Semaglutide for the Treatment of Cognitive Dysfunction in Major Depressive Disorder

Study Overview
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Brief Summary
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This study will examine whether semaglutide may improve cognitive function in individuals with major depressive disorder (MDD).

Detailed Description
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This is a 16-week, placebo-controlled, randomized, double-blind, clinical trial, involving 60 overweight individuals with MDD and pre-treatment cognitive dysfunction. Study participants will receive one of the following study interventions in addition to 'standard of care' treatment: once-daily semaglutide, initiated at 3 mg/day for 4 weeks, increased to 7 mg/day for 4 more weeks and titrated to 14 mg/day for the subsequent 8 weeks; or matching placebo. Participants will be assessed to examine the effect of semaglutide on their cognitive function.

Official Title
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Adjunctive Semaglutide for the Treatment of Cognitive Dysfunction in Major Depressive Disorder: a Randomized, Double-Blind, Placebo-Controlled Study

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Biological: Semaglutide
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent before study-related activity Individuals between the ages of 18 and 60 who meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for MDD Overweight (i.e. BMI ≥ 25 kg/m2) Below-average (i.e. >1 SD below norm) performance in the Trail Making Test-B (TMTB) Exclusion Criteria: Current, or in the past 4 weeks, treatment with other oral hypoglycemic agents and/or insulin Diagnosis of possible or probable Alzheimer's Disease, Mild Cognitive Impairment, or any other dementia History of neurological disorder, or evidence of neurologic or other physical illness that could produce cognitive deterioration Severe mood episode, defined as a Hamilton Depression Rating Scale (HAMD-17) score of >23 Actively suicidal or evaluated as being a suicide risk (operationalized as a score of ≥3 on HAMD-17 suicide item and/or by clinical assessment). Substance use disorder within 3 months before screening or a positive baseline toxicology screen DSM-5 diagnosis of obsessive compulsive disorder, posttraumatic stress disorder (current or within the last year), or borderline personality disorder as assessed by a study investigator Presence of absolute or relative contraindication to semaglutide (e.g. hypersensitivity to semaglutide, hepatic impairment, renal impairment with chronic kidney disease stage 3 and above, personal or familial history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2) History of diabetic retinopathy History of pancreatitis or pancreatic cancer Presence of clinically unstable general medical illness Pregnancy or breastfeeding women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide<br>Participants receive semaglutide once daily orally, initiated at 3 mg/day for 4 weeks, increased to 7 mg/day for 4 more weeks and titrated to 14 mg/day for the subsequent 8 weeks (i.e., duration of 16 weeks in total). | Biological: Semaglutide<br>* 3 mg/day for 4 weeks, increased to 7 mg/day for 4 more weeks and titrated to 14 mg/day for the subsequent 8 weeks<br>|
| Placebo Comparator: Placebo<br>Participants receive matching semaglutide placebo capsules once daily (duration of 16 weeks). | Biological: Placebo<br>* Semaglutide placebo capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Executive Function Composite Score | The primary outcome will be an executive function composite score. This score will be comprised of the Digit Symbol Substitution Test (DSST - number of symbols), the Stroop test (time to completion in the congruent and incongruent conditions), and the Spatial n-back (reaction times and accuracy in four conditions,1-back, 2-back, 3-back, and 4-back). | 16 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Digit Symbol Substitution Test (DSST) | DSST is a neurocognitive test designed to assess motor speed and concentration. | 16 Weeks | 
| Rey Auditory Verbal Learning Test (RAVLT) | RAVLT is a neurocognitive test designed to assess verbal learning and memory. | 16 Weeks | 
| Stroop Test | The Stroop Test is a neurocognitive test designed to assess the ability to inhibit cognitive interference. | 16 Weeks | 
| Trail Making Test A (TMTA) | TMTA is a neurocognitive test designed to assess visual scanning and attention. | 16 Weeks | 
| Perceived Deficits Questionnaire (PDQ) | PDQ is used to assess subjective cognitive dysfunction. | 16 Weeks | 
| 36-Item Short Form Health Survey (SF-36) | SF-36 is used to assess quality of life. | 16 Weeks | 
| Sheehan Disability Scale (SDS) | SDS is used to assess functional impairment in work/school, social life, and family life. | 12 Weeks | 
| Endicott Workplace Productivity Scale (EWPS) | EWPS is used to assess workplace productivity. | 16 Weeks | 
| Height | Unit: cm | 16 Weeks | 
| Weight | Unit: kg | 16 Weeks | 
| fasting glucose - Blood laboratorial marker |  | 16 Weeks | 
| Diet History Questionnaire III (DHQ) | DHQ is a freely available questionnaire used to assess dietary intake (https://epi.grants.cancer.gov/dhq3/). | 16 Weeks | 
| Physical Activity Questionnaire (IPAQ) | IPAQ is used to assess physical activity. | 16 Weeks | 
| Pittsburgh Sleep Quality Index (PSQI) | PSQI is used to assess sleep quality. | 16 Weeks | 
| Trail Making Test B (TMTB) | TMTB is a neurocognitive test designed to assess attention and concentration. | 16 Weeks |