Metabolomics in Schizophrenia and Major Depressive Disorder

Abstract

Defining pathophenotype, a systems level consequence of a disease genotype, together with environmental and stochastic influences, is an arduous task in psychiatry. It is also an appealing goal, given growing need for appreciation of brain disorders biological complexity, aspiration for diagnostic tests development and ambition to identify novel drug targets. Here, we focus on the Schizophrenia and Major Depressive Disorder and highlight recent advances in metabolomics research. As a systems biology tool, metabolomics holds a promise to take part in elucidating interactions between genes and environment, in complex behavioral traits and psychopathology risk translational research.

Keywords

Schizophrenia / Major Depressive Disorder / omics / metabolomics / systems biology

References

[1] Abrusán G (2012). Somatic transposition in the brain has the potential to influence the biosynthesis of metabolites involved in Parkinson’s disease and schizophrenia. Biol Direct, 7(1): 41

[2] Alkondon M, Pereira E F, Yu P, Arruda E Z, Almeida L E, Guidetti P, Fawcett W P, Sapko M T, Randall W R, Schwarcz R, Tagle D A, Albuquerque E X (2004). Targeted deletion of the kynurenine aminotransferase ii gene reveals a critical role of endogenous kynurenic acid in the regulation of synaptic transmission via α7 nicotinic receptors in the hippocampus. J Neurosci, 24(19): 4635–4648

[3] Allen G I, Maletić-Savatić M (2011). Sparse non-negative generalized PCA with applications to metabolomics. Bioinformatics, 27 (21): 3029–3035

[4] Andreou D, Söderman E, Axelsson T, Sedvall G C, Terenius L, Agartz I, Jönsson E G (2014). Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis. Behav Brain Funct, 10(1): 26

[5] Appleton K M, Rogers P J, Ness A R (2008). Is there a role for n-3 long-chain polyunsaturated fatty acids in the regulation of mood and behaviour? A review of the evidence to date from epidemiological studies, clinical studies and intervention trials. Nutr Res Rev, 21(1): 13–41

[6] Arai M, Yuzawa H, Nohara I, Ohnishi T, Obata N, Iwayama Y, Haga S, Toyota T, Ujike H, Arai M, Ichikawa T, Nishida A, Tanaka Y, Furukawa A, Aikawa Y, Kuroda O, Niizato K, Izawa R, Nakamura K, Mori N, Matsuzawa D, Hashimoto K, Iyo M, Sora I, Matsushita M, Okazaki Y, Yoshikawa T, Miyata T, Itokawa M (2010). Enhanced carbonyl stress in a subpopulation of schizophrenia. Arch Gen Psychiatry, 67(6): 589–597

[7] Arnold J M, Choi W T, Sreekumar A, Maletić-Savatić M(2015). Analytical strategies for studying stem cell metabolism, Front Biol, 10 (2): 141–153

[8] Asberg M, Bertilsson L, Mårtensson B, Scalia-Tomba G P, Thorén P, Träskman-Bendz L (1984). CSF monoamine metabolites in melancholia. ActaPsychiatrScand, 69(3): 201–219

[9] Ashcroft G W, Crawford T B, Eccleston D, Sharman D F, MacDougall E J, Stanton J B, Binns J K (1966). 5-hydroxyindole compounds in the cerebrospinal fluid of patients with psychiatric or neurological diseases. Lancet, 2(7472): 1049–1052

[10] Bernstein H G, Bogerts B, Keilhoff G (2005). The many faces of nitric oxide in schizophrenia. A review. Schizophr Res, 78(1): 69–86

[11] Bitanihirwe B K, Woo T U (2011). Oxidative stress in schizophrenia: an integrated approach. NeurosciBiobehav Rev, 35(3): 878–893

[12] Botas A, Campbell H M,Han X , Maletic-Savatic M(2015). Metabolomics of neurodegenerative diseases, Int Rev Neurobiol, 122: 53–80

