title: Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ACADIA Pharmaceuticals.
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cummings
authors.affiliation: Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Isaacson
authors.affiliation: ACADIA Pharmaceuticals, San Diego, CA, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Mills
authors.affiliation: ACADIA Pharmaceuticals, San Diego, CA, USA.
authors.forename: Hilde
authors.initials: H
authors.lastname: Williams
authors.affiliation: ACADIA Pharmaceuticals, San Diego, CA, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Chi-Burris
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College, London, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Corbett
authors.affiliation: Barrow Neurology Institute, Phoenix, AZ, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Dhall
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College, London, UK. Electronic address: clive.ballard@kcl.ac.uk.
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy / Q000523:psychology*; D010880:Piperidines / Q000627:therapeutic use*; D011618:Psychotic Disorders / Q000188:drug therapy*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000627:therapeutic use*; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D010880:Piperidines; D058826:Serotonin 5-HT2 Receptor Agonists; D014508:Urea; C510793:pimavanserin