Kynurenine pathway of tryptophan metabolism in pathophysiology and therapy of major depressive disorder

Abstract

Serotonin deficiency in major depressive disorder (MDD) has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan (Trp)-degrading enzyme, liver Trp 2,3-dioxygenase (TDO), by cortisol, leading to decreased Trp availability to the brain for serotonin synthesis. Subsequently, the serotonin deficiency was proposed to involve induction of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase (IDO) by proinflammatory cytokines, with inflammation being the underlying cause. Recent evidence, however, challenges this latter concept, as not all MDD patients are immune-activated and, when present, inflammation is mild and/or transient. A wide range of antidepressant drugs inhibit the activity of liver TDO and bind specifically to the enzyme, but not to IDO. IDO induction is not a major event in MDD, but, when it occurs, its metabolic consequences may be masked and overridden by upregulation of kynurenine monooxygenase (KMO), the gateway to production of modulators of immune and neuronal functions. KMO appears to be activated in MDD by certain proinflammatory cytokines and antidepressants with anti-inflammatory properties may block this activation. We demonstrate the ability of the antidepressant ketamine to dock (bind) to KMO. The pathophysiology of MDD may be underpinned by both the serotonin deficiency and glutamatergic activation mediated respectively by TDO induction and N-methyl-D-aspartate receptor activation. Inhibition of TDO and KMO should be the focus of MDD pharmacotherapy.

Research fronts and researchers of World Journal of Psychiatry in 2023: A visualization and analysis of mapping knowledge domains

“…Among them, the paper titled “Delivering substance use prevention interventions for adolescents in educational settings: A scoping review” by Liu et al [ 23 ] garnered the highest number of citations, with a total of 10 times. The following closely followed was “Kynurenine pathway of tryptophan metabolism in pathophysiology and therapy of major depressive disorder” by Badawy et al [ 24 ], cited three times.…”

Kynurenine pathway and suicidal ideation in treatment-resistant depression

“…Naghmeh Nikkheslat 1,2 , Maria Antonietta Nettis 1,2 and Valeria Mondelli 1,2 Badawy (2023) provided comments and interpretations of our recent findings on the interaction between kynurenine pathway, suicidal ideation and augmentation therapy with minocycline in patients with treatment-resistant depression. We thank the author for finding our study of interest due to having measured a range of kynurenine metabolites and for suggesting the use of available information to further enhance interpretation of the study findings and to provide crucial conclusions regarding Kynurenine pathway dysfunction in this population of treatment-resistant depressed patients.…”

“…have demonstrated that the KP dysfunction in treatment-resistant depression with suicidal ideation involves enhanced conversion of Kyn to neurotoxic QA at the expense of impaired formation of the neuroprotective KA. I suggest that KMO is likely to be activated and that its inhibition should be a therapeutic target in this subgroup of MDD patients, as has indeed been suggested for the entire MDD population (Badawy et al, 2023;Dawood et al, 2022). Of the wide array of cytokines measured, focused on three that correlated with KP parameters, but have not stated if levels of other cytokines were elevated.…”

Optimizing Treatment for Major Depressive Disorder in Adolescents: The Impact of Intradermal Acupuncture - A Randomized Controlled Trial Protocol

“…Additionally, this occurrence is linked to the activation of N-methyl-D-aspartate receptors. 13–15 Anhedonia, loss of motivation, energy, and attention, which are fundamental symptoms of MDD, have been associated with dysfunction in the DA system. 16 Changes in DA function are likely responsible for altered neural response to rewards and decision-making behavior in rewarded conditions.…”