Semaglutide for Antipsychotic Weight Gain: What the Clozapine and Olanzapine Trials Show

Second-generation antipsychotics such as clozapine and olanzapine raise the risk of obesity, prediabetes and type 2 diabetes.^[1] Two Danish randomized trials published in JAMA Psychiatry in 2025 and 2026 found that adding semaglutide to these medicines took off about 9 kg more than placebo over 6 to 7 months, without making psychiatric symptoms worse.^[1][2] A 2026 network meta-analysis of 95 trials ranked semaglutide first of 39 drugs tested for antipsychotic-related weight gain, at about 11 kg more loss than placebo.^[6] This article covers what those trials found, how semaglutide compares with metformin and older options, and the safety points that matter for people on clozapine.

The short answer

• Semaglutide produces substantial weight loss in this group. Two placebo-controlled trials in people taking second-generation antipsychotics each found about 9.2 kg more weight loss with semaglutide 1 mg a week.^[1][2]
• It ranks first among the drugs tested. Across 95 trials, the weight difference against placebo was −10.98 kg for semaglutide, −5.43 kg for liraglutide, −3.95 kg for topiramate, −3.86 kg for metformin and −2.97 kg for exenatide.^[6]
• Psychiatric symptoms did not get worse. Neither trial found a difference in schizophrenia symptom scores, and psychiatric adverse events were similar to placebo.^[1][2]
• The usual side effects apply, and constipation matters more here. Semaglutide roughly tripled the risk of constipation in these trials.^[7] Clozapine already carries an FDA warning for severe gut slowing, so the combination needs watching.^[10]
• The weight comes back if it stops. One year after a 16-week liraglutide course ended, most of the metabolic gains had disappeared.^[5]

Why antipsychotics cause weight gain, and why it matters

The trials below describe people with schizophrenia as being at “heightened risk for obesity, prediabetes, and type 2 diabetes, contributing to increased cardiovascular morbidity and premature mortality.”^[1] The older liraglutide trial notes that people with schizophrenia have a 2- to 3-fold higher mortality rate, mainly from heart disease, and that earlier attempts to counteract antipsychotic weight gain had “limited effects.”^[4]

Switching antipsychotics is not always an option. Clozapine, for example, is FDA-approved for “severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.”^[10] So for many people the real question is how to manage the weight while staying on the medicine that keeps them well.

The 2025–2026 semaglutide trials

HISTORI was the larger trial. It ran in community mental health services in two regions of Denmark, and 96% of people on semaglutide completed it. Semaglutide lowered HbA1c by 0.46 percentage points, and 81% of people on it reached an HbA1c below 5.7% compared with 19% on placebo. HDL cholesterol rose and triglycerides fell. Physical quality of life improved by 3.75 points on the SF-36, but there was “no significant effect on mental QoL scores or PANSS-6 score,” the schizophrenia symptom scale.^[2] A follow-up analysis estimated that about half of the physical quality-of-life gain at week 30 came through the weight loss itself, but that indirect effect was “not statistically significant,” so it is a hint rather than a finding.^[3]

The Sass trial focused on people earlier in the process: within five years of starting clozapine or olanzapine, with blood sugar only starting to rise. At 26 weeks, 43% of people on semaglutide had an HbA1c in the low-risk range (below 5.4%) compared with 3% on placebo. The authors found “no differences in lipid levels, liver function, blood pressure, or psychiatric symptoms.”^[1] They frame semaglutide as a possible early intervention, started before diabetes sets in.

A 2026 meta-analysis pooled three semaglutide trials (258 people, 1.0–2.0 mg for 26–36 weeks) and found −11.32 kg of weight loss and −0.37% HbA1c compared with placebo. No trials of tirzepatide in this population had been published.^[7]

How semaglutide compares with metformin and other options

The most complete comparison is a 2026 JAMA Psychiatry network meta-analysis of 95 randomized trials (5,898 people) testing 39 drugs for weight loss in people taking antipsychotics for schizophrenia-spectrum disorders.^[6]

Only semaglutide and metformin produced weight change of 5% or more, which the authors treated as clinically meaningful. The review found “no major concerns with gastrointestinal adverse effects or leaving the study early” across the drugs.^[6] Metformin has far more trials behind it and is cheap, so many psychiatrists still try it first. Semaglutide produces about three times as much weight loss, but rests on only three trials.

