Semaglutide achieves 13.9% weight loss in schizophrenia patients on clozapine without worsening psychosis | Research

The takeaway

In the COaST RCT, semaglutide produced 13.88% weight loss vs 0.42% placebo (p<0.0001) over 36 weeks in clozapine-treated schizophrenia patients, without affecting psychotic symptoms or clozapine levels.

-13.88% weight loss
Semaglutide produced dramatic weight reduction in clozapine-treated schizophrenia patients without worsening psychosis—first RCT in this population

What the researchers found

Semaglutide: -13.88% weight vs placebo -0.42% (difference -13.46%, p<0.0001). No change in clozapine/norclozapine levels. No change in PANSS psychosis scores. No treatment-related SAEs. Low constipation rates. 31 patients (15 sema, 16 placebo).

Why it matters

Clozapine users have the worst metabolic profiles of all psychiatric patients, contributing to 16-20 year shorter life expectancy. This trial shows semaglutide can produce dramatic weight loss in this population without psychiatric risks—a potential life-saving intervention.

How the study worked

Phase 2 multi-site Australian RCT (COaST). Double-blind, placebo-controlled. 31 adults with schizophrenia on clozapine ≥18 weeks, BMI ≥26. Semaglutide titrated to 2.0 mg SC weekly for 36 weeks.

What this study cannot tell us

Very small sample (31 vs planned 80) due to supply issues. Phase 2 trial. Short follow-up. Predominantly White sample. Single-country. Recruitment challenges suggest real-world feasibility concerns.

How to read the evidence

Phase 2 RCT—highest quality design but small sample. Remarkably large effect size strengthens confidence despite n=31.

When this study was published

Published in 2025; ACTRN12621001539820.

The bigger picture

This trial addresses one of psychiatry's biggest unmet needs: the metabolic consequences of antipsychotic treatment that contribute to premature death. If confirmed in larger trials, semaglutide could become standard co-prescription with clozapine.

Questions still open

Will larger trials confirm these dramatic results?
Should semaglutide be co-prescribed with clozapine from initiation?
Does the weight loss translate to reduced cardiovascular events in this population?

Common questions

Can people with schizophrenia safely take semaglutide?

This trial suggests yes. Semaglutide did not worsen psychotic symptoms, change clozapine blood levels, or cause any treatment-related serious side effects in 15 patients over 36 weeks. It produced dramatic weight loss (nearly 14%) in a population that typically gains significant weight from clozapine.

Why is weight loss so important for people on clozapine?

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it causes severe weight gain and metabolic problems that contribute to a 16-20 year shorter life expectancy. Finding a way to manage this weight gain without compromising mental health treatment could literally save years of life.

Read the original research

Efficacy and safety of semaglutide versus placebo for people with schizophrenia on clozapine with obesity (COaST): a phase 2, multi-centre, participant and investigator- blinded, randomised controlled trial in Australia.

The lancet. Psychiatry, 12(7), 493-503

View on PubMed ↗Publisher’s paper ↗

Citation

Siskind, Dan; Baker, Andrea; Arnautovska, Urska; Warren, Nicola; Russell, Anthony; DeMonte, Veronica; Halstead, Sean; Iyer, Ravi; Korman, Nicole; McKeon, Gemma; Medland, Sarah; Parker, Stephen; Stedman, Terry; Trott, Mike. (2025). Efficacy and safety of semaglutide versus placebo for people with schizophrenia on clozapine with obesity (COaST): a phase 2, multi-centre, participant and investigator- blinded, randomised controlled trial in Australia.. The lancet. Psychiatry, 12(7), 493-503. https://doi.org/10.1016/S2215-0366(25)00129-4