Major depressive disorder (MDD) is associated with significant cognitive impairment throughout the life-course, which may progress toward MCI and dementia with age. Antidepressant medications are the first line of treatment; however, they fail to adequately address cognitive deficits and prevent relapse. Sustained cognitive impairment into euthymic periods may relate to underlying neurobiological changes, which could potentially be addressed through Cognitive Behavioural Therapy (CBT). Notably, CBT has been shown to improve cognitive domains including divided attention, memory, and processing speed while preventing depression relapse. Midlife represents a critical period in which shared neurobiological factors (such as brain changes on a vascular, morphological, and functional level) underlying depression and cognitive impairment could accelerate toward MCI and dementia. An updated understanding of neurobiological correlates of midlife depression and CBT response through multimodal neuroimaging is critical to improving affective and cognitive outcomes in this population.

The overarching objective of this project is to use multimodal neuroimaging to quantify the neurobiological and clinical impact of CBT in midlife depression. Specifically, we aim to:

1. Investigate the clinical impact of CBT on cognitive function and mood outcomes in midlife depression
2. Examine functional connectivity and microstructural determinants of CBT response in midlife depression using neuroimaging
3. Identify vascular modulators of neural connectivity and CBT response in midlife depression.

We hypothesize that midlife depression will be associated with functional and structural neural connectivity changes, which will be accompanied by vascular pathology. Adequate CBT response (i.e., improvements in mood and cognitive function) will be associated with amelioration of neurobiological changes.

Inclusion Criteria:

1. Age 40-60 years, inclusive.
2. Diagnosis of MDD as per the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)6 determined through a structured clinical interview.
3. Current major depressive episode of at least 3 months in length.
4. Depression of at least mild severity defined by a total score of ≥7 on the Montgomery Asberg Depression Rating Scale (MADRS)7.
5. Ability to understand and comply with the requirements of the study, as judged by the investigator(s).

Exclusion Criteria:

1. Presence of comorbid post-traumatic stress disorder, obsessive-compulsive disorder, eating disorder(s), schizophrenia, or other psychiatric disorders.
2. History of a manic, hypomanic, or mixed depressive episode.
3. Treatment with electroconvulsive therapy, intravenous and/or intranasal ketamine in the 6-weeks prior to study enrolment.
4. History of substance-use disorder in the past 12 months.
5. Presence of current alcohol-use disorder
6. A positive urine toxicology screen for non-prescribed substance use.
7. A positive pregnancy test at screening.
8. A history of major medical or neurological illness.
9. A history of traumatic brain injury, stroke, seizures, or previous brain surgery.
10. Contraindications to magnetic resonance imaging (MRI) scanning.