Effectiveness of clozapine as a transdiagnostic treatment for aggression: a systematic review

Clozapine has been used for treatment-resistant aggression across a range of psychiatric diagnoses. We aimed to comprehensively review the effectiveness of clozapine in the management of aggression. We searched PubMed, Web of Science, Cochrane Library, PsycINFO, and MEDLINE up to 8 June 2025. Full-text articles examining the effects of clozapine on aggression and violence in psychotic and non-psychotic disorders were included. In total, 75 papers were included; 49 papers focused on patients with schizophrenia and consisted of randomised controlled trials (n = 9), registry studies (n = 3), prospective pre-post studies (n = 8), prospective comparative studies (n = 6), retrospective studies (n = 21), and case series (n = 2). The remaining 26 papers primarily consisted of case series and focused on patients with non-psychotic disorders, including autism spectrum disorder (n = 4), conduct disorder (n = 3), intellectual disability (n = 5), personality disorders (n = 6), dementia (n = 6), and mixed diagnoses (n = 2). All studies showed reductions in violence and aggression associated with clozapine, particularly in treatment-resistant cases. Clozapine may also offer benefits in selected non-psychotic conditions. Further research is needed to clarify the role of clozapine as a transdiagnostic treatment for aggressive behaviour associated with mental illness.