Clozapine for persons with neurodevelopmental disorders: a systematic review and expert recommendations for clinical practice

Introduction: We aimed to synthesize the information on the risks and benefits of clozapine prescription for resistant challenging behavior in persons with neurodevelopmental disorders. Methods: Articles were identified with MEDLINE, Web of Sciences, and PsycINFO search from inception through January 2024. The review was restricted to persons with intellectual disability (ID) and/or autism spectrum disorder (ASD) without comorbid psychotic or affective disorder. Data were synthesized narratively. Results: We identified 24 articles (13 case reports, eight chart studies, two controlled studies, one pharmaco-epidemiological study) including 296 patients with ID (n = 222) or ASD (n = 74) (10% aged ≤ 18 years). After clozapine initiation, a decreased frequency of challenging behavior persisting over time was reported in most participants included in clinical studies, and a significant reduction in the number of admissions in the population-based two-year mirror-image study. Adverse drug reactions were those commonly observed with clozapine, i.e. constipation, sedation, and weight gain. Conclusions: Since only four participants were included in the controlled studies, the benefits of clozapine in neurodevelopmental disorders are supported by a body of evidence exclusively drawn from observational studies. Further studies are required to clarify the indications of clozapine with respect to the unmet need induced by resistant challenging behavior. Registration: PROSPERO database registration number CRD42024522343.