Depression Symptoms May Be Tied to Systemic Inflammation

Unemployed businesswoman depressed sitting on a path due to company bankrupted while coronavirus spreading situation
Biomarker research has revealed a connection between systemic inflammation and depression.

Some, but not all, symptoms of depression may stem from systemic inflammation according to a pooled analysis published in the American Journal of Psychiatry.

Biomarker research has revealed a connection between systemic inflammation and depression. In addition, researchers suspect pro-inflammatory systemic cytokines affect depression related endocrine functioning and neurotransmitter metabolism by crossing the blood brain barrier or by activating the vagus nerve.

A multicohort study of more than 56,000 individuals addressed the connection between systemic inflammation and depression further. Researchers identified 15 large cohort studies that involved adults and addressed circulating inflammatory biomarkers, depressive symptoms and covariates such as smoking status, alcohol consumption, chronic illness, and “adverse” childhood experiences.

After adjusting for illness, socioeconomic and behavioral risk factors, the researchers found high C-reactive protein levels were “robustly” associated with 4 physical symptoms (changes in appetite, felt everything was an effort, could not get going or loss of energy, sleep problems), 2 cognitive symptoms (trouble concentrating, little interest in doing things/unmotivated), and 1 emotional symptom (felt depressed). High IL-6 levels were associated with many of these same symptoms.

The researchers also found evidence against an association between systemic inflammation and other emotional symptoms, including fearfulness, feeling bothered by things, hopelessness about the future, and feeling life had been a failure.

While the large sample size and use of multiple inflammatory markers make for a strong study, use of observational data is a limitation. In addition, systemic inflammation was measured only at baseline and depression symptoms were self-reported. Furthermore, repeated measurements could have yielded additional valuable information.

“Our findings may pave the way toward a new inflammatory depression phenotype and can guide systematic efforts to develop novel inflammation targeted treatments,” the researchers conclude. “Patient recruitment to future anti-inflammatory drug trials should be based on symptom profiles characterized by the inflammation related depressive symptoms observed in this study.”


Frank P, Jokela M, Batty GD, Cadar D, Steptoe A, Kivimäki M. Association Between Systemic Inflammation and Individual Symptoms of Depression: A Pooled Analysis of 15 Population-Based Cohort Studies. Am J Psychiatry. Published online October 14, 2021. doi:10.1176/appi.ajp.2021.20121776