Thirty-five drugs later, FDA-approved options still come out on top
STUDY: Wang Z et al, Journal of Psychopharmacology 2026
STUDY TYPE: Systematic review and network meta-analysis (43 randomized controlled trials)
FUNDING: Independent
Background
Irritability in autism comes with physical aggression, tantrums, and self-injury. Only risperidone and aripiprazole are FDA-approved for it, but dozens of other agents have been tested. This review ranked them.
The Study
- 43 randomized trials, 2,711 children and teens with autism and marked irritability; 26 trials came from Iran.
- 17 trials tested a medication alone; 26 tested add-ons to risperidone, mostly over 8 to 12 weeks.
- Outcome: Irritability scale (ABC-I, scored 0 to 45), where a 3.4-point drop counts as meaningful.
Results
Across all meds, irritability scores fell 3.4 points more than placebo. Children under 12 responded better than teens.
Risperidone ranked highest for efficacy (8.8 points better than placebo), followed by aripiprazole (5.5 points). Lurasidone, omega-3, and vitamin D trailed.
Among add-ons to risperidone, topiramate ranked first (7.6 points beyond risperidone alone), followed by prednisolone and pentoxifylline. Ginkgo, buspirone, and metformin didn’t help.
Side Effects
Medication added about 8 adverse events per 100 children, mostly increased appetite, sleepiness, and stomach upset. No severe events were reported.
Limitations
- Most comparisons were indirect, with low or very low confidence.
- Most trials were small, and 19 had a high risk of bias.
- Aripiprazole’s advantage faded when trials with missing data were excluded.
Practice Implications
- Although risperidone rises to the top in this analysis, I’d start with aripiprazole for its greater tolerability when using an antipsychotic, and reserve antipsychotics for severe cases where physical danger, major consequences, or need for hospitalization is imminent.
- Topiramate is a reasonable add-on, though watch for cognitive side effects.
- Cariprazine also has data, from a trial that came out after this analysis.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
