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

C L Raison, A H Miller, C L Raison, A H Miller

Abstract

Given the manifold ways that depression impairs Darwinian fitness, the persistence in the human genome of risk alleles for the disorder remains a much debated mystery. Evolutionary theories that view depressive symptoms as adaptive fail to provide parsimonious explanations for why even mild depressive symptoms impair fitness-relevant social functioning, whereas theories that suggest that depression is maladaptive fail to account for the high prevalence of depression risk alleles in human populations. These limitations warrant novel explanations for the origin and persistence of depression risk alleles. Accordingly, studies on risk alleles for depression were identified using PubMed and Ovid MEDLINE to examine data supporting the hypothesis that risk alleles for depression originated and have been retained in the human genome because these alleles promote pathogen host defense, which includes an integrated suite of immunological and behavioral responses to infection. Depression risk alleles identified by both candidate gene and genome-wide association study (GWAS) methodologies were found to be regularly associated with immune responses to infection that were likely to enhance survival in the ancestral environment. Moreover, data support the role of specific depressive symptoms in pathogen host defense including hyperthermia, reduced bodily iron stores, conservation/withdrawal behavior, hypervigilance and anorexia. By shifting the adaptive context of depression risk alleles from relations with conspecifics to relations with the microbial world, the Pathogen Host Defense (PATHOS-D) hypothesis provides a novel explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates that bespeak an adaptive function.

Conflict of interest statement

The authors declare no conflict of interest. Charles L Raison serves as a consultant for Pamlab, Biolex Therapeutics and Bristol Myers Squibb. Andrew H Miller has served as a consultant for Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Lundbeck Research USA, F. Hoffmann-La Roche, Schering-Plough Research Institute and Wyeth/Pfizer and has received research support from Centocor, GlaxoSmithKline and Schering-Plough Research Institute.

Figures

Figure 1
Figure 1
The integrated suite of immunological and behavioral responses to infection and wounding that comprise pathogen host defense. Upon encountering a pathogen or cellular debris from tissue damage or destruction, the body reacts with an orchestrated local and systemic response that recruits both immunological and nervous system elements. The response is initiated by interaction of pathogens and/or cellular debris with pattern recognition receptors such as Toll-like receptors on relevant immune cells including macrophages that in turn are linked to inflammatory signaling pathways such as nuclear factor-κB (NF-κB), a lynchpin transcription factor in the host defense cascade. Release of cytokines (including tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6 and interferon-α (IFN-α)) and chemokines as well as the induction of adhesion molecules attracts and activates cells such as T cells at the site of infection/wounding, leading to the cardinal signs of inflammation (redness, heat, swelling and pain) and ultimately promoting local pathogen elimination and wound healing. Cytokines and cells in the peripheral circulation mediate the systemic host response that engages neurocircuits in the brain that mediate hypervigilance (dorsal anterior cingulate cortex (dACC)) to avoid further wounding and pathogen exposure and conservation/withdrawal (basal ganglia), which promotes the shunting of energy resources to pathogen elimination and wound healing. PowerPoint slide

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