title: 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.
abstract: 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.
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. hmiura@med.nagoya-u.ac.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Miura
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Sawada
authors.forename: Kenichi
authors.initials: K
authors.lastname: Isobe
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ohta
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nagatsu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D003863:Depression / Q000276:immunology / Q000503:physiopathology*; D003865:Major Depressive Disorder / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007737:Kynurenine / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism*; D013315:Stress, Psychological / Q000276:immunology / Q000503:physiopathology*; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D016207:Cytokines; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan