Research square · 2026
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.
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Galvañ Joaquín, Distefano Giacomo, Echeverria Iván, Aymerich Clàudia, Abregú-Crespo Renzo, Lorente Marién Martín Argila, Cruz Nadia, López-Larriba Laura, Moreno Dolores, Parellada Mara, Arango Celso, Pablo Gonzalo Salazar, Díaz-Caneja Covadonga M
Аннотация
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.
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.