Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The kynurenine pathway: a finger in every pie

Abstract

The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+). Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system. Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission. As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation. However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogs of depression and schizophrenia-like cognitive deficits. Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems. This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders. Novel therapeutic approaches targeting the KP are discussed. Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have utility as treatment response or therapeutic monitoring biomarkers.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Bender DA. Effects of a dietary excess of leucine on the metabolism of tryptophan in the rat: a mechanism for the pellagragenic action of leucine. Br J Nutr. 1983;50:25–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Kanai M, Funakoshi H, Takahashi H, Hayakawa T, Mizuno S, Matsumoto K, et al. Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol Brain. 2009;2:8.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357:eaaf9794.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Foster AC, Vezzani A, French ED, Schwarcz R. Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid. Neurosci Lett. 1984;48:273–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Kessler M, Terramani T, Lynch G, Baudry M. A glycine site associated with N-methyl-D-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem. 1989;52:1319–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Carpenedo R, Pittaluga A, Cozzi A, Attucci S, Galli A, Raiteri M, et al. Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur J Neurosci. 2001;13:2141–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci. 2001;21:7463–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem. 2006;281:22021–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Guo J, Williams DJ, Puhl HL 3rd, Ikeda SR. Inhibition of N-type calcium channels by activation of GPR35, an orphan receptor, heterologously expressed in rat sympathetic neurons. J Pharmacol Exp Ther. 2008;324:342–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Wirthgen E, Hoeflich A, Rebl A, Gunther J. Kynurenic acid: the Janus-faced role of an immunomodulatory tryptophan metabolite and its link to pathological conditions. Front Immunol. 2017;8:1957.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478:197–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Stone TW, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol. 1981;72:411–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS J. 2012;279:1356–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Guillemin GJ, Croitoru-Lamoury J, Dormont D, Armati PJ, Brew BJ. Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes. Glia. 2003;41:371–81.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Kaindl AM, Degos V, Peineau S, Gouadon E, Chhor V, Loron G, et al. Activation of microglial N-methyl-d-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Ann Neurol. 2012;72:536–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Garrison AM, Parrott JM, Tunon A, Delgado J, Redus L, O’Connor JC. Kynurenine pathway metabolic balance influences microglia activity: targeting kynurenine monooxygenase to dampen neuroinflammation. Psychoneuroendocrinology. 2018;94:1–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Fukui S, Schwarcz R, Rapoport SI, Takada Y, Smith QR. Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem. 1991;56:2007–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kita T, Morrison PF, Heyes MP, Markey SP. Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain. J Neurochem. 2002;82:258–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Heyes MP, Morrison PF. Quantification of local de novo synthesis versus blood contributions to quinolinic acid concentrations in brain and systemic tissues. J Neurochem. 1997;68:280–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Skaper SD. Impact of Inflammation on the blood-neural barrier and blood-nerve interface: from review to therapeutic preview. Int Rev Neurobiol. 2017;137:29–45.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Pollak TA, Drndarski S, Stone JM, David AS, McGuire P, Abbott NJ. The blood-brain barrier in psychosis. Lancet Psychiatry. 2018;5:79–92.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Heyes MP, Brew BJ, Saito K, Quearry BJ, Price RW, Lee K, et al. Inter-relationships between quinolinic acid, neuroactive kynurenines, neopterin and beta 2-microglobulin in cerebrospinal fluid and serum of HIV-1-infected patients. J Neuroimmunol. 1992;40:71–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15:393–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Yoshida R, Imanishi J, Oku T, Kishida T, Hayaishi O. Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proc Natl Acad Sci USA. 1981;78:129–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Connor TJ, Starr N, O’Sullivan JB, Harkin A. Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: a role for IFN-gamma? Neurosci Lett. 2008;441:29–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Zunszain PA, Anacker C, Cattaneo A, Choudhury S, Musaelyan K, Myint AM, et al. Interleukin-1beta: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology. 2012;37:939–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Babcock TA, Carlin JM. Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells. Cytokine. 2000;12:588–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    O’Connor JC, Andre C, Wang Y, Lawson MA, Szegedi SS, Lestage J, et al. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci. 2009;29:4200–9.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Moffett JR, Namboodiri MA. Tryptophan and the immune response. Immunol Cell Biol. 2003;81:247–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Molteni R, Macchi F, Zecchillo C, Dell’agli M, Colombo E, Calabrese F, et al. Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine. Eur Neuropsychopharmacol. 2013;23:1645–55.

