Malaise, melancholia and madness: the evolutionary legacy of an inflammatory bias.

Evolutionary imperatives bred a vigorous and highly orchestrated behavioral and immune response to the microbial world that served to promote species survival and propagation. The resultant legacy is an inflammatory bias which goes largely unchecked in the modern world and is provoked not only by pathogens but also now by people. In this commentary, the authors' contributions to the special issue on Inflammation and Mental Health are described, beginning with the origins of the inflammatory bias, its roots in genetic predispositions to behavioral adaptations and ultimately maladaptations, and its consequences on the developing brain. In addition, the mechanisms by which the immune system engages behavior are described including a central role for the inflammasome which may serve to link psychological stress with inflammatory and behavioral responses. Neurotransmitter systems that mediate effects of the immune system on behavior are also described along with interactions of the inflammatory bias with depression and their convergent impact on the response to stress and medical illness. Finally, translational implications are discussed including data from a clinical trial using a cytokine antagonist in depressed patients, which suggests an interaction of the inflammatory bias with other evolutionary legacies including those related to food consumption and their modern consequences of obesity and the metabolic syndrome. Taken together, the articles offer a sampling of the rich literature that has evolved regarding the role of the immune system in behavioral disorders. The grounding of this relationship in our evolutionary past may serve to inform future research both theoretically and therapeutically.