The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
31
07
2020
accepted:
02
11
2020
revised:
29
09
2020
pubmed:
25
11
2020
medline:
28
1
2022
entrez:
24
11
2020
Statut:
ppublish
Résumé
The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges' g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.
Identifiants
pubmed: 33230205
doi: 10.1038/s41380-020-00951-9
pii: 10.1038/s41380-020-00951-9
doi:
Substances chimiques
Kynurenine
343-65-7
Kynurenic Acid
H030S2S85J
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4158-4178Subventions
Organisme : Department of Health
ID : ICA-CL-2017-03-001
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Informations de copyright
© 2020. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Myint AM. Kynurenines: from the perspective of major psychiatric disorders. FEBS J. 2012;279:1375–85.
pubmed: 22404766
Pu J, Liu Y, Zhang H, Tian L, Gui S, Yu Y, et al. An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-0645-4 . [Epub ahead of print].
Höglund E, Øverli Ø, Winberg S. Tryptophan metabolic pathways and brain serotonergic activity: a comparative review. Front Endocrinol. 2019;10:158.
Fernstrom JD. A perspective on the safety of supplemental tryptophan based on its metabolic fates. J Nutr. 2016;146:2601S–2608S.
pubmed: 27934651
Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA. Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med. 2006;8:1–27.
pubmed: 16942634
Schwarcz R, Bruno JP, Muchowski PJ, Wu H-Q. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13:465–77.
pubmed: 22678511
pmcid: 3681811
Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357:eaaf9794. https://doi.org/10.1126/science.aaf9794 .
doi: 10.1126/science.aaf9794
pubmed: 28751584
Stone TW, Forrest CM, Darlington LG. Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. FEBS J. 2012;279:1386–97.
pubmed: 22248239
Stone TW, Darlington LG. Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Disco. 2002;1:609–20.
Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. 2017;112(Pt B):399–412.
pubmed: 27392632
Lovelace MD, Varney B, Sundaram G, Lennon MJ, Lim CK, Jacobs K, et al. Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. Neuropharmacology. 2017;112(Pt B):373–88.
pubmed: 26995730
Campbell BM, Charych E, Lee AW, Möller T. Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci. 2014;8:12.
pubmed: 24567701
pmcid: 3915289
Espey MG, Chernyshev ON, Reinhard JF Jr, Namboodiri MA, Colton CA. Activated human microglia produce the excitotoxin quinolinic acid. Neuroreport. 1997;8:431–4.
pubmed: 9080423
Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199–229.
pubmed: 23644052
Tavares RG, Tasca CI, Santos CE, Alves LB, Porciuncula LO, Emanuelli T, et al. Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int. 2002;40:621–7.
pubmed: 11900857
Erhardt S, Schwieler L, Imbeault S, Engberg G. The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology. 2017;112(Pt B):297–306.
pubmed: 27245499
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: 20729465
Olsson SK, Samuelsson M, Saetre P, Lindstrom L, Jonsson EG, Nordin C, et al. Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. J Psychiatry Neurosci. 2010;35:195–9.
pubmed: 20420770
pmcid: 2861136
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.
pubmed: 23030601
Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25:455–67.
pubmed: 11557159
de Lucena D, Fernandes BS, Kunz M, Fries GR, Stertz L, Aguiar B, et al. Lack of association between serum brain-derived neurotrophic factor levels and improvement of schizophrenia symptoms in a double-blind, randomized, placebo-controlled trial of memantine as adjunctive therapy to clozapine. J Clin psychiatry. 2010;71:91.
pubmed: 20129011
Plitman E, Iwata Y, Caravaggio F, Nakajima S, Chung JK, Gerretsen P, et al. Kynurenic acid in schizophrenia: a systematic review and meta-analysis. Schizophrenia Bull. 2017;43:764–77.
Arnone D, Saraykar S, Salem H, Teixeira AL, Dantzer R, Selvaraj S. Role of Kynurenine pathway and its metabolites in mood disorders: a systematic review and meta-analysis of clinical studies. Neurosci Biobehav Rev. 2018;92:477–85.
pubmed: 29940237
pmcid: 6686193
Ogyu K, Kubo K, Noda Y, Iwata Y, Tsugawa S, Omura Y, et al. Kynurenine pathway in depression: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2018;90:16–25.
pubmed: 29608993
Moher D, Liberati A, Tetzlaff J, Altman DG. The PG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.
pubmed: 19621072
pmcid: 2707599
Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135.
pubmed: 25524443
pmcid: 4383202
Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat methods Med Res. 2018;27:1785–805.
pubmed: 27683581
Borenstein MHLV, Higgins JPT, Rothstein HR, Comprehensive meta-analysis version 3. Biostat 104 Englewood, NJ, 2011.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin trials. 1986;7:177–88.
pubmed: 3802833
Mander A, Clayton D. Assessing the influence of a single study in meta-analysis. Stata Tech Bull Repr. 1999;8:108–10.