    CAS  PubMed  Google Scholar 

  31. 31.

    Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71:171–86.

    CAS  PubMed  Google Scholar 

  32. 32.

    Savitz J, Frank MB, Victor T, Bebak M, Marino JH, Bellgowan PS, et al. 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. 2013;31:161–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Leday GGR, Vertes PE, Richardson S, Greene JR, Regan T, Khan S, et al. Replicable and coupled changes in innate and adaptive immune gene expression in two case–control studies of blood microarrays in major depressive disorder. Biol Psychiatry. 2018;83:70–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Capuron L, Hauser P, Hinze-Selch D, Miller AH, Neveu PJ. Treatment of cytokine-induced depression. Brain Behav Immun. 2002;16:575–80.

    CAS  PubMed  Google Scholar 

  35. 35.

    Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun. 2010;24:558–63.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA, et al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010;197:372–7.

    PubMed  Google Scholar 

  37. 37.

    Van der Kooy K, van Hout H, Marwijk H, Marten H, Stehouwer C, Beekman A. Depression and the risk for cardiovascular diseases: systematic review and meta analysis. Int J Geriatr Psychiatry. 2007;22:613–26.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Dalton EJ, Heinrichs RW. Depression in multiple sclerosis: a quantitative review of the evidence. Neuropsychology. 2005;19:152–8.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268–75.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Mechawar N, Savitz J. Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl Psychiatry. 2016;6:e946.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Parrott JM, Redus L, Santana-Coelho D, Morales J, Gao X, O’Connor JC. Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation. Transl Psychiatry. 2016;6:e918.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry. 2002;7:468–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005;10:538–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Baranyi A, Meinitzer A, Breitenecker RJ, Amouzadeh-Ghadikolai O, Stauber R, Rothenhausler HB. 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. 2015;10:e0137022.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord. 2007;98:143–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Savitz J, Drevets WC, Smith CM, Victor TA, Wurfel BE, Bellgowan PS, et al. Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder. Neuropsychopharmacology. 2015;40:463–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Savitz J, Drevets WC, Wurfel BE, Ford BN, Bellgowan PS, Victor TA, et al. Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder. Brain Behav Immun. 2015;46:55–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Wurfel BE, Drevets WC, Bliss SA, McMillin JR, Suzuki H, Ford BN, et al. Serum kynurenic acid is reduced in affective psychosis. Transl Psychiatry. 2017;7:e1115.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Bay-Richter C, Linderholm KR, Lim CK, Samuelsson M, Traskman-Bendz L, Guillemin GJ, et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality. Brain Behav Immun. 2015;43:110–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Doolin K, Allers KA, Pleiner S, Liesener A, Farrell C, Tozzi L, et al. Altered tryptophan catabolite concentrations in major depressive disorder and associated changes in hippocampal subfield volumes. Psychoneuroendocrinology. 2018;95:8–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Allen AP, Naughton M, Dowling J, Walsh A, O’Shea R, Shorten G, et al. Kynurenine pathway metabolism and the neurobiology of treatment-resistant depression: comparison of multiple ketamine infusions and electroconvulsive therapy. J Psychiatr Res. 2018;100:24–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Birner A, Platzer M, Bengesser SA, Dalkner N, Fellendorf FT, Queissner R, et al. Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder. PLoS ONE. 2017;12:e0172699.

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Poletti S, Myint AM, Schuetze G, Bollettini I, Mazza E, Grillitsch D, et al. Kynurenine pathway and white matter microstructure in bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2018;268:157–68.

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Schwieler L, Samuelsson M, Frye MA, Bhat M, Schuppe-Koistinen I, Jungholm O, et al. Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients. J Neuroinflamm. 2016;13:51.

    Google Scholar 

  57. 57.

    Maes M, Galecki P, Verkerk R, Rief W. 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. 2011;32:264–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Parrott JM, Redus L, O’Connor JC. Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge. J Neuroinflammation. 2016;13:124.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Meier TB, Drevets WC, Wurfel BE, Ford BN, Morris HM, Victor TA, et al. Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder. Brain Behav Immun. 2016;53:39–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Meier TB, Savitz J, Singh R, Teague TK, Bellgowan PS. Smaller dentate gyrus and CA2 and CA3 volumes are associated with kynurenine metabolites in collegiate football athletes. J Neurotrauma. 2016;33:1349–57.

