The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D)

Raison, C L; Miller, A H

If depressogenic alleles contribute to protection against pathogen invasion, the circumstances in which such invasion was likely or already a fait accompli should be especially potent activators of these genes, and hence especially likely to induce depression. Moreover, if these alleles heighten host defense in large part by increasing inflammation, inflammatory mediators released in response to environments rife with pathogen danger would be expected to induce depressive symptoms. These predictions are borne out by many studies demonstrating the depressogenic effects of inflammatory mediators, 10,162-173 as well as the remarkably diverse array of conditions that activate inflammatory processes and also increase the risk for depression. Psychosocial stress may be especially relevant in this regard. Stress is a universal and powerful risk for the development of depression both during development and adulthood. [222] [223] [224] [225] This squares nicely with social theories of depression, and at first glance appears to challenge host defense perspectives. But if we consider that the vast majority of stressors in mammals over evolutionary time boiled down to risks inherent in hunting, being hunted or fighting conspecifics in dominance hierarchies for reproductive access/status, it is not surprising that these states are also circumstances in which the risk of pathogen invasion-and subsequent death from infection-was greatly increased as a result of traumatic opening of the protective skin barrier from wounding. 226 Such wounding is common in social species and was a significant source of morbidity and mortality among humans in the ancestral environment, and indeed well into the historical period. [227] [228] [229] Given this, it is not surprising that-to quote Firdaus Dhabhar-'stress perception by the brain may serve as an early warning signal to activate the immune system in preparation for a markedly increased likelihood of subsequent infection'. 230 And although chronic stress is best known to suppress immune function, 231 the types of acute and/or psychosocial stressors most likely to be associated with immediate risk of wounding and hence infection activate both innate and adaptive immunity. [232] [233] [234] [235] [236] [237] [238] [239] [240] [241] [242] And while suppressing certain measures of adaptive immunity, chronic stress (whether experienced during childhood or as an adult) has been repeatedly associated with increased peripheral inflammatory biomarkers. 233, [243] [244] [245] [246] [247] [248] From a PATHOS-D perspective, then, psychosocial stress may increase the risk for depression, at least in part, because it activates host defense mechanisms that reliably induce depressive symptoms. In ancestral environments, the association between stress perception and risk of subsequent wounding was reliable enough that evolution, operating by the so-called 'smoke detector' principle, 249 favored organisms that prepotently activated inflammatory systems in response to a wide array of environmental threats and challenges (including psychosocial stressors), even if this activation was often in vain. This perspective provides a parsimonious explanation for why psychosocial stressors reliably induce depression, even though depressive reactions to stressors often appear so patently maladaptive. Across evolutionary time, the benefit that depressive symptoms (and their underlying physiology) conferred in terms of host defense in situation