In psychiatry, the age of simple answers is over.
I’ve done as much as anyone to propagate the notion that depression is an inflammatory condition, which is one of those simple statements that fills us with hope for easy solutions. But despite my proselytizing on this issue, it is increasingly clear that blanket statements like this hide as much as they reveal.
Sure, it’s true that, as a group, people with major depressive disorder (MDD) have elevations in various peripheral inflammatory markers. But a new study in JAMA Psychiatry highlights how we are often the victims of our own categories, especially in a field such as psychiatry where clinical categories are all we’ve had.
Emil Coccaro and colleagues report that, as a group, individuals who meet criteria for intermittent explosive disorder have higher levels of plasma high-sensitivity c-reactive protein (CRP) and interleukin (IL)-6 than either normal control subjects or individuals with other psychiatric diagnoses. Within the population as a whole, measures of aggression were highly correlated with inflammation: the more aggressive people were, the higher their levels of CRP and IL-6 were likely to be.
Importantly, aggression trumped all other psychiatric conditions in this study, raising two immediate questions. First, is it possible that feelings of anger and aggression within depression explain much of the association of the condition with inflammation? Second, when people are exposed to chronic inflammation are they more likely to become aggressive or depressed?
As far as I know, the answer to the first question is unknown. But I am always amazed at how little of the world’s literature I know, even in my own field of expertise. If someone knows of data pertaining to this question, please post it as a comment to this article
We do know the answer to the second question, based largely on many studies conducted in humans receiving the cytokine interferon (IFN)-alpha for cancer or chronic hepatitis C virus infection. IFN-alpha powerfully activates the body’s inflammatory system, and we and others have shown that the more it does this in any given person, the more likely that person is to develop psychiatric symptoms. So does IFN-alpha cause more depression or more aggression?
The short answer is that although IFN-alpha induces high rates of depression, it provokes equally high rates of anger and hostility . And while anger and hostility are not synonymous with aggression, they are certainly close companions.
Furthermore, when researchers in France applied strict DSM-IV criteria to what IFN-alpha actually produces—rather than just assessing for depression—they found that most people who developed symptoms evinced various types of mixed states, or what in DSM-5 might be considered “major depression with mixed features”. Importantly, anger, irritability, and impulsivity are prominent features of these conditions.
Although we would do well to abandon simple answers in psychiatry, we would also do well to flexibly hold satisfying theories that provide deep explanations for the phenomena that we see. I truly believe that evolutionary understandings provide one of the most promising pathways for coming to such explanations.
So why should inflammation produce both depression and aggression/irritability/anger? We and others have hypothesized that this pattern is a relic of the challenge mammals faced in balancing their energy expenditures toward internal and external threats. 
Clearly, inflammation evolved as a primary mechanism for fighting internal infectious threats. To do this, inflammation produces sickness, which essentially siphons off the body’s energy to produce fever and to ramp up immune activity, both of which are huge metabolic costs. To compensate, sickness produces lethargy, anhedonia (so no energy is spent pursuing pleasurable activities), and psychomotor retardation. Other symptoms, such as appetite loss, probably evolved to deprive invading organisms of the nutrients they need.
All this is good for fighting germs, but protracted sickness places an animal at significantly increased risk of attack from external threats. Sick animals are often the first to fall to predators. In social species such as humans, sickness can also be a signal that one’s status is “up for grabs” in the group. If you think this still isn’t relevant, consider how carefully John F. Kennedy hid his Addison’s disease, how Eisenhower hid his heart attack in office, and how FDR tried to hide his paralysis.
We think the fact that inflammation induces both depression and aggression reflects an ancient, but uneasy, evolutionary compromise between the need to divert energies to the immune system and to fever when infected, while at the same time being on heightened alert to avoid the dangers of predation and loss of social status that follow in the wake of sickness-induced vulnerability. This compromise takes the form of sickness/depression when we are infected or stressed out, but in a safe place, and it manifests as irritability, hostility, and heightened aggression whenever we are stressed/infected and think we are at risk of harm either to life or limb or status.
A clear prediction of these ideas has never been tested: specifically, that inflammation should make people feel depressed when they are not threatened by external circumstances and more hostile and aggressive when they are.
Although not all cases of depression are associated with chronically increased inflammation, the underlying ideas we present here are likely relevant to other biological causes of depression.
Does this line of thinking help you make more sense of why depression and irritability and anger should be so highly comorbid?
1. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. Jan 2006;27(1):24-31.
2. Coccaro EF, Lee R, Coussons-Read M. Elevated plasma inflammatory markers in individuals with intermittent explosive disorder and correlation with aggression in humans. JAMA Psychiatry. Dec 18 2013.
3. Raison CL, Borisov AS, Woolwine BJ, Massung B, Vogt G, Miller AH. Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry. May 2010;15(5):535-547.
4. Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. Journal of Clinical Psychiatry. 2003;64(6):708-714.
5. Constant A, Castera L, Dantzer R, et al. Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. Journal of Clinical Psychiatry. 2005;66(8):1050-1057.
6. Raison CL, Miller AH. The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Mol Psychiatry. Jan 31 2012.
7. Raison CL, Miller AH. Malaise, melancholia and madness: the evolutionary legacy of an inflammatory bias. Brain Behav Immun. Jul 2013;31:1-8.
Charles L. Raison, MD, is an associate professor in the Department of Psychiatry, College of Medicine and the Barry and Janet Lang Associate Professor of Integrative Mental Health in the Norton School of Family and Consumer Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ. He is also the behavioral health expert for CNN.com, and he is a Psych Congress Steering Committee member.
The views expressed on this blog are solely those of the blog post author and do not necessarily reflect the views of Psych Congress Network or other Psych Congress Network authors.