Semaglutide for Weight Management in Clozapine-Treated Schizophrenia: Results from the COaST Phase 2 RCT in Australia

Highlights

• Semaglutide resulted in a clinically significant 13.9% reduction in body weight over 36 weeks compared to placebo in people with schizophrenia and obesity treated with clozapine.
• No adverse effect on psychotic symptoms or clozapine/norclozapine levels was observed.
• Semaglutide was well tolerated, with no serious treatment-related adverse events.
• Findings support the need for larger trials to confirm efficacy and safety in this high-risk population.

Study Background and Disease Burden

People with schizophrenia face a profound reduction in life expectancy—estimated at 16–20 years—primarily attributed to increased cardiometabolic disease risk. Clozapine remains the gold standard for treatment-resistant schizophrenia, yet is notoriously associated with substantial weight gain, insulin resistance, and metabolic syndrome. These adverse metabolic effects represent a critical unmet clinical need, as they drive heightened morbidity and mortality, compounding the already significant health disparities in this patient group.

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide have demonstrated robust weight loss and glycemic benefits in the general population and in those with type 2 diabetes, their safety and efficacy profile in people with schizophrenia—particularly those on clozapine—remains unestablished. The COaST trial directly addresses this gap, evaluating whether semaglutide can safely provide weight reduction in this uniquely vulnerable cohort.

Study Design

The COaST (Clozapine Obesity and Semaglutide Trial) study was a multicentre, randomized, double-blind, placebo-controlled, phase 2 trial conducted across six Australian sites. The trial was independent of pharmaceutical industry support and incorporated input from individuals with lived experience of schizophrenia.

Eligibility criteria included adults (18–64 years) diagnosed with schizophrenia or schizoaffective disorder, prescribed clozapine for at least 18 weeks, and with a BMI ≥26 kg/m², but with relatively stable recent weight (less than 5% change in the previous three months). Participants were randomized 1:1 to receive either semaglutide (titrated to 2.0 mg once weekly subcutaneously) or matching placebo for 36 weeks. Randomization and allocation were blinded to both participants and investigators.

The primary endpoint was percentage change in body weight from baseline to week 36, analyzed using a mixed model for repeated measures. Key secondary endpoints included changes in clozapine and norclozapine serum concentrations and changes in psychosis symptoms as assessed by the Positive and Negative Syndrome Scale (PANSS).

Key Findings

A total of 166 individuals were screened, with 31 ultimately randomized (15 to semaglutide, 16 to placebo). The mean participant age was 38.9 years (range 21–58), and the majority were White (84%), with smaller representation from other ethnic groups. Recruitment was halted early due to non-availability of the investigational product, short of the intended 80 participants.

At week 36, the mean percentage body weight reduction in the semaglutide group was 13.88% (SE 0.90), compared to 0.42% (SE 0.93) in the placebo group. The between-group difference was –13.46% (p<0.0001), a magnitude that is both statistically and clinically substantial. This result aligns with, and in some respects exceeds, weight loss observed with semaglutide in non-psychiatric populations.

Importantly, there were no observed differences between groups in clozapine or norclozapine concentrations, indicating that semaglutide does not alter clozapine metabolism or exposure. Additionally, no difference in psychotic symptomatology (PANSS scores) was detected, suggesting that semaglutide does not exacerbate or improve psychiatric status in this setting.

Safety data were reassuring. Semaglutide was well tolerated, with no serious adverse events attributed to treatment. Constipation, a common side effect of both clozapine and GLP-1 RAs, was infrequent. No treatment-emergent psychiatric instability or suicidality was reported.

Outcome	Semaglutide	Placebo	Difference	p-value
Body weight change (%)	–13.88 (SE 0.90)	–0.42 (SE 0.93)	–13.46	<0.0001
Clozapine level change	No significant change	No significant change	NS	—
PANSS score change	No significant change	No significant change	NS	—
Serious adverse events	None related	None	—	—

Expert Commentary

The COaST trial provides the first high-quality, controlled evidence supporting the use of semaglutide for weight management in people with schizophrenia on clozapine—an area of enormous unmet clinical need. The magnitude of weight loss is noteworthy, especially given the profound metabolic challenges associated with clozapine and the difficulty of achieving weight reduction in this population using conventional lifestyle or pharmacological approaches.

The absence of adverse effects on psychotic symptoms or clozapine pharmacokinetics is particularly reassuring, addressing key concerns that have limited the use of weight-lowering agents in severe mental illness. This is consistent with the pharmacological profile of GLP-1 RAs, which do not cross the blood-brain barrier in significant amounts or impact dopamine pathways.

Limitations include the small sample size and early termination of recruitment, which may limit statistical power for detecting rare adverse events or subgroup effects. The generalizability is also somewhat restricted by the predominantly White sample and the exclusion of those with recent significant weight fluctuation. Nonetheless, the robust methodology, blinding, and use of real-world, clozapine-treated participants enhance external validity.

From a mechanistic perspective, GLP-1 RAs modulate satiety and energy balance through effects on the gut-brain axis, and mounting evidence suggests potential benefits for cardiometabolic health beyond weight loss, including glycemic control, blood pressure reduction, and anti-inflammatory actions. These properties are highly relevant for the schizophrenia population, who are at elevated risk for diabetes, dyslipidemia, and cardiovascular disease.

Current guidelines for the management of antipsychotic-induced weight gain (e.g., from NICE, APA) recommend non-pharmacological interventions as first-line, but acknowledge limited efficacy, especially in the context of clozapine. Pharmacotherapies such as metformin and topiramate have modest and inconsistent effects. The COaST results, if replicated in larger studies, could prompt inclusion of GLP-1 RAs in future guideline recommendations for this high-risk subgroup.

Conclusion

Semaglutide, administered once weekly, yielded substantial weight loss without adverse impact on psychiatric stability or clozapine levels in adults with schizophrenia and obesity on clozapine. The drug was well tolerated with a favorable safety profile. These findings provide a strong rationale for larger, definitive trials to confirm effectiveness, evaluate long-term cardiometabolic outcomes, and guide clinical practice. Given the disproportionate burden of premature mortality in this population, safe and effective interventions for antipsychotic-induced obesity should be considered a public health priority.

References

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