Clinical trial NCT05333003: Semaglutide in Comorbid Schizophrenia Spectrum Disorder and Obesity
Official title: Semaglutide in Comorbid Schizophrenia Spectrum Disorder and Obesity for Metformin Non-responders: a Single-blind Randomized Control Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Schizophrenia Spectrum Disorders
Keywords: Schizophrenia spectrum disorders
GLP-1 receptor agonists
Weight
Antipsychotics
Lead sponsor: Centre for Addiction and Mental Health
Sponsor class: OTHER
First posted: 2022-04-18
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Eligibility criteria: 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)

Primary outcomes:
measure: Weight change
timeFrame: 32 weeks
Secondary outcomes:
measure: Body Mass Index (BMI)
timeFrame: 32 weeks
measure: Waist circumference
timeFrame: 32 weeks
measure: Oral glucose tolerance test
timeFrame: 32 weeks
measure: Visceral and hepatic adiposity
timeFrame: 32 weeks
measure: Fasting lipid profile
timeFrame: 32 weeks
measure: Psychopathology - Brief Psychiatric Rating Scale (BPRS)
timeFrame: 32 weeks
measure: Psychopathology - Calgary Depression Scale for Schizophrenia (CDSS)
timeFrame: 32 weeks
measure: Psychopathology - Global Assessment of Functioning (GAF)
timeFrame: 32 weeks
measure: Psychopathology - Clinical Global Impression scale (CGI)
timeFrame: 32 weeks
measure: Change in cognitive performance
timeFrame: 32 weeks
measure: Lifestyle assessment - Assessment of Quality of life (AQoL)
timeFrame: 32 weeks
measure: Lifestyle assessment - WHO Disability Assessment Schedule 2.0 (WHODAS 2.0)
timeFrame: 32 weeks
measure: Lifestyle assessment - International Physical Activity Questionnaire (IPAQ)
timeFrame: 32 weeks
measure: Lifestyle assessment - The Fagerstrom Test of Nicotine Dependence (FTND)
timeFrame: 32 weeks
measure: Lifestyle assessment - Penn State Nicotine Dependence Index-Cigarette/Electronic Cigarette
timeFrame: 32 weeks
measure: Lifestyle assessment - Canadian Diet History Questionnaire II (C-DHQ II)
timeFrame: 32 weeks
measure: Lifestyle assessment - Food Cravings Questionnaire (FCQ)
timeFrame: 32 weeks
Other outcomes:
measure: Structural MRI
timeFrame: 32 weeks
measure: Resting state functional MRI (rsfMRI)
timeFrame: 32 weeks
measure: Arterial spin labeling (ASL)
timeFrame: 32 weeks
measure: 1H-Magnetic resonance spectroscopy (MRS)
timeFrame: 32 weeks
Locations:
city: Toronto
country: Canada
facility: Centre for Addiction and Mental Health
state: Ontario
Study officials:
affiliation: Centre for Addiction and Mental Health
name: Margaret Hahn, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: