Semaglutide Safely Improves Metabolic Health in Schizophrenia—HISTORI Trial Findings
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📌 Background
Patients with schizophrenia face a markedly reduced life expectancy—largely driven by cardiometabolic disease caused by antipsychotic-induced weight gain and insulin resistance. Conventional interventions (diet, metformin, lifestyle programs) often yield limited success.
Semaglutide, a GLP-1 receptor agonist, has shown strong efficacy in type 2 diabetes and obesity. The HISTORI trial tested whether semaglutide could safely improve metabolic health in patients with schizophrenia without worsening psychiatric stability.
🧪 Study Design
Type: Double-blind, placebo-controlled RCT
Duration: 30 weeks
Population: 154 adults (aged 18–60 years) with schizophrenia, prediabetes (HbA1c 5.7–6.4%), and BMI ≥27 on stable second-generation antipsychotics
Intervention: Weekly semaglutide 1.0 mg SC (titrated over 8 weeks) vs placebo
Primary outcome: Change in HbA1c
Secondary outcomes:
Body weight
PANSS-6 (psychotic symptom score)
Physical and mental quality of life (SF-36v2)
📊 Key Results:
Sample & Demographics
- Total of 154 participants randomized 1:1 to semaglutide vs placebo
- 87 female participants (56.5%)
- Mean age: 38.3 years (SD = 10.7)
Completion Rates
- 141 participants (91.5%) completed the trial
- Semaglutide group: 74 of 77 (96%)
- Placebo group: 67 of 77 (87%)
Primary Outcomes
- HbA1c reduction: −0.46% (95% CI: −0.56 to −0.36)
- Body weight reduction: −9.21 kg (95% CI: −11.68 to −6.75)
- HbA1c < 5.7% achieved in 81% semaglutide vs 19% placebo (P < .001)
Lipid Profile Improvements
- HDL cholesterol: ↑ 10.81 mg/dL (95% CI: 2.70–18.53; P = .007)
- Triglycerides: ↓ 29.20 mg/dL (95% CI: −55.75 to −2.65; P = .03)
Quality of Life (QoL)
- Physical QoL (SF-36v2): ↑ 3.75 points (95% CI: 1.52–5.98; P = .001)
- No significant effect on mental QoL or PANSS-6 scores
Adverse Effects
- GI symptoms more frequent in semaglutide group
- Slightly higher hospitalization rates in semaglutide group
- No difference in the number of serious adverse events between groups
🩺 Clinical Implications
This study confirms that semaglutide is safe and highly effective for improving metabolic health in patients with schizophrenia receiving antipsychotics.
Key takeaways for clinicians:
⚖️ Significant weight reduction and glycemic improvement within 7 months
🧠 No psychiatric destabilization, addressing a key safety concern
💊 Could redefine metabolic management in antipsychotic-treated patients
🏥 Supports integration of GLP-1 agonists into psychiatry-endocrinology collaboration models
📚 References
- 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 (article)
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