Higgins JPT, GSe. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration, 2011. The Cochrane Collaboration: Available at: http://www.cochrane-handbook.org . Accessed 28 May 2014.
Anderson I, Parry-Billings M, Newsholme E, Poortmans J, Cowen P. Decreased plasma tryptophan concentration in major depression: relationship to melancholia and weight loss. J Affect Disord. 1990;20:185–91.
pubmed: 2148339
Baranyi A, Amouzadeh-Ghadikolai O, Von Lewinski D, Breitenecker RJ, Stojakovic T, März W, et al. Beta-trace protein as a new non-invasive immunological marker for quinolinic acid-induced impaired blood-brain barrier integrity. Sci Rep. 2017;7:43642.
pubmed: 28276430
pmcid: 5343478
Barry S, Clarke G, Scully P, Dinan T. Kynurenine pathway in psychosis: evidence of increased tryptophan degradation. J Psychopharmacol. 2009;23:287–94.
pubmed: 18562404
Bhagwagar Z, Hafizi S, Cowen P. Cortisol modulation of 5-HT-mediated growth hormone release in recovered depressed patients. J Affect Disord. 2002;72:249–55.
pubmed: 12450642
Brundin L, Sellgren C, Lim C, Grit J, Pålsson 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.
pubmed: 27483383
pmcid: 5022080
Cao B, Wang D, Brietzke E, McIntyre RS, Pan Z, Cha D, et al. Characterizing amino-acid biosignatures amongst individuals with schizophrenia: a case–control study. Amino acids. 2018;50:1013–23.
pubmed: 29796929
Castillo MFR, Murata S, Schwarz M, Schütze G, Moll N, Martin B, et al. Celecoxib augmentation of escitalopram in treatment-resistant bipolar depression and the effects on quinolinic acid. Neurol, Psychiatry Brain Res. 2019;32:22–9.
Chiappelli J, Notarangelo FM, Pocivavsek A, Thomas MA, Rowland LM, Schwarcz R, et al. Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia. Neuropsychopharmacology. 2018;43:1675–80.
pubmed: 29520060
pmcid: 6006321
Chiappelli J, Postolache TT, Kochunov P, Rowland LM, Wijtenburg SA, Shukla DK, et al. Tryptophan metabolism and white matter integrity in schizophrenia. Neuropsychopharmacology. 2016;41:2587–95.
pubmed: 27143602
pmcid: 4987857
Chiaroni P, Azorin J-M, Bovier P, Widmer J, Jeanningros R, Barré A, et al. A multivariate analysis of red blood cell membrane transports and plasma levels of L-tyrosine and L-tryptophan in depressed patients before treatment and after clinical improvement. Neuropsychobiology. 1990;23:1–7.
pubmed: 2280825
Cho HJ, Savitz J, Dantzer R, Teague TK, Drevets WC, Irwin MR. Sleep disturbance and kynurenine metabolism in depression. J Psychosom Res. 2017;99:1–7.
pubmed: 28712413
pmcid: 5526094
Coppen A, Eccleston E, Peet M. Total and free tryptophan concentration in the plasma of depressive patients. Lancet. 1973;302:60–63.
Cowen P, Parry-Billings M, Newsholme E. Decreased plasma tryptophan levels in major depression. J Affect Disord. 1989;16:27–31.
pubmed: 2521647
Czermak C, Hauger R, Drevets WC, Luckenbaugh DA, Geraci M, Charney DS, et al. Plasma NPY concentrations during tryptophan and sham depletion in medication-free patients with remitted depression. J Affect Disord. 2008;110:277–81.
pubmed: 18281099
pmcid: 3102760
Dahl J, Andreassen OA, Verkerk R, Malt UF, Sandvik L, Brundin L, et al. Ongoing episode of major depressive disorder is not associated with elevated plasma levels of kynurenine pathway markers. Psychoneuroendocrinology. 2015;56:12–22.
pubmed: 25770856
DeMyer MK, Shea PA, Hendrie HC, Yoshimura NN. Plasma tryptophan and five other amino acids in depressed and normal subjects. Arch Gen psychiatry. 1981;38:642–6.
pubmed: 7247626
Domingo EF, Krause RR. Plasma tryptophan tolerance curves in drug free normal controls, schizophrenic patients and prisoner volunteers. J Psychiatr Res. 1974;10:247–61.
