02. Does Semaglutide Reverse Clozapine-Induced Weight Gain in Schizophrenia? Results from the COaST Trial

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Semaglutide for Clozapine-Induced Weight Gain

In this Quick Take, I want to talk about an important clinical trial that may change how we manage weight gain in patients on clozapine. Specifically, we’re going to look at the COaST trial—short for Clozapine Obesity and Semaglutide Treatment—recently published in The Lancet Psychiatry by Dan Siskind and colleagues in Australia.

The acronym is pretty good, as it studied the GLP-1 agonist Semaglutide as an add-on treatment for obese Schizophrenia patients treated with Clozapine.

Antipsychotic-Induced Weight Gain: A Life-or-Death Matter

Managing antipsychotic-induced weight gain and its metabolic consequences is critical for our patients’ longevity. This is particularly true for those on metabolically high-risk antipsychotics like Clozapine.

The iatrogenic morbidity and mortality from antipsychotics such as the weight gain is one factor that translates downstream to a reduced life expectancy from premature death mainly from cardiovascular disease. And while we have some experience with Metformin as an adjunctive treatment to reduce that risk, Metformin is clearly insufficient for most patients.

GLP-1 Agonists: A Game-Changer in Weight Management

GLP-1 agonists have revolutionized diabetes care and weight management in the general population. Newer, second-generation agents like Semaglutide are more efficacious than their predecessors.

However, we’ve lacked clinical trial evidence for using these newer GLP-1 agonists in patients with psychosis, as they’re typically excluded from such trials. The COaST trial fills this knowledge gap.

COaST Study: Design and Challenges

The COaST trial was a randomized, placebo-controlled study of 31 patients with Schizophrenia treated with Clozapine. Participants received either weekly 2 mg subcutaneous Semaglutide or placebo. The trial was double-blind, except for the study nurses, since the team couldn’t get placebo injection pens.

The global semaglutide shortage at the time led to two limitations:

• They used 2 mg instead of the usual 2.4 mg dose for obesity.
• Recruitment ended early, leaving them with just 31 participants.

The trial ran for 36 weeks. Participants had to be obese and weight-stable on clozapine—meaning they had already gained weight on it and were no longer in the acute weight-gain phase. This was a Phase 2 trial, as semaglutide was not approved in Australia or New Zealand for obesity at the time.

Results: Substantial Weight Loss With Semaglutide

The results were impressive:

• Semaglutide group: 13.88% body weight loss
• Placebo group: 0.42% body weight loss

This translates to a Cohen’s d effect size of 1.68.

Secondary outcomes showed similar benefits:

• Hemoglobin A1c dropped from 5.4% to 5% with Semaglutide
• No change in the placebo group

The magnitude of the weight loss was comparable or even better to weight loss seen in Semaglutide trials in the general population. And importantly, 2/3 of participants lost at least 10% which is quite significant at the individual patient level.

Safety and Stability Considerations

Given the small sample size, we can’t draw definitive conclusions about safety. However:

• Diarrhea was observed, as expected with GLP-1 agonists
• No worsening of constipation (though self-reporting is unreliable)
• Clozapine blood levels were unaffected
• Psychopathology remained stable or slightly improved. This is important as GLP-1 agonists are also CNS active drugs with effects on motivational systems.

Clinical Implications and Access Challenges

Adding Semaglutide to Clozapine-treated patients with obesity leads to significant weight loss and appears medically and psychiatrically safe. The big question for you is going to be, how are you going to work in your setting to make this treatment available to all patients? Are you going to become an expert yourself in prescribing GLP-1 agonists like you may be doing with Metformin already?

Do you have access to specialists or is the patient’s primary care doctor going to be prescribing Semaglutide? All solutions are going to be local depending on your particular situation including insurance access to the medication.

Bridging the Research-to-Practice Gap

I think this is a milestone trial in our field and we ought to be excited about the possibility of having better tools to help our clozapine patients stay on Clozapine safely. Clearly, larger trials are needed for details including a better safety assessment but I think the main finding of substantial weight loss in this group with improved hemoglobin A1c will stand.

