Major Depressive DisorderNCT05571878
Is Brain Insulin Resistance a Feature of the Biology of Depression in Adolescents
A study testing Humalog and Saline nasal spray in people with Major Depressive Disorder and Depression, run by Centre for Addiction and Mental Health at 1 site in Canada.
Trial summary
This study will examine if brain insulin resistance is a feature of depression in humans using magnetic resonance imaging (MRI) measures sensitive to brain insulin action. This study will examine adolescents, as depression onset commonly occurs during this age, and the impacts of cumulative medication exposure and… Read more about this study
- Who is it for?
- Ages 14 to 18 yearsHealthy volunteers can take part
- Conditions the study is for
- Major Depressive Disorder, Depression
- What is being tested?
- Humalog and Saline nasal spray
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteCanada
- Study dates
- 1 Sep 2021to 13 May 2025
- Phase
- Interventional
- 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 14 to 18 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- Age 14- 18
- One of the following: Diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder (PDD); or score ≥22 on the Mood and Feeling Questionnaire and confirmation of depression with the Mini International Neuropsychiatric Interview Kid (MINI Kid)
- BMI between 5-95th population percentile and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≤2.5 calculated using fasting blood work values (glucose and insulin)
Who cannot join
- History of primary psychotic illness
- Use of antipsychotics or mood stabilizers
- History of current substance use disorder (moderate to severe)
- Pre-diabetes or diabetes (fasting glucose ≥6.0 mmol/l or use of anti-diabetic drug)
- Evidence of impaired glucose tolerance on screening oral glucose tolerance test (OGTT)
- Use of weight, lipids, or blood pressure reducing agents
Show all 12Show fewer
- History of liver disease or AST>2 times upper limit of normal
- History of kidney disease
- MRI contraindications
- Positive pregnancy test
- Allergic to exogenous insulin
- Positive result on urine drug screen (participants with positive cannabis and alcohol urine drug screens may still be eligible for the study; positive drug screens for other substances will be exclusionary)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Is Brain Insulin Resistance a Feature of the Biology of Depression: A Pilot Multi-modality Neuroimaging Study in Adolescents
This study will examine if brain insulin resistance is a feature of depression in humans using magnetic resonance imaging (MRI) measures sensitive to brain insulin action. This study will examine adolescents, as depression onset commonly occurs during this age, and the impacts of cumulative medication exposure and other lifestyle-related confounds are also lower in this age group, improving our ability to understand the underlying biology.
Read the detailed description
BACKGROUND: Major depressive disorder (MDD) is associated with metabolic dysfunction, including higher body mass index and increased risk for type 2 diabetes (T2D). This relationship is bidirectional as insulin resistance is associated with greater depressive symptom severity and worse cognition. These nested relationships between metabolic and mental health have encouraged a reconceptualization of MDD as a metabolic disorder. In this context, insulin in the brain has been implicated as a potential mediator unifying the mechanisms underlying metabolic and mental health. There is early evidence supporting this hypothesis; mice with brain-specific knockout of insulin receptor exhibited depression-like behavior that was reversed by treatment with monoamine oxidase inhibitors, while anti-diabetic agents that can potentially cross the blood-brain barrier have shown initial promise in reducing depressive symptoms.
HYPOTHESES: 1) Adolescents diagnosed with MDD will have greater brain insulin resistance in comparison to matched healthy controls. 2) Greater brain insulin resistance will be associated with increased illness severity, worse cognitive performance, and worse short-term outcomes (i.e., at 6 months) in the depression group. 3) Greater peripheral insulin resistance (measured using fasting blood work) and hepatic and visceral adiposity (measured using MRI) will be associated with greater brain insulin resistance.
APPROACH AND METHODOLOGY: Twelve adolescents with depression (14 to 18 years old) and 12 age-, sex-, and BMI-matched healthy controls will be recruited for the study. In a single-blinded crossover design, all 24 participants will undergo fasting blood work (glucose, insulin, and c-peptide) followed by an MRI-based protocol of brain insulin action. This includes two MRI scans; one with intranasal insulin challenge (80 IU) and one with intranasal placebo. This protocol leverages the property of intranasal insulin to induce resting state connectivity and blood flow changes in the brain. This will be achieved using a 3 Tesla (3T) MRI scanner, where participants will undergo a high-resolution T1-weighted structural scan, a resting state functional MRI scan, and an arterial spin labeling scan. Single voxel 1H-magnetic resonance spectroscopy will also be employed to examine changes in glutamate levels in the frontal and temporal cortex. The difference in change induced by intranasal insulin compared to that with intranasal placebo will be utilized as an index of insulin activity since any difference observed between placebo and insulin during this controlled manipulation is likely to be due to the intranasal insulin. THINC-it, a brief cognitive assessment, will also be performed to measure cognitive function in relation to insulin induced brain changes. An abdominal surface coil scan will also be used to measure visceral and hepatic adiposity. Participants with depression will be invited for a six-month follow-up visit to repeat fasting blood work, along with clinical and cognitive assessments. Age, sex, and BMI will be used as covariates in all analyses.
