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Inflammation-Associated Depression: Evidence, Mechanisms and Implications pp 249–267Cite as

Role of Kynurenine Metabolism Pathway Activation in Major Depressive Disorders

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Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 31))

Abstract

A proportion of depressed individuals show evidence of inflammation. Both animal, quasi-experimental, and longitudinal studies indicate that inflammatory processes may play a causal role in the developmental of depressive illness. While there may be multiple causal pathways through which inflammatory processes affect mood, activation of the kynurenine pathway is essential for the development of depression-like behavior in rodents. Studies of hepatitis C or cancer patients receiving treatment with inflammation-inducing medications show increased activation of the kynurenine pathway and decreased levels of tryptophan that correlate with inflammation-induced depression. Further, this treatment has been shown to lead to increased production of neurotoxic kynurenine pathway metabolites such as quinolinic acid (QA). Similarly, in non-medically ill patients with major depression, multiple studies have found activation of the kynurenine pathway and/or preferential activation of the neurotoxic (QA) pathway at the expense of the production of the NMDA antagonist, kynurenic acid. Initially, activation of the kynurenine pathway was believed to precipitate depressive symptoms by depleting brain serotonin, however, the weight of the evidence now suggests that an imbalance between neurotoxic and neuroprotective metabolites may be the principal driver of depression; conceivably via its effects on glutamatergic neurotransmission.

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Notes

  1. 1.

    A second isoform of IDO, IDO 2 also exists but less is known about its function. Further, the enzyme, tryptophan-2,3-dioxygenase (TDO) which is produced in the liver, also catalyzes the conversion of tryptophan to kynurenine but is induced by tryptophan and glucocorticoids.

References

  1. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU (2012) Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res 21:169–184. doi:10.1002/mpr.1359

    Article  PubMed  PubMed Central  Google Scholar 

  2. Global Burden of Disease Study C (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386:743–800. doi:10.1016/S0140-6736(15)60692-4

    Article  Google Scholar 

  3. Bostwick JM, Pankratz VS (2000) Affective disorders and suicide risk: a reexamination. Am J Psychiatry 157:1925–1932. doi:10.1176/appi.ajp.157.12.1925

    Article  CAS  PubMed  Google Scholar 

  4. Zivin K, Yosef M, Miller EM, Valenstein M, Duffy S, Kales HC, Vijan S, Kim HM (2015) Associations between depression and all-cause and cause-specific risk of death: a retrospective cohort study in the Veterans Health Administration. J Psychosom Res 78:324–331. doi:10.1016/j.jpsychores.2015.01.014

    Article  PubMed  Google Scholar 

  5. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC (2015) The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry 76:155–162. doi:10.4088/JCP.14m09298

    Article  PubMed  Google Scholar 

  6. Thase ME, Entsuah AR, Rudolph RL (2001) Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 178:234–241

    Article  CAS  PubMed  Google Scholar 

  7. Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35:298–306

    Article  CAS  PubMed  Google Scholar 

  8. Maes M, Smith R, Scharpe S (1995) The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinology 20:111–116

    Article  CAS  PubMed  Google Scholar 

  9. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–457

    Article  CAS  PubMed  Google Scholar 

  10. Howren MB, Lamkin DM, Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71:171–186

    Article  CAS  PubMed  Google Scholar 

  11. Dargel AA, Godin O, Kapczinski F, Kupfer DJ, Leboyer M (2015) C-reactive protein alterations in bipolar disorder: a meta-analysis. J Clin Psychiatry 76:142–150. doi:10.4088/JCP.14r09007

    Article  PubMed  Google Scholar 

  12. Modabbernia A, Taslimi S, Brietzke E, Ashrafi M (2013) Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 74:15–25. doi:10.1016/j.biopsych.2013.01.007

    Article  CAS  PubMed  Google Scholar 

  13. Munkholm K, Brauner JV, Kessing LV, Vinberg M (2013) Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res 47:1119–1133. doi:10.1016/j.jpsychires.2013.05.018

