Metabolomics: A Global Biochemical Approach to the Discovery of Biomarkers for Psychiatric Disorders

  • Rima Kaddurah-Daouk
  • Jair C. Soares
  • Marlon P. Quinones


A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal or pathogenic processes, as well as responses to therapeutic interventions. The discovery of biomarkers for psychiatric disorders and their incorporation into clinical decision-making could dramatically change the future delivery of health care. Thus, there is great need for the discovery, evaluation, and clinical validation of biomarkers. Abnormalities present in psychiatric illness might be related to changes in cellular metabolism leading to measurable differences in the composition and levels of the universe of all plasma metabolites known as the metabolome. Characterizing these biochemical changes could be very useful in the identification of disease biomarkers. Metabolomics is the study of metabolism at the global level. The concept that a metabolic state is representative of the overall physiologic status of the organism lies at the heart of metabolomics. Metabolomic studies capture global biochemical events by assaying thousands of small molecules in cells, tissues, organs, or biological fluids, followed by the application of informatic techniques to define metabolomic signatures. Metabolomic studies can lead to enhanced understanding of disease mechanisms in psychiatric illnesses, as demonstrated by early work in schizophrenia and mood disorders. This chapter begins with an overview of the principles underlying biomarker research and changes in metabolism associated with psychiatric disorders. Then, it describes the conceptual basis for metabolomics, the analytical and informatic techniques used to define metabolomic signatures, and how to use this information to identify biomarkers for psychiatric disorders.


Bipolar Disorder Major Depressive Disorder Mood Disorder Surrogate Endpoint Metabolomic Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



5-hydroxyindoleacetic acid






Antioxidant defense system


Bipolar Disorder


Cerebrospinal fluid




Discriminant function analysis


Gamma-aminobutyric acid


Gas chromatography




Homovanillic acid


Liquid chromatography


Liquid chromatography coupled with electrochemical array detection


Liquid chromatography coupled with mass spectroscopy




Major Depressive Disorder




Mass spectrometry

NE (or NA)



Nuclear magnetic resonance spectroscopy


Neurotransmitter pathways




Principal components analysis


Psychiatric disorders biomarkers




Partial least squares




Selective serotonin reuptake inhibitors





Supported in part by National Institutes of Health grants R24 GM078233, “The Metabolomics Research Network” (R.K.D., B.S.K., R.M.W.); SMRI (R.K.-D.), NARSAD (R.K.-D.), Stanley Medical Research Institute (M.P.Q. and J.C.S.); MH 68766 (J.C.S.), MH 69774 (J.C.S.), MH 068662 (J.C.S.), RR 20571 (J.C.S.), UTHSCSA's GCRC (M01-RR-01346) (J.C.S.) and Department of Psychiatry Friends of Psychiatry Grant (M.P.Q. and J.C.S.), NARSAD (J.C.S.), Veterans Administration (Merit Review) (J.C.S.), and the Krus Endowed Chair in Psychiatry (J.C.S.).


