This systematic review and frequentist random-effects network meta-analysis evaluated 39 pharmacological interventions for antipsychotic-induced weight gain in adults with schizophrenia spectrum disorders (SSDs), drawing from 95 RCTs (pooled N = 5,898) identified through searches up to December 2025.
Semaglutide produced the largest weight reduction vs. placebo (MD −10.98 kg; 95% CI −13.33 to −8.62; moderate certainty), followed by liraglutide (−5.43 kg), topiramate (−3.95 kg), metformin (−3.86 kg), and exenatide (−2.97 kg). Clinically meaningful weight loss (≥5%) was observed only with semaglutide and metformin. No major safety signals for GI adverse effects or dropout rates were identified across interventions.
- Full text was under embargo; results are drawn from the abstract only, limiting appraisal of methodological detail. - Individual trial durations varied, and no restriction on study length was applied, which may introduce heterogeneity. - Several interventions (e.g., ramelteon, nizatidine, aripiprazole) had very low certainty evidence, limiting confidence in their effect estimates.
For patients with schizophrenia on antipsychotics who have gained significant weight, semaglutide or metformin offer the strongest evidence for clinically meaningful weight loss (≥5%) and should be considered first-line pharmacological options. Liraglutide, topiramate, and exenatide are reasonable alternatives with moderate-certainty evidence.
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