Abstract
INTRODUCTION: We aimed to synthesize the information relevant for clinical practice on involuntary clozapine treatment. METHODS: Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through September 2025 (PROSPERO database registration CRD420251234475). We included all articles addressing issues related to involuntary clozapine treatment irrespective of the route of administration, i.e., oral, intra-muscular (IM) or nasogastric. Data were synthesized narratively. RESULTS: Of the 29 identified articles, most clinical studies (n = 18) on people prescribed involuntary clozapine treatment (n = 236) were case reports/series or chart reviews. IM or nasogastric routes were the last-resort treatment for people with extremely severe psychotic disorders presenting with risky behavior. The decisional process was often lengthy due to the complex legal and ethical issues raised by involuntary treatment and restricted access to the unlicensed IM formulation. In nearly half of cases, the oral route was accepted after the decision to perform IM or nasogastric administration. Pain at the injection site was the most frequent adverse event after IM administration. Transition to this route occurred rapidly in the vast majority of the other cases, most often allowing a dramatic reduction in the severity of target symptoms and coercive measures. Clozapine was maintained orally after the acute phase in the majority of people with involuntary administration. CONCLUSIONS: Although the body of evidence supporting the use of involuntary clozapine treatment is mostly drawn from small observational studies, their findings suggest that this last-resort option may save the life and promote recovery of people for whom other treatments have failed. Access to IM clozapine is currently restricted in most countries. Whether this barrier to clozapine treatment for severely ill people with impaired decision-making capacities should be overcome in other countries needs to be further addressed. REGISTRATION: PROSPERO database registration CRD420251234475.