A Link Between Stress and Depression: Shifts in the Balance Between the Kynurenine and Serotonin Pathways of Tryptophan Metabolism and the Etiology and Pathophysiology of Depression

Stress. 2008 May;11(3):198-209. doi: 10.1080/10253890701754068.


Alteration of tryptophan (TRP) metabolism elicited by proinflammatory cytokines has gained attention as a new concept to explain the etiological and pathophysiological mechanisms of major depression. The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is the main TRP metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. Proinflammatory cytokines induce IDO under stress, promote the KYN pathway, deprive the 5-HT pathway of TRP, and reduce 5-HT synthesis. The resultant decrease in 5-HT production may relate to the monoamine hypothesis of major depression. Furthermore, metabolites of the KYN pathway have neurotoxic/neuroprotective activities; 3-hydroxykynurenine and quinolinic acid are neurotoxic, whereas kynurenic acid is neuroprotective. The hippocampal atrophy that appears in chronic depression may be associated with imbalances in neurotoxic/neuroprotective activities. Because proinflammatory cytokines also activate the hypothalamo-pituitary-adrenal (HPA) axis, these imbalances may inhibit the hippocampal negative feedback system. Thus, changes in the TRP metabolism may also relate to the HPA axis-hyperactivity hypothesis of major depression. In this article, we review the changes in TRP metabolism by proinflammatory cytokines under stress, which is assumed to be a risk factor for major depression, and the relationship between physiological risk factors for major depression and proinflammatory cytokines.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Biogenic Monoamines / metabolism
  • Brain / metabolism*
  • Cytokines / biosynthesis
  • Depression / immunology
  • Depression / physiopathology*
  • Depressive Disorder, Major / metabolism
  • Humans
  • Hypothalamo-Hypophyseal System / physiopathology
  • Kynurenine / metabolism*
  • Metabolic Networks and Pathways
  • Models, Biological
  • Pituitary-Adrenal System / physiopathology
  • Serotonin / metabolism*
  • Stress, Psychological / immunology
  • Stress, Psychological / physiopathology*
  • Tryptophan / metabolism*


  • Antidepressive Agents
  • Biogenic Monoamines
  • Cytokines
  • Serotonin
  • Kynurenine
  • Tryptophan