  1. Appleton KM, Hayward RC, Gunnell D, et al.: Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr 84:1308–1316, 2006.PubMedGoogle Scholar
  2. Audenaert K, Peremans K, Goethals I, et al.: Functional imaging, serotonin and the suicidal brain. Acta Neurol Belg 106:125–131, 2006.PubMedGoogle Scholar
  3. Bakhtiar R: Biomarkers in drug discovery and development. J Pharmacol Toxicol Meth, 2007.Google Scholar
  4. Bell C, Abrams J, Nutt D: Tryptophan depletion and its implications for psychiatry. Br J Psychiatr 178:399–405, 2001.Google Scholar
  5. Berger GE, Wood SJ, Pantelis C, et al.: Implications of lipid biology for the pathogenesis of schizophrenia. Aust New Zeal J Psychiatr 36:355–366, 2002.Google Scholar
  6. Berrettini WH, Nurnberger JI, Jr., Scheinin M, et al.: Cerebrospinal fluid and plasma monoamines and their metabolites in euthymic bipolar patients. Biol Psychiatr 20:257–269, 1985.Google Scholar
  7. Bhagwagar Z, Wylezinska M, Jezzard P, et al.: Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol 1–6, 2007.Google Scholar
  8. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95, 2001.Google Scholar
  9. Birkenhager TK, van den Broek WW, Fekkes D, et al.: Lithium addition in antidepressant-resistant depression: effects on platelet 5-HT, plasma 5-HT and plasma 5-HIAA concentration. Prog Neuropsychopharmacol Biol Psychiatr 31:1084–1088, 2007.Google Scholar
  10. Bowers MB, Jr., Mazure CM, Nelson JC, et al.: Lithium in combination with perphenazine: effect on plasma monoamine metabolites. Biol Psychiatr 32:1102–1107, 1992.Google Scholar
  11. Brambilla P, Perez J, Barale F, et al.: GABAergic dysfunction in mood disorders. Mol Psychiatr 8:721–737, 715, 2003.Google Scholar
  12. Breier A: Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res 14:187–202, 1995.PubMedGoogle Scholar
  13. Brindle JT, Antti H, Holmes E, et al.: Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nat Med 8:1439–1444, 2002.PubMedGoogle Scholar
  14. Brindle JT, Nicholson JK, Schofield PM, et al.: Application of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertension. Analyst 128:32–36, 2003.PubMedGoogle Scholar
  15. Brown AS, Gewirtz G, Harkavy-Friedman J, et al.: Effects of clozapine on plasma catecholamines and relation to treatment response in schizophrenia: a within-subject comparison with haloperidol. Neuropsychopharmacology 17:317–325, 1997.PubMedGoogle Scholar
  16. Casey DE: Dyslipidemia and atypical antipsychotic drugs. J Clin Psychiatr 65(Suppl. 18):27–35, 2004.Google Scholar
  17. Chou JC, Czobor P, Tuma I, et al.: Pretreatment plasma HVA and haloperidol response in acute mania. J Affect Disord 59:55–59, 2000.PubMedGoogle Scholar
  18. Coen M, Ruepp SU, Lindon JC, et al.: Integrated application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse. J Pharm Biomed Anal 35:93–105, 2004.PubMedGoogle Scholar
  19. Coppen A: Electrolytes and mental illness. Proc Annu Meet Am Psychopathol Assoc 58:397–409, 1969.PubMedGoogle Scholar
  20. Correll CU, Frederickson AM, Kane JM, et al.: Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res 89:91–100, 2007.PubMedGoogle Scholar
  21. Crocker IP, Kenny LC, Thornton WA, et al.: Excessive stimulation of poly(ADP-ribosyl)ation contributes to endothelial dysfunction in pre-eclampsia. Br J Pharmacol 144:772–780, 2005.PubMedGoogle Scholar
  22. Curzon G: Relationships between plasma, CSF and brain tryptophan. J Neural Transm (Suppl.):81–92, 1979.Google Scholar
  23. Curzon G: Influence of plasma tryptophan on brain 5HT synthesis and serotonergic activity. Adv Exp Med Biol 133:207–219, 1981.PubMedGoogle Scholar
  24. Dauner M, Bailey JE, U. S: Metabolic flux analysis with a comprehensive isotopomer model in Bacillus subtilis. Biotechnol Bioeng 76:1440156, 2001.Google Scholar
  25. Davila R, Zumarraga M, Basterreche N, et al.: Influence of the catechol-O-methyltransferase Val108/158Met polymorphism on the plasma concentration of catecholamine metabolites and on clinical features in type I bipolar disorder—a preliminary report. J Affect Disord 92:277–281, 2006.PubMedGoogle Scholar
  26. de Graaf AA, Mahle M, Möllney M, et al.: Determination of full 13C isotopomer distributions for metabolic flux analysis using heteronuclear spin echo difference NMR spectroscopy. J Biotechnol 77:25035, 2000.Google Scholar
  27. De Milito A, Titanji K, Zazzi M: Surrogate markers as a guide to evaluate response to antiretroviral therapy. Curr Med Chem 10:349–365, 2003.PubMedGoogle Scholar
  28. Deeks JJ, Altman DG: Diagnostic tests 4: likelihood ratios. BMJ 329:168–169, 2004.PubMedGoogle Scholar
  29. Delgado PL, Moreno FA: Role of norepinephrine in depression. J Clin Psychiatr 61(Suppl. 1):5–12, 2000.Google Scholar
  30. Delgado PL: How antidepressants help depression: mechanisms of action and clinical response. J Clin Psychiatr 65(Suppl. 4):25–30, 2004.Google Scholar
  31. Delgado PL: Monoamine depletion studies: implications for antidepressant discontinuation syndrome. J Clin Psychiatr 67 (Suppl. 4):22–26, 2006.Google Scholar
  32. Denkert C, Budczies J, Kind T, et al.: Mass spectrometry-based metabolic profiling reveals different metabolite patterns in invasive ovarian carcinomas and ovarian borderline tumors. Cancer Res 66:10795–10804, 2006.PubMedGoogle Scholar
  33. Dunne VG, Bhattachayya S, Besser M, et al.: Metabolites from cerebrospinal fluid in aneurysmal subarachnoid haemorrhage correlate with vasospasm and clinical outcome: a pattern-recognition 1H NMR study. NMR Biomed 18:24–33, 2005.PubMedGoogle Scholar
  34. Ebuehi OA, Bishop SA, Fanmuyiwa OO, et al.: Biogenic amines metabolism and blood chemistry of psychiatric patients. Afr J Med Med Sci 30:269–273, 2001.PubMedGoogle Scholar
  35. Ellis PM, Mellsop GW, Beeston R, et al.: Platelet tritiated imipramine binding in patients suffering from mania. J Affect Disord 22:105–110, 1991.PubMedGoogle Scholar
  36. Ellison G: Stimulant-induced psychosis, the dopamine theory of schizophrenia, and the habenula. Brain Res Brain Res Rev 19:223–239, 1994.PubMedGoogle Scholar
  37. Fan C, Oh DS, Wessels L, et al.: Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 355:560–569, 2006.PubMedGoogle Scholar
  38. Fan TW-M, Lane AN: Structure-based profiling of metabolites and isotopomers by NMR. Prog NMR Spectrosc, in press.Google Scholar
  39. Fan X, Bai J, Shen P: Diagnosis of breast cancer using HPLC metabonomics fingerprints coupled with computational methods. Conf Proc IEEE Eng Med Biol Soc 6:6081–6084, 2005.PubMedGoogle Scholar
  40. Fortunati F, Mazure C, Preda A, et al.: Plasma catecholamine metabolites in antidepressant-exacerbated mania and psychosis. J Affect Disord 68:331–334, 2002.PubMedGoogle Scholar
  41. Frank R, Hargreaves R: Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2:566–580, 2003.PubMedGoogle Scholar
  42. Freeman MP, Hibbeln JR, Wisner KL, et al.: Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatr 67:1954–1967, 2006.Google Scholar
  43. Frye MA, Tsai GE, Huggins T, et al.: Low cerebrospinal fluid glutamate and glycine in refractory affective disorder. Biol Psychiatr 61:162–166, 2007.Google Scholar
  44. Garcia -Portilla MP, Saiz PA, Benabarre A, et al.: The prevalence of metabolic syndrome in patients with bipolar disorder. J Affect Disord, 2007.Google Scholar
  45. Garfinkel PE, Warsh JJ, Stancer HC: Depression: new evidence in support of biological differentiation. Am J Psychiatr 136:535–539, 1979.PubMedGoogle Scholar
  46. German JB, Gillies LA, Smilowitz JT, et al.: Lipidomics and lipid profiling in metabolomics. Curr Opin Lipidol 18:66–71, 2007.PubMedGoogle Scholar
  47. Gerner RH, Fairbanks L, Anderson GM, et al.: CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls. Am J Psychiatr 141:1533–1540, 1984.PubMedGoogle Scholar
  48. Goodwin FK, Sack RL: Central dopamine function in affective illness: evidence from precursors, enzyme inhibitors, and studies of central dopamine turnover. Adv Biochem Psychopharmacol 12:261–279, 1974.PubMedGoogle Scholar
  49. Goodwin FK, Jamison KR, Ghaemi SN: Manic-depressive illness: bipolar disorders and recurrent depression, 2nd Edition. New York: Oxford University Press, 2007.Google Scholar
  50. Greenspan K, Schildkraut JJ, Gordon EK, et al.: Catecholamine metabolism in affective disorders. 3. MHPG and other catecholamine metabolites in patients treated with lithium carbonate. J Psychiatr Res 7:171–183, 1970.PubMedGoogle Scholar
  51. Grossman F, Potter WZ: 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. Psychiatr Res 87:21–27, 1999.Google Scholar
  52. Hall JA, Brown R, Paul J: An exploration into study design for biomarker identification: issues and recommendations. Cancer Genomics Proteomics 4:111–119, 2007.PubMedGoogle Scholar
  53. Han X, Holtzman DM, McKeel DW, Jr., et al.: Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis. J Neurochem 82:809–818, 2002.PubMedGoogle Scholar
  54. Harrigan G, Goodacre R: Metabolic profiling: its role in biomarker discovery and gene function analysis. Boston: Kluwer, 2003.Google Scholar
  55. Hasler G, van der Veen JW, Tumonis T, et al.: Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatr 64:193–200, 2007.PubMedGoogle Scholar
  56. Heritch AJ: Evidence for reduced and dysregulated turnover of dopamine in schizophrenia. Schizophr Bull 16:605–615, 1990.PubMedGoogle Scholar
  57. Hoekstra R, Fekkes D, Loonen AJ, et al.: Bipolar mania and plasma amino acids: increased levels of glycine. Eur Neuropsychopharmacol 16:71–77, 2006.PubMedGoogle Scholar
  58. Holmes E, Tsang TM, Huang JT, et al.: Metabolic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Med 3:e327, 2006.PubMedGoogle Scholar
  59. Horrobin DF: The roles of prostaglandins and prolactin in depression, mania and schizophrenia. Postgrad Med J 53 (Suppl. 4):160–165, 1977.PubMedGoogle Scholar
  60. Horrobin DF, Manku MS, Hillman H, et al.: Fatty acid levels in the brains of schizophrenics and normal controls. Biol Psychiatr 30:795–805, 1991.Google Scholar
  61. Horrobin DF: Schizophrenia as a membrane lipid disorder which is expressed throughout the body. Prostaglandins Leukot Essent Fatty Acids 55:3–7, 1996.PubMedGoogle Scholar
  62. Horrobin DF: The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 30:193–208, 1998.PubMedGoogle Scholar
  63. Janowsky DS, el-Yousef MK, Davis JM, et al.: Cholinergic reversal of manic symptoms. Lancet 1:1236–1237, 1972.PubMedGoogle Scholar
  64. Janowsky DS, el-Yousef MK, Davis JM, et al.: A cholinergic-adrenergic hypothesis of mania and depression. Lancet 2:632–635, 1972.PubMedGoogle Scholar
  65. Joyce PR, Fergusson DM, Woollard G, et al.: Urinary catecholamines and plasma hormones predict mood state in rapid cycling bipolar affective disorder. J Affect Disord 33:233–243, 1995.PubMedGoogle Scholar
  66. Kaddurah-Daouk R: Metabolic profiling of patients with schizophrenia. PLoS Med 3:e363, 2006.PubMedGoogle Scholar
  67. Kaddurah-Daouk R, McEvoy J, Baillie RA, et al.: Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Mol Psychiatr 12:934–945, 2007.Google Scholar
  68. Kaddurah-Daouk R, Kristal BS, Weinshilboum RM: Metabolomics: A global biochemical approach to drug response and disease. Annu Rev Pharmacol Toxicol 48:653–683, 2008.PubMedGoogle Scholar
  69. Kasa K, Otsuki S, Yamamoto M, et al.: Cerebrospinal fluid gamma-aminobutyric acid and homovanillic acid in depressive disorders. Biol Psychiatr 17:877–883, 1982.Google Scholar
  70. Kell DB: Metabolomics and systems biology: making sense of the soup. Curr Opin Micro 7:296–307, 2004.Google Scholar
  71. Kelley ME, Yao JK, van Kammen DP: Plasma catecholamine metabolites as markers for psychosis and antipsychotic response in schizophrenia. Neuropsychopharmacology 20:603–611, 1999.PubMedGoogle Scholar
  72. Kessler RC, Berglund P, Demler O, et al.: The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289:3095–3105, 2003.PubMedGoogle Scholar
  73. Khan MM, Evans DR, Gunna V, et al.: Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res 58:1–10, 2002.PubMedGoogle Scholar
  74. Knable MB, Weinberger DR: Dopamine, the prefrontal cortex and schizophrenia. J Psychopharmacol 11:123–131, 1997.PubMedGoogle Scholar
  75. Koslow SH, Maas JW, Bowden CL, et al.: CSF and urinary biogenic amines and metabolites in depression and mania. A controlled, univariate analysis. Arch Gen Psychiatr 40:999–1010, 1983.PubMedGoogle Scholar
  76. Kristal BS, Kaddurah-Daouk R, Beal MF, et al.: Metabolomics: concept and potential neuroscience application, in Handbook of Neurochemistry and Molecular Neurobiology: Brain Energetics. Integration of Molecular and Cellular Processes. Edited by. Berlin Heidelberg New York, Springer, 2007, pp. 889–912.Google Scholar
  77. Kristal BS, Shurubor YI, Kaddurah-Daouk R, et al.: Metabolomics in the study of aging and caloric restriction. Methods Mol Biol 371:393–409, 2007.PubMedGoogle Scholar
  78. Kugaya A, Sanacora G: Beyond monoamines: glutamatergic function in mood disorders. CNS Spectrum 10:808–819, 2005.Google Scholar
  79. Lake CR, Pickar D, Ziegler MG, et al.: High plasma norepinephrine levels in patients with major affective disorder. Am J Psychiatr 139:1315–1318, 1982.PubMedGoogle Scholar