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Savitz J, Dantzer R, Wurfel BE, Victor TA, Ford BN, Bodurka J, et al. Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder. Psychoneuroendocrinology. 2015;52:200–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Young KD, Drevets WC, Dantzer R, Teague TK, Bodurka J, Savitz J. Kynurenine pathway metabolites are associated with hippocampal activity during autobiographical memory recall in patients with depression. Brain Behav Immun. 2016;56:335–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ. The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS ONE. 2009;4:e6344.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Jones SP, Franco NF, Varney B, Sundaram G, Brown DA, de Bie J, et al. Expression of the kynurenine pathway in human peripheral blood mononuclear cells: implications for inflammatory and neurodegenerative disease. PLoS ONE. 2015;10:e0131389.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK, et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry. 2004;61:450–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Du F, Yuksel C, Chouinard VA, Huynh P, Ryan K, Cohen BM, et al. Abnormalities in high-energy phosphate metabolism in first-episode bipolar disorder measured using (31)P-magnetic resonance spectroscopy. Biol Psychiatry. 2018;84:797–802.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Castellano-Gonzalez G, Jacobs KR, Don E, Cole NJ, Adams S, Lim CK, et al. Kynurenine 3-monooxygenase activity in human primary neurons and effect on cellular bioenergetics identifies new neurotoxic mechanisms. Neurotox Res. 2019;35:530–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Saha S, Shalova IN, Biswas SK. Metabolic regulation of macrophage phenotype and function. Immunol Rev. 2017;280:102–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Palsson-McDermott EM, O’Neill LA. The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays. 2013;35:965–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Foster AC, Miller LP, Oldendorf WH, Schwarcz R. Studies on the disposition of quinolinic acid after intracerebral or systemic administration in the rat. Exp Neurol. 1984;84:428–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Latif-Hernandez A, Shah D, Ahmed T, Lo AC, Callaerts-Vegh Z, Van der Linden A, et al. Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity. Sci Rep. 2016;6:36489.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Forrest CM, McNair K, Pisar M, Khalil OS, Darlington LG, Stone TW. Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine. Neuroscience. 2015;310:91–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Potter MC, Elmer GI, Bergeron R, Albuquerque EX, Guidetti P, Wu HQ, et al. Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology. 2010;35:1734–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Miller AH. Conceptual confluence: the kynurenine pathway as a common target for ketamine and the convergence of the inflammation and glutamate hypotheses of depression. Neuropsychopharmacology. 2013;38:1607–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology. 2013;38:1609–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Brundin L, Bryleva EY, Thirtamara Rajamani K. Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacology. 2017;42:271–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Bradley KA, Case JA, Khan O, Ricart T, Hanna A, Alonso CM, et al. The role of the kynurenine pathway in suicidality in adolescent major depressive disorder. Psychiatry Res. 2015;227:206–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Okusaga O, Duncan E, Langenberg P, Brundin L, Fuchs D, Groer MW, et al. Combined Toxoplasma gondii seropositivity and high blood kynurenine—linked with nonfatal suicidal self-directed violence in patients with schizophrenia. J Psychiatr Res. 2016;72:74–81.

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Erhardt S, Lim CK, Linderholm KR, Janelidze S, Lindqvist D, Samuelsson M, et al. Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology. 2013;38:743–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflamm. 2011;8:94.

    CAS  Google Scholar 

  81. 81.

    Brundin L, Sellgren CM, Lim CK, Grit J, Palsson E, Landen M, et al. An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation. Transl Psychiatry. 2016;6:e865.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Grant RS, Coggan SE, Smythe GA. The physiological action of picolinic acid in the human brain. Int J Tryptophan Res. 2009;2:71–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol. 2015;29:97–115.

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995;52:998–1007.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13:465–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Olsson SK, Sellgren C, Engberg G, Landen M, Erhardt S. Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder. Bipolar Disord. 2012;14:719–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Lavebratt C, Olsson S, Backlund L, Frisen L, Sellgren C, Priebe L, et al. 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. 2014;19:334–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Nilsson LK, Linderholm KR, Erhardt S. Subchronic treatment with kynurenine and probenecid: effects on prepulse inhibition and firing of midbrain dopamine neurons. J Neural Transm. 2006;113:557–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry. 2001;50:521–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Erhardt S, Blennow K, Nordin C, Skogh E, Lindstrom LH, Engberg G. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett. 2001;313:96–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull. 2012;38:426–32.

