Antipsychotic-Induced Weight Gain in Children and Adolescents: Comparative Efficacy of Metformin, Topiramate, and Behavioral Intervention

Abstract

Introduction: Second-generation antipsychotics (SGAs) cause rapid weight gain in youth, increasing cardiometabolic risk. Adjunctive metformin, topiramate, or lifestyle interventions are used off-label, but comparative effectiveness is unknown.

Methods: Systematic review and network meta-analysis of RCTs (≥12 weeks) of adjunctive interventions for SGA-induced weight gain in children and adolescents (5–18 years) on stable SGA dose. Primary outcome: body mass index (BMI) z-score change from baseline. Interventions: metformin (500–2000 mg/day), topiramate (50–200 mg/day), behavioral nutrition/exercise, placebo. Databases: PubMed, Embase, CENTRAL.

Results: Fourteen RCTs (n=1,106 youth; 68% male, mean age 13.2 years) were included. Metformin produced the largest BMI z-score reduction (mean difference –0.22, 95% CI –0.31 to –0.13 vs. placebo), followed by topiramate (–0.16, –0.26 to –0.06), then behavioral intervention (–0.08, –0.15 to –0.01). Metformin was superior to topiramate (p=0.04) and behavioral (p<0.001). Gastrointestinal adverse events (nausea, diarrhea) occurred in 28% on metformin vs. 8% placebo. Topiramate caused paresthesias (15%) and cognitive dulling (12%), leading to higher dropout (19% vs. 9% metformin).

Discussion: Metformin is most effective for countering SGA-induced weight gain in youth, with a number needed to treat of 5 to prevent 0.2 BMI z-score increase. Topiramate is effective but less tolerated. Behavioral intervention alone has minimal effect. Limitations: short trials (max 24 weeks), no data on long-term cardiometabolic outcomes.

Conclusions: Metformin should be first-line adjunctive treatment for clinically significant SGA-induced weight gain (>0.5 BMI z-score increase) in children and adolescents. Topiramate reserved for metformin intolerance or non-response.