  80. Lassere MN, Johnson KR, Boers M, et al.: Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema. J Rheumatol 34:607–615, 2007.PubMedGoogle Scholar
  81. Leonard BE: Evidence for a biochemical lesion in depression. J Clin Psychiatr 61 (Suppl. 6):12–17, 2000.Google Scholar
  82. Leoni V, Masterman T, Patel P, et al.: Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers. J Lipid Res 44:793–799, 2003.PubMedGoogle Scholar
  83. Levine J, Panchalingam K, Rapoport A, et al.: Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatr 47:586–593, 2000.Google Scholar
  84. Levine J, Sela BA, Osher Y, et al.: High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog Neuropsychopharmacol Biol Psychiatr 29:1181–1191, 2005.Google Scholar
  85. Lewine RR, Risch SC, Risby E, et al.: Lateral ventricle-brain ratio and balance between CSF HVA and 5-HIAA in schizophrenia. Am J Psychiatr 148:1189–1194, 1991.PubMedGoogle Scholar
  86. Lieb J, Karmali R, Horrobin D: Elevated levels of prostaglandin E2 and thromboxane B2 in depression. Prostaglandins Leukot Med 10:361–367, 1983.PubMedGoogle Scholar
  87. Lieberman JA, Mailman RB, Duncan G, et al.: Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatr 44:1099–1117, 1998.Google Scholar
  88. Lin PY, Su KP: A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatr 68:1056–1061, 2007.Google Scholar
  89. Lindon JC, Nicholson JK, Holmes E, et al.: Metabonomics: metabolic processes studied by NMR spectroscopy of biofluids. Concepts Magn Reson 12:289–320, 2000.Google Scholar
  90. Lindon JC, Nicholson JK, Holmes E, et al.: Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. Toxicol Appl Pharmacol 187:137–146, 2003.PubMedGoogle Scholar
  91. Lindon JC, Holmes E, Nicholson JK: Metabonomics in pharmaceutical R&D. FEBS J 274:1149–1151, 2007.Google Scholar
  92. Lucini V, Lucca A, Catalano M, et al.: Predictive value of tryptophan/large neutral amino acids ratio to antidepressant response. J Affect Disord 36:129–133, 1996.PubMedGoogle Scholar
  93. Maas JW, Dekirmenjian H, Fawcett JA: MHPG excretion by patients with affective disorders. Int Pharmacopsychiatr 9:14–26, 1974.Google Scholar
  94. Maeng S, Zarate CA, Jr., Du J, et al.: Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptors. Biol Psychiatr, 2007.Google Scholar
  95. Maes M, Scharpe S, Meltzer HY, et al.: Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatr Res 54:143–160, 1994.Google Scholar
  96. Mahadik SP, Mukherjee S, Correnti EE, et al.: Plasma membrane phospholipid and cholesterol distribution of skin fibroblasts from drug-naive patients at the onset of psychosis. Schizophr Res 13:239–247, 1994.PubMedGoogle Scholar
  97. Mahmood T, Silverstone T: Serotonin and bipolar disorder. J Affect Disord 66:1–11, 2001.PubMedGoogle Scholar
  98. Maier B, Laurer HL, Rose S, et al.: Physiological levels of pro- and anti-inflammatory mediators in cerebrospinal fluid and plasma: a normative study. J Neurotrauma 22:822–835, 2005.PubMedGoogle Scholar
  99. Maj M, Ariano MG, Arena F, et al.: Plasma cortisol, catecholamine and cyclic AMP levels, response to dexamethasone suppression test and platelet MAO activity in manic-depressive patients. A longitudinal study. Neuropsychobiology 11:168–173, 1984.PubMedGoogle Scholar
  100. Makatsori A, Duncko R, Moncek F, et al.: Modulation of neuroendocrine response and non-verbal behavior during psychosocial stress in healthy volunteers by the glutamate release-inhibiting drug lamotrigine.Google Scholar
  101. Makatsori A, Duncko R, Moncek F, et al.: Modulation of neuroendocrine response and non-verbal behavior during psychosocial stress in healthy volunteers by the glutamate release-inhibiting drug lamotrigine. Neuroendocrinology 79:34–42, 2004.PubMedGoogle Scholar
  102. Mann JJ, Oquendo M, Underwood MD, et al.: The neurobiology of suicide risk: a review for the clinician. J Clin Psychiatr 60 (Suppl. 2):7–11; discussion 18–20, 113–116, 1999.Google Scholar
  103. Mazure CM, Bowers MB: Pretreatment plasma HVA predicts neuroleptic response in manic psychosis. J Affect Disord 48:83–86, 1998.PubMedGoogle Scholar
  104. Meisenzahl EM, Schmitt GJ, Scheuerecker J, et al.: The role of dopamine for the pathophysiology of schizophrenia. Int Rev Psychiatr 19:337–345, 2007.Google Scholar
