Leadership Blog Series – Psychoneuroimmunology and Depression

Welcome back to our leadership blog series! This month, your NMSA President, Brice Thompson, writes to you regarding a special research interest of his:


Psychoneuroimmunology and Depression

How our mental health can directly impact our physical health.

Depression is one of the most common chief complaints that the primary care physician will manage. It is expected that by 2030, depression will be one of the three leading causes of disease burden in the world, next to HIV/AIDS and ischemic heart disease.1 Increasing our understanding of how depression impacts the health of the entire organism is essential in order to ensure proper treatment of the condition. The field of psychoneuroimmunology is the study of how mental health, neurophysiology, and immunology interact with one another. By viewing depression through the lens of psychoneuroimmunology, we gain a more holistic model of the impacts on the entire organism, and as Naturopathic Physicians in-training, it’s our charge to see the whol(istic) picture, correct?

Research of how depression and immune function interact goes back as far as 1945.2 A flurry of research in the 50s and 60s began to understand that sufferers of depression had altered immune function. It wasn’t until the 80s that we had the technology to start to understand why. In the 80s, we developed the technology to measure how the immune system communicates. We were finally able to measure cytokines.3

We quickly discovered that specific cytokines released in high concentrations during infection resulted in ‘sickness behaviors.’ Specifically, IL-1 inducing malaise/fatigue, IL-6 inducing depressive behavior (and yes, those suffering from major depressive disorder (MDD) have high levels of IL-6), and TNF-alpha inducing hostility.4 The discovery that these cytokines link immunologic function to behavior was the connection scientists were looking for; the relationship gave them the clue they needed to associate our mental health with our physical health in a way that had yet to be thoroughly investigated. Shortly after, they began to look at health outcomes and how they related to co-morbid depression. I bet you all know what was found, my brilliant colleagues. It was found that a diagnosis of MDD accurately predicts morbidity and mortality in cardiovascular disease, rheumatoid arthritis, HIV, and cancer.5–7 That’s just the tip of the iceberg. More and more studies are starting to connect the dots between MDD and other health conditions such as IBD, dementia, type 2 diabetes, and Alzheimer’s disease, just to name a few.

How’s this happening? Well, those suffering from MDD have a very characteristic cascade of hormones and chemical messengers that result in a depressed adaptive immune response, decreased immunological memory, and an increased secretion of proinflammatory cytokines. Corticotrophin-releasing hormone (CRH), a neuropeptide in the brain released during times of high stress, is also released at high concentrations in those with MDD. An increase in CRH has effects cortically and immunologically. Cortically, high CRH results in decreased synaptic activity in the executive centers of the brain and an increase in activity in the amygdala.8 Since the balance between these two neural structures is essential for proper regulation of emotions, reasoning, and logic, the decreased ability of the executive cortex to regulate amygdala function results in the amygdala running rampant throughout the consciousness.9 CRH also has effects immunologically. High doses of CRH in the brain results in reduced natural killer (NK) cell activity (independent of cortisol levels).10 NK cells, as we know them, have significant implications in the defense against cancer and viral infections. This coincides with observational data showing those suffering from chronic depression are at an increased risk of developing cancer.11

With significant increases in CRH, it’s no guess that the hypothalamic-pituitary-adrenal axis (HPA axis) also becomes dysregulated. This system is primarily mediated by the hormone, cortisol. Those that suffer from depression have an increase in serum cortisol levels. Which, as we know, depresses adaptive immunologic function and increases innate defenses by moving mononuclear cells to peripheral tissues and increasing inflammatory cytokine secretions.12 This inflammatory immune response increases risk of CVD and risk of viral infections, compounding with the effects of CRH listed above, it’s no wonder that those suffering from depression with other co-morbid autoimmune conditions have poorer outcomes.13 (Side note: Since it’s biology, thus making things complicated, there is research that supports that this relationship between cortisol and depression can work in the opposite direction as well. Chronic stress leading to chronically high cortisol levels can induce depression and it’s characteristic cascade)14

Lastly, the direct connection between the CNS and the immunologic system, the sympathetic nervous system, increases in activity. Those suffering from depression have an increased catecholamine response when put under stress. Catecholamines have direct inhibitory effects on immunologic function, and it’s been noted that catecholamines affect the microbiome by promoting the expression of virulence factors in pathogenic gut bacteria.

