks (p=0.0009). These results did not strongly correlate with psychosis or sleep improvements, suggesting broader benefits of Pimavanserin not captured by other study measures. More caregiver benefit was observed for patients with less dementia and less co-morbid disease. In the OLS, CBS scores remained generally stable (+1-point difference) for up to 9 months.CONCLUSIONS: Improvements on caregiver burden among Pimavanserin-treated people with PDP, provide important context around the benefit-risk profile of this selective 5-HT2A inverse-agonist that has shown significant benefit on psychosis and sleep and a well-tolerated safety profile. Disclosure: Dr. Aarsland has nothing to disclose. Dr. Mills has received personal compensation for activities with Acadia Pharmaceuticals, Inc. as an employee. Dr. Williams has received personal compensation for activities with ACADIA Pharmaceuticals Inc. as an employee. Dr. Chi-Burris has nothing to disclose. Dr. Karistedt has nothing to disclose. Dr. Ballard has received personal compensation for activities with Novartis, Eisai, ACADIA Pharmaceuticals, and Lundbeck Research USA, Inc. as a consultant.
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on the discovery and development of Pimavanserin a novel drug candidate for parkinson s psychosis
Neurochemical Research, 2014Co-Authors: Uli Hacksell, Roger Mills, Ethan S Burstein, Krista Mcfarland, Hilde WilliamsAbstract:Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of Pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, Pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that Pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.
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Pimavanserin for patients with parkinson s disease psychosis a randomised placebo controlled phase 3 trial
The Lancet, 2014Co-Authors: Jeffrey L Cummings, Kathy Chiburris, Roger Mills, Hilde Williams, Stuart Isaacson, Anne Corbett, Rohit Dhall, Clive BallardAbstract:Summary Background Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of Pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. Methods In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive Pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. Findings Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of Pimavanserin included in the primary analysis, Pimavanserin was associated with a −5·79 decrease in SAPS-PD scores compared with −2·73 for placebo (difference −3·06, 95% CI −4·91 to −1·20; p=0·001; Cohen's d 0·50). Ten patients in the Pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, Pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. Interpretation Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. Funding ACADIA Pharmaceuticals.
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Pimavanserin, a Serotonin_2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis
Neuropsychopharmacology, 2010Co-Authors: Herbert Y Meltzer, Roger Mills, Hilde Williams, Stephen Revell, Ann Johnson, Daun Bahr, Joseph H FriedmanAbstract:Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD). Clozapine and quetiapine, two atypical antipsychotic drugs, at doses markedly lower than those effective in schizophrenia, which, nevertheless, still cause sedation, hypotension, and other side effects, are widely used to treat psychotic symptoms in patients with PD psychosis (PDP), although quetiapine has never been shown to be effective in a placebo-controlled study. The demonstrated efficacy of clozapine in PDP has been attributed to serotonin (5-HT_2A) receptor blockade. We postulated that Pimavanserin (ACP-103), a highly selective 5-HT_2A inverse agonist, would attenuate psychosis in patients with PDP, but avoid motoric worsening and non-motoric side effects. In this double-blind, randomized multicenter 28-day study, the tolerability and efficacy of Pimavanserin was compared with placebo in 60 patients with L -DOPA or dopamine (DA) agonist-induced PDP. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. Antipsychotic efficacy was evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS) and a UPDRS Part I psychosis-relevant item. Pimavanserin did not differentiate from placebo with regard to motor impairment, sedation, hypotension, or other side effects. The principal measures of efficacy of antipsychotic response to Pimavanserin, the SAPS total domain score, only showed a trend. However, the Pimavanserin-treated patients showed significantly greater improvement in some but not all measures of psychosis, including SAPS global measures of hallucinations and delusions, persecutory delusions, and the UPDRS measure of delusions and hallucinations. Pimavanserin showed significantly greater improvement in psychosis in patients with PDP at a dose which did not impair motor function, or cause sedation or hypotension Thus, Pimavanserin may represent a novel treatment for PDP. Furthermore, these results support the hypothesis that attenuation of psychosis secondary to DA receptor stimulation in PDP may be achieved through selective 5-HT_2A receptor antagonism.
Clive Ballard - One of the best experts on this subject based on the ideXlab platform.
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Pimavanserin in Alzheimer's Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms.
