For people living with schizophrenia, the struggle often extends far beyond the mind. While antipsychotic medications can stabilize symptoms and restore daily functioning, they frequently come with heavy costs to physical health. Weight gain, impaired glucose tolerance, and elevated cardiovascular risk are common side effects of second-generation antipsychotics. These issues accumulate into a devastating reality: individuals with schizophrenia face a life expectancy shortened by up to two decades, much of it driven by preventable cardiometabolic disease.
Against this backdrop, scientists are working to find treatments that not only safeguard mental health but also protect physical well-being. A new multicenter study from Denmark provides one of the clearest signals yet that this balance is possible. By testing semaglutide—a drug already used to treat type 2 diabetes and obesity—the researchers explored whether a once-weekly injection could counteract antipsychotic-induced weight gain and prediabetes in patients with schizophrenia. Their findings, published in JAMA Psychiatry, may mark a turning point in how we think about integrated treatment for this vulnerable population.
The HISTORI Trial: A Landmark Study
The study, titled Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial, brought together 154 adults aged 18 to 60 years across two Danish regions. All participants were receiving second-generation antipsychotics, the very medications that often worsen metabolic health. After randomization, 141 individuals completed the full 30 weeks of treatment, receiving either semaglutide or a placebo.
What made this trial unique was its rigor and patient-centered approach. It was double-blinded and placebo-controlled, with a carefully designed titration period to reach 1.0 mg of semaglutide or the highest tolerated dose. Importantly, assessments were performed not just in clinical centers but often directly in participants’ homes—an effort to reduce barriers and increase accessibility for a population that often faces obstacles in accessing physical health care.
The trial’s primary outcome was glycemic control, measured by changes in HbA1c, a marker of average blood sugar levels. Secondary outcomes included weight loss, lipid profiles, and quality of life measures, alongside close monitoring of psychiatric stability using the Positive and Negative Syndrome Scale–6 (PANSS-6).
Results That Speak for Themselves
The findings were striking. After 30 weeks, patients receiving semaglutide showed a reduction in HbA1c of 0.46% compared with placebo. This improvement emerged as early as week 15 and persisted through the end of treatment. For individuals hovering on the edge of type 2 diabetes, this shift was not just statistically significant but clinically meaningful. In fact, 81% of those receiving semaglutide reached HbA1c levels below the prediabetic threshold of 5.7%, compared with just 19% of those on placebo.
Even more dramatic was the effect on body weight. Participants treated with semaglutide lost an average of 9.21 kilograms—more than 20 pounds—relative to placebo. This level of weight reduction is rarely seen in psychiatric populations, where lifestyle interventions often struggle against the metabolic impacts of antipsychotics.
Lipid profiles also improved. HDL cholesterol rose by an average of 10.81 mg/dL, while triglycerides decreased by 29.20 mg/dL. However, here the study encountered a reporting issue: the published confidence intervals for triglyceride reduction appeared inconsistent with the stated p-values, likely due to a sign error in the statistical tables. Although this discrepancy does not negate the broader positive trends, it highlights the importance of careful data interpretation in clinical research.
Equally important, semaglutide did not worsen psychiatric outcomes. PANSS-6 scores remained stable, and no between-group differences were found in mental quality of life. Instead, participants experienced a meaningful boost in physical quality of life, improving by 3.75 points. Adverse effects, mostly gastrointestinal symptoms like nausea, were more common in the semaglutide group early on but typically resolved over time. Serious adverse events were similar across both groups, underscoring the treatment’s safety in this population.
Why This Study Matters
The HISTORI trial is more than a proof of concept—it is a lifeline for a group too often left at the margins of medical care. For decades, people with schizophrenia have faced a cruel trade-off: stabilize the mind with antipsychotics but suffer the physical consequences that erode health and shorten lives. Interventions such as diet, exercise, and behavioral counseling, while valuable, rarely fully counterbalance the biological effects of these medications.
Semaglutide’s success suggests that this trade-off may no longer be inevitable. By addressing both blood sugar and weight, the drug not only reduces the risk of diabetes and cardiovascular disease but also enhances daily functioning and well-being. The improvements in physical quality of life reported by participants speak to something larger than numbers on a chart—they reflect the possibility of reclaiming vitality, energy, and hope.
Beyond the Numbers: The Human Dimension
Imagine being a patient living with schizophrenia, fighting not just the voices of psychosis but also the crushing fatigue of obesity and the looming threat of diabetes. Each doctor’s visit brings reminders of elevated blood sugar, climbing cholesterol, and shrinking years of expected life. For many, these realities compound stigma and reduce motivation to pursue care.
Now imagine that after 30 weeks of treatment, the scale reads 20 pounds lighter, blood tests show glucose levels back in the normal range, and everyday activities feel just a little easier. These are not abstract outcomes—they are tangible shifts in how a person moves through the world, interacts with others, and envisions the future.
That is the power of integrating psychiatric and physical health care. It is not simply about managing symptoms but about restoring dignity, hope, and possibility.
Looking Ahead: Challenges and Opportunities
While the HISTORI trial offers grounds for optimism, it also raises important questions. Cost is a significant concern. Semaglutide is an expensive therapy, and widespread adoption in psychiatric populations would require careful health-economic analysis. The authors of the study argue that the potential benefits—in preventing diabetes, reducing hospitalizations, and improving long-term outcomes—may justify the investment.
Another challenge is access. Patients with schizophrenia often face systemic barriers to care, from fragmented services to stigma within the health system. Ensuring that innovations like semaglutide reach those most in need will require coordinated policies, training for clinicians, and efforts to reduce disparities.
There is also the matter of long-term safety and efficacy. The trial lasted 30 weeks, offering a robust snapshot but not a full picture of what sustained treatment may look like over years or decades. Larger and longer trials will be needed to confirm benefits, track risks, and refine guidelines.
Yet the opportunity is undeniable. If semaglutide or similar GLP-1 receptor agonists can consistently improve both physical and psychiatric well-being, they could transform the standard of care for millions of people worldwide.
A Step Toward Wholeness
The story of semaglutide in schizophrenia is not just about a drug—it is about a shift in perspective. For too long, psychiatric care has been siloed from physical medicine, leaving patients to navigate the consequences. The HISTORI trial challenges that division, showing that we can—and must—treat the whole person.
In the end, physics may explain the forces of the universe, but medicine carries its own universal truth: the health of the body and mind are inseparable. By embracing treatments that honor this connection, we take a step toward wholeness, compassion, and a more just vision of health.
The Danish researchers have shown us what is possible. Now it is up to clinicians, policymakers, and society as a whole to build on this work and ensure that the promise of semaglutide reaches those who need it most. In doing so, we may not only extend lives but also enrich them—restoring hope where too often it has been diminished.
More information: Ashok A. Ganeshalingam et al, Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity, JAMA Psychiatry (2025). DOI: 10.1001/jamapsychiatry.2025.2332
