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Metabolic dysfunctions in the kynurenine pathway, noradrenergic and purine metabolism in schizophrenia and bipolar disorders

Published online by Cambridge University Press:  14 March 2019

Nils Eiel Steen Open the ORCID record for Nils Eiel Steen [Opens in a new window] ,
Ingrid Dieset ,
Sigrun Hope ,
Trude S.J. Vedal ,
Olav B. Smeland ,
Wayne Matson ,
Rima Kaddurah-Daouk ,
Ingrid Agartz ,
Ingrid Melle  and
Srdjan Djurovic
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Nils Eiel Steen*
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Ingrid Dieset
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Sigrun Hope
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Neurohabilitation, Oslo University Hospital, Oslo, Norway
Trude S.J. Vedal
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Olav B. Smeland
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Neuroscience, University of California San Diego, La Jolla, CA92093, USA
Wayne Matson
Affiliation:
Bedford VA Medical Center, Bedford, MA, USA
Rima Kaddurah-Daouk
Affiliation:
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA Duke Institute of Brain Sciences, Duke University, Durham, NC, USA Department of Medicine, Duke University, Durham, NC, USA
Ingrid Agartz
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
Ingrid Melle
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Srdjan Djurovic
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Medical Genetics, Oslo University Hospital, Oslo, Norway Department of Clinical Science, University of Bergen, Bergen, Norway
Erik G. Jönsson
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden
Mikhail Bogdanov
Affiliation:
Weill Medical College, Cornell University, New York, USA
Ole A. Andreassen
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
*
Author for correspondence: Nils Eiel Steen, E-mail: n.e.steen@medisin.uio.no
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Abstract

Background

We aimed at exploring potential pathophysiological processes across psychotic disorders, applying metabolomics in a large and well-characterized sample of patients and healthy controls.

Methods

Patients with schizophrenia and bipolar disorders (N = 212) and healthy controls (N = 68) had blood sampling with subsequent metabolomics analyses using electrochemical coulometric array detection. Concentrations of 52 metabolites including tyrosine, tryptophan and purine pathways were compared between patients and controls while controlling for demographic and clinical characteristics. Significant findings were further tested in medication-free subsamples.

Results

Significantly decreased plasma concentrations in patients compared to healthy controls were found for 3-hydroxykynurenine (3OHKY, p = 0.0008), xanthurenic acid (XANU, p = 1.5×10−5), vanillylmandelic acid (VMA, p = 4.5×10−5) and metanephrine (MN, p = 0.0001). Plasma concentration of xanthine (XAN) was increased in the patient group (p = 3.5×10−5). Differences of 3OHKY, XANU, VMA and XAN were replicated across schizophrenia spectrum disorders and bipolar disorders subsamples of medication-free individuals.

Conclusions

Although prone to residual confounding, the present results suggest the kynurenine pathway of tryptophan metabolism, noradrenergic and purinergic system dysfunction as trait factors in schizophrenia spectrum and bipolar disorders. Of special interest is XANU, a metabolite previously not found to be associated with bipolar disorders.

Keywords

Metabolomicspsychotic disorderstryptophantyrosine
Type
Original Articles
Information
Psychological Medicine , Volume 50 , Issue 4 , March 2020 , pp. 595 - 606
Copyright
Copyright © Cambridge University Press 2019

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References

Aarsland, TI, Landaas, ET, Hegvik, TA, Ulvik, A, Halmoy, A, Ueland, PM and Haavik, J (2015) Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): a case-control study. Behavioral and Brain Functions 11, 36.CrossRefGoogle ScholarPubMed