The journal of prevention of Alzheimer's disease, 2020Co-Authors: Clive Ballard, James M Youakim, Bruce Coate, Srdjan StankovicAbstract:BACKGROUND: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. OBJECTIVE: Evaluate the efficacy of Pimavanserin on symptoms of psychosis in patients with Alzheimer's disease (AD). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Nursing home residents. PARTICIPANTS: Patients with AD psychosis. INTERVENTIONS: Pimavanserin 34 mg or placebo daily for 12 weeks. MEASUREMENTS: The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated. RESULTS: Of 181 patients randomized (n=90 Pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 Pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen's d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p
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A POST HOC ANALYSIS OF STUDY ACP-103-019 EVALUATING THE IMPACT OF A REDUCTION IN PSYCHOSIS ON THE SEVERITY OF AGITATION AND AGGRESSION IN PATIENTS WITH ALZHEIMER'S DISEASE
American Journal of Geriatric Psychiatry, 2019Co-Authors: Michael T Guskey, Srdjan Stankovic, Bruce Coate, Randy Owen, James C Norton, Clive BallardAbstract:Introduction The objective of this post hoc analysis was to evaluate whether Alzheimer's disease (AD) patients with psychosis who experience an improvement in their hallucinations and delusions with Pimavanserin treatment also experience an improvement in agitation and aggression. Methods ACP-103-019 was a 12 week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of Pimavanserin (PIM) 34mg once-daily in reducing the frequency and/or severity of hallucinations and delusions in patients with AD psychosis. The primary endpoint was change from baseline in the Neuropsychiatric Inventory Nursing Home Version Psychosis Score (NPI-NH PS) [domain A (delusions) + domain B (hallucinations)] at Week 6. A post hoc analysis was conducted to determine if there was a greater reduction in agitation and aggression, as measured by NPI-NH Domain C (agitation/aggression) and Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF), in patients who experienced a reduction in the frequency and/or severity of their hallucinations and delusions when compared with those who did not experience a reduction in hallucinations and delusions. Results Overall in ACP-103-019, there were only minor differences between the placebo (n=91) and PIM (n=87) treatment arms when evaluating changes from baseline to Week 6 in Agitation/Aggression based on CMAI SF total score or NPI-NH Domain C score (0.30 [p=0.8031] and -0.66 [p=0.254], respectively). However, when subjects treated with PIM who responded to the treatment (n=48), defined as a 30% reduction in NPI-NH PS at Week 6, were compared with those who did not respond to PIM treatment (n=28), there was a greater reduction in both CMAI-SF and NPI-NH Domain C scores: -3.74 (p=0.0550) and -2.75 (p=0.0021), respectively. When response was defined as a 50% reduction in NPI-NH PS at Week 6, the greater improvement of agitation/aggression in responders (n=44) vs non-responders (n=32) was also observed for both CMAI-SF and NPI-NH Domain C: -3.714 (p=0.0483) and -3.64 (p Conclusions In this post-hoc analysis, some AD patients whose hallucinations and delusions responded to Pimavanserin also experienced improvement in their symptoms of agitation and aggression. These results suggest a correlation between a reduction in hallucinations and delusions and a reduction in agitation/aggression in AD patients with psychosis. This research was funded by Sponsored by ACADIA Pharmaceuticals Inc. (San Diego, CA, USA).
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Pimavanserin in alzheimer s disease psychosis efficacy in patients with more pronounced psychotic symptoms
The journal of prevention of Alzheimer's disease, 2019Co-Authors: Clive Ballard, James M Youakim, Bruce Coate, Srdjan StankovicAbstract:BACKGROUND: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. OBJECTIVE: Evaluate the efficacy of Pimavanserin on symptoms of psychosis in patients with Alzheimer's disease (AD). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Nursing home residents. PARTICIPANTS: Patients with AD psychosis. INTERVENTIONS: Pimavanserin 34 mg or placebo daily for 12 weeks. MEASUREMENTS: The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated. RESULTS: Of 181 patients randomized (n=90 Pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 Pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen's d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p<0.001) and ≥50% improvement was 77.8% vs. 43.3% (p=0.008) for Pimavanserin and placebo, respectively. The rate of adverse events (AEs) in the severe subgroup was similar between treatment groups, and urinary tract infection, fall, and agitation were most frequent. Serious AEs was similar with Pimavanserin (17.9%) and placebo (16.7%) with fewer discontinuations due to AEs with Pimavanserin (7.1%) compared to placebo (10.0%). Minimal change from baseline occurred for the mean MMSE score over 12 weeks. CONCLUSIONS: Pimavanserin demonstrated significant efficacy in AD psychosis in patients with higher baseline severity of psychotic symptoms (NPI-NH-PS ≥12). Treatment with Pimavanserin showed an acceptable tolerability profile.
