Semaglutide, metformin and antipsychotic weight acquire in schizophrenia

Daniel was 36 when the voices lastly went quiet. It took a number of antipsychotic trials, however he’s lastly fascinated about going again to work. Nonetheless, within the mirror he seems fairly completely different, his trousers don’t match, and he’s now diabetic. He was warned that this would possibly occur, and tried to regulate his food regimen and train, but it surely hardly labored.

Daniel represents many individuals with schizophrenia spectrum issues. Ian, a lived expertise group member, put it plainly:

It’s not me placing on weight, it’s the treatment that’s making me placed on weight (McPin Basis, 2025).

Antipsychotics are the cornerstone of therapy for schizophrenia, and although clozapine and olanzapine are among the many only, they’re related to weight acquire and metabolic hurt (Pillinger et al., 2020). And the associated fee goes effectively past look. Individuals with extreme psychological sickness have a 54% increased threat of coronary coronary heart illness and an 85% increased threat of cardiovascular demise than the overall inhabitants (Correll et al., 2017). Weight acquire additionally provides a second stigma to the situation (Gerlinger et al., 2013), pushing folks to decide on between their psychological and bodily well being. Christopher, prescribed olanzapine after a manic episode, described the identical bind:

I needed to cease taking the treatment however I knew that might make me worse too (YoungMinds, 2020)

For years, the reply was disappointing: some life-style recommendation, possibly metformin (Tonini E , 2026), and hope. Then glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide (model: Ozempic; Snowden J, 2026) appeared. The query then turned: do we all know what medication may assist sufferers reduce weight after receiving antipsychotic therapy? Stogios et al., (2026) tried to reply precisely that.

Two legs standing on a weighing scales — Weight acquire related to antipsychotic use can have an effect on each psychological and bodily well being.

Strategies

This systematic evaluation and community meta-analysis of metabolic interventions in antipsychotic-treated sufferers with schizophrenia spectrum issues (SSDs) was pre-registered on PROSPERO (CRD42024610768) and 7 databases have been searched, together with unpublished registry information and non-English papers. Grownup randomised medical trials (RCT) have been included, no matter sickness size, stage, state or therapy setting. Research the place >50% of sufferers had a non-schizophrenia-related prognosis have been excluded.

The authors used an “automation software” (barely obscure) to exclude some information, and additional screened the remaining information by hand. All screening, information extraction and bias evaluation was accomplished by two impartial folks, with disagreements resolved by dialogue among the many wider creator group.

Eligible research have been included within the frequentist random-effects community meta-analysis, with the first deal with weight imply distinction (kg). Weight reduction remedies have been in contrast in opposition to placebo or ‘standard care’. Certainty of proof was rated utilizing the Confidence in Community Meta-Evaluation (CINeMA) software.

Outcomes

A whopping 18,498 information have been discovered! Of those, 9,162 have been eliminated earlier than screening (5,036 flagged by the automation software and 4,126 duplicates), leaving 9,336 to be screened by hand. This was whittled right down to 95 eligible RCTs from 1965 to 2025 that examined 39 medication in 5,898 sufferers. Ten trials have been solely narratively described: 3 had no good information, 7 have been medication now not marketed.

Curiously, there have been solely 69 RCTs and 28 medication that contributed to the first end result of common weight distinction. 5 medication decreased weight in contrast with placebo, with average certainty of proof: semaglutide (-10.98 kg, 95% confidence interval (CI) -13.33 to -8.62; 3 trials), liraglutide (-5.43 kg; 2 trials), topiramate (-3.95 kg; 5 trials), metformin (-3.86 kg; 16 trials), and exenatide (-2.97 kg; 3 trials). Semaglutide confirmed the biggest weight discount, whereas metformin was supported by probably the most trials. Three different medication (ramelteon, nizatidine, and aripiprazole) additionally confirmed some profit, however the certainty of proof was very low.

The authors additionally tried to quantify medical significance by reporting “clinically significant weight reduction”. This was outlined as 5% or extra weight reduction from baseline and was in comparison with placebo. This was nevertheless solely carried out for 8 research which had satisfactory information. Solely semaglutide and metformin confirmed statistically vital advantages. Semaglutide had an odds ratio (OR) of 210.00 (95% CI 3.97 to 11,115.99; 1 trial), whereas metformin had an OR of 10.39 (95% CI 1.81 to 59.54; 4 trials). In different phrases, sufferers taking metformin had roughly 10 instances the percentages of attaining clinically significant weight reduction in contrast with placebo or standard care.

The authors additionally ran sensitivity analyses (for instance, eradicating research at excessive threat of bias), and the 5 fundamental medication held up, though ramelteon and nizatidine dropped out. Additionally they ran subgroup analyses. After they examined solely “long-term” trials (not less than 24 weeks of therapy), the consequences of semaglutide (ok=3) and metformin (ok=6) held up. In clozapine-only handled sufferers, semaglutide (ok=1) had the strongest imply weight distinction, adopted by exenatide (ok=1). In olanzapine-only handled sufferers, there was no sturdy proof to recommend that any drug had an impact as in comparison with placebo.

A semaglutide injection pen — Semaglutide reveals promise for weight reduction in folks taking antipsychotics, however who advantages most?

