Inflamed Depression: A Subsyndrome of MDD?


Researchers may have cracked the code to the mystery of depression, inflammation, and C-reactive protein.


A multicenter British research team working under the auspices of the Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer’s Disease may have cracked the code regarding the association between depression, inflammation, and C-reactive protein (CRP).1 Whereas earlier studies have shown a modest association between serum CRP levels and MDD, Chamberlain and colleagues demonstrated that CRP levels are particularly high in patients with treatment-resistant depression and that specific phenotypes account for variance in CRP levels in patients with MDD.

The researchers recruited a study population of 198 subjects, including 102 symptomatic, medicated patients with treatment-resistant depression; 48 asymptomatic, medicated patients with treatment-responsive MDD; 48 unmedicated patients with MDD; and 54 healthy controls. “Actively medicated” was defined as having received a monoaminergic drug at a therapeutic dose for at least 6 weeks leading up to study participation. “Untreated” was defined as lack of receipt of a monoaminergic drug for at least 6 weeks. Total Hamilton Rating Scale for Depression (HAM-D) scores were > 13, < 7, and > 17 for treatment-resistant, treatment-responsive, and untreated subjects, respectively.

In addition to HAM-D scores, lifetime antidepressant medication use was quantified by the Antidepressant Treatment Response Questionnaire. Psychological symptoms and childhood adversity were assessed by the Beck Depression Inventory, Spielberger State-Trait Anxiety Rating scale, Chalder Fatigue Score, Snaith-Hamilton Pleasure Scale, and the Childhood Trauma Questionnaire. High-sensitivity CRP in peripheral venous blood was measured in a fasted state, and subjects were instructed to refrain from strenuous exercised for 72 hours prior to the blood draw. Body mass index (BMI) also was measured.

The authors found that mean CRP level was significantly increased in all patients with MDD compared with healthy controls (P = .007). Mean high-sensitivity CRP was significantly higher for treatment-resistant and treatment-responsive groups than controls (P = .004 and P = .010, respectively). Further, drug treatment class did not significantly affect CRP levels. Post hoc analysis, however, showed that treatment-resistant-but not treatment-responsive or untreated-subjects had significantly higher mean BMI-corrected CRP compared with healthy controls (t = 2.71, P = .007; Cohen’s d = 0.47).

Partial least squares analysis provided insight regarding a 35% variation in clinical measures and a 36% variation in CRP: clinical phenotypes most strongly associated with CRP included vegetative depressive symptoms, BMI, state anxiety, and feeling unloved as a child or wishing for a different childhood.

It should be noted that higher BMI has been associated with higher inflammatory response, according to the authors. In addition, they explained that inflammatory challenges on the cellular level impede serotonin transport and tryptophan metabolism, which may explain why some patients fail to satisfactorily respond to selective serotonin reuptake inhibitors. They proposed a subsyndrome of MDD termed “inflamed depression” and suggested that patients with MDD be stratified for presence of CRP and other proinflammatory biomarkers. In their view, patients testing positive for proinflammatory markers would likely benefit from second-line treatment with anti-inflammatory drugs.

Further reading:

Where There’s Smoke, There’s Fire

Five Things to Know About Inflammation and Depression


1. Chamberlain SR, Cavanagh J, de Boer P, et al. Treatment-resistant depression and peripheral C-reactive protein. Br J Psychiatry. 2018;16:1-9.

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