Antipsychotics will be life-changing medicines, however they usually include an unwelcome plus-one: weight achieve. For individuals 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 eating regimen plans, train programmes and metformin, tackling antipsychotic-related weight achieve stays one of many largest challenges in psychiatric observe.
Individuals dwelling 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 circumstances. Heart problems related to weight problems and metabolic syndrome is a serious offender, with antipsychotic-induced weight achieve taking part in a big function.
Enter semaglutide. Already well-known for reworking weight problems remedy within the basic inhabitants (you will have heard of brand name names Ozempic and Wegovy), this GLP-1 receptor agonist, used within the remedy of diabetes because the early 2000s, has been making headlines for serving to individuals lose substantial quantities of weight. Older GLP-1 receptor agonists equivalent to exenatide and liraglutide have beforehand proven modest promise in individuals with schizophrenia, however their results have been comparatively restricted and negative effects have been frequent. Newer brokers, significantly semaglutide and tirzepatide, can produce weight reduction exceeding 15% of physique weight within the basic inhabitants, elevating hopes that they might provide a simpler answer for individuals with SSDs.
Nonetheless, there’s a catch. Individuals with extreme psychological sickness are often excluded from the big, industry-funded weight problems trials that drive scientific pointers. Because of this, we all know surprisingly little about how nicely these medicines work in individuals with SSDs. A brand new systematic overview and meta-analysis by Trott et al., (2026), revealed in British Journal of Psychiatry Open, got down to discover the reply.
Strategies
The authors performed 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 issues.
To maintain issues rigorous, two unbiased reviewers screened research and extracted knowledge, with a senior reviewer out there 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, knowledge have been pooled utilizing random-effects meta-analysis. This included key measures equivalent to 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 software and graded the understanding 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 knowledge from a complete of 258 contributors. Two research have been performed 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 basic inhabitants, which usually use 2.4 mg for a yr or longer.
And what about tirzepatide (AKA Mounjaro or Zepbound)? Regardless of all the thrill surrounding it elsewhere, no eligible research have been recognized in individuals 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 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 course.
Maybe most reassuringly for psychiatrists, there was no proof that semaglutide destabilised psychological well being. Psychotic signs, total 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 negative effects, there have been no main surprises. Semaglutide elevated the danger of gastrointestinal signs, together with:
- Nausea
- Vomiting
- Belly 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 threat of significant antagonistic occasions.
The decision? Semaglutide seems to be like a promising new software within the metabolic toolbox for individuals 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 vital plot twist but to be written. There’s a price component right here that can be not considered so who would this remedy be accessible to and the way?
Conclusions
The authors concluded that semaglutide produced clinically significant enhancements in weight and metabolic well being in individuals with schizophrenia spectrum issues. The principle trade-off seems to be gastrointestinal negative effects, relatively than any sign of significant bodily hurt or psychiatric deterioration.
General, semaglutide emerges as an thrilling potential adjunctive remedy for certainly one of psychiatry’s most irritating scientific challenges: serving to individuals 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 knowledge 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 lowering the affect of confounding and choice bias.
The largest limitation is the small proof base. Three trials and 258 contributors present encouraging alerts, 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 remedy, or whether or not semaglutide finally reduces the danger 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 troublesome to know whether or not some teams profit greater than others.
Lastly, one of the vital placing findings of the overview was really what it didn’t discover: not a single trial of tirzepatide in individuals with SSDs. Given the superior weight-loss results noticed within the basic inhabitants, this hole feels more and more troublesome 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 observe
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 isn’t clinically possible, semaglutide might present an alternative choice for addressing the substantial cardiometabolic burden skilled by individuals with SSDs.
That mentioned, enthusiasm needs to be accompanied by sensible warning. Gastrointestinal negative effects have been frequent, so gradual dose escalation, proactive administration of nausea and constipation, and cautious monitoring throughout remedy initiation appear significantly wise. This can be particularly vital for individuals taking clozapine, who usually carry an already appreciable burden of antagonistic 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 can even be vital 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 larger advantages.
For now, semaglutide seems to be punching nicely above its weight within the combat in opposition to 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 larger.
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 individuals with schizophrenia spectrum issues: 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 individuals with schizophrenia: a scientific overview 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 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 individuals 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 Overview and Meta-Evaluation. PLOS ONE. 11. e0156208.
