Weight loss and gut microbial changes associated with semaglutide among people living with schizophrenia receiving clozapine or olanzapine: An open-label 24-week semaglutide intervention and 76-week trial.

OBJECTIVES: In individuals with schizophrenia receiving either clozapine or olanzapine, this study examined changes in 1) body weight and other cardiometabolic measures and microbiota biodiversity and composition between commencement and completion of 24-week semaglutide intervention; 2) body weight between commencement and 76-week follow-up. METHODS: 24-week intervention (16-weeks full-dose (1.0 mg/week) after 8-weeks' titration) of open-label nurse-administered semaglutide in a public mental health setting, with one-year post-intervention follow-up (76-week trial-completion). PARTICIPANTS: people with schizophrenia without diabetes receiving clozapine or olanzapine with BMI > 27 kg/m. PRIMARY ENDPOINTS: %body weight change at 24-weeks, and 76-weeks. Secondary endpoints: %change in waist circumference, HbA1c at 24-weeks and 76-weeks, body composition at 24-weeks. Gut microbiota changes were compared at baseline, 10-weeks and 24-weeks intervention completion. RESULTS: Mean age: 41.5 years (range 18-61), 65.4% female. Intervention completed by 65.4% (n = 17/26). 24-week intervention: intention-to-treat body weight reduction: -9.8% (95% CI: [-12.7%, -6.8%], p < 0.001) or - 10.1 kg (95% CI [-13.6, -6.6]); waist circumference reduction: -7.3% (95% CI: [-10.1%, -4.4%], p < 0.001); HbA1c non-significant reduction: -5.3% (95% CI [-10.4%, 0.1%], p = 0.055). Microbial alpha diversity decreased as time on semaglutide increased, with enrichment of Parasutterella excrementihominis. Trial completion: 88.2% (n = 15/17). Average body weight change baseline-76-weeks: -5.1% (95% CI: [-8.3%, -1.9%], p = 0.001) or - 5.3 kg (95% CI: [-8.9, -1.7]). DISCUSSION: Semaglutide was associated with significant weight loss in overweight/obese people with schizophrenia. These benefits attenuated following semaglutide discontinuation. Gut microbial compositional differences consistent with improvement in health outcomes may occur in semaglutide-treated people living with schizophrenia.