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

Raison, C L; Miller, A H

Although once viewed as a maladaptive consequence of immune activation, 311 several decades of research have produced a consensus that sickness behavior is an adaptive central motivational state evolved to promote survival and necessitated to a large degree by the metabolic costs of mounting a fever. 163, 169, [311] [312] [313] [314] Fever, in turn, has been shown to enhance resistance to both viral and bacterial pathogens, over and above other antipathogen effects of the inflammatory mechanisms by which fever is induced. In addition to retarding pathogen replication/spread, [315] [316] [317] [318] febrile range temperatures have multiple stimulatory effects on the immune system relevant to host defense. [319] [320] [321] [322] [323] [324] [325] Because these effects are enhanced in conditions of low iron availability, it should not be surprising that in addition to causing fever, inflammatory cytokines deplete bodily iron stores. 326 Nor should it be surprising that sickness is associated with hypoferremia, 327,328 which-after fever-is probably the feature of sickness that has been best established as of adaptive value. [329] [330] [331] For example, low bodily iron stores protect against infection in children in the developing world, 332 and multiple studies suggest that iron supplementation worsens an array of infection-related health outcomes and increases infectious mortality. [333] [334] [335] [336] [337] If depressive symptoms aid in pathogen defense and if fever and hypoferremia are important in this regard, one would expect that MDD should be associated with elevated body temperature and reduced bodily iron stores, even in individuals with no evidence of an infectious process. In this regard, it is surprising, given the centrality of fever to the adaptive function of sickness behavior, 163, 169, 315 that so little attention has been paid to the fact that MDD appears to be reliably characterized by an elevation in body temperature into the range known to be maximally protective in the context of infection. [338] [339] [340] [341] [342] [343] [344] [345] As with elevated body temperature, a number of studies have reported that depressive symptoms are associated with reductions in various measures of bodily iron stores. [346] [347] [348] [349] [350] Because fever and hypoferremia are central to the adaptive purposes of sickness, their presence in depression is mandated from a PATHOS-D perspective, and their absence would strongly argue against the validity of this approach. On the other hand, their presence in depression is not parsimoniously explained by theories that focus on potential social benefits of depression. Similarly, if depression is simply a nonadaptive phenomenon, why would such ancient, highly conserved and highly complex physiological responses be a hallmark of the disorder?