Inflammation-induced depression: Evidence and mechanisms

      Anyone who has experienced a viral or bacterial infection knows very well the feelings of sickness, in the form of malaise, lassitude, fatigue, numbness, chills, muscle and joint aches, and reduced appetite. Because of the commonality of these symptoms, physicians tend to dismiss them as uncomfortable but essentially unhelpful components of the pathogen induced debilitation process with no benefit to the sufferer's wellbeing. This view has turned out to be incorrect. The psychological and behavioral components of sickness represent a highly organized strategy of the organism to fight infection. This strategy is referred to as sickness behavior. Sickness behavior is induced by activation of immune-to-brain communication pathways by the proinflammatory cytokines that are produced at the site of inflammation and it is usually reversible. However, when the peripheral immune responses is too intense or lasts too long, the behavioral response to cytokines can become maladaptive and culminate in an episode of decreased motivation, anergy and depression. The transition from sickness to depression is mediated by activation of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase (IDO), which is the first and rate-limiting enzyme of the kynurenine metabolic pathway. IDO activation was initially thought to lead to tryptophan starvation and decreased bioavailability of serotonin. However, this is not the case. IDO activation induces the formation of kynurenine that is transported into the brain where it is further metabolized into neurotoxic kynurenine metabolites including quinolinic acid. Quinolic acid acts as an agonist of brain NMDA receptors as demonstrated by the ability of ketamine to block and NBQX to restore inflammation-induced depression. Elucidation of the mechanisms of inflammation-induced depression reveals a wide array of new targets for the development of new antidepressant drugs.
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