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 occupied with going again to work. Nevertheless, within the mirror he seems fairly totally different, his trousers don’t match, and he’s now diabetic. He was warned that this may occur, and tried to regulate his weight loss plan and train, however it hardly labored.

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

It’s not me placing on weight, it’s the medicine 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 price goes effectively past look. Individuals with extreme psychological sickness have a 54% larger threat of coronary coronary heart illness and an 85% larger threat of cardiovascular dying 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 medicine however I knew that might make me worse too (YoungMinds, 2020)

For years, the reply was disappointing: some way of life 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 grew to become: do we all know what medicine might assist sufferers drop some pounds 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 evaluate and community meta-analysis of metabolic interventions in antipsychotic-treated sufferers with schizophrenia spectrum problems (SSDs) was pre-registered on PROSPERO (CRD42024610768) and 7 databases had been searched, together with unpublished registry information and non-English papers. Grownup randomised medical trials (RCT) had been included, no matter sickness size, stage, state or therapy setting. Research the place >50% of sufferers had a non-schizophrenia-related analysis had been excluded.

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

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

Outcomes

A whopping 18,498 information had been discovered! Of those, 9,162 had been eliminated earlier than screening (5,036 flagged by the automation device 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 medicine in 5,898 sufferers. Ten trials had been solely narratively described: 3 had no good information, 7 had been medicine now not marketed.

Curiously, there have been solely 69 RCTs and 28 medicine that contributed to the first final result of common weight distinction. 5 medicine lowered weight in contrast with placebo, with reasonable 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 medicine (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 enough information. Solely semaglutide and metformin confirmed statistically important 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 chances of attaining clinically significant weight reduction in contrast with placebo or typical care.

The authors additionally ran sensitivity analyses (for instance, eradicating research at excessive threat of bias), and the 5 principal medicine held up, though ramelteon and nizatidine dropped out. Additionally they ran subgroup analyses. After they examined solely “long-term” trials (a minimum of 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 robust 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 medicine examined, semaglutide, liraglutide, exenatide, metformin and topiramate had been the simplest, in folks with schizophrenia spectrum problems. 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 medicine (not simply versus placebo), and inclusion of newer medicine like tirzepatide.

A brass weighing scales — Future research ought to weigh the advantages and dangers of two weight reduction medicine instantly towards each other.

Strengths and limitations

The authors have invested an unimaginable quantity of effort and time to reply a very essential problem that sufferers with SSDs should take care of. This was carried out 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 lately printed instruments corresponding to CINeMA and RoB2 had been additionally carried out. Additionally they included (comparatively) newer medicine corresponding to semaglutide, which might be in contrast not directly to different medicine that had been in the marketplace for an extended time period. Results had been reported on the product-level (fairly than at a drug class-level) which permits for clinicians and sufferers to grasp which drug may work greatest.

Whereas the findings of the research have proven attention-grabbing traits, I stay cautious concerning the interpretation of its outcomes. That is for quite a few 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: totally different nations, outpatient/inpatient setting, size of therapy, dose, sickness stage or chronicity of sickness, diagnostic standards for SSDs and so forth. Which means the consequences reported might 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 device’ that they used throughout screening is unclear.

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

Lastly, it might be essential to contemplate what’s ‘clinically significant’ weight reduction for the affected person, which might transcend the usual “5%” threshold used right here. There might 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 had 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 most certainly to profit?

Implications for follow

My private take is that this research has additional solidified that metformin can contribute to some weight reduction in sufferers with SSDs who’re at present taking antipsychotics. Nevertheless, 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 needs to be examined in larger element in future work. Who would profit probably the most? Is it protected to make use of for lengthy intervals of time, and the way does it influence different psychiatric outcomes (e.g., relapse, symptom scores, suicidality)? Are there antipsychotic-specific combos that work higher (i.e., why is there no robust proof for weight reduction in olanzapine customers)?

As an example, a recognized aspect impact of clozapine is slowing of intestine actions (Each-Palmer S. & Ellis P. M., 2017). Can semaglutide, which can also be recognized to have gastrointestinal unwanted side effects, worsen that? (Wharton et al., 2022). This would want a extra thorough investigation earlier than it may be routinely advisable 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 medicine for weight acquire that has already occurred following antipsychotic use. That is totally different from beginning weight reduction medicine to stop weight acquire when beginning antipsychotics (Agarwal S. M. et al., 2022). The best state of affairs for Daniel could be the latter, which is at present the main focus of many ongoing and deliberate research (extra to return quickly!).

Typewriter with page that says "PREVENTION" — Might 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 research in preliminary phases of planning the content material of this text, however all opinions mirrored listed here 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 Ok. Hahn (2026) Pharmacological interventions for weight discount in sufferers with schizophrenia handled with antipsychotics: a scientific evaluate and community meta-analysis. JAMA Psychiatry 2026 83(9) 912-920.