Risk of Agranulocytosis and Neutropenia in Patients With Parkinson's Disease Psychosis Receiving Clozapine Treatment: A Systematic Review and Meta-Analysis

Background Clozapine is one of the most effective therapies for managing Parkinson's disease psychosis (PDP). However, its use is complicated by the risk of agranulocytosis, a potentially fatal condition. Aims & Objectives This study aims to evaluate the cumulative incidence of severe neutropenia/agranulocytosis (SNA), as well as mild/moderate neutropenia (MMN), in patients with PDP undergoing clozapine treatment. Method A comprehensive search was conducted across various databases from their inception until September 29, 2024. Incidence rates were analyzed over different monitoring periods: short-term (up to 1 month), medium-term (up to 6 months), and long-term (beyond 6 months). A proportional meta-analysis was performed utilizing random-effects and generalized linear mixed models (GLMMs). Results The analysis included 691 PDP patients from 19 studies, comprising 8 retrospective studies, 7 open-label studies, and 4 randomized controlled trials. In short-term monitoring phase, none of 573 participants (N) from 16 studies (k) developed SNA. The pooled incidence of SNA was found to be 0.001 (95% confidence intervals [CIs]: 0.000-0.253, N = 525, k = 15) during medium-term period and 0.002 (95% CI: 0.000-0.015, N = 475, k = 12) in long-term period. The pooled incidence of MMN was 0.004 (95% CI: 0.000-0.281, N = 164, k = 7) for both short- and medium-term periods, and 0.013 (95% CI: 0.002-0.094, N = 193, k = 7) for long-term period. Funnel plot analysis suggested potential bias in medium-term dataset for SNA (p = 0.035). Discussion & Conclusions The findings indicate that clozapine treatment in patients with PDP is linked to a very low risk of SNA and a low risk of MMN. In this systematic review and meta-analysis, no cases of SNA were reported during short-term monitoring period (≤ 1 month) following clozapine initiation. The cumulative incidence rates for SNA during medium-term (>1 to 6 months) and long-term (> 6 months) monitoring were approximately 0.1% to 0.2%. The occurrence of MMN associated with short- to long-term clozapine treatment ranged from 0.4% to 1.3% in this population.