Inflammation and Depression – Specific Symptom Cluster

adminBasic Science, Depression, Diagnosis, Major Depression, Physical Conditions and Health, Psychobiology Leave a Comment

A study of 15 population-based cohorts, totalling 56,351 individuals, suggests that there is a correlation between inflammation as measured by elevated  C-reactive protein (CRP) and interleukin-6 (IL-6) and a specific sub-group of symptoms of depression.

The inflammation cluster consisted of four physical symptoms: changes in appetite, felt everything was an effort, loss of energy, sleep problems; and one cognitive symptom: little interest in doing things.

There were four exclusively emotional symptoms that had no correlation with inflammation: bothered by things, hopelessness about the future, felt fearful, life had been a failure.

Symptoms of depression that are associated with inflammation, neutral or associated with non-inflammatory depression

These results confirm the findings of previous studies showing stronger associations between systemic inflammation and changes in appetite, lower energy levels, and sleep problems than to other symptoms of depression. 

The study also supports the sickness behavior theory. The theory suggests that inflammation in the body can, in certain people, lead to a set of initially helpful depressive-like symptoms, collectively known as sickness behavior. These include a lack of energy (lethargy), changes in appetite, sleepiness, reduced social exploration, and, at times, confusion. Sickness behavior is also characterized by depressed mood and increased sensitivity to pain. 

Over time, according to this theory, sickness behavior becomes less adaptive and may turn into a chronic depressive state.

Another study suggested that low level inflammation may change cognition. They may start to focus on avoiding punishments rather than seeking rewards.

The results are also consistent with recent findings of a relationship between chronic depression, low level inflammation and the metabolic syndrome, specifically weight gain. The association appears to go both directions. Chronic depression increases the odds of weight gain and inflammation, and weight gain increases the likelihood of inflammation and depression.

Unadjusted and serially adjusted cross-sectional association between C-reactive protein (CRP) and 24 symptoms of depression (random-effects meta-analysis)
Association between C-reactive protein (CRP) and six depressive symptoms in subgroups, after additional adjustments and longitudinally (random-effects meta-analysis)

Treatment Implications

This blog post is still relevant for its review of some of the treatment options for people with low level inflammation, they include fish oil, exercise, perhaps SNRI medications. Medications such as celecoxib have continued to be studied as adjunctive treatments for some patients with chronic depression or bipolar depression, but the evidence remains weak and contradictory.

Testing Options

We have used C reactive protein as a fairly routine lab study when evaluating patient with depression and fatigue. A review of other tests, including interleukin 6 (IL-6) is to be found here. The results in this study support the notion that CRP is the most stable single test, whether or not to add IL-6 to that test remains somewhat unclear.


Association Between Systemic Inflammation and Individual Symptoms of Depression: A Pooled Analysis of 15 Population-Based Cohort Studies. Philipp Frank, Markus Jokela, G. David Batty, Dorina Cadar, Andrew Steptoe, and Mika KivimäkiAmerican Journal of Psychiatry 2021 178:12, 1107-1118

Fried EI, von Stockert S, Haslbeck J, et al.: Using network analysis to examine links between individual depressive symptoms, inflammatory markers, and covariates. Psychol Med 2020; 50:2682–2690

Jokela M, Virtanen M, Batty GD, et al.: Inflammation and specific symptoms of depression. JAMA Psychiatry 2016; 73:87–88

White J, Kivimäki M, Jokela M, et al.: Association of inflammation with specific symptoms of depression in a general population of older people: the English Longitudinal Study of Ageing. Brain Behav Immun 2017; 61:27–30

Lamers F, Milaneschi Y, de Jonge P, et al.: Metabolic and inflammatory markers: associations with individual depressive symptoms. Psychol Med 2018; 48:1102–1110

Dantzer R, O’Connor JC, Freund GG, et al.: From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9:46–56