• Clozapine’s immune-modulating effects may increase infection vulnerability. • Clozapine exposure is associated with more severe clinical presentations of COVID-19 • Clozapine exposure was associated with higher SARS-CoV-2 infection risk (OR = 1.53). • High heterogeneity (I² = 91.2%) suggests variability across study populations. 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.
Sagués et al. (Sun,) studied this question.