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Pimavanserin in Alzheimer’s Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms
The Journal of Prevention of Alzheimer's Disease, 2019Co-Authors: Clive Ballard, James M Youakim, Bruce Coate, S. StankovicAbstract:Background Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Objective Evaluate the efficacy of Pimavanserin on symptoms of psychosis in patients with Alzheimer’s disease (AD). Design Randomized, double-blind, placebo-controlled trial Setting Nursing home residents Participants Patients with AD psychosis Interventions Pimavanserin 34 mg or placebo daily for 12 weeks Measurements The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated. Results Of 181 patients randomized (n=90 Pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 Pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen’s d =-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p
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Pimavanserin for Parkinson's Disease psychosis: Effects stratified by baseline cognition and use of cognitive‐enhancing medications
Movement Disorders, 2018Co-Authors: Alberto J Espay, Clive Ballard, Bruce Coate, James C Norton, Joseph H Friedman, Michael T Guskey, Joaquin A Vizcarra, Stewart A Factor, Anthony E Lang, Niccole J. LarsenAbstract:Background: PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. Objective: To evaluate the differential effect of the antipsychotic Pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive‐enhancing medications. Methods: Data from the pivotal randomized clinical trial of Pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21‐24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive‐enhancing medications. The primary outcome measure was change in the PD‐adapted Scale for the Assessment of Positive Symptoms. Results: Mean (Pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; –6.62 vs. –0.91; P = 0.002) versus the cognitively unimpaired (n = 135; –5.50 vs. –3.23; p = 0.046) group. The comparable change was –6.04 versus –2.18 (P = 0.012) and –5.66 versus –3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive‐enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive‐enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. Conclusions: The antipsychotic effect of Pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive‐enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Srdjan Stankovic - One of the best experts on this subject based on the ideXlab platform.
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Pimavanserin in Alzheimer's Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms.
The journal of prevention of Alzheimer's disease, 2020Co-Authors: Clive Ballard, James M Youakim, Bruce Coate, Srdjan StankovicAbstract:BACKGROUND: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. OBJECTIVE: Evaluate the efficacy of Pimavanserin on symptoms of psychosis in patients with Alzheimer's disease (AD). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Nursing home residents. PARTICIPANTS: Patients with AD psychosis. INTERVENTIONS: Pimavanserin 34 mg or placebo daily for 12 weeks. MEASUREMENTS: The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated. RESULTS: Of 181 patients randomized (n=90 Pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 Pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen's d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p
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improvement of sexual functioning during treatment of mdd with adjunctive Pimavanserin a secondary analysis
Depression and Anxiety, 2020Co-Authors: Marlene P Freeman, Maurizio Fava, Bryan Dirks, George I Papakostas, Richard C Shelton, Michael E Thase, Madhukar H Trivedi, Srdjan StankovicAbstract:BACKGROUND: Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive Pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of Pimavanserin on sexual function from the CLARITY study. METHODS: Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Asberg Depression Rating Scale total score >20 were randomized to Pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of Pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined. RESULTS: Among 203 patients (51 on Pimavanserin; 152 on placebo), Pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for Pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with Pimavanserin versus placebo. CONCLUSIONS: Adjunctive Pimavanserin improved sexual function in patients with MDD. Adding Pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction.
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Improvement of sexual functioning during treatment of MDD with adjunctive Pimavanserin: A secondary analysis.
