Antipsychotics can be life-changing medications, but they often come with an unwelcome plus-one: weight gain. For people taking clozapine or olanzapine, the numbers on the scales can climb alarmingly fast, bringing increased risks of diabetes, cardiovascular disease, stigma, and poorer quality of life. Despite our best efforts with diet plans, exercise programmes and metformin, tackling antipsychotic-related weight gain remains one of the biggest challenges in psychiatric practice.
People living with schizophrenia spectrum disorders (SSDs) die, on average, one to two decades earlier than the general population (Correll et al, 2022), and much of this mortality gap is driven not by mental illness itself, but by preventable physical health conditions. Cardiovascular disease associated with obesity and metabolic syndrome is a major culprit, with antipsychotic-induced weight gain playing a significant role.
Enter semaglutide. Already famous for transforming obesity treatment in the general population (you may have heard of brand names Ozempic and Wegovy), this GLP-1 receptor agonist, used in the treatment of diabetes since the early 2000s, has been making headlines for helping people lose substantial amounts of weight. Older GLP-1 receptor agonists such as exenatide and liraglutide have previously shown modest promise in people with schizophrenia, but their effects have been relatively limited and side effects were common. Newer agents, particularly semaglutide and tirzepatide, can produce weight loss exceeding 15% of body weight in the general population, raising hopes that they may offer a more effective solution for people with SSDs.
However, there’s a catch. People with severe mental illness are frequently excluded from the large, industry-funded obesity trials that drive clinical guidelines. As a result, we know surprisingly little about how well these medications work in people with SSDs. A new systematic review and meta-analysis by Trott et al., (2026), published in British Journal of Psychiatry Open, set out to find the answer.
Methods
The authors conducted a preregistered systematic review and meta-analysis following PRISMA guidance. They searched five major databases (PubMed, EMBASE, PsycINFO, Scopus and CENTRAL) for placebo-controlled randomised controlled trials of semaglutide and/or tirzepatide (a related drug which activates both the GLP-1 receptor and GIP receptors) in adults with schizophrenia spectrum disorders.
To keep things rigorous, two independent reviewers screened studies and extracted data, with a senior reviewer available to resolve disagreements if needed (although impressively, none arose and reviewer agreement was 100% throughout).
Where at least three studies reported comparable outcomes, data were pooled using random-effects meta-analysis. This included key measures such as body weight, BMI and blood glucose. Adverse events were analysed as risk ratios. Outcomes reported by fewer than three studies were summarised narratively. The authors assessed study quality using the Cochrane Risk of Bias 2 tool and graded the certainty of evidence using the GRADE framework.
Results
When it came to eligible studies, the cupboard was not exactly overflowing.
Only three trials met the inclusion criteria, contributing data from a total of 258 participants. Two studies were conducted in Denmark and one in Australia. All examined semaglutide at doses of 1.0 mg or 2.0 mg over periods of 26 to 36 weeks. Notably, these doses and durations were lower than those commonly used in landmark obesity trials in the general population, which typically use 2.4 mg for a year or longer.
And what about tirzepatide (AKA Mounjaro or Zepbound)? Despite all the excitement surrounding it elsewhere, no eligible studies were identified in people with SSDs.
The good news is that all three included trials were judged to be at low risk of bias.
Compared with placebo, semaglutide produced clinically meaningful improvements:
- Average weight loss of just over 11 kg
- Average reduction in BMI of around 3.6 kg/m²
- Average reduction in HbA1c of 0.37 percentage points
- Significant improvements in fasting glucose levels
These were rated as high- or moderate-certainty findings. Measures that were not pooled statistically, including waist circumference, body fat percentage and visceral fat, generally pointed in the same encouraging direction.
Perhaps most reassuringly for psychiatrists, there was no evidence that semaglutide destabilised mental health. Psychotic symptoms, overall clinical severity and cognitive outcomes were broadly similar between semaglutide and placebo groups. In the study that measured them, clozapine and norclozapine blood levels also remained unchanged.
As for side effects, there were no major surprises. Semaglutide increased the risk of gastrointestinal symptoms, including:
- Nausea
- Vomiting
- Abdominal pain
- Constipation
In other words, pretty much the same side-effect profile we’ve already come to expect from GLP-1 receptor agonists in the wider population. Importantly, there was no evidence of an increased risk of serious adverse events.
The verdict? Semaglutide looks like a promising new tool in the metabolic toolbox for people with schizophrenia spectrum disorders, offering meaningful weight loss without upsetting psychiatric stability. The catch is that we’re still working with an evidence base that’s more “promising first chapter” than “finished story”, and the absence of tirzepatide studies leaves an important plot twist yet to be written. There is a cost element here that is also not taken into consideration so who would this treatment be accessible to and how?
