Depression, Inflammation and Tryptophan Metabolism

From both a clinical and preclinical perspective, it has become widely accepted that inflammatory stimuli can initiate or accentuate symptoms of depression. With the development of drugs that alleviate depression, particularly those that putatively act via inhibition of serotonin reuptake in the brain, a link between tryptophan metabolism and depression became evident leading to the Monoamine/5-HT Theory of Depression. In this chapter, shifting tryptophan metabolism from serotonin synthesis to the generation of neuroactive metabolites, such as quinolinic acid and kynurenic acid, by the kynurenine pathway is now considered to play an important a role in the pathogenesis of inflammation-dependent depression. The balance between serotonergic and kynurenine pathways is controlled by expression of three rate-limiting enzymes within a class of dioxygenases that convert tryptophan to kynurenine: indolamine 2, 3 dioxygenase (IDO1), IDO2 and tryptophan 2, 3 dioxygenase (TDO2). Expression of these enzymes is tightly regulated by the innate immune system.