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

Raison, C L; Miller, A H

On the other hand, findings from patients undergoing treatment with IFN-a suggest a more inclusive scenario for the role of pathogen defense in the evolution/persistence of depressogenic alleles. Specifically, although standardized dosages of IFN-a are employed, a wide range of behavioral responses are observed during treatment, from mild neurovegetative/sickness symptoms, such as fatigue, to completed suicide in response to catastrophic major depression. Individuals who develop significant depressive symptoms evince changes in CNS and neuroendocrine functioning that are also observed in idiopathic MDD, [305] [306] [307] [308] [309] [310] but that are not observed to a significant degree in patients on IFN-a who do not develop depression. These findings raise the possibility that depression reflects a state of immune response element amplification, such that for any given amount of inflammatory input, depressed individuals react with enhanced downstream CNS/neuroendocrine activity. If so, depressogenic alleles that do not promote an increase in inflammatory biomarkers may nonetheless have undergone positive selection because they enhanced host pathogen defense via sensitization of downstream CNS/neuroendocrine pathways that themselves promote survival during infection. Some evidence for this hypothesis comes from the finding, noted above, that individuals who develop depression during IFN-a manifest enhanced sickness behavior at the start of treatment, which may aid in acutely clearing pathogens from the body during infection. 302 Moreover, a clear prediction of PATHOS-D theory is that changes in CNS/neuroendocrine function that typically accompany MDD should enhance survival in the context of acute infection. To date, few data support this possibility, although it is intriguing to note that glucocorticoid resistance, which is common in MDD 392 and is associated with the development of depressive symptoms during IFN-a treatment (Raison et al., unpublished observations), has been associated with improved T-cell function in HIV infection, 393 and that enrichment paradigms known to enhance glucocorticoid sensitivity in animal models increase mortality in response to Escherichia coli infection. 394 These two possibilities (that is, distinct additive social and immunological risks vs inflammatory mediation of social risk) might be genetically discriminated based on their contrasting implications for the functional relationship between social-environmental precipitants and immune-related genetic risks for MDD. In the former model, one would expect to find largely additive effects of social risk factors and immune-related genetic risk alleles, whereas the meditational model would suggest a product-term interaction (that is, a social stimulus shows larger depressogenic 'gain' in the context of a sensitizing genotype). This approach could be extended to use an instrumental variables analysis (for example, a Mendelian randomization study) to determine whether inflammatory signals function as mediators of, moderators of, or functionally independent additional additive influences with respect to, social precipitants of MDD.