Domingues DS, Crevelin EJ, de Moraes LAB, Cecilio Hallak JE, de Souza Crippa JA, Costa Queiroz ME. Simultaneous determination of amino acids and neurotransmitters in plasma samples from schizophrenic patients by hydrophilic interaction liquid chromatography with tandem mass spectrometry. J Sep Sci. 2015;38:780–7.
pubmed: 25545460
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.
pubmed: 29787958
Ebesunun M, Eruvulobi H, Olagunju T, Owoeye O. Elevated plasma homocysteine in association with decreased vitamin B12, folate, serotonin, lipids and lipoproteins in depressed patients. Afr J Psychiatry. 2012;15:25–29.
Fazio F, Lionetto L, Curto M, Iacovelli L, Cavallari M, Zappulla C, et al. Xanthurenic acid activates mGlu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia. Sci Rep. 2015;5:17799.
pubmed: 26643205
pmcid: 4672300
Fekkes D, Bode WT, Zijlstra FJ, Pepplinkhuizen L. Eicosanoid and amino acid metabolism in transient acute psychoses with psychedelic symptoms. Prostaglandins, Leukotrienes Essent Fat acids. 1996;54:261–4.
Freedman DX, Belendiuk K, Belendiuk GW, Crayton JW. Blood tryptophan metabolism in chronic schizophrenics. Arch Gen Psychiatry. 1981;38:655–9.
pubmed: 7247628
Fukushima T, Iizuka H, Yokota A, Suzuki T, Ohno C, Kono Y, et al. Quantitative analyses of schizophrenia-associated metabolites in serum: serum D-lactate levels are negatively correlated with gamma-glutamylcysteine in medicated schizophrenia patients. PloS One. 2014;9:e101652. https://doi.org/10.1371/journal.pone.0101652 .
doi: 10.1371/journal.pone.0101652
pubmed: 25004141
pmcid: 4086900
Guicheney P, Leger D, Barrat J, Trevoux R, LIGNIÈRES BD, Roques P, et al. Platelet serotonin content and plasma tryptophan in peri‐and postmenopausal women: variations with plasma oestrogen levels and depressive symptoms. Eur J Clin Investig. 1988;18:297–304.
Hayward G, Goodwin GM, Cowen PJ, Harmer CJ. Low-dose tryptophan depletion in recovered depressed patients induces changes in cognitive processing without depressive symptoms. Biol Psychiatry. 2005;57:517–24.
pubmed: 15737667
Healy D, Carney P, Leonard B. Monoamine-related markers of depression: changes following treatment. J Psychiatr Res. 1982;17:251–60.
pubmed: 6821276
Hennings A, Schwarz MJ, Riemer S, Stapf TM, Selberdinger VB, Rief W. Exercise affects symptom severity but not biological measures in depression and somatization–results on IL-6, neopterin, tryptophan, kynurenine and 5-HIAA. Psychiatry Res. 2013;210:925–33.
pubmed: 24140252
Hoekstra R, Fekkes D, Loonen A, Pepplinkhuizen L, Tuinier S, Verhoeven W. Bipolar mania and plasma amino acids: increased levels of glycine. Eur Neuropsychopharmacol. 2006;16:71–7.
pubmed: 16023835
Hoekstra R, van den Broek WW, Fekkes D, Bruijn JA, Mulder PG, Pepplinkhuizen L. Effect of electroconvulsive therapy on biopterin and large neutral amino acids in severe, medication-resistant depression. Psychiatry Res. 2001;103:115–23.
pubmed: 11549400
Hu L-J, Li X-F, Hu J-Q, Ni X-J, Lu H-Y, Wang J-J, et al. A simple HPLC–MS/MS method for determination of tryptophan, kynurenine and kynurenic acid in human serum and its potential for monitoring antidepressant therapy. J Anal Toxicol. 2017;41:37–44.
