Semaglutide in Comorbid Schizophrenia Spectrum Disorder and Obesity (Sema)

Semaglutide in Comorbid Schizophrenia Spectrum Disorder and Obesity for Metformin Non-responders: a Single-blind Randomized Control Trial

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).

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia Spectrum Disorders
• Intervention / Treatment: Drug: Semaglutide; Other: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Margaret Hahn, MD, PhD; Phone Number: 34368 416-535-8501; Email: margaret.hahn@camh.ca
• Study Contact Backup: Name: Mahavir Agarwal, MD, PhD; Phone Number: 30546 416-535-8501; Email: mahavir.agarwal@camh.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M6J 1H4
      • Recruiting
      • Centre for Addiction and Mental Health
      • Contact: Margaret Hahn, MD, PhD; Phone Number: 34368 416-535-8501; Email: margaret.hahn@camh.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Stable outpatients or inpatients aged 18-70 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 either failure to tolerate metformin or 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.
• 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)
• History of gallstones with intact gallbladder or those at increased risk of gallbladder complications (with intact gallbladder)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semaglutide; Semaglutide medication will be taken by participants on a weekly schedule, and adherence tracked	Drug: Semaglutide; The semaglutide dose will start with 0.25 mg/week, and slowly increased every four weeks as tolerated up to a maximal dose of 2 mg/week
Placebo Comparator: Placebo; Placebo will be taken by participants on a weekly schedule, and adherence tracked	Other: Placebo; Placebo will be provided to participants

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight change	Percentage change in body weight (kg)	32 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body Mass Index (BMI)	A person's weight in kilograms divided by height in metres squared	32 weeks
Waist circumference	Measured in centimetres	32 weeks
Oral glucose tolerance test	A standard glucose drink (75g) is given orally, and bloodwork containing insulin (pmol/L) and glucose (mmol/L) levels are obtained both at baseline and 2 hours after the glucose drink. These measures will help indicate B cell function and whole body insulin sensitivity, allowing for the proportion of individuals converting to impaired glucose tolerance, prediabetes, or type 2 diabetes to be determined.	32 weeks
Visceral and hepatic adiposity	An abdominal surface coil on the MRI will be used for this body composition measure	32 weeks
Fasting lipid profile	Cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglyceride levels will be collected through bloodwork in mmol/L	32 weeks
Psychopathology - Brief Psychiatric Rating Scale (BPRS)	Structured scale used to measure psychiatric symptoms	32 weeks
Psychopathology - Calgary Depression Scale for Schizophrenia (CDSS)	Structured scale used to measure depression in schizophrenia	32 weeks
Psychopathology - Global Assessment of Functioning (GAF)	Structured scale used to rate the global functioning of patient	32 weeks
Psychopathology - Clinical Global Impression scale (CGI)	Structured scale used to rate the global impression of patient	32 weeks
Change in cognitive performance	Evaluated through a standard scale called the MATRICS Consensus Cognitive Battery (MCCB)	32 weeks
Lifestyle assessment - Assessment of Quality of life (AQoL)	A structured scale used to measure health-related quality of life	32 weeks
Lifestyle assessment - WHO Disability Assessment Schedule 2.0 (WHODAS 2.0)	A structured measure of health and disability	32 weeks
Lifestyle assessment - International Physical Activity Questionnaire (IPAQ)	A structured measure of physical activity practices	32 weeks
Lifestyle assessment - The Fagerstrom Test of Nicotine Dependence (FTND)	A structured scale used to measure the intensity of nicotine dependence related to cigarette smoking	32 weeks
Lifestyle assessment - Penn State Nicotine Dependence Index-Cigarette/Electronic Cigarette	A structured measure used to quantify the intensity of physical dependence across various nicotine products	32 weeks
Lifestyle assessment - Canadian Diet History Questionnaire II (C-DHQ II)	A structured, comprehensive questionnaire used to measure food frequency	32 weeks
Lifestyle assessment - Food Cravings Questionnaire (FCQ)	A structured item used to measure frequency and intensity of food cravings	32 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Structural MRI	High-resolution anatomical image of the brain will be acquired	32 weeks
Resting state functional MRI (rsfMRI)	The resting-state echo-planar imaging will be used to analyze fronto-temporal network connectivity	32 weeks
Arterial spin labeling (ASL)	This scan will be performed to assess the effects on cerebral blood flow	32 weeks
1H-Magnetic resonance spectroscopy (MRS)	A single voxel spectra will be acquired for a volume of interest placed over the bilateral striatum, to measure glutamate levels	32 weeks

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Investigators: Principal Investigator: Margaret Hahn, MD, PhD, Centre for Addiction and Mental Health

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2022
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: March 25, 2022
• First Submitted That Met QC Criteria: April 11, 2022
• First Posted (Actual): April 18, 2022

Study Record Updates

• Last Update Posted (Estimated): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Weight; Antipsychotics; Schizophrenia spectrum disorders; GLP-1 receptor agonists
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Hypoglycemic Agents; Physiological Effects of Drugs; Glucagon-Like Peptide-1 Receptor Agonists; Semaglutide
• Other Study ID Numbers: 139/2020

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No