Can Metformin Curb Weight Gain From Antipsychotics?

Weight gain is one of the biggest barriers to staying on antipsychotic treatment in young people, and researchers in the United States have now taken the largest look to date at how to manage it.

A 2-year trial across 64 clinics found that metformin, a low-cost diabetes drug, produced a modest but steady reduction in antipsychotic-related weight gain.

Metformin and antipsychotic-related weight gain in youth

Young people diagnosed with bipolar spectrum disorders are often prescribed second-generation antipsychotics. These medicines help stabilize mood, but they also bring a persistent problem: rapid weight gain. This effect is stronger in children and teenagers than in adults, and it can set off a chain of health issues. Studies report that well over half of young people on these medicines put on significant weight, often within the first few months.

Extra weight increases the risk of heart disease and problems with insulin and cholesterol. These health risks can add stress for families and make it harder for young people to stay on their medication.

Co-author Dr. Christina Klein, a research associate professor at the University of Cincinnati, explained: “You’re not just looking at the mental health, but you're looking at the physical health of the whole person.”

Clinicians have tried to manage this weight gain through lifestyle advice focused on food and exercise, but these programs tend to have a modest impact. They can also be hard for families to follow, and sometimes even reinforce unhelpful messages about weight.

Because of these limits, researchers have turned to metformin, a common diabetes drug that, in several small trials, reduced weight gain linked to antipsychotics. These early studies were short, usually running for only a few months, and involved relatively small groups of young people. Metformin also isn’t widely used in practice, despite the early data, with only a small fraction of eligible patients receiving it.

The MOBILITY trial aimed to understand whether metformin would work in everyday clinics, outside of tightly controlled research settings.

Testing metformin in real-world clinical settings

The study was designed to reflect everyday clinical practice rather than a tightly controlled lab setting, using a randomized, open-label trial that followed 1,565 young people aged 8–19 years who were overweight or living with obesity, and had a bipolar spectrum or related mood disorder. All were taking, or about to start taking, a second-generation antipsychotic.

Each participant was assigned to one of two groups. One group received metformin plus a short, seven-minute session on healthy eating and activity (MET+LIFE). The other group received the lifestyle session alone (LIFE). The trial took place across 39 community clinics and 25 academic centers in the United States, and the team followed participants for up to 24 months.

At 6 months, the metformin group showed a modest drop in BMI Z-score compared with the lifestyle-only group, a difference that was still present at 24 months, although smaller.

However, some of the reduction may be linked to cross-over, as more than a third of the LIFE group eventually started metformin.

Changes in metabolic markers were small, with participants taking metformin seeing a slightly smaller drop in HDL cholesterol, and there were no clear group differences in glucose or insulin markers. However, only one in five participants had follow-up blood tests.

Gastrointestinal symptoms were more common in the metformin group, resulting in ~11% of participants stopping the medication, but no unexpected reactions were reported. Serious events and reports of suicidal thoughts were similar between groups. Young people who reached a daily dose of 1,500 mg or higher saw slightly better outcomes.

Metformin use in routine care

MOBILITY is the largest and longest study to test metformin in young people taking antipsychotics, and it shows a consistent, modest effect on limiting weight gain.

“The effect on weight is modest, but for most patients the benefits of metformin outweigh the risks,” said Klein.

Metformin is also low-cost, widely available and has a long history of safe use.

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“The suggestion is that clinicians prescribe metformin for youths who have bipolar spectrum disorders who are overweight or obese and are treated with a second-generation antipsychotic,” Klein added.

Using metformin from the start of antipsychotic treatment could support long-term physical health and may make it easier for young people to stay on the medication they need.

Other weight-loss drugs, such as GLP-1 agonists, are getting attention; however, they come with barriers. They are expensive and there is little information on how safe they are for young people with mental health conditions.

However, the study does have limitations. Only a small number of participants were new to antipsychotics, making it harder to judge how well metformin prevents early weight gain. Many participants did not complete lab tests, which restricts the metabolic findings.

The authors point to several areas for future work, including better behavioral programs that do not add pressure or stigma. More research into which young people respond best, and the development of antipsychotics with lower metabolic impact, would also move the field forward.

“The results of MOBILITY are consistent with recent practice guidelines and support the new standard of care: youth with overweight or obesity should be started on metformin at the same time a second-generation antipsychotic is initiated,” concluded lead author Dr. Melissa DelBello, the Dr. Stanley and Mickey Kaplan Endowed Chair and Professor at the University of Cincinnati.

Reference: DelBello MP, Welge JA, Klein CC, et al. Metformin for overweight and obese children and adolescents with bipolar spectrum and related mood disorders treated with second-generation antipsychotics: a randomised, pragmatic trial. Lancet Psychiatry. 2025;12(12):893-905. doi: 10.1016/S2215-0366(25)00273-1

This article is a rework of a press release issued by the University of Cincinnati. Material has been edited for length and content.