  105. Miyamoto S, LaMantia AS, Duncan GE, et al.: Recent advances in the neurobiology of schizophrenia. Mol Interv 3:27–39, 2003.PubMedGoogle Scholar
  106. Mooney JJ, Schatzberg AF, Cole JO, et al.: Urinary 3-methoxy-4-hydroxyphenylglycol and the depression-type score as predictors of differential responses to antidepressants. J Clin Psychopharmacol 11:339–343, 1991.PubMedGoogle Scholar
  107. Morvan D, Demidem A: Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways. Cancer Res 67:2150–2159, 2007.PubMedGoogle Scholar
  108. Mueller PS, Davis JM, Bunney WE, Jr., et al.: Plasma free fatty acids concentration in depressive illness. Arch Gen Psychiatr 22:216–221, 1970.PubMedGoogle Scholar
  109. Muller N, Riedel M, Schwarz MJ: Psychotropic effects of COX-2 inhibitors—a possible new approach for the treatment of psychiatric disorders. Pharmacopsychiatry 37:266–269, 2004.PubMedGoogle Scholar
  110. Muller N, Schwarz MJ, Dehning S, et al.: The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatr 11:680–684, 2006.Google Scholar
  111. Murakami M, Kudo I: Phospholipase A2. J Biochem (Tokyo) 131:285–292, 2002.Google Scholar
  112. Nanda BL, Nataraju A, Rajesh R, et al.: PLA2 mediated arachidonate free radicals: PLA2 inhibition and neutralization of free radicals by anti-oxidants—a new role as anti-inflammatory molecule. Curr Top Med Chem 7:765–777, 2007.PubMedGoogle Scholar
  113. Nicholson JK: Global systems biology, personalized medicine and molecular epidemiology. Mol Syst Biol 2:52, 2006.PubMedGoogle Scholar
  114. Obeid R, Kostopoulos P, Knapp JP, et al.: Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid. Clin Chem 53:326–333, 2007.PubMedGoogle Scholar
  115. Odunsi K, Wollman RM, Ambrosone CB, et al.: Detection of epithelial ovarian cancer using 1H-NMR-based metabonomics. Int J Cancer 113:782–788, 2005.PubMedGoogle Scholar
  116. Paige LA, Mitchell MW, Krishnan KR, et al.: A preliminary metabolomic analysis of older adults with and without depression. Int J Geriatr Psychiatr 22:418–423, 2007.Google Scholar
  117. Palomino A, Gonzalez-Pinto A, Aldama A, et al.: Decreased levels of plasma glutamate in patients with first-episode schizophrenia and bipolar disorder. Schizophr Res 95:174–178, 2007.PubMedGoogle Scholar
  118. Pani L, Pira L, Marchese G: Antipsychotic efficacy: relationship to optimal D2-receptor occupancy. Eur Psychiatr 22:267–275, 2007.Google Scholar
  119. Patterson AD, Li H, Eichler GS, et al.: UPLC-ESI-TOFMS-based metabolomics and gene expression dynamics inspector self-organizing metabolomic maps as tools for understanding the cellular response to ionizing radiation. Anal Chem, 2008.Google Scholar
  120. Peet M, Moody JP, Worrall EP, et al.: Plasma tryptophan concentration in depressive illness and mania. Br J Psychiatr 128:255–258, 1976.Google Scholar
  121. Petty F, Schlesser MA: Plasma GABA in affective illness. A preliminary investigation. J Affect Disord 3:339–343, 1981.PubMedGoogle Scholar
  122. Petty F, Rush AJ, Davis JM, et al.: Plasma GABA predicts acute response to divalproex in mania. Biol Psychiatr 39:278–284, 1996.Google Scholar
  123. Piccirillo G, Fimognari FL, Infantino V, et al.: High plasma concentrations of cortisol and thromboxane B2 in patients with depression. Am J Med Sci 307:228–232, 1994.PubMedGoogle Scholar
  124. Portilla D, Li S, Nagothu KK, et al.: Metabolomic study of cisplatin-induced nephrotoxicity. Kidney Int 69:2194–2204, 2006.PubMedGoogle Scholar
  125. Rapoport SI, Bosetti F: Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Arch Gen Psychiatr 59:592–596, 2002.PubMedGoogle Scholar
  126. Reddy R, Keshavan M, Yao JK: Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res 62:205–212, 2003.PubMedGoogle Scholar
  127. Ross BM, Seguin J, Sieswerda LE: Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids Health Dis 6:21, 2007.PubMedGoogle Scholar
  128. Roy A, Guthrie S, Pickar D, et al.: Plasma norepinephrine responses to cold challenge in depressed patients and normal controls. Psychiatr Res 21:161–168, 1987.Google Scholar
  129. Roy A: Plasma HVA levels in depressed patients and controls. J Affect Disord 14:293–296, 1988.PubMedGoogle Scholar
  130. Rozen S, Cudkowicz ME, Bogdanov M, et al.: Metabolomic analysis and signatures in motor neuron disease. Metabolomics 1:101–108, 2005.PubMedGoogle Scholar
  131. Sabatine MS, Liu E, Morrow DA, et al.: Metabolomic identification of novel biomarkers of myocardial ischemia. Circulation 112:3868–3875, 2005.PubMedGoogle Scholar
