Role of Kynurenine Metabolism Pathway Activation in Major Depressive Disorders

A proportion of depressed individuals show evidence of inflammation. Both animal, quasi-experimental, and longitudinal studies indicate that inflammatory processes may play a causal role in the developmental of depressive illness. While there may be multiple causal pathways through which inflammatory processes affect mood, activation of the kynurenine pathway is essential for the development of depression-like behavior in rodents. Studies of hepatitis C or cancer patients receiving treatment with inflammation-inducing medications show increased activation of the kynurenine pathway and decreased levels of tryptophan that correlate with inflammation-induced depression. Further, this treatment has been shown to lead to increased production of neurotoxic kynurenine pathway metabolites such as quinolinic acid (QA). Similarly, in non-medically ill patients with major depression, multiple studies have found activation of the kynurenine pathway and/or preferential activation of the neurotoxic (QA) pathway at the expense of the production of the NMDA antagonist, kynurenic acid. Initially, activation of the kynurenine pathway was believed to precipitate depressive symptoms by depleting brain serotonin, however, the weight of the evidence now suggests that an imbalance between neurotoxic and neuroprotective metabolites may be the principal driver of depression; conceivably via its effects on glutamatergic neurotransmission.