Aberg, KA, Liu, Y, Bukszar, J, McClay, JL, Khachane, AN, Andreassen, OA, Blackwood, D, Corvin, A, Djurovic, S, Gurling, H, Ophoff, R, Pato, CN, Pato, MT, Riley, B, Webb, T, Kendler, K, O'Donovan, M, Craddock, N, Kirov, G, Owen, M, Rujescu, D, St, CD, Werge, T, Hultman, CM, Delisi, LE, Sullivan, P and van den Oord, EJ (2013) A comprehensive family-based replication study of schizophrenia genes. JAMA Psychiatry 70, 573–581.CrossRefGoogle ScholarPubMed
Addington, D, Addington, J and Schissel, B (1990) A depression rating scale for schizophrenics. Schizophrenia Research 3, 247–251.CrossRefGoogle ScholarPubMed
Agren, H, Niklasson, F and Hallgren, R (1983) Brain purinergic activity linked with depressive symptomatology: hypoxanthine and xanthine in CSF of patients with major depressive disorders. Psychiatry Research 9, 179–189.CrossRefGoogle ScholarPubMed
Akyol, O, Herken, H, Uz, E, Fadillioglu, E, Unal, S, Sogut, S, Ozyurt, H and Savas, HA (2002) The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients. The possible role of oxidant/antioxidant imbalance. Progress in Neuro-Psychopharmacology and Biological Psychiatry 26, 995–1005.CrossRefGoogle ScholarPubMed
Albert, U, De Cori, D, Aguglia, A, Barbaro, F, Bogetto, F and Maina, G (2015) Increased uric acid levels in bipolar disorder subjects during different phases of illness. Journal of Affective Disorders 173, 170–175.CrossRefGoogle Scholar
Anttila, V, Bulik-Sullivan, B, Finucane, HK, Walters, RK, Bras, J, Duncan, L, Escott-Price, V, Falcone, GJ, Gormley, P, Malik, R, Patsopoulos, NA, Ripke, S, Wei, Z, Yu, D, Lee, PH, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, JF, Duron, E, Vardarajan, BN, Reitz, C, Goate, AM, Huentelman, MJ, Kamboh, MI, Larson, EB, Rogaeva, E, St George-Hyslop, P, Hakonarson, H, Kukull, WA, Farrer, LA, Barnes, LL, Beach, TG, Demirci, FY, Head, E, Hulette, CM, Jicha, GA, Kauwe, JSK, Kaye, JA, Leverenz, JB, Levey, AI, Lieberman, AP, Pankratz, VS, Poon, WW, Quinn, JF, Saykin, AJ, Schneider, LS, Smith, AG, Sonnen, JA, Stern, RA, Van Deerlin, VM, Van Eldik, LJ, Harold, D, Russo, G, Rubinsztein, DC, Bayer, A, Tsolaki, M, Proitsi, P, Fox, NC, Hampel, H, Owen, MJ, Mead, S, Passmore, P, Morgan, K, Nothen, MM, Rossor, M, Lupton, MK, Hoffmann, P, Kornhuber, J, Lawlor, B, McQuillin, A, Al-Chalabi, A, Bis, JC, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, van der Lee, SJ, De Jager, PL, Geschwind, DH, Riemenschneider, M, Riedel-Heller, S, Rotter, JI, Ransmayr, G, Hyman, BT, Cruchaga, C, Alegret, M, Winsvold, B, Palta, P, Farh, KH, Cuenca-Leon, E, Furlotte, N, Kurth, T, Ligthart, L, Terwindt, GM, Freilinger, T, Ran, C, Gordon, SD, Borck, G, Adams, HHH, Lehtimaki, T, Wedenoja, J, Buring, JE, Schurks, M, Hrafnsdottir, M, Hottenga, JJ, Penninx, B, Artto, V, Kaunisto, M, Vepsalainen, S, Martin, NG, Montgomery, GW, Kurki, MI, Hamalainen, E, Huang, H, Huang, J, Sandor, C, Webber, C, Muller-Myhsok, B, Schreiber, S, Salomaa, V, Loehrer, E, Gobel, H, Macaya, A, Pozo-Rosich, P, Hansen, T, Werge, T, Kaprio, J, Metspalu, A, Kubisch, C, Ferrari, MD, Belin, AC, van den Maagdenberg, A, Zwart, JA, Boomsma, D, Eriksson, N, Olesen, J, Chasman, DI, Nyholt, DR, Avbersek, A, Baum, L, Berkovic, S, Bradfield, J, Buono, R, Catarino, CB, Cossette, P, De Jonghe, P, Depondt, C, Dlugos, D, Ferraro, TN, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kalviainen, R, Kunz, WS, Lerche, H, Leu, C, Lindhout, D, Lo, W, Lowenstein, D, McCormack, M, Moller, RS, Molloy, A, Ng, PW, Oliver, K, Privitera, M, Radtke, R, Ruppert, AK, Sander, T, Schachter, S, Schankin, C, Scheffer, I, Schoch, S, Sisodiya, SM, Smith, P, Sperling, M, Striano, P, Surges, R, Thomas, GN, Visscher, F, Whelan, CD, Zara, F, Heinzen, EL, Marson, A, Becker, F, Stroink, H, Zimprich, F, Gasser, T, Gibbs, R, Heutink, P, Martinez, M, Morris, HR, Sharma, M, Ryten, M, Mok, KY, Pulit, S, Bevan, S, Holliday, E, Attia, J, Battey, T, Boncoraglio, G, Thijs, V, Chen, WM, Mitchell, B, Rothwell, P, Sharma, P, Sudlow, C, Vicente, A, Markus, H, Kourkoulis, C, Pera, J, Raffeld, M, Silliman, S, Boraska Perica, V, Thornton, LM, Huckins, LM, William Rayner, N, Lewis, CM, Gratacos, M, Rybakowski, F, Keski-Rahkonen, A, Raevuori, A, Hudson, JI, Reichborn-Kjennerud, T, Monteleone, P, Karwautz, A, Mannik, K, Baker, JH, O'Toole, JK, Trace, SE, Davis, OSP, Helder, SG, Ehrlich, S, Herpertz-Dahlmann, B, Danner, UN, van