Between MAGIC and MEDICINE: 2012

Whether attacked by a hot or a cold pernicious wind, i.e. when we catch a flu or a cold, we often experience more than the physical discomforts that come with being sick, we also manifest what is termed ‘sickness behavior’ which includes feelings of malaise, fatigue, poor appetite, irritably, depressed mood for example. Our physical symptoms, the aches and pains, the runny nose, the sore throat, the acquired aversion to wind, cold or heat, this is the viral infection taking hold, most likely at the Qi level or the Tai yin level depending on the differentiation between cold or febrile disease. But what of the behavioral changes, this ‘sickness behavior’? It turns out that these behavioral changes, as evinced through more and more studies sponsored by the likes of the National Institute of Health in cooperation with the National Center for Complimentary and Alternative Medicine, as well as studies funded by the National Institute of Mental Health, are most likely manifest from our own body’s defenses. An inflammatory reaction, these studies are finding, such as that cascaded by our own immune response toward infection does yield symptoms of anhedonia. Likewise, depression, whether mild or chronic does elicit an inflammatory response, and the greater the depression, the greater the inflammation.

Depressive behavior or clinical depression, once regarded clinically as “melancholia” is a cluster of symptoms that include low mood, low-self esteem and loss of interest or pleasure in usually enjoyable activities. It was first classified as a mood disorder in the 1980 edition of the American Psychiatric Association’s diagnostic manual.

There are presently over two million published articles regarding the subject of acute and systemic inflammation and its effect on disease--cardiovascular disease, MS, irritable bowel, for example. Most interesting, though, are the studies that suggest that inflammation may have a bi-directional relationship with depressive disorders. This is the cytokine hypothesis of depression. These studies include both experimental and clinical administration of cytokines or endotoxins such as cytokines-based immunotherapy for Hep-C and IFN-alpha to treat some cancers and chronic infection. The current understanding (as of February 28, 2012) is that there is a comorbidity of depression with chronic illness. When a pathogen infects the body or tissue is damaged the first responders are alerted and these macrophages and monocytes initiate an inflammatory response locally or systemically, releasing the pro-inflammatory cytokines (interleukin-1-beta, 6 and TNF-alpha). Local and systemic inflammation includes hepatic synthesis and the release of acute phase proteins (C-reactive protein) and fibrinogen. Pro- inflammatory cytokines can penetrate the blood-brain barrier. It has been observed that these cytokines will then stimulate the production of “central” pro-inflammatory cytokines by the brain’s immune cells (microglia cells) in the mood regulation and reward processing regions of the brain.

This this new insight to depression and this further study of the patho-generative nature of inflammation in the body is interesting to scientists and clinicians because it can help them better target their treatment strategies. Could an anti-inflammatory treatment better serve those presenting with mild to severe depression, for example, than a selective serotonin reputable inhibitor (SSRI)?
In his 2009 reticle on the subject, Dr. Robert Heydaya, Clinical Professor of Psychiatry at Georgetown University, Department of Psychiatry, shares four studies that further shines light on the subject. The first two suggest that reducing inflammation may help alleviate depression. The final two observations in his article are concerned with the core stress response system in the brain. The first study split patients exhibiting severe depressive behaviors into two groups. One group was given a combination of Celebrex (a cox-2 inhibitor) and Reboxetine (a non-adrenergic inhibitor) while the other group received a placebo. The study group reported fewer depressive symptoms. As depressed patients have elevated levels of plasma Tumor Necrosis Factor (TNF), so the next study split a group of patients with mild to moderate psoriasis and depressive behavior. The study group was administered Etanercept (a TNF blocker) while the second group received the placebo. Independent of any improvement in the psoriasis, the patients in the study group reported reduced depressive symptoms than did the placebo group. The final two studies explain the core-stress-response system in the brain that activates and regulates the adrenalin-immune connection. This stress can be activated by both exogenous pathogens and infections and such internal, psychological factors like common stress which engages our sympathetic nervous system through the release of cortisol from the adrenal gland which in turn suppresses our immune system (downregulating the Interleukein-2 receptor [IL-2R] on the “Helper [CD4+] T-cells) and increases our blood sugar levels through glycogenolysis and reduction of glucose intake into cells. Our fight-or-flight response is online and a pro-inflammatory cascade that can precipitate depressive behavior.

So, if the immune system and the brain are in communion through the nervous system, as with the sympathetic and its causal relationship to depression then to our favor the vagus nerve is important here. The vagus nerve is the tenth of twelve cranial nerves that extends from the medulla to the anus; and when activated, as through deep belly breathing, for example, the "motivational centers" in the brain are stimulated directly and the adrenalin pump can be arrested. The microglia cells in the brain will this time increase levels of nor-adrenalin and serotonin, a neurotransmitter popularly thought to be a contributor to feelings of well-being and happiness, in the system. So, when there is inflammation in the body, locally or systemically, the microglia actually stop the brain from making serotonin.