  132. Sajda P: Machine learning for detection and diagnosis of disease. Annu Rev Biomed Eng 8:537–565, 2006.PubMedGoogle Scholar
  133. Sanacora G, Saricicek A: GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. CNS Neurol Disord Drug Targets 6:127–140, 2007.PubMedGoogle Scholar
  134. Schatzberg AF, Orsulak PJ, Rosenbaum AH, et al.: Catecholamine measures for diagnosis and treatment of patients with depressive disorders. J Clin Psychiatr 41:35–39, 1980.Google Scholar
  135. Schatzberg AF, Orsulak PJ, Rosenbaum AH, et al.: Toward a biochemical classification of depressive disorders, V: heterogeneity of unipolar depressions. Am J Psychiatr 139:471–475, 1982.PubMedGoogle Scholar
  136. Schildkraut JJ: Biogenic amines and affective disorders. Annu Rev Med 25:333–348, 1974.PubMedGoogle Scholar
  137. Schmitt A, Maras A, Petroianu G, et al.: Effects of antipsychotic treatment on membrane phospholipid metabolism in schizophrenia. J Neural Transm 108:1081–1091, 2001.PubMedGoogle Scholar
  138. Segal M, Avital A, Drobot M, et al.: Serum creatine kinase level in unmedicated nonpsychotic, psychotic, bipolar and schizoaffective depressed patients. Eur Neuropsychopharmacol 17:194–198, 2007a.Google Scholar
  139. Segal M, Avital A, Drobot M, et al.: CK levels in unmedicated bipolar patients. Eur Neuropsychopharmacol 17:763–767, 2007b.Google Scholar
  140. Sher L, Carballo JJ, Grunebaum MF, et al.: A prospective study of the association of cerebrospinal fluid monoamine metabolite levels with lethality of suicide attempts in patients with bipolar disorder. Bipolar Disord 8:543–550, 2006.PubMedGoogle Scholar
  141. Shin H, Markey MK: A machine learning perspective on the development of clinical decision support systems utilizing mass spectra of blood samples. J Biomed Inform 39:227–248, 2006.PubMedGoogle Scholar
  142. Sicras -Mainar A, Blanca-Tamayo M, Rejas-Gutierrez J, et al.: Metabolic syndrome in outpatients receiving antipsychotic therapy in routine clinical practice: a cross-sectional assessment of a primary health care database. Eur Psychiatr, 2007.Google Scholar
  143. Skosnik PD, Yao JK: From membrane phospholipid defects to altered neurotransmission: is arachidonic acid a nexus in the pathophysiology of schizophrenia? Prostaglandins Leukot Essent Fatty Acids 69:367–384, 2003.PubMedGoogle Scholar
  144. Sobczak S, Honig A, van Duinen MA, et al.: Serotonergic dysregulation in bipolar disorders: a literature review of serotonergic challenge studies. Bipolar Disord 4:347–356, 2002.PubMedGoogle Scholar
  145. Steuer R, Morgenthal K, Weckwerth W, et al.: A gentle guide to the analysis of metabolomic data. Methods Mol Biol 358:105–126, 2007.PubMedGoogle Scholar
  146. Sublette ME, Russ MJ, Smith GS: Evidence for a role of the arachidonic acid cascade in affective disorders: a review. Bipolar Disord 6:95–105, 2004.PubMedGoogle Scholar
  147. Swann AC, Secunda S, Davis JM, et al.: CSF monoamine metabolites in mania. Am J Psychiatr 140:396–400, 1983.PubMedGoogle Scholar
  148. Swann AC, Petty F, Bowden CL, et al.: Mania: gender, transmitter function, and response to treatment. Psychiatr Res 88:55–61, 1999.Google Scholar
  149. Tandon R, Channabasavanna SM, Greden JF: CSF biochemical correlates of mixed affective states. Acta Psychiatr Scand 78:289–297, 1988.PubMedGoogle Scholar
  150. Taylor V, MacQueen G: Associations between bipolar disorder and metabolic syndrome: a review. J Clin Psychiatr 67:1034–1041, 2006.Google Scholar
  151. Tkachev D, Mimmack ML, Huffaker SJ, et al.: Further evidence for altered myelin biosynthesis and glutamatergic dysfunction in schizophrenia. Int J Neuropsychopharmacol 10:557–563, 2007.PubMedGoogle Scholar
  152. Tsang TM, Huang JT, Holmes E, et al.: Metabolic profiling of plasma from discordant schizophrenia twins: correlation between lipid signals and global functioning in female schizophrenia patients. J Proteome Res 5:756–760, 2006.PubMedGoogle Scholar
  153. Underwood B, Broadhurst D, Dunn WB, et al.: Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles. Brain 129:877–886, 2006.PubMedGoogle Scholar
  154. van der Greef J, Martin S, Juhasz P, et al.: The art and practice of systems biology in medicine: mapping patterns of relationships. J Proteome Res 6:1540–1559, 2007.PubMedGoogle Scholar
