Semaglutide beats the old standbys, but access and evidence gaps remain
STUDY: Stogios N et al, JAMA Psychiatry 2026
STUDY TYPE: Systematic review and network meta-analysis
FUNDING: Academic Scholars Awards (University of Toronto), CAMH Discovery Fund, Danish Diabetes Academy, UK National Institute for Health Research
Background
Weight gain is one of the most common reasons patients stop antipsychotics, and the metabolic risks that go along with it add to morbidity. Metformin has long been the default add-on, but with newer GLP-1 receptor agonists like semaglutide, it’s a good time to reanalyze the trials.
The Study
- Pooled data from 95 randomized trials (5,898 patients) testing 39 drugs against placebo or usual care for antipsychotic-related weight gain.
- Compared weight change, metabolic markers, and dropout rates across agents using a network meta-analysis.
- Most trials ran under 24 weeks.
Results
Semaglutide produced the largest weight loss, nearly 11 kg more than placebo. Liraglutide (about 5.4 kg), topiramate (about 4 kg), metformin (about 3.9 kg), and exenatide (about 3 kg) also beat placebo, all with moderate-certainty evidence.
Semaglutide and metformin were the only drugs that got a meaningful share of patients to lose 5% or more of their body weight, with metformin quadrupling the odds and semaglutide doing far better still, though based on just one trial. Aripiprazole, ramelteon, and nizatidine showed weight loss signals too, but the evidence behind them was very low certainty.
Side Effects
No drug showed more dropouts or gastrointestinal side effects than placebo. In practice, most of these cause side effects, but patients are likely to stick with them toward the goal of weight loss.
Limitations
The comparisons in this analysis are indirect, based on separate placebo-controlled trials. The trials are few and small, and follow-up beyond six months was rare.
Practice Implications
- If your patient needs an add-on for antipsychotic weight gain, semaglutide has the strongest effect size, but cost and access will often push you toward metformin first.
- Metformin also improves insulin sensitivity, triglycerides, and possibly prolactin. It works best when started early, before weight gain is out of control. Fun fact: It is the most studied medication for potential anti-aging properties.
- Reserve topiramate for patients who can tolerate its cognitive effects (that improves by starting 25 mg and raise by 25 mg per week toward 100-200 mg qhs),
- Check a baseline weight, waist circumference, and metabolic panel before starting any of these, then recheck after around 3 months.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
