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

NCT05571878 | Completed

• 1 other identifier: 030/2020
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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 other lifestyle-related confounds are also lower in this age group, improving our ability to understand the underlying biology.

Conditions

Major Depressive Disorder; Depression

Keywords

Major Depressive Disorder; Insulin Resistance; Type 2 Diabetes; Depression

Outcome Measures

Primary Outcomes (1)

• 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). 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.

  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

  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

  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

Other Outcomes (2)

• Correlation between brain insulin resistance and peripheral insulin resistance at baseline and 6-month study follow up

  Peripheral Insulin Resistance: Study Visit 1, pre-MRI #1 and post-MRI #2, and 6-month follow-up study visit; Brain Insulin Resistance: Study Visit 1, during MRI scan #1 and #2

• Correlation between brain insulin 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

Study Arms (1)

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).

Drug: Humalog; Drug: Saline nasal spray

Interventions

Humalog DRUG

All participants will be given an intranasal insulin challenge (80 IU) to assess brain insulin signalling via MRI based assay

Also known as: Intranasal Insulin

Crossover: Insulin and Placebo

Saline nasal spray DRUG

All participants will be given an intranasal saline placebo (0.8 mL) in order to establish baseline brain insulin signalling via MRI based assay

Also known as: Intranasal Placebo

Crossover: Insulin and Placebo

Eligibility Criteria

• Age: 14 Years - 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead

Study Sites (1)

Centre for Addiction and Mental Health

Toronto, Ontario, M6J 1H3, Canada

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Depression; Insulin Resistance; Diabetes Mellitus, Type 2

Interventions

Insulin Lispro

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Insulin, Short-Acting; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Mahavir Agarwal, MD, PhD

  Centre for Addiction and Mental Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Masking Details: Participants will be blinded to the order of the intranasal spray condition (insulin or placebo).
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 30, 2022
• First Posted: October 7, 2022
• Study Start: September 1, 2021
• Primary Completion: May 13, 2025
• Study Completion: May 13, 2025
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)