GLP-1 Medicines for Antipsychotic Weight Gain: What the Liraglutide, Exenatide and Semaglutide Trials Show

Can GLP-1 medicines offset antipsychotic weight gain? In randomized trials of people with schizophrenia, they have. Semaglutide, liraglutide and exenatide all reduced weight and blood sugar compared with placebo or usual care, and in a 2026 network meta-analysis of 39 drugs tested for this problem, semaglutide had the largest weight reduction among those backed by moderate-certainty evidence. The trials are small, though, and none of them tested a microdose.

Antipsychotic weight gain is not a cosmetic side effect. People with schizophrenia have a 2- to 3-fold higher mortality rate than the general population, mostly from cardiovascular disease, according to the authors of the first liraglutide trial in this group. Clozapine and olanzapine, two of the most effective antipsychotics, are also the ones that push weight, glucose and triglycerides up the most.

This article covers how much weight different antipsychotics add, what each GLP-1 trial in this population found, how the GLP-1 drugs compare with metformin and topiramate, and what happens after treatment stops.

Which antipsychotics cause the most weight gain?

Pillinger and colleagues, Lancet Psychiatry, 2020

Clozapine and olanzapine cause the most. Pillinger and colleagues pooled 100 blinded randomized trials covering 25,952 patients and 18 antipsychotics. The median trial lasted only 6 weeks, and even in that short window clozapine added 3.01 kg against placebo, while haloperidol sat at -0.23 kg. Clozapine also raised triglycerides by 0.98 mmol/L and fasting glucose by 1.05 mmol/L, the largest increases in the analysis.

Aripiprazole, brexpiprazole, cariprazine, lurasidone and ziprasidone had the most benign metabolic profiles. Higher starting weight and male sex predicted larger glucose increases, and non-white ethnicity predicted larger cholesterol increases.

One finding explains why switching drugs is often not the answer. In the same analysis, improvement in psychotic symptoms went along with gains in weight and BMI. The antipsychotics that help some people most can be the ones that cost them most metabolically, which is why adding a weight medicine rather than changing the antipsychotic has become a serious research question.

Does liraglutide work for clozapine and olanzapine weight gain?

Larsen and colleagues, JAMA Psychiatry, 2017

In the first proper test, liraglutide worked. Larsen and colleagues randomized 103 adults with schizophrenia spectrum disorders at two Danish sites. Everyone was on stable clozapine or olanzapine, had prediabetes and was overweight or obese, with a mean BMI of 33.8. They took a once-daily liraglutide or placebo injection for 16 weeks, with the dose titrated over the first 2 weeks.

The main target was blood sugar, and the result was striking. 63.8% of the liraglutide group developed normal glucose tolerance, against 16.0% on placebo, a number needed to treat of 2. Body weight fell 5.3 kg more than on placebo. Waist circumference dropped 4.1 cm, systolic blood pressure 4.9 mm Hg and LDL cholesterol 15.4 mg/dL relative to placebo.

Side effects were mainly gastrointestinal, and 93.2% of randomized participants completed the trial. For a population where adherence to any extra medicine is often hard, that completion rate mattered as much as the weight result. The glucose side of this story links to our article on GLP-1 medicines and prediabetes.

What did the HISTORI semaglutide trial find?

Ganeshalingam and colleagues, JAMA Psychiatry, 2025

HISTORI found semaglutide cut weight by 9.21 kg against placebo over 30 weeks. The trial enrolled 154 adults aged 18 to 60 with schizophrenia, prediabetes and a BMI of 27 or more, all on second-generation antipsychotics, through community mental health services in two Danish regions. Semaglutide was titrated to 1.0 mg a week over 8 weeks, lower than the top dose used in the semaglutide obesity trials.

HbA1c fell 0.46 points more than on placebo, and 81% of the semaglutide group ended with an HbA1c under 5.7%, out of the prediabetes range, against 19% on placebo. Physical quality of life rose by 3.75 points on the SF-36. Retention was high: 96% of the semaglutide group finished, against 87% of the placebo group.

The psychiatric safety result is the one clinicians watch most closely. Semaglutide had no significant effect on PANSS-6 symptom scores or on mental quality of life, so psychotic symptoms did not worsen. Gastrointestinal symptoms were more frequent on semaglutide, and the authors reported somewhat more hospitalizations in the semaglutide group, but the number of serious adverse events did not differ between groups. Broader mood findings are covered in our article on GLP-1 medicines and suicidal thoughts.

What about exenatide?

Siskind and colleagues, the CODEX trial, 2018

Exenatide helped, but less. The Australian CODEX pilot randomized 28 obese adults on clozapine to once-weekly extended-release exenatide or usual care for 24 weeks. The trial was open label, so participants knew which group they were in. Six people on exenatide lost more than 5% of their body weight, against one on usual care.

Mean weight change was -5.29 kg on exenatide against -1.12 kg on usual care, and HbA1c moved -0.21% against 0.03%. The other parts of the metabolic syndrome did not change significantly. With only 14 people per group, CODEX was a feasibility study, and it is best read as an early signal that sits alongside the larger liraglutide and semaglutide trials.