Elburg, AA, Clementi, M, Forzan, M, Docampo, E, Lissowska, J, Hauser, J, Tortorella, A, Maj, M, Gonidakis, F, Tziouvas, K, Papezova, H, Yilmaz, Z, Wagner, G, Cohen-Woods, S, Herms, S, Julia, A, Rabionet, R, Dick, DM, Ripatti, S, Andreassen, OA, Espeseth, T, Lundervold, AJ, Steen, VM, Pinto, D, Scherer, SW, Aschauer, H, Schosser, A, Alfredsson, L, Padyukov, L, Halmi, KA, Mitchell, J, Strober, M, Bergen, AW, Kaye, W, Szatkiewicz, JP, Cormand, B, Ramos-Quiroga, JA, Sanchez-Mora, C, Ribases, M, Casas, M, Hervas, A, Arranz, MJ, Haavik, J, Zayats, T, Johansson, S, Williams, N, Dempfle, A, Rothenberger, A, Kuntsi, J, Oades, RD, Banaschewski, T, Franke, B, Buitelaar, JK, Arias Vasquez, A, Doyle, AE, Reif, A, Lesch, KP, Freitag, C, Rivero, O, Palmason, H, Romanos, M, Langley, K, Rietschel, M, Witt, SH, Dalsgaard, S, Borglum, AD, Waldman, I, Wilmot, B, Molly, N, Bau, CHD, Crosbie, J, Schachar, R, Loo, SK, McGough, JJ, Grevet, EH, Medland, SE, Robinson, E, Weiss, LA, Bacchelli, E, Bailey, A, Bal, V, Battaglia, A, Betancur, C, Bolton, P, Cantor, R, Celestino-Soper, P, Dawson, G, De Rubeis, S, Duque, F, Green, A, Klauck, SM, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, De-Luca, DM, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, TG, Thompson, RC, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, McIntosh, A, Bergen, SE, Schalling, M, Jamain, S, Maaser, A, Fischer, SB, Reinbold, CS, Fullerton, JM, Guzman-Parra, J, Mayoral, F, Schofield, PR, Cichon, S, Muhleisen, TW, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, PB, Gershon, ES, Rice, J, Potash, JB, Zandi, PP, Craddock, N, Ferrier, IN, Alda, M, Rouleau, GA, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, PM, Cruceanu, C, Jones, IR, Posthuma, D, Andlauer, TFM, Forstner, AJ, Streit, F, Baune, BT, Air, T, Sinnamon, G, Wray, NR, MacIntyre, DJ, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, CM, Hickie, I, Pergadia, M, Mehta, D, Smit, JH, Jansen, R, de Geus, E, Dunn, E, Li, QS, Nauck, M, Schoevers, RA, Beekman, AT, Knowles, JA, Viktorin, A, Arnold, P, Barr, CL, Bedoya-Berrio, G, Bienvenu, OJ, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, EM, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, GL, Hartmann, A, Hirschtritt, ME, Hoekstra, PJ, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, GJ, Macciardi, F, Madruga-Garrido, M, Malaty, IA, Maras, A, McGrath, L, Miguel, EC, Mir, P, Nestadt, G, Nicolini, H, Okun, MS, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, EM, Reus, V, Richter, MA, Riddle, MA, Robertson, MM, Roessner, V, Rosario, M, Samuels, JF, Sandor, P, Stein, DJ, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, JR, Wolanczyk, T, Worbe, Y, Zai, G, Goes, FS, McLaughlin, N, Nestadt, PS, Grabe, HJ, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, SA, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, DeLisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kucinskas, V, Lee Chee Keong, J, Limborska, S, Loughland, C, Lonnqvist, J, Maher, B, Mattheisen, M, McDonald, C, Murphy, KC, Nenadic, I, van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, AR, Schall, U, Schwab, SG, Sim, K, So, HC, Stogmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, PV, Henskens, F, Mattingsdal, M, Oh, SY, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, CM, Daly, M, Dichgans, M, Faraone, SV, Guerreiro, R, Holmans, P, Kendler, KS, Koeleman, B, Mathews, CA, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, NW, Cotsapas, C, Palotie, A, Smoller, JW, Sullivan, P, Rosand, J, Corvin, A, Neale, BM, Schott, JM, Anney, R, Elia, J, Grigoroiu-Serbanescu, M, Edenberg, HJ and Murray, R (2018) Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757.Google ScholarPubMed
Bartoli, F, Crocamo, C, Gennaro, GM, Castagna, G, Trotta, G, Clerici, M and Carra, G (2016) Exploring the association between bipolar disorder and uric acid: a mediation analysis. Journal of Psychosomatic Research 84, 56–59.CrossRefGoogle ScholarPubMed
Bartoli, F, Crocamo, C, Clerici, M and Carra, G (2017 a) Allopurinol as add-on treatment for mania symptoms in bipolar disorder: systematic review and meta-analysis of randomised controlled trials. British Journal of Psychiatry 210, 10–15.CrossRefGoogle ScholarPubMed