    Article  PubMed  Google Scholar 

  14. Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, de Ridder D, Kupka RW, Nolen WA, Drexhage HA (2008) A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry 65:395–407

    Article  CAS  PubMed  Google Scholar 

  15. Savitz J, Frank MB, Victor T, Bebak M, Marino JH, Bellgowan PS, McKinney BA, Bodurka J, Kent Teague T, Drevets WC (2013) Inflammation and neurological disease-related genes are differentially expressed in depressed patients with mood disorders and correlate with morphometric and functional imaging abnormalities. Brain Behav Immun 31:161–171. doi:10.1016/j.bbi.2012.10.007

    Article  CAS  PubMed  Google Scholar 

  16. Hannestad J, DellaGioia N, Bloch M (2011) The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36:2452–2459. doi:10.1038/npp.2011.132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dalton EJ, Heinrichs RW (2005) Depression in multiple sclerosis: a quantitative review of the evidence. Neuropsychology 19:152–158. doi:10.1037/0894-4105.19.2.152

    Article  PubMed  Google Scholar 

  18. Nouwen A, Winkley K, Twisk J, Lloyd CE, Peyrot M, Ismail K, Pouwer F (2010) Type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis. Diabetologia. doi:10.1007/s00125-010-1874-x

    PubMed  PubMed Central  Google Scholar 

  19. Van der Kooy K, van Hout H, Marwijk H, Marten H, Stehouwer C, Beekman A (2007) Depression and the risk for cardiovascular diseases: systematic review and meta analysis. Int J Geriatr Psychiatry 22:613–626. doi:10.1002/gps.1723

    Article  PubMed  Google Scholar 

  20. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70:31–41. doi:10.1001/2013.jamapsychiatry.4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Savitz J, Preskorn S, Teague TK, Drevets D, Yates W, Drevets W (2012) Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial. BMJ Open 2, e000643. doi:10.1136/bmjopen-2011-000643

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kent S, Bluthe RM, Kelley KW, Dantzer R (1992) Sickness behavior as a new target for drug development. Trends Pharmacol Sci 13:24–28

    Article  CAS  PubMed  Google Scholar 

  24. Yirmiya R (1996) Endotoxin produces a depressive-like episode in rats. Brain Res 711:163–174

    Article  CAS  PubMed  Google Scholar 

  25. Bonaccorso S, Puzella A, Marino V, Pasquini M, Biondi M, Artini M, Almerighi C, Levrero M, Egyed B, Bosmans E, Meltzer HY, Maes M (2001) Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. Psychiatry Res 105:45–55

    Article  CAS  PubMed  Google Scholar 

  26. Capuron L, Hauser P, Hinze-Selch D, Miller AH, Neveu PJ (2002) Treatment of cytokine-induced depression. Brain Behav Immun 16:575–580

    Article  CAS  PubMed  Google Scholar 

  27. Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH (2003) Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry 160:1342–1345

    Article  PubMed  Google Scholar 

  28. Wichers M, Maes M (2002) The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol 5:375–388

    Article  CAS  PubMed  Google Scholar 

  29. Capuron L, Miller AH (2004) Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 56:819–824. doi:10.1016/j.biopsych.2004.02.009

    Article  CAS  PubMed  Google Scholar 

  30. Capuron L, Miller AH (2011) Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 130:226–238. doi:10.1016/j.pharmthera.2011.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR (2010) Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 68:748–754. doi:10.1016/j.biopsych.2010.06.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hannestad J, Subramanyam K, Dellagioia N, Planeta-Wilson B, Weinzimmer D, Pittman B, Carson RE (2012) Glucose metabolism in the insula and cingulate is affected by systemic inflammation in humans. J Nucl Med 53:601–607. doi:10.2967/jnumed.111.097014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD (2009) Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 66:407–414. doi:10.1016/j.biopsych.2009.03.015

