REVIEW OF: Siskind D et al, Lancet Psychiatry 2025;12:493–503; Patino LR et al, J Affect Disord 2025;382:116–122
STUDY TYPE: Two RCTs

GLP-1 receptor agonists (GLP-1 RAs) have revolutionized obesity treatment. Can they reverse antipsychotic-related weight gain? Two RCTs put this question to the test.

In the first study, Siskind et al ran a 36-week, multi-site trial in Australia involving 31 participants with schizophrenia on clozapine. (Recruitment ended early due to global semaglutide shortages.) Subjects received once-weekly semaglutide (titrated to 2.0 mg) or placebo. The primary endpoint was reduction in body weight. Semaglutide yielded a 13.88% reduction in body weight versus 0.42% in the placebo group, with a large effect size of 1.66. Two-thirds of participants lost at least 10% of their body weight, with no changes in PANSS scores or clozapine concentrations.

In the second study (which was industry funded), Patino and colleagues conducted a 16-week trial where 54 adults with obesity and taking olanzapine for schizophrenia, schizoaffective disorder, or bipolar disorder were randomized to twice-daily exenatide (titrated to 10 mcg BID) or placebo. This study’s primary outcome was also reduction in body weight. Patients on exenatide lost 0.6% of total body weight, while those on placebo gained 2.8%.

Across both studies, psychiatric symptoms remained stable in both the treatment and placebo groups, and GLP-1 RAs were safe, effective, and well tolerated—with diarrhea being the most common side effect.

CARLAT TAKE
Although the semaglutide trial was small and ended early, it was on par with other evidence that 68 weeks of semaglutide for obesity yielded approximately 15% total body weight loss at a dose of 2.4 mg (Wilding JPH et al, N Engl J Med 2021;384:989–1002). Exenatide also prevented weight gain in patients on olanzapine. The studies support recent guidelines from INTEGRATE and Germany that recommend GLP-1 RAs for antipsychotic-induced obesity.