Bartoli, F, Crocamo, C, Dakanalis, A, Brosio, E, Miotto, A, Capuzzi, E, Clerici, M and Carra, G (2017 b) Purinergic system dysfunctions in subjects with bipolar disorder: a comparative cross-sectional study. Comprehensive Psychiatry 73, 1–6.CrossRefGoogle ScholarPubMed
Bicikova, M, Hill, M, Ripova, D, Mohr, P and Hampl, R (2013) Determination of steroid metabolome as a possible tool for laboratory diagnosis of schizophrenia. Journal of Steroid Biochemistry and Molecular Biology 133, 77–83.CrossRefGoogle ScholarPubMed
Birner, A, Platzer, M, Bengesser, SA, Dalkner, N, Fellendorf, FT, Queissner, R, Pilz, R, Rauch, P, Maget, A, Hamm, C, Herzog-Eberhard, S, Mangge, H, Fuchs, D, Moll, N, Zelzer, S, Schutze, G, Schwarz, M, Reininghaus, B, Kapfhammer, HP and Reininghaus, EZ (2017) Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder. PLoS One 12, e0172699.CrossRefGoogle ScholarPubMed
Bogdanov, M, Matson, WR, Wang, L, Matson, T, Saunders-Pullman, R, Bressman, SS and Flint, BM (2008) Metabolomic profiling to develop blood biomarkers for Parkinson's disease. Brain 131, 389–396.CrossRefGoogle ScholarPubMed
Bowman, GL, Shannon, J, Frei, B, Kaye, JA and Quinn, JF (2010) Uric acid as a CNS antioxidant. Journal of Alzheimer's disease 19, 1331–1336.CrossRefGoogle ScholarPubMed
Brunstein, MG, Ghisolfi, ES, Ramos, FL and Lara, DR (2005) A clinical trial of adjuvant allopurinol therapy for moderately refractory schizophrenia. Journal of Clinical Psychiatry 66, 213–219.CrossRefGoogle ScholarPubMed
Cardno, AG and Owen, MJ (2014) Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder. Schizophrenia Bulletin 40, 504–515.CrossRefGoogle ScholarPubMed
Carlborg, A, Jokinen, J, Jonsson, EG, Erhardt, S and Nordstrom, P (2013) CSF kynurenic acid and suicide risk in schizophrenia spectrum psychosis. Psychiatry Research 205, 165–167.CrossRefGoogle ScholarPubMed
Chaves Filho, AJM, Lima, CNC, Vasconcelos, SMM, de Lucena, DF, Maes, M and Macedo, D (2018) IDO chronic immune activation and tryptophan metabolic pathway: a potential pathophysiological link between depression and obesity. Progress in Neuro-Psychopharmacology and Biological Psychiatry 80, 234–249.CrossRefGoogle ScholarPubMed
Chiappelli, J, Pocivavsek, A, Nugent, KL, Notarangelo, FM, Kochunov, P, Rowland, LM, Schwarcz, R and Hong, LE (2014) Stress-induced increase in kynurenic acid as a potential biomarker for patients with schizophrenia and distress intolerance. JAMA Psychiatry 71, 761–768.CrossRefGoogle ScholarPubMed
Condray, R, Dougherty, GG Jr, Keshavan, MS, Reddy, RD, Haas, GL, Montrose, DM, Matson, WR, McEvoy, J, Kaddurah-Daouk, R and Yao, JK (2011) 3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia. International Journal of Neuropsychopharmacology 14, 756–767.CrossRefGoogle ScholarPubMed
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379.CrossRefGoogle Scholar
Day, RO, Kamel, B, Kannangara, DR, Williams, KM and Graham, GG (2016) Xanthine oxidoreductase and its inhibitors: relevance for gout. Clinical Science (London) 130, 2167–2180.CrossRefGoogle ScholarPubMed
Dieset, I, Djurovic, S, Tesli, M, Hope, S, Mattingsdal, M, Michelsen, A, Joa, I, Larsen, TK, Agartz, I, Melle, I, Rossberg, JI, Aukrust, P, Andreassen, OA and Ueland, T (2012) Up-regulation of NOTCH4 gene expression in bipolar disorder. American Journal of Psychiatry 169, 1292–1300.CrossRefGoogle ScholarPubMed
Erhardt, S, Schwieler, L, Imbeault, S and Engberg, G (2017) The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology 112, 297–306.CrossRefGoogle ScholarPubMed
Esler, MD, Lambert, GW, Ferrier, C, Kaye, DM, Wallin, BG, Kalff, V, Kelly, MJ and Jennings, GL (1995) Central nervous system noradrenergic control of sympathetic outflow in normotensive and hypertensive humans. Clinical and Experimental Hypertension 17, 409–423.CrossRefGoogle ScholarPubMed
Fazio, F, Lionetto, L, Curto, M, Iacovelli, L, Cavallari, M, Zappulla, C, Ulivieri, M, Napoletano, F, Capi, M, Corigliano, V, Scaccianoce, S, Caruso, A, Miele, J, De Fusco, A, Di Menna, L, Comparelli, A, De Carolis, A, Gradini, R, Nistico, R, De Blasi, A, Girardi, P, Bruno, V, Battaglia, G, Nicoletti, F and Simmaco, M (2015) Xanthurenic acid activates mGlu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia. Scientific Reports 5, 17799.CrossRefGoogle Scholar
