Antipsychotics may be life-changing medicines, however they usually include an unwelcome plus-one: weight achieve. 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 weight loss program plans, train programmes and metformin, tackling antipsychotic-related weight achieve stays one of many greatest challenges in psychiatric follow.
Individuals residing with schizophrenia spectrum problems (SSDs) die, on common, one to twenty years sooner than the final 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 offender, with antipsychotic-induced weight achieve taking part in a major function.
Enter semaglutide. Already well-known for reworking weight problems therapy within the normal inhabitants (you’ll have heard of name names Ozempic and Wegovy), this GLP-1 receptor agonist, used within the therapy of diabetes because the early 2000s, has been making headlines for serving to folks lose substantial quantities of weight. Older GLP-1 receptor agonists similar to exenatide and liraglutide have beforehand proven modest promise in folks with schizophrenia, however their results have been comparatively restricted and unwanted side effects have been widespread. Newer brokers, notably semaglutide and tirzepatide, can produce weight reduction exceeding 15% of physique weight within the normal inhabitants, elevating hopes that they could provide a simpler answer for folks with SSDs.
Nonetheless, there’s a catch. Individuals with extreme psychological sickness are continuously excluded from the massive, industry-funded weight problems trials that drive scientific pointers. In consequence, we all know surprisingly little about how properly these medicines work in folks with SSDs. A brand new systematic overview 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 overview and meta-analysis following PRISMA steerage. 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 problems.
To maintain issues rigorous, two impartial reviewers screened research and extracted information, with a senior reviewer obtainable to resolve disagreements if wanted (though impressively, none arose and reviewer settlement was 100% all through).
The place not less than three research reported comparable outcomes, information have been pooled utilizing random-effects meta-analysis. This included key measures similar to physique weight, BMI and blood glucose. Adversarial occasions have been analysed as danger ratios. Outcomes reported by fewer than three research have been summarised narratively. The authors assessed research high quality utilizing the Cochrane Threat 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 members. 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 durations 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 generally use 2.4 mg for a 12 months 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 each one three included trials have been judged to be at low danger 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 share 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 share and visceral fats, typically pointed in the identical encouraging path.
Maybe most reassuringly for psychiatrists, there was no proof that semaglutide destabilised psychological well being. Psychotic signs, general scientific 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 unwanted side effects, there have been no main surprises. Semaglutide elevated the chance 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 anticipate from GLP-1 receptor agonists within the wider inhabitants. Importantly, there was no proof of an elevated danger of great opposed occasions.
The decision? Semaglutide seems to be like a promising new instrument within the metabolic toolbox for folks with schizophrenia spectrum problems, 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 essential plot twist but to be written. There’s a value component right here that can also 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 problems. The principle trade-off seems to be gastrointestinal unwanted side effects, relatively than any sign of great bodily hurt or psychiatric deterioration.
Total, semaglutide emerges as an thrilling potential adjunctive therapy for one in all psychiatry’s most irritating scientific challenges: serving to folks keep bodily wholesome whereas persevering with the antipsychotic therapies they want.
Strengths and limitations
This overview 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 members present encouraging indicators, however hardly a definitive verdict. A number of outcomes relied closely on particular person research, and confidence intervals remained comparatively vast.
The follow-up durations have been additionally brief. Six to 9 months tells us little about whether or not the burden loss is maintained over years, how sufferers fare after stopping therapy, or whether or not semaglutide in the end reduces the chance of diabetes, coronary heart assaults or cardiovascular dying.
The included research additionally enrolled sufferers taking completely 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, some of the hanging findings of the overview 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 12 months. 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 might present another choice for addressing the substantial cardiometabolic burden skilled by folks with SSDs.
That mentioned, enthusiasm needs to be accompanied by sensible warning. Gastrointestinal unwanted side effects have been widespread, so gradual dose escalation, proactive administration of nausea and constipation, and cautious monitoring throughout therapy initiation appear notably smart. This can be particularly essential for folks taking clozapine, who usually carry an already appreciable burden of opposed results.
For researchers and funders, the following priorities are clear: bigger research, longer follow-up durations, standardised consequence reporting, and a greater understanding of which sufferers profit most. Devoted trials of tirzepatide needs to be excessive on the agenda. It should even be essential 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 assist can obtain even higher advantages.
For now, semaglutide seems to be punching properly above its weight within the battle towards antipsychotic-related metabolic issues. The subsequent problem is discovering out whether or not these encouraging early outcomes maintain up over the long run and whether or not tirzepatide would possibly elevate 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 security and efficacy of semaglutide in folks with schizophrenia spectrum problems: systematic overview 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 overview and meta-analysis of relative danger 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 danger of mortality, hospitalization, and suicidal conduct in sufferers with schizophrenia spectrum problems: 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 Obese 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.
