Pimavanserin for Parkinson’s Disease Psychosis: A Meta-analysis of Placebo-controlled Randomized Trials
Matthew George Petruncio1, Jamir Pitton Rissardo2, Omar Elmandouh2, Ana Leticia Fornari Caprara2, Ian M. Walker2
1Cooper Medical School of Rowan University, 2Cooper University Hospital
Objective:

To evaluate the efficacy and safety of pimavanserin in Parkinson’s disease psychosis (PDP) through a meta-analysis of placebo-controlled randomized controlled trials (RCTs).

Background:
Psychosis affects up to 60% of patients with Parkinson’s disease and is associated with increased morbidity and caregiver burden. Pimavanserin, a selective 5-HT2A inverse agonist, is the only FDA-approved drug for PDP, but its overall benefit-risk profile remains debated.
Design/Methods:

RCTs comparing pimavanserin with placebo in PDP were identified through systematic searches of PubMed and ClinicalTrials.gov. The primary outcome was psychosis severity measured by SAPS-PD or SAPS-H+D. Secondary outcomes included UPDRS II/III (motor function) and adverse events such as falls, orthostatic hypotension, hallucinations, headache, and confusional state. Random-effects models were used to calculate standardized mean differences (SMD), mean differences (MD), or risk ratios (RR) with 95% confidence intervals (CI).

Results:

Four trials (PMID 19907417, NCT01174004, NCT00477672, NCT00658567) were included. Pimavanserin significantly reduced psychosis severity (SAPS: SMD −0.86; 95% CI −1.53 to −0.20; p = 0.011). Motor function showed no significant change (UPDRS II/III: MD −0.08; 95% CI −1.55 to 1.39; p = 0.92). Most adverse events were not significantly different from placebo, including falls (RR 0.69; 95% CI 0.42–1.12), hallucinations (RR 0.96; 95% CI 0.24–3.81), headache (RR 0.58; 95% CI 0.28–1.21), and confusional state (RR 1.42; 95% CI 0.67–3.02). Orthostatic hypotension showed a lower risk with pimavanserin (RR 0.36; 95% CI 0.17–0.76). Heterogeneity was high for efficacy outcomes (I² > 90%) but low for safety outcomes.

Conclusions:

Pimavanserin significantly improves psychosis in PDP without worsening motor symptoms. Most adverse events, including confusion, were not significantly different from placebo, except for a possible reduction in orthostatic hypotension. High heterogeneity and wide prediction intervals warrant cautious interpretation and further head-to-head trials.

10.1212/WNL.0000000000215026
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