The earlier GLP-1 evidence came from liraglutide. In a 2017 trial of 103 people on clozapine or olanzapine with prediabetes, 16 weeks of daily liraglutide reduced weight by 5.3 kg more than placebo, and 63.8% developed normal glucose tolerance compared with 16.0% on placebo.^[4]

What happens after stopping

The liraglutide trial followed people for a year after the 16 weeks of treatment ended. Weight crept back up, though people were still 3.8 kg lighter than the placebo group. Fasting glucose, HbA1c and lipids “had each returned to baseline levels.”^[5] An Australian open-label study of semaglutide in people on clozapine or olanzapine found the same pattern: −9.8% body weight at 24 weeks, falling to −5.1% a year after the drug was stopped.^[9]

This matches what happens in the general population, covered in our review of rebound weight gain after stopping GLP-1s. For someone who will be on clozapine for years, a GLP-1 should be thought of as long-term treatment rather than a short course.

Safety points for people on antipsychotics

Constipation and clozapine

In the pooled semaglutide trials, the drug raised the risk of constipation (risk ratio 3.23), vomiting (2.57) and abdominal pain (2.93), with no increase in serious adverse events.^[7] This needs particular attention with clozapine, because its own label carries a warning for gut slowing:

“Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus.”

— CLOZARIL (clozapine) US Prescribing Information §5.7, DailyMed

The Wegovy label, separately, warns that semaglutide “causes a delay of gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications,” and advises more monitoring for oral drugs “that have a narrow therapeutic index or that require clinical monitoring.”^[11] Neither label addresses the combination directly, so anyone adding semaglutide to clozapine, lithium or another medicine that needs regular blood tests should agree a plan with their prescriber for watching bowel habits and drug levels. For practical constipation steps, see our GLP-1 constipation protocol. If you take lithium, see GLP-1s with lithium and mood stabilizers.

Mental health

Neither randomized trial found that semaglutide worsened psychotic symptoms. In the Sass trial, “psychiatric adverse events were similar across groups.”^[1] HISTORI reported no change in symptom scores, and the number of serious adverse effects did not differ between groups, though a few people on semaglutide were hospitalized more often than those on placebo.^[2] The trials were small and lasted under a year, so rare psychiatric effects can't be ruled out. For the broader evidence, see GLP-1s, depression and suicidality.

Could it lower the death rate? What the observational data suggest

People with schizophrenia have a 2- to 3-fold higher death rate than the general population, mainly from heart disease.^[4] A 2026 study of more than 1.5 million propensity-matched adults compared people starting a GLP-1 drug with people starting an SGLT2 inhibitor, with separate groups for people with and without serious mental illness (bipolar disorder, major depression or schizophrenia). Among those with serious mental illness, deaths over four years were lower in the GLP-1 group: 4.91% compared with 6.45% (hazard ratio 0.76). The authors said the benefit was “driven by semaglutide and tirzepatide.”^[8]

This is an observational study of health records. It compares two active drugs, not a GLP-1 drug with no treatment, and the main result pools bipolar disorder, depression and schizophrenia. Results for people with diabetes and for schizophrenia alone came from sensitivity and exploratory analyses. It shows an association, not proof that the drug caused the lower death rate, and the authors call for randomized trials.

Getting it prescribed and covered

No FDA label lists antipsychotic-induced weight gain as an indication. Wegovy is approved for adults “with obesity” or “with overweight in the presence of at least one weight-related comorbid condition,”^[11] and many people on clozapine or olanzapine meet those criteria. Prediabetes, which most people in these trials had, can count in some coverage rules. Medicare's temporary GLP-1 Bridge, for example, accepts a BMI of 27 or more with prediabetes. See what disqualifies you from semaglutide for the label rules and GLP-1 insurance coverage for how Medicaid and commercial plans handle weight-loss prescriptions. The trials used semaglutide 1.0 mg weekly, not the 2.4 mg Wegovy dose, and none tested compounded semaglutide.

Bottom line

For people who need clozapine or olanzapine and are gaining weight, semaglutide now has the strongest randomized evidence of any add-on drug. That means about 9–11 kg more weight loss than placebo, better blood sugar, and no sign so far that it worsens psychiatric symptoms. The trials are small and short, constipation needs watching on clozapine, and the benefits fade when the drug stops. It is a decision for the psychiatrist and the prescriber together, not a reason to change or stop the antipsychotic.