Is a GLP-1 better than metformin for antipsychotic weight gain?

Stogios and colleagues, JAMA Psychiatry, 2026

On the current evidence, semaglutide produces the biggest effect, while metformin has the deepest evidence base. Stogios and colleagues pooled 95 randomized trials of 39 drugs in 5,898 antipsychotic-treated patients with schizophrenia spectrum disorders. Against placebo, semaglutide was associated with 10.98 kg of weight loss, liraglutide 5.43 kg, topiramate 3.95 kg, metformin 3.86 kg and exenatide 2.97 kg. All five estimates were rated moderate certainty.

The numbers of trials behind each estimate differ sharply. Metformin rested on 16 trials, semaglutide on 3 and liraglutide on 2. Only semaglutide and metformin produced a clinically meaningful weight change of 5% or more. The authors found no major differences in gastrointestinal side effects or dropouts between the drugs.

A separate 2026 meta-analysis by Moubarak and colleagues, limited to GLP-1 drugs, pooled 8 randomized trials and 664 patients. It found an average weight reduction of 6.74 kg, a semaglutide subgroup estimate of 11.06 kg, and higher rates of nausea, vomiting and constipation, with serious adverse events and discontinuations similar to control. Combining a GLP-1 with metformin is a separate question, covered in our article on metformin and GLP-1s together.

Who loses the most weight on a GLP-1 while taking antipsychotics?

Siskind and colleagues, Diabetes, Obesity and Metabolism, 2019

People on clozapine or olanzapine lose the most. Siskind and colleagues pooled participant-level data from 3 trials, two of exenatide and one of liraglutide, covering 164 patients with a mean body weight of 105.8 kg. After about 16.2 weeks, the GLP-1 groups had lost 3.71 kg more than controls, and the number needed to treat for a weight loss of 5% or more was 3.8.

The split by antipsychotic was the most useful result. In the 141 patients on clozapine or olanzapine, the GLP-1 drugs produced 4.70 kg of extra weight loss. In the 27 on other antipsychotics, the figure was 1.5 kg, and that estimate was not statistically significant. Sex, age, psychosis severity and which GLP-1 drug was used did not change the outcome.

One plausible reading is that the GLP-1 drugs work best where the antipsychotic has pushed metabolism furthest off course. The authors were careful, though: with so few patients, they said more studies were needed before routine use could be recommended.

How common is nausea on a GLP-1 with antipsychotics?

The main tolerability cost

Nausea affects about half of people in these trials. In the Siskind participant-level analysis, 53.6% reported nausea on a GLP-1 receptor agonist, against 27.5% on control, a number needed to harm of 3.8. Nausea did not predict how much weight people lost, so it is not a sign that the drug is working.

The control rate is worth noticing. More than a quarter of people on placebo or usual care also reported nausea, a reminder that antipsychotics and their other side effects already affect the gut. Constipation needs particular attention in people on clozapine, which is itself known for slowing the gut, and the Moubarak meta-analysis found constipation was more common on GLP-1 drugs than on control. Slow titration was built into every trial here: 2 weeks for liraglutide and 8 weeks for semaglutide. Practical ways to manage the problem are in our guide to GLP-1 nausea and vomiting.

What happens after the GLP-1 is stopped?

Svensson and colleagues, Acta Psychiatrica Scandinavica, 2019

Part of the weight loss lasts, and the metabolic gains do not. Svensson and colleagues re-examined the Danish liraglutide participants 1 year after the 16-week treatment ended. Body weight had risen in the liraglutide group since the end of treatment. Compared with baseline, the placebo-subtracted loss was still 3.8 kg, down from 5.3 kg at the end of the trial.

Fasting glucose, HbA1c, C-peptide and blood lipids had all returned to baseline levels. The antipsychotic, the underlying driver, was still there after the GLP-1 was gone. That pattern matches what is seen in the general obesity trials, and it frames the treatment as ongoing rather than a short course. Our article on GLP-1 maintenance looks at what the step-down evidence shows.

Has microdosing a GLP-1 been tested in people on antipsychotics?

What the evidence can and cannot support

No. Every trial described here used a standard dose: daily liraglutide titrated over 2 weeks, weekly extended-release exenatide, or semaglutide titrated to 1.0 mg a week. HISTORI's dose is lower than the top obesity dose, but it is still a full approved diabetes dose, not a microdose.

There are reasons someone might wonder about a lower dose in this group. Nausea was common, and many people taking antipsychotics already deal with sedation, constipation and other side effects. But the weight and glucose effects in these trials were measured at full doses, and there is no evidence on whether a fraction of the dose would keep enough of them.

The safest conclusions are narrow. GLP-1 drugs have the strongest trial evidence of any add-on for antipsychotic weight gain, especially with clozapine or olanzapine. No one should stop or change an antipsychotic to manage weight without their psychiatrist, and any GLP-1 use in this setting should be planned with both the psychiatric and the prescribing clinician.

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