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

Raison, C L; Miller, A H

Thus far, we have focused on the possibility that risk alleles promote depressive symptoms primarily as a result of increasing activity in inflammatory and/or immune-relevant downstream physiological pathways (that is, gene-immune effects-depression). However, many of the associations cited in this review could be equally well accounted for by the hypothesis that alleles directly influence CNS functioning to increase MDD risk, and that MDD subsequently affects immune function (that is, genedepression-immune effects). This possibility is especially likely for genes such as NPY, which we have described in immune terms, but that also has well-documented effects on CNS functioning relevant to depression. In addition to downstream immune effects, such genes may also have enhanced host defense in ancestral environments by promoting behavioral patterns likely to reduce the risk of becoming infected, spreading infection to kin or of dying once an infection had commenced. 395, 396 Just such effects have been proposed for the short allele of the serotonin transporter, which has been associated with collectivistic social behavior relevant to host defense. 104 Immune changes associated with MDD are not only specific but also occur in other severe mental disorders, including bipolar disorder and schizophrenia. Although the high prevalence of depression in these conditions is consistent with a PATHOS-D perspective, it is hard to imagine that other behavioral states associated with these diseases, including mania and psychosis, are adaptive for pathogen host defense. Indeed, the impaired decision-making characteristic of both states and the social isolation/ reduced access to resources that is common in psychosis would be expected to increase vulnerability to pathogen exposure. Given overlapping genetic risk factors for these conditions and MDD, it is possible that they are best understood as purely maladaptive states supported at relatively low levels in the human population, at least in part, because their genetic antecedents enhanced host defense in carriers of immune-relevant risk alleles who responded to infectious challenges with enhanced immune activation and sickness behavior/depression without developing the full disease phenotype. Another possibility is that very severe disorders such as bipolar disorder and schizophrenia have been maintained in the human genome because immune benefits accrued to afflicted individuals that counteracted the fitnessreducing behavioral profiles (including increased risk of infection) associated with these diseases. This scenario would suggest that immune changes seen in schizophrenia and bipolar disorder should be more robust than those seen in depression, because they would have to be large enough to offset behavioral costs not present in depression. Although not entirely consistent, 397 some data support this possibility. [398] [399] [400] Summary By shifting the adaptive context of depressogenic alleles from any purported benefit of depressive symptoms on relations with conspecifics to the potential benefits of sickness behavior (and its attendant physiology) on relations with the microbial world, the PATHOS-D hypothesis provides a straightforward explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates suggesting an adaptive function. Across vertebrate evolution, innate immune inflammatory responses were essential for eff