Podcast: Inflammation, Anhedonia, and Depression -- A Randomized Controlled Trial

3/27/2025

Approximately 1/3 of individuals with major depressive disorder (MDD) exhibit low-grade systemic
inflammation based on levels of C-reactive protein (CRP); the American Heart Association defines high risk as a CRP as >3mg/L (1). At the behavioral level, anhedonia appears to be the symptom most closely tied to inflammation (2-4). In healthy participants, inflammatory challenge with low-dose lipopolysaccharide (LPS) - a reliable, safe, and well-validated method of inducing robust peripheral and CNS inflammation (5-8) - transiently increases motivational anhedonia and decreases ventral striatal response to anticipatory reward (9-11).
However, to our knowledge, no study has tested whether depressed individuals with and without systemic inflammation show differential anhedonic responses to an acute inflammatory exposure. Such experimental substantiation would constitute clear evidence of a biological subtype of MDD and corroborate previously proposed mechanistic links between inflammation and anhedonia (2-4). This would also have implications for treatment as it has been proposed that clinical trials of immune-modulating therapies in depression are confounded by a failure to selectively recruit participants with evidence of inflammation (12-15). Here, we present results from a randomized controlled trial (NCT03142919) designed to test whether MDD participants with elevated serum CRP levels (≥3mg/L), as compared to those with non-elevated CRP (≤1.5mg/L), display a greater increase in anhedonic symptoms at the approximate peak of the inflammatory response to LPS, i.e. ~1.5 hours post infusion.