Conclusions
The authors concluded that semaglutide produced clinically meaningful improvements in weight and metabolic health in people with schizophrenia spectrum disorders. The main trade-off appears to be gastrointestinal side effects, rather than any signal of serious physical harm or psychiatric deterioration.
Overall, semaglutide emerges as an exciting potential adjunctive treatment for one of psychiatry’s most frustrating clinical challenges: helping people stay physically healthy while continuing the antipsychotic treatments they need.
Strengths and limitations
This review has several notable strengths. The protocol was preregistered, searching was comprehensive, study selection and data extraction were independently performed, and evidence certainty was formally assessed using GRADE. Restricting inclusion to placebo-controlled RCTs also strengthens confidence in the findings by reducing the influence of confounding and selection bias.
The biggest limitation is the small evidence base. Three trials and 258 participants provide encouraging signals, but hardly a definitive verdict. Several outcomes relied heavily on individual studies, and confidence intervals remained relatively wide.
The follow-up periods were also short. Six to nine months tells us little about whether the weight loss is maintained over years, how patients fare after stopping treatment, or whether semaglutide ultimately reduces the risk of diabetes, heart attacks or cardiovascular death.
The included studies also enrolled patients taking different antipsychotic regimens, ranging from clozapine alone to broader collections of second-generation antipsychotics. This makes it difficult to know whether some groups benefit more than others.
Finally, one of the most striking findings of the review was actually what it didn’t find: not a single trial of tirzepatide in people with SSDs. Given the superior weight-loss effects observed in the general population, this gap feels increasingly difficult to ignore. There is a 2026 retrospective cohort study (n=3,618; 1,809 matched pairs), which found that tirzepatide initiation in patients with SSDs was associated with lower risks of all-cause mortality, hospitalisation, and suicidal behaviour over one year. Perhaps there are other trials underway?
Implications for practice
For clinicians, these findings offer a welcome dose of optimism. When lifestyle interventions have stalled, metformin has delivered only modest benefits, and switching antipsychotics is not clinically feasible, semaglutide may provide another option for addressing the substantial cardiometabolic burden experienced by people with SSDs.
That said, enthusiasm should be accompanied by practical caution. Gastrointestinal side effects were common, so gradual dose escalation, proactive management of nausea and constipation, and careful monitoring during treatment initiation seem particularly sensible. This may be especially important for people taking clozapine, who often carry an already considerable burden of adverse effects.
For researchers and funders, the next priorities are clear: larger studies, longer follow-up periods, standardised outcome reporting, and a better understanding of which patients benefit most. Dedicated trials of tirzepatide should be high on the agenda. It will also be important to explore whether appetite suppression affects nutritional quality, and whether combining GLP-1 receptor agonists with structured lifestyle support can achieve even greater benefits.
For now, semaglutide appears to be punching well above its weight in the fight against antipsychotic-related metabolic problems. The next challenge is finding out whether these encouraging early results hold up over the long term and whether tirzepatide might raise the bar even higher.
Statement of interests
Jasmine Snowden has no conflicts of interest to declare.
Edited by
Simon Bradstreet
Links
Primary paper
Mike Trott, Urska Arnautovska, Donni Johnston , Gabrielle Ritchie and Dan Siskind (2026) The safety and efficacy of semaglutide in people with schizophrenia spectrum disorders: systematic review and meta-analysis of randomised controlled trials. BJPsych Open, 12, e147.
Other references
Correll CU, Solmi M, Croatto G. et al (2022) Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors (PDF). World Psychiatry 2022 21(2) 248-271.
Liu TH, Hsu CH, Wu JY, Huang PY, Chang CC, Lai CC. (2025) Association between tirzepatide use and risk of mortality, hospitalization, and suicidal behavior in patients with schizophrenia spectrum disorders: A one-year retrospective cohort study of 3618 patients. 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) Once-Weekly Semaglutide in Adults with Overweight or Obesity. The New England Journal of Medicine , 384 (11) pp. 989-1002.
Siskind D, Baker A, Arnautovska U et al. Efficacy and safety of semaglutide versus placebo for people with schizophrenia on clozapine with obesity (COaST): a phase 2, multi-centre, participant and investigator- blinded, randomised controlled trial in Australia. The Lancet Psychiatry, 12, 493-503
Siskind, Dan & Leung, Janni & Wysoczanski, Daniel & Kisely, Steve. (2016). Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis. PLOS ONE. 11. e0156208.
