Inflammation and Depression

Question:

“I’ve heard you talk about inflammation and depression at the Treating the Whole Patient sessions at the  24th Annual U.S. Psychiatric and Mental Health Congress, and I’m hearing more and more about this topic in psychiatric publications. Is it time we started thinking about major depression as an inflammatory condition?”

Charles Raison, MD:

I’ve bet a lot of my academic career on proving the association between depression and inflammation, so it might surprise you that my answer to your question is “no.” Depression is not an inflammatory condition as we commonly think of these disease states. I’ll discuss this in some detail in this Q&A, but you might also consider listening to my lectures “ Reversing the Long Day’s Journey into Night: Mind-Body Perspectives on Treatment Resistant Depression ” and “ Inflammatory Perspectives on the Future of Psychiatry ” presented at the  24th Annual U.S. Psychiatric and Mental Health Congress .

By way of a thought experiment, suppose you are a rheumatologist seeing a middle-aged patient who complains of a painful right knee. To help diagnose the condition you aspirate synovial fluid from the offending knee and send if off for analysis. Suspecting rheumatoid arthritis (RA), you are surprised when the results come back completely normal in terms of inflammatory markers in the synovial fluid. Had inflammatory measures been high that would not have confirmed RA because other autoimmune and infectious causes for arthritis are also characterized by increased synovial inflammation. However, knowing that concentrations of an inflammatory cytokine such as interleukin-6 are typically a thousand times higher in the synovial fluid of an affected RA joint than in the blood of a healthy adult, what would be your conclusion regarding the likelihood of RA in this patient? I bet it would be: no joint inflammation, no RA. That’s more or less what we mean when we say that RA is an inflammatory disorder.

Now compare this to an analogous clinical situation, but this time you are a psychiatrist seeing a middle-aged patient complaining of severe depression. Hearing that major depressive disorder (MDD) is an inflammatory condition, you measure plasma concentrations of inflammatory cytokines and the acute phase reactant C-reactive protein (CRP). Believing MDD to be a brain disease, you also go beyond the call of duty and perform a lumbar puncture in your office to measure cerebrospinal fluid concentrations of the same inflammatory markers. A few days later the patient returns, and you hold the lab results in your hands. No evidence of increased inflammation in either the central nervous system or periphery. The patient is weeping and says he can think of nothing but killing himself. Would you decide that because the patient’s inflammatory measures are normal he cannot be depressed?

Based on these scenarios, I have to conclude that the answer to the question of whether depression is an inflammatory disorder is a resounding “no.” Even with a nod of recognition toward the fact that all disease processes have an inherent “sloppiness” that precludes absolute one-to-one correspondences between putative causes and observed symptomatic outcomes, it is clear that inflammation is neither necessary nor sufficient to cause MDD. Desperately depressed people often have low levels of systemic inflammation, and people with ragingly high inflammatory activity are often—but less commonly—able to retain a good mood and hopeful stance toward their lives.

If depression is not an inflammatory disorder in the sense that autoimmune conditions are inflammatory disorders, how should we best understand the growing database (which now includes three meta-analyses ^1-3 ) indicating that depression is associated with increased inflammation? Three points are most important here.

First, what studies actually report is that, on average, the mean value for an array of inflammatory mediators tends to be higher in depressed groups than in groups of non-depressed individuals. In many studies, this increase in the mean is independent of other factors associated with increased inflammation, such as body mass index and sex. In other studies, the difference between depressed and non-depressed groups goes away when these types of factors (many of which are overrepresented in depression) are taken into account. ⁴

Second, the elevations in proinflammatory cytokines and other inflammatory elements observed in groups of depressed individuals are far more modest than increases typically observed in autoimmune or infectious diseases, with mean values in depression typically not exceeding two to three times the values found in normal control groups. ¹  Consistent with these modest differences, mean values for inflammatory markers in groups of depressed individuals are typically in the “normal” range when such norms have been established, ^5-10 as is the case with CRP. ¹¹