SIGNIFICANCE: Demonstrating disrupted brain insulin action can provide novel insights into poorly understood mechanisms underlying the relationship between MDD and T2D. Evidence of brain insulin resistance early in the course of illness may also identify a modifiable risk factor that can be targeted using brain insulin sensitizers at the earliest stages of the illness. Thus, this work that lies at the intersection of psychiatry, physiology, and psychopharmacology has the potential to generate new knowledge and improve outcomes in an area of significant unmet need.
- Conditions
- Major Depressive Disorder, Depression
- Being tested
- Humalog, Saline nasal spray
- Keywords
- Major Depressive Disorder, Insulin Resistance, Type 2 Diabetes, Depression
- Medical subject headings
- Depressive Disorder, Major, Depression, Insulin Resistance, Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HumalogDrug
Also called Intranasal Insulin
All participants will be given an intranasal insulin challenge (80 IU) to assess brain insulin signalling via MRI based assay
Saline nasal sprayDrug
Also called Intranasal Placebo
All participants will be given an intranasal saline placebo (0.8 mL) in order to establish baseline brain insulin signalling via MRI based assay
| Study group | Role | What they receive |
|---|---|---|
| Crossover: Insulin and Placebo | Experimental | Twelve adolescents who have a confirmed depression diagnosis or experiencing depression will be used as the study population group against 12 healthy adolescents who will be used as the healthy study population group.
Both the health control group and medication-free adolescents with depression will receive the same drug conditions (intranasal insulin and intranasal placebo). Receives: Drug: Humalog; Drug: Saline nasal spray |
What is being measured
The primary outcome is the main question the study is designed to answer.
The change in brain imaging outcomes, measuring brain insulin resistance, following intranasal insulin or placebo challenges, compared between the participants with depression and healthy controls.
Brain insulin resistance will be measured by changes in fMRI, 1H- MRS, and ASL measured during MRI scans following intranasal insulin and placebo challenge. These changes will be compared within subjects and between groups (depression vs controls).
- Resting state functional MRI (fMRI) will measure connectivity between prefrontal brain regions and hippocampus.
- Single voxel proton magnetic resonance spectroscopy (1H- MRS) will measure the glutamate levels in the temporal and frontal cortex.
- Arterial spin labeling (ASL) will be used to measure cerebral blood flow in the hypothalamus and the prefrontal cortex.
Measured: Study Visit 1- MRI #1 15 minutes after intranasal challenge #1, MRI #2 15 minutes after intranasal challenge #2
Secondary outcomes (2)
Correlation between brain insulin resistance with illness severity and cognitive functioning at baseline and 6-month study follow up
Primary outcome measures will be used to assess the correlation between brain insulin resistance (MRI measures; described in Outcome 1) and illness severity.
Illness Severity- Center for Epidemiological Studies- Depression Scale for Children (CES-DC). 20 item self-report depression inventory with possible scores ranging from 0-60. Higher scores are indicative of worse illness severity. A cut-off score of 15 is suggestive of depressive symptoms in children and adolescents.
Measured: Illness Severity: Study Visit 1, pre-intervention (MRI scan #1), and 6-month follow-up study visit following fasting blood work; Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2
Correlation between brain insulin resistance with cognitive functioning at baseline and 6-month study follow up
Primary outcome measures will be used to assess the correlation between brain insulin resistance (MRI measures; described in Outcome 1) with cognitive functioning.
Cognitive Functioning- THINC-it® (interactive cognitive assessment tool). Brief screening tool designed to measure cognition and determine whether cognitive functioning is impaired. Higher score is indicative of better performance, scores can range from 0-4000.
