Semaglutide for Cognitive Impairment in Depression

Overseen By Rodrigo B. Mansur, MD, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Oral hypoglycemics, Insulin

Disqualifiers: Alzheimer's, Neurological disorder, Severe mood, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether semaglutide can improve thinking and brain function in people with major depressive disorder (MDD). Participants will take semaglutide daily for 16 weeks. The trial compares semaglutide to a placebo (a pill with no active ingredient) to determine its effectiveness. Suitable candidates for this trial have depression, are overweight, and have noticed issues with their thinking skills. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you've been treated with oral hypoglycemic agents or insulin in the past 4 weeks.

Is there any evidence suggesting that semaglutide is likely to be safe for humans?

Research has shown that semaglutide, also known as Ozempic or Wegovy, is generally safe for brain health. Studies indicate it does not increase the risk of memory or thinking problems and might even improve these functions. This is reassuring for those concerned about mental side effects.

One study found that semaglutide did not cause more mental health issues than other diabetes medications. However, rare reports exist of mental side effects, especially in older adults, including problems like eating disorders or feelings of depression.

Overall, evidence suggests that semaglutide is well-tolerated, with most people not experiencing serious side effects. It is important to discuss any concerns with a healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Most treatments for cognitive impairment in depression, like antidepressants or cognitive therapies, address symptoms indirectly. But semaglutide works differently, targeting metabolic pathways involved in brain health. Originally used to manage diabetes, semaglutide is a GLP-1 receptor agonist that shows promise in improving cognitive function by enhancing brain cell signaling and energy utilization. Researchers are excited because this unique mechanism could offer a direct approach to alleviating cognitive issues in depression, potentially providing benefits beyond what current therapies offer.

What evidence suggests that semaglutide might be an effective treatment for cognitive impairment in depression?

Research has shown that semaglutide might help improve brain function. In this trial, participants will receive either semaglutide or a placebo. Semaglutide is a type of medicine that can protect brain cells and possibly enhance brain function. Studies with mice found that semaglutide improved brain performance and reduced signs of depression. Other research suggests that semaglutide is safe for brain health and might even lower the risk of cognitive problems. Overall, the evidence supports the idea that semaglutide could help with cognitive issues in people with major depressive disorder. ^{1 2 6 7 8}

Who Is on the Research Team?

Rodrigo B. Mansur, MD, PhD

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

This trial is for adults aged 18-60 with major depressive disorder (MDD) who have cognitive issues and are overweight. Participants must perform below average on a specific cognitive test and not be severely depressed, drug-dependent, pregnant, or breastfeeding. They can't have certain mental health conditions or be taking diabetes medications.

Inclusion Criteria

My BMI is 25 or higher, indicating I am overweight.

Below-average (i.e. >1 SD below norm) performance in the Trail Making Test-B (TMTB)

Informed consent before study-related activity

Exclusion Criteria

I have used diabetes medication or insulin in the last 4 weeks.

I have a history of neurological disorders or illnesses that could affect my thinking.

I have been diagnosed with Alzheimer's, Mild Cognitive Impairment, or another form of dementia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive semaglutide or placebo once daily, with dosage adjustments over 16 weeks

16 weeks

Regular visits for dosage adjustments and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Semaglutide

Trial Overview The study tests if semaglutide improves brain function in people with MDD. It's a comparison between semaglutide and a placebo (a substance with no active drug). Participants will receive either the real medication or placebo without knowing which one they're getting.

How Is the Trial Designed?

Group I: Semaglutide Experimental Treatment 1 Intervention

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).

Group II: Placebo Placebo Group 1 Intervention

Participants receive matching semaglutide placebo capsules once daily (duration of 16 weeks).

Semaglutide is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Canada as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Japan as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Wegovy for:

• Obesity

Approved in United States as Rybelsus for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

In a 12-week trial involving 75 adults with type 2 diabetes, semaglutide significantly improved both first- and second-phase insulin secretion, indicating enhanced beta cell function.

Semaglutide also led to better glycaemic control, with reduced fasting and postprandial glucose levels, and was well tolerated by participants, suggesting it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial. Kapitza, C., Dahl, K., Jacobsen, JB., et al.[2022]

Oral semaglutide, particularly at doses of 14 mg or flexibly dosed, significantly reduced HbA1c levels and body weight in patients with type 2 diabetes compared to other treatments, especially in those with higher baseline HbA1c levels.

The safety profile of oral semaglutide was comparable to that of other treatments, although it was associated with a higher incidence of gastrointestinal adverse events, which were consistent across different patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Aroda, VR., Bauer, R., Christiansen, E., et al.[2022]

In a study of 20 patients with type 2 diabetes in Slovenia, oral semaglutide significantly reduced HbA1c levels and fasting plasma glucose, indicating its efficacy in improving glycaemic control.

Patients reported high satisfaction with the treatment, and while some experienced mild gastrointestinal side effects, the overall safety profile was considered good, suggesting that oral semaglutide is a promising option for diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety, and patient satisfaction with oral semaglutide: first single-centre clinical experience. Janić, M., Jovanović, M., Janež, A., et al.[2023]

In two phase III trials involving 2764 participants with overweight or obesity, semaglutide 2.4 mg once weekly significantly improved cardiometabolic risk factors, including reductions in waist circumference, blood pressure, and fasting glucose compared to placebo.