[13] Bowers M BJr (1973). 5-Hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) following probenecid in acute psychotic patients treated with phenothiazines. Psychopharmacologia, 28(4): 309–318

[14] Bundo M, Toyoshima M, Okada Y, Akamatsu W, Ueda J, Nemoto-Miyauchi T, Sunaga F, Toritsuka M, Ikawa D, Kakita A, Kato M, Kasai K, Kishimoto T, Nawa H, Okano H, Yoshikawa T, Kato T, Iwamoto K (2014). Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron, 81(2): 306–313

[15] Cantoni G L, Mudd S H, Andreoli V (1989). Affective disorders and S-adenosylmethionine: a new hypothesis. Trends Neurosci, 12(9): 319–324

[16] Capuron L, Neurauter G, Musselman D L, Lawson D H, Nemeroff C B, Fuchs D, Miller A H (2003). Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry, 54(9): 906–914

[17] Cherlyn S Y, Woon P S, Liu J J, Ong W Y, Tsai G C, Sim K (2010). Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance. Neurosci Biobehav Rev, 34(6): 958–977

[18] Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard F P, Maurice K, Essioux L, Millasseau P, Grel P, Debailleul V, Simon A M, Caterina D, Dufaure I, Malekzadeh K, Belova M, Luan J J, Bouillot M, Sambucy J L, Primas G, Saumier M, Boubkiri N, Martin-Saumier S, Nasroune M, Peixoto H, Delaye A, Pinchot V, Bastucci M, Guillou S, Chevillon M, Sainz-Fuertes R, Meguenni S, Aurich-Costa J, Cherif D, Gimalac A, Van Duijn C, Gauvreau D, Ouellette G, Fortier I, Raelson J, Sherbatich T, Riazanskaia N, Rogaev E, Raeymaekers P, Aerssens J, Konings F, Luyten W, Macciardi F, Sham P C, Straub R E, Weinberger D R, Cohen N, Cohen D (2002). Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A, 99(21): 13675–13680

[19] Craft S, Watson G S (2004). Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol, 3(3): 169–178

[20] Domino E F, Krause R R (1974). Free and bound serum tryptophan in drug-free normal controls and chronic schizophrenic patients. Biol Psychiatry, 8(3): 265–279

[21] Erhardt S, Blennow K, Nordin C, Skogh E, Lindström L H, Engberg G (2001). Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett, 313(1-2): 96–98

[22] Evrony G D, Lee E, Mehta B K, Benjamini Y, Johnson R M, Cai X, Yang L, Haseley P, Lehmann H S, Park P J, Walsh C A (2015). Cell lineage analysis in human brain using endogenous retroelements. Neuron, 85(1): 49–59

[23] Ferentinos P, Dikeos D (2012). Genetic correlates of medical comorbidity associated with schizophrenia and treatment with antipsychotics. Curr Opin Psychiatry, 25(5): 381–390

[24] Fernández-Novoa L, Cacabelos R (2001). Histamine function in brain disorders. Behav Brain Res, 124(2): 213–233

[25] 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, 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(7): e101652

[26] Garelis E, Gillin J C, Wyatt R J, Neff N (1975). Elevated blood serotonin concentration in unmedicated chronic schizophrenic patients. Am J Psychiatry, 132(2): 184–186

[27] Gattaz W F, Brunner J, Schmitt A, Maras A (1994). Accelerated breakdown of membrane phospholipids in schizophrenia—implications for the hypofrontality hypothesis. Fortschr Neurol Psychiatr, 62(12): 489–496

[28] Gattaz W F, Hübner C V, Nevalainen T J, Thuren T, Kinnunen P K (1990). Increased serum phospholipase A2 activity in schizophrenia: a replication study. Biol Psychiatry, 28(6): 495–501

[29] Gattaz W F, Köllisch M, Thuren T, Virtanen J A, Kinnunen P K J (1987). Increased plasma phospholipase-A2 activity in schizophrenic patients: reduction after neuroleptic therapy. Biol Psychiatry, 22(4): 421–426