First, MB, Spitzer, RL, Gibbon, M and Williams, JBW (1995) Structured Clinical Interview for DSM-IV Axis I Disorders: Patient Edition (SCID-P), Version 2. New York: Biometrics Research, New York State Psychiatric Institute.CrossRefGoogle Scholar
Fitzgerald, PJ (2014) Is elevated norepinephrine an etiological factor in some cases of schizophrenia? Psychiatry Research 215, 497–504.CrossRefGoogle ScholarPubMed
Fukui, S, Schwarcz, R, Rapoport, SI, Takada, Y and Smith, QR (1991) Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. Journal of Neurochemistry 56, 2007–2017.CrossRefGoogle ScholarPubMed
Fukushima, T, Iizuka, H, Yokota, A, Suzuki, T, Ohno, C, Kono, Y, Nishikiori, M, Seki, A, Ichiba, H, Watanabe, Y, Hongo, S, Utsunomiya, M, Nakatani, M, Sadamoto, K and Yoshio, T (2014) Quantitative analyses of schizophrenia-associated metabolites in serum: serum D-lactate levels are negatively correlated with gamma-glutamylcysteine in medicated schizophrenia patients. PLoS One 9, e101652.CrossRefGoogle ScholarPubMed
Gobaille, S, Kemmel, V, Brumaru, D, Dugave, C, Aunis, D and Maitre, M (2008) Xanthurenic acid distribution, transport, accumulation and release in the rat brain. Journal of Neurochemistry 105, 982–993.CrossRefGoogle ScholarPubMed
Goldstein, DS, Eisenhofer, G and Kopin, IJ (2003) Sources and significance of plasma levels of catechols and their metabolites in humans. Journal of Pharmacology and Experimental Therapeutics 305, 800–811.CrossRefGoogle ScholarPubMed
Grande, I, Berk, M, Birmaher, B and Vieta, E (2016) Bipolar disorder. Lancet 387, 1561–1572.CrossRefGoogle ScholarPubMed
Grossman, F and Potter, WZ (1999) Catecholamines in depression: a cumulative study of urinary norepinephrine and its major metabolites in unipolar and bipolar depressed patients versus healthy volunteers at the NIMH. Psychiatry Research 87, 21–27.CrossRefGoogle ScholarPubMed
Guest, PC, Guest, FL and Martins-de, SD (2015) Making sense of blood-based proteomics and metabolomics in psychiatric research. International Journal of Neuropsychopharmacology 19, 1–10.Google ScholarPubMed
Gupta, M, Neavin, D, Liu, D, Biernacka, J, Hall-Flavin, D, Bobo, WV, Frye, MA, Skime, M, Jenkins, GD, Batzler, A, Kalari, K, Matson, W, Bhasin, SS, Zhu, H, Mushiroda, T, Nakamura, Y, Kubo, M, Wang, L, Kaddurah-Daouk, R and Weinshilboum, RM (2016) TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics. Molecular Psychiatry 21, 1717–1725.CrossRefGoogle ScholarPubMed
Gysin, R, Kraftsik, R, Sandell, J, Bovet, P, Chappuis, C, Conus, P, Deppen, P, Preisig, M, Ruiz, V, Steullet, P, Tosic, M, Werge, T, Cuenod, M and Do, KQ (2007) Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proceedings of the National Academy of Sciences of the United States of America 104, 16621–16626.CrossRefGoogle ScholarPubMed
Hartwig, FP, Borges, MC, Horta, BL, Bowden, J and Davey, SG (2017) Inflammatory biomarkers and risk of schizophrenia: a 2-sample mendelian randomization study. JAMA Psychiatry 74, 1226–1233.CrossRefGoogle ScholarPubMed
Hestad, KA, Engedal, K, Whist, JE and Farup, PG (2017) The relationships among tryptophan, kynurenine, indoleamine 2,3-dioxygenase, depression, and neuropsychological performance. Frontiers in Psychology 8, 1561.CrossRefGoogle ScholarPubMed
Johansen, KK, Wang, L, Aasly, JO, White, LR, Matson, WR, Henchcliffe, C, Beal, MF and Bogdanov, M (2009) Metabolomic profiling in LRRK2-related Parkinson's disease. PLoS One 4, e7551.CrossRefGoogle ScholarPubMed
Johansson, AS, Owe-Larsson, B, Asp, L, Kocki, T, Adler, M, Hetta, J, Gardner, R, Lundkvist, GB, Urbanska, EM and 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. Journal of Psychiatric Research 47, 1815–1823.CrossRefGoogle ScholarPubMed
Kaddurah-Daouk, R and Krishnan, KR (2009) Metabolomics: a global biochemical approach to the study of central nervous system diseases. Neuropsychopharmacology 34, 173–186.CrossRefGoogle Scholar
Kaddurah-Daouk, R, Yuan, P, Boyle, SH, Matson, W, Wang, Z, Zeng, ZB, Zhu, H, Dougherty, GG, Yao, JK, Chen, G, Guitart, X, Carlson, PJ, Neumeister, A, Zarate, C, Krishnan, RR, Manji, HK and Drevets, W (2012) Cerebrospinal fluid metabolome in mood disorders-remission state has a unique metabolic profile. Scientific Reports 2, 667.CrossRefGoogle Scholar
