Semaglutide in Comorbid Schizophrenia Spectrum Disorder and Obesity

Sponsor

Centre for Addiction and Mental Health (Other)

Overall Status

Recruiting

CT.gov ID

NCT05333003

Collaborator

(none)

Enrollment

Location

Arms

38.2

Anticipated Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia Spectrum Disorders	Drug: Semaglutide Other: Placebo	N/A

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:

Percentage change in body weight
Measures of glucose metabolism and cardiovascular risk factors
Psychopathology
Cognition
Lifestyle-based assessments

Study Design

Study Type:

Interventional

Anticipated Enrollment :

92 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Participant)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 25, 2022

Anticipated Primary Completion Date :

Aug 1, 2025

Anticipated Study Completion Date :

Aug 1, 2025

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Weight change [32 weeks]
Percentage change in body weight (kg)

Secondary Outcome Measures

Body Mass Index (BMI) [32 weeks]
A person's weight in kilograms divided by height in metres squared
Waist circumference [32 weeks]
Measured in centimetres
Oral glucose tolerance test [32 weeks]
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.
Visceral and hepatic adiposity [32 weeks]
An abdominal surface coil on the MRI will be used for this body composition measure
Fasting lipid profile [32 weeks]
Cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglyceride levels will be collected through bloodwork in mmol/L
Psychopathology - Brief Psychiatric Rating Scale (BPRS) [32 weeks]
Structured scale used to measure psychiatric symptoms
Psychopathology - Calgary Depression Scale for Schizophrenia (CDSS) [32 weeks]
Structured scale used to measure depression in schizophrenia
Psychopathology - Global Assessment of Functioning (GAF) [32 weeks]
Structured scale used to rate the global functioning of patient
Psychopathology - Clinical Global Impression scale (CGI) [32 weeks]
Structured scale used to rate the global impression of patient
Change in cognitive performance [32 weeks]
Evaluated through a standard scale called the MATRICS Consensus Cognitive Battery (MCCB)
Lifestyle assessment - Assessment of Quality of life (AQoL) [32 weeks]
A structured scale used to measure health-related quality of life
Lifestyle assessment - WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) [32 weeks]
A structured measure of health and disability
Lifestyle assessment - International Physical Activity Questionnaire (IPAQ) [32 weeks]
A structured measure of physical activity practices
Lifestyle assessment - The Fagerstrom Test of Nicotine Dependence (FTND) [32 weeks]
A structured scale used to measure the intensity of physical dependence on nicotine
Lifestyle assessment - Food Cravings Questionnaire (FCQ); [32 weeks]
A structured item used to measure frequency and intensity of food cravings

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Stable outpatients aged 18-55 years, diagnosed with SCZ, or schizoaffective disorder
On maintenance treatment (> 9 months) 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.
History of failure to lose ≥5% body weight over a three month period on the highest tolerated trial of metformin

Exclusion Criteria:

Patients with severe substance disorder other than tobacco or caffeine use disorder
Liver, or renal dysfunction
A positive drug urine screen
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 history of Type 2 Diabetes (T2D), diagnosis of T2D on OGTT screen, HbA1c > 6.5%
Medications with significant renal impact or weight-lowering agents
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
Hypothyroidism or being treated with levothyroxine
Treatment with warfarin or coumarin derivatives
History of metabolic acidosis or lactic acidosis
History of heart rhythm disturbances, conduction system abnormalities, or evidence of 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)