Semaglutide helps best for antipsychotic weight gain

Clinical takeaway: For patients gaining weight on antipsychotics, GLP-1 receptor agonists like semaglutide may offer the largest reductions, though metformin has the deepest evidence base and lower cost.

Weight gain is one of the most common reasons patients stop taking antipsychotics, and lifestyle changes rarely move it much. GLP-1 receptor agonists have transformed obesity care, but whether that benefit holds when the weight is driven by antipsychotics hasn't been settled. A new network meta-analysis suggests it does. Across 95 randomized trials, semaglutide produced the largest drop of any drug studied.

Semaglutide led by a wide margin. It reduced body weight by about 11 kg (24 lbs) compared with placebo, more than double the next-best agent. That roughly matches its effect in general obesity trials, suggesting the benefit carries into patients whose weight gain is antipsychotic-driven.

Four other agents followed with moderate evidence: liraglutide at 5.4 kg (12 lbs), topiramate at 4.0 kg (9 lbs), metformin at 3.9 kg (9 lbs), and exenatide at 3.0 kg (7 lbs). But only semaglutide and metformin produced clinically meaningful weight loss, defined as 5% or more of body weight. Metformin's advantage is depth of evidence: 16 trials measured its effect on weight, against just three for semaglutide. A few older drugs showed weight loss too, but the evidence was too weak to trust.

Attrition was similar between active drugs and placebo across 53 trials, and no agent showed a clear excess of gastrointestinal side effects.

The review pooled 95 randomized trials of adults with schizophrenia spectrum disorders who had gained weight on antipsychotics, testing 39 drugs against placebo or usual care. Because few trials compared active drugs head to head, the network meta-analysis mostly relied on indirect comparisons through placebo, and most individual drugs were backed by only one or two trials.

Antipsychotic weight gain often comes with weak drug options and lifestyle advice that rarely worked. Now clinicians have agents that produce weight loss that's noticeable to patients. The strongest effects come from the newer, expensive drugs that have not yet been tested in head-to-head trials for this use. Starting with metformin and moving to a GLP-1 if weight gain persists may be the most practical approach for now.

Source: Stogios N, et al. (2026 Jul 8) JAMA Psychiatry. Pharmacological Interventions for Weight Reduction in Patients With Schizophrenia Treated With Antipsychotics: A Systematic Review and Network Meta-Analysis