Clozapine use and COVID-19 risk: A systematic review, meta-analysis, and retrospective cohort evidence

Clozapine's immune-modulating effects, including neutropenia and suppression of adaptive immunity, have raised concerns about its potential impact on SARS-CoV-2 infection risk and COVID-19 severity in individuals with treatment-resistant schizophrenia. Findings in the literature remain inconsistent.

First, we conducted a longitudinal retrospective study in which we analysed 995 outpatients with severe mental disorders receiving antipsychotic treatment to assess the association between clozapine use and SARS-CoV-2 infection and disease severity. Secondly, we performed a systematic review of the literature and searched for studies published up to July 2025 examining the link between clozapine exposure and SARS-CoV-2 infection. Eight cohort studies plus our dataset were meta-analysed using a random-effects model.

In our cohort, clozapine users demonstrated a higher rate of SARS-CoV-2 infection (18% vs. 10%, p < 0.001) and increased COVID-19 severity compared to non-users. The meta-analysis comprised 155,945 participants, with individual study ORs ranging from 0.40 to 2.80. The pooled random-effects OR was 1.53 (95% CI: 1.02-2.30, p = 0.044), indicating a significant association between clozapine exposure and increased infection risk. However, high heterogeneity (I² = 91.2%) suggests variation in effects across studies.

Clozapine treatment is associated with an increased risk and severity of SARS-CoV-2 infection. Although meta-analytic results support this association, substantial heterogeneity in pooled estimates highlights the need for further research to clarify underlying clinical and methodological factors influencing risk.