When put this way, the connection between depression and increased inflammation seems underwhelming, and one might be tempted to dismiss it as physiologically irrelevant. But this would be a mistake of the first order, and a profound misunderstanding of the huge effect that small physiological differences can have over time if they are consistently skewed in one direction. As it turns out depression is far from alone in being a condition characterized by reliable—but often only mildly increased—inflammatory activity. Other modern illnesses with evidence of moderately increased inflammatory signaling include cardiovascular disease, stroke, cancer, diabetes, and dementia. Conversely, even minor increases in inflammation—such as are observed in depression—are enough to strongly predict the development over time of many of these modern disease states. ^12-17

Finally, we come to a third point that is vital for understanding the nature of the association between inflammation and depression: the values for any given inflammatory marker always overlap between groups of depressed and non-depressed individuals, regardless of how much higher the marker’s mean value may be in the depressed group. Thus it is not unheard of for the highest value in any particular study to be in the non-depressed group and the lowest value to be in the depressed group. More importantly, it also means that a large proportion of the depressed group in any given study will have values similar to the non-depressed group, which—at least on first blush—makes it hard to envision these people as suffering from a disease state caused by increased inflammation. On the other hand, even though values tend to be fairly evenly distributed across the whole range in both depressed and non-depressed populations typically about one-third or so of the depressed group has values that are clearly higher than the majority of non-depressed comparison participants. These are the people responsible for the finding that depression is associated with increased inflammation. It is a dirty little secret of sorts that they have been pulling all their non-inflamed depressed colleagues along with them in publication after publication, giving the world a slightly misguided sense that depression—as a whole—is driven by increased inflammation.

I don’t have enough space in this Q&A to raise the next obvious question, which is whether the one-third or so of patients with elevations in inflammatory biomarkers represent a biologically distinct (or semi-distinct) subtype of depression. Recent work from our group seems to indicate that this might be the case, but these findings haven’t been published yet so I can’t elaborate on them at this time.

—Charles Raison, MD

  References

1.              Dowlati Y, Herrmann N, Swardfager W, et al  . A meta-analysis of cytokines in major depression.  Biol Psychiatry .2010;67(5):446-457. 
2.              Howren MB, Lamkin DM, Suls J  . Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis.  Psychosom Med .2009;71(2):171-186. 
3.              Zorilla E, Luborsky L, McKay J, Roesnthal R, et al  . The relationship of depression and stressors to immunological assays: a meta-analytic review.  Brain Behav Immun .2001;15:199-226. 
4.              O'Connor MF, Bower JE, Cho HJ, et al  . To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers.  Brain Behav Immun .2009;23(7):887-897. 
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6.              Vaccarino V, Johnson BD, Sheps DS, et al  . Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study.  J Am Coll Cardiol .2007;50(21):2044-2050. 
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9.              Panagiotakos DB, Pitsavos C, Chrysohoou C, et al  . Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study.  Eur Heart J .2004;25(6):492-499. 
10.            Danner M, Kasl SV, Abramson JL, Vaccarino V  . Association between depression and elevated C-reactive protein.  Psychosom Med .2003;65(3):347-356. 
11.            Pearson TA, Mensah GA, Alexander RW, et al  . Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. [see comment].  Circulation .2003;107(3):499-511. 
12.            Vidula H, Tian L, Liu K, et al  . Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study.  Ann Intern Med .2008;148(2):85-93. 
13.            Ridker PM  . C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.  N Engl J Med .2000;342(12):836-843. 
14.            Ridker PM  . Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity.  Nutr Rev .2007;65(12 Pt 2):S253-259. 
15.            Heikkila K, Ebrahim S, Lawlor DA  . A systematic review of the association between circulating concentrations of C reactive protein and cancer.  J Epidemiol Community Health .2007;61(9):824-833. 
16.            Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM  . C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. [see comment]. JAMA .2001;286(3):327-334. 
17.            Laurin D, David Curb J, Masaki KH, White LR, Launer LJ  . Midlife C-reactive protein and risk of cognitive decline: a 31-year follow-up.  Neurobiol Aging .2009;30(11):1724-1727.