[30] Gillin J C, Kaplan J A, Wyatt R J (1976). Clinical effects of tryptophan in chronic schizophrenic patients. Biol Psychiatry, 11(5): 635–639

[31] Glinsky G V (2015). Transposable elements and DNA methylation create in embryonic stem cells human-specific regulatory sequences associated with distal enhancers and noncoding RNAs. Genome Biol Evol, 7(6): 1432–1454

[32] Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P, Deppen P, Preisig M, Ruiz V, Steullet P, Tosic M, Werge T, Cuénod M, Do K Q (2007). Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci U S A, 104(42): 16621–16626

[33] Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, Nakazato M, Kumakiri C, Okada S, Hasegawa H, Imai K, Iyo M (2003). Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry, 60(6): 572–576

[34] Hashimoto K, Shimizu E, Iyo M (2005). Dysfunction of glia-neuron communication in pathophysiology of schizophrenia. Curr Psychiatry Rev, 1(2): 151–163

[35] He Y, Yu Z, Giegling I, Xie L, Hartmann A M, Prehn C, Adamski J, Kahn R, Li Y, Illig T, Wang-Sattler R, Rujescu D (2012). Schizophrenia shows a unique metabolomics signature in plasma. Transl Psychiatry, 2(8): e149

[36] Hernández-Benítez R, Vangipuram S D, Ramos-Mandujano G, Lyman W D, Pasantes-Morales H (2013). Taurine enhances the growth of neural precursors derived from fetal human brain and promotes neuronal specification. Dev Neurosci, 35(1): 40–49

[37] Hilmas C, Pereira E F, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque E X (2001). The brain metabolite kynurenic acid inhibits α7 nicotinic receptor activity and increases non-α7 nicotinic receptor expression: physiopathological implications. J Neurosci, 21(19): 7463–7473

[38] Hosak L (2013). New findings in the genetics of schizophrenia. World J Psychiatry, 3(3): 57–61

[39] Inoue K, Okamoto M, Shibato J, Lee M C, Matsui T, Rakwal R, Soya H (2015). Long-term mild, rather than intense, exercise enhances adult hippocampal neurogenesis and greatly changes the transcriptomic profile of the hippocampus. PLoS One, 10(6): e0128720

[40] Iwayama Y, Hattori E, Maekawa M, Yamada K, Toyota T, Ohnishi T, Iwata Y, Tsuchiya K J, Sugihara G, Kikuchi M, Hashimoto K, Iyo M, Inada T, Kunugi H, Ozaki N, Iwata N, Nanko S, Iwamoto K, Okazaki Y, Kato T, Yoshikawa T (2010). Association analyses between brain-expressed fatty-acid binding protein (FABP) genes and schizophrenia and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet, 153B(2): 484–493

[41] Jackman H, Luchins D, Meltzer H Y (1983). Platelet serotonin levels in schizophrenia: relationship to race and psychopathology. Biol Psychiatry, 18(8): 887–902

[42] Joseph M H, Owen F, Baker H F, Bourne R C (1977). Platelet serotonin concentration and monoamine oxidase activity in unmedicated chronic schizophrenic and in schizoaffective patients. Psychol Med, 7(1): 159–162

[43] Kaddurah-Daouk R, Yuan P, Boyle S H, Matson W, Wang Z, Zeng Z B, Zhu H, Dougherty G G, Yao J K, Chen G, Guitart X, Carlson P J, Neumeister A, Zarate C, Krishnan R R, Manji H K, Drevets W (2012). Cerebrospinal fluid metabolome in mood disorders-remission state has a unique metabolic profile. Sci Rep, 2(667): 667

[44] Kempf L, Nicodemus K K, Kolachana B, Vakkalanka R, Verchinski B A, Egan M F, Straub R E, Mattay V A, Callicott J H, Weinberger D R, Meyer-Lindenberg A (2008). Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function. PLoS Genet, 4(11): e1000252

[45] Kolakowska T, Molyneux S G (1987). Platelet serotonin concentration in schizophrenic patients. Am J Psychiatry, 144(2): 232–234

