TCPR: Dr. Raison, you are involved in some interesting research about the connections between inflammation and depression. Tell us about it.
Dr. Raison: My research focuses on inflammation and the development of depression in response to illness and stress. This is arguably one of the hottest areas of research in mood disorders today.
TCPR: So what have you and others found?
Dr. Raison: Many studies show that people with depression have higher measures of various inflammatory markers in the blood than people who are not depressed (Howren MB et al., Psychosom Med 2009;71(2):171–186).
TCPR: Can you remind us of how inflammation occurs?
Dr. Raison: Inflammation is a very complex set of reactions that traditionally occur when the body’s immune system recognizes some sort of foreign invader. White blood cells called macrophages are activated and engulf the invader. This leads to the production of chemicals called cytokines that serve as messengers that travel around the body spreading the word that there is an invader. These cytokines activate various other mediators of the innate immune system. This is how you get things like fever, as well as pain and heat at the site of an injury. The innate immune system also helps activate what is called the adaptive immune system. This gets T-cells and B-cells fired up to kill the invader and help tissue heal. The symptoms of sickness, although uncomfortable, are good things, as they are proof that the cells are attacking and killing the invader—the bacteria or virus, for example. Meanwhile, the cytokines get a lot other cells in the body to start working on fighting the invader, too. So the liver might take a break from its usual job of making albumin and start producing C-reactive protein (CRP), which is a classic marker of inflammation.
TCPR: So what does this have to do with depression?
Dr. Raison: Well, what’s interesting from a psychiatric point of view is that cytokines are able to signal across the blood brain barrier. Cytokines in the gut can cause the production of cytokines in the brain, and vice versa.
TCPR: How did the discovery of this connection come about?
Dr. Raison: It actually started with the discovery that whether an animal was given an injection of bacteria to make it sick, or it was subjected to some sort of psychological stress, you got the same type of symptoms in response. These symptoms include loss of appetite, increased anxiety behavior, decreased sexual activity, and increased body temperature. This led to the idea that maybe there was some tie between sickness and stress-related disorders. The literature in animal and human studies supports the idea that psychological stress activates inflammation (Maier SF et al., Psychological Review 1998;105(1):83–107; Steptoe A et al., Brain, Behav, Immun 2007;7:901–912; Kiecolt-Glaser JK et al., P Natl Acad Sci USA 2003;100(15):9090–9095).
TCPR: So you’re saying that psychological stress can cause the body to react in the same way as it would to a foreign invader, like a bacterium or a virus?
Dr. Raison: Exactly. It turns out that inflammatory processes that originally evolved to respond to a foreign microorganism can also be activated from perceptual states of the brain. What I mean is that danger, loss, and fear—all the things that indicate that your ability to survive or reproduce might be threatened—can activate the production of cytokines in the same way an infection can.
TCPR: How have you tested this idea?
Dr. Raison: In our research, we bring a group of people into the lab in a relaxed state, hook them up and start drawing their blood. Then we bring in a psychosocial stressor by making them perform a stressful task in front of a judgmental panel of experts. If we measure the blood before, during, and after they are stressed, we can see that the cytokines go up in response to the stress (Pace TW et al., Am J Psychiatry 2006;163(9):1630–1633; Bierhaus A et al., P Natl Acad Sci USA 2003;100(4):1920–1925).
TCPR: And you associate the stress response with depression.
Dr. Raison: Stress is known to be one of the major risk factors for depression. Stress causes cytokines to be turned on. Moreover, if you look at the physiology of many people with depression, they look like they are “forever being chased by the tiger” as I like to say, meaning that they exist in states of chronic stress system hyperactivity, as measured by increased sympathetic and decreased parasympathetic activity, as well as resistance to cortisol and activation of inflammatory pathways (Raison CL et al., Am J Psychiatry 2003;160:1554–1565; Raison CL et al., Trends in Immunology 2006;27(1):24–31). Given these tendencies in depression, it is perhaps not surprising that on average, people who are depressed have higher levels of cytokines than people who are not depressed. Furthermore, a number of studies have shown that people who are depressed have inflammatory markers that put them at risk for heart disease, diabetes and dementia (Miller AH et al., Biol Psychiatry 2009;65(9):732–741). The chronic mild rise in inflammation over time exerts wear and tear on the body.
