02. GLP-1s in Schizophrenia: Should Semaglutide Be Added for Metabolic Management?

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Semaglutide and Early-Stage Metabolic Abnormalities in Schizophrenia

In this Quick Take today, I’m going to look at a GLP-1 agonist clinical trial for patients with schizophrenia and metabolic abnormalities. Specifically, I’ll discuss the glucagon-like peptide-1 (GLP-1) agonist semaglutide.

The GLP-1 agonists are of course the weight loss medications with brand names like Wegovy or Zepbound that every celebrity in the United States seems to be taking to lose weight. Given that many of your patients with schizophrenia are overweight, I suspect you may already be using a GLP-1 agonist to manage weight gain in your patients if you are an early adopter or you are strongly considering it. So this is an important clinical trial for you to know about.

WHO Reframes Obesity as Chronic Disease

Before going into details about the trial, this this is an important and timely article because the World Health Organization just published their first ever obesity guideline. This guideline makes the important statement that obesity is a complex, relapsing and chronic disease that needs to be managed just like other chronic diseases, including with long-term medications, similar to say hypertension or high blood pressure.

We certainly accept the need for possibly lifelong medications for hypertension and not only time-limited treatment as a goal. Of course, like with antihypertensives, medications for obesity are most effective when combined with lifestyle modifications. So the GLP-1 agonists are not magic bullets by themselves but ultimately will need to be part of a comprehensive treatment approach.

Trial Design and Methodology

Let’s now go to the clinical trial of semaglutide as an add-on for olanzapine- or clozapine-treated schizophrenia patients. It was just published in December 2025 in JAMA Psychiatry with Marie Sass as the first author. The study was a double-blind, placebo-controlled randomized trial conducted at three clinical sites in Denmark.

Patients eligible had to have a schizophrenia spectrum disorder and either diabetes or early-stage glycemic dysregulation defined as a hemoglobin A1c of 5.4% as the cutoff. This is a bit lower than the 5.7% that you may be familiar with from diabetes guidelines as the upper limit of normal. However, the authors make the convincing case that the metabolic risk accelerates above 5.4%, so this lower number is in fact a better target for prevention.

For this study, they also wanted people to be treated with antipsychotics for less than five years to avoid the issue of chronicity. And importantly, patients needed to be treated with one of the two metabolically high-risk antipsychotics olanzapine or clozapine.

Key trial parameters:

• Duration: 26 weeks
• Intervention: semaglutide at a dose of 1 mg subcutaneously every month (which you may recognize as a low dose)
• Primary outcome: change in hemoglobin A1c from baseline to week 26
• Secondary outcomes: a host of metabolic and psychiatric variables

Results and Clinical Outcomes

They ended up with 73 patients who got randomized, consisting of a mostly white group, more females than males, with a mean age of 35. The average BMI was around 36, putting most in the obesity category, and the average patient was only treated with clozapine or olanzapine for one year.

The good news is that the intervention worked. Patients who received semaglutide had 0.25% lower hemoglobin A1c compared to placebo. This moved almost 50% of this cohort of treated patients into the metabolically low-risk category below the 5.4% cutoff.

Here is a number that makes the results even more concrete:

• The intervention group lost 8.7 kg (19 pounds).
• The placebo group remained essentially stable.
• Lipid markers or blood pressure were not different between the two groups, probably because the trial duration was too short and the group was not chronic.

They also did not see any difference in psychopathology, which is a good thing. Interestingly, they saw a reduction in nicotine dependence measured with the Fagerström, which is a very good result. GI complaints, including constipation, were the most common problem, though not limited only to the treatment group.

Clinical Implications for Serious Mental Illness

This trial is important because it shows that GLP-1 agonists work in our patients with serious mental illness, something that was not a given. There was the concern that the antipsychotic would physiologically counteract the efficacy of added GLP-1 agonist, which turned out to be wrong. I also like that they did not just enroll any patient with schizophrenia but that they selected a high-risk group where medical management may be particularly important to reduce long-term morbidity and mortality.

Weight loss alone is important for patients as weight gain is a major reason for treatment discontinuation or deal-breaker to even try an antipsychotic. So using a GLP-1 agonist early to blunt or prevent weight gain may increase adherence and, for example, clozapine utilization even if other markers like hemoglobin, high blood pressure, or cholesterol don’t change that much.

I’m also hopeful that the GLP-1 agonists may become a new approach to manage addictions given that they appear to affect central reward circuitry beyond food and satiety. And as I said, they noticed this here with the measure of nicotine dependence. They didn’t see a measure of alcoholism but this was also a group that was actually not clinically addicted.

Practical Use and Future Directions

This is by no means the end of the story but it is the end of the beginning. We can now shift to figuring out how to use these medications, not if we should use them. Who needs to be on the patient’s team? How much can a psychiatrist do? Where do we need a primary care doctor or endocrinologist?

There’s also the vexing issue of cost of equity but I suspect that the price of GLP-1 agonists will come down eventually and we will have oral pills. In fact, Wegovy was just made available in the United States early January 2026 as an oral pill.