Conclusions

The authors concluded that amongst all of the 39 medication examined, semaglutide, liraglutide, exenatide, metformin and topiramate have been the best, in folks with schizophrenia spectrum issues. Metformin was studied probably the most.

The authors additionally emphasised the necessity for adequately-powered and longer trials, extra direct head-to-head comparisons between medication (not simply versus placebo), and inclusion of newer medication like tirzepatide.

A brass weighing scales — Future research ought to weigh the advantages and dangers of two weight reduction medication immediately in opposition to each other.

Strengths and limitations

The authors have invested an unimaginable quantity of effort and time to reply a extremely essential problem that sufferers with SSDs need to take care of. This was accomplished comprehensively (looking a number of databases, even together with non-English research to make sure wider seize), and robustly (duplicate screening, information extraction, threat of bias evaluation, with a number of sensitivity and subgroup analyses). Extra just lately printed instruments corresponding to CINeMA and RoB2 have been additionally applied. Additionally they included (comparatively) newer medication corresponding to semaglutide, which may very well be in contrast not directly to different medication that had been available on the market for an extended time frame. Results have been reported on the product-level (somewhat than at a drug class-level) which permits for clinicians and sufferers to grasp which drug would possibly work greatest.

Whereas the findings of the examine have proven attention-grabbing traits, I stay cautious in regards to the interpretation of its outcomes. That is for plenty of causes:

Firstly, most of the reported results on the product-level are solely supported by a small variety of RCTs. Moreover, the person trials are characteristically very distinct: completely different international locations, outpatient/inpatient setting, size of therapy, dose, sickness stage or chronicity of sickness, diagnostic standards for SSDs and many others. Because of this the consequences reported may very well be distinctive to a particular inhabitants with a sure ethnicity, severity of sickness, at a particular dose and size of therapy of the drug. This makes it troublesome for clinicians to know whether or not the findings apply to their sufferers.

Secondly, whereas it’s comprehensible the authors needed to feasibly exclude irrelevant research, the validity of the ‘automation software’ that they used throughout screening is unclear.

Thirdly, the inclusion of research extending again to 1965 may enhance the quantity of obtainable proof, however therapy practices, affected person populations and existence might have modified significantly since then, probably limiting the relevance of older findings to present follow.

Lastly, it could be essential to contemplate what’s ‘clinically significant’ weight reduction for the affected person, which may transcend the usual “5%” threshold used right here. There may very well be two views:

What’s the threshold wanted to cut back cardiovascular threat?
What’s the weight reduction desired by the affected person? Is that this the burden earlier than antipsychotics have been began?

Bunch of yellow plastic ducks with one blue peacock duck in the middle — Weight reduction remedies may match otherwise throughout sufferers, however do we all know who’s more than likely to profit?

Implications for follow

My private take is that this examine has additional solidified that metformin can contribute to some weight reduction in sufferers with SSDs who’re presently taking antipsychotics. Nonetheless, the extent of weight reduction and whether or not that’s significant to the affected person physiologically or psychologically (lowering the stigma related to weight acquire) stays to be seen. Semaglutide appears to indicate promise, and ought to be examined in better element in future work. Who would profit probably the most? Is it secure to make use of for lengthy durations of time, and the way does it impression different psychiatric outcomes (e.g., relapse, symptom scores, suicidality)? Are there antipsychotic-specific combos that work higher (i.e., why is there no sturdy proof for weight reduction in olanzapine customers)?

For example, a recognized facet impact of clozapine is slowing of intestine actions (Each-Palmer S. & Ellis P. M., 2017). Can semaglutide, which can be recognized to have gastrointestinal unintended effects, worsen that? (Wharton et al., 2022). This would want a extra thorough investigation earlier than it may be routinely really helpful in follow.

Additionally, because the authors have highlighted, as an essential nuance within the article is what’s being examined: the consequences of beginning weight reduction medication for weight acquire that has already occurred following antipsychotic use. That is completely different from beginning weight reduction medication to forestall weight acquire when beginning antipsychotics (Agarwal S. M. et al., 2022). The best scenario for Daniel can be the latter, which is presently the main focus of many ongoing and deliberate research (extra to come back quickly!).

Typewriter with page that says "PREVENTION" — May stopping antipsychotic-associated weight acquire be higher than treating it after it happens?

Assertion of pursuits

Aaron Yap (he/him) is funded by the Wellcome Belief and has no related conflicts of curiosity to declare. Claude was used to summarise the examine in preliminary phases of planning the content material of this text, however all opinions mirrored listed below are his personal.

Editor

Edited by Éimear Foley. ChatGPT assisted with language refinement and formatting through the editorial section.

Hyperlinks

Major paper

Nicolette Stogios, Sri Mahavir Agarwal, Kateryna Maksyutynska, Halima Faisal, Lora Lee Pless, Toby Pillinger, Bailey Humber, Valerie H. Taylor, Gary Remington, Man E. J. Faulkner, Margaret Okay. Hahn (2026) Pharmacological interventions for weight discount in sufferers with schizophrenia handled with antipsychotics: a scientific evaluation and community meta-analysis. JAMA Psychiatry 2026 83(9) 912-920.