Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 42 (1), 5-27

Pathogen-Host Defense in the Evolution of Depression: Insights Into Epidemiology, Genetics, Bioregional Differences and Female Preponderance


Pathogen-Host Defense in the Evolution of Depression: Insights Into Epidemiology, Genetics, Bioregional Differences and Female Preponderance

Charles L Raison et al. Neuropsychopharmacology.


Significant attention has been paid to the potential adaptive value of depression as it relates to interactions with people in the social world. However, in this review, we outline the rationale of why certain features of depression including its environmental and genetic risk factors, its association with the acute phase response and its age of onset and female preponderance appear to have evolved from human interactions with pathogens in the microbial world. Approaching the relationship between inflammation and depression from this evolutionary perspective yields a number of insights that may reveal important clues regarding the origin and epidemiology of the disorder as well as the persistence of its risk alleles in the modern human genome.


Figure 1
Figure 1
Man meets microbes. In ancestral environments, heavy pathogen loads applied significant evolutionary pressure on human survival that ultimately entailed a host of adaptations that, according to the pathogen–host theory of depression, shaped interactions between the immune system (inflammation in particular) and the brain, leading to a unique set of behaviors. These behaviors, including anhedonia, fatigue, and psychomotor slowing as well as anxiety, arousal and alarm supported energy conservation for fighting infection and wound healing and hypervigilance to prevent future attack. In addition, these evolutionary forces instantiated a coupling of these behavioral responses with the acute phase response including not only increases in acute phase reactants such as c-reactive protein but also hypoferremia and zinc deficiency, as well as fever, which are better suited for interactions with pathogens than people. In addition, evolutionary pressures from human interactions with the microbial world can explain risk alleles that are specific to the pathogens to which given populations were exposed as well as epidemiologic features of depression such as female sex preponderance, an early age of onset, and occurrence in the postpartum period that supported reproductive success. Finally, the pathogen–host theory of depression is consistent with modern risk factors for depressive symptoms, including obesity, processed-food-based diets, sedentary lifestyle, and sleep deprivation, all of which serve to exacerbate the inflammatory bias that is the legacy of our evolutionary past.

Similar articles

See all similar articles

Cited by 9 PubMed Central articles

See all "Cited by" articles