Journal Club: Managing Clozapine's Metabolic Burden - The Role of Semaglutide

Course overview

Schizophrenia shortens life expectancy by 16-20 years, largely due to cardiovascular and metabolic disease. Clozapine, while the most effective treatment for refractory illness, carries the highest risk for weight gain, insulin resistance, and dyslipidemia, driven by receptor effects at histamine H1, serotonin 5-HT2C, and muscarinic M3 sites. Lifestyle programs, metformin, and first-generation GLP-1 receptor agonists provide only modest benefit. The COaST trial, a phase 2 randomized study, evaluated semaglutide in clozapine-treated adults and found significant reductions in weight, BMI, fat mass, visceral adiposity, and HbA1c compared with placebo. Clozapine levels and psychiatric symptoms were unchanged, and adverse events were mainly gastrointestinal.