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Plitman E, Iwata Y, Caravaggio F, Nakajima S, Chung JK, Gerretsen P, et al. Kynurenic acid in Schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2017;43:764–77.

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Kirkpatrick B, Miller BJ. Inflammation and schizophrenia. Schizophr Bull. 2013;39:1174–9.

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, et al. Microglial activity in people at ultra high risk of psychosis and in Schizophrenia: an [(11)C]PBR28 PET Brain Imaging Study. Am J Psychiatry. 2016;173:44–52.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Myint AM, Schwarz MJ, Verkerk R, Mueller HH, Zach J, Scharpe S, et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naive and medication-free schizophrenic patients. Brain Behav Immun. 2011;25:1576–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Salter M, Pogson CI. The role of tryptophan 2,3-dioxygenase in the hormonal control of tryptophan metabolism in isolated rat liver cells. Effects of glucocorticoids and experimental diabetes. Biochem J. 1985;229:499–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Chiappelli J, Rowland LM, Notarangelo FM, Wijtenburg SA, Thomas MAR, Pocivavsek A, et al. Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia. Neuropsychopharmacology. 2018;43:1706–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Kuster OC, Laptinskaya D, Fissler P, Schnack C, Zugel M, Nold V, et al. Novel blood-based biomarkers of cognition, stress, and physical or cognitive training in older adults at risk of dementia: preliminary evidence for a role of BDNF, irisin, and the kynurenine pathway. J Alzheimers Dis. 2017;59:1097–111.

    PubMed  PubMed Central  Google Scholar 

  99. 99.

    Heisler JM, O’Connor JC. Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory. Brain Behav Immun. 2015;50:115–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Platzer M, Dalkner N, Fellendorf FT, Birner A, Bengesser SA, Queissner R, et al. Tryptophan breakdown and cognition in bipolar disorder. Psychoneuroendocrinology. 2017;81:144–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Erhardt S, Schwieler L, Emanuelsson C, Geyer M. Endogenous kynurenic acid disrupts prepulse inhibition. Biol Psychiatry. 2004;56:255–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Pocivavsek A, Wu HQ, Potter MC, Elmer GI, Pellicciari R, Schwarcz R. Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology. 2011;36:2357–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Alexander KS, Wu HQ, Schwarcz R, Bruno JP. Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine. Psychopharmacology. 2012;220:627–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Wonodi I, McMahon RP, Krishna N, Mitchell BD, Liu J, Glassman M, et al. Influence of kynurenine 3-monooxygenase (KMO) gene polymorphism on cognitive function in schizophrenia. Schizophr Res. 2014;160:80–87.

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Kim H, Chen L, Lim G, Sung B, Wang S, McCabe MF, et al. Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest. 2012;122:2940–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Huang L, Ou R, Rabelo de Souza G, Cunha TM, Lemos H, Mohamed E, et al. Virus infections incite pain hypersensitivity by inducing indoleamine 2,3 dioxygenase. PLoS Pathog. 2016;12:e1005615.

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Bannister K, Kucharczyk M, Dickenson AH. Hopes for the future of pain control. Pain Ther. 2017;6:117–28.

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Laumet G, Zhou W, Dantzer R, Edralin JD, Huo X, Budac DP, et al. Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain. Brain Behav Immun. 2017;66:94–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Walker AK, Kavelaars A, Heijnen CJ, Dantzer R. Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev. 2014;66:80–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Arnow BA, Blasey CM, Lee J, Fireman B, Hunkeler EM, Dea R, et al. Relationships among depression, chronic pain, chronic disabling pain, and medical costs. Psychiatr Serv. 2009;60:344–50.

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Husain MM, Rush AJ, Trivedi MH, McClintock SM, Wisniewski SR, Davis L, et al. Pain in depression: STAR*D study findings. J Psychosom Res. 2007;63:113–22.

