Antipsychotic weight gain: five drugs with moderate-certainty evidence, metformin the best studied

Design

Systematic review and frequentist network meta-analysis of 95 randomised trials

Population

5,898 people with schizophrenia-spectrum disorders taking antipsychotics

Primary outcome

Change in body weight vs placebo or standard care

Effect

Semaglutide −10.98 kg (95% CI −13.33 to −8.62); metformin −3.86 kg (−5.02 to −2.70)

A systematic review and network meta-analysis in JAMA Psychiatry (1 September 2026) pooled 95 randomised trials of 39 drugs given to reduce weight in people with schizophrenia-spectrum disorders taking antipsychotics, a total of 5,898 participants.

Against placebo, five drugs reduced weight with moderate-certainty evidence: semaglutide (mean difference −10.98 kg, three trials), liraglutide (−5.43 kg, two trials), topiramate (−3.95 kg, five trials), metformin (−3.86 kg, 16 trials) and exenatide (−2.97 kg, three trials). Weight loss of 5% or more, the usual threshold for clinical benefit, was seen with semaglutide and metformin. Ramelteon, nizatidine and adjunctive aripiprazole showed effects with very low certainty. Dropout and gastrointestinal effects raised no major concern.

The semaglutide estimate is large but rests on three trials; metformin has the depth of evidence. Neither is a reason to avoid addressing the antipsychotic itself.

For most patients, metformin is the drug to reach for first when weight climbs on an antipsychotic: cheap, familiar, widely available in India, and supported by the most trials. A GLP-1 receptor agonist is the stronger option where weight gain is marked or diabetes is present and cost and supply allow.

• Consider metformin when a patient gains weight on an antipsychotic; it has the most trial support.
• Consider a GLP-1 receptor agonist such as semaglutide for marked weight gain or coexisting diabetes, where cost allows.
• Topiramate is an option with moderate-certainty evidence; check for cognitive and mood side-effects.
• Review whether a lower-liability antipsychotic is possible before adding a weight drug.
• Re-weigh at three months after starting any weight drug to judge whether it is working.

Why it matters

It turns weight gain from something to warn about into something to treat, with a ranked list of options.

Don't overread it

The semaglutide estimate comes from only three trials, so its size is less certain than metformin's.

The statistics, in plain English

Mean differences are average kilograms lost compared with placebo. A network meta-analysis lets drugs be compared even when they were never tested head to head, but rankings drawn from two or three trials are less stable than those from sixteen. Moderate certainty means the true effect is probably close to the estimate but could differ substantially.

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