In a landmark 154-patient randomized trial published in JAMA Psychiatry, semaglutide reduced HbA1c by 0.46%, body weight by 9.21 kg, and reversed prediabetes in 81% of antipsychotic-treated schizophrenia patients without worsening psychiatric symptoms.
81% reversed prediabetes vs 19% on placeboFour out of five schizophrenia patients on semaglutide had their prediabetes completely reversed (HbA1c returned to normal) within 30 weeks — a dramatic result in a population previously considered very difficult to treat metabolically.
What the researchers found
In 154 antipsychotic-treated schizophrenia patients with prediabetes and obesity, semaglutide (up to 1.0 mg/week for 30 weeks) versus placebo:
- HbA1c reduced by 0.46% (95% CI -0.56 to -0.36)
- Body weight reduced by 9.21 kg (95% CI -11.68 to -6.75)
- 81% vs 19% achieved HbA1c <5.7% (prediabetes reversal, p<0.001)
- HDL cholesterol improved by 10.81 mg/dL (p=0.007)
- Triglycerides improved by -29.20 mg/dL (p=0.03)
- Physical quality of life improved by 3.75 points on SF-36v2 (p=0.001)
- No significant effect on PANSS-6 schizophrenia symptom score or mental QoL
- 96% completion rate in semaglutide group vs 87% in placebo
- GI symptoms more common with semaglutide; serious adverse events similar between groups
Why it matters
This is a landmark trial for one of the most vulnerable and medically underserved populations in healthcare. Antipsychotic-induced weight gain and metabolic syndrome contribute to a 15-20 year mortality gap in schizophrenia, yet metabolic interventions have shown limited success in this group. The HISTORI trial demonstrates that semaglutide is both safe (no psychiatric worsening) and highly effective (81% prediabetes reversal, 9.21 kg weight loss) in these patients, potentially changing clinical practice for millions of antipsychotic-treated individuals worldwide.
How the study worked
Multicenter, double-blinded, placebo-controlled randomized clinical trial (HISTORI) conducted January 2022 to May 2024 across community-based mental health services in two Danish regions. 154 SGA-treated adults (18-60 years) with schizophrenia, prediabetes (HbA1c 5.7-6.4%), and BMI ≥27 were randomized 1:1 to semaglutide (titrated to 1.0 mg/week over 8 weeks) or placebo for 30 weeks. Primary outcome: HbA1c change. ClinicalTrials.gov: NCT05193578.
What this study cannot tell us
The study used semaglutide up to 1.0 mg/week (not the higher 2.4 mg used for obesity treatment), so weight loss may be even greater at higher doses. The 30-week duration doesn't address long-term outcomes or what happens after stopping semaglutide. A few more hospitalizations were noted in the semaglutide group, though serious adverse events were similar between groups. The study population was from Denmark, and results may vary in other populations. Mental QoL did not improve, suggesting semaglutide's benefits are primarily metabolic rather than psychiatric.
How to read the evidence
This is a high-quality, multicenter, double-blinded, randomized, placebo-controlled trial published in one of the top psychiatric journals. The sample size (154), high completion rate (91.5%), registered protocol, and comprehensive outcome assessment including both metabolic and psychiatric endpoints make this strong evidence. The only limitation is the single-country (Denmark) population.
When this study was published
Published in 2025, this is one of the most recent and important trials of GLP-1 drugs in a psychiatric population. It directly informs current clinical practice and is likely to influence treatment guidelines for metabolic management in schizophrenia.
The bigger picture
Published in JAMA Psychiatry, this trial addresses a critical equity gap in medicine: patients with severe mental illness are often excluded from metabolic drug trials despite having the highest metabolic risk. The finding that semaglutide doesn't worsen psychosis removes a major barrier to prescribing. Combined with the growing evidence of GLP-1 drugs' benefits across multiple conditions, this trial could catalyze integration of metabolic management into psychiatric care, potentially helping close the mortality gap for people with schizophrenia.
Questions still open
- Would higher doses of semaglutide (2.4 mg) produce even greater metabolic benefits in schizophrenia patients, and would they remain psychiatrically safe?
- Do the metabolic improvements from semaglutide translate to reduced cardiovascular events and mortality in long-term follow-up of schizophrenia patients?
- Should semaglutide be initiated proactively when antipsychotic treatment begins, rather than waiting for prediabetes to develop?
Common questions
Why do people with schizophrenia have such high rates of diabetes and heart disease?
Is it safe to take semaglutide with antipsychotic medications?
Read the original research
Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial.
JAMA psychiatry, 82(11), 1065-1074
Citation
Ganeshalingam, Ashok A; Uhrenholt, Nicolai; Arnfred, Sidse; Gæde, Peter; Düring, Signe; Stenager, Elsebeth N; Bünger, Nick; Pedersen, Andreas K; Bilenberg, Niels; Frystyk, Jan. (2025). Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial.. JAMA psychiatry, 82(11), 1065-1074. https://doi.org/10.1001/jamapsychiatry.2025.2332