It has been estimated that one in three people with major depressive disorder (MDD) exhibits low-grade systemic inflammation. That is to say, they chronically show elevated levels of inflammatory markers in their blood—higher than is typical in healthy people.

What impact might bodily inflammation—whether at low or high levels—have on symptoms of major depression? Past research has broadly suggested that in depressed people, inflammation is most likely to affect the symptom of anhedonia, which is the loss of interest in or motivation to pursue rewards or pleasurable experiences.

A team of researchers led by Joanathan Savitz, Ph.D., a 2015 and 2009 BBRF Young Investigator at the Laureate Institute for Brain Research (LIBD), explored the relationship between systemic inflammation and major depression in closer detail. They asked whether MDD patients with high vs. low levels of systemic inflammation had different responses to an acute inflammatory challenge, particularly with respect to anhedonia symptoms. The team included three other BBRF grant recipients, including Martin P. Paulus, M.D., a 2000 BBRF Young Investigator who is Scientific Director and President of LIBD.

The researchers recruited 68 MDD patients for a double-blinded study, 64 of whom were included in an analysis recently published in the American Journal of Psychiatry. The participants were randomly assigned to receive either an intravenous infusion of a drug called LPS which induces a short-term acute immune response, or a placebo injection.

26 of the participants were found to have “high” baseline levels of the immune marker C reactive protein (CRP), while 38 had “low” CRP levels. In each of these groups, half of the participants received LPS and half received placebo. (“High” in this study was defined as a CRP of 3 mg/L or greater; “low” was 1.5 mg/L or less. Any prospective participants who fell in between were not included in the study. The typical participant had a CRP of 7.4 in the “high” groups and 0.75 in the “low” groups.)

Most participants were in their late 20s or 30s; they had symptoms of moderate major depressive disorder; a majority were White; and between one-third and two-thirds had comorbid generalized anxiety disorder in addition to major depression.

Following their baseline blood analysis, participants had blood drawn at 1, 1.5, 3.5, 6, and 24 hours after the infusion of LPS or placebo. At each point, they also completed self-assessments of anhedonia symptoms, using a standard measurement instrument designed to register rapid changes in affect. Comprehensive depression symptoms were assessed with a similar tool at baseline and 6 and 24 hours after injection. The team also measured levels of three immune markers in the blood in addition to CRP: IL-6, IL-10, and TNF (all are chemical messengers produced by the immune system during an immune response).

The investigators were most interested in results when pro-inflammatory effects of the injection peaked 1.5 hours post-injection, among those who received the LPS immune-activating drug. Would they be able to detect a difference in anhedonia symptoms between those in the high vs. low CRP groups?

Analysis revealed significantly greater increases in anhedonia and IL-6 levels between baseline and 1.5 hours after injection in the high-CRP compared with the low-CRP group. There were no significant differences in TNF and IL-10 levels between the groups. At 1.5 hours post-injection, anhedonia scores in the high-CRP group in fact increased twofold more from baseline levels than did scores among participants with low CRP.

The team wrote that “these results suggest that depressed individuals with high systemic inflammation are, on average, biologically primed to respond more strongly to inflammatory stimuli,” and that this was behaviorally “reflected at least in part by greater anhedonia.”

Taken a step further, the findings “could be interpreted to suggest that depressed adults who have high systemic levels of inflammation may be at increased risk for anhedonia following an inflammatory exposure related to an infection or worsening of an underlying inflammatory disorder.”

While different symptoms of depression may be sensitive in different ways or not at all to inflammatory challenges, the team said, “our results support the longstanding hypothesis that anhedonia is a symptom strongly associated with inflammation.” The IL-6 result similarly suggested to the team that it too could be “particularly relevant to inflammation-induced anhedonia.”

More broadly, the existence of a “mechanistic link” between anhedonia and inflammation supports the theory that depressed individuals with inflammation “differ biologically from their counterparts with low-level inflammation.” Such a depression subtype, if replicated in future research involving greater numbers of patients, would argue for stratification of participants in future clinical trials of medicines designed to lower inflammation, and also “highlights the potential vulnerability” of people with MDD and high CRP levels to infectious agents, the team noted.

The team also included: Yoon-Hee Cha, M.D., 2016 BBRF Young Investigator; and Sahib S. Khalsa M.D., Ph.D., 2015 BBRF Young Investigator.