It’s my first day again in the neighborhood psychological well being clinic working as a psychiatric resident physician. Brompton within the nook, Kelston Roundhill out the window. Jim’s telling me that the threatening voices have began coming again. After some dialogue, I’m telling Jim I believe he ought to restart an antipsychotic. He explains that aripiprazole made him stressed and solely olanzapine labored nicely final time, however he gained a whole lot of weight. What ought to we do?
The 2020 Maudsley Superior Prescribing in Psychosis Tips inform me prevention of weight acquire is best than remedy, and that weight loss program, train, switching antipsychotics or including aripiprazole, metformin, topiramate, orlistat or Glucagon-Like Peptide-1 (GLP-1) receptor agonists may also help (Morrison et al., 2020). A 2022 Cochrane Evaluate tells me that there’s low certainty proof from 4 randomised managed trials (RCTs) that metformin could also be efficient in stopping weight acquire (Agarwal et al., 2022). A Psychological Elf weblog from final month highlights a 2025 Lancet Fee report, which recommends including metformin if beginning clozapine or olanzapine (Lawson, 2025).
Effectively, these assets are suggesting metformin, however I can’t bear in mind ever seeing a affected person beginning metformin similtaneously an antipsychotic. What’s going on? Am I a nasty physician? Including to my confusion, the 2025 Maudsley Prescribing Tips in Psychiatry say that medicines to deal with weight acquire ought to solely be thought of if way of life interventions or antipsychotic switching haven’t labored or weight problems is a direct bodily threat (Taylor et al., 2025). It will be nice to see what clinicians are doing across the UK. Fortunately, some glorious psychiatric epidemiologists have already had that very same thought (Trajano et al., 2025).
Regardless of robust guideline help for utilizing metformin to forestall weight acquire attributable to antipsychotic remedy, its use in observe stays unusual, elevating questions on scientific habits and real-world prescribing.
Strategies
Trajano and colleagues used two major care databases from the Medical Apply Analysis Datalink to determine 26,537 sufferers who began aripiprazole, olanzapine, quetiapine or risperidone between 2005 and 2019, and had beforehand had schizophrenia, bipolar dysfunction or different non-organic psychoses famous of their data.
In Half 1, they measured whether or not these individuals have been ever prescribed metformin and when. Then, for those who weren’t initially prescribed metformin, they measured the cumulative incidence of being prescribed metformin 1 and a couple of years down the road. In addition they measured the proportion of antipsychotic customers prescribed metformin annually.
In Half 2, they in contrast the traits of these prescribed metformin inside 2 years of beginning the antipsychotic in comparison with these not ever prescribed any metformin.
In Half 3, they in contrast the adjustments in weight between sufferers who began metformin when beginning the antipsychotic and those who by no means took metformin. In addition they stratified by substance in addition to utilizing multivariate linear regression fashions to estimate the impact of beginning metformin. Mannequin 1 was adjusted for baseline weight alone and mannequin 2 included baseline weight plus antipsychotic remedy, age at index date, ethnicity, social deprivation, prior prognosis of diabetes and prior prognosis of poly-cystic ovarian syndrome (PCOS).
Outcomes
Half 1
Of the 26,537 sufferers who began an antipsychotic, 2,873 had began metformin earlier than beginning the antipsychotic. Among the many remaining 23,664, there was a cumulative incidence of 1.9% beginning metformin inside a yr and three.3% beginning it inside 2 years. This equated to 696 individuals beginning metformin inside 2 years. 1,083 began metformin greater than 2 years after beginning an antipsychotic, and 21,885 by no means took metformin.
The proportion of individuals prescribed metformin elevated from 1.31% in 2005 to five.84% in 2017.
Half 2
In comparison with the 21,885 that by no means took metformin, the 696 that took metformin inside 2 years of beginning the antipsychotic have been extra prone to have diabetes, have hypertension, be overweight, and take lipid-regulating medicines. There have been additionally extra delicate variations in recorded ethnicity and native relative deprivation and the proportion with schizophrenia, dyslipidaemia, PCOS (polycystic ovarian syndrome), insulin-prescriptions, in addition to imply HbA1c and glucose ranges. Distributions of intercourse, ages, geographical areas and different well being situations and medicines appeared comparable between the 2 teams. It appeared like 51% of these beginning metformin had documented diabetes or PCOS as possible indications for its use.
Half 3
The 21,885 sufferers who by no means began metformin have been 76.1kg on common when beginning the antipsychotic and 78.7kg two years later. So, their weight elevated 4.2% on common. 212 sufferers began metformin between 1 month earlier than and three months after beginning the antipsychotic. On common they have been 90.4kg at the beginning and 89.3kg at 2 years, thus shedding 0.7% on common. There have been no clear variations between totally different antipsychotics within the stratified analyses.
