Role of the kynurenine metabolism pathway in inflammation-induced depression: Preclinical approaches

Physically ill patients with chronic inflammation often present with symptoms of depression. Our understanding of the pathophysiology of inflammation-associated depression has benefited from preclinical studies on the mechanisms of sickness and clinical studies on the symptoms of sickness and depression that develop in patients treated with immunotherapy. Sickness behavior develops when the immune system is activated by pathogen- or damage-associated molecular patterns. It is a normal biological response to infection and cell injury. It helps the organism to mobilize its immune and metabolic defenses to fight the danger. Depression emerges on the background of sickness when the inflammatory response is too intense and long lasting or the resolution process is deficient. The transition from sickness to depression is mediated by activation of the kynurenine metabolism pathway that leads to the formation of neurotoxic kynurenine metabolites including quinolinic acid, an agonist of N-methyl-D-aspartate receptors. The neuroimmune processes and molecular factors that have been identified in the studies of inflammation-associated depression represent potential new targets for the development of innovative therapies for the treatment of major depressive disorders.