Schizophrenia Biomarkers: A Means to Advance Disease Understanding, Diagnosis and Treatment

  • Emanuel Schwarz
  • Sabine Bahn


Schizophrenia is a multifaceted neuropsychiatric disorder affecting approximately 1% of the population worldwide. Its onset is the result of a complex interplay of genetic predisposition and environmental factors. The heterogeneity inherent to schizophrenia has so far been a great obstacle hindering advances to elucidate disease mechanisms and the discovery of useful biomarkers. Recently, technological advances have been implemented that allow a search for molecular alterations with unprecedented sensitivity. In this chapter, we describe the findings generated using multi-omics approaches. The accessibility, complexity and heterogeneity of samples are some of the greatest challenges connected to biomarker discovery and other proteomic approaches for schizophrenia. We illustrate how far these challenges can be met using current technology and describe promising emerging techniques, which have yet to be applied to research in schizophrenia. Finally, we address challenges faced when analyzing large scale datasets and present methods that have been successfully applied to discover biomarkers for this devastating disorder.


Matrix Assisted Lased Desorption Ionization Partial Little Square Schizophrenic Patient Schizophrenia Patient Nuclear Magnetic Resonance Spectroscopy 
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.



Central Nervous System


Cerebrospinal Fluid


Family Wise Error rate


Low Density Lipoprotein


Matrix Assisted Lased Desorption Ionisation


Nuclear Magnetic Resonance


Partial Least Squares Discriminant Analysis


Positive False Discovery Rate


Post Translational Modification


Principal Component Analysis


Surface Enhanced Laser Desorption Ionisation


Very Low Density Lipoprotein



This research was kindly supported by the Stanley Medical Research Institute (SMRI). We thank all members of the Bahn Laboratory, especially Yishai Levin, for discussions, help and encouragement. E.S. holds a Cambridge European Trust scholarship and S. B. holds a NARSAD Essel Independent Investigator Fellowship.


