Design: Systematic review and network meta-analysis of 95 randomised trials
Population: 5,898 people with schizophrenia spectrum disorders on antipsychotics
Primary outcome: Change in body weight vs placebo
Effect: Semaglutide −10.98 kg (−13.33 to −8.62); metformin −3.86 kg (−5.02 to −2.70)

A network meta-analysis pooled 95 randomised trials of 39 drugs for weight loss in 5,898 people with schizophrenia spectrum disorders on antipsychotics. Certainty was graded with CINeMA.

Against placebo, semaglutide gave the largest reduction (−10.98 kg, 95% CI −13.33 to −8.62; 3 trials), then liraglutide (−5.43 kg), topiramate (−3.95 kg), metformin (−3.86 kg, −5.02 to −2.70; 16 trials) and exenatide (−2.97 kg), all at moderate certainty. Only semaglutide and metformin achieved clinically meaningful loss of 5% or more. Dropouts and gastrointestinal effects did not differ importantly between drugs.

This gives a clear ladder. Metformin has by far the most trials and is cheap. Semaglutide has the largest effect but only three trials. Aripiprazole, ramelteon and nizatidine had very low certainty evidence and should not be relied on.

Offer metformin first where weight has risen on an antipsychotic.
Consider semaglutide where metformin is insufficient or not tolerated, and cost allows.
Topiramate is an option but watch for cognitive slowing.
Do not add aripiprazole purely for weight; the evidence is very low certainty.
Pair any drug with dietary and activity support.

Why it matters

Weight gain is often accepted as the price of treatment; there is now a ranked, evidence-based response.

The statistics, in plain English

A mean difference of −11 kg means people on semaglutide lost about 11 kg more than those on placebo. It rests on three trials, so it could shift as more arrive. Metformin's smaller effect is supported by sixteen trials, which makes it the more certain estimate. A network meta-analysis compares drugs indirectly through shared placebo arms, which is weaker than head-to-head trials.