Metformin reduces weight gain in young people taking antipsychotics

People walking on a street pictured from above with long shadows

In the past decade, accumulating evidence has shown the efficacy of second-generation antipsychotics (SGA) for young people with bipolar spectrum disorder (Garcia-Rodriguez et al., 2023; DeBello et al., 2022). Consequently, SGA are now routinely prescribed in this population (Doane et al., 2021). However, a major concern with SGA treatment, especially in young people, is substantial weight gain (Collares et al., 2025).

Discontinuing SGA without an alternative treatment is not an option for many young people with bipolar spectrum disorder. Thus, strategies and interventions to successfully manage this side effect are needed. One potential strategy is the adjunction of metformin, a first-line medication, usually used to manage type-2 diabetes that works by reducing liver glucose production and increasing insulin sensitivity (Foretz et al., 2023).

In this study (DelBello et al, 2025), the authors conducted a large pragmatic trial investigating the short- and long-term effectiveness of metformin in overweight or obese young people with a current or historical bipolar spectrum disorder receiving second-generation antipsychotics treatment. The effects of metformin are evaluated for up to 24 months for the first time. Authors hypothesised that metformin in combination with a healthy lifestyle intervention would mitigate weight gain and related metabolic markers more than a healthy lifestyle intervention alone.

Despite being widely prescribed to treat young people with bipolar disorder, second-generation antipsychotics can often cause considerable weight gain, which increases the risk of cardiovascular disease and premature mortality.

Methods

The study was a multi-site, open-label, pragmatic parallel group randomised superiority trial.

Eligible participants were:

aged 8-19 years old;
had a BMI at or greater than the 85th percentile;
were diagnosed with either of the following: bipolar I, bipolar II, unspecified bipolar and related disorders, cyclothymic disorders, other specified bipolar and related disorders, disruptive mood dysregulation disorder or mood disorder not otherwise specified; and
received a new or ongoing prescription for a second-generation antipsychotic (SGA).

Participants were recruited across 64 clinical sites in the USA from November 2015 to February 2022 and were followed for up to 24 months. Sites were selected to maintain a geographically, racially, ethnically, and socioeconomically diverse and clinically representative sample.

Participants were randomly assigned to (a) metformin and a brief healthy diet and exercise education [MET plus LIFE] or to (b) only the brief healthy diet and exercise education [LIFE]; and stratified in a 1:1 ratio on the following factors: (1) baseline BMI percentile (85^th to <95^th vs >95^th), (2) SGA naïve (starting vs continuing), (3) sex-assigned at birth.

The primary outcomes were changes in BMI after 6 months and 24 months. Secondary outcomes included change in metabolic measures (high-density lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol, triglycerides, glucose, glycated haemoglobin, and insulin), and patient-reported adherence and treatment satisfaction, clinician-rated psychiatric symptoms, overall functioning and weight-related quality of life.

Results

A total of 1,565 young people were randomly assigned to receive either MET plus LIFE (N=777; Mean age=13.9±2.8; 47% Female; 66% White; Mean baseline BMI=29.5±6.2) or LIFE only (N=788; Mean age=13.9±2.9; 47% Female; 64% White; Mean baseline BMI=29.1±5.9).

Participants with no follow-up data (n=228) were excluded from the analyses. Thus, 565 participants in the MET plus LIFE group and 687 participants in the LIFE group had data at 6 months, and 579 vs 720 participants, respectively, at 24 months.

Participants receiving metformin plus lifestyle intervention gained significantly less weight than those receiving lifestyle intervention alone:

At 6 months:

Metformin plus lifestyle group: BMI increased by 0.05
Lifestyle-only group: BMI increased by 0.64
Effect size: 0.26 (95% CI 0.15 to 0.37, p<0.001)

At 24 months:

Metformin plus lifestyle group: BMI increased by 0.58
Lifestyle-only group: BMI increased by 1.07
Effect size: 0.11 (95% CI 0.00 to 0.22, p=0.047)

In other words, metformin reduced weight gain compared to lifestyle intervention alone, with the strongest effect at 6 months.

HDL levels decreased significantly less in the MET plus LIFE participants compared to those in the LIFE group. There were no significant changes on other metabolic parameters, psychiatric outcomes measures, or functioning and quality of life outcomes at either time points.

None of the investigated stratified factors (BMI class, sex assigned at birth, age at randomisation, race, ethnicity, insurance type, insulin resistance, SGA type, and duration of SGA exposure) had a significant moderator role on the effect of metformin on BMI change at 6 months and 24 months.

Gastrointestinal events, considered adverse events, were 2-4 times more common in the MET plus LIFE group. There were no other between-group differences in commonly reported side effects or adverse events. However, a total of 45 suicide attempts were recorded within the duration of the study.

Additionally, 34% (n=195 of 579) of participants in the MET plus LIFE group discontinued the treatment. The main reason (n=80) was gastrointestinal events, followed by non-adherence (n=55) and lack of efficacy (n=28). On the opposite, 38% (n=271 of 720) of participants assigned to the LIFE group subsequently started to take metformin, weight gain or failure to lose weight as predominant reason.

