Clozapine for Severe Treatment-Resistant Disruptive Behaviors in Youth with Autism Spectrum Disorder: A Prospective Real-World Interventional Study

Objective: Severe disruptive behaviors in youth with autism spectrum disorder (ASD) frequently persist despite conventional treatments, contributing to functional impairment. Although clozapine has antiaggressive properties, evidence guiding its use in treatment-resistant cases in autistic youth remains predominantly observational and retrospective. This study aimed to evaluate systematically and prospectively the effectiveness and safety of clozapine for treatment-resistant disruptive behaviors (TR-DB) in youth with ASD under routine conditions. Methods: This single-arm, open-label trial enrolled participants aged 10–17 with ASD. Inclusion required TR-DB after ≥2 antipsychotic trials and a Clinical Global Impression–Severity score ≥5. Following flexible titration, clozapine was maintained for 12 weeks. The primary outcome was change on the caregiver-rated Aberrant Behavior Checklist–Irritability (ABC-I). Secondary measures included global improvement, autism symptom severity, adaptive behavior, and caregiver quality of life. Response was defined as ≥30% ABC-I reduction plus a CGI–Improvement (CGI-I) of 1 to 2; remission required ≥80% ABC-I reduction and a CGI-I of 1. Results: Thirty-one participants initiated clozapine treatment (mean age 13.4 years; 90.3% male), and 28 completed the trial. ABC-I scores decreased from 32.0 ± 7.7 to 7.4 ± 5.1 (Cohen’s d z −2.5; p < 0.001). Overall, 83.9% responded, and 38.7% remitted. Global severity improved from 6.1 ± 0.6 to 3.8 ± 1.6 ( p < 0.001). Significant improvements were observed in daily living skills, caregiver quality of life, and reduced polypharmacy. Adverse drug reactions were mostly mild-to-moderate; however, metabolic changes comprised significant weight gain and triglyceride elevation (both p < 0.05). Serious events included seizures ( n = 4) and pneumonia ( n = 1). Conclusions: Clozapine was associated with robust, rapid TR-DB reductions and high retention in autistic youth. However, safety risks mandate rigorous monitoring. Controlled trials are needed to confirm efficacy and refine the benefit–risk profile.