A multi‑site study carried out by researchers in Denmark has found that once‑weekly injections of semaglutide over a 30‑week period lowered blood sugar levels and body weight, and enhanced physical quality of life among adults with schizophrenia who were treated with antipsychotics and had prediabetes.
Cardiometabolic complications reduce life expectancy for people with schizophrenia, and lifestyle risks coupled with barriers to physical care add to this burden. Second‑generation antipsychotic medications can accelerate weight gain and worsen glucose tolerance.
Earlier trials of GLP‑1 receptor agonists in psychiatric populations explored shorter courses or different drugs, leaving a gap for treatments that address both glycaemia and weight while maintaining psychiatric stability.
The investigation, titled “Semaglutide Treatment of Antipsychotic‑Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial,” appeared in JAMA Psychiatry. Researchers performed a placebo‑controlled, double‑blind randomized clinical trial to evaluate whether semaglutide improves glycaemic control, weight, and quality of life in this group.
JAMA Psychiatry
The study enrolled 154 adults aged 18‑60 who were receiving second‑generation antipsychotics across two Danish regions; 141 participants completed the 30‑week intervention. Randomisation was provided by Novo Nordisk, the drug manufacturer, which supplied semaglutide and a matching placebo.
Participants received once‑weekly subcutaneous injections of either semaglutide or placebo for 30 weeks, with an eight‑week titration period up to 1.0 mg or the highest tolerated dose.
Clinic visits and assessments were primarily conducted in participants’ homes. The primary endpoint was change in glycated haemoglobin (HbA1c). Secondary endpoints included body weight, fasting glucose, lipid measures, and schizophrenia symptoms assessed with the Positive and Negative Syndrome Scale‑6 (PANSS‑6). Physical and mental health were measured with the SF‑36v2 physical and mental component scores.
Results demonstrated a mean reduction in HbA1c of 0.46 % with semaglutide compared with placebo at week 30, with a significant effect evident by week 15 and maintained through the final on‑treatment assessment. Body weight decreased by 9.21 kg with semaglutide versus placebo. An HbA1c below 5.7 % was achieved by 81 % of semaglutide recipients compared with 19 % of placebo recipients. High‑density lipoprotein increased by 10.81 mg/dL, and triglycerides decreased by 29.20 mg/dL.
The study authors note that the triglyceride reduction shows an inconsistent statistical significance, which requires further explanation.
Physical quality of life improved by 3.75 points. No significant between‑group differences were observed in mental quality of life or PANSS‑6 scores. Gastrointestinal complaints were more common early in the semaglutide group but improved over time. Serious adverse events did not differ between the two groups.
Authors conclude that a weekly dose of 1.0 mg semaglutide over 30 weeks is safe for this population, improves glycaemic control and weight, and enhances physical well‑being without worsening psychiatric symptoms.
These findings suggest a potential therapeutic option for individuals receiving second‑generation antipsychotics who also have prediabetes and obesity, and the authors note that the benefits of weight loss and diabetes prevention may justify the cost of treatment.
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