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Vecsei L, Szalardy L, Fulop F, Toldi J. Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov. 2013;12:64–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Badawy AA. Hypothesis kynurenic and quinolinic acids: the main players of the kynurenine pathway and opponents in inflammatory disease. Med Hypotheses. 2018;118:129–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Badawy AA, Namboodiri AM, Moffett JR. The end of the road for the tryptophan depletion concept in pregnancy and infection. Clin Sci. 2016;130:1327–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Durr S, Kindler V. Implication of indolamine 2,3 dioxygenase in the tolerance toward fetuses, tumors, and allografts. J Leukoc Biol. 2013;93:681–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Badawy AA. Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements. Neuropharmacology. 2017;112:248–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Suzuki H, Savitz J, Kent Teague T, Gandhapudi SK, Tan C, Misaki M, et al. Altered populations of natural killer cells, cytotoxic T lymphocytes, and regulatory T cells in major depressive disorder: association with sleep disturbance. Brain Behav Immun. 2017;66:193–200.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Irwin M, Lacher U, Caldwell C. Depression and reduced natural killer cytotoxicity: a longitudinal study of depressed patients and control subjects. Psychol Med. 1992;22:1045–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Cohen S, Tyrrell DA, Smith AP. Psychological stress and susceptibility to the common cold. N Engl J Med. 1991;325:606–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Irwin MR, Levin MJ, Laudenslager ML, Olmstead R, Lucko A, Lang N, et al. Varicella zoster virus-specific immune responses to a herpes zoster vaccine in elderly recipients with major depression and the impact of antidepressant medications. Clin Infect Dis. 2013;56:1085–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Ford BN, Yolken RH, Dickerson FB, Teague TK, Irwin MR, Paulus MP et al. Reduced immunity to measles in adults with major depressive disorder. Psychol Med. 2019;49:243–49.

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Satin JR, Linden W, Phillips MJ. Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer. 2009;115:5349–61.

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Kohl C, Walch T, Huber R, Kemmler G, Neurauter G, Fuchs D, et al. Measurement of tryptophan, kynurenine and neopterin in women with and without postpartum blues. J Affect Disord. 2005;86:135–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Bailara KM, Henry C, Lestage J, Launay JM, Parrot F, Swendsen J, et al. Decreased brain tryptophan availability as a partial determinant of post-partum blues. Psychoneuroendocrinology. 2006;31:407–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Veen C, Myint AM, Burgerhout KM, Schwarz MJ, Schutze G, Kushner SA, et al. Tryptophan pathway alterations in the postpartum period and in acute postpartum psychosis and depression. J Affect Disord. 2016;189:298–305.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Wang SY, Duan KM, Tan XF, Yin JY, Mao XY, Zheng W, et al. Genetic variants of the kynurenine-3-monooxygenase and postpartum depressive symptoms after cesarean section in Chinese women. J Affect Disord. 2017;215:94–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Dadvar S, Ferreira DMS, Cervenka I, Ruas JL. The weight of nutrients: kynurenine metabolites in obesity and exercise. J Intern Med. 2018;284:519–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Laurans L, Venteclef N, Haddad Y, Chajadine M, Alzaid F, Metghalchi S, et al. Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health. Nat Med. 2018;24:1113–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Oxenkrug G. Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol. 2013;48:294–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Lemieux GA, Cunningham KA, Lin L, Mayer F, Werb Z, Ashrafi K. Kynurenic acid is a nutritional cue that enables behavioral plasticity. Cell. 2015;160:119–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Agudelo LZ, Ferreira DMS, Cervenka I, Bryzgalova G, Dadvar S, Jannig PR, et al. Kynurenic acid and Gpr35 regulate adipose tissue energy homeostasis and inflammation. Cell Metab. 2018;27:378–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Milaneschi Y, Simmons WK, van Rossum EFC, Penninx BW. Depression and obesity: evidence of shared biological mechanisms. Mol Psychiatry. 2019;24:18–33.

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Capuron L, Lasselin J, Castanon N. Role of adiposity-driven inflammation in depressive morbidity. Neuropsychopharmacology. 2017;42:115–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Tabak AG, Akbaraly TN, Batty GD, Kivimaki M. Depression and type 2 diabetes: a causal association? Lancet Diabetes Endocrinol. 2014;2:236–45.

