Comparative efficacy of pharmacological, adjunctive, and non-pharmacological interventions across behavioral domains in children and adolescents with autism spectrum disorder: a network meta-analysis

OBJECTIVE: To systematically compare the efficacy of pharmacological, adjunctive, and non-pharmacological interventions across multiple behavioral domains in children and adolescents with autism spectrum disorder (ASD), including irritability, hyperactivity, social withdrawal, stereotypic behavior, and inappropriate speech. METHODS: Following the 2020 PRISMA guidelines, five databases were searched from inception to March 2026 for randomized controlled trials (RCTs). A frequentist network meta-analysis was conducted to estimate the comparative efficacy and ranking probabilities of different interventions across behavioral domains (PROSPERO: CRD420261368925). RESULTS: Sixty-seven RCTs (N = 4,203) were included. For irritability, structured exercise ranked highest (SUCRA = 88.0%; SMD = - 1.48, 95% CI -2.24 to - 0.73), followed by risperidone plus adjunctive anti-inflammatory agents (SUCRA = 72.9%) and neuromodulatory agents (SUCRA = 67.8%). For hyperactivity, pharmacological interventions were most effective, with other antipsychotic/ADHD medications ranking highest (SUCRA = 95.1%; SMD = - 1.85, 95% CI -2.50 to - 1.20), followed by structured exercise (SUCRA = 76.1%). Similarly, for stereotypic behavior, pharmacological treatments dominated, with other antipsychotic/ADHD medications achieving the best performance (SUCRA = 92.0%; SMD = - 1.10, 95% CI -1.67 to - 0.52). In contrast, for social withdrawal, structured exercise emerged as the most effective intervention (SUCRA = 98.9%; SMD = - 1.28, 95% CI -1.96 to - 0.60), followed by risperidone plus neuromodulatory agents (SUCRA = 75.3%). For inappropriate speech, structured exercise (SUCRA = 80.1%) and probiotics plus oxytocin (SUCRA = 76.4%) demonstrated the highest rankings, with structured exercise showing a significant effect (SMD = - 0.80, 95% CI -1.40 to - 0.19). CONCLUSION: This study establishes a domain-specific treatment hierarchy for ASD, demonstrating that intervention effects vary substantially across behavioral domains. Pharmacological approaches are more effective for hyperactivity and stereotypic behaviors, whereas structured exercise shows superior benefits for irritability and social withdrawal. Combination strategies consistently rank highly across multiple domains, supporting the value of multimodal interventions. These findings underscore the importance of individualized, symptom-targeted, and mechanism-informed treatment strategies to optimize clinical outcomes in ASD.