The randomised clinical trial published in JAMA Psychiatry by Marie R. Sass from the Mental Health Center Copenhagen and collaborators has provided important insights into the potential of semaglutide as an early metabolic intervention in schizophrenia spectrum disorders.
Individuals receiving second-generation antipsychotics (SGAs) are known to face a substantially higher risk of weight gain, insulin resistance, and type 2 diabetes—factors that contribute to excess cardiovascular mortality in this population. The study explored whether adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) early in treatment could counteract these metabolic disturbances.
The multicenter, double-blind trial enrolled adults aged 18 to 65 years across three Danish clinical sites between 2021 and 2024. Eligible participants had schizophrenia spectrum disorders, had initiated clozapine or olanzapine within the previous five years, and showed signs of early glycemic abnormalities with HbA1c levels ranging from 5.4% to 7.4%. None of the participants were receiving antidiabetic medication at baseline.
A total of 73 individuals were randomized to receive either weekly subcutaneous semaglutide (1 mg) or a matching placebo for 26 weeks, alongside their existing antipsychotic therapy. The primary focus of the study was the change in HbA1c from baseline to week 26.
Key Findings:
- Semaglutide produced a clear and statistically significant improvement in glycemic control, with an HbA1c reduction of −0.25% compared with placebo.
- Nearly 50% of participants receiving semaglutide achieved low-risk HbA1c levels below 5.4%, whereas only 3% of those on placebo reached this target.
- The results suggest that semaglutide may help reverse early metabolic abnormalities before they progress to overt diabetes.
- Participants on semaglutide experienced substantial weight loss, averaging 9.2 kg over 26 weeks.
- Significant reductions in waist circumference (−7.0 cm) and fat mass (−6.1 kg) were also observed, indicating improved body composition.
- No meaningful changes were noted in lipid levels, blood pressure, liver function, or psychiatric symptoms, showing that metabolic benefits did not compromise mental health status.
- Adverse events were largely gastrointestinal, mild, and short-lived, consistent with known GLP-1RA effects.
- Psychiatric adverse events appeared at similar rates in both groups, reinforcing the overall tolerability of semaglutide in individuals with severe mental illness.
The authors conclude that early use of semaglutide may serve as an effective adjunctive strategy to mitigate the metabolic burden associated with SGAs. By intervening during the initial stages of metabolic dysregulation, clinicians may help reduce long-term cardiometabolic complications in individuals with schizophrenia spectrum disorders.
Reference:
Sass MR, Klausen MK, Schwarz CR, et al. Semaglutide and Early-Stage Metabolic Abnormalities in Individuals With Schizophrenia Spectrum Disorders: A Randomized Clinical Trial. JAMA Psychiatry. Published online December 03, 2025. doi:10.1001/jamapsychiatry.2025.3639
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