pubmed: 27590037
Joaquim HP, Costa AC, Gattaz WF, Talib LL. Kynurenine is correlated with IL-1β in plasma of schizophrenia patients. J Neural Transm. 2018;125:869–73.
pubmed: 29306989
Joseph MS, Brewerton TD, Reus VI, Stebbins GT. Plasma-tryptophan/neutral amino acid ratio and dexamethasone suppression in depression. Psychiatry Res. 1984;11:185–92.
pubmed: 6587412
Karege F, Widmer J, Bovier P, Gaillard J-M. Platelet serotonin and plasma tryptophan in depressed patients: effect of drug treatment and clinical outcome. Neuropsychopharmacology. 1994;10:207–14.
pubmed: 7916918
Kim Y-K, Myint A-M, Verkerk R, Scharpe S, Steinbusch H, Leonard B. Cytokine changes and tryptophan metabolites in medication-naive and medication-free schizophrenic patients. Neuropsychobiology. 2009;59:123–9.
pubmed: 19390223
Krause D, Kirnich VB, Stapf TM, Hennings A, Riemer S, Riedel M, et al. Values of cytokines and tryptophan metabolites over a 12 weeks time course in patients with depression and somatoform disorder. Clin Psychopharmacol Neurosci. 2019;17:34.
pubmed: 30690938
pmcid: 6361033
Krause D, Myint A-M, Schuett C, Musil R, Dehning S, Cerovecki A, et al. High kynurenine (a tryptophan metabolite) predicts remission in patients with major depression to add-on treatment with celecoxib. Front Psychiatry. 2017;8:16.
pubmed: 28243208
pmcid: 5304105
Kuwano N, Kato TA, Setoyama D, Sato-Kasai M, Shimokawa N, Hayakawa K, et al. Tryptophan-kynurenine and lipid related metabolites as blood biomarkers for first-episode drug-naïve patients with major depressive disorder: an exploratory pilot case-control study. J Affect Disord. 2018;231:74–82.
pubmed: 29454180
Lee M, Jayathilake K, Dai J, Meltzer HY. Decreased plasma tryptophan and tryptophan/large neutral amino acid ratio in patients with neuroleptic-resistant schizophrenia: relationship to plasma cortisol concentration. Psychiatry Res. 2011;185:328–33.
pubmed: 20699195
Leppik L, Kriisa K, Koido K, Koch K, Kajalaid K, Haring L, et al. Profiling of amino acids and their derivatives biogenic amines before and after antipsychotic treatment in first-episode psychosis. Front Psychiatry. 2018;9:155.
pubmed: 29740359
pmcid: 5928450
Liu H, Ding L, Zhang H, Mellor D, Wu H, Zhao D, et al. The metabolic factor kynurenic acid of kynurenine pathway predicts major depressive disorder. Front psychiatry. 2018;9:552.
pubmed: 30510519
pmcid: 6252326
Lucca A, Lucini V, Piatti E, Ronchi P, Smeraldi E. Plasma tryptophan levels and plasma tryptophan/neutral amino acids ratio in patients with mood disorder, patients with obsessive-compulsive disorder, and normal subjects. Psychiatry Res. 1992;44:85–91.
pubmed: 1480681
Maes M, De Backer G, Suy E, Minner B. Increased plasma serine concentrations in depression. Neuropsychobiology. 1995;31:10–5.
pubmed: 7708176
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. Neuroendocrinol Lett. 2011;32:264–73.
pubmed: 21712776
Maes M, Jacobs MP, Suy E, Minner B, Leclercq C, Christiaens F, et al. Suppressant effects of dexamethasone on the availability of plasma L-tryptophan and tyrosine in healthy controls and in depressed patients. Acta Psychiatr Scandinavica. 1990;81:19–23.
Maes M, Meltzer HY, Scharpè S, Bosmans E, Suy E, De Meester I, et al. Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Res. 1993;49:151–65.
pubmed: 7908745
Maes M, Verkerk R, Vandoolaeghe E, Van Hunsel F, Neels H, Wauters A, et al. Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response. Eur Arch Psychiatry Clin Neurosci. 1997;247:154–61.
pubmed: 9224908
Maes M, Wauters A, Verkerk R, Demedts P, Neels H, Van Gastel A, et al. Lower serum L-tryptophan availability in depression as a marker of a more generalized disorder in protein metabolism. Neuropsychopharmacology. 1996;15:243–51.
pubmed: 8873107
Mauri MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, et al. Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology. 1998;37:124–9.
pubmed: 9597668
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.
