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

Raison, C L; Miller, A H

Major depression is so detrimental to survival and reproduction that it is hard to understand why allelic variants that promote the disorder have not been culled from the human genome, why in fact-far from being culled-genes that promote depression are so common and numerous and appear to have actually increased in prevalence during recent human evolution. 1 To address this issue, we have developed a novel theoretical framework positing that risk alleles for depression originated and have been largely retained in the human genome because these alleles encode for an integrated suite of immunological and behavioral responses that promote host defense against pathogens. This enhanced pathogen defense is accomplished primarily via heightened innate immune system activation, which results in reduced death from infectious causes, 2-5 especially in infancy when selection pressure from infection is strongest, 6 and the adaptive immune system is not yet fully operational. [6] [7] [8] [9] A vast literature has associated depressive symptoms and/or major depressive disorder (MDD) with increased innate immune inflammatory responses, 10 with meta-analyses reporting the most consistent findings for increased plasma concentrations of tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), C-reactive protein and haptoglobin. [11] [12] [13] Recent longitudinal studies extend these cross-sectional observations by reporting that increased inflammatory markers in nondepressed individuals predict the later development of depression. [14] [15] [16] Because infection has been the primary cause of early mortality and hence reproductive failure across human evolution, 9, [17] [18] [19] [20] [21] it would be expected that if depressive symptoms were an integral part of a heightened immunological response, allelic variants that support this response would have undergone strong positive selection pressure and thus would be both numerous and prevalent, as they appear to be. However, because the survival benefits of inflammatory processes are tempered by their costs in terms of increased mortality from septic shock, 22, 23 pathogen manipulation, 21, 24 long-term tissue damage and chronic disease, 10 these alleles would not be predicted to go to fixation (that is, 100% prevalence) but would be expected to manifest an intermediate prevalence reflecting the benefit of enhanced host defense in any given environment minus attendant costs. Again, this is consistent with current findings in the genetics of depression.