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Mudry JM, Alm PS, Erhardt S, Goiny M, Fritz T, Caidahl K, et al. Direct effects of exercise on kynurenine metabolism in people with normal glucose tolerance or type 2 diabetes. Diabetes Metab Res Rev. 2016;32:754–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Yu E, Papandreou C, Ruiz-Canela M, Guasch-Ferre M, Clish CB, Dennis C, et al. Association of tryptophan metabolites with incident type 2 diabetes in the PREDIMED trial: a case-cohort study. Clin Chem. 2018;64:1211–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Favennec M, Hennart B, Caiazzo R, Leloire A, Yengo L, Verbanck M, et al. The kynurenine pathway is activated in human obesity and shifted tward kynurenine mono-oxygenase activation. Obesity. 2015;23:2066–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Sun N, Youle RJ, Finkel T. The Mitochondrial basis of aging. Mol Cell. 2016;61:654–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Villena JA. New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond. FEBS J. 2015;282:647–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, et al. Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell. 2014;159:33–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Maddison DC, Giorgini F. The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol. 2015;40:134–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Lim CK, Fernandez-Gomez FJ, Braidy N, Estrada C, Costa C, Costa S, et al. Involvement of the kynurenine pathway in the pathogenesis of Parkinson’s disease. Prog Neurobiol. 2017;155:76–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Hartai Z, Juhasz A, Rimanoczy A, Janaky T, Donko T, Dux L, et al. Decreased serum and red blood cell kynurenic acid levels in Alzheimer’s disease. Neurochem Int. 2007;50:308–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Ogawa T, Matson WR, Beal MF, Myers RH, Bird ED, Milbury P, et al. Kynurenine pathway abnormalities in Parkinson’s disease. Neurology. 1992;42:1702–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Thirtamara-Rajamani K, Li P, Escobar Galvis ML, Labrie V, Brundin P, Brundin L. Is the enzyme ACMSD a novel therapeutic target in parkinson’s disease? J Parkinsons Dis. 2017;7:577–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011;145:863–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Gregoire L, Rassoulpour A, Guidetti P, Samadi P, Bedard PJ, Izzo E, et al. Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys. Behav Brain Res. 2008;186:161–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Campesan S, Green EW, Breda C, Sathyasaikumar KV, Muchowski PJ, Schwarcz R, et al. The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Curr Biol. 2011;21:961–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Sutphin GL, Backer G, Sheehan S, Bean S, Corban C, Liu T, et al. Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity. Aging Cell. 2017;16:672–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Cai N, Chang S, Li Y, Li Q, Hu J, Liang J, et al. Molecular signatures of major depression. Curr Biol. 2015;25:1146–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Herbert J, Lucassen PJ. Depression as a risk factor for Alzheimer’s disease: genes, steroids, cytokines and neurogenesis—What do we need to know? Front Neuroendocrinol. 2016;41:153–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Gustafsson H, Nordstrom A, Nordstrom P. Depression and subsequent risk of Parkinson disease: a nationwide cohort study. Neurology. 2015;84:2422–9.

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16:626–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Hewagama A, Patel D, Yarlagadda S, Strickland FM, Richardson BC. Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun. 2009;10:509–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Kadel S, Kovats S. Sex hormones regulate innate immune cells and promote sex differences in respiratory virus infection. Front Immunol. 2018;9:1653.

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Mason M, Gullekson EH. Estrogen-enzyme interactions: Inhibition and protection of kynurenine transaminase by the sulfate esters of diethylstilbestrol, estradiol, and estrone. J Biol Chem. 1960;235:1312–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Jayawickrama GS, Nematollahi A, Sun G, Gorrell MD, Church WB. Inhibition of human kynurenine aminotransferase isozymes by estrogen and its derivatives. Sci Rep. 2017;7:17559.

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Reddy AP, Bethea CL. Preliminary array analysis reveals novel genes regulated by ovarian steroids in the monkey raphe region. Psychopharmacology. 2005;180:125–40.

    CAS  PubMed  Google Scholar 

  160. 160.

    de Bie J, Lim CK, Guillemin GJ. Progesterone alters kynurenine pathway activation in IFN-gamma-activated macrophages—relevance for neuroinflammatory diseases. Int J Tryptophan Res. 2016;9:89–93.

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Kessler RC. Epidemiology of women and depression. J Affect Disord. 2003;74:5–13.

    PubMed  Google Scholar 

  162. 162.

    Meier TB, Drevets WC, Teague TK, Wurfel BE, Mueller SC, Bodurka J, et al. Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression. Brain Behav Immun. 2018;67:59–64.

    CAS  PubMed  Google Scholar 

  163. 163.

    Bao AM, Swaab DF. Sex differences in the brain, behavior, and neuropsychiatric disorders. Neuroscientist. 2010;16:550–65.

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3:51.