TCPR: When you say there is inflammation, what specifically is getting inflamed?
Dr. Raison: When I say “inflammation,” what I mean is that there are increased levels of cytokines in the blood. Evidence suggests that brain levels also rise—especially shown in animal models, where we see that stress activates pro-inflammatory cytokines in the central nervous system. Something as simple as social isolation can cause the cytokine IL-1 beta to suppress the production of an important neural protein called BDNF (brain-derived neurotrophic factor) in the hippocampus (Barrientos RM et al., Neuroscience 2003;121(4):847– 853; Rachal Pugh C et al., Neurosci & Biobehav Rev 2001;25(1):29–41). A deficit of BDNF has been repeatedly implicated in the pathogenesis of depression, so this finding really links inflammatory pathways to other brain systems known to be abnormal in depression (Aguilera M et al., Psychol Med 2009;39(9):1425–1432; Schmidt HD et al., Behav Pharmacol 2007;18(5–6):391–418; Mossner R et al., World J Biol Psychiatry 2007;8(3):141–174). If you block the cytokine in the CNS, you can prevent this whole process.
TCPR: This is all very interesting research, but how do we apply what you’ve learned to the treatment of our patients with depression?
Dr. Raison: Depression is such a nuanced condition that this unfortunately does not translate into a simple answer—give all patients an ”anticytokine” medication, for example. The data suggest that inflammatory processes contribute to depression. However, depression comes from a combination of your genes and environmental adversity—all things being equal, if your cytokines run high you are more likely to develop depression than someone whose cytokines run low (Gimeno D et al., Psychol Med 2009;39:413–423; van den Biggelaar AHJ et al., Clin Exp Immunol 2010;160(1):42–47).
TCPR: So it’s not just a matter of stopping the production of cytokines to stop depression.
Dr. Raison: No, depression is too multifactorial for that to be likely to fix everyone who suffers from a mood disorder. I can say that research supports the idea that if you can reduce the cytokines of people with depression, they might feel better. Most standard antidepressants lower inflammation in the blood of depressed people (Miller AH, Biol Psychiatry, op.cit).
TCPR: Beside the cytokine-lowering effects of regular antidepressants, is there anything else we can try?
Dr. Raison: Some data suggest that people who don’t respond well to SSRIs have higher cytokine levels (Miller AH, ibid). If you test a patient’s blood and find that he or she has a high C-reactive protein (CRP) level—say about four or so—some research shows that adding a Cox-2 inhibitor could improve response (Muller N et al., Mol Psychiatry 2006;11(7):680–684). But that’s not always the case, and CRP levels do not directly correlate with mood. Anything over about three for CRP is in the high range. However, I could have a CRP of two and be completely miserable and depressed, and you could have a CRP of five and be fine.
TCPR: Any other suggestions?
Dr. Raison: A couple of open trials have examined adding 325 mg of aspirin a day to Prozac nonresponders and have reported a response within about week or two (Brunello N et al., Int Clin Psychopharmacol 2006;21(4):219–225; Mendlewicz J et al., Int Clin Psychopharmacol2006;21(4):227–231).
TCPR: To sum up the evidence—cytokines are a part of the inflammatory process. There is some evidence that an increase in cytokines may contribute to the development and maintenance of depression. So in some cases adding an anti-cytokine or anti-inflammatory agent, such as Celebrex or aspirin, may help with depression.
Dr. Raison: All true. There is no magic bullet with depression. This research butts up against our tradition of compartmentalizing depression as a sort of discrete disease state. These systems interact in very complex ways that we are just beginning to understand.
TCPR: Thank You, Dr. Raison.