Metabolic-Protective Strategies for Antipsychotic-Associated Weight Gain in Children and Adolescents: A Systematic Review.

Second-generation antipsychotics are effective for a range of pediatric psychiatric and behavioral conditions but are commonly associated with weight gain and metabolic dysfunction. Metformin is the most extensively studied pharmacological strategy for preventing or treating this adverse effect; however, the randomized evidence base has evolved substantially with the publication of recent large trials. This study aimed to systematically review and meta-analyze randomized controlled trials of metformin and other metabolic-protective strategies, including topiramate, melatonin, and antipsychotic switching, for preventing or treating antipsychotic-associated weight gain in children and adolescents. PubMed/MEDLINE, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched for records published between January 2000 and June 2026. Randomized controlled trials enrolling participants aged 19 years or younger who were receiving a second-generation antipsychotic were eligible. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analyses using restricted maximum likelihood estimation with the Hartung-Knapp adjustment pooled mean differences and risk ratios when at least two trials contributed comparable data; prevention and treatment indications were analyzed separately. Seven unique randomized controlled trials reported across eight publications met eligibility criteria, including 1,871 participants: five trials evaluated metformin, one evaluated topiramate, and one evaluated melatonin. The pooled effect of metformin on body mass index (BMI) z-score, the primary outcome, favored treatment at all time windows but was not statistically significant (short-term, three trials: mean difference [MD] = -0.093, 95% confidence interval [CI] -0.250 to 0.063; medium-term, two trials: MD = -0.090, 95% CI -0.346 to 0.166; long-term, one trial: MD = -0.07, 95% CI -0.145 to 0.005). Short-term body weight was significantly reduced with metformin (three trials: MD = -2.30 kg, 95% CI -4.28 to -0.32). Metabolic laboratory outcomes were imprecise and inconsistent in direction, and diarrhea was numerically more frequent with metformin. Evidence for topiramate, melatonin, and antipsychotic switching was limited to single trials or trial arms. No included trial was rated as having an overall low risk of bias. Metformin has the largest randomized pediatric evidence base among metabolic-protective strategies and consistently attenuated weight gain compared with control; however, its pooled effect on the primary outcome did not reach statistical significance at any time window, and metabolic benefits could not be confirmed. Decisions regarding metabolic-protective strategies should be individualized rather than universally applied, and larger, longer, standardized pediatric trials are needed.