Semaglutide for Schizophrenia and Obesity

(Sema Trial)

Overseen By Mahavir Agarwal, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Centre for Addiction and Mental Health

Must be taking: Antipsychotics

Must not be taking: GLP-1RA, Weight-lowering agents

Disqualifiers: Severe substance disorder, Diabetes, others

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 32 weeks

92 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if semaglutide, a medication typically used for weight management, can aid weight loss in individuals with schizophrenia-spectrum disorders. Many people with these conditions face obesity, often due to their medications. Participants will receive either semaglutide or a placebo to compare effects. The trial seeks individuals with schizophrenia, major depression with psychotic features, or bipolar disorder who are overweight and have not lost weight with metformin. As an unphased trial, this study provides a unique opportunity to explore potential weight loss benefits for those facing these challenges.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not be on metformin for at least one week before joining. You also need to be on a stable dose of antipsychotic medication for at least three months.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that semaglutide is generally safe for people. One study found that semaglutide helped people lose more weight than a placebo and did not worsen psychotic symptoms in those taking antipsychotic medications, indicating it is well-tolerated by this group. Another study confirmed that semaglutide is safe for people with schizophrenia who are overweight, as it helps lower both blood sugar and weight.

Additionally, the FDA has approved semaglutide for long-term weight management, indicating it has passed strict safety tests for another use. This approval underscores the treatment's safety.

Overall, current evidence suggests that semaglutide is a safe option for managing weight in people with schizophrenia who are also on antipsychotic medications. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike the standard treatments for schizophrenia and obesity, which often involve antipsychotics and lifestyle changes or weight-loss medications, semaglutide offers a distinctive approach. Researchers are excited about semaglutide because it is originally a medication for diabetes that mimics a hormone called GLP-1, which helps control appetite and blood sugar levels. This unique mechanism may address both schizophrenia symptoms and obesity simultaneously, offering a novel dual-action benefit. Additionally, semaglutide is administered weekly, which could improve adherence compared to daily medications.

What evidence suggests that semaglutide might be an effective treatment for obesity in individuals with schizophrenia-spectrum disorders?

In this trial, participants will receive either semaglutide or a placebo. Research has shown that semaglutide can significantly aid weight loss. In one study, 69.1% of participants lost at least 10% of their body weight, compared to only 12.0% of those not taking semaglutide. Additionally, 32.0% of those taking semaglutide lost at least 20% of their starting weight. Another study found that semaglutide led to more weight loss than a placebo and did not affect schizophrenia symptoms. This makes semaglutide a promising option for managing weight in people with schizophrenia who experience weight gain from their medications. ^{5 6 7 8 9}

Who Is on the Research Team?

Margaret Hahn, MD, PhD

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with schizophrenia spectrum disorder or related conditions, who are obese due to antipsychotic medications and haven't lost weight on metformin. Participants must have a BMI of at least 30, or 27 with certain health issues, and can't be pregnant, nursing, or without contraception if applicable.

Inclusion Criteria

My BMI is over 30, or over 27 with a weight-related health issue, or over 25 and I've gained more than 5% of my weight due to AP treatment.

I have been on a stable dose of antipsychotic medication for over 3 months.

I couldn't lose 5% of my weight on metformin over 16 weeks and haven't taken it for at least a week.

Exclusion Criteria

I have diabetes, with an HbA1c level over 6.5%.

You have a serious addiction to drugs or alcohol, except for tobacco or caffeine. Only severe addiction to cannabis would exclude you from participating.

Any condition that interferes with the safe acquisition of MRI data such as metal implants, pacemakers, aneurysm clips, cochlear implants (only for the MRI component; can participate in the remainder of the trial)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive semaglutide or placebo on a weekly schedule, with adherence tracked

32 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Semaglutide

Trial Overview The study tests whether semaglutide helps overweight individuals with schizophrenia spectrum disorders lose weight compared to a placebo. These patients struggle with obesity partly because of their antipsychotic medication and haven't had success losing weight on metformin.

How Is the Trial Designed?

Group I: Semaglutide Experimental Treatment 1 Intervention

Semaglutide medication will be taken by participants on a weekly schedule, and adherence tracked

Group II: Placebo Placebo Group 1 Intervention

Placebo will be taken by participants on a weekly schedule, and adherence tracked

Semaglutide is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Canada as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Japan as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Wegovy for:

• Obesity

Approved in United States as Rybelsus for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Published Research Related to This Trial

High-dose once-weekly semaglutide has been shown to significantly reduce weight in patients with obesity or overweight, as demonstrated in four phase 3 clinical trials involving various populations, including those with diabetes.

While gastrointestinal side effects were common, semaglutide was generally well tolerated and also led to improvements in cardiometabolic risk factors, such as waist circumference and blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Once-Weekly Semaglutide: A New Option for Obesity Management. Bradley, CL., McMillin, SM., Hwang, AY., et al.[2022]

This study will evaluate the long-term effects of semaglutide, a medication approved for type 2 diabetes and obesity, as an add-on treatment for patients with schizophrenia who are taking clozapine or olanzapine, focusing on its impact on metabolic health over 26 weeks.

With 104 participants aged 18-65, the trial aims to measure changes in HbA1c levels, body weight, and various metabolic markers, providing insights into whether semaglutide can mitigate the weight gain and metabolic disturbances associated with these antipsychotic medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of the GLP-1 receptor agonist semaglutide on metabolic disturbances in clozapine-treated or olanzapine-treated patients with a schizophrenia spectrum disorder: study protocol of a placebo-controlled, randomised clinical trial (SemaPsychiatry). Sass, MR., Danielsen, AA., Köhler-Forsberg, O., et al.[2023]

Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to produce the largest weight loss of any obesity medication, with an average reduction of about 15% of initial body weight over 68 weeks.

