REVIEW OF: Harris K et al, J Child Adolesc Psychopharmacol 2025;35(6):337–346

STUDY TYPE: Retrospective chart review

Aggression, self-injury, and severe irritability in youth with autism or intellectual disability often leave clinicians searching for treatments when FDA-approved options like risperidone and aripiprazole fall short. Clozapine has a unique antipsychotic profile, but what role—if any—should it play for these patients? This study offers new insight.

This retrospective chart review examined 58 patients (ages 7–31) with autism and/or intellectual disability who were prescribed clozapine between 2012 and 2020 at a single academic center to treat severe aggression and irritability. At the study’s endpoint, 40 remained on clozapine. Data were collected for one year before and after clozapine initiation, focusing on emergency department (ED) visits, hospitalizations, Clinical Global Impression scores (Severity [CGI-S] and Improvement [CGI-I] scales), concomitant medications, and adverse effects. Most patients received clozapine for severe irritability, with doses of 50–850 mg/day and close monitoring for adverse events.

Patients who continued clozapine showed meaningful improvement. ED visits and hospitalizations dropped from 3.48 to 2.13 per year (p = 0.01), and CGI-I scores improved from 3.96 to 2.52 (p < 0.001). There was a nonsignificant trend toward reduced antipsychotic polypharmacy (38.5% to 25%; p = 0.232). CGI-S scores remained unchanged, reflecting persistent overall severity, even as CGI-I showed symptomatic gains. Side effects were common but generally manageable—mainly constipation, drooling, and drowsiness. Surprisingly, there was no statistically significant increase in BMI. Only one patient developed neutropenia, and few stopped due to monitoring demands, aided by strong behavioral support for blood draws. Those who discontinued clozapine typically did so because of side effects or limited benefit, with little change in CGI scores over time.

There were numerous limitations to this study, including the small sample size and uncontrolled, nonrandomized retrospective design; single-site sample; complex medication histories; challenges with directly measuring irritability; and lack of long-term follow-up, all of which make clozapine’s effects harder to isolate.

CARLAT TAKE
Clozapine showed potential benefits for youth with autism or intellectual disability and severe, refractory irritability or aggression. Patients who continued treatment had fewer hospital visits and meaningful symptom improvement. When safer, evidence-based nonpharmacologic and milder medication strategies (central alpha agonists, SSRIs, less problematic antipsychotics) have been exhausted, clozapine may be worth considering—with close monitoring, constipation prevention, and clinically required blood draws.