Semaglutide cuts body weight by 9.8% and improves gut microbiota in schizophrenia patients on clozapine/olanzapine

Individuals with schizophrenia often face significant metabolic challenges, including weight gain and cardiometabolic disturbances, largely due to highly effective but metabolically burdensome antipsychotics like clozapine and olanzapine. This antipsychotic-induced weight gain (AIWG) exacerbates cardiovascular risk and reduces quality of life, often leading to poor treatment adherence. Current interventions are often insufficient, leaving a critical gap in managing these severe side effects. GLP-1 receptor agonists (GLP-1RAs) like semaglutide, known for their weight loss and glucose-lowering effects, offer a promising therapeutic avenue to counteract AIWG and improve overall metabolic health in this vulnerable population.

This open-label, 24-week intervention study enrolled 26 individuals with schizophrenia (BMI > 27 kg/m2, no diabetes) receiving clozapine or olanzapine. Participants received nurse-administered semaglutide titrated over 8 weeks to a full dose of 1.0 mg/week subcutaneously, followed by 16 weeks at full dose. Primary endpoints were percentage body weight change at 24 weeks and 76 weeks (post-intervention follow-up). Secondary endpoints included changes in waist circumference, HbA1c, and body composition. Gut microbiota changes were assessed at baseline, 10 weeks, and 24 weeks using 16S rRNA gene sequencing.

Of the 26 participants, 65.4% (n=17) completed the 24-week intervention. Intention-to-treat analysis showed a significant body weight reduction of -9.8% (95% CI: [-12.7%, -6.8%], p < 0.001) or -10.1 kg at 24 weeks. Waist circumference also significantly decreased by -7.3% (95% CI: [-10.1%, -4.4%], p < 0.001). HbA1c showed a non-significant reduction of -5.3% (95% CI [-10.4%, 0.1%], p = 0.055). Gut microbial alpha diversity decreased with semaglutide exposure, accompanied by an enrichment of Parasutterella excrementihominis. At 76-week follow-up, 88.2% (n=15) of completers were assessed, revealing an average body weight change from baseline of -5.1% (95% CI: [-8.3%, -1.9%], p = 0.001) or -5.3 kg, indicating attenuation after discontinuation.

Semaglutide led to a significant 9.8% reduction in body weight and a 7.3% reduction in waist circumference at 24 weeks in patients with schizophrenia.