Background Psychosis affects over half of people with Parkinson’s disease (PD) over the disease course and severely worsens quality of life. Clinicians often face a trade-off between reducing dopaminergic therapies to control hallucinations/delusions and maintaining motor function. Multiple atypical antipsychotics are used, but their comparative efficacy and safety remain uncertain.

Methods We conducted a prespecified systematic review and network meta-analysis (NMA) following PRISMA 2020 and registered in PROSPERO (CRD420251143957). PubMed, Embase, Scopus, and CENTRAL were searched to August 2025 without language restrictions. Randomized controlled trials evaluating atypical antipsychotics for PD psychosis were eligible. Two reviewers independently screened studies, extracted data, and assessed risk of bias (RoB 2); certainty was appraised with GRADE. Continuous outcomes (BPRS, CGI-S, UPDRS-II) were synthesized as mean differences; binary outcomes (adverse events, discontinuation, mortality, cardiovascular events) as risk ratios in a random-effects NMA, with placebo as the common comparator.

Results A total of 22 trials with 2,047 participants (mean age 70.6 ± 12 years; 1,038 males and 997 females) were included, with a mean follow-up of 2.73 ± 1.0 months. Across treatment arms, 1,091 patients received active interventions and 1,036 placebo. The active groups included clozapine (n=139), olanzapine (n=111), pimavanserin (n=746), quetiapine (n=126), risperidone (n=5), and ziprasidone (n=8). None of the drugs demonstrated consistent or statistically significant superiority over placebo in reducing psychosis severity as measured by BPRS or CGI-S, although clozapine and quetiapine showed trends toward improvement and risperidone suggested possible benefit with very wide intervals due to small samples. Motor and daily living outcomes assessed with UPDRS-II revealed no significant changes across treatments, with pooled effects for clozapine, olanzapine, quetiapine, pimavanserin, risperidone, and ziprasidone all overlapping the null. Safety analyses indicated no meaningful increase in risk of PD worsening, insomnia, cardiovascular events, or mortality compared with placebo, with overall pooled risk ratios approximating unity and showing no heterogeneity. SUCRA rankings suggested risperidone and clozapine as potentially more efficacious on BPRS, olanzapine as higher on CGI-S, and ziprasidone on UPDRS-II, though none achieved robust statistical significance.

Conclusions No antipsychotic showed clear superiority over placebo; clozapine and pimavanserin remain the most relevant options, but stronger evidence is needed.

The authors have declared no competing interest.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251143957

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Supplementary file