The authors then estimated weight at 2 years utilizing a linear regression mannequin that included solely metformin use and baseline weight as unbiased variables. Females that took metformin have been predicted to be 2.04 kg lighter (95percentCI: -0.47 to 4.55) than females that didn’t, and males 3.02 kg lighter (95percentCI: 0.20 to five.84). When utilizing a mannequin that additionally included antipsychotic remedy, age at index date, ethnicity, social deprivation, prior prognosis of diabetes and prior prognosis of PCOS, the values have been 1.48 kg (95percentCI: -1.07 to 4.03) amongst females and 1.84 kg (95percentCI: -0.98 to 4.67) amongst males.
Amongst over 26,000 sufferers beginning antipsychotics, metformin was not often prescribed, sometimes reserved for these with diabetes or polycystic ovarian syndrome, and its use was related to modest weight reduction in comparison with those that by no means obtained it.
Conclusions
The authors concluded that:
- There’s low utilisation of metformin, regardless of pointers supporting its use,
- Additional research are required to reliably estimate the impact of metformin exterior of trial settings and who may profit most, and
- Clinicians want clear steerage on implementing present steerage round cardiometabolic care when utilizing second era antipsychotics.
Metformin stays underused regardless of guideline help, and clearer implementation methods and additional real-world analysis are wanted to information its function in cardiometabolic care alongside second era antipsychotics.
Strengths and limitations
It’s thrilling to see the researchers harness giant population-representative datasets to evaluate clinically necessary questions:
- Are we prescribing metformin?
- Who’re we prescribing it to?
- Are we seeing the anticipated results on weight acquire?
Strengths of the examine embody the big examine inhabitants and detailed comparability between these beginning metformin and never. Being based mostly on routinely collected information in major care, it needs to be at low threat of the wholesome volunteer bias and Hawthorne impact (i.e., behaviour change in response to being noticed) and the sharing of analytical code is invaluable for understanding and constructing upon this work.
The information supply and broad inclusion standards imply that examine inhabitants must also be consultant of the broader inhabitants beginning antipsychotics. Nevertheless, with the common age of sufferers coming into this examine being over 50 years previous, the outcomes will not be generalisable to youthful adults of the ages at which extreme psychological sickness (SMI) is more than likely to be first identified. The exclusion of over 120,000 sufferers due being registered on the GP for lower than 6 months or not having a file of SMI earlier than the antipsychotic, probably contributed to underrepresentation of younger adults. Whereas these exclusion standards have been vital for examine validity and relevance, the exclusion of 36,800 sufferers (as a result of there have been no lipids or HbA1c recorded in prior 2 years) was probably pointless and a contributor to choice bias.
One other limitation is that at every time level after antipsychotic initiation solely 33 to 41% of contributors had weight recorded (Richards-Belle et al., 2025). The authors stuffed within the lacking information based mostly on the idea that the likelihood of a variable being lacking may be calculated from noticed information. Nevertheless, this will not be legitimate as individuals who acquire weight are maybe extra prone to get their weight measured. Sensitivity analyses might be used to estimate the believable impression of this (Madley-Dowd et al., 2025), however it might be further difficult as a result of the connection between weight acquire and whether or not weight is measured might be affected by whether or not somebody is taking metformin.
Ideally, for a fuller image of healthcare practices this examine would additionally embody info on secondary care prescribing or different weight administration interventions. Further limitations referring to half 3 of the examine are the inherent issue in causal analyses of weight adjustments (Tennant et al., 2023) and the inevitable presence of unmeasured confounding. Lastly, it’s a disgrace that there was an absence of energy to check outcomes between antipsychotics: we’d count on the usefulness of metformin to be higher for these beginning olanzapine than aripiprazole.
This massive examine makes use of consultant information to discover metformin prescribing and weight outcomes, however exclusions, lacking data, and confounding restrict its relevance to youthful sufferers and broader prescribing choices.
Implications for observe
Half 1 of this examine needs to be a wake-up name that we’re most likely not doing sufficient to forestall or handle antipsychotic induced weight acquire.
Half 2 of this examine signifies that even among the many few individuals co-prescribed metformin, the explanation was largely diabetes or PCOS, once more reinforcing the message that we don’t appear to be specializing in the prevention of weight acquire sufficient.
Half 3 of the examine serves as a contribution to triangulating the proof across the impact of metformin in stopping antipsychotic-induced weight acquire. We had proof from RCTs that metformin helps stop weight acquire, however these research might not have been very generalisable and will have been affected by volunteer bias or the Hawthorne impact. That this examine of major care data attracts comparable conclusions, regardless of having totally different sources of bias, strengthens our confidence within the conclusions (Lawlor et al., 2016).
What different types of observational proof might reinforce the conclusion that metformin helps stop weight acquire? We may carry out cross-context comparisons utilizing different nations with totally different healthcare techniques and confounding constructions. Alternatively, we may examine the outcomes to these for a adverse management publicity that we don’t count on to trigger giant weight reduction, akin to statins, or a adverse management consequence that we don’t count on to be affected by metformin, for instance blood strain in non-diabetic sufferers. Finally, there stays sufficient uncertainty in regards to the professionals, cons and affected person experiences round beginning metformin with antipsychotics that inclusive RCTs with substantial follow-up instances seem warranted.
