PROJECT SUMMARY: Chronic inflammation likely underlies the pathogenesis of major depressive disorder (MDD) in a significant number of cases but we do not understand why these individuals get stuck in an inflammatory state. We hypothesize that this subgroup of depressed patients has a defective homeostatic or regulatory response to inflammatory stimuli such that appropriate, acute inflammatory responses fail to resolve, leading to chronic inflammation which increases the risk for (a) developing depression, (b) its recurrence, and (c) treatment failure. To test this hypothesis, we propose challenging the immune system of both MDD subjects and healthy controls (HC) with an inflammatory stimulus (lipopolysaccharide, LPS) to induce a homeostatic response. Specifically, 90 MDD and 90 HC participants will be randomized (2:1) to LPS (0.8ng/kg) or saline. Serial blood draws will be obtained to quantify the pattern of inflammatory response using several inflammatory markers. At the same time, participants will complete clinical ratings and undergo a pre- and post-LPS MRI scan to measure how the transient inflammatory response affects the brain processing of interoceptive (bodily- relevant) stimuli. Participants will also return one day and one week after LPS/saline infusion to complete identical psychometric measures and blood draws. The MDD group, only, will also complete psychological assessments once per month for 6 months in order to determine whether the acute response to LPS predicts the clinical course of MDD. The main hypotheses are that: (1) relative to HC, the MDD group will show a greater acute increase in inflammatory mediators but a blunted acute response of the neural circuitry mediating interoceptive processes (insula and cingulate cortex) in the LPS vs. placebo condition. For the acute outcomes we focus on the changes that occur at the peak of the inflammatory response, i.e. 2 hours post-infusion. (2). Within the MDD group, LPS-associated changes in interoceptive processing and functional connectivity will be correlated with the strength of the acute pro-inflammatory response. (3) These acute effects will be more salient in MDD participants with chronic inflammation (baseline CRP ³3mg/L). That is, relative to the low inflammation MDD group (CRP £1mg/L), the high inflammation MDD group will display a blunted hemodynamic response of the insula and cingulate during internally-focused attention. In exploratory analyses we will also examine whether there is a sex by diagnosis interaction effect on inflammatory and insular response to LPS and whether the acute effects of LPS will relate to depressive symptoms over the 6-month follow-up. This research is innovative and highly impactful because it will open up a new program of research that will allow us to draw strong conclusions about the biological mechanisms underlying the failure to resolve inflammation-related depressive behavior. This knowledge can ultimately be used to develop new brain or immune-based treatments to jump-start the neural circuitry normally engaged by inflammatory stimuli, and to target these interventions at specific patient populations.

R01MH123652

2021-05-14

2026-04-30