  155. van Doorn M, Vogels J, Tas A, et al.: Evaluation of metabolite profiles as biomarkers for the pharmacological effects of thiazolidinediones in Type 2 diabetes mellitus patients and healthy volunteers. Br J Clin Pharmacol 63:562–574, 2007.PubMedGoogle Scholar
  156. Vasan RS: Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 113:2335–2362, 2006.PubMedGoogle Scholar
  157. Wang C, Kong H, Guan Y, et al.: Plasma phospholipid metabolic profiling and biomarkers of type 2 diabetes mellitus based on high-performance liquid chromatography/electrospray mass spectrometry and multivariate statistical analysis. Anal Chem 77:4108–4116, 2005.PubMedGoogle Scholar
  158. Watkins SM, Reifsnyder PR, Pan HJ, et al.: Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. J Lipid Res 43:1809–1811, 2002.PubMedGoogle Scholar
  159. Watkins SM: Lipomic profiling in drug discovery, development and clinical trial evaluation. Curr Opin Drug Discov Devel 7:112–117, 2004.PubMedGoogle Scholar
  160. Watson AD: Thematic review series: systems biology approaches to metabolic and cardiovascular disorders. Lipidomics: a global approach to lipid analysis in biological systems. J Lipid Res 47:2101–2111, 2006.PubMedGoogle Scholar
  161. Weljie AM, Dowlatabadi R, Miller BJ, et al.: An inflammatory arthritis-associated metabolite biomarker pattern revealed by 1H NMR spectroscopy. J Proteome Res 6:3456–3464, 2007.PubMedGoogle Scholar
  162. Wichers MC, Koek GH, Robaeys G, et al.: IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatr 10:538–544, 2005.Google Scholar
  163. Wiest MM, Watkins SM: Biomarker discovery using high-dimensional lipid analysis. Curr Opin Lipidol 18:181–186, 2007.PubMedGoogle Scholar
  164. Wong DF, Wagner HN, Jr., Tune LE, et al.: Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234:1558–1563, 1986.PubMedGoogle Scholar
  165. Yang J, Xu G, Zheng Y, et al.: Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive result from hepatitis and hepatocirrhosis diseases. J Chromatogr B Analyt Technol Biomed Life Sci 813:59–65, 2004.PubMedGoogle Scholar
  166. Yao JK, Reddy R, McElhinny LG, et al.: Reduced status of plasma total antioxidant capacity in schizophrenia. Schizophr Res 32:1–8, 1998a.Google Scholar
  167. Yao JK, Reddy R, van Kammen DP: Reduced level of plasma antioxidant uric acid in schizophrenia. Psychiatr Res 80:29–39, 1998b.Google Scholar
  168. Yao JK, Reddy RD, van Kammen DP: Human plasma glutathione peroxidase and symptom severity in schizophrenia. Biol Psychiatr 45:1512–1515, 1999.Google Scholar
  169. Yao JK, Reddy R, van Kammen DP: Abnormal age-related changes of plasma antioxidant proteins in schizophrenia. Psychiatr Res 97:137–151, 2000.Google Scholar
  170. Yao JK, Reddy RD, van Kammen DP: Oxidative damage and schizophrenia: an overview of the evidence and its therapeutic implications. CNS Drugs 15:287–310, 2001.PubMedGoogle Scholar
  171. Yao JK, Thomas EA, Reddy RD, et al.: Association of plasma apolipoproteins D with RBC membrane arachidonic acid levels in schizophrenia. Schizophr Res 72:259–266, 2005.PubMedGoogle Scholar
  172. Yao JK, Leonard S, Reddy R: Altered glutathione redox state in schizophrenia. Dis Markers 22:83–93, 2006.PubMedGoogle Scholar
  173. Yoshimura R, Nakano Y, Hori H, et al.: Effect of risperidone on plasma catecholamine metabolites and brain-derived neurotrophic factor in patients with bipolar disorders. Hum Psychopharmacol 21:433–438, 2006.PubMedGoogle Scholar
  174. Young LT, Warsh JJ, Kish SJ, et al.: Reduced brain 5-HT and elevated NE turnover and metabolites in bipolar affective disorder. Biol Psychiatr 35:121–127, 1994.Google Scholar
  175. Yuan K, Kong H, Guan Y, et al.: A GC-based metabonomics investigation of type 2 diabetes by organic acids metabolic profile. J Chromatogr B Analyt Technol Biomed Life Sci 850:236–240, 2007.PubMedGoogle Scholar
  176. Yumru M, Savas HA, Kurt E, et al.: Atypical antipsychotics related metabolic syndrome in bipolar patients. J Affect Disord 98:247–252, 2007.PubMedGoogle Scholar
  177. Zarate CA, Jr., Singh JB, Carlson PJ, et al.: A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatr 63:856–864, 2006.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Rima Kaddurah-Daouk
    • 1
  • Jair C. Soares
  • Marlon P. Quinones
  1. 1.Department of Psychiatry and Behavioral SciencesDuke University Medical CenterDurhamUSA

Personalised recommendations