Effects of Semaglutide on Body Weight in Clozapine-Treated Individuals With Schizophrenia and Obesity: A Randomized Controlled Trial

Background People with schizophrenia experience significantly higher rates of obesity and related cardiometabolic disorders, largely due to antipsychotic medications, especially clozapine. This metabolic burden contributes to decreased life expectancy and increased health complications. Current pharmacological interventions, such as metformin, show limited efficacy in addressing antipsychotic-induced weight gain. Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated promise in reducing body weight and improving metabolic health. Aims & Objectives This study investigates the efficacy of semaglutide in managing clozapine-associated obesity. Method The Clozapine associated Obesity and Semaglutide Treatment (COaST) trial is a 36-week, double-blinded, placebo-controlled randomized study. It will include 32 adults diagnosed with schizophrenia or schizoaffective disorder, currently treated with clozapine, and presenting with obesity (BMI ≥ 26 kg/m²). Participants are randomly assigned to receive either 2.0 mg of semaglutide subcutaneously or a placebo once weekly (titrated over 16 weeks). The primary outcome measure is the percentage change in body weight from baseline to 36 weeks. Secondary outcomes include changes in metabolic syndrome components, insulin resistance, and cognitive function. Results This will be world’s first reporting of an RCT of semaglutide for clozapine associated obesity. The trial will assess whether semaglutide produces significant weight reduction and metabolic improvements in clozapine-treated individuals compared to placebo. Secondary analyses will explore the impact on metabolic syndrome, insulin resistance, and cognitive outcomes. Discussion & Conclusions The COaST trial is expected to provide critical data on the efficacy of semaglutide as a weight loss intervention for individuals with schizophrenia experiencing clozapine-induced obesity. If successful, this could lead to new therapeutic strategies for reducing cardiometabolic risk in this population. Results will inform future clinical guidelines and public health interventions.