    Article  PubMed  PubMed Central  Google Scholar 

  34. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB (2014) Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.1332

    PubMed  PubMed Central  Google Scholar 

  35. Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA, Schneider HG, Leonard BE, Berk M (2010) Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry 197:372–377. doi:10.1192/bjp.bp.109.076430

    Article  PubMed  Google Scholar 

  36. Wium-Andersen MK, Orsted DD, Nordestgaard BG (2015) Elevated C-reactive protein and late-onset bipolar disorder in 78,809 individuals from the general population. Br J Psychiatry. doi:10.1192/bjp.bp.114.150870

    PubMed  Google Scholar 

  37. Pandey GN, Rizavi HS, Ren X, Fareed J, Hoppensteadt DA, Roberts RC, Conley RR, Dwivedi Y (2012) Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J Psychiatr Res 46:57–63. doi:10.1016/j.jpsychires.2011.08.006

    Article  PubMed  Google Scholar 

  38. Pandey GN, Rizavi HS, Ren X, Bhaumik R, Dwivedi Y (2014) Toll-like receptors in the depressed and suicide brain. J Psychiatr Res 53:62–68. doi:10.1016/j.jpsychires.2014.01.021

    Article  PubMed  PubMed Central  Google Scholar 

  39. Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, Bernstein HG, Bogerts B (2008) Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res 42:151–157

    Article  PubMed  Google Scholar 

  40. Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N (2014) Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun 42:50–59. doi:10.1016/j.bbi.2014.05.007

    Article  CAS  PubMed  Google Scholar 

  41. Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229. doi:10.1016/j.neuroscience.2013.04.060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Miller AH, Raison CL (2015) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16:22–34. doi:10.1038/nri.2015.5

    Article  CAS  Google Scholar 

  43. Lawson MA, Parrott JM, McCusker RH, Dantzer R, Kelley KW, O’Connor JC (2013) Intracerebroventricular administration of lipopolysaccharide induces indoleamine-2,3-dioxygenase-dependent depression-like behaviors. J Neuroinflammation 10:87. doi:10.1186/1742-2094-10-87

    CAS  PubMed  PubMed Central  Google Scholar 

  44. O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14:511–522. doi:10.1038/sj.mp.4002148

    Article  PubMed  CAS  Google Scholar 

  45. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13:465–477. doi:10.1038/nrn3257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Guillemin GJ (2012) Quinolinic acid, the inescapable neurotoxin. FEBS J 279:1356–1365. doi:10.1111/j.1742-4658.2012.08485.x

    Article  CAS  PubMed  Google Scholar 

  47. Kim H, Chen L, Lim G, Sung B, Wang S, McCabe MF, Rusanescu G, Yang L, Tian Y, Mao J (2012) Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest 122:2940–2954. doi:10.1172/JCI61884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Maes M, Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, Almerighi C, Meltzer H (2001) Treatment with interferon-alpha (IFN alpha) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFN alpha-induced depressive and anxiety symptoms and immune activation. Mol Psychiatry 6:475–480. doi:10.1038/sj.mp.4000872

    Article  CAS  PubMed  Google Scholar 

  49. Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R (2002) Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7:468–473. doi:10.1038/sj.mp.4000995

    Article  CAS  PubMed  Google Scholar 

  50. Botwinick IC, Pursell L, Yu G, Cooper T, Mann JJ, Chabot JA (2014) A biological basis for depression in pancreatic cancer. HPB (Oxford) 16:740–743. doi:10.1111/hpb.12201