So, ought to Jim begin metformin? If he’s going to start out olanzapine, most likely sure. However first it is going to be necessary to debate the effectiveness of way of life interventions, the potential unwanted side effects of metformin, together with lactic acidosis and vitamin B12 deficiency, and be clear in regards to the ongoing monitoring of this remedy use, whether or not in major or secondary care. Will I like to recommend metformin for everybody beginning second-generation antipsychotics based mostly on the outcomes of this examine? No, we’ll make shared choices based mostly on particular person threat components and preferences, with the assistance of the most recent pointers (e.g. Carolan et al., 2025). Will the rules look the identical in 5 years’ time? GLP-1 agonists will certainly characteristic extra prominently, gained’t they?
Clinicians ought to contemplate metformin for sufferers beginning olanzapine or clozapine, however stay conscious of particular person dangers, the worth of way of life interventions, and the evolving function of newer remedies like GLP-1 agonists.
Assertion of pursuits
I’ve by no means met the authors, but in addition use CPRD for psychiatric epidemiology analysis, and have taken a lot inspiration from their earlier work.
Hyperlinks
Main paper
Farache Trajano L, Hayes JF, Launders N, Davies NM, Osborn DPJ, Richards-Belle A. (2025) Co-prescription of metformin and antipsychotics in extreme psychological sickness: a UK major care cohort examine. BMJ Psychological Well being. 2025;28:e301505. https://doi.org/10.1136/bmjment-2024-301505
Different references
Agarwal, S. M., Stogios, N., Ahsan, Z. A., Lockwood, J. T., Duncan, M. J., Takeuchi, H., Cohn, T., Taylor, V. H., Remington, G., Faulkner, G. E. J., & Hahn, M. (2022). Pharmacological interventions for prevention of weight acquire in individuals with schizophrenia. The Cochrane Database of Systematic Evaluations, 10(10), CD013337. https://doi.org/10.1002/14651858.CD013337.pub2
Carolan, A., Hynes-Ryan, C., Agarwal, S. M., Bourke, R., Cullen, W., Gaughran, F., Hahn, M. Ok., Krivoy, A., Lally, J., Leucht, S., Lyne, J., McCutcheon, R. A., Norton, M. J., O’Connor, Ok., Perry, B. I., Pillinger, T., Shiers, D., Siskind, D., Thompson, A., … O’Donoghue, B. (2025). Metformin for the Prevention of Antipsychotic-Induced Weight Achieve: Guideline Improvement and Consensus Validation. Schizophrenia Bulletin, 51(5), 1193–1205. https://doi.org/10.1093/schbul/sbae205
Lawlor, D. A., Tilling, Ok., & Davey Smith, G. (2016). Triangulation in aetiological epidemiology. Worldwide Journal of Epidemiology, 45(6), 1866–1886. https://doi.org/10.1093/ije/dyw314
Lawson, Ok. (2025, August 13). Bodily well being unwanted side effects of psychotropic remedy. Nationwide Elf Service. https://www.nationalelfservice.internet/remedy/antipsychotics/physical-health-side-effects-of-psychotropic-medication-holistic-prevention-and-management/
Madley-Dowd, P., Hughes, R. A., Mathur, M. B., Heron, J., & Tilling, Ok. (2025). Utilizing directed acyclic graphs to find out whether or not a number of imputation or subsample a number of imputation estimates of an exposure-outcome affiliation are unbiased (No. arXiv:2503.24035). arXiv. https://doi.org/10.48550/arXiv.2503.24035
Morrison, P., Taylor, D. M., & McGuire, P. (2020). The Maudsley pointers on superior prescribing in psychosis (pp. xii, 93). Wiley Blackwell.
Richards-Belle, A., Launders, N., Hardoon, S., Richards, A., Man, Ok. Ok. C., Davies, N. M., Bramon, E., Hayes, J. F., & Osborn, D. P. J. (2025). Comparative cardiometabolic security and effectiveness of aripiprazole in individuals with extreme psychological sickness: A goal trial emulation. PLOS Medication, 22(1), e1004520. https://doi.org/10.1371/journal.pmed.1004520
Taylor, D. M., Barnes, T. R. E., & Younger, A. H. (2025). The Maudsley Prescribing Tips in Psychiatry. John Wiley & Sons.
Tennant, P. W. G., Tomova, G. D., Murray, E. J., Arnold, Ok. F., Fox, M. P., & Gilthorpe, M. S. (2023). Lord’s ‘paradox’ defined: The 50-year warning on the usage of ‘change scores’ in observational information (No. arXiv:2302.01822). arXiv. https://doi.org/10.48550/arXiv.2302.01822
Trajano, L. F., Hayes, J. F., Launders, N., Davies, N. M., Osborn, D. P. J., & Richards-Belle, A. (2025). Co-prescription of metformin and antipsychotics in extreme psychological sickness: A UK major care cohort examine. BMJ Psychological Well being, 28(1). https://doi.org/10.1136/bmjment-2024-301505