Kaddurah-Daouk, R, Zhu, H, Sharma, S, Bogdanov, M, Rozen, SG, Matson, W, Oki, NO, Motsinger-Reif, AA, Churchill, E, Lei, Z, Appleby, D, Kling, MA, Trojanowski, JQ, Doraiswamy, PM and Arnold, SE (2013) Alterations in metabolic pathways and networks in Alzheimer's disease. Translational Psychiatry 3, e244.CrossRefGoogle ScholarPubMed
Kanchanatawan, B, Sirivichayakul, S, Ruxrungtham, K, Carvalho, AF, Geffard, M, Ormstad, H, Anderson, G and Maes, M (2018) Deficit, but not nondeficit, schizophrenia is characterized by mucosa-associated activation of the tryptophan catabolite (TRYCAT) pathway with highly specific increases in IgA responses directed to picolinic, xanthurenic, and quinolinic acid. Molecular Neurobiology 55, 1524–1536.CrossRefGoogle Scholar
Kay, SR, Fiszbein, A and Opler, LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276.CrossRefGoogle Scholar
Kegel, ME, Bhat, M, Skogh, E, Samuelsson, M, Lundberg, K, Dahl, ML, Sellgren, C, Schwieler, L, Engberg, G, Schuppe-Koistinen, I and Erhardt, S (2014) Imbalanced kynurenine pathway in schizophrenia. International Journal of Tryptophan Research 7, 15–22.CrossRefGoogle Scholar
Kurita, M, Nishino, S, Numata, Y, Okubo, Y and Sato, T (2014) The noradrenaline metabolite MHPG is a candidate biomarker from the manic to the remission state in bipolar disorder I: a clinical naturalistic study. PLoS One 9, e100634.CrossRefGoogle Scholar
Lewis, DA (2002) The human brain revisited: opportunities and challenges in postmortem studies of psychiatric disorders. Neuropsychopharmacology 26, 143–154.CrossRefGoogle ScholarPubMed
Lichtenstein, P, Yip, BH, Bjork, C, Pawitan, Y, Cannon, TD, Sullivan, PF and Hultman, CM (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234–239.CrossRefGoogle ScholarPubMed
Lieberman, JA and First, MB (2018) Psychotic disorders. New England Journal of Medicine 379, 270–280.CrossRefGoogle ScholarPubMed
Lindberg, D, Shan, D, Ayers-Ringler, J, Oliveros, A, Benitez, J, Prieto, M, McCullumsmith, R and Choi, DS (2015) Purinergic signaling and energy homeostasis in psychiatric disorders. Current Molecular Medicine 15, 275–295.CrossRefGoogle ScholarPubMed
Liu, ML, Zheng, P, Liu, Z, Xu, Y, Mu, J, Guo, J, Huang, T, Meng, HQ and Xie, P (2014) GC-MS based metabolomics identification of possible novel biomarkers for schizophrenia in peripheral blood mononuclear cells. Molecular Biosystems 10, 2398–2406.CrossRefGoogle ScholarPubMed
Lim, CK, Essa, MM, de Paula Martins, R, Lovejoy, DB, Bilgin, AA, Waly, MI, Al-Farsi, YM, Al-Sharbati, M, Al-Shaffae, MA and Guillemin, GJ (2016) Altered kynurenine pathway metabolism in autism: implication for immune-induced glutamatergic activity. Autism Research 9, 621–631.CrossRefGoogle ScholarPubMed
Maas, JW, Contreras, SA, Miller, AL, Berman, N, Bowden, CL, Javors, MA, Seleshi, E and Weintraub, S (1993) Studies of catecholamine metabolism in schizophrenia/psychosis--I. Neuropsychopharmacology 8, 97–109.CrossRefGoogle Scholar
Maletic, V, Eramo, A, Gwin, K, Offord, SJ and Duffy, RA (2017) The role of norepinephrine and its alpha-adrenergic receptors in the pathophysiology and treatment of major depressive disorder and schizophrenia: a systematic review. Frontiers in Psychiatry 8, 42.CrossRefGoogle ScholarPubMed
Manji, HK, Quiroz, JA, Payne, JL, Singh, J, Lopes, BP, Viegas, JS and Zarate, CA (2003) The underlying neurobiology of bipolar disorder. World Psychiatry 2, 136–146.Google ScholarPubMed
Michel, TM, Sheldrick, AJ, Camara, S, Grunblatt, E, Schneider, F and Riederer, P (2011) Alteration of the pro-oxidant xanthine oxidase (XO) in the thalamus and occipital cortex of patients with schizophrenia. World Journal of Biological Psychiatry 12, 588–597.CrossRefGoogle ScholarPubMed
Motsinger-Reif, AA, Zhu, H, Kling, MA, Matson, W, Sharma, S, Fiehn, O, Reif, DM, Appleby, DH, Doraiswamy, PM, Trojanowski, JQ, Kaddurah-Daouk, R and Arnold, SE (2013) Comparing metabolomic and pathologic biomarkers alone and in combination for discriminating Alzheimer's disease from normal cognitive aging. Acta Neuropathologica Communications 1, 28.CrossRefGoogle ScholarPubMed
