Abstract

Rationale: Individuals with autism spectrum disorder (ASD) exhibit a wide variety of symptoms related to social interaction and behaviour. Atypical antipsychotics have been widely evaluated and prescribed to treat distressing symptoms (e.g. irritability, aggression, obsessions, repetitive behaviours, etc.) in children and adults with ASD. Still, their effects and relative efficacy remain unclear. Objectives: Primary: to assess the comparative benefits of atypical antipsychotics for irritability through network meta-analyses in children and adults with ASD at short-term follow-up. Secondary: to assess the benefits and harms of atypical antipsychotics, compared to placebo or any other atypical antipsychotic, for different symptoms (e.g. aggression, obsessive-compulsive behaviours, inappropriate speech) and side effects (e.g. extrapyramidal symptoms, weight gain, metabolic side effects) in children and adults with ASD at short-, medium- and long-term follow-up. Search methods: We searched CENTRAL, MEDLINE, 10 other databases, and two trial registers, together with reference checking, citation searching and contact with study authors to identify studies for inclusion. The latest search was 3 January 2024. Eligibility criteria: Randomised controlled trials (RCTs) comparing any atypical antipsychotic drug with placebo or another atypical antipsychotic drug for adults and children with a clinical diagnosis of ASD. Outcomes: Critical outcomes included irritability, aggression, weight gain, extrapyramidal side effects, obsessive-compulsive behaviours and inappropriate speech. Risk of bias: We used the Cochrane RoB 2 tool to assess risk of bias in the included studies. Synthesis methods: We performed statistical analyses using a frequentist network meta-analysis for combined estimates for the outcome irritability and a random-effects model for pairwise comparisons for other outcomes. We rated the certainty of the evidence using GRADE. Included studies: We included 17 studies with 1027 randomised participants. One study evaluated adults (31 participants); the remaining 16 studies evaluated children (996 participants). The interventions were risperidone, aripiprazole, lurasidone and olanzapine. Synthesis of results: Comparative efficacy on irritability. Based on the network meta-analysis, risperidone and aripiprazole may reduce symptoms of irritability compared to placebo in the short term in children with ASD (risperidone: mean difference (MD) −7.89, 95% confidence interval (CI) −9.37 to −6.42; 13 studies, 906 participants; low-certainty evidence; aripiprazole: MD −6.26, 95% CI −7.62 to −4.91; 13 studies, 906 participants; low-certainty evidence). Lurasidone probably results in little to no difference in irritability compared to placebo in the short term (MD −1.30, 95% CI −5.46 to 2.86; 13 studies, 906 participants; moderate-certainty evidence). Efficacy and safety on other outcomes. We are very uncertain about the effects of atypical antipsy