Is Brain Insulin Resistance a Feature of the Biology of Depression in Adolescents

Sponsor
Centre for Addiction and Mental Health (Other)
Overall Status
Recruiting
CT.gov ID
NCT05571878
Collaborator
(none)
24
1
1
36
0.7

Study Details

Study Description

Brief Summary

This study will examine if brain insulin resistance is a feature of major depressive disorder (MDD) in humans using magnetic resonance imaging (MRI) measures sensitive to brain insulin action. This study will examine adolescents, as MDD 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.

Condition or Disease Intervention/Treatment Phase
N/A

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 depressive symptom severity and worse cognitive performance. 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 medication-naïve or medication-free (>3 months off antidepressants/other psychotropic medications) MDD patients aged 14 to 18 years old and 12 age-, sex-, and weight-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. 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

Study Type:
Interventional
Anticipated Enrollment :
24 participants
Allocation:
N/A
Intervention Model:
Sequential Assignment
Intervention 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.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.
Masking:
None (Open Label)
Masking Description:
Participants will be blinded to the order of the intranasal spray condition (insulin or placebo).
Primary Purpose:
Basic Science
Official Title:
Is Brain Insulin Resistance a Feature of the Biology of Depression: A Pilot Multi-modality Neuroimaging Study in Adolescents
Actual Study Start Date :
Sep 1, 2021
Anticipated Primary Completion Date :
Sep 1, 2023
Anticipated Study Completion Date :
Sep 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Crossover: Insulin and Placebo

12 medication-free or naive adolescents who have a confirmed depression diagnosis 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).

Drug: Humalog
All participants will be given an intranasal insulin challenge (80 IU) to assess brain insulin signalling via MRI based assay
Other Names:
  • Intranasal Insulin
  • Drug: Saline nasal spray
    All participants will be given an intranasal saline placebo (0.8 mL) in order to establish baseline brain insulin signalling via MRI based assay
    Other Names:
  • Intranasal Placebo
  • Outcome Measures

    Primary Outcome Measures

    1. The change in brain imaging outcomes measuring brain insulin resistance following intranasal insulin or placebo challenges, compared between the medication-naive MDD and healthy control groups. [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 (MDD 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.

    Secondary Outcome Measures

    1. Correlation between brain insulin resistance with illness severity and cognitive functioning [Illness Severity: Study Visit 1, pre-intervention (MRI scan #1); Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2]

      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 cutoff score of 15 is suggestive of depressive symptoms in children and adolescents.

    2. Correlation between brain insulin resistance with cognitive functioning [Cognitive Function: Study Visit 1, during break between MRI scan #1 and #2; Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2]

      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.

    Other Outcome Measures

    1. Correlation between brain inulin resistance and peripheral insulin resistance [Peripheral Insulin Resistance: Study Visit 1, pre-MRI #1 and post-MRI #2; Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2]

      Primary outcome measures will be used to assess the correlation between brain insulin resistance (MRI measures; described in Outcome 1) with peripheral insulin resistance. Peripheral Insulin Resistance - Fasting bloodwork: Glucose (mmol/L), insulin (pmol/L), C-peptide (pmol/L).

    2. Correlation between brain inulin resistance, and hepatic and visceral adiposity [Hepatic and Visceral Adiposity: Study Visit 1, during MRI #1; Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2]

      Primary outcome measures will be used to assess the correlation between brain insulin resistance (MRI measures; desired in Outcome 1) with hepatic and visceral adiposity Hepatic and Visceral Adiposity- Abdominal MRI Scan (cm^3)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    14 Years to 18 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    • Age 14- 18

    • MDD diagnosis (MDD group subjects)

    • Medication-naive or free (>3 months off antidepressants/ other psychotropic)

    • BMI between 18.5 and 24.9 kg/m^2

    • Right handed

    Exclusion Criteria:
    • History of primary psychotic illness

    • History of current substance use disorder

    • Pre-diabetes or diabetes

    • First degree relative with diabetes

    • Use of weight, lipids, or blood pressure reducing agents

    • History of liver disease

    • MRI contraindications

    • Positive pregnancy test

    • Allergic to exogenous insulin

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Centre for Addiction and Mental Health Toronto Ontario Canada M6J 1H3

    Sponsors and Collaborators

    • Centre for Addiction and Mental Health

    Investigators

    • Principal Investigator: Mahavir Agarwal, MD, PhD, Centre for Addiction and Mental Health

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Centre for Addiction and Mental Health
    ClinicalTrials.gov Identifier:
    NCT05571878
    Other Study ID Numbers:
    • 030/2020
    First Posted:
    Oct 7, 2022
    Last Update Posted:
    Oct 7, 2022
    Last Verified:
    Oct 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Centre for Addiction and Mental Health
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Oct 7, 2022