Antipsychotics will be life-changing medicines, however they usually include an unwelcome plus-one: weight acquire. For folks taking clozapine or olanzapine, the numbers on the scales can climb alarmingly quick, bringing elevated dangers of diabetes, heart problems, stigma, and poorer high quality of life. Regardless of our greatest efforts with food plan plans, train programmes and metformin, tackling antipsychotic-related weight acquire stays one of many largest challenges in psychiatric follow.
Individuals residing with schizophrenia spectrum issues (SSDs) die, on common, one to 20 years sooner than the overall inhabitants (Correll et al, 2022), and far of this mortality hole is pushed not by psychological sickness itself, however by preventable bodily well being situations. Heart problems related to weight problems and metabolic syndrome is a significant perpetrator, with antipsychotic-induced weight acquire enjoying a big function.
Enter semaglutide. Already well-known for reworking weight problems therapy within the normal inhabitants (you will have heard of brand name names Ozempic and Wegovy), this GLP-1 receptor agonist, used within the therapy of diabetes for the reason that early 2000s, has been making headlines for serving to folks lose substantial quantities of weight. Older GLP-1 receptor agonists reminiscent of exenatide and liraglutide have beforehand proven modest promise in folks with schizophrenia, however their results have been comparatively restricted and uncomfortable side effects have been frequent. Newer brokers, notably semaglutide and tirzepatide, can produce weight reduction exceeding 15% of physique weight within the normal inhabitants, elevating hopes that they might provide a simpler resolution for folks with SSDs.
Nonetheless, there’s a catch. Individuals with extreme psychological sickness are incessantly excluded from the big, industry-funded weight problems trials that drive medical tips. Consequently, we all know surprisingly little about how effectively these medicines work in folks with SSDs. A brand new systematic evaluate and meta-analysis by Trott et al., (2026), printed in British Journal of Psychiatry Open, got down to discover the reply.
Strategies
The authors carried out a preregistered systematic evaluate and meta-analysis following PRISMA steering. They searched 5 main databases (PubMed, EMBASE, PsycINFO, Scopus and CENTRAL) for placebo-controlled randomised managed trials of semaglutide and/or tirzepatide (a associated drug which prompts each the GLP-1 receptor and GIP receptors) in adults with schizophrenia spectrum issues.
To maintain issues rigorous, two unbiased reviewers screened research and extracted information, with a senior reviewer accessible to resolve disagreements if wanted (though impressively, none arose and reviewer settlement was 100% all through).
The place at the very least three research reported comparable outcomes, information have been pooled utilizing random-effects meta-analysis. This included key measures reminiscent of physique weight, BMI and blood glucose. Antagonistic occasions have been analysed as threat ratios. Outcomes reported by fewer than three research have been summarised narratively. The authors assessed research high quality utilizing the Cochrane Danger of Bias 2 instrument and graded the knowledge of proof utilizing the GRADE framework.
Outcomes
When it got here to eligible research, the cabinet was not precisely overflowing.
Solely three trials met the inclusion standards, contributing information from a complete of 258 individuals. Two research have been carried out in Denmark and one in Australia. All examined semaglutide at doses of 1.0 mg or 2.0 mg over intervals of 26 to 36 weeks. Notably, these doses and durations have been decrease than these generally utilized in landmark weight problems trials within the normal inhabitants, which usually use 2.4 mg for a yr or longer.
And what about tirzepatide (AKA Mounjaro or Zepbound)? Regardless of all the joy surrounding it elsewhere, no eligible research have been recognized in folks with SSDs.
The excellent news is that every one three included trials have been judged to be at low threat of bias.
In contrast with placebo, semaglutide produced clinically significant enhancements:
- Common weight lack of simply over 11 kg
- Common discount in BMI of round 3.6 kg/m²
- Common discount in HbA1c of 0.37 proportion factors
- Vital enhancements in fasting glucose ranges
These have been rated as high- or moderate-certainty findings. Measures that weren’t pooled statistically, together with waist circumference, physique fats proportion and visceral fats, usually pointed in the identical encouraging route.
Maybe most reassuringly for psychiatrists, there was no proof that semaglutide destabilised psychological well being. Psychotic signs, total medical severity and cognitive outcomes have been broadly related between semaglutide and placebo teams. Within the research that measured them, clozapine and norclozapine blood ranges additionally remained unchanged.
As for uncomfortable side effects, there have been no main surprises. Semaglutide elevated the danger of gastrointestinal signs, together with:
- Nausea
- Vomiting
- Stomach ache
- Constipation
In different phrases, just about the identical side-effect profile we’ve already come to count on from GLP-1 receptor agonists within the wider inhabitants. Importantly, there was no proof of an elevated threat of significant hostile occasions.
The decision? Semaglutide seems to be like a promising new instrument within the metabolic toolbox for folks with schizophrenia spectrum issues, providing significant weight reduction with out upsetting psychiatric stability. The catch is that we’re nonetheless working with an proof base that’s extra “promising first chapter” than “completed story”, and the absence of tirzepatide research leaves an necessary plot twist but to be written. There’s a price component right here that can be not considered so who would this therapy be accessible to and the way?
