JAMA Psychiatry

Semaglutide shows promise for weight, glucose control in schizophrenia patients on antipsychotics

September 8, 2025

Study details: The randomized HISTORI trial (NCT05193578) enrolled 154 adults (mean age, 38.3 years; 56.5% female) with schizophrenia, prediabetes (HbA1c 5.7–6.4%), and BMI ≥27 kg/m², all receiving second-generation antipsychotics (SGAs). Participants were randomized 1:1 to once-weekly SC semaglutide (titrated to 1.0 mg/week over 8 weeks) or placebo for 30 weeks.

Results: Semaglutide significantly reduced HbA1c by 0.46% (95% confidence interval [CI], −0.56% to −0.36%) and body weight by 9.21 kg (95% CI, −11.68 to −6.75) compared with placebo. Normoglycemia (HbA1c <5.7%) was achieved in 81% of semaglutide recipients vs. 19% with placebo (P < .001). Improvements were also seen in HDL-C (+10.81 mg/dL; 95% CI, 2.70-18.53; P=.007) and triglycerides (−29.20 mg/dL; 95% CI, -55.75 to 2.65; P=.03). Semaglutide was also associated with a 3.75-point (95% CI 1.52-5.98) improvement in physical quality of life measured by the 36-item Short Form Survey, version 2. Mental quality-of-life scores and Positive and Negative Syndrome Scale 6 score didn't differ. GI symptoms were more frequent with semaglutide, but serious adverse events were similar between groups.

Clinical impact: Semaglutide (1.0 mg/week) is safe and effective for reversing prediabetes and reducing weight in SGA-treated patients with schizophrenia and obesity, without worsening psychiatric symptoms. These findings support consideration of semaglutide in this high-risk population to mitigate cardiometabolic morbidity and mortality.

Source:

Ganeshalingam AA, et al. (2025, September 3). JAMA Psychiatry. Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial. https://pubmed.ncbi.nlm.nih.gov/40900607/