Semaglutide in Comorbid Schizophrenia Spectrum Disorder and Obesity (Sema)

  • End date
    Aug 4, 2025
  • participants needed
  • sponsor
    Centre for Addiction and Mental Health
Updated on 4 April 2023


Rates of obesity in patients with schizophrenia-spectrum disorder (SSD)s have reached epidemic proportions, with established contributing effects of antipsychotic (AP) medications. Among agents approved for chronic weight management, glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with reductions in cardiovascular mortality, with recent FDA approval for once weekly semaglutide for this indication. This study will investigate whether semaglutide is effective in reducing body weight in overweight or obese individuals with SSDs who are on APs and do not demonstrate adequate weight loss on metformin (the first line treatment for weight loss in SSDs).


People with SSDs die early of iatrogenic cardiometabolic disease. Clinically, metformin remains the first line agent to mitigate this risk. In real-world clinical practice, metformin is likely to remain the first line treatment for AP-induced weight gain (given low cost, efficacy, and safety data). However, metformin is only effective in ~20% of patients. Hence, there is a need for interventions for AP-induced weight gain non-responsive to metformin. GLP-1RAs might represent the next rational step as they have a good safety profile, advantages of weekly administration, and early efficacy evidence to support their use in SSD and comorbid obesity, with benefits on dysglycemia, and visceral adiposity. Semaglutide, recently approved for chronic weight loss is an attractive option given a similar adverse effect profile but superior metabolic efficacy compared to other GLP-1 agents. The observations supporting an association between metabolic perturbations and cognition, along with preliminary evidence for neuroprotective effects of GLP-1RAs, suggest that by modifying metabolic risk factors, the investigators may be able to target difficult-to-treat domains of the illness such as cognitive dysfunction.

This study will examine the effect of semaglutide on:

  1. Percentage change in body weight
  2. Measures of glucose metabolism and cardiovascular risk factors
  3. Psychopathology
  4. Cognition
  5. Lifestyle-based assessments

Condition Schizophrenia Spectrum Disorders
Treatment Placebo, semaglutide
Clinical Study IdentifierNCT05333003
SponsorCentre for Addiction and Mental Health
Last Modified on4 April 2023


Yes No Not Sure

Inclusion Criteria

Stable outpatients or inpatients aged 18-65 years, diagnosed with schizophrenia spectrum disorder, or major depressive disorder with psychotic features, or bipolar disorder (does not need to have psychotic features)
On maintenance treatment with an AP (stable dose for ≥3 months)
BMI must be ≥30 kg/m2, OR ≥27 kg/m2 with the presence of at least one weight-related comorbidity (treated or untreated): hypertension, dyslipidaemia, obstructive sleep apnea, or impaired fasting glucose, OR BMI ≥25 with individual having gained >5% bodyweight in association with AP treatment
History of failure to lose ≥5% body weight over at least 16 weeks on the highest tolerated trial of metformin, and who are not currently being treated with metformin (minimum of 1 week metformin-free prior to study entry)

Exclusion Criteria

Patients with severe substance disorder other than tobacco or caffeine use disorder; only severe substance use disorder is exclusionary for cannabis use
Liver, or renal dysfunction
A positive drug urine screen other than cannabis as per PI discretion
Sexually active females of child-bearing age not on a regular contraceptive, or nursing or with a positive pregnancy test
Clinical or laboratory evidence of uncompensated cardiovascular, endocrine, haematological, or pulmonary disease
History of reactive hypoglycaemia
Treatment within 3 months, or failure to tolerate GLP-1RA
Type 1 Diabetes (T1D) or current diagnosis of Type 2 Diabetes (T2D), diagnosis of T2D on OGTT screen, or HbA1c > 6.5%
Use of Health Canada approved weight-lowering agents, warfarin, coumarin derivatives, or medication with significant renal impact
Major medical or surgical event within the preceding 3 months
Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome
History of pancreatitis or elevated amylase on screen
History of severe gastrointestinal disease, (i.e. gastroparesis)
Acute suicidal risk
Uncompensated thyroid disorder
History of heart rhythm disturbances, conduction system abnormalities, or evidence of clinically relevant abnormalities on screening ECG
History of gallstones with intact gallbladder or those at increased risk of gallbladder complications (with intact gallbladder)
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)
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