Kynurenine pathway dysregulation in major depressive disorder: the convergence of excitotoxicity, neuroinflammation, and oxidative stress

Major depressive disorder (MDD) has traditionally been linked to deficient serotonergic neurotransmission, chronic stress, and heightened inflammation. Compelling evidence implicates the kynurenine pathway (KP), activated by inflammatory cytokines and stress-related signals, as a critical mediator connecting these factors. The KP degrades tryptophan, the metabolic precursor of serotonin, into neuroactive metabolites called kynurenines, such as quinolinic acid and kynurenic acid. Patients with MDD exhibit KP dysregulation, often marked by an overproduction of quinolinic acid, an N-Methyl-D-aspartic acid receptor (NMDAR) agonist that drives excitotoxicity, alongside reduced production of kynurenic acid, an NMDAR antagonist that protects from excitotoxicity and has anti-inflammatory effects. This review examines dysregulation of the KP in MDD, emphasizing KP metabolites – particularly quinolinic acid and kynurenic acid – as biomarkers and mediators of excitotoxicity, neuroinflammation, and oxidative stress, and discusses the therapeutic efficacy of antidepressants that modulate this pathway. Understanding KP dysregulation could inform the development of targeted interventions that address the underlying biological drivers of MDD, offering new hope for patients who do not respond to conventional treatments.