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

Raison, C L; Miller, A H

ective host defense against pathogens. In humans, these responses are especially relevant during the first several years of life when infectious mortality was highest and adaptive immunity was not yet fully functional. Given these considerations, it is not surprising that the immune system alterations most frequently observed in MDD are proinflammatory in nature, and that the best characterized MDD risk alleles appear to generally produce a proinflammatory phenotype. However, we should not infer from this that any given depressogenic allele will uniformly increase innate immune function or enhance host defense against all microbes. Rather, what PATHOS-D suggests is that depressogenic allelesand the physiological processes they promote-can be understood as reflecting a summation of the most successful pathogen defense mechanisms against the wide array of pathogens encountered during human evolution, with all the imperfections and tradeoffs this has entailed. Moreover, knowing the effects of depressogenic alleles on outcomes following infection with specific pathogens may cast light on the relative importance of each pathogen for driving human evolution, because the high price imposed by depressogenic alleles mandates a compensatory high payoff in terms of pathogen defense. If confirmed in future studies, this perspective raises the intriguing possibility that gaining a better understanding of how genes promote MDD may significantly advance the field of immunology and that-conversely-a better understanding of the ongoing evolutionary 'arms race' between pathogens and their human hosts may suggest novel theoretical paradigms and treatment strategies for MDD.