There is of course the question of durability of the result and how to integrate Semaglutide with behavioral interventions or using it earlier before there is weight gain. However, I’m mostly worried about something else, the so-called research to practice gap or the time it takes for evidence-based treatments to reach every patient in clinical care.

I am worried that 10 years from now I will still be asking that you consider using GLP-1 agonists to manage Clozapine-induced weight gain as we will not have figured out how to make the GLP-1 agonists the standard of care with assured access to anyone who wants to try it.

As a field, we need to figure out how to disseminate evidence-based treatments earlier and better. Otherwise, our patients will continue to lag behind in mortality. Let me end with this message of advocacy, if you will, for our patients with serious mental illness.

Abstract

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

Prof Dan Siskind, PhD; Andrea Baker, MMH; Urska Arnautovska, PhD; Nicola Warren, PhD; Prof Anthony Russell, PhD; Veronica DeMonte, PhD & et al.

Background

People with schizophrenia have a 16–20-year reduction in life expectancy, primarily due to cardiometabolic disease. Clozapine, the most efficacious antipsychotic for treatment-resistant schizophrenia, is associated with weight gain and metabolic dysfunction. Glucagon-like peptide-1 receptor agonists, including semaglutide, contribute to substantial weight loss in the general population, but their effect and safety profile in people with schizophrenia remain unknown. We evaluated the efficacy and safety of semaglutide for weight reduction in individuals with schizophrenia who were prescribed clozapine.

Methods

COaST was an Australian randomised, placebo-controlled, multi-site trial, independent of pharmaceutical industry support, with methods informed by people with lived experience. Adults (aged 18–64 years) across six sites were randomly assigned (1:1) to once weekly subcutaneous semaglutide titrated to 2·0 mg or placebo for 36 weeks. Participants were included if they fulfilled criteria for schizophrenia or schizoaffective disorder, were prescribed clozapine for 18 weeks or more, had a BMI of at least 26 kg/m², and had less than 5% bodyweight increase or loss in the previous 3 months. The primary outcome was percentage body weight change, analysed using a mixed model for repeated measures, at 36 weeks post-baseline assessment. All investigators and participants were masked to medication allocation. Secondary measures included clozapine and norclozapine concentrations and psychosis symptoms as measured by the Positive and Negative Syndrome Scale (PANSS). The protocol was prospectively registered with the Australia New Zealand Clinical Trials Registry (ACTRN12621001539820; recruitment finished, pending follow-up assessments).

Findings

166 individuals were screened for eligibility, 135 were excluded, and the remaining 31 were randomly assigned to either the semaglutide group (n=15) or the control group (n=16). 21 males and ten females were included in the study, with a mean age of 38·9 years (range 21–58). All participants assigned to each group were included in the analysis of the primary outcome. 84% of participants were White, 7% were from the Indian Subcontinent, 3% were Asian (not including from the Indian Subcontinent), 3% were Australian Aboriginal or Torres Strait Islanders, and 3% were New Zealand Māori or Pacific Islanders. Recruitment commenced on Aug 30, 2022 and was suspended in June, 2024 before achieving the intended number of 80 participants due to non-availability of the investigational product. At week 36, semaglutide yielded a 13·88% (SE 0·90) body weight reduction compared with 0·42% (SE 0·93) for placebo (between-group difference: –13·46%; p<0·0001). No differences were observed in clozapine or norclozapine concentrations or PANSS scores. Semaglutide was well tolerated, with no serious adverse events that were deemed to be related to the treatment, and low rates of constipation.

Interpretation

Semaglutide led to significantly greater weight loss than placebo in this small trial without affecting psychotic symptoms or clozapine concentrations. Semaglutide appears to be safe and well tolerated in this population. These encouraging findings highlight the need for larger confirmatory trials.

Funding

National Health and Medical Research Council, Qld Advancing Clinical Research Fellowship, and Metro South Health Research Support Scheme Program.

Reference

Prof Dan Siskind, PhD; Andrea Baker, MMH; Urska Arnautovska, PhD; Nicola Warren, PhD; Prof Anthony Russell, PhD; Veronica DeMonte, PhD & et al. (2025). 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, Volume 12, Issue 7, 493 – 503.