GLP-1 Receptor Agonists Improve Metabolic Outcomes in Schizophrenia Patients on Antipsychotics: JAMA
Denmark: Researchers have found in a new randomized HISTORI trial that schizophrenia patients on antipsychotics experienced greater weight loss and HbA1c reduction with 1 mg semaglutide compared to placebo. This suggests GLP-1 receptor agonists may improve metabolic health in this high-risk group, who face elevated diabetes and cardiovascular mortality and are often excluded from prior GLP-1 trials.
The study, published in JAMA Psychiatry, was conducted by Ashok A. Ganeshalingam and colleagues from the Department of Endocrinology, Odense University Hospital, Denmark. It is one of the first randomized controlled trials to explore the safety and effectiveness of semaglutide in patients with schizophrenia, obesity, and prediabetes—conditions that commonly overlap due to the metabolic side effects of second-generation antipsychotics.
A total of 154 adults aged 18–60 years with schizophrenia, overweight or obesity (BMI ≥27), and prediabetes (HbA1c 5.7%–6.4%) were recruited from community-based mental health services across two Danish regions between January 2022 and May 2024. Participants were randomized to receive once-weekly subcutaneous semaglutide, titrated to 1.0 mg over eight weeks, or placebo for 30 weeks.
The primary outcome was change in HbA1c, with secondary measures including body weight, schizophrenia symptoms, and physical and mental quality of life. Of the 154 patients enrolled, 141 completed the trial (96% in the semaglutide group and 87% in the placebo group).
The following were the key findings of the study:
- Semaglutide lowered HbA1c by 0.46% of total hemoglobin compared to placebo.
- 81% of patients receiving semaglutide achieved HbA1c levels below 5.7%, versus 19% in the placebo group.
- Average body weight dropped by 9.21 kg in the semaglutide group, while placebo patients showed minimal change.
- Lipid profiles improved, with HDL cholesterol increasing by 10.81 mg/dL and triglycerides decreasing by 29.20 mg/dL.
- Physical quality of life improved by 3.75 points, though no significant changes were seen in mental quality of life or schizophrenia symptom severity.
- Psychiatric outcomes remained stable, addressing concerns about GLP-1 therapies negatively affecting mental health.
- Gastrointestinal side effects were the most common adverse events in the semaglutide group.
- A slightly higher number of hospitalizations occurred with semaglutide, but serious adverse event rates were similar to placebo.
The authors highlighted the clinical significance of these findings, noting that individuals with schizophrenia have a markedly reduced life expectancy, in large part due to cardiometabolic diseases exacerbated by antipsychotic treatment. With lifestyle interventions often showing limited effectiveness, semaglutide may represent a viable therapeutic option to reduce this burden.
"The HISTORI trial demonstrates that 30 weeks of semaglutide treatment is safe and effective in reducing blood glucose levels, body weight, and improving physical well-being among schizophrenia patients with prediabetes and obesity," the authors wrote. "The study supports the potential of GLP-1 receptor agonists as a targeted intervention for this underserved group, although further long-term research is warranted to confirm the durability of benefits and clarify safety in larger populations."
Reference:
Ganeshalingam AA, Uhrenholt N, Arnfred S, et al. Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial. JAMA Psychiatry. Published online September 03, 2025. doi:10.1001/jamapsychiatry.2025.2332
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