Risk and management of cancer in clozapine users: A systematic review

Objectives The safety profile of clozapine raises specific questions regarding risk and management of cancer. We aimed to synthesize the information on cancer in clozapine users relevant for clinical practice. Methods Articles were identified with MEDLINE and Web of Sciences from inception through December 2025 (PROSPERO CRD420251247617). We included articles on cancer addressing issues related to risk, diagnosis and treatment of cancer in clozapine users, and management of drug-drug interactions (DDI) and adverse drug reactions. Data were synthesized narratively. Results We identified 73 articles of which most were case reports (n = 41). Long-term clozapine use is associated with a small increased risk of hematological malignancies (HM), but the existence of a causal link, if any, is not yet established. The literature on cancer care is mostly focused on the risk of neutropenia. Initiating myelosuppressive anti-cancer drugs should not lead to clozapine discontinuation, since there is no evidence of any additive interaction, and adequate curative or palliative treatment of cancer may be dramatically impeded by psychotic decompensation. Few studies have investigated other potentially lethal risks associated with clozapine use at all stages of cancer, such as constipation or intoxication due to DDI or cancer-related factors (smoking cessation, weight loss, inflammation, etc.). Conclusions Considering the reduced mortality associated with clozapine use, the very low absolute risk of HM should not discourage its use. Further studies are needed to determine the most effective strategies for preventing, diagnosing, and treating cancer in clozapine users, in order to provide clinicians with structured guidelines.