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.