The benefits of semaglutide were not sustained after stopping the treatment, indicating that ongoing administration may be necessary to maintain improvements in health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses. Kosiborod, MN., Bhatta, M., Davies, M., et al.[2023]

Semaglutide has shown potential protective effects against Alzheimer's disease by enhancing autophagy and inhibiting apoptosis in SH-SY5Y cells treated with Aβ25-35, a model for Alzheimer's.

The study found that semaglutide increased levels of autophagy-related proteins (like LC3II and Beclin-1) and decreased apoptosis-related proteins (like Bax), suggesting a mechanism through which it may help protect against neurodegeneration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide-mediated protection against Aβ correlated with enhancement of autophagy and inhibition of apotosis. Chang, YF., Zhang, D., Hu, WM., et al.[2021]

In a pooled analysis of phase 3a trials involving patients with type 2 diabetes, semaglutide demonstrated significant reductions in HbA1c and body weight, with greater efficacy observed in patients with higher baseline HbA1c levels.

The safety profile of semaglutide was consistent with other GLP-1 receptor agonists, primarily featuring gastrointestinal side effects, indicating it is a safe option for a wide range of patients with varying diabetes characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous once-weekly semaglutide: A patient-level, pooled analysis of the SUSTAIN 1-5 trials. Aroda, VR., Capehorn, MS., Chaykin, L., et al.[2022]

Semaglutide significantly reduced HbA1c levels in both non-elderly (1.2%-1.5%) and elderly (1.3%-1.5%) patients with type 2 diabetes compared to comparators, demonstrating its efficacy across age groups.

The safety profile of semaglutide was comparable in both age groups, with no increased risk of severe hypoglycemia, making it a suitable treatment option for elderly patients with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide as a therapeutic option for elderly patients with type 2 diabetes: Pooled analysis of the SUSTAIN 1-5 trials. Warren, M., Chaykin, L., Trachtenbarg, D., et al.[2022]

Semaglutide 2.4 mg led to significant weight loss in adults with overweight/obesity, achieving a mean change of -15.7% for those on antidepressants compared to -0.2% for placebo, demonstrating its efficacy regardless of antidepressant use.

The safety profile of semaglutide was consistent with previous studies, showing a similar prevalence of adverse events between the semaglutide and placebo groups among participants taking antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of semaglutide 2.4 mg according to antidepressant use at baseline: A post hoc subgroup analysis. Kushner, RF., Fink-Jensen, A., Frenkel, O., et al.[2023]

Oral semaglutide (Rybelsus®) has been shown to provide better glycaemic control and promote weight loss in patients with type 2 diabetes (T2DM) compared to standard oral glucose-lowering medications, based on data from the PIONEER clinical trial program involving 9543 patients.

The safety profile of oral semaglutide is similar to other GLP-1 receptor agonists, and it demonstrated cardiovascular safety comparable to placebo in high-risk patients, making it a viable option for T2DM management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oral semaglutide, first oral GLP-1 receptor agonist (Rybelsus®)]. Paquot, N.[2022]

In a 56-week study involving 1231 participants with type 2 diabetes, semaglutide significantly reduced HbA1c levels by 1.3% and 1.6% for the 0.5 mg and 1.0 mg doses, respectively, compared to a 0.5% reduction with sitagliptin, demonstrating superior efficacy in glycaemic control.

Semaglutide also led to greater weight loss, with reductions of 4.3 kg and 6.1 kg for the two doses, compared to 1.9 kg with sitagliptin, while maintaining a similar safety profile, primarily with gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Ahrén, B., Masmiquel, L., Kumar, H., et al.[2022]

Citations

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New study finds semaglutide safe for brain health with ... Semaglutide – widely known as Ozempic/Wegovy – does not negatively impact brain health and is associated with lower risk of cognitive problems ...

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12-month neurological and psychiatric outcomes of ... Semaglutide is not associated with higher 12-month risk of adverse neuropsychiatric outcomes compared to other antidiabetic medications.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11084700/

A Systematic Review of Semaglutide's Influence on Cognitive ... Evidence suggests that GLP-1 receptor agonists, like semaglutide, might offer neuroprotective qualities, potentially enhancing cognitive functions [11,12]. ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12109977/

Semaglutide and High-Intensity Interval Exercise Attenuate ... Results: Over 8 weeks, both HIIE and semaglutide improved neuronal morphology and cognitive performance while reducing depression in db/db mice.

5. nature.com nature.com/articles/s44220-025-00390-x

An analysis on the role of glucagon-like peptide-1 receptor ... First, there is supporting evidence for the safety of GLP-1RAs across the board of cognitive and mental disorders, as we retrieved very few ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40759509/

Neuropsychiatric side effects of semaglutide in patients ... This case underscores the importance of recognising potential psychiatric side effects of semaglutide, especially in older adults with cognitive ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0261561425001657

Psychiatric and psychological adverse effects associated ... The study found no significant increase in overall psychiatric ADR reporting for GLP-1 RAs, except for eating disorders and depression/suicidality in ...

8. jamanetwork.com jamanetwork.com/journals/jamainternalmedicine/fullarticle/2823084

Psychiatric Safety of Semaglutide for Weight Management ... The results of this post hoc analysis suggest that treatment with semaglutide, 2.4 mg, did not increase the risk of developing symptoms of depression or ...