    Article  Google Scholar 

  51. Martinez P, Tsai AC, Muzoora C, Kembabazi A, Weiser SD, Huang Y, Haberer JE, Martin JN, Bangsberg DR, Hunt PW (2014) Reversal of the kynurenine pathway of tryptophan catabolism may improve depression in ART-treated HIV-infected Ugandans. J Acquir Immune Defic Syndr 65:456–462. doi:10.1097/QAI.0000000000000062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Nikkheslat N, Zunszain PA, Horowitz MA, Barbosa IG, Parker JA, Myint AM, Schwarz MJ, Tylee AT, Carvalho LA, Pariante CM (2015) Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression. Brain Behav Immun 48:8–18. doi:10.1016/j.bbi.2015.02.002

    Article  CAS  PubMed  Google Scholar 

  53. Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA, Mann JJ, Postolache TT (2011) Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun 25:1272–1278. doi:10.1016/j.bbi.2011.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bradley KA, Case JA, Khan O, Ricart T, Hanna A, Alonso CM, Gabbay V (2015) The role of the kynurenine pathway in suicidality in adolescent major depressive disorder. Psychiatry Res 227:206–212. doi:10.1016/j.psychres.2015.03.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ogawa S, Fujii T, Koga N, Hori H, Teraishi T, Hattori K, Noda T, Higuchi T, Motohashi N, Kunugi H (2014) Plasma L-tryptophan concentration in major depressive disorder: new data and meta-analysis. J Clin Psychiatry 75:e906–915. doi:10.4088/JCP.13r08908

    Article  CAS  PubMed  Google Scholar 

  56. Lapin IP, Oxenkrug GF (1969) Intensification of the central serotonergic processes as a possible determinant of the thymoleptic effect. Lancet 1:132–136

    Article  CAS  PubMed  Google Scholar 

  57. Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D (2002) Neopterin production, tryptophan degradation, and mental depression – what is the link? Brain Behav Immun 16:590–595

    Article  CAS  PubMed  Google Scholar 

  58. Dunn AJ, Welch J (1991) Stress- and endotoxin-induced increases in brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity. J Neurochem 57:1615–1622

    Article  CAS  PubMed  Google Scholar 

  59. Savitz J, Dantzer R, Wurfel BE, Victor TA, Ford BN, Bodurka J, Bellgowan PS, Teague TK, Drevets WC (2015) Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder. Psychoneuroendocrinology 52:200–211. doi:10.1016/j.psyneuen.2014.11.015

    Article  CAS  PubMed  Google Scholar 

  60. Savitz J, Drevets WC, Smith CM, Victor TA, Wurfel BE, Bellgowan PS, Bodurka J, Teague TK, Dantzer R (2015) Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder. Neuropsychopharmacology 40:463–471. doi:10.1038/npp.2014.194

    Article  CAS  PubMed  Google Scholar 

  61. Savitz J, Drevets WC, Wurfel BE, Ford BN, Bellgowan PS, Victor TA, Bodurka J, Teague TK, Dantzer R (2015) Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder. Brain Behav Immun 46:55–59. doi:10.1016/j.bbi.2015.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Myint AM, Kim YK (2003) Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61:519–525

    Article  CAS  PubMed  Google Scholar 

  63. Guillemin GJ, Smythe G, Takikawa O, Brew BJ (2005) Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia 49:15–23. doi:10.1002/glia.20090

    Article  PubMed  Google Scholar 

  64. Heyes MP, Achim CL, Wiley CA, Major EO, Saito K, Markey SP (1996) Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochem J 320(Pt 2):595–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Saito K, Markey SP, Heyes MP (1992) Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neuroscience 51:25–39

    Article  CAS  PubMed  Google Scholar 

  66. Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, Kelley KW, Dantzer R (2013) NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology 38:1609–1616. doi:10.1038/npp.2013.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bay-Richter C, Linderholm KR, Lim CK, Samuelsson M, Traskman-Bendz L, Guillemin GJ, Erhardt S, Brundin L (2015) A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality. Brain Behav Immun 43:110–117. doi:10.1016/j.bbi.2014.07.012

    Article  CAS  PubMed  Google Scholar 

  68. Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B (2007) Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 98:143–151. doi:10.1016/j.jad.2006.07.013