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Rojewska E, Piotrowska A, Makuch W, Przewlocka B, Mika J. Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model. Neuropharmacology. 2016;102:80–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Wilkinson ST, Sanacora G. A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug Discov Today. 2018;24:606–15.

    PubMed  PubMed Central  Google Scholar 

  167. 167.

    Walker AK, Wing EE, Banks WA, Dantzer R. Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0076-7. [Epub ahead of print].

    PubMed  PubMed Central  Google Scholar 

  168. 168.

    Guloksuz S, Arts B, Walter S, Drukker M, Rodriguez L, Myint AM, et al. The impact of electroconvulsive therapy on the tryptophan-kynurenine metabolic pathway. Brain Behav Immun. 2015;48:48–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Moaddel R, Shardell M, Khadeer M, Lovett J, Kadriu B, Ravichandran S, et al. Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects. Psychopharmacology. 2018;235:3017–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Zhou Y, Zheng W, Liu W, Wang C, Zhan Y, Li H, et al. Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression. Brain Behav Immun. 2018;74:205–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Harvey SB, Overland S, Hatch SL, Wessely S, Mykletun A, Hotopf M. Exercise and the prevention of depression: results of the HUNT Cohort Study. Am J Psychiatry. 2018;175:28–36.

    PubMed  Google Scholar 

  172. 172.

    Mura G, Moro MF, Patten SB, Carta MG. Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review. CNS Spectr. 2014;19:496–508.

    PubMed  Google Scholar 

  173. 173.

    Schlittler M, Goiny M, Agudelo LZ, Venckunas T, Brazaitis M, Skurvydas A, et al. Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans. Am J Physiol Cell Physiol. 2016;310:C836–40.

    PubMed  Google Scholar 

  174. 174.

    Metcalfe AJ, Koliamitra C, Javelle F, Bloch W, Zimmer P. Acute and chronic effects of exercise on the kynurenine pathway in humans—a brief review and future perspectives. Physiol Behav. 2018;194:583–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Savitz J, Preskorn S, Teague TK, Drevets D, Yates W, Drevets W. 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. 2012;2:e000643.

    PubMed  PubMed Central  Google Scholar 

  176. 176.

    Savitz JB, Teague TK, Misaki M, Macaluso M, Wurfel BE, Meyer M, et al. Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2x2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry. 2018;8:27.

    PubMed  PubMed Central  Google Scholar 

  177. 177.

    Edwards SR, Mather LE, Lin Y, Power I, Cousins MJ. Glutamate and kynurenate in the rat central nervous system following treatments with tail ischaemia or diclofenac. J Pharm Pharmacol. 2000;52:59–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Schwieler L, Erhardt S, Erhardt C, Engberg G. Prostaglandin-mediated control of rat brain kynurenic acid synthesis—opposite actions by COX-1 and COX-2 isoforms. J Neural Transm. 2005;112:863–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Maciejak P, Szyndler J, Turzynska D, Sobolewska A, Kolosowska K, Lehner M, et al. The kynurenine pathway: a missing piece in the puzzle of valproate action? Neuroscience. 2013;234:135–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Fukunaga M, Yamamoto Y, Kawasoe M, Arioka Y, Murakami Y, Hoshi M, et al. Studies on tissue and cellular distribution of indoleamine 2,3-dioxygenase 2: the absence of IDO1 upregulates IDO2 expression in the epididymis. J Histochem Cytochem. 2012;60:854–60.

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LM, et al. IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. Int Immunol. 2014;26:357–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Espey MG, Chernyshev ON, Reinhard JF Jr., Namboodiri MA, Colton CA. Activated human microglia produce the excitotoxin quinolinic acid. Neuroreport. 1997;8:431–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Stone TW. Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Prog Neurobiol. 2001;64:185–218.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, et al. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood. 2006;108:4118–25.

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol. 2009;183:2475–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Scott GN, DuHadaway J, Pigott E, Ridge N, Prendergast GC, Muller AJ, et al. The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. J Immunol. 2009;182:7509–17.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Support was received from the National Institute of General Medical Sciences (P20GM121312), the National Institute of Mental Health (R21MH113871), and the Laureate Institute for Brain Research (LIBR).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jonathan Savitz.

Ethics declarations

Conflict of interest

The author declares that he has no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Savitz, J. The kynurenine pathway: a finger in every pie. Mol Psychiatry 25, 131–147 (2020). https://doi.org/10.1038/s41380-019-0414-4

Download citation

Further reading

Search

Quick links