Effects of Semaglutide on Body Weight in Clozapine-Treated Individuals with Schizophrenia and Obesity: A Randomized Controlled Trial
D. Siskind, M. Trott, U. ArnautovskaIntroduction
People with schizophrenia have a markedly reduced life expectancy, largely due to cardiometabolic disease. Clozapine, the most effective antipsychotic for treatment-resistant schizophrenia, carries the highest risk of weight gain and metabolic dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, have demonstrated substantial weight loss in the general population, but their efficacy and safety in people with schizophrenia remain unknown.
Objectives
This study aimed to evaluate the efficacy and safety of semaglutide for weight reduction in individuals with schizophrenia treated with clozapine.
Methods
The COaST trial was a phase 2, multi-centre, randomised, placebo-controlled, participant and assessor-blinded trial conducted across six Australian sites. Adults (≥18 years) with schizophrenia or schizoaffective disorder, BMI ≥26 kg/m², and on clozapine for ≥18 weeks were randomised 1:1 to receive once-weekly subcutaneous semaglutide (titrated to 2.0 mg) or placebo for 36 weeks. The primary outcome was percentage body weight change. Secondary outcomes included BMI, metabolic parameters, psychosis symptoms (PANSS), and clozapine/norclozapine levels. Adverse events were systematically recorded.
Results
A total of 31 participants were randomised (semaglutide n=15; placebo n=16). At 36 weeks, semaglutide resulted in a mean 13.88% (SE=0.90) reduction in body weight compared to 0.42% (SE=0.93) with placebo (between-group difference −13.46%; p<0.001). Additionally, 66.7% of semaglutide-treated participants achieved ≥10% weight loss versus 0% in placebo. There were no significant differences in clozapine/norclozapine levels or psychotic symptom severity. Semaglutide was generally well tolerated, with gastrointestinal adverse events (nausea, vomiting, diarrhoea) being the most reported but not leading to study withdrawal in most cases.
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