Measured: Cognitive Function: Study Visit 1, during break between MRI scan #1 and #2, and 6-month follow-up study visit following fasting blood work; Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Oct 2022
- Study start1 Sep 2021
- Primary completion13 May 2025
- Study completion13 May 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by Centre for Addiction and Mental HealthThe 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 N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Sequential
- Model description
- The study will follow a single blind, crossover design wherein each participant will complete an MRI based protocol of brain insulin action. After an overnight fast, fasting bloodwork will be obtained, followed by two MRI scans: one with intranasal placebo and one with intranasal insulin challenge (80 IU; 40 IU per nostril). Between scans they will have a short break and be asked to complete a cognitive assessment. Participants with depression will complete a 6-month follow-up visit to track changes in metabolic health, illness severity, and cognitive function.
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre for Addiction and Mental Health
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Mahavir Agarwal, MD, PhD, Principal investigator, Centre for Addiction and Mental Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05571878
- Sponsor's protocol ID
- 030/2020
- Status last verified
- Mar 2026
- First submitted
- 30 Sep 2022
- Last updated
- 31 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 31 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Is Brain Insulin Resistance a Feature of the Biology of Depression: A Pilot Multi-modality Neuroimaging Study in Adolescents
- ClinicalTrials.gov ID
- NCT05571878
- Acronym / sponsor ID
- 030/2020
- Conditions
- Major Depressive Disorder, Depression
- Keywords
- Major Depressive Disorder, Insulin Resistance, Type 2 Diabetes, Depression
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Centre for Addiction and Mental HealthUniversity, hospital or other
- Study start
- 1 Sep 2021 (actual)
- Primary completion
- 13 May 2025 (actual)
- Study completion
- 13 May 2025 (actual)
- First posted
- 7 Oct 2022 (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 if brain insulin resistance is a feature of depression in humans using magnetic resonance imaging (MRI) measures sensitive to brain insulin action. This study will examine adolescents, as depression onset commonly occurs during this age, and the impacts of cumulative medication exposure and other lifestyle-related confounds are also lower in this age group, improving our ability to understand the underlying biology.
Detailed description
BACKGROUND: Major depressive disorder (MDD) is associated with metabolic dysfunction, including higher body mass index and increased risk for type 2 diabetes (T2D). This relationship is bidirectional as insulin resistance is associated with greater depressive symptom severity and worse cognition. These nested relationships between metabolic and mental health have encouraged a reconceptualization of MDD as a metabolic disorder. In this context, insulin in the brain has been implicated as a potential mediator unifying the mechanisms underlying metabolic and mental health. There is early evidence supporting this hypothesis; mice with brain-specific knockout of insulin receptor exhibited depression-like behavior that was reversed by treatment with monoamine oxidase inhibitors, while anti-diabetic agents that can potentially cross the blood-brain barrier have shown initial promise in reducing depressive symptoms.
HYPOTHESES: 1) Adolescents diagnosed with MDD will have greater brain insulin resistance in comparison to matched healthy controls. 2) Greater brain insulin resistance will be associated with increased illness severity, worse cognitive performance, and worse short-term outcomes (i.e., at 6 months) in the depression group. 3) Greater peripheral insulin resistance (measured using fasting blood work) and hepatic and visceral adiposity (measured using MRI) will be associated with greater brain insulin resistance.
APPROACH AND METHODOLOGY: Twelve adolescents with depression (14 to 18 years old) and 12 age-, sex-, and BMI-matched healthy controls will be recruited for the study. In a single-blinded crossover design, all 24 participants will undergo fasting blood work (glucose, insulin, and c-peptide) followed by an MRI-based protocol of brain insulin action. This includes two MRI scans; one with intranasal insulin challenge (80 IU) and one with intranasal placebo. This protocol leverages the property of intranasal insulin to induce resting state connectivity and blood flow changes in the brain. This will be achieved using a 3 Tesla (3T) MRI scanner, where participants will undergo a high-resolution T1-weighted structural scan, a resting state functional MRI scan, and an arterial spin labeling scan. Single voxel 1H-magnetic resonance spectroscopy will also be employed to examine changes in glutamate levels in the frontal and temporal cortex. The difference in change induced by intranasal insulin compared to that with intranasal placebo will be utilized as an index of insulin activity since any difference observed between placebo and insulin during this controlled manipulation is likely to be due to the intranasal insulin. THINC-it, a brief cognitive assessment, will also be performed to measure cognitive function in relation to insulin induced brain changes. An abdominal surface coil scan will also be used to measure visceral and hepatic adiposity. Participants with depression will be invited for a six-month follow-up visit to repeat fasting blood work, along with clinical and cognitive assessments. Age, sex, and BMI will be used as covariates in all analyses.