[46] Kotronen A, Velagapudi V R, Yetukuri L, Westerbacka J, Bergholm R, Ekroos K, Makkonen J, Taskinen M R, Oresic M, Yki-Järvinen H (2009). Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations. Diabetologia, 52(4): 684–690

[47] Kotronen A, Yki-Järvinen H (2008). Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol, 28(1): 27–38

[48] Lee L H, Shui G, Farooqui A A, Wenk M R, Tan C H, Ong W Y (2009). Lipidomic analyses of the mouse brain after antidepressant treatment: evidence for endogenous release of long-chain fatty acids? Int J Neuropsychopharmacol, 12(7): 953–964

[49] Liu H, Heath S C, Sobin C, Roos J L, Galke B L, Blundell M L, Lenane M, Robertson B, Wijsman E M, Rapoport J L, Gogos J A, Karayiorgou M (2002). Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci U S A, 99(6): 3717–3722

[50] Liu X, Zheng P, Zhao X, Zhang Y, Hu C, Li J, Zhao J, Zhou J, Xie P, Xu G (2015). Discovery and validation of plasma biomarkers for major depressive disorder classification based on liquid chromatography-mass spectrometry. J Proteome Res, 14(5): 2322–2330

[51] Luykx J J, Bakker S C, Lentjes E, Neeleman M, Strengman E, Mentink L, DeYoung J, de Jong S, Sul J H, Eskin E, van Eijk K, van Setten J, Buizer-Voskamp J E, Cantor R M, Lu A, van Amerongen M, van Dongen E P, Keijzers P, Kappen T, Borgdorff P, Bruins P, Derks E M, Kahn R S, Ophoff R A (2014). Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid. Mol Psychiatry, 19(2): 228–234

[52] Madeira C, Freitas M E, Vargas-Lopes C, Wolosker H, Panizzutti R (2008). Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia. Schizophr Res, 101(1-3): 76–83

[53] Maekawa M, Owada Y, Yoshikawa T (2011). Role of polyunsaturated fatty acids and fatty acid binding protein in the pathogenesis of schizophrenia. Curr Pharm Des, 17(2): 168–175

[54] Maletić-Savatić M, Vingara L K, Manganas L N, Li Y, Zhang S, Sierra A, Hazel R, Smith D, Wagshul M E, Henn F, Krupp L, Enikolopov G, Benveniste H, Djurić P M, Pelczer I (2008). Metabolomics of neural progenitor cells: a novel approach to biomarker discovery. Cold Spring Harb Symp Quant Biol, 73:389–401

[55] Manowitz P, Gilmour D G, Racevskis J (1973). Low plasma tryptophan levels in recently hospitalized schizophrenics. Biol Psychiatry, 6(2): 109–118

[56] Martins-de-Souza D (2014). Proteomics, metabolomics, and protein interactomics in the characterization of the molecular features of major depressive disorder. Dialogues Clin Neurosci, 16(1): 63–73

[57] Middleton F A, Mirnics K, Pierri J N, Lewis D A, Levitt P (2002). Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci, 22(7): 2718–2729

[58] Milanovic S M, Thermenos H W, Goldstein J M, Brown A, Gabrieli S W, Makris N, Tsuang M T, Buka S L, Seidman L J(2011). Medial prefrontal cortical activation during working memory differentiates schizophrenia and bipolar psychotic patients: a pilot fMRI study. Schizophr Res, 129(2-3): 208–210

[59] Moon M L, Joesting J J, Lawson M A, Chiu G S, Blevins N A, Kwakwa K A, Freund G G (2014). The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice. Metabolism, 63(9): 1131–1140

[60] Moreno F A, Parkinson D, Palmer C, Castro W L, Misiaszek J, El Khoury A, Mathé A A, Wright R, Delgado P L (2010). CSF neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls. Eur Neuropsychopharmacol, 20(1): 18–24