    Article  CAS  PubMed  Google Scholar 

  69. Birch PJ, Grossman CJ, Hayes AG (1988) Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. Eur J Pharmacol 154:85–87

    Article  CAS  PubMed  Google Scholar 

  70. Stone TW, Stoy N, Darlington LG (2013) An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34:136–143. doi:10.1016/j.tips.2012.09.006

    Article  CAS  PubMed  Google Scholar 

  71. Lugo-Huitron R, Blanco-Ayala T, Ugalde-Muniz P, Carrillo-Mora P, Pedraza-Chaverri J, Silva-Adaya D, Maldonado PD, Torres I, Pinzon E, Ortiz-Islas E, Lopez T, Garcia E, Pineda B, Torres-Ramos M, Santamaria A, La Cruz VP (2011) On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol Teratol 33:538–547. doi:10.1016/j.ntt.2011.07.002

    Article  CAS  PubMed  Google Scholar 

  72. Sapko MT, Guidetti P, Yu P, Tagle DA, Pellicciari R, Schwarcz R (2006) Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: implications for Huntington’s disease. Exp Neurol 197:31–40. doi:10.1016/j.expneurol.2005.07.004

    Article  CAS  PubMed  Google Scholar 

  73. Harris CA, Miranda AF, Tanguay JJ, Boegman RJ, Beninger RJ, Jhamandas K (1998) Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid. Br J Pharmacol 124:391–399. doi:10.1038/sj.bjp.0701834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Colin-Gonzalez AL, Maldonado PD, Santamaria A (2013) 3-Hydroxykynurenine: an intriguing molecule exerting dual actions in the central nervous system. Neurotoxicology 34:189–204. doi:10.1016/j.neuro.2012.11.007

    Article  CAS  PubMed  Google Scholar 

  75. Okuda S, Nishiyama N, Saito H, Katsuki H (1996) Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proc Natl Acad Sci U S A 93:12553–12558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chiarugi A, Meli E, Moroni F (2001) Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid. J Neurochem 77:1310–1318

    Article  CAS  PubMed  Google Scholar 

  77. Schwarz MJ, Guillemin GJ, Teipel SJ, Buerger K, Hampel H (2013) Increased 3-hydroxykynurenine serum concentrations differentiate Alzheimer’s disease patients from controls. Eur Arch Psychiatry Clin Neurosci 263:345–352. doi:10.1007/s00406-012-0384-x

    Article  PubMed  Google Scholar 

  78. Ogawa T, Matson WR, Beal MF, Myers RH, Bird ED, Milbury P, Saso S (1992) Kynurenine pathway abnormalities in Parkinson’s disease. Neurology 42:1702–1706

    Article  CAS  PubMed  Google Scholar 

  79. Stone TW, Forrest CM, Darlington LG (2012) Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. FEBS J 279:1386–1397. doi:10.1111/j.1742-4658.2012.08487.x

    Article  CAS  PubMed  Google Scholar 

  80. Ting KK, Brew BJ, Guillemin GJ (2009) Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer’s disease. J Neuroinflammation 6:36. doi:10.1186/1742-2094-6-36

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Vogelgesang SA, Heyes MP, West SG, Salazar AM, Sfikakis PP, Lipnick RN, Klipple GL, Tsokos GC (1996) Quinolinic acid in patients with systemic lupus erythematosus and neuropsychiatric manifestations. J Rheumatol 23:850–855

    CAS  PubMed  Google Scholar 

  82. Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, Giorgini F, Leys D, Scrutton NS (2013) Structural basis of kynurenine 3-monooxygenase inhibition. Nature 496:382–385. doi:10.1038/nature12039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Moroni F, Carpenedo R, Cozzi A, Meli E, Chiarugi A, Pellegrini-Giampietro DE (2003) Studies on the neuroprotective action of kynurenine mono-oxygenase inhibitors in post-ischemic brain damage. Adv Exp Med Biol 527:127–136

