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

Raison, C L; Miller, A H

Pathogen Host Defense and depression CL Raison and AH Miller allocation, conservation-withdrawal symptoms may have also proved adaptive by reducing interpersonal contact and thereby limiting infectious exposure. 25 Because ancestral humans typically lived in small coalitional groups of genetically related individuals, the logic of inclusive fitness suggests that social withdrawal might have been adaptive for an individual's genes by reducing the risk of infection in kin, even if such withdrawal limited the provision of much needed care from others and thus reduced individual survival. 354, 355 As would be predicted from this line of reasoning, acute exposure to an inflammatory mediator has been shown to induce feelings of social isolation/withdrawal in humans, 356 and increased neural sensitivity to social rejection (indexed by changes in activity in dorsal anterior cingulate and anterior insula cortices) is associated with increased inflammatory responses to psychosocial stress. 357 However, in addition to potential benefits related to kin selection, significant data demonstrate that viral infections promote aggressive immune responses to bacterial superinfections that can greatly increase mortality; 358-364 therefore, any decrement in survival from loss of social aid might have been more than offset by reduced risk of exposure to other pathogens while in a vulnerable state due to a pre-existing infection. Moreover, social withdrawal and reduced environmental exploration might also have promoted individual survival by limiting a sick person's contact with immunologically dissimilar out-group members who potentially harbored pathogens against which the sick person would have had reduced immunity compared with pathogens endemic in the home group. 354, 365 Hypervigilance Although withdrawal-conservation-type behavior is prominent in MDD, depressed individuals also often manifest metabolically expensive symptoms more consistent with behavioral activation, including anxiety/agitation and insomnia. [366] [367] [368] [369] [370] By siphoning energy away from immune activity, these symptoms would be expected to impair host defense and hence to argue against a PATHOS-D perspective. However, sickness behavior-although of benefit for surviving infection-carries its own survival and reproduction costs as a result of increased risk for predation and reduced ability to care for one's young, as well as potential loss of status in a social species and/or loss of breeding territory. 371 Therefore, evolutionary logic dictates that inflammatory processesespecially when chronic-might promote hypervigilant behavior that, while shunting energy away from fighting infection, would nonetheless serve adaptive purposes by protecting against environmental dangers engendered by sickness. In fact, significant data demonstrate that chronic cytokine activation reliably produces hypervigilant behaviors/ symptoms, including anxiety/agitation, insomnia and anger/irritability. 305, 353, 372 Neurobiological substrates for the mixture of withdrawal-conservation and behavioral activation/hypervigilance symptoms that is common to chronic inflammation/medical illness and MDD have been recently identified, including the effects of cytokines on both the basal ganglia (withdrawal-conservation) and the dorsal anterior cingulate cortex (hypervigilance) (Figure 1) . 303, 309, 357, [373] [374] [375] [376] Anorexia