Semaglutide reduced HbA1c levels by nearly half a percentage point and helped patients lose an average of 20 pounds over 30 weeks in the first randomized trial of the diabetes drug in patients with schizophrenia, prediabetes, and obesity.
The study of 154 patients receiving second-generation antipsychotics found 81% of those taking semaglutide achieved HbA1c levels below the prediabetes threshold, compared with 19% receiving placebo. Mental health scores and schizophrenia symptoms remained unchanged, suggesting the drug does not worsen psychiatric outcomes. Patients also showed improvements in high-density lipoprotein cholesterol, triglycerides, waist and hip circumference, and physical quality-of-life scores.
“On this basis, we speculate that overweight or obese patients without diabetes with [schizophrenia] and [second-generation antipsychotic] treatment have an increased responsiveness to semaglutide, but whether this is caused by reductions in the adverse effects of [second-generation antipsychotics] (eg, appetite) or the psychiatric disease per se remains unknown,” wrote Ashok A. Ganeshalingam, MD, Department of Endocrinology, Odense University Hospital, Denmark, and colleagues.
The trial was conducted in Denmark from January 2022 to May 2024, with analysis completed in January 2025. Patients aged 18 to 60 years with schizophrenia spectrum disorders, prediabetes, and body mass index of 27 or greater were included. All were on stable treatment with second-generation antipsychotics. Patients with diabetes or those treated with other glucose-lowering drugs were excluded. Semaglutide was titrated to 1 milligram weekly by week 8, with 91% of patients completing the trial, and similar retention rates across groups.
The trial was limited by its 30-week duration, which may not reflect long-term effects on glucose control, weight, or psychiatric outcomes. The maximum dose was 1 milligram weekly, lower than the dose approved for obesity in other populations. Exclusion of patients with diabetes limited generalizability. Gastrointestinal adverse events were more common with semaglutide, and a small number of patients experienced repeated hospitalizations, although overall serious adverse events were similar between groups.
The findings suggest semaglutide can improve metabolic outcomes without compromising psychiatric stability in patients with schizophrenia receiving antipsychotic therapy.
Full disclosures can be found in the study.
Source: JAMA Psychiatry