    Article  CAS  PubMed  Google Scholar 

  84. Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M (2005) IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 10:538–544

    Article  CAS  PubMed  Google Scholar 

  85. Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, Spivey JR, Saito K, Miller AH (2010) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 15:393–403. doi:10.1038/mp.2009.116

    Article  CAS  PubMed  Google Scholar 

  86. Baranyi A, Meinitzer A, Breitenecker RJ, Amouzadeh-Ghadikolai O, Stauber R, Rothenhausler HB (2015) Quinolinic acid responses during interferon-alpha-induced depressive symptomatology in patients with chronic hepatitis C infection – a novel aspect for depression and inflammatory hypothesis. PLoS One 10:e0137022. doi:10.1371/journal.pone.0137022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Georgin-Lavialle S, Moura DS, Salvador A, Chauvet-Gelinier JC, Launay JM, Damaj G, Cote F, Soucie E, Chandesris MO, Barete S, Grandpeix-Guyodo C, Bachmeyer C, Alyanakian MA, Aouba A, Lortholary O, Dubreuil P, Teyssier JR, Trojak B, Haffen E, Vandel P, Bonin B, French Mast Cell Study G, Hermine O, Gaillard R (2016) Mast cells’ involvement in inflammation pathways linked to depression: evidence in mastocytosis. Mol Psychiatry. doi:10.1038/mp.2015.216

    PubMed  Google Scholar 

  88. Maes M, Galecki P, Verkerk R, Rief W (2011) Somatization, but not depression, is characterized by disorders in the tryptophan catabolite (TRYCAT) pathway, indicating increased indoleamine 2,3-dioxygenase and lowered kynurenine aminotransferase activity. Neuro Endocrinol Lett 32:264–273

    CAS  PubMed  Google Scholar 

  89. Singh R, Savitz J, Teague TK, Polanski DW, Mayer AR, Bellgowan PS, Meier TB (2015) Mood symptoms correlate with kynurenine pathway metabolites following sports-related concussion. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2015-311369

    PubMed  Google Scholar 

  90. Meier TB, Savitz J, Singh R, Teague TK, Bellgowan PS (2016) Smaller dentate gyrus and CA2 and CA3 volumes are associated with kynurenine metabolites in collegiate football athletes. J Neurotrauma. doi:10.1089/neu.2015.4118

    PubMed Central  Google Scholar 

  91. Cobb JA, Simpson J, Mahajan GJ, Overholser JC, Jurjus GJ, Dieter L, Herbst N, May W, Rajkowska G, Stockmeier CA (2013) Hippocampal volume and total cell numbers in major depressive disorder. J Psychiatr Res 47:299–306. doi:10.1016/j.jpsychires.2012.10.020

    Article  PubMed  Google Scholar 

  92. Gosche KM, Mortimer JA, Smith CD, Markesbery WR, Snowdon DA (2002) Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun study. Neurology 58:1476–1482

    Article  CAS  PubMed  Google Scholar 

  93. Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, Uylings HB, Friedman L, Rajkowska G (2004) Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry 56:640–650

    Article  PubMed  PubMed Central  Google Scholar 

  94. Arnone D, Job D, Selvaraj S, Abe O, Amico F, Cheng Y, Colloby SJ, O’Brien JT, Frodl T, Gotlib IH, Ham BJ, Kim MJ, Koolschijn PC, Perico CA, Salvadore G, Thomas AJ, Van Tol MJ, van der Wee NJ, Veltman DJ, Wagner G, McIntosh AM (2016) Computational meta-analysis of statistical parametric maps in major depression. Hum Brain Mapp. doi:10.1002/hbm.23108

    PubMed  Google Scholar 

  95. Kempton MJ, Salvador Z, Munafo MR, Geddes JR, Simmons A, Frangou S, Williams SC (2011) Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch Gen Psychiatry 68:675–690. doi:10.1001/archgenpsychiatry.2011.60