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.
pubmed: 30116859
pmcid: 6193489
Møller S, Kirk L, Honore P. Relationship between plasma ratio of tryptophan to competing amino acids and the response to L-tryptophan treatment in endogenously depressed patients. J Affect Disord. 1980;2:47–59.
pubmed: 6448880
Møller SE, Group DUA. Plasma amino acid profiles in relation to clinical response to moclobemide in patients with major depression. J Affect Disord. 1993;27:225–31.
pubmed: 8509523
Moreno FA, Gelenberg AJ, Heninger GR, Potter RL, McKnight KM, Allen J, et al. Tryptophan depletion and depressive vulnerability. Biol psychiatry. 1999;46:498–505.
pubmed: 10459399
Moreno J, Gaspar E, López-Bello G, Juárez E, Alcazar-Leyva S, González-Trujano E, et al. Increase in nitric oxide levels and mitochondrial membrane potential in platelets of untreated patients with major depression. Psychiatry Res. 2013;209:447–52.
pubmed: 23357685
Mukherjee D, Krishnamurthy VB, Millett CE, Reider A, Can A, Groer M, et al. Total sleep time and kynurenine metabolism associated with mood symptom severity in bipolar disorder. Bipolar Disord. 2018;20:27–34.
pubmed: 28833866
Myint A, Schwarz MJ, Verkerk R, Mueller H, 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.
Myint AM, Kim YK, Verkerk R, Park SH, Scharpe S, Steinbusch HW, et al. Tryptophan breakdown pathway in bipolar mania. J Affect Disord. 2007;102:65–72.
pubmed: 17270276
Myint A-M, Kim YK, Verkerk R, Scharpé S, Steinbusch H, Leonard B. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord. 2007;98:143–51.
pubmed: 16952400
Ogawa S, Koga N, Hattori K, Matsuo J, Ota M, Hori H, et al. Plasma amino acid profile in major depressive disorder: Analyses in two independent case-control sample sets. J Psychiatr Res. 2018;96:23–32.
pubmed: 28950111
Oxenkrug G, van der Hart M, Roeser J, Summergrad P. Anthranilic acid: a potential biomarker and treatment target for schizophrenia. Ann Psychiatry Ment Health. 2016;4:1059.
pubmed: 27042691
pmcid: 4817843
Pan J-X, Xia J-J, Deng F-L, Liang W-W, Wu J, Yin B-M, et al. Diagnosis of major depressive disorder based on changes in multiple plasma neurotransmitters: a targeted metabolomics study. Transl Psychiatry. 2018;8:1–10.
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.
pubmed: 28482311
Poletti S, Myint AM, Schüetze 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: 27619930
Porter RJ, Gallagher P, Watson S, Smith MS, Young AH. Elevated prolactin responses to L-tryptophan infusion in medication-free depressed patients. Psychopharmacology. 2003;169:77–83.
pubmed: 12728300
Potkin SG, Cannon-Spoor HE, DeLisi LE, Neckers LM, Wyatt RJ. Plasma phenylalanine, tyrosine, and tryptophan in schizophrenia. Arch Gen Psychiatry. 1983;40:749–52.
pubmed: 6860076
Quintana J. Platelet serotonin and plasma tryptophan decreases in endogenous depression. Clinical, therapeutic, and biological correlations. J Affect Disord. 1992;24:55–62.
pubmed: 1541767
Rao ML, Gross G, Strebel B, Bräunig P, Huber G, Klosterkötter J. Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects. Psychiatry Res. 1990;34:243–57.
pubmed: 1981623
Rao ML, Gross G, Strebel B, Halaris A, Huber G, Bräunig P, et al. Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia. Biol Psychiatry. 1994;35:151–63.
pubmed: 7909693
Ravikumar A, Deepadevi K, Arun P, Manojkumar V, Kurup P. Tryptophan and tyrosine catabolic pattern in neuropsychiatric disorders. Neurol India. 2000;48:231.
pubmed: 11025626
Reininghaus EZ, McIntyre RS, Reininghaus B, Geisler S, Bengesser SA, Lackner N, et al. Tryptophan breakdown is increased in euthymic overweight individuals with bipolar disorder: a preliminary report. Bipolar Disord. 2014;16:432–40.