In addition to significant weight loss, semaglutide also improves cardiovascular risk factors and physical functioning, making it a promising option for chronic weight management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide for the treatment of obesity. Chao, AM., Tronieri, JS., Amaro, A., et al.[2023]

Semaglutide, a glucagon-like peptide-1 receptor agonist, is effective for treating type 2 diabetes and obesity, providing significant weight loss and cardiovascular benefits, making it crucial for high-risk patients.

However, during the SUSTAIN clinical trial program, a safety concern arose regarding the worsening of diabetic retinopathy, potentially linked to rapid reductions in HbA1c levels, which requires further investigation and careful clinical management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide-eye-catching results. Cigrovski Berkovic, M., Strollo, F.[2023]

In a pilot trial involving 47 participants with schizophrenia or related disorders, liraglutide 3.0 mg daily led to a significant average weight loss of 5.7 kg over 6 months, compared to no significant change in the placebo group.

The study demonstrated good retention rates, with 79% of participants completing the trial, indicating that liraglutide is a feasible and acceptable option for managing obesity in individuals with severe mental illness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of liraglutide 3.0 mg daily in the management of overweight and obesity in people with schizophrenia, schizoaffective disorder and first episode psychosis: Results of a pilot randomized, double-blind, placebo-controlled trial. Whicher, CA., Price, HC., Phiri, P., et al.[2022]

In a meta-analysis of 164 patients with schizophrenia, glucagon-like peptide-1 receptor agonists (GLP-1RAs) led to a significant body weight loss of 3.71 kg compared to controls after about 16 weeks, particularly benefiting those treated with clozapine or olanzapine.

While GLP-1RAs were effective in reducing weight and improving metabolic markers, they were associated with a higher incidence of nausea compared to controls, indicating a need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 receptor agonists for antipsychotic-associated cardio-metabolic risk factors: A systematic review and individual participant data meta-analysis. Siskind, D., Hahn, M., Correll, CU., et al.[2019]

Semaglutide 2.4 mg led to significant weight loss in adults with overweight/obesity, achieving a mean change of -15.7% for those on antidepressants compared to -0.2% for placebo, demonstrating its efficacy regardless of antidepressant use.

The safety profile of semaglutide was consistent with previous studies, showing a similar prevalence of adverse events between the semaglutide and placebo groups among participants taking antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of semaglutide 2.4 mg according to antidepressant use at baseline: A post hoc subgroup analysis. Kushner, RF., Fink-Jensen, A., Frenkel, O., et al.[2023]

In a phase 3 trial involving 667 adults with overweight or obesity, oral semaglutide 50 mg taken daily resulted in a significant average weight loss of 15.1% compared to only 2.4% with placebo over 68 weeks, demonstrating its efficacy in weight management.

While semaglutide was effective, it was associated with a higher incidence of adverse events, particularly gastrointestinal issues, affecting 80% of participants, indicating that while it is effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Knop, FK., Aroda, VR., do Vale, RD., et al.[2023]

In a study of 12 patients with severe mental illness who did not respond to metformin for antipsychotic-associated weight gain, semaglutide treatment resulted in significant weight loss over 12 months, averaging 8.67 kg (p=0.04).

Semaglutide was well-tolerated with manageable side effects, suggesting it could be a promising alternative for patients struggling with weight gain from antipsychotic medications, although further randomized control trials are needed to confirm these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide for the treatment of antipsychotic-associated weight gain in patients not responding to metformin - a case series. Prasad, F., De, R., Korann, V., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12313766/

Obesity and Schizophrenia: Results of a Feasibility Study with ... Semaglutide led to 69.1% (vs. 12.0%) losing ≥ 10% weight (69.1 vs. 12.0%) with ≥ 20% reduction of baseline weight achieved in 32.0% (vs. 1.7%) ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2215036625001294

Articles Efficacy and safety of semaglutide versus placebo ... Semaglutide led to significantly greater weight loss than placebo in this small trial without affecting psychotic symptoms or clozapine concentrations.

3. icer.org icer.org/wp-content/uploads/2025/10/ICER_Obesity_Evidence-Report_For-Publication_102925.pdf

Semaglutide and Tirzepatide for Obesity: Effectiveness and ... Readers should be aware that new evidence may emerge following the publication of this report that could potentially influence the results. ICER.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05333003

Study Details | NCT05333003 | Semaglutide in Comorbid ... Semaglutide, recently approved for chronic weight loss is an attractive option given a similar adverse effect profile but superior metabolic efficacy compared ...

5. nature.com nature.com/articles/s41591-024-02996-7

Long-term weight loss effects of semaglutide in obesity ... Semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years.

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2307563

Semaglutide and Cardiovascular Outcomes in Obesity ... Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40506208/

Efficacy and safety of semaglutide versus placebo for ... Semaglutide led to significantly greater weight loss than placebo in this small trial without affecting psychotic symptoms or clozapine concentrations.

8. nature.com nature.com/articles/s41591-025-03978-z

A systematic review and meta-analysis of the efficacy and ... This systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of ...

9. jamanetwork.com jamanetwork.com/journals/jamapsychiatry/article-abstract/2838205

Semaglutide Treatment of Antipsychotic-Treated Patients ... Meaning Semaglutide is safe and effective for lowering blood glucose and weight in patients with schizophrenia who also experience overweight or ...