    Article  PubMed  Google Scholar 

  96. Savitz J, Drevets WC (2009) Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neurosci Biobehav Rev 33:699–771. doi:10.1016/j.neubiorev.2009.01.004

    Article  PubMed  PubMed Central  Google Scholar 

  97. Savitz JB, Drevets WC (2009) Imaging phenotypes of major depressive disorder: genetic correlates. Neuroscience 164:300–330. doi:10.1016/j.neuroscience.2009.03.082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Heisler JM, O’Connor JC (2015) Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory. Brain Behav Immun 50:115–124. doi:10.1016/j.bbi.2015.06.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Meier TB, Drevets WC, Wurfel BE, Ford BN, Morris HM, Victor TA, Bodurka J, Teague TK, Dantzer R, Savitz J (2015) Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder. Brain Behav Immun. doi:10.1016/j.bbi.2015.11.003

    PubMed Central  Google Scholar 

  100. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, Mawrin C, Brisch R, Bielau H, Meyer zu Schwabedissen L, Bogerts B, Myint AM (2011) Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation 8:94. doi:10.1186/1742-2094-8-94

    Google Scholar 

  101. Savitz J, Dantzer R, Wurfel BE, Victor TA, Ford BN, Bodurka J, Bellgowan PS, Teague TK, Drevets WC (2014) Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder. Psychoneuroendocrinology 52C:200–211. doi:10.1016/j.psyneuen.2014.11.015

    Google Scholar 

  102. Myint AM, Kim YK, Verkerk R, Park SH, Scharpe S, Steinbusch HW, Leonard BE (2007) Tryptophan breakdown pathway in bipolar mania. J Affect Disord 102:65–72. doi:10.1016/j.jad.2006.12.008

    Article  CAS  PubMed  Google Scholar 

  103. Johansson AS, Owe-Larsson B, Asp L, Kocki T, Adler M, Hetta J, Gardner R, Lundkvist GB, Urbanska EM, Karlsson H (2013) Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine. J Psychiatr Res 47:1815–1823. doi:10.1016/j.jpsychires.2013.08.008

    Article  PubMed  Google Scholar 

  104. Guloksuz S, Arts B, Walter S, Drukker M, Rodriguez L, Myint AM, Schwarz MJ, Ponds R, van Os J, Kenis G, Rutten BP (2015) The impact of electroconvulsive therapy on the tryptophan-kynurenine metabolic pathway. Brain Behav Immun 48:48–52. doi:10.1016/j.bbi.2015.02.029

    Article  CAS  PubMed  Google Scholar 

  105. Olsson SK, Samuelsson M, Saetre P, Lindstrom L, Jonsson EG, Nordin C, Engberg G, Erhardt S, Landen M (2010) Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. J Psychiatry Neurosci 35:195–199

    Article  PubMed  PubMed Central  Google Scholar 

  106. Olsson SK, Sellgren C, Engberg G, Landen M, Erhardt S (2012) Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder. Bipolar Disord 14:719–726. doi:10.1111/bdi.12009

    Article  CAS  PubMed  Google Scholar 

  107. Lavebratt C, Olsson S, Backlund L, Frisen L, Sellgren C, Priebe L, Nikamo P, Traskman-Bendz L, Cichon S, Vawter MP, Osby U, Engberg G, Landen M, Erhardt S, Schalling M (2014) The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression. Mol Psychiatry 19:334–341. doi:10.1038/mp.2013.11

    Article  CAS  PubMed  Google Scholar 

  108. Cobb JA, O’Neill K, Milner J, Mahajan GJ, Lawrence TJ, May WL, Miguel-Hidalgo J, Rajkowska G, Stockmeier CA (2016) Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder. Neuroscience 316:209–220. doi:10.1016/j.neuroscience.2015.12.044

