Clozapine for Severe Treatment-Resistant Disruptive Behaviors in Youth with Autism Spectrum Disorder: A Prospective Real-World Interventional Study.
TL;DR
Clozapine was associated with robust, rapid TR-DB reductions and high retention in autistic youth, however, safety risks mandate rigorous monitoring.
Abstract
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 dz -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.