GLP-1s and Antipsychotic Weight Gain: A Trial Cut Short

People with schizophrenia die 16 to 20 years earlier than the general population, mostly from cardiometabolic disease — and clozapine, the most effective antipsychotic there is for treatment-resistant illness, causes weight gain and metabolic dysfunction.^[1] That is one of the sharpest trade-offs in medicine. A 2025 trial tested whether semaglutide could ease it, and got a striking answer from a very small number of people. A second Danish trial has since asked the same question at more than twice the size and in a broader group — antipsychotics and metabolic harm.

What COaST found

COaST was an Australian randomized, placebo-controlled, blinded trial, run independently of pharmaceutical industry support, with its methods informed by people with lived experience. Adults aged 18 to 64 with schizophrenia or schizoaffective disorder, on clozapine for at least 18 weeks and with a BMI of 26 or more, were assigned to weekly semaglutide titrated to 2.0 mg or to placebo for 36 weeks.^[1]

At 36 weeks the semaglutide group had lost 13.88% of body weight against 0.42% on placebo — a between-group difference of 13.46 percentage points, with p below 0.0001.^[1]

Why it ended at 31

The trial intended to recruit 80 participants. Recruitment began in August 2022 and was suspended in June 2024 — not because of a safety problem, and not because of a lack of interest. It stopped because of the non-availability of the investigational product.^[1]

The shortage that emptied pharmacy shelves also stopped a trial in one of the most under-served populations in medicine, at 31 of an intended 80.

This register spends most of its time on the commercial side of GLP-1 supply — who is selling what, at what price, and whether it is what it claims to be. This is the same shortage, arriving somewhere else. When demand for a weight-loss drug outruns manufacturing, the research that would tell clinicians how to use it safely in the people who need it most is competing for the same vials.

The findings that mattered most were not about weight

For anyone taking clozapine, two questions come before weight loss, and COaST measured both.

• Clozapine levels did not change. There were no differences in clozapine or norclozapine concentrations between the groups.^[1] Clozapine has a narrow therapeutic window and a serious monitoring burden, so a drug that shifted its levels would be a genuine problem.
• Psychotic symptoms did not change. No differences appeared in PANSS scores.^[1] The worry that metabolic treatment might destabilize psychiatric illness was not borne out here.
• Tolerability was unremarkable. No serious adverse events were judged related to treatment, and rates of constipation were low.^[1]

The wider literature points the same way on the safety question. A 2024 systematic review and meta-analysis of GLP-1 drugs in antipsychotic-induced weight gain — which could only pool exenatide and liraglutide, since nothing newer had enough data — found that neither adversely affected psychopathology.^[2]

What the older drugs achieved

That same meta-analysis is a useful calibration, because it shows how much the newer drugs changed the picture. Across five randomized trials and one cohort study, liraglutide produced a mean weight loss of 4.70 kg and exenatide 2.48 kg — and the exenatide result did not reach statistical significance.^[2]

Against that, a 13.88% body-weight reduction is a different order of result. It is also from a much smaller sample, on a newer drug, and the comparison is across separate trials rather than a head-to-head. Our note on reading evidence across trials covers why that distinction matters.