[61] Mück-Seler D, Jakovljević M, Deanović Z (1988). Time course of schizophrenia and platelet 5-HT level. Biol Psychiatry, 23(3): 243–251

[62] Nichenametla S N, Ellison I, Calcagnotto A, Lazarus P, Muscat J E, Richie J P Jr (2008). Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of gamma-glutamylcysteine ligase. Free Radic Biol Med, 45(5): 645–650

[63] Nunes A F, Amaral J D, Lo A C, Fonseca M B, Viana R J, Callaerts-Vegh Z, D’Hooge R, Rodrigues C M (2012). TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-β deposition in APP/PS1 mice. Mol Neurobiol, 45(3): 440–454

[64] Olney J W, Farber N B (1995). Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry, 52(12): 998–1007

[65] Orešič M, Tang J, Seppänen-Laakso T, Mattila I, Saarni S E, Saarni S I, Lönnqvist J, Sysi-Aho M, Hyötyläinen T, Perälä J, Suvisaari J (2011). Metabolome in schizophrenia and other psychotic disorders: a general population-based study. Genome Med, 3(3): 19

[66] Paoletti L, Elena C, Domizi P, Banchio C (2011). Role of phosphatidylcholine during neuronal differentiation. IUBMB Life, 63(9): 714–720

[67] Park H R, Kim J Y, Park K Y, Lee J (2011). Lipotoxicity of palmitic Acid on neural progenitor cells and hippocampal neurogenesis. Toxicol Res, 27(2): 103–110

[68] Payne I R, Walsh E M, Whittenburg E J (1974). Relationship of dietary tryptophan and niacin to tryptophan metabolism in schizophrenics and nonschizophrenics. Am J Clin Nutr, 27(6): 565–571

[69] Peterson C, Vannucci M, KarakasC, Choi W, Ma L, Maletic-Savatic M(2013). Inferring metabolic networks using the Bayesian adaptive graphical lasso with informative priors. Stat Interface, 6(4): 547–558

[70] Prell G D, Green J P, Kaufmann C A, Khandelwal J K, Morrishow A M, Kirch D G, Linnoila M, Wyatt R J (1995). Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms. Schizophr Res, 14(2): 93–104

[71] Raffa M, Mechri A, Othman L B, Fendri C, Gaha L, Kerkeni A (2009). Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry, 33(7): 1178–1183

[72] Ramos-Loyo J, Medina-Hernández V, Estarrón-Espinosa M, Canales-Aguirre A, Gómez-Pinedo U, Cerdán-Sánchez L F (2013). Sex differences in lipid peroxidation and fatty acid levels in recent onset schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 44: 154–161

[73] Reiter R J, Tan D X, Jou M J, Korkmaz A, Manchester L C, Paredes S D (2008). Biogenic amines in the reduction of oxidative stress: melatonin and its metabolites. Neuro Endocrinol Lett, 29(4): 391–398

[74] Santin L J, Bilbao A, Pedraza C, Matas-Rico E, López-Barroso D, Castilla-Ortega E, Sánchez-López J, Riquelme R, Varela-Nieto I, de la Villa P, Suardíaz M, Chun J, De Fonseca F R, Estivill-Torrús G (2009). Behavioral phenotype of maLPA1-null mice: increased anxiety-like behavior and spatial memory deficits. Genes Brain Behav, 8(8): 772–784

[75] Santos-Soto I J, Chorna N, Carballeira N M, Vélez-Bartolomei J G, Méndez-Merced A T, Chornyy A P, Peña de Ortiz S (2013). Voluntary running in young adult mice reduces anxiety-like behavior and increases the accumulation of bioactive lipids in the cerebral cortex. PLoS One, 8(12): e81459

[76] Schell M J, Brady R O Jr, Molliver M E, Snyder S H (1997). D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J Neurosci, 17(5): 1604–1615

[77] Schwarcz R, Rassoulpour A, Wu H Q, Medoff D, Tamminga C A, Roberts R C (2001). Increased cortical kynurenate content in schizophrenia. Biol Psychiatry, 50(7): 521–530

