Systemic Inflammation and Anhedonic Responses to an Inflammatory Challenge in Adults With Major Depressive Disorder: A Randomized Controlled Trial
Jonathan Savitz, Leandra K. Figueroa‐Hall, T. Kent Teague, Hung‐Wen Yeh, Haixia Zheng, Rayus Kuplicki, Kaiping Burrows, Nour El-Sabbagh, MacGregor Thomas, Isaac Ewers, Yoon‐Hee Cha, Salvador Guinjoan, Sahib S. Khalsa, Martin P. Paulus, Michael R. Irwin
Abstract
OBJECTIVE: The authors sought to determine whether an inflammatory challenge with lipopolysaccharide (LPS) differentially impacts symptoms of anhedonia in participants with major depressive disorder with high (≥3 mg/L) and low (≤1.5 mg/L) serum C-reactive protein (CRP) concentrations. METHODS: Sixty-eight participants with major depressive disorder were randomly assigned, in a 1:1 ratio, to receive LPS (0.8 ng/kg body weight) or placebo (saline) in a parallel-group double-blind design. Participants were stratified according to baseline CRP concentrations, yielding four groups: high-CRP LPS (N=13), low-CRP LPS (N=19), high-CRP placebo (N=13), and low-CRP placebo (N=19). Blood was sampled at baseline, at 1, 1.5, 3.5, 6, and 24 hours, and 1 week after LPS or saline administration, with concurrent assessment of psychological outcomes. The primary outcome measure was the Snaith-Hamilton Pleasure Scale (SHAPS), and the primary contrast of interest was the change between baseline and 1.5 hours (peak of the inflammatory response) in the high-CRP versus low-CRP groups receiving LPS. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS) and serum levels of three cytokines: interleukin-6 (IL-6), IL-10, and tumor necrosis factor (TNF). Data were analyzed with linear mixed models. RESULTS: Significantly greater increases in self-reported anhedonia (on the SHAPS) and IL-6 levels were observed between baseline and 1.5 hours in the high-CRP versus low-CRP LPS groups. There were no significant differences for TNF and IL-10. The MADRS was not administered at 1.5 hours; secondary analyses showed a significant group-by-condition-by-time interaction driven by a greater decrease in MADRS scores between baseline and 24 hours in the high-CRP group. CONCLUSIONS: Depressed individuals with systemic inflammation appeared to be biologically primed to respond more strongly to inflammatory stimuli, and psychologically, this sensitization impacted the symptom of anhedonia, the primary outcome.