Clozapine for older adults with severe mental illness: a systematic review and expert recommendations for clinical practice

Introduction: We aimed to synthesize the information relevant for clinical practice on the initiation and adaptation of clozapine treatment in new and long-term older adult users with severe mental illness (SMI). Methods: Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through March 2025. The search was restricted to studies including clozapine users with SMI aged ≥50 years. Data were synthesized narratively. Results: We identified 16 studies (14 chart studies, one controlled study, one pharmaco-epidemiological study) including 1244 participants. All observational studies reported a clinical benefit of clozapine, but few used structured assessments. The single controlled study in a small sample did not find clozapine superior to chlorpromazine. No fatal case attributable to clozapine exposure was reported. The increased risks of aspiration pneumonia, constipation, postural hypotension, and falls were identified early by the first chart studies. Most studies included new clozapine users, and none explored the adaptation of clozapine treatment in long-term users reaching old age. Conclusions: Gaps in knowledge are of particular concern for older adults with SMI who are long-term clozapine users. Further studies are required to document how to adapt clozapine treatment to physiological aging or incident comorbidities and co-prescriptions. Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD420251038600.