    Article  CAS  PubMed  Google Scholar 

  109. Torres-Platas SG, Nagy C, Wakid M, Turecki G, Mechawar N (2015) Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Mol Psychiatry. doi:10.1038/mp.2015.65

    PubMed  Google Scholar 

  110. Webster MJ, O’Grady J, Kleinman JE, Weickert CS (2005) Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia. Neuroscience 133:453–461

    Article  CAS  PubMed  Google Scholar 

  111. Ernst C, Deleva V, Deng X, Sequeira A, Pomarenski A, Klempan T, Ernst N, Quirion R, Gratton A, Szyf M, Turecki G (2009) Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. Arch Gen Psychiatry 66:22–32. doi:10.1001/archpsyc.66.1.22

    Article  CAS  PubMed  Google Scholar 

  112. Ernst C, Nagy C, Kim S, Yang JP, Deng X, Hellstrom IC, Choi KH, Gershenfeld H, Meaney MJ, Turecki G (2011) Dysfunction of astrocyte connexins 30 and 43 in dorsal lateral prefrontal cortex of suicide completers. Biol Psychiatry 70:312–319. doi:10.1016/j.biopsych.2011.03.038

    Article  CAS  PubMed  Google Scholar 

  113. Nagy C, Suderman M, Yang J, Szyf M, Mechawar N, Ernst C, Turecki G (2015) Astrocytic abnormalities and global DNA methylation patterns in depression and suicide. Mol Psychiatry 20:320–328. doi:10.1038/mp.2014.21

    Article  CAS  PubMed  Google Scholar 

  114. Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, Myers RM, Bunney WE Jr, Akil H, Watson SJ, Jones EG (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102:15653–15658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, Rehal S, Klempan T, Gratton A, Benkelfat C, Rouleau GA, Mechawar N, Turecki G (2009) Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 4:e6585. doi:10.1371/journal.pone.0006585

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Miller AH (2013) Conceptual confluence: the kynurenine pathway as a common target for ketamine and the convergence of the inflammation and glutamate hypotheses of depression. Neuropsychopharmacology 38:1607–1608. doi:10.1038/npp.2013.140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Steiner J, Bogerts B, Sarnyai Z, Walter M, Gos T, Bernstein HG, Myint AM (2012) Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: potential role of glial NMDA receptor modulators and impaired blood-brain barrier integrity. World J Biol Psychiatry 13:482–492. doi:10.3109/15622975.2011.583941

    Article  PubMed  Google Scholar 

  118. Haroon E, Woolwine BJ, Chen X, Pace TW, Parekh S, Spivey JR, Hu XP, Miller AH (2014) IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy. Neuropsychopharmacology 39:1777–1785. doi:10.1038/npp.2014.25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Haroon E, Fleischer CC, Felger JC, Chen X, Woolwine BJ, Patel T, Hu XP, Miller AH (2016) Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol Psychiatry. doi:10.1038/mp.2015.206

    Google Scholar 

  120. Raison CL, Miller AH (2013) Do cytokines really sing the blues? Cerebrum 2013:10

    PubMed  PubMed Central  Google Scholar 

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  1. Laureate Institute for Brain Research and Faculty of Community Medicine, The University of Tulsa, 6655 S. Yale Ave., Tulsa, OK, 74136, USA

    Jonathan Savitz

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  1. Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Robert Dantzer

  2. Nutrition and Integrative Neurobiology, INRA, University of Bordeaux, Bordeaux, France

    Lucile Capuron

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Savitz, J. (2016). Role of Kynurenine Metabolism Pathway Activation in Major Depressive Disorders. In: Dantzer, R., Capuron, L. (eds) Inflammation-Associated Depression: Evidence, Mechanisms and Implications. Current Topics in Behavioral Neurosciences, vol 31. Springer, Cham. https://doi.org/10.1007/7854_2016_12

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