In their book, Psychiatry Under the Influence (2015), Whitaker and Cosgrove suggest that researchers of the human condition might improve the integrity of their investigations by foregoing connections to marketing interests. The research examining the ways in which depressive/anxious behaviors correlate with markers of inflammation has been conducted outside of psychiatry, although a few psychiatrists have contributed. Early studies were conducted by neuroscientists Steven Maier and Linda Watkins and veterinarian Robert Dantzer. Psychiatrist Michael Maes was also an early pioneer. Psychiatrist Andrew Miller entered the field later having worked with Robert Dantzer. Michael Irwin is also a psychiatrist, but he works with Naomi Eisenberger and Matt Lieberman, who are social psychologists. Chris Lowry is a neuroscientist. In my reading of this literature and my conversations with some of these luminaries, they seem primarily driven by curiosity. When these scientists publish their work, they generally talk about their findings in terms of behavioral observations rather than diagnostic categories. For the most part, they aren’t concerned with diseases. Rather, they examine those conditions which change behavioral outcomes. An assumption made by all these researchers, is that behavior originates in the brain. Members of the International Society for Ethical Psychology and Psychiatry call for a day when clinicians will ask “what happened to you?” rather than “what is wrong with you?” However, what happens to you must change brain function in some way, if a change in behavior results. Scientists in the field of psychoneuroimmunology have investigated these connections.
Links among depression, stress and inflammation. An explosion of research has documented the link between the experience of stressful conditions, markers of inflammation in the blood, and the experience of depressive feelings and behaviors. Inflammatory hormones (called cytokines) are elevated in persons diagnosed with depression (Raison, Capuron, & Miller, 2006). Persons undergoing the stress of caring for a loved one with Alzheimer’s disease show elevations in inflammatory markers (Kiecolt-Glaser, et al., 2003). In the Whitehall studies of employees in the British Civil Service system, those who were paid less and had less control over their work schedules, as a group, were higher on inflammatory markers even after controlling for possible differences in diet and smoking (Steptoe et al., 2003). Most recently, Setiawan et al. (2015), using brain imaging strategies, measured the level of activated white blood cells in brain and found a correlation between level of depression and activation of microglia, the brain’s major type of white blood cell. About 1/3 of persons diagnosed with major depressive disorder exhibit elevations in inflammatory white blood cell hormones (cytokines) (Tartter, Hammen, Bower, Brennan, & Cole, 2015).
Showing Causal Association between Stress and Inflammation. Beyond the correlational studies, there is research in which animals have been manipulated in some way and then inflammation has been measured. Animals have been subjected to bouts of foot shock that they were unable to control. Subsequently, these animals display depressed behavior (not eating sweet foods, avoiding other animals, moving less). They also had higher amounts of inflammatory cytokines in brain and when the researchers put in a molecular sponge to bind up the inflammatory cytokine in brain, the animals reverted to normal behavior (Maier & Watkins, 1998). These studies showed that stressing the animal results in both more depressive behaviors and that these depressive behaviors are caused by the brain inflammatory factors.
Showing a causal link between infection and depression. Researchers also know that another way to cause inflammatory factors to rise in the brain is by inducing infection in the periphery. A number of experimenters have placed the wall of a bacterium into the paw of a rodent. Subsequently, inflammatory cytokines increase in brain and the animal loses preference for sweet liquids, avoids other animals and moves less. Again, if the researcher puts in a molecular sponge to bind up the inflammatory factors, the behavior of the animal reverts to normal (Maier & Watkins, 1998).
Showing causal link between inflammation and distress in people. The accumulation of the animal findings has prompted similar studies in people. Researchers have placed the wall of a bacterium into the periphery. The wall of the bacterium in the body results in activation of areas of the brain associated with alarm, less response to money in reward areas, and stronger activation in the amygdala (an anxiety center) in response to scary images (Eisenberger et al., 2009, 2011; Inagaki et al., 2012). In another approach, researchers arranged for research-participants to feel bad. They had their research-participants play a computer game with others tossing a frisbee type object around. Then suddenly the research-participant gets excluded. Again, activation in the brain’s alarm area is noted. However, if the research-participant had taken acetaminophen (Tylenol), an anti-inflammatory, prior to the study, then the alarm area remained quiet and people reported less distress (Dewall et al., 2010).
The causal role that inflammation plays in producing depression and anxiety has many implications. Many reports of depression preceding dementia, heart disease, strokes, cancer have been published in samples of persons who were not taking antidepressants. The common factor in all of these conditions is inflammatory processes.
In order to promote my new book, Neuroscience for Psychologists and Other Mental Health Professionals: Promoting Well-Being and Treating Mental Illness, I have launched a website, www.littrellsneuroscienceofwellbeing.org . My book covers the story on how inflammation influences mood, hearing voices, and depressed/anxious behaviors. The book covers the pathways through which diet, exercise, meditation, and yoga can influence inflammation and thereby ameliorate distress. On my website, I will be updating the findings in this fast-changing area. Since the material should have broad interest, I will after a little editing, post many of these findings and my comments on this site as well.
Dewall, C. N, Macdonald, G., Webster, G. D., Masten, C. L., Baumeister, R. F., Powell, C., . . . Eisenberger, N. I. (2010). Acetaminophen reduces social pain: behavioral and neural evidence. Psychological Science, 21 (7), 931-947.
Eistenberger, N. L., Berkman, E. T., Inagaki, T. K., Rameson, L. T., Mashal, N. M., & Irwin, M. R. (2100) Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biological Psychiatry, 68(8), 748-754.
Eisenberg, N., Inagaki, T. K., Rameson, L. T., Marshal, N. M., & Irwin, M. R. (2009). An fMRI study of cytokine-induced depressed mood and social pain: the role of sex differences. Neuroimage, 47(3), 881-890.
Inagki, T. K., Muscatell, K. A., Irwin, M. R., Cole, S. W., & Eisenberger, N. I. (2012). Inflammation selectively enhances amygdala activity to socially threatening images. Neuroimage 59(4), 3222-3226.
Kiecolt-Glaser, J. K., Preacher, K. J., MacCallum, R. C., Atkinson, C., Marlarkey, W. B., Emery, C. F., & Glaser, r. (2003). Chronic stress and age-related increases in proinflammatory cytokine IL-6. PNAS, 100(15), 9090-9095.
Maier, S. F., & Watkins, L. R. (1998). Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychological Review, 105(1), 83-107.
Raison, C. L., Capuron, L., & Miller, A. H. (2006). Cytokine sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology, 27(1), 24-31.
Setiawan, E., Wilson, A. A., Mizrahi, R., Rusjan, P. J., Miller, L., Rajkowska, G., Suridjan, I., Kennedy, J. L., Rekkas, P. V., Houle, S., & Meyer, J. H. (2015). Role of translocator protein density, a marker of neuroinflammation in the rain during major depressive episodes. JAMA Psychiatry, 72 (3), 268-275.
Steptoe, A., Kunz-Ebrecht, S., Owen, N., Feldman, P. J., Rumley, A., Lowe, G. D., & Marmot, M. (2003). Influence of socioeconomic status and job control of plasma fibrinogen responses to acute mental stress. Psychosomatic Medicine, 65(1), 137-144.
Tartter, M., Hamman, C., Bower, J. E., Brennan, P. A., & Cole, S. (2015). Effects of chronic interpersonal stress exposure on depressive symptoms are moderated by genetic variation at IL6 and Il1β in youth. Brain, Behavior, and Immunity, 46, 104-111.
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