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

72 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial will test if semaglutide can improve thinking skills in overweight people with depression. Semaglutide is a medication that helps control blood sugar and might also help the brain work better. It is used for weight loss and blood sugar control, and has shown potential benefits for brain function.

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.

What data supports the effectiveness of the drug Semaglutide for cognitive impairment in depression?

Research suggests that Semaglutide may protect against Alzheimer's disease by enhancing autophagy (the body's way of cleaning out damaged cells) and inhibiting apoptosis (cell death), which could be relevant for cognitive impairment in depression. ^{1 2 3 4 5}

Is semaglutide safe for humans?

Semaglutide, used in treatments like Rybelsus, Ozempic, and Wegovy, has been tested in people with type 2 diabetes and is generally considered safe. It has a similar safety profile to other drugs in its class and does not increase heart-related risks compared to a placebo. ^{1 2 6 7 8}

How is the drug semaglutide unique for treating cognitive impairment in depression?

Semaglutide is unique because it is a glucagon-like peptide-1 (GLP-1) analogue that is typically used for diabetes and weight loss, but it may also protect against cognitive decline by enhancing autophagy (the body's way of cleaning out damaged cells) and inhibiting apoptosis (cell death). This mechanism is different from traditional antidepressants, which primarily focus on altering brain chemicals. ^{5 9 10 11 12}

Research Team

Rodrigo B. Mansur, MD, PhD

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

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.

I am between 18 and 60 years old and have been diagnosed with major depression.

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Efficacy, safety, and patient satisfaction with oral semaglutide: first single-centre clinical experience. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Effects of oral semaglutide on energy intake, food preference, appetite, control of eating and body weight in subjects with type 2 diabetes. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses. [2023]

5. Scotland pubmed.ncbi.nlm.nih.gov

Semaglutide-mediated protection against Aβ correlated with enhancement of autophagy and inhibition of apotosis. [2021]

6. Belgium pubmed.ncbi.nlm.nih.gov

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

7. England 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. [2022]

8. England 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. [2022]

9. Germany 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. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of semaglutide 2.4 mg according to antidepressant use at baseline: A post hoc subgroup analysis. [2023]

11. England 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. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Semaglutide-associated depression: a report of two cases. [2023]