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.
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.
Miura
Hideki
H
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. hmiura@med.nagoya-u.ac.jp
Ozaki
Norio
N
Sawada
Makoto
M
Isobe
Kenichi
K
Ohta
Tatsuro
T
Nagatsu
Toshiharu
T
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*
D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D016207:Cytokines; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan