Major Depressive DisorderPhase 2NCT04466345
Semaglutide for the Treatment of Cognitive Dysfunction in Major Depressive Disorder
A Phase 2 study testing Semaglutide in people with Major Depressive Disorder, run by University Health Network, Toronto at 1 site in Canada.
Trial summary
This study will examine whether semaglutide may improve cognitive function in individuals with major depressive disorder (MDD). Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Semaglutide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 72 participants
- Where
- 1 siteCanada
- Study dates
- 6 Oct 2021to 27 Dec 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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)
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Adjunctive Semaglutide for the Treatment of Cognitive Dysfunction in Major Depressive Disorder: a Randomized, Double-Blind, Placebo-Controlled Study
This study will examine whether semaglutide may improve cognitive function in individuals with major depressive disorder (MDD).
Read the detailed description
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.
- Conditions
- Major Depressive Disorder
- Being tested
- Semaglutide, Placebo
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SemaglutideBiological
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
PlaceboBiological
Semaglutide placebo capsules
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: Biological: Semaglutide |
| Placebo | Placebo comparator | Participants receive matching semaglutide placebo capsules once daily (duration of 16 weeks). Receives: Biological: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 16 Weeks
Secondary outcomes (15)
Digit Symbol Substitution Test (DSST)
DSST is a neurocognitive test designed to assess motor speed and concentration.
Measured: 16 Weeks
Rey Auditory Verbal Learning Test (RAVLT)
RAVLT is a neurocognitive test designed to assess verbal learning and memory.
Measured: 16 Weeks
Stroop Test
The Stroop Test is a neurocognitive test designed to assess the ability to inhibit cognitive interference.
Measured: 16 Weeks
Trail Making Test A (TMTA)
TMTA is a neurocognitive test designed to assess visual scanning and attention.
Measured: 16 Weeks
Perceived Deficits Questionnaire (PDQ)
PDQ is used to assess subjective cognitive dysfunction.
Measured: 16 Weeks
36-Item Short Form Health Survey (SF-36)
SF-36 is used to assess quality of life.
Measured: 16 Weeks
Sheehan Disability Scale (SDS)
SDS is used to assess functional impairment in work/school, social life, and family life.
Measured: 12 Weeks
Endicott Workplace Productivity Scale (EWPS)
EWPS is used to assess workplace productivity.
Measured: 16 Weeks
Height
Unit: cm
Measured: 16 Weeks
Weight
Unit: kg
Measured: 16 Weeks
fasting glucose - Blood laboratorial marker
Measured: 16 Weeks
Diet History Questionnaire III (DHQ)
DHQ is a freely available questionnaire used to assess dietary intake (https://epi.grants.cancer.gov/dhq3/).
Measured: 16 Weeks
Physical Activity Questionnaire (IPAQ)
IPAQ is used to assess physical activity.
Measured: 16 Weeks
Pittsburgh Sleep Quality Index (PSQI)
PSQI is used to assess sleep quality.
Measured: 16 Weeks
Trail Making Test B (TMTB)
TMTB is a neurocognitive test designed to assess attention and concentration.
Measured: 16 Weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jul 2020
- Study start6 Oct 2021
- Primary completion27 Dec 2024
- Study completion27 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 72 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Rodrigo B. Mansur, MD, PhD, Principal investigator, University Health Network, Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04466345
- Sponsor's protocol ID
- 19-6283
- Status last verified
- Aug 2024
- First submitted
- 8 Jun 2020
- Last updated
- 2 Oct 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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 Jul 1;83(7):751-754. doi: 10.1001/jamapsychiatry.2026.0594.
PubMed 42054055Badulescu 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.
PubMed 41218611
Study at a glance
From the registry record, last updated by the sponsor on 2 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Adjunctive Semaglutide for the Treatment of Cognitive Dysfunction in Major Depressive Disorder: a Randomized, Double-Blind, Placebo-Controlled Study
- ClinicalTrials.gov ID
- NCT04466345
- Acronym / sponsor ID
- 19-6283
- Conditions
- Major Depressive Disorder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 72 participants (actual)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Study start
- 6 Oct 2021 (actual)
- Primary completion
- 27 Dec 2024 (actual)
- Study completion
- 27 Dec 2024 (actual)
- First posted
- 10 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will examine whether semaglutide may improve cognitive function in individuals with major depressive disorder (MDD).
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Semaglutide | Experimental | Biological: SemaglutideParticipants 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 | Biological: PlaceboParticipants receive matching semaglutide placebo capsules once daily (duration of 16 weeks). |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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)
Key exclusion criteria (12 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Semaglutide3 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 | Biological | Semaglutide |
| PlaceboSemaglutide placebo capsules | Biological | Placebo |
Primary outcome
Executive Function Composite Score
Time frame: 16 Weeks
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).
15 secondary outcomes
Digit Symbol Substitution Test (DSST)
Time frame: 16 Weeks
Rey Auditory Verbal Learning Test (RAVLT)
Time frame: 16 Weeks
Stroop Test
Time frame: 16 Weeks
Trail Making Test A (TMTA)
Time frame: 16 Weeks
Perceived Deficits Questionnaire (PDQ)
Time frame: 16 Weeks
36-Item Short Form Health Survey (SF-36)
Time frame: 16 Weeks
Sheehan Disability Scale (SDS)
Time frame: 12 Weeks
Endicott Workplace Productivity Scale (EWPS)
Time frame: 16 Weeks
Height
Time frame: 16 Weeks
Weight
Time frame: 16 Weeks
fasting glucose - Blood laboratorial marker
Time frame: 16 Weeks
Diet History Questionnaire III (DHQ)
Time frame: 16 Weeks
Physical Activity Questionnaire (IPAQ)
Time frame: 16 Weeks
Pittsburgh Sleep Quality Index (PSQI)
Time frame: 16 Weeks
Trail Making Test B (TMTB)
Time frame: 16 Weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Oct 2025.
- Derived from this study: PubMed 42054055Gill 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 Jul 1;83(7):751-754. doi: 10.1001/jamapsychiatry.2026.0594.
- Derived from this study: PubMed 41218611Badulescu 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rodrigo B. Mansur, MD, PhD principal investigator
University Health Network, Toronto
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Semaglutide in people with Major Depressive Disorder, run by University Health Network, Toronto at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Executive Function Composite Score (time frame: 16 Weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04466345, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Oct 2025.