[78] Sekar A, Bialas A R, de Rivera H, Davis A, Hammond T R, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose S A, Handsaker R E, Daly M J, Carroll M C, Stevens B, McCarroll S A, and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (2016). Schizophrenia risk from complex variation of complement component 4. Nature, 530(7589): 177–183

[79] Shimazu T, Hirschey M D, Newman J, He W, Shirakawa K, Le Moan N, Grueter C A, Lim H, Saunders L R, Stevens R D, Newgard C B, Farese R VJr, de Cabo R, Ulrich S, Akassoglou K, Verdin E (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science, 339(6116): 211–214

[80] Singer T, McConnell M J, Marchetto M C, Coufal N G, Gage F H (2010). LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? Trends Neurosci, 33(8): 345–354

[81] Smith Q R (2000). Transport of glutamate and other amino acids at the blood-brain barrier. J Nutr, 130(4SSuppl): 1016S–1022S

[82] Smoller J W (2016). The genetics of stress-related disorders: PTSD, depression, and anxiety disorders. Neuropsychopharmacology, 41(1): 297–319

[83] Stahl S M, Woo D J, Mefford I N, Berger P A, Ciaranello R D (1983). Hyperserotonemia and platelet serotonin uptake and release in schizophrenia and affective disorders. Am J Psychiatry, 140(1): 26–30

[84] Steffens D C, Jiang W, Krishnan K R, Karoly E D, Mitchell M W, O’Connor C M, Kaddurah-Daouk R (2010). Metabolomic differences in heart failure patients with and without major depression. J Geriatr Psychiatry Neurol, 23(2): 138–146

[85] Stone J M, Morrison P D, Pilowsky L S (2007). Glutamate and dopamine dysregulation in schizophrenia—a synthesis and selective review. J Psychopharmacol, 21(4): 440–452

[86] Stone T W (1993). Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev, 45(3): 309–379

[87] Stone W S, Faraone S V, Su J, Tarbox S I, Van Eerdewegh P, Tsuang M T (2004). Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample. Am J Med Genet B Neuropsychiatr Genet, 127B(1): 5–10

[88] Tandon N, Bolo N R, Sanghavi K, Mathew I T, Francis A N, Stanley J A, Keshavan M S (2013). Brain metabolite alterations in young adults at familial high risk for schizophrenia using proton magnetic resonance spectroscopy. Schizophr Res, 148(1-3): 59–66

[89] Tortorella A, Monteleone P, Fabrazzo M, Viggiano A, De Luca L, Maj M (2001). Plasma concentrations of amino acids in chronic schizophrenics treated with clozapine. Neuropsychobiology, 44(4): 167–171

[90] UptonK r,GerhardtD J, Jesuadian J S, Richardson S R, Sánchez-Luque F J, Bodea G O, Ewing A D, Salvador-PalomequeC,van der Knaap M S, Brennan P M, Vanderver A, Faulkner G J(2015). Ubiquitous L1 mosaicism in hippocampal neurons. Cell, 161(2): 228–239

[91] Vaz A R, Cunha C, Gomes C, Schmucki N, Barbosa M, Brites D (2015). Glycoursodeoxycholic acid reduces matrix metalloproteinase-9 and caspase-9 activation in a cellular model of superoxide dismutase-1 neurodegeneration. Mol Neurobiol, 51(3): 864–877

[92] Vingara L K, Yu H J,Wagshul M E , Serafin D,Christodoulou C , Pelczer I, Krupp L B, Maletić-Savatić M(2013). Metabolomic approach to human brain spectroscopy identifies associations between clinical features and the frontal lobe metabolome in multiple sclerosis. Neuroimage, 82: 586–594

[93] Wang S M, Han C, Lee S J, Patkar A A, Masand P S, Pae C U (2014). A review of current evidence for acetyl-l-carnitine in the treatment of depression. J Psychiatr Res, 53: 30–37

