Antipsychotics are effective but can also lead to weight gain, impacting treatment adherence

Semaglutide reduced body weight by more than 24 pounds compared with placebo in antipsychotic-treated patients with schizophrenia spectrum disorders, the largest reduction among 39 pharmacological interventions evaluated in a new systematic review and network meta-analysis. Mahavir Agarwal, M.D., Ph.D., a psychiatrist and scientist in the Schizophrenia Division at the Centre for Addiction and Mental Health (CAMH) in Toronto and an associate professor in the Department of Psychiatry at the University of Toronto, was a co-author of the study, ‘Pharmacological Interventions for Weight Reduction in Patients With Schizophrenia Treated With Antipsychotics: A Systematic Review and Network Meta-Analysis.’ It was published July 8, 2026, in JAMA Psychiatry.

In this video, Agarwal walks through the biological mechanisms researchers believe are responsible: disrupted appetite and fullness signaling, insulin release from the pancreas that produces hyperinsulinemia and interference with neurohormonal appetite control in the brain.

The review pooled 95 randomized controlled trials and approximately 5,900 patients, searching literature through December 2025. Beyond semaglutide, liraglutide, topiramate, metformin and exenatide were also associated with meaningful weight reductions and were backed by moderate-certainty evidence, with liraglutide cutting weight by about 12 pounds, topiramate by about 8.7 pounds, metformin by about 8.5 pounds, and exenatide by about 6.5 pounds compared with placebo. Only semaglutide and metformin produced weight loss that crossed the 5% threshold generally considered clinically meaningful.

Agarwal, who holds the Tier 2 Canada Research Chair in Metabolic and Cognitive Health in Mental Illness and co-leads CAMH's Metabolic Clinic and Clozapine Clinic, has focused much of his research on why antipsychotics drive this kind of weight gain in the first place.

Those mechanisms, Agarwal said, are still not fully mapped out. "I wish we knew more about the mechanisms,” he said. "We don't fully understand them yet."