Project 466627

I will examine whether brain insulin resistance is involved in the pathophysiology of major depressive disorder (MDD). This research question evolved following the observation that MDD is often co-morbid with metabolic dysfunction such as weight gain and type 2 diabetes (T2D), and that insulin resistance is associated with greater depressive symptom severity and worse cognition. To explore this bidirectional relationship, 12 medication-naïve/free MDD patients aged 14 to 18 years old, and 12 age-, sex-, and weight-matched healthy controls, will participate in a single-blind crossover magnetic resonance imaging (MRI) study. This will include completing fasting blood work and two MRI sessions: the first following intranasal placebo, and after a short break, the second following intranasal insulin challenge (80 IU). The MRI sessions will measure insulin induced changes in connectivity, blood flow, and glutamate levels within brain regions of interest using resting state functional MRI, arterial spin labeling, and magnetic resonance spectroscopy, respectively. A brief cognitive assessment and an abdominal surface coil scan will also be performed to measure visceral and hepatic adiposity to identify the relationship between brain insulin resistance and these outcomes. It is hypothesized that brain insulin resistance will be higher in MDD participants compared to the healthy controls, and will also be associated with greater illness severity, worse cognitive performance, and greater hepatic and visceral adiposity. Demonstrating disrupted brain insulin action can provide novel insights into poorly understood mechanisms underlying the relationship between MDD and T2D, and help uncover modifiable risk factors that can be targeted at the earliest stages of the illness.