Breaking Barriers: How Semaglutide Can Improve Health for Patients with Schizophrenia

Breaking Barriers: How Semaglutide Can Improve Health for Patients with Schizophrenia

A recent randomized clinical trial published in JAMA Psychiatry has shed new light on an important but often overlooked issue: the physical health of individuals living with schizophrenia (Ganeshalingam et al., 2025). While psychiatric treatment focuses on managing symptoms, many clients also face significant health risks related to weight gain, diabetes, and heart disease—much of it driven by the very medications that stabilize their mental health.

The Challenge

Second-generation antipsychotics (SGAs) are lifesaving for many clients with schizophrenia, but they come with a heavy price: weight gain, insulin resistance, and a higher risk of type 2 diabetes. As a result, individuals with schizophrenia often have a reduced life expectancy of 10–20 years, largely due to cardiovascular disease and obesity-related complications.

For years, we’ve known that weight gain and metabolic disease are among the most difficult side effects to manage when prescribing SGAs. In some cases, clinicians have turned to metformin, which can help but often causes significant gastrointestinal distress that limits its tolerability.

What makes this challenge even more pressing is that the most effective antipsychotics—those with the strongest effect sizes (Cohen’s d) such as Clozaril (clozapine) and olanzapine—are also the ones most strongly associated with severe weight gain and metabolic disturbances. In other words, the medications that can bring the greatest psychiatric benefit may also bring the greatest physical health burden.

The Study

The HISTORI randomized clinical trial examined whether semaglutide—a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist—could safely address these health challenges (Ganeshalingam et al., 2025). The trial included 154 adults with schizophrenia, prediabetes, and overweight or obesity who were already being treated with SGAs.

Key findings after 30 weeks of treatment with semaglutide (1.0 mg/week):

• Blood sugar control: HbA1c dropped by 0.46%, with 81% of clients returning to normal glucose levels compared to only 19% in the placebo group.
• Weight reduction: Participants lost an average of 9.2 kg (20 lbs)—a clinically meaningful amount.
• Improved cholesterol and triglycerides: Semaglutide improved lipid profiles, lowering cardiovascular risk.
• Better physical quality of life: Clients reported improved day-to-day functioning without worsening psychiatric symptoms.
• Safety: While gastrointestinal side effects were more common, semaglutide was overall safe and did not negatively impact mental health stability.

Why This Matters

This study is groundbreaking for several reasons:

1. Bridging psychiatry and physical health – It underscores the reality that mental health cannot be separated from physical health. Treating schizophrenia effectively means also addressing diabetes and obesity risks.
2. Expanding treatment options – For decades,psychiatrists and primary care providers have had few effective tools to counteract the metabolic side effects of antipsychotics. Metformin has been used but is not well-tolerated by everyone. Now, semaglutide may represent a more effective and better-tolerated option.
3. Balancing effectiveness and side effects – The fact that the most effective antipsychotics, like clozapine and olanzapine,also cause the most metabolic harm highlights the urgent need for add-on treatments like semaglutide. This could allow clients to stay on the medications that work best for their psychiatric symptoms while protecting their long-term health.
4. Reducing premature mortality – By improving metabolic health, semaglutide could help close the life expectancy gap that individuals with schizophrenia face.
5. Quality of life improvements – The fact that participants reported better physical quality of life is just as important as lab values. Feeling healthier, lighter, and more energetic can empower clients to engage more fully in treatment and daily living.

Looking Ahead

While more research is needed—including long-term follow-up and real-world application—this trial highlights the importance of integrated care. Psychiatrists, primary care providers, and endocrinologists must work together to bring treatments like semaglutide into practice for those who stand to benefit most.

From my perspective on an Assertive Community Treatment (ACT) team, this could be a game changer. Many of the clients we serve are stabilized on antipsychotics that are metabolically unforgiving, yet switching medications isn’t always possible without risking relapse. If semaglutide can give them a chance at better physical health without sacrificing psychiatric stability, it could transform how we approach long-term treatment and improve both quality and length of life for some of our most vulnerable clients.

And with studies like this, clinicians have more tools in the belt to assist clients—knowing that, for the most part, these medications are safe in the populations we’re treating and compatible with the antipsychotics they are already taking. It’s another step toward truly comprehensive psychiatric care.

The takeaway? Managing schizophrenia isn’t just about controlling hallucinations or stabilizing mood—it’s also about fighting the silent killers of diabetes and cardiovascular disease. And now, with medications like semaglutide, we may finally have a tool to do both.

Reference

Ganeshalingam, A. A., Uhrenholt, N., Arnfred, S., et al. (2025). Semaglutide treatment of antipsychotic-treated patients with schizophrenia, prediabetes, and obesity: The HISTORI randomized clinical trial. JAMA Psychiatry. Advance online publication. https://doi.org/10.1001/jamapsychiatry.2025.2332

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