pubmed: 24330408
Rief W, Pilger F, Ihle D, Verkerk R, Scharpe S, Maes M. Psychobiological aspects of somatoform disorders: contributions of monoaminergic transmitter systems. Neuropsychobiology. 2004;49:24–9.
pubmed: 14730197
Roiser JP, Levy J, Fromm SJ, Nugent AC, Talagala SL, Hasler G, et al. The effects of tryptophan depletion on neural responses to emotional words in remitted depression. Biol Psychiatry. 2009;66:441–50.
pubmed: 19539268
pmcid: 2745906
Savitz J, Dantzer R, Meier TB, Wurfel BE, Victor TA, McIntosh SA, et al. Activation of the kynurenine pathway is associated with striatal volume in major depressive disorder. Psychoneuroendocrinology. 2015;62:54–8.
pubmed: 26232650
pmcid: 4637239
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 Neuroinflammation. 2016;13:51.
pubmed: 26925576
pmcid: 4772340
Sellgren CM, Gracias J, Jungholm O, Perlis RH, Engberg G, Schwieler L, et al. Peripheral and central levels of kynurenic acid in bipolar disorder subjects and healthy controls. Transl Psychiatry. 2019;9:1–9.
Shaw DM, Tidmarsh SF, Karajgi BM. Tryptophan, affective disorder and stress: an hypothesis. J Affect Disord. 1980;2:321–5.
pubmed: 6450792
Shovestul BJ, Glassman M, Rowland LM, McMahon RP, Liu F, Kelly DL. Pilot study examining the relationship of childhood trauma, perceived stress, and medication use to serum kynurenic acid and kynurenine levels in schizophrenia. Schizophrenia Res. 2017;185:200.
Song C, Lin A, Bonaccorso S, Heide C, Verkerk R, Kenis G, et al. The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord. 1998;49:211–9.
pubmed: 9629951
Sorgdrager F, Doornbos B, Penninx B, de Jonge P, Kema IP. The association between the hypothalamic pituitary adrenal axis and tryptophan metabolism in persons with recurrent major depressive disorder and healthy controls. J Affect Disord. 2017;222:32–9.
pubmed: 28668713
Sperner-Unterweger B, Miller C, Holzner B, Laich A, Widner B, Fleischhacker WW, et al. Immunologic alterations in schizophrenia: neopterin, L-kynurenine, tryptophan and T-cell subsets in the acute stage of illness. Pteridines. 2002;13:9–14.
Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA, et al. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain, Behav, Immun. 2011;25:1272–8.
Szymona K, Zdzisińska B, Karakuła-Juchnowicz H, Kocki T, Kandefer-Szerszeń M, Flis M, et al. Correlations of kynurenic acid, 3-hydroxykynurenine, sIL-2R, IFN-α, and IL-4 with clinical symptoms during acute relapse of schizophrenia. Neurotox Res. 2017;32:17–26.
pubmed: 28275903
Teraishi T, Hori H, Sasayama D, Matsuo J, Ogawa S, Ota M, et al. 13 C-tryptophan breath test detects increased catabolic turnover of tryptophan along the kynurenine pathway in patients with major depressive disorder. Sci Rep. 2015;5:15994.
pubmed: 26524975
pmcid: 4630584
Tortorella A, Monteleone P, Fabrazzo M, Viggiano A, De Luca B, Maj M. Plasma concentrations of amino acids in chronic schizophrenics treated with clozapine. Neuropsychobiology. 2001;44:167–71.
pubmed: 11702015
Umehara H, Numata S, Watanabe S-y, Hatakeyama Y, Kinoshita M, Tomioka Y, et al. Altered KYN/TRP, Gln/Glu, and Met/methionine sulfoxide ratios in the blood plasma of medication-free patients with major depressive disorder. Sci Rep. 2017;7:1–8.
van de Kerkhof NW, Fekkes D, van der Heijden FM, Hoogendijk WJ, Stöber G, Egger JI, et al. Cycloid psychoses in the psychosis spectrum: evidence for biochemical differences with schizophrenia. Neuropsychiatr Dis Treat. 2016;12:1927.
pubmed: 27536115
pmcid: 4977096
Van der Heijden F, Fekkes D, Tuinier S, Sijben A, Kahn R, Verhoeven W. Amino acids in schizophrenia: evidence for lower tryptophan availability during treatment with atypical antipsychotics? J Neural Transm. 2005;112:577–85.
pubmed: 15372327
Wei J, Xu H, Ramchand C, Hemmings GP. Low concentrations of serum tyrosine in neuroleptic-free schizophrenics with an early onset. Schizophrenia Res. 1995;14:257–60.