Depression and Anxiety, 2020Co-Authors: Marlene P Freeman, Maurizio Fava, Bryan Dirks, George I Papakostas, Richard C Shelton, Michael E Thase, Madhukar H Trivedi, Srdjan StankovicAbstract:BACKGROUND: Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive Pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of Pimavanserin on sexual function from the CLARITY study. METHODS: Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Asberg Depression Rating Scale total score >20 were randomized to Pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (
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a phase 2 randomized double blind placebo controlled study of adjunctive Pimavanserin in patients with major depressive disorder and an inadequate response to therapy clarity
The Journal of Clinical Psychiatry, 2019Co-Authors: Maurizio Fava, Marlene P Freeman, Bryan Dirks, George I Papakostas, Richard C Shelton, Michael E Thase, Madhukar H Trivedi, Srdjan StankovicAbstract:OBJECTIVE: Pimavanserin is a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist. This phase 2 study examined the efficacy and safety of Pimavanserin as adjunctive therapy in patients with major depressive disorder (MDD). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in patients with DSM-5-defined MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Using a 2-stage sequential parallel-comparison design, patients were initially randomized in a 3:1 ratio to placebo or Pimavanserin added to ongoing SSRI or SNRI therapy; at 5 weeks, placebo nonresponders were re-randomized to placebo or Pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage in 17-item Hamilton Depression Rating Scale (HDRS-17) total score and Sheehan Disability Scale (SDS) score. RESULTS: Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled Sequential Parallel Comparison Design analyses of Stages 1 and 2, the least squares (LS) mean (SE) difference for the HDRS-17 total score was -1.7 (0.85) (P = .039) and for the SDS score was -0.8 (0.29) (P = .004). At week 5 of Stage 1, LS mean (SE) difference for Pimavanserin versus placebo was significant for changes on the HDRS-17 (-4.0 [1.09], P = .0003) and SDS (-1.2 [0.40], P = .0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of Pimavanserin from placebo (P < .05) occurred at 1 week. The most common adverse events with Pimavanserin were dry mouth, nausea, and headache. CONCLUSIONS: Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI or SNRI. Tolerability was consistent with previous experience. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03018340.
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A POST HOC ANALYSIS OF STUDY ACP-103-019 EVALUATING THE IMPACT OF A REDUCTION IN PSYCHOSIS ON THE SEVERITY OF AGITATION AND AGGRESSION IN PATIENTS WITH ALZHEIMER'S DISEASE
American Journal of Geriatric Psychiatry, 2019Co-Authors: Michael T Guskey, Srdjan Stankovic, Bruce Coate, Randy Owen, James C Norton, Clive BallardAbstract:Introduction The objective of this post hoc analysis was to evaluate whether Alzheimer's disease (AD) patients with psychosis who experience an improvement in their hallucinations and delusions with Pimavanserin treatment also experience an improvement in agitation and aggression. Methods ACP-103-019 was a 12 week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of Pimavanserin (PIM) 34mg once-daily in reducing the frequency and/or severity of hallucinations and delusions in patients with AD psychosis. The primary endpoint was change from baseline in the Neuropsychiatric Inventory Nursing Home Version Psychosis Score (NPI-NH PS) [domain A (delusions) + domain B (hallucinations)] at Week 6. A post hoc analysis was conducted to determine if there was a greater reduction in agitation and aggression, as measured by NPI-NH Domain C (agitation/aggression) and Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF), in patients who experienced a reduction in the frequency and/or severity of their hallucinations and delusions when compared with those who did not experience a reduction in hallucinations and delusions. Results Overall in ACP-103-019, there were only minor differences between the placebo (n=91) and PIM (n=87) treatment arms when evaluating changes from baseline to Week 6 in Agitation/Aggression based on CMAI SF total score or NPI-NH Domain C score (0.30 [p=0.8031] and -0.66 [p=0.254], respectively). However, when subjects treated with PIM who responded to the treatment (n=48), defined as a 30% reduction in NPI-NH PS at Week 6, were compared with those who did not respond to PIM treatment (n=28), there was a greater reduction in both CMAI-SF and NPI-NH Domain C scores: -3.74 (p=0.0550) and -2.75 (p=0.0021), respectively. When response was defined as a 50% reduction in NPI-NH PS at Week 6, the greater improvement of agitation/aggression in responders (n=44) vs non-responders (n=32) was also observed for both CMAI-SF and NPI-NH Domain C: -3.714 (p=0.0483) and -3.64 (p Conclusions In this post-hoc analysis, some AD patients whose hallucinations and delusions responded to Pimavanserin also experienced improvement in their symptoms of agitation and aggression. These results suggest a correlation between a reduction in hallucinations and delusions and a reduction in agitation/aggression in AD patients with psychosis. This research was funded by Sponsored by ACADIA Pharmaceuticals Inc. (San Diego, CA, USA).