In summary, depression presents with a decreased NK cell count, inhibiting our ability for cancer and viral immunity. We have a reduced adaptive immune response to novel and known antigens as well as an increased risk of CVD, CA, and autoimmune complications, to name a few. The physiologic consequences of depression represent areas where treatment can be leveraged to improve treatment outcomes. Managing the risks, gaining a more thorough understanding, and delivering targeted therapies can undoubtedly gain us the upper hand in managing this complicated condition. A targeted, multidisciplinary approach to treatment is required. Know of a type of practitioner who utilizes such an integrative, holistic, and thorough approach? I think I can name a few.  



  1. Mathers, C. D. & Loncar, D. Projections of Global Mortality and Burden of Disease from 2002 to 2030. PLOS Med. 3, e442 (2006).
  2. Wertham, F. A psychosomatic study of myself. J. Clin. Exp. Psychopathol. 7, 371–378n2 (1945).
  3. Libert, C. Cytokine anniversary: TNF trailblazers five centuries apart. Nature (2015). doi:10.1038/523158e
  4. Kelley, K. W. et al. Cytokine-induced sickness behavior. Brain. Behav. Immun. 17 Suppl 1, S112-118 (2003).
  5. Lespérance, F., Frasure-Smith, N., Théroux, P. & Irwin, M. The Association Between Major Depression and Levels of Soluble Intercellular Adhesion Molecule 1, Interleukin-6, and C-Reactive Protein in Patients With Recent Acute Coronary Syndromes. Am. J. Psychiatry 161, 271–277 (2004).
  6. Nanni, M. G., Caruso, R., Mitchell, A. J., Meggiolaro, E. & Grassi, L. Depression in HIV Infected Patients: a Review. Curr. Psychiatry Rep. 17, 530 (2015).
  7. Zautra, A. J. et al. Immune activation and depression in women with rheumatoid arthritis. J. Rheumatol. 31, 457–463 (2004).
  8. Majzoub, J. A. Corticotropin-releasing hormone physiology. Eur. J. Endocrinol. 155, S71–S76 (2006).
  9. Miller, C. H., Hamilton, J. P., Sacchet, M. D. & Gotlib, I. H. Meta-analysis of Functional Neuroimaging of Major Depressive Disorder in Youth. JAMA Psychiatry 72, 1045–1053 (2015).
  10. Zorrilla, E. P. et al. The Relationship of Depression and Stressors to Immunological Assays: A Meta-Analytic Review. Brain. Behav. Immun. 15, 199–226 (2001).
  11. Musselman, D. L. et al. Higher Than Normal Plasma Interleukin-6 Concentrations in Cancer Patients With Depression: Preliminary Findings. Am. J. Psychiatry 158, 1252–1257 (2001).
  12. Dhabhar, F. S. Stress-Induced Enhancement of Cell-Mediated Immunitya. Ann. N. Y. Acad. Sci. 840, 359–372 (1998).
  13. Moussavi, S. et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. The Lancet 370, 851–858 (2007).
  14. Claes, S. J. CRH, Stress, and Major Depression: A Psychobiological Interplay. in Vitamins & Hormones 69, 117–150 (Academic Press, 2004). 

About the Author:


Brice Thompson is a 5th-year Naturopathic Doctoral and M.S. in Integrative Medical Research student at the National University of Natural Medicine. His undergraduate experience at Colorado State University, where he obtained his B.S. in Horticultural Science with a minor in Organic Agriculture, is where he first became aware of the importance of nutrition in health. While attaining his B.S., Brice worked in a Mycobacterial research laboratory where he was involved in helping elucidate the transmission of Mycobacterium ulcerans and assisted in the purification of Mycobacterium tuberculosis products for use around the world in the fight against TB. His time in the research setting instilled a deep passion for research that has continued during his time at NUNM. Brice’s current recent research interests include the immunology, infectious disease, and cancer. His thesis project investigates the use of herbs as novel therapeutic agents in cancer growth inhibition and radio/chemo-sensitization. Brice has served in the NMSA for three years and is a die-hard believer in the necessity of the collective student voice being represented at our profession’s planning tables.


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