The Connection Between Inflammation and Depression

Researchers investigate the link between RA inflammation and depression.


Patients with rheumatoid arthritis (RA) are two to four times more likely than the general population to have depression. This has posed an interesting question among researchers: Does body-wide inflammation, seen in RA, lead directly to depression or does inflammation increase disease activity, which in turn can result in depression?

“We know that traditional risk factors, such as pain and disability, cause depression in RA, but there is this novel idea that inflammation plays a role as well. This idea that inflammation contributes to depression in RA is gaining more acceptance,” says Mary Margaretten, MD, a rheumatologist at the University of California San Francisco (UCSF).

“There is a body of literature recognizing depression as an inflammatory state. There is a well-documented event called cytokine-induced depression, where cytokines are increased and depression occurs,” explains Patricia Katz, PhD, a professor of medicine at the University of California San Francisco (UCSF) whose research has focused on the relationship between function and psychological status among adults with chronic health conditions like RA. “However, there are some people who think that…the depression causes the inflammation. There is some evidence going that way, too. But I think in a disease that has an inflammatory underpinning as RA does, there is more work needed,” she says. 

Which comes first: depression or RA?

Katz and her colleague Mary Margaretten, MD, co-authored a 2011 report in the International Journal of Clinical Rheumatology that reviewed what is currently known about the link between RA and depression and what role inflammation might play. “It’s analogous to cardiovascular disease in RA. There is this high risk of heart disease in patients with RA due to traditional risk factors and novel risk factors like inflammation. Similarly, there is a disproportionate burden of depression in our patients,” explains Dr. Margaretten, an assistant professor of medicine in the division of rheumatology at UCSF. 

Studies have reported a general link between inflammation and depression.  Johns Hopkins University researchers reported in the Archives of Internal Medicine in 2004 that major depression in men was strongly associated with increased levels of a marker of inflammation called C-reactive protein (CRP). Researchers say C-reactive protein (CRP) is helpful to study because it’s an objective marker of inflammation that is easily measured in clinical practice. 

A 2009 study published in Arthritis & Rheumatism reported a similar association. The study researchers analyzed CRP levels and self-reported questionnaires from 218 RA patients and found that inflammation and depression independently increased the likelihood that someone was experiencing severe pain. When inflammation and depression occurred together, the risk of severe pain increased even more. 

“With that study, one does not know what came first. Based on that study you can say depression and inflammation are associated, but you can’t say inflammation causes depression,” Dr. Margaretten explains.
Inflammatory markers play a role

Laboratory researchers are also focusing on pro-inflammatory cytokines, which promote inflammation. In an April 2012 study in the International Journal of Rheumatic Diseases, Singapore researchers compared the pro-inflammatory cytokine levels of 18 RA patients and 18 healthy patients and found that tumor necrosis factor-alpha, or TNF-a, interleukin (IL)-6 and IL-17 were all much higher in RA patients than the control group. IL-17 levels were especially raised in the RA group that had higher rates of anxiety. 

“We increasingly recognize that the occurrence of mood disorders in patients with rheumatic diseases may not be just reactive in nature. There is a potential biological mechanism behind this,” explains lead investigator Anselm Mak, MD, an assistant professor and consultant in the division of rheumatology at the National University of Singapore. 

Dr. Mak says the biological explanation appears linked to a neurotransmitter called substance P that affects the pain response. Theoretically, chronic pain as a result of RA stimulates the release of substance P in the sensory nerve endings, and substance P has been shown to enhance cells that produce IL-17 and other cytokines. However, Dr. Mak stresses that more research is needed to confirm this theory. 

 Katz says continuing to focus on what inflammatory markers play a role in depression is key that could make a difference in treatment. “If increased inflammation is leading to depression and you find out that the primary driver of that inflammation is TNF, then that might suggest that treatment with a TNF inhibitor would make a difference,” she explains. “If it is CRP, that is more generalizable, and there’s not a specific drug that attacks CRP. On the other hand, there are things, such as weight loss and physical activity, that we know lowers inflammation. If people increase their physical activity and lose weight, does that help just as much? I don’t know, but it’s a reasonable question to ask,” she adds. 

Daniel Claw, MD, professor of medicine and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor, agrees this is an intriguing form of research, but says more work needs to be done to confirm it. “I think there’s been too rapid a move in the psychiatry field into believing cytokines are directly causing depression and might be an appropriate therapeutic target,” Dr. Clauw offers. “That is a reasonable hypothesis and may turn out to be true, but I don’t think we are there yet.” 

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