Pimavanserin and Clozapine Outperform Other Atypical Antipsychotics in Treating Parkinson Disease Psychosis

Ismaeel Yunusa, PharmD, PhD

A recently published systematic review and network meta-analysis of atypical antipsychotics to treat patients with Parkinson disease psychosis (PDP) showed that pimavanserin (Nuplazid; Acadia) and clozapine significantly improved symptoms the best without affecting motor function. The study investigators also suggested that quetiapine should be avoided in patients with PDP with reduced cognitive abilities.

Using 19 unique studies that totaled 1242 patients with PDP, efficacy of each medication was compared using the Clinical Global Impression Scale for Severity (GCI-S). After collecting data on pimavanserin, quetiapine, olanzapine, clozapine, ziprasidone, and risperidone, atypical antipsychotics, pimavanserin (standardized mean differences [SMD], –4.81; 95% CI, –5.39 to –4.24) and clozapine (SMD, –4.25; 95% CI, –5.24 to –3.26) showed significant ability to improve symptoms relative to placebo.

Led by Ismaeel Yunusa, PharmD, PhD, assistant professor, Department of Clinical Pharmacy, University of South Carolina, pimavanserin continued to significantly improve psychotic symptoms, as indicated by scores on Scale for Assessment of Positive Symptoms for Parkinson’s Disease Psychosis/Hallucinations and Delusions. Using the Unified Parkinson’s Disease Rating Scale, study findings showed that clozapine (SMD, –0.69; 95% CI, –1.35 to –0.02), pimavanserin (SMD, –0.01; 95% CI, –0.56 to 0.53), and quetiapine (SMD, 0.00; 95% CI, –0.68 to 0.69) did not impair motor function.

SUCRA suggested that clozapine (78%) had the highest probability of being safe in avoiding impairment of motor function. Decline in cognitive function, assessed through the Mini-Mental State Examination, was associated with quetiapine treatment (SMD, 0.60; 95% CI, 0.07-1.14). Although not significant, olanzapine (SMD, 0.28; 95% CI, –0.03 to 0.60) and ziprasidone (SMD, 0.18; 95% CI, –0.95 to 1.31) also reported higher MMSE scores indicating worsened cognitive function compared with placebo.

When compared with clozapine, quetiapine (SMD, 0.77; 95% CI, 0.12-1.42) significantly worsened cognitive function. Notably, clozapine had the highest probability of being safe in avoiding cognitive impairment on surface under the cumulative ranking curve (SUCRA). Investigators wrote, "Despite the lack of strong evidence to support the efficacy of quetiapine and its significant risk of clinically meaningful AEs, it is the most used off-label AAP for treating PDP. Based on findings from the current study, quetiapine can induce excessive sleepiness and significantly impair cognition and may need to be avoided in PD patients with sleep problems and severely reduced cognitive ability."

They continued, "With risperidone being the most acceptable AAP in terms of discontinuation due to all causes, the lack of evidence to support its efficacy in improving psychosis and safety on motor function suggested that it is not an ideal option for patients with PDP."

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Compared with placebo, clozapine (OR, 4.64; 95% CI, 1.53-14.01) and quetiapine (OR, 2.38; 95% CI, 0.99-5.73) had higher odds of somnolence. When compared with each other, pimavanserin had numerically lower odds of somnolence than clozapine (OR, 0.23; 95% CI, 0.04-1.53) and quetiapine (OR, 0.46; 95% CI, 0.08-2.63). Olanzapine demonstrated the highest probability (91.8%) of being safe in avoiding somnolence on SUCRA.

In terms of discontinuations due to adverse events (AEs), SUCRA ranking suggested that risperidone (73.8%) was the most acceptable based discontinuation due to any AEs, followed by placebo (71.4%). Cluster ranking of the 5 antipsychotics for CGI-S (efficacy) vs UPDRS (safety) demonstrated that pimavanserin and clozapine were most efficacious and most safe, with pimavanserin having the greatest probability of being efficacious. Olanzapine was the least efficacious, with placebo falling into the same cluster.

REFERENCE
1. Yunusa I, Rashid N, Rajagopalan K, et al. Comparative efficacy, safety, and acceptability of pimavanserin and other atypical antipsychotics for Parkinson’s disease psychosis: systematic review and network meta-analysis. J Geriatr Psychiatry Neurol. Published online January 31, 2023. doi:10.1177/08919887231154933