Risk factors for sudden cardiac death or sudden unexplained death in patients treated with clozapine: systematic review

BACKGROUND: Clozapine is the gold-standard treatment for treatment-resistant schizophrenia but carries serious cardiac risks, including sudden cardiac death (SCD). Specific risk factors for SCD in clozapine-treated patients remain poorly defined. AIMS: To systematically identify and synthesise evidence on risk factors for SCD and sudden unexplained death (SUD) in clozapine-treated patients, to guide clinical monitoring. METHOD: We conducted a systematic review following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (PROSPERO, no. CRD420250646384). Five databases were searched from inception to 13 October 2025. Studies reporting SCD or SUD in clozapine-treated patients were included without restrictions on study design, demographics or diagnosis. Two reviewers independently screened studies and extracted data. Quality was assessed using Joanna Briggs Institute checklists and Risk Of Bias In Non-randomised Studies of Exposures tools. Given study heterogeneity, we performed structured narrative synthesis. RESULTS: Twenty-one studies (1989-2023) were included, comprising 498 cases of SCD/SUD in clozapine-treated patients. Risk factors were grouped into four categories: treatment intensity (high doses (≥525 mg/day), rapid titration), drug interactions (valproate, benzodiazepines, polypharmacy), lifestyle factors (smoking, obesity, diabetes, substance use) and monitoring. Two patterns emerged: early inflammatory myocarditis (weeks 2-6) and late-onset cardiomyopathy (months-years). CONCLUSIONS: Clozapine-associated SCD appears multifactorial. These findings suggest a role for gradual titration, avoidance of high-risk co-medications, baseline biomarker monitoring and ongoing management of metabolic and cardiovascular risk factors. Increased multidisciplinary surveillance may help identify patients at higher risk and inform clinical decision-making in clozapine-treated patients.