  1. Abou-Saleh, M. T. (2006). Neuroimaging in psychiatry: An update. J Psychosom Res 61(3): 289–93.PubMedCrossRefGoogle Scholar
  2. Anderson, L. (2005). Candidate-based proteomics in the search for biomarkers of cardiovascular disease. J Physiol 563(Pt 1): 23–60.PubMedGoogle Scholar
  3. Anderson, N. L. and N. G. Anderson (2002). The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics 1(11): 845–67.PubMedCrossRefGoogle Scholar
  4. Barker, M. and W. Rayens (2003). PLS for discrimination. J. Chemometrics 17: 166–73.CrossRefGoogle Scholar
  5. Benjamini, Y. and Y. Hochberg (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. B (57): 289–300.Google Scholar
  6. Berger, G. E., S. Smesny and G. P. Amminger (2006). Bioactive lipids in schizophrenia. Int Rev Psychiatr 18(2): 85–98.CrossRefGoogle Scholar
  7. Bondarenko, P. V., D. Chelius and T. A. Shaler (2002). Identification and relative quantitation of protein mixtures by enzymatic digestion followed by capillary reversed-phase liquid chromatography-tandem mass spectrometry. Anal Chem 74(18): 4741–9.PubMedCrossRefGoogle Scholar
  8. Bosveld-van Haandel, L., R. Knegtering, H. Kluiter and R. J. van den Bosch (2006). Niacin skin flushing in schizophrenic and depressed patients and healthy controls. Psychiatry Res 143(2–3): 303–6.PubMedCrossRefGoogle Scholar
  9. Cardno, A. G. and Gottesman, II (2000). Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 97(1): 12–7.PubMedCrossRefGoogle Scholar
  10. Chelius, D. and P. V. Bondarenko (2002). Quantitative profiling of proteins in complex mixtures using liquid chromatography and mass spectrometry. J Proteome Res 1(4): 317–23.PubMedCrossRefGoogle Scholar
  11. Choudhary, J. and S. G. Grant (2004). Proteomics in postgenomic neuroscience: the end of the beginning. Nat Neurosci 7(5): 440–5.PubMedCrossRefGoogle Scholar
  12. Corthals, G. L., V. C. Wasinger, D. F. Hochstrasser and J. C. Sanchez (2000). The dynamic range of protein expression: a challenge for proteomic research. Electrophoresis 21(6): 1104–15.PubMedCrossRefGoogle Scholar
  13. Do, K. Q., C. J. Lauer, W. Schreiber, M. Zollinger, U. Gutteck-Amsler, M. Cuenod and F. Holsboer (1995). Gamma-Glutamylglutamine and taurine concentrations are decreased in the cerebrospinal fluid of drug-naive patients with schizophrenic disorders. J Neurochem 65(6): 2652–62.PubMedCrossRefGoogle Scholar
  14. Dror, N., E. Klein, R. Karry, A. Sheinkman, Z. Kirsh, M. Mazor, M. Tzukerman and D. Ben-Shachar (2002). State-dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia. Mol Psychiatr 7(9): 995–1001.CrossRefGoogle Scholar
  15. Fatemi, S. H., J. L. Kroll and J. M. Stary (2001). Altered levels of Reelin and its isoforms in schizophrenia and mood disorders. Neuroreport 12(15): 3209–15.PubMedCrossRefGoogle Scholar
  16. Freedman, R. (2003). Schizophrenia. N Engl J Med 349(18): 1738–49.PubMedCrossRefGoogle Scholar
  17. Fu, Q., C. P. Garnham, S. T. Elliott, D. E. Bovenkamp and J. E. Van Eyk (2005). A robust, streamlined, and reproducible method for proteomic analysis of serum by delipidation, albumin and IgG depletion, and two-dimensional gel electrophoresis. Proteomics 5(10): 2656–64.PubMedCrossRefGoogle Scholar
  18. Gafken, P. R. and P. D. Lampe (2006). Methodologies for characterizing phosphoproteins by mass spectrometry. Cell Commun Adhes 13(5–6): 249–62.PubMedCrossRefGoogle Scholar
  19. Geyer, H. and R. Geyer (2006). Strategies for analysis of glycoprotein glycosylation. Biochim Biophys Acta 1764(12): 1853–69.PubMedGoogle Scholar
  20. Glatt, S. J., I. P. Everall, W. S. Kremen, J. Corbeil, R. Sasik, N. Khanlou, M. Han, C. C. Liew and M. T. Tsuang (2005). Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia. Proc Natl Acad Sci U S A 102(43): 15533–8.PubMedCrossRefGoogle Scholar
  21. Goodacre, R., S. Vaidyanathan, W. B. Dunn, G. G. Harrigan and D. B. Kell (2004). Metabolomics by numbers: acquiring and understanding global metabolite data. Trends Biotechnol 22(5): 245–52.PubMedCrossRefGoogle Scholar
  22. Greenbaum, D., A. Baruch, L. Hayrapetian, Z. Darula, A. Burlingame, K. F. Medzihradszky and M. Bogyo (2002). Chemical approaches for functionally probing the proteome. Mol Cell Proteomics 1(1): 60–8.PubMedCrossRefGoogle Scholar
  23. Greenbaum, D., K. F. Medzihradszky, A. Burlingame and M. Bogyo (2000). Epoxide electrophiles as activity-dependent cysteine protease profiling and discovery tools. Chem Biol 7(8): 569–81.PubMedCrossRefGoogle Scholar