Conclusions
The authors concluded that semaglutide produced clinically significant enhancements in weight and metabolic well being in folks with schizophrenia spectrum issues. The principle trade-off seems to be gastrointestinal uncomfortable side effects, reasonably than any sign of significant bodily hurt or psychiatric deterioration.
General, semaglutide emerges as an thrilling potential adjunctive therapy for considered one of psychiatry’s most irritating medical challenges: serving to folks keep bodily wholesome whereas persevering with the antipsychotic remedies they want.
Strengths and limitations
This evaluate has a number of notable strengths. The protocol was preregistered, looking out was complete, research choice and information extraction have been independently carried out, and proof certainty was formally assessed utilizing GRADE. Proscribing inclusion to placebo-controlled RCTs additionally strengthens confidence within the findings by decreasing the affect of confounding and choice bias.
The most important limitation is the small proof base. Three trials and 258 individuals present encouraging alerts, however hardly a definitive verdict. A number of outcomes relied closely on particular person research, and confidence intervals remained comparatively huge.
The follow-up intervals have been additionally quick. Six to 9 months tells us little about whether or not the load loss is maintained over years, how sufferers fare after stopping therapy, or whether or not semaglutide finally reduces the danger of diabetes, coronary heart assaults or cardiovascular loss of life.
The included research additionally enrolled sufferers taking totally different antipsychotic regimens, starting from clozapine alone to broader collections of second-generation antipsychotics. This makes it tough to know whether or not some teams profit greater than others.
Lastly, probably the most putting findings of the evaluate was really what it didn’t discover: not a single trial of tirzepatide in folks with SSDs. Given the superior weight-loss results noticed within the normal inhabitants, this hole feels more and more tough to disregard. There’s a 2026 retrospective cohort research (n=3,618; 1,809 matched pairs), which discovered that tirzepatide initiation in sufferers with SSDs was related to decrease dangers of all-cause mortality, hospitalisation, and suicidal behaviour over one yr. Maybe there are different trials underway?
Implications for follow
For clinicians, these findings provide a welcome dose of optimism. When life-style interventions have stalled, metformin has delivered solely modest advantages, and switching antipsychotics is just not clinically possible, semaglutide could present an alternative choice for addressing the substantial cardiometabolic burden skilled by folks with SSDs.
That stated, enthusiasm must be accompanied by sensible warning. Gastrointestinal uncomfortable side effects have been frequent, so gradual dose escalation, proactive administration of nausea and constipation, and cautious monitoring throughout therapy initiation appear notably wise. This can be particularly necessary for folks taking clozapine, who usually carry an already appreciable burden of hostile results.
For researchers and funders, the following priorities are clear: bigger research, longer follow-up intervals, standardised final result reporting, and a greater understanding of which sufferers profit most. Devoted trials of tirzepatide must be excessive on the agenda. It can even be necessary to discover whether or not urge for food suppression impacts dietary high quality, and whether or not combining GLP-1 receptor agonists with structured life-style help can obtain even better advantages.
For now, semaglutide seems to be punching effectively above its weight within the combat towards antipsychotic-related metabolic issues. The following problem is discovering out whether or not these encouraging early outcomes maintain up over the long run and whether or not tirzepatide may increase the bar even greater.
Assertion of pursuits
Jasmine Snowden has no conflicts of curiosity to declare.
Edited by
Simon Bradstreet
Hyperlinks
Major paper
Mike Trott, Urska Arnautovska, Donni Johnston , Gabrielle Ritchie and Dan Siskind (2026) The protection and efficacy of semaglutide in folks with schizophrenia spectrum issues: systematic evaluate and meta-analysis of randomised managed trials. BJPsych Open, 12, e147.
Different references
Correll CU, Solmi M, Croatto G. et al (2022) Mortality in folks with schizophrenia: a scientific evaluate and meta-analysis of relative threat and aggravating or attenuating elements (PDF). World Psychiatry 2022 21(2) 248-271.
Liu TH, Hsu CH, Wu JY, Huang PY, Chang CC, Lai CC. (2025) Affiliation between tirzepatide use and threat of mortality, hospitalization, and suicidal habits in sufferers with schizophrenia spectrum issues: A one-year retrospective cohort research of 3618 sufferers. Eur Neuropsychopharmacol. 2026 Feb;103:112739. doi: 10.1016/j.euroneuro.2025.11.016. Epub 2025 Dec 12. PMID: 41389474.
Wilding, JPH; Batterham, RL; Calanna, S; Davies, M; Van Gaal, LF; Lingvay, I; McGowan, BM; … Kushner, RF (2021) As soon as-Weekly Semaglutide in Adults with Chubby or Weight problems. The New England Journal of Drugs , 384 (11) pp. 989-1002.
Siskind D, Baker A, Arnautovska U et al. Efficacy and security of semaglutide versus placebo for folks with schizophrenia on clozapine with weight problems (COaST): a part 2, multi-centre, participant and investigator- blinded, randomised managed trial in Australia. The Lancet Psychiatry, 12, 493-503
Siskind, Dan & Leung, Janni & Wysoczanski, Daniel & Kisely, Steve. (2016). Metformin for Clozapine Related Weight problems: A Systematic Assessment and Meta-Evaluation. PLOS ONE. 11. e0156208.
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