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Brief: Stress, Depression and Biomarkers of Allostatic Load

According to the Centers for Disease Control and Prevention (CDC), nearly 1 in 10 US adults report current depression. The severity and types of depression range from two days to two weeks to two years and from mild feelings of sadness to clinically defined major depression. Major depression is a serious illness and is more than a temporary feeling of sadness or loss. Major depression is more commonly diagnosed in women compared to men. The lifetime incidence of major depression is 20% in women and about half that observed in men. Depression increases with age as does the incidence of suicide; a leading cause of death in the US and the most common complication to depression. In the clinical setting, the presenting complaints of major depression are often somatic such as fatigue, headache, change in weight and abdominal problems. Having at least five of the following symptoms nearly every day for at least two weeks to the point of significant distress or impairment of function, defines the diagnosis of major depression:

The cause of major depression is multifactorial. Chronic health conditions have been associated with higher rates of depression (e.g.: obesity, neurological illness, autoimmune disease and chronic pain) including certain medications, abused substances, alcohol and low socioeconomic status. Genetic susceptibility also plays a contributing role; a family history of affective disorders or panic disorder puts one at a higher risk for major depression. Although it is believed that major depression may arise without any precipitating psychosocial stressors, stress and interpersonal losses with diminished social support and conflictual relationships certainly increase one’s risk. Significant losses and abuse experienced in early life, especially, may predispose one to major depression in the later years.

Psychological stress in itself induces the production of pro-inflammatory cytokines. Pro-inflammatory cytokines (i.e.: IL-1, IL-6, TNF-α, IFN-γ) are a known risk factor for major depression. Major depression is associated with both an increased production and concentration of these mediators, which have been found to effect tryptophan metabolism in the brain. Tryptophan is an essential amino acid involved in the synthesis of serotonin, our “piece of mind” neurotransmitter that is responsible for “filtering out” feelings of anxiousness, restlessness, impulsiveness, aggression and depression.

There are two pathways of tryptophan metabolism; the kynurenine and the serotonin pathways. The former is initiated by the enzyme indoleamine 2, 3-dioxygenase (IDO) which is induced by pro-inflammatory cytokines. The intermediates of this pathway include: the neuroprotective kynurenic acid (KYNA) in addition to the neurotoxic 3-hydroxykynurenine (3-OH KYN) and quinolinic acid (QUIN). Imbalances in the protective vs. degenerative kynurenine pathway metabolites (i.e.: increased QUIN/KYNA ratio) is thought to play an important role in neurodegenerative changes associated with chronic depression. In addition, activated IDO shifts the balance of these two pathways to favor the kynurenine pathway of tryptophan metabolism. This consequently deprives the serotonin pathway of its substrate. As a result, serotonin synthesis is reduced. This shortage or depletion of serotonin in the brain subsequently leads to depression.

The shift in the balance between the kynurenine and serotonin pathways of tryptophan metabolism is elicited by stress. Prolonged and/or repeated exposures to perceived stressful events, for example, from our living environment, work, relationships, and community, or health damaging behaviors, precedes the onset of major depression and increases our risk of age-related health problems and disability over time. In the short-term, exposure to stress evokes adaptive and protective actions by the hypothalamic-pituitary-adrenal axis (HPA), the autonomic nervous system (sympathetic and parasympathetic), cardiovascular and immune systems, with enhanced catecholamine, glucocorticoid, cytokine and serotonin turnover. Long-term effects though, from frequent and excessive cycles of response in these systems can result in overexposure to these mediators and cause damage to the organs of the body.

The term allostatic load is often used to describe the cumulative negative effects, or wear and tear, from physiologic stress over time. A classic example is seen in the price the body pays for overspending the adrenal glucocorticoid, cortisol. During times of stress, its short-term net effects are increased production and conservation of glucose. However, repeated HPA activity resulting in prolonged elevated blood cortisol levels leads to allostatic load with insulin resistance, abdominal obesity, atherosclerosis, and hypertension.

In practice, a variety of biomarkers are used by clinicians to measure allostatic load including the QUIN/KYNA ratio. Examples are waist-hip ratio, cardiovascular markers, glycoslyated hemoglobin, inflammatory markers, urinary serotonin and catecholamine metabolites, and assessment of anabolic vs. catabolic balance through a 24-hour urine hormone analysis.

Kynurenate and Quinolinate in addition to Serotonin and Catecholamine Metabolites are available through our Urinary Metabolic Profile (Organic Acids through Dip ’N Dry specimen collection). To view complete profile information please click here. To view Organic Acids in Central Energy Pathways including the Kynurenine and Serotonin Pathway please click here.

Anabolic (DHEA, Testosterone, Total 17-Ketosteroids) and Catabolic (Cortisol, Total 17-Hydroxysteroids) Steroids are available through our 24-hour Urinary Steroid Hormone Profile. To view complete profile information please click here.

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