Michael Maes M.D. Ph.D writes in Neuroendocrinology Letters in 2008 that there is now a “shift” in the serotonin deficiency hypothesis regarding depression. Depression, he’s concluded, is not due to tryptophan (precursor to serotonin)/serotonin deficiency but “due to inflammation-induced tryptophan degradation with consequent formation of neurotoxic TRYCATs” (tryptophan catabolites). Every biological function in our aerobic body is a process of reactions, i.e., the loss or gain of electrons between molecular bonds that will increase or decrease their oxidation state. A simple example of a redox process is the oxidation of carbon to yield carbon dioxide. A complex example is the oxidation of glucose through a series of electron transfer processes. Cellular respiration, the set of metabolic reactions that fuels every biological function, requires two things: oxygen and a reactant. Though the consumption and metabolism of carbohydrates, proteins and fats (of which cortisol aides in) can be reactive, the preferred method is glycolosis, the metabolic pathway that converts glucose into pyruvate to enter the mitochondria of the cell. This produces high-energy compounds of ATP, but it also produces a waste material called reactive oxygen species (ROS). This by-product potentiates cellular damage and has been contributed to the physiology of aging as it can damage DNA, RNA and proteins.

When the normal redox state is disturbed as through chronic stress or infection the tissues can cause toxic effects by producing additional ROS such as free radicals and peroxides that damage all components of the cell including DNA, lipids and proteins. This is called oxidative stress and it has been implicated in many diseases such as atheroclerosis, parkinson’s disease, heart failure, heart attacks, schizophrenia, bipolar disorder, and chronic fatigue syndrome (all other research subjects to explore). Dr. Maes’s study includes the same observations that Dr. Hedaya wrote about in his article one year later, hypothesizing that stress-sensitive cytokines may cause depressive behavior. But Dr. Maes proposes too that inflammation and depression is accompanied by increases in oxidative stress. Likewise, depression, he notes, is accompanied by increased levels of malondialdehyde, a marker for oxidative stress. He proposes that the oxidative stress in the tissues are pathways that reflect the psychological and organic stressors in the body and can be tracked, measured and therapeutically targeted.

What is the biology of the proper function of the depressive response?

Cell of Perkinje (cerebellum)

This is the question that Dr. Athina Markou and post-doctoral student Karen Wager-Smith postulated in their 2010 article on chronic depression in the September issue of Neuroscience and Behavioral Reviews. They observe that chronic depression is the adaptive, reparable neuro- biologic process gone wrong. It is a by-product of the body dealing with physical injury, pain, tissue repair and recovering from illness. Depression, they hypothesize, is triggered by a stress- induced injury to the brain. The injury they’re alluding to is their observation of an injury repair response including phases of neuro-inflammation and neuro-regeneration and the release of inflammatory mediators (“central” pro-inflammatory cytokines released by the microglia cells in the brain) which elicited “sickness behavior” and psychological pain in subjects. They noted that the injury was normally resolved through the neurotrophin and neurogenesis regeneration; however, the neuro-inflammation and the psychological pain was prone to chronicity. Why these are not resolved with the injury is unknown. Could be due to residual oxidative stress as Dr. Maes proposes? We can not neglect that there may also be an emotional root that precipitated the original “injury” to the brain. Could this be still unresolved even after neurotrophin and neurogenesis regeneration resolved the injury?

Negative mood states, stress, even antagonistic dispositions can activate periferal physiological pathways that modulate immune function. For example, a negative mood activates the hypothalamic-pituitary-adrenal (HPA) axis which initiates the peripheral release of cortisol which increases the activity of the sympathetic nervous system with lowered activity of the parasympathetic nervous system. I’m curious how studies such as these might influence treatment strategies for the affective and anhedonic symptoms of depressive behavior. Could depression be targeted through anti-inflammatory treatments (pharmacutical as well as herbs); regular administration of quality, bio-available antioxidants to ameliorate oxidative stress; meditation or simple relaxation?

***

Bibliography:

Messay, Berhane; Lim, Alvin; Marshal, L. Anna; “Current Understanding of the Bi-Directional Relationship of MAjor Depression with Inflammation”, Biology of Mood and Anxiety Disorders, 28, February, 2012

Markou, Athina Ph.D, Smith-Wager, Karen, “Chronic Depression--Adaptive, reparable Neurological Process Gone Wrong”, Neuroscience and Behavioral Reviews, September 2010.

Heydaya, J. Robert M.D., DFAPA, “Depression, Inflammation, Immunity and Infection”, Psychology Today, March 31, 2009

Between MAGIC and MEDICINE

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