Efficacy and Safety of Second‐Generation Antipsychotics for Irritability Associated With Autism Spectrum Disorder: A Systematic Review and Network Meta‐Analysis

ABSTRACT Objective To assess, by a systematic review and network meta‐analysis, the comparative efficacy and safety of second‐generation antipsychotics in managing aggressive behavior associated with autism spectrum disorder in children and adults. Methods Searches were conducted in MEDLINE, Embase, CENTRAL, PsycINFO, LILACS, CINAHL, trial registries, and grey literature from database inception to July 2025. Randomized controlled trials comparing second‐generation antipsychotics with placebo or other antipsychotics in individuals with autism were included. Outcomes were irritability (Aberrant Behavior Checklist–Irritability subscale—ABC‐I), global clinical impression (CGI), treatment discontinuation, and central nervous system–related adverse events. Data extraction and risk‐of‐bias assessment (RoB 2.0) were performed independently. Certainty of evidence was evaluated using CINeMA. Frequentist random‐effects network meta‐analyses reported mean differences (MD) or relative risks (RR) with 95% confidence intervals (CI). Incoherence and small‐study effects were assessed. Results Fourteen trials including 1195 children with autism were analyzed; no studies involved adults. Aripiprazole at low (MD: −5.83; 95% CI: −8.63, −3.02), recommended (MD: −5.69; 95% CI: −7.34, −4.04), and high doses (MD: −6.91; 95% CI: −10.04, −3.77), and recommended‐dose risperidone (MD: −6.91; 95% CI: −9.52, −4.31) reduced irritability versus placebo; lurasidone showed no benefit. No significant differences were observed for CGI. Recommended‐dose aripiprazole (RR: 0.57; 95% CI: 0.36, 0.90) and risperidone (RR: 0.29; 95% CI: 0.10, 0.83) lowered discontinuation risk. Both drugs increased sedation, drowsiness, and tremor. Evidence certainty ranged from very low to moderate. Head‐to‐head comparisons were inconclusive, and evidence was limited by the absence of adult studies and the small number of trials for some comparisons. Conclusions Risperidone and aripiprazole reduce irritability in pediatric autism but increase sedation, drowsiness, and tremor. No robust differences between active treatments were identified. PROSPERO Registration: 42022353795