Wood K, Harwood J, Coppen A. The effect of antidepressant drugs on plasma kynurenine in depressed patients. Psychopharmacology. 1978;59:263–6.
pubmed: 104330
Wu Y, Mai N, Zhong X, Wen Y, Zhou Y, Li H, et al. Kynurenine pathway changes in late-life depression with memory deficit. Psychiatry Res. 2018;269:45–49.
pubmed: 30145300
Wu Y, Zhong X, Mai N, Wen Y, Shang D, Hu L, et al. Kynurenine pathway changes in late-life depression. J Affect Disord. 2018;235:76–81.
pubmed: 29655078
Wurfel B, Drevets W, Bliss S, McMillin J, Suzuki H, Ford B, et al. Serum kynurenic acid is reduced in affective psychosis. Transl psychiatry. 2017;7:e1115.
pubmed: 28463241
pmcid: 5534956
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.
Zhou Y, Zheng W, Liu W, Wang C, Zhan Y, Li H, et al. Cross-sectional relationship between kynurenine pathway metabolites and cognitive function in major depressive disorder. Psychoneuroendocrinology. 2019;101:72–9.
pubmed: 30419374
Andreazza AC, Laksono I, Fernandes BS, Toben C, Lewczuk P, Riederer P, et al. Guidelines for the standardized collection of blood-based biomarkers in psychiatry: Steps for laboratory validity–a consensus of the Biomarkers Task Force from the WFSBP. World J Biol Psychiatry. 2019;20:340–51.
pubmed: 30907211
pmcid: 6728424
Fernandes B, Steiner J, Berk M, Molendijk M, Gonzalez-Pinto A, Turck C, et al. Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Mol psychiatry. 2015;20:1108–19.
pubmed: 25266124
Haroon E, Welle JR, Woolwine BJ, Goldsmith DR, Baer W, Patel T, et al. Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression. Neuropsychopharmacology. 2020;45:998–1007. https://doi.org/10.1038/s41386-020-0607-1 .
doi: 10.1038/s41386-020-0607-1
pubmed: 31940661
pmcid: 7162907
Fernandes BS, Williams LM, Steiner J, Leboyer M, Carvalho AF, Berk M. The new field of ‘precision psychiatry’. BMC Med. 2017;15:80.
pubmed: 28403846
pmcid: 5390384
Fernandes BS, Borgwardt S, Carvalho AF, Steiner J. Back to the future: on the road towards precision psychiatry. Front Psychiatry. 2020;11:112. https://doi.org/10.3389/fpsyt.2020.00112 .
doi: 10.3389/fpsyt.2020.00112
pubmed: 32174859
pmcid: 7054451
Gostner JM, Becker K, Croft KD, Woodman RJ, Puddey IB, Fuchs D, et al. Regular consumption of black tea increases circulating kynurenine concentrations: a randomized controlled trial. BBA Clin. 2015;3:31–5.
pubmed: 26673554
Gualdoni GA, Fuchs D, Zlabinger GJ, Gostner JM. Resveratrol intake enhances indoleamine-2, 3-dioxygenase activity in humans. Pharmacol Rep. 2016;68:1065–8.
pubmed: 27552061
Rudzki L, Ostrowska L, Pawlak D, Małus A, Pawlak K, Waszkiewicz N, et al. Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study. Psychoneuroendocrinology. 2019;100:213–22.
pubmed: 30388595
Teasdale SB, Ward PB, Samaras K, Firth J, Stubbs B, Tripodi E, et al. Dietary intake of people with severe mental illness: systematic review and meta-analysis. Br J Psychiatry. 2019;214:251–9.
pubmed: 30784395
Zhu C, Sawrey-Kubicek L, Beals E, Rhodes CH, Houts HE, Sacchi R, et al. Human gut microbiome composition and tryptophan metabolites were changed differently by fast food and Mediterranean diet in four days: A pilot study. Nutr Res. 2020.
Carl GF, Brogan MP, Young BK. Is plasma serine a marker for psychosis? Biol Psychiatry. 1992;31:1130–5.
pubmed: 1525276
Domino EF, Krause RR. Free and bound serum tryptophan in drug-free normal controls and chronic schizophrenic patients. Biol Psychiatry. 1974;8:265–79.
pubmed: 4604492