Clinically, we need to now figure out how to use them optimally including who we should prioritize. I definitely think patients on clozapine and to some extent patients on olanzapine where you cannot easily switch fall into this group, where we need to actively manage the metabolic risk including using GLP-1 agonists early. There may be special considerations with psychiatric drugs like clozapine, for example, as clozapine causes GI hypomotility and GLP-1 agonists may increase the risk for bowel obstruction as they also affect GI transit time.

Prevention May Improve Long-Term Outcomes

In the future, maybe we will be using the GLP-1 agonists as obesity prevention, not just as a treatment after years of gaining weight and accruing medical morbidities. I would guess that our patients may stick with the psychiatric treatment longer if we prevent weight gain as I mentioned earlier. They may also live longer, although the latter still would have to be proven as hemoglobin A1c is a surrogate outcome marker, albeit a well-established one.

For a definite answer about whether we can improve mortality in our patients by using these drugs, we will need long-term trials with hard outcomes including myocardial infarction, stroke, or death.

Bottom Line

In the Sass trial, the GLP-1 agonist semaglutide meaningfully reduced weight and reversed beginning metabolic abnormalities in patients with schizophrenia who were treated with olanzapine or clozapine for less than five years.

This is an exciting time for the medically inclined psychiatrist who is trying to manage patients with serious mental illness like schizophrenia holistically, paying attention to symptoms and medical morbidity and mortality. Up until now, we really only had metformin or topiramate to manage antipsychotic-induced weight gain and neither of them worked that well.

I believe the GLP-1 agonists will turn out to be true game changers not just for Medicine but also for Psychiatry. It is a fast-moving field with several GLP-1 agonists either already on the market or under development that are both more potent than semaglutide or can be taken as a daily pill—although I just told you that semaglutide actually has become available as a pill as well.

I will keep you posted about new developments as those GLP-1 agonists as a class become more entrenched in a positive way in our field and if there’s any new developments with these drugs for our patients with serious mental illness.

Abstract

Semaglutide and Early-Stage Metabolic Abnormalities in Individuals With Schizophrenia Spectrum Disorders

Marie R. Sass, PhD; Mette Kruse Klausen, PhD; Christine R. Schwarz, PhD; et al

Importance  Individuals with schizophrenia spectrum disorders treated with second-generation antipsychotics (SGAs) are at heightened risk for obesity, prediabetes, and type 2 diabetes, contributing to increased cardiovascular morbidity and premature mortality. Early intervention with glucagon-like peptide–1 receptor agonists (GLP-1RAs) may help mitigate long-term cardiometabolic risk.

Objective  To evaluate the efficacy of adjunctive semaglutide on glycemic control, weight-associated outcomes, and cardiometabolic risk factors in individuals with schizophrenia spectrum disorders receiving clozapine or olanzapine and exhibiting early glycemic abnormalities.

Design, Setting, and Participants  This was a multicenter, double-blind, placebo-controlled, randomized clinical trial. Participants were enrolled from 3 clinical sites in Denmark between September 2021 and August 2024. Screening individuals were aged 18 to 65 years with schizophrenia spectrum disorders and clozapine or olanzapine treatment initiated within the past 5 years. Participants had early-stage glycemic dysregulation (hemoglobin A_1c [HbA_1c], 5.4%-7.4%) and were not receiving antidiabetic therapy.

Interventions  Participants received once-weekly subcutaneous semaglutide (1 mg) or a matching placebo, administered adjunctively to SGA therapy for 26 weeks.

Main Outcomes and Measures  The prespecified primary outcome was change in HbA_1c level from baseline to week 26. The primary analysis adhered to the intention-to-treat principle.

Results  Of 104 individuals screened, 73 were randomized and 57 (78%) completed the trial. Baseline characteristics were comparable between groups. Mean (SD) age was 35 (12) years, 48 were female (65%), and mean (SD) body mass index was 36.1 (7.9). At week 26, semaglutide significantly reduced HbA_1c level compared with placebo (mean difference, −0.25%; 95% CI, −0.33 to −0.16; P < .001); 43% of participants (12 of 28) treated with semaglutide achieved low-risk HbA_1c levels (<5.4%) vs 3% with placebo. Greater reductions in body weight (−9.2 kg; 95% CI, −13.3 to −5.1 kg; P < .001), waist circumference (−7.0 cm; 95% CI, −10.6 to −3.3 cm; P < .001), and fat mass (−6.1 kg; 95% CI, −10.2 to −1.9 kg; P = .006) were observed with semaglutide. No differences in lipid levels, liver function, blood pressure, or psychiatric symptoms were observed. Gastrointestinal adverse events were common but mild and transient; psychiatric adverse events were similar across groups.

Conclusions and Relevance  Results of this randomized clinical trial show that adjunctive semaglutide significantly improved glycemic control and weight outcomes in individuals with schizophrenia spectrum disorders. Secondary outcomes were exploratory. These findings support the use of GLP-1RAs as a potential early intervention strategy to reduce cardiometabolic risk in this vulnerable population.

Trial Registration  ClinicalTrials.gov Identifier: NCT04892199

Reference

Sass, M., PhD; Klausen, M., PhD; Schwarz, C., PhD; et al. (2026). Semaglutide and Early-Stage Metabolic Abnormalities in Individuals With Schizophrenia Spectrum Disorders: A Randomized Clinical Trial. JAMA Psychiatry;83(2):128–138.