MOBILITY was a pragmatic, open-label, randomised trial following the effects of metformin on weight gain for up to 24 months for the first time.

Conclusions

In a large sample of overweight or obese young people with bipolar disorder and prescribed second-generation antipsychotics (SGA), metformin was found effective at mitigating weight gain, although average effects were modest. This study was the first to examine the effects of metformin for up to 24 months. Overall, metformin was safe and generally well tolerated.

The authors concluded by recommending that:

metformin should be routinely prescribed when young people initiate or continue treatment with second-generation antipsychotics.

They also state the future research on novel pharmacological interventions and structured behavioural strategies targeting healthy eating and exercise are needed.

A women looks up a sun drenched path with her hands on her head

Metformin plus a healthy lifestyle intervention had a significant, yet modest, effect in mitigating weight gain at 6 months and 24 months.

Strengths and limitations

The main strength of this study is its use of a pragmatic trial design (Ford & Norrie, 2016). While exploratory trials investigate if and how an intervention works in a controlled setting (i.e. the efficacy), pragmatic trials focus on whether an intervention actually works in real life or routine practice settings (i.e. the effectiveness). This approach maximises feasibility and generalisability and usually allows for a larger sample size. Thus, while effect sizes were modest, they better reflect what could be expected of an integration of metformin in routine care. Additionally, the large sample size and variety of clinical sites, including community-based mental health centre and academic health centres, allows for high external validity.

Another strength of the study is the reporting of findings in the intention-to-treat sample and in the per-protocol sample. Intention-to-treat approaches analyse participants according to their original group assignment, regardless of adherence or completion, which represent real-world effectiveness, while per-protocol approaches include only those who completed the intervention as intended, thus, reflecting ideal efficacy. Reporting both provides complementary pictures of the effect of the trial.

Despite its strengths, this study also has a few limitations. While pragmatic trials have advantages, they generally offer less experimental control, which may have led to confounding effects. Notably, while second-generation antipsychotics (SGA) had to be prescribed at the randomisation visit, participants remained eligible if their prescription was discontinued. Further, follow-up visits did not take place at identical times for all participants. Instead, these visits were defined as the scheduled clinic appointments closest to the 6-month and 24-month marks. This meant that first follow-up occurred between day 91-274 and, and the second between day 548-913 from the start of assigned treatment.

The authors highlight further limitations of their study and two are of particular importance. First, very few participants were SGA-naïve, i.e. had not previously had this treatment, (N=12 of 1,565; <1%) at baseline. Weight gain linked to SGA use may have already occurred in most participants. Thus, the effectiveness of metformin to prevent weight gain could not be determined (read this blog to learn more about prevention with metformin). Second, more than half of participants (54%) were not titrated to the recommended metformin dose of 1500mg/day, although guidelines for dosing metformin had been provided to clinicians.

Overall, these discrepancies may have diluted the true effect of the intervention.

Person in white coat holding stethoscope

Pragmatic trials allow us to measure the effectiveness of interventions in real-life clinical settings.

Implications for practice

Metformin as adjunctive treatment

Overall, this randomised, pragmatic trial adds support for metformin as an adjunct treatment for young people who experience weight gain while taking second-generation antipsychotics (SGA). The decision to start an antipsychotic treatment should be informed by assessing metabolic risk, including personal and family history, leading to a more personalised prescribing approach. Metformin is a globally affordable and easily accessible treatment. Its widespread integration into treatment of young people taking SGA would not have major additional healthcare costs.

Routine metabolic monitoring

Additionally, this study reinforces the need for routine metabolic monitoring in individuals with severe mental illness. Compared to the general population, young people with bipolar spectrum disorder are at higher risk of being obese and of developing metabolic syndrome (Girela-Serrano et al., 2022). Metabolic syndromes are also risk factors for worse outcomes of bipolar disorder, including poorer global functioning, treatment response, and chronicity of illness (Kadriu et al., 2024). Earlier detection of metabolic disturbances in this population would allow clinics to intervene sooner with potential to improve long-term outcomes.

Physical and mental health care

Finally, the study also highlights the need to not only address mental and psychological symptoms, but also physical health in young people with bipolar spectrum disorder, and more broadly, severe mental illness. Chronic physical health conditions are now widely reported in this population (Pizzol et a., 2023). Multidisciplinary approaches, potentially pharmacological strategies complemented by lifestyle interventions, are needed to improve physical and mental outcomes.

Routine metabolic monitoring in individuals with severe mental illness is key for early identification and better long-term outcomes.

Statement of interests

None declared by Emiliana Tonini.

Edited by

Dr Simon Bradstreet.

Links

Primary paper

Melissa DelBello, Jeffrey Welge, Christina Klein, Thomas Blom, Victor Fornari, Claudine Higdon, Michael Sorter, Brian Kurtz, Cindy Starrj, Andrew Smith, Bin Huang, Chen Chen, Avani Modi, Nancy Crimmins, Christoph Correll, and the MOBILITY Consortium (2025). Metformin for overweight and obese children and adolescents with bipolar spectrum and related mood disorders treated with second-generation antipsychotics: a randomised, pragmatic trial. The Lancet Psychiatry, 12(12), 893–905.