[94] Wang Z J, Li G M, Tang W L, Yin M (2006). Neuroprotective effects of stearic acid against toxicity of oxygen/glucose deprivation or glutamate on rat cortical or hippocampal slices. Acta Pharmacol Sin, 27(2): 145–150

[95] Weber H, Klamer D, Freudenberg F, Kittel-Schneider S, Rivero O, Scholz C J, Volkert J, Kopf J, Heupel J, Herterich S, Adolfsson R, Alttoa A, Post A, Grußendorf H, Kramer A, Gessner A, Schmidt B, Hempel S, Jacob C P, Sanjuán J, Moltó M D, Lesch K P, Freitag C M, Kent L, Reif A (2014). The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: further evidence and meta-analysis. Eur Neuropsychopharmacol, 24(1): 65–85

[96] Whitfield-Gabrieli S, Thermenos H W, Milanovic S, Tsuang M T,Faraone S V, McCarley R W, Shenton M E, Green A I, Nieto-Castanon A, LaViolette P, Wojcik J, Gabrieli J D, Seidman L J (2009). Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U S A. 106(4): 1279–1284

[97] Wichers M C, Koek G H, Robaeys G, Verkerk R, Scharpé S, Maes M (2005). IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry, 10(6): 538–544

[98] Woo H I, Chun M R, Yang J S, Lim S W, Kim M J, Kim S W, Myung W J, Kim D K, Lee S Y (2015). Plasma amino acid profiling in major depressive disorder treated with selective serotonin reuptake inhibitors. CNS Neurosci Ther, 21(5): 417–424

[99] Wood P L (2014). Accumulation of N-acylphosphatidylserines and N-acylserines in the frontal cortex in schizophrenia. Neurotransmitter (Houst), 1(1): e263

[100] Wood P L, Holderman N R (2015). Dysfunctional glycosynapses in schizophrenia: disease and regional specificity. Schizophr Res, 166(1-3): 235–237

[101] Wyatt R J, Vaughan T, Galanter M, Kaplan J, Green R (1972). Behavioral changes of chronic schizophrenic patients given L-5-hydroxytryptophan. Science, 177(4054): 1124–1126

[102] Xuan J, Pan G, Qiu Y, Yang L, Su M, Liu Y, Chen J, Feng G, Fang Y, Jia W, Xing Q, He L (2011). Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action. J Proteome Res, 10(12): 5433–5443

[103] Yang J, Chen T, Sun L, Zhao Z, Qi X, Zhou K, Cao Y, Wang X, Qiu Y, Su M, Zhao A, Wang P, Yang P, Wu J, Feng G, He L, Jia W, Wan C (2013). Potential metabolite markers of schizophrenia. Mol Psychiatry, 18(1): 67–78

[104] Yanik M, Vural H, Kocyigit A, Tutkun H, Zoroglu S S, Herken H, Savaş H A, Köylü A, Akyol O (2003). Is the arginine-nitric oxide pathway involved in the pathogenesis of schizophrenia? Neuropsychobiology, 47(2): 61–65

[105] Yao J K, Dougherty G GJr, Reddy R D, Keshavan M S, Montrose D M, Matson W R, Rozen S, Krishnan R R, McEvoy J, Kaddurah-Daouk R (2010). Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia. Mol Psychiatry, 15(9): 938–953

[106] Yao J K, Reddy R (2011). Oxidative stress in schizophrenia: pathogenetic and therapeutic implications. Antioxid Redox Signal, 15(7): 1999–2002

[107] Zheng P, Gao H C, Li Q, Shao W H, Zhang M L, Cheng K, Yang Y, Fan S H, Chen L, Fang L, Xie P (2012). Plasma metabonomics as a novel diagnostic approach for major depressive disorder. J Proteome Res, 11(3): 1741–1748

[108] Zheng P, Wang Y, Chen L, Yang D, Meng H, Zhou D, Zhong J, Lei Y, Melgiri N D, Xie P (2013). Identification and validation of urinary metabolite biomarkers for major depressive disorder. Mol Cell Proteomics, 12(1): 207–214

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