SIGNIFICANCE: Demonstrating disrupted brain insulin action can provide novel insights into poorly understood mechanisms underlying the relationship between MDD and T2D. Evidence of brain insulin resistance early in the course of illness may also identify a modifiable risk factor that can be targeted using brain insulin sensitizers at the earliest stages of the illness. Thus, this work that lies at the intersection of psychiatry, physiology, and psychopharmacology has the potential to generate new knowledge and improve outcomes in an area of significant unmet need.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The study will follow a single blind, crossover design wherein each participant will complete an MRI based protocol of brain insulin action. After an overnight fast, fasting bloodwork will be obtained, followed by two MRI scans: one with intranasal placebo and one with intranasal insulin challenge (80 IU; 40 IU per nostril). Between scans they will have a short break and be asked to complete a cognitive assessment. Participants with depression will complete a 6-month follow-up visit to track changes in metabolic health, illness severity, and cognitive function.
| Arm | Type | Receives |
|---|---|---|
| Crossover: Insulin and Placebo | Experimental | Drug: Humalog, Drug: Saline nasal sprayTwelve adolescents who have a confirmed depression diagnosis or experiencing depression will be used as the study population group against 12 healthy adolescents who will be used as the healthy study population group. Both the health control group and medication-free adolescents with depression will receive the same drug conditions (intranasal insulin and intranasal placebo). |
Who may qualify
- Ages
- 14 to 18 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- Age 14- 18
- One of the following: Diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder (PDD); or score ≥22 on the Mood and Feeling Questionnaire and confirmation of depression with the Mini International Neuropsychiatric Interview Kid (MINI Kid)
- BMI between 5-95th population percentile and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≤2.5 calculated using fasting blood work values (glucose and insulin)
Key exclusion criteria (12 listed)
- History of primary psychotic illness
- Use of antipsychotics or mood stabilizers
- History of current substance use disorder (moderate to severe)
- Pre-diabetes or diabetes (fasting glucose ≥6.0 mmol/l or use of anti-diabetic drug)
- Evidence of impaired glucose tolerance on screening oral glucose tolerance test (OGTT)
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 |
|---|---|---|
| HumalogAlso: Intranasal InsulinAll participants will be given an intranasal insulin challenge (80 IU) to assess brain insulin signalling via MRI based assay | Drug | Crossover: Insulin and Placebo |
| Saline nasal sprayAlso: Intranasal PlaceboAll participants will be given an intranasal saline placebo (0.8 mL) in order to establish baseline brain insulin signalling via MRI based assay | Drug | Crossover: Insulin and Placebo |
Primary outcome
The change in brain imaging outcomes, measuring brain insulin resistance, following intranasal insulin or placebo challenges, compared between the participants with depression and healthy controls.
Time frame: Study Visit 1- MRI #1 15 minutes after intranasal challenge #1, MRI #2 15 minutes after intranasal challenge #2
Brain insulin resistance will be measured by changes in fMRI, 1H- MRS, and ASL measured during MRI scans following intranasal insulin and placebo challenge. These changes will be compared within subjects and between groups (depression vs controls). 1. Resting state functional MRI (fMRI) will measure connectivity between prefrontal brain regions and hippocampus. 2. Single voxel proton magnetic resonance spectroscopy (1H- MRS) will measure the glutamate levels in the temporal and frontal cortex. 3. Arterial spin labeling (ASL) will be used to measure cerebral blood flow in the hypothalamus and the prefrontal cortex.
2 secondary outcomes
Correlation between brain insulin resistance with illness severity and cognitive functioning at baseline and 6-month study follow up
Time frame: Illness Severity: Study Visit 1, pre-intervention (MRI scan #1), and 6-month follow-up study visit following fasting blood work; Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2
Correlation between brain insulin resistance with cognitive functioning at baseline and 6-month study follow up
Time frame: Cognitive Function: Study Visit 1, during break between MRI scan #1 and #2, and 6-month follow-up study visit following fasting blood work; Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2
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 31 Mar 2026.
- 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.
Mahavir Agarwal, MD, PhD principal investigator
Centre for Addiction and Mental Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Humalog and Saline nasal spray in people with Major Depressive Disorder and Depression, run by Centre for Addiction and Mental Health 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 3 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 31 Mar 2026. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
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?
The change in brain imaging outcomes, measuring brain insulin resistance, following intranasal insulin or placebo challenges, compared between the participants with depression and healthy controls. (time frame: Study Visit 1- MRI #1 15 minutes after intranasal challenge #1, MRI #2 15 minutes after intranasal challenge #2). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 31 Mar 2026.