Mukherjee, D, Krishnamurthy, VB, Millett, CE, Reider, A, Can, A, Groer, M, Fuchs, D, Postolache, TT and Saunders, EFH (2018) Total sleep time and kynurenine metabolism associated with mood symptom severity in bipolar disorder. Bipolar Disorder 20, 27–34.CrossRefGoogle ScholarPubMed
Neale, SA, Copeland, CS, Uebele, VN, Thomson, FJ and Salt, TE (2013) Modulation of hippocampal synaptic transmission by the kynurenine pathway member xanthurenic acid and other VGLUT inhibitors. Neuropsychopharmacology 38, 1060–1067.CrossRefGoogle ScholarPubMed
Niklasson, F, Agren, H and Hallgren, R (1983) Purine and monoamine metabolites in cerebrospinal fluid: parallel purinergic and monoaminergic activation in depressive illness? Journal of Neurology, Neurosurgery and Psychiatry 46, 255–260.CrossRefGoogle ScholarPubMed
Oresic, M, Tang, J, Seppanen-Laakso, T, Mattila, I, Saarni, SE, Saarni, SI, Lonnqvist, J, Sysi-Aho, M, Hyotylainen, T, Perala, J and Suvisaari, J (2011) Metabolome in schizophrenia and other psychotic disorders: a general population-based study. Genome Medicine 3, 19.CrossRefGoogle ScholarPubMed
Ortiz, R, Ulrich, H, Zarate, CA Jr and Machado-Vieira, R (2015) Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics. Progress in Neuro-Psychopharmacology and Biological Psychiatry 57, 117–131.CrossRefGoogle ScholarPubMed
Owen, MJ, Sawa, A and Mortensen, PB (2016) Schizophrenia. Lancet 388, 86–97.CrossRefGoogle ScholarPubMed
Pedersen, G, Hagtvet, KA and Karterud, S (2007) Generalizability studies of the global assessment of functioning-split version. Comprehensive Psychiatry 48, 88–94.CrossRefGoogle ScholarPubMed
Plitman, E, Iwata, Y, Caravaggio, F, Nakajima, S, Chung, JK, Gerretsen, P, Kim, J, Takeuchi, H, Chakravarty, MM, Remington, G and Graff-Guerrero, A (2017) Kynurenic acid in schizophrenia: a systematic review and meta-analysis. Schizophrenia Bulletin 43, 764–777.CrossRefGoogle ScholarPubMed
Reddy, R, Keshavan, M and Yao, JK (2003) Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophrenia Research 62, 205–212.CrossRefGoogle ScholarPubMed
Rotroff, DM, Corum, DG, Motsinger-Reif, A, Fiehn, O, Bottrel, N, Drevets, WC, Singh, J, Salvadore, G and Kaddurah-Daouk, R (2016) Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants. Translational Psychiatry 6, e894.CrossRefGoogle ScholarPubMed
Roussel, G, Bessede, A, Klein, C, Maitre, M and Mensah-Nyagan, AG (2016) Xanthurenic acid is localized in neurons in the central nervous system. Neuroscience 329, 226–238.CrossRefGoogle ScholarPubMed
Rozen, S, Cudkowicz, ME, Bogdanov, M, Matson, WR, Kristal, BS, Beecher, C, Harrison, S, Vouros, P, Flarakos, J, Vigneau-Callahan, K, Matson, TD, Newhall, KM, Beal, MF, Brown, RH Jr and Kaddurah-Daouk, R (2005) Metabolomic analysis and signatures in motor neuron disease. Metabolomics 1, 101–108.CrossRefGoogle ScholarPubMed
Rush, AJ, Gullion, CM, Basco, MR, Jarrett, RB and Trivedi, MH (1996) The inventory of depressive symptomatology (IDS): psychometric properties. Psychological Medicine 26, 477–486.CrossRefGoogle ScholarPubMed
Sathyasaikumar, KV, Tararina, M, Wu, HQ, Neale, SA, Weisz, F, Salt, TE and Schwarcz, R (2017) Xanthurenic acid formation from 3-hydroxykynurenine in the mammalian brain: neurochemical characterization and physiological effects. Neuroscience 367, 85–97.CrossRefGoogle ScholarPubMed
Schwarcz, R, Bruno, JP, Muchowski, PJ and Wu, HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nature Reviews. Neuroscience 13, 465–477.CrossRefGoogle ScholarPubMed
Sellgren, CM, Kegel, ME, Bergen, SE, Ekman, CJ, Olsson, S, Larsson, M, Vawter, MP, Backlund, L, Sullivan, PF, Sklar, P, Smoller, JW, Magnusson, PK, Hultman, CM, Walther-Jallow, L, Svensson, CI, Lichtenstein, P, Schalling, M, Engberg, G, Erhardt, S and Landen, M (2016) A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder. Molecular Psychiatry 21, 1342–1350.CrossRefGoogle ScholarPubMed
Sethi, S and Brietzke, E (2015) Omics-Based biomarkers: application of metabolomics in neuropsychiatric disorders. International Journal of Neuropsychopharmacology 19, 1–13.Google ScholarPubMed
Tasic, L, Pontes, JGM, Carvalho, MS, Cruz, G, Dal, MC, Sethi, S, Pedrini, M, Rizzo, LB, Zeni-Graiff, M, Asevedo, E, Lacerda, ALT, Bressan, RA, Poppi, RJ, Brietzke, E and Hayashi, MAF (2017) Metabolomics and lipidomics analyses by 1H nuclear magnetic resonance of schizophrenia patient serum reveal potential peripheral biomarkers for diagnosis. Schizophrenia Research 185, 182–189.CrossRefGoogle ScholarPubMed
