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

Raison, C L; Miller, A H

Microbial activation of the mammalian inflammatory response produces a highly regulated suite of symptoms known as sickness behavior that bears a striking resemblance to behavioral changes induced by stress in laboratory animals, as well as to the symptoms of MDD in humans. 10, [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] Many of these symptoms can be ameliorated by antidepressants in animal models, [291] [292] [293] [294] [295] further suggesting that cytokineinduced behavioral changes are either closely aligned with, or identical to, MDD in humans. Studies report that 20-70% of patients undergoing chronic immune activation as a result of treatment with the cytokine IFN-a meet symptom criteria for MDD, providing additional evidence in this regard. 164, 296 Moreover, IFN-a-induced depression shares symptom homology with idiopathic MDD, 297 and responds to treatment with antidepressants. 164, [298] [299] [300] [301] In addition to a remarkable symptom overlap, sickness and depression during cytokine exposure also appear to be causally linked, given the strong association between sickness in the first week of treatment with IFN-a and the development of cognitive/emotional symptoms of depression over the ensuing 6 months of therapy. 302 Finally, peripheral inflammatory activation induces many-if not all-of the most replicated CNS and neuroendocrine abnormalities observed in MDD (Figure 1 ). [303] [304] [305] [306] [307] [308] [309] [310] The PATHOS-D theory asserts that depressogenic alleles are common not because depression is adaptive in managing social negotiations, but because these alleles promote symptoms and behaviors that decreased mortality from infectious causes across mammalian evolution. However, from an evolutionary perspective, there is no a priori reason why these antipathogen effects should overlap with the depressogenic effects of these risk alleles. That they do so is powerful evidence, we would suggest, for the primacy of immune defense in the pathogenesis of depression, regardless of the environmental adversity that initiates the disorder in individual cases. In keeping with this perspective is the possibility that some of the symptoms of depression promote survival in response to infection.