We read with great interest the recent review by Chopra et al. Citation[1], in which the authors concluded that the pathogenesis of schizophrenia and major depression involved an altered peripheral immune system and kynurenine pathway. We appreciate this study and want to present an extended hypothesis regarding the relationship between the kynurenine pathway and antidepressant effects exerted by ketamine.
Recently, a number of studies have demonstrated that ketamine is potent enough to exert therapeutic effects for depression, especially for treatment-resistant depression Citation[2]. However, the relevant underlying mechanisms are still unclear. The kynurenine pathway mediates tryptophan metabolism, which is involved in depression and some other mood disorders. As we know, indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in mediating kynurenine metabolism. Furthermore, a previous study showed that proinflammatory cytokines could activate IDO, which causes tryptophan depletion, and ultimately results in depression Citation[3]. Additionally, our recent hypothesis suggests that ketamine exerts a fast-acting antidepressant effect potentially via the inhibition of proinflammatory cytokines; this was subsequently confirmed by others Citation[4]. So we suggest that ketamine may exert the antidepressant effects via suppressing the activation of IDO and indirectly increasing tryptophan.
Additionally, tryptophan 2,3-dioxygenase(TDO) plays a critical role in the tryptophan mechanism and in the pathogenesis of depression. Chronic stress may increase the levels of cortisol, whereas antidepressant agents could normalize it. Furthermore, the higher levels of cortisol may increase the activation of TDO, which may also cause tryptophan depletion and tend to induce depression Citation[5]. From this point, we suppose that ketamine could inhibit tryptophan depletion via inhibiting the activation of TDO. Thus, we propose a hypothesis that ketamine exerts antidepressant effects potentially via mediating the kynurenine pathway.
Declaration of interest
The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Bibliography
- Chopra K, Kumar B, Kuhad A. Pathobiological targets of depression. Expert Opin Ther Targets 2011;15:379-400
- Machado-Vieira R, Salvadore G, Diazgranados N, Zarate CA Jr. Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Ther 2009;123:143-50
- Christmas DM, Potokar J, Davies SJ. A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase. Neuropsychiatr Dis Treat 2011;7:431-9
- Yang JJ, Zhou ZQ, Yang C. Letter to the editor: does ketamine exert a fast-acting antidepressant effect via inhibition of pro-inflammatory cytokines? Psychol Med 2011;41:1787-9
- Laugeray A, Launay JM, Callebert J, Evidence for a key role of the peripheral kynurenine pathway in the modulation of anxiety- and depression-like behaviours in mice: focus on individual differences. Pharmacol Biochem Behav 2011;98:161-8