An extensive and recently released Dutch study has found that inflammation is consistently linked to symptoms of depression and anxiety, as well as subtle impairments in cognitive function, particularly memory and attention.

Both observational and genetic approaches were used to better understand whether these associations might be causal.  Most associations were small; however, the results offer compelling support for the idea that chronic low-grade inflammation can influence emotional well-being and mental performance.

Considerations around depression and anxiety have put low-grade inflammation in the spotlight for some time, as shown by the following studies:

• Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22-34.
• Khandaker GM, Dantzer R, Jones PB. Immunopsychiatry: important facts. Psychol Med. 2017;47(13):2229-2237.

Higher inflammatory markers

Studies have begun to consistently show that people with major depressive disorder (MDD) have higher blood levels of inflammatory markers such as:

• C-reactive protein (CRP)
• Interleukin-6 (IL-6)
• Tumor necrosis factor-alpha (TNF-α)

Meta-analyses have confirmed that, on average, these markers are higher in those with depression compared to healthy controls.

• Reference: Howren MB et al., Biol Psychiatry 2009; Dowlati Y et al., Biol Psychiatry 2010.

The exact mechanism involved here is still under consideration, and whether these proteins cause depression or are simply a byproduct of poor health is not yet settled.

“There is growing evidence that some individuals develop depression because of underlying immune dysfunction. Evaluating this scientifically is hard because there are many factors that are associated with both depression and immune dysfunction (substance use, poor diet, stress, adiposity), which makes disentangling causal relationships challenging,” says Naoise Mac Giollabhui, author of the Netherlands study.

Typically, factors such as poor diet, obesity, chronic stress and lack of exercise are linked to higher rates of depression.

Currently, the science leans towards strong correlational evidence of higher inflammation in depressed patients. The experimental evidence (although much of it in animals) shows that inflammatory stimuli can cause depressive symptoms. The predictive evidence is that inflammation can precede depression, and the interventional evidence is that reducing inflammation may reduce depressive symptoms in some cases.

Modest antidepressant effects

Preliminary trials of anti-inflammatory drugs (e.g., NSAIDs, cytokine inhibitors, minocycline) have shown only modest antidepressant effects, especially in individuals with increased inflammation.

Naoise Mac Giollabhui, who is an assistant professor and clinical psychologist at Massachusetts General Hospital/Harvard Medical School says, “the paper was an opportunity to explore the association between inflammatory biomarkers and a range of mental health outcomes using a very large Dutch cohort study and to use an approach that would allow us to probe whether some specific immune biomarkers are causally linked with specific mental health outcomes.”

The study used data from the Lifelines cohort, a large, population-based study in the Netherlands that follows tens of thousands of individuals over time. More than 55,000 adults took part in the observational portion of the study, which examined levels of C-reactive protein in the blood, as well as symptoms of depression, anxiety, and performance on cognitive tests. Additionally, genetic data were available for over 57,000 participants, allowing the researchers to calculate genetic scores linked to several inflammatory markers, including interleukin-6, its receptor, and a compound known as GlycA.

The study has limitations. The sample was largely composed of individuals of European descent, which may limit the broad applicability of the results.

“More work is needed to determine whether these results generalize to other groups,” Mac Giollabhui said.

“Second, the impact of genetics as operationalised in this study on our biomarkers was pretty modest in size, and it’s hard to know whether larger increases in immune biomarkers might have a cumulative and potentially greater effect on the outcomes we were looking at.”

Study authors ……………….

The study, “Role of inflammation in depressive and anxiety disorders, affect, and cognition: genetic and non-genetic findings in the lifelines cohort study,” was authored by Naoise Mac Giollabhui, Chloe Slaney, Gibran Hemani, Éimear M. Foley, Peter J. van der Most, Ilja M. Nolte, Harold Snieder, George Davey Smith, Golam M. Khandaker, and Catharina A. Hartman.