Risk of extrapyramidal symptoms associated with antipsychotic drugs in children and adolescents: a systematic review and meta-analysis of double-blind randomised placebo-controlled trials

Abstract Background Antipsychotic drugs are increasingly prescribed to children and adolescents (C&A) across a range of neuropsychiatric and neurodevelopmental disorders. Extrapyramidal symptoms (EPS) are well-established adverse effects of antipsychotics in adults, yet evidence in paediatric populations remains limited. This study aimed to quantify the risk of antipsychotic-related EPS in C&A and to explore potential moderating factors. Methods This PRISMA-compliant systematic review and meta-analysis (PROSPERO; CRD42024564227) searched MEDLINE, Embase, and Web of Science from inception until the 6th of January 2026, for double-blind randomised controlled trials (RCTs) comparing antipsychotics with placebo in individuals aged < 18 years. EPS were assessed through either adverse event reporting or predefined thresholds on validated clinical rating scales and harmonised into a dichotomous outcome (presence vs. absence). Data were extracted by three pairs of independent researchers. Random-effects meta-analyses were conducted to estimate pooled risk ratios (RRs), alongside meta-regression and subgroup analyses examining potential moderators. Risk of bias was assessed using Cochrane Rob2. Results Thirty-seven RCTs including 5,128 participants (3,141 receiving antipsychotics, 1,987 receiving placebo) were included. Exposure to antipsychotics was associated with a significantly increased risk of EPS compared with placebo (RR = 2.24, 95% CI = 1.71–2.93, p < 0.0001), corresponding to a number needed to harm of 7 (95% CI = 5–13). The highest risk estimates compared with placebo were observed for ziprasidone (RR = 3.59, 95% CI = 2.03–6.35, k = 3), risperidone (RR = 2.84, 95% CI = 1.89–4.28, k = 11), and aripiprazole (RR = 2.07, 95% CI = 1.12–3.82, k = 9). A higher proportion of female participants was associated with an increased risk of EPS (β = 0.0136, 95% CI = 0.0019–0.0254, p = 0.023), whereas longer treatment duration was associated with reduced risk (β=−0.0349, 95% CI = − 0.0573–−0.0124, p = 0.002). No significant associations were observed for diagnosis, age, ethnicity, antipsychotic exposure, or non-antipsychotic concomitant medication use (all p > 0.05). Conclusions Antipsychotic drugs are associated with EPS in approximately 1 out of 7 C&A with a more than twofold increased risk compared with placebo. The highest risk estimates were observed for ziprasidone, risperidone, and aripiprazole. Careful risk–benefit assessment, tailored prescribing, and systematic monitoring of EPS in routine paediatric clinical practice are warranted.