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This study will examine whether semaglutide may improve cognitive function in individuals with major depressive disorder (MDD).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Semaglutide | Experimental | 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). |
|
| Placebo | Placebo Comparator | Participants receive matching semaglutide placebo capsules once daily (duration of 16 weeks). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Semaglutide | Biological | 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 |
|
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rodrigo B. Mansur, MD, PhD | University Health Network, Toronto | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Toronto Western Hospital | Toronto | Ontario | M5T 2S8 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42054055 | Derived | Gill H, Badulescu S, Shah H, Brudner RM, Phan L, Di Vincenzo JD, Tabassum A, Thanarajah SE, Llach CD, Rosenblat JD, McIntyre RS, Mansur RB. Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2026 Apr 29:e260594. doi: 10.1001/jamapsychiatry.2026.0594. Online ahead of print. | |
| 41218611 |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C000591245 | semaglutide |
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| Placebo | Biological | Semaglutide placebo capsules |
|
| 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 |
| Badulescu S, Gill H, Shah H, Brudner R, Phan L, Di Vincenzo JD, Tabassum A, Armanyous M, Llach CD, Rosenblat JD, McIntyre RS, Mansur RB. Semaglutide for the treatment of cognitive dysfunction in major depressive disorder: A randomized clinical trial. Med. 2026 Jan 9;7(1):100916. doi: 10.1016/j.medj.2025.100916. Epub 2025 Nov 10. |