Tesli, M, Espeseth, T, Bettella, F, Mattingsdal, M, Aas, M, Melle, I, Djurovic, S and Andreassen, OA (2014) Polygenic risk score and the psychosis continuum model. Acta Psychiatrica Scandinavica 130, 311–317.CrossRefGoogle ScholarPubMed
Turck, CW and Filiou, MD (2015) What have mass spectrometry-based proteomics and metabolomics (Not) taught us about psychiatric disorders? Molecular Neuropsychiatry 1, 69–75.CrossRefGoogle ScholarPubMed
Van Snellenberg, JX and de Candia, T (2009) Meta-analytic evidence for familial coaggregation of schizophrenia and bipolar disorder. Archives of General Psychiatry 66, 748–755.CrossRefGoogle ScholarPubMed
van Winkel, R, Stefanis, NC and Myin-Germeys, I (2008) Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophrenia Bulletin 34, 1095–1105.CrossRefGoogle ScholarPubMed
Volk, DW, Chitrapu, A, Edelson, JR, Roman, KM, Moroco, AE and Lewis, DA (2015) Molecular mechanisms and timing of cortical immune activation in schizophrenia. American Journal of Psychiatry 172, 1112–1121.CrossRefGoogle Scholar
Volk, DW, Sampson, AR, Zhang, Y, Edelson, JR and Lewis, DA (2016) Cortical GABA markers identify a molecular subtype of psychotic and bipolar disorders. Psychological Medicine 46, 2501–2512.CrossRefGoogle ScholarPubMed
Wonodi, I, Stine, OC, Sathyasaikumar, KV, Roberts, RC, Mitchell, BD, Hong, LE, Kajii, Y, Thaker, GK and Schwarcz, R (2011) Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Archives of General Psychiatry 68, 665–674.CrossRefGoogle ScholarPubMed
Wright, BL, Lai, JT and Sinclair, AJ (2012) Cerebrospinal fluid and lumbar puncture: a practical review. Journal of Neurology 259, 1530–1545.CrossRefGoogle ScholarPubMed
Xu, XJ, Zheng, P, Ren, GP, Liu, ML, Mu, J, Guo, J, Cao, D, Liu, Z, Meng, HQ and Xie, P (2014) 2,4-Dihydroxypyrimidine is a potential urinary metabolite biomarker for diagnosing bipolar disorder. Molecular Biosystems 10, 813–819.CrossRefGoogle ScholarPubMed
Yao, JK, Dougherty, GG Jr, Reddy, RD, Keshavan, MS, Montrose, DM, Matson, WR, McEvoy, J and Kaddurah-Daouk, R (2010 a) Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naive patients with schizophrenia. PLoS One 5, e9508.CrossRefGoogle ScholarPubMed
Yao, JK, Dougherty, GG Jr, Reddy, RD, Keshavan, MS, Montrose, DM, Matson, WR, Rozen, S, Krishnan, RR, McEvoy, J and Kaddurah-Daouk, R (2010 b) Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia. Molecular Psychiatry 15, 938–953.CrossRefGoogle ScholarPubMed
Yao, JK, Condray, R, Dougherty, GG Jr, Keshavan, MS, Montrose, DM, Matson, WR, McEvoy, J, Kaddurah-Daouk, R and Reddy, RD (2012) Associations between purine metabolites and clinical symptoms in schizophrenia. PLoS One 7, e42165.CrossRefGoogle Scholar
Yao, JK, Dougherty, GG, Reddy, RD, Matson, WR, Kaddurah-Daouk, R and Keshavan, MS (2013) Associations between purine metabolites and monoamine neurotransmitters in first-episode psychosis. Frontiers in Cellular Neuroscience 7, 90.CrossRefGoogle ScholarPubMed
Yoshimi, N, Futamura, T, Kakumoto, K, Salehi, AM, Sellgren, CM, Holmen-Larsson, J, Jakobsson, J, Palsson, E, Landen, M and Hashimoto, K (2016) Blood metabolomics analysis identifies abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism in bipolar disorder. BBA Clinical 5, 151–158.CrossRefGoogle ScholarPubMed
Young, RC, Biggs, JT, Ziegler, VE and Meyer, DA (1978) A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429–435.CrossRefGoogle ScholarPubMed
Zhang, R, Zhang, T, Ali, AM, Al, WM, Pickard, B and Watson, DG (2016) Metabolomic profiling of post-mortem brain reveals changes in amino acid and glucose metabolism in mental illness compared with controls. Computational and Structural Biotechnology Journal 14, 106–116.CrossRefGoogle ScholarPubMed
Zhu, H, Bogdanov, MB, Boyle, SH, Matson, W, Sharma, S, Matson, S, Churchill, E, Fiehn, O, Rush, JA, Krishnan, RR, Pickering, E, Delnomdedieu, M and Kaddurah-Daouk, R (2013) Pharmacometabolomics of response to sertraline and to placebo in major depressive disorder - possible role for methoxyindole pathway. PLoS One 8, e68283.CrossRefGoogle ScholarPubMed
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