  24. Gygi, S. P., G. L. Corthals, Y. Zhang, Y. Rochon and R. Aebersold (2000). Evaluation of two-dimensional gel electrophoresis-based proteome analysis technology. Proc Natl Acad Sci U S A 97(17): 9390–5.PubMedCrossRefGoogle Scholar
  25. Gygi, S. P., B. Rist, S. A. Gerber, F. Turecek, M. H. Gelb and R. Aebersold (1999). Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 17(10): 994–9.PubMedCrossRefGoogle Scholar
  26. Haab, B. B., M. J. Dunham and P. O. Brown (2001). Protein microarrays for highly parallel detection and quantitation of specific proteins and antibodies in complex solutions. Genome Biol 2(2): RESEARCH0004.Google Scholar
  27. Higgs, R. E., M. D. Knierman, V. Gelfanova, J. P. Butler and J. E. Hale (2005). Comprehensive label-free method for the relative quantification of proteins from biological samples. J Proteome Res 4(4): 1442–50.PubMedCrossRefGoogle Scholar
  28. Holmes, E., T. M. Tsang, J. T. Huang, F. M. Leweke, D. Koethe, C. W. Gerth, B. M. Nolden, S. Gross, D. Schreiber, J. K. Nicholson and S. Bahn (2006). Metabolic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Med 3(8): e327.PubMedCrossRefGoogle Scholar
  29. Horrobin, D. F. (1980). Schizophrenia: a biochemical disorder? Biomedicine 32(2): 54–5.PubMedGoogle Scholar
  30. Huang, J. T., F. M. Leweke, D. Oxley, L. Wang, N. Harris, D. Koethe, C. W. Gerth, B. M. Nolden, S. Gross, D. Schreiber, B. Reed and S. Bahn (2006). Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis. PLoS Med 3(11): e428.PubMedCrossRefGoogle Scholar
  31. Ilani, T., D. Ben-Shachar, R. D. Strous, M. Mazor, A. Sheinkman, M. Kotler and S. Fuchs (2001). A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes. Proc Natl Acad Sci U S A 98(2): 625–8.PubMedCrossRefGoogle Scholar
  32. Issaq, H. J., T. D. Veenstra, T. P. Conrads and D. Felschow (2002). The SELDI-TOF MS approach to proteomics: protein profiling and biomarker identification. Biochem Biophys Res Commun 292(3): 587–92.PubMedCrossRefGoogle Scholar
  33. Jiang, L., K. Lindpaintner, H. F. Li, N. F. Gu, H. Langen, L. He and M. Fountoulakis (2003). Proteomic analysis of the cerebrospinal fluid of patients with schizophrenia. Amino Acids 25(1): 49–57.PubMedGoogle Scholar
  34. Kidd, D., Y. Liu and B. F. Cravatt (2001). Profiling serine hydrolase activities in complex proteomes. Biochemistry 40(13): 4005–15.PubMedCrossRefGoogle Scholar
  35. Kozlovsky, N., W. T. Regenold, J. Levine, A. Rapoport, R. H. Belmaker and G. Agam (2004). GSK-3beta in cerebrospinal fluid of schizophrenia patients. J Neural Transm 111(8): 1093–8.PubMedCrossRefGoogle Scholar
  36. La[AU2], Y. J., C. L. Wan, H. Zhu, Y. F. Yang, Y. S. Chen, Y. X. Pan, G. Y. Feng and L. He (2006). Decreased levels of apolipoprotein A-I in plasma of schizophrenic patients. J Neural Transm.Google Scholar
  37. Lawrie, S. M. and S. S. Abukmeil (1998). Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatr 172: 110–20.CrossRefGoogle Scholar
  38. Lawrie, S. M., H. Whalley, J. N. Kestelman, S. S. Abukmeil, M. Byrne, A. Hodges, J. E. Rimmington, J. J. Best, D. G. Owens and E. C. Johnstone (1999). Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet 353(9146): 30–3.PubMedCrossRefGoogle Scholar
  39. Lawrie, S. M., H. C. Whalley, S. S. Abukmeil, J. N. Kestelman, L. Donnelly, P. Miller, J. J. Best, D. G. Owens and E. C. Johnstone (2001). Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia. Biol Psychiatr 49(10): 811–23.CrossRefGoogle Scholar
  40. Liu, H., R. G. Sadygov and J. R. Yates, III (2004). A model for random sampling and estimation of relative protein abundance in shotgun proteomics. Anal Chem 76(14): 4193–201.PubMedCrossRefGoogle Scholar
  41. Manning, G., D. B. Whyte, R. Martinez, T. Hunter and S. Sudarsanam (2002). The protein kinase complement of the human genome. Science 298(5600): 1912–34.PubMedCrossRefGoogle Scholar
  42. McDonald, L., D. H. Robertson, J. L. Hurst and R. J. Beynon (2005). Positional proteomics: selective recovery and analysis of N-terminal proteolytic peptides. Nat Methods 2(12): 955–7.PubMedCrossRefGoogle Scholar
  43. McGlashan, T. H., R. B. Zipursky, D. Perkins, J. Addington, T. Miller, S. W. Woods, K. A. Hawkins, R. E. Hoffman, A. Preda, I. Epstein, D. Addington, S. Lindborg, Q. Trzaskoma, M. Tohen and A. Breier (2006). Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatr 163(5): 790–9.PubMedCrossRefGoogle Scholar
  44. McGorry, P. D., A. R. Yung, L. J. Phillips, H. P. Yuen, S. Francey, E. M. Cosgrave, D. Germano, J. Bravin, T. McDonald, A. Blair, S. Adlard and H. Jackson (2002). Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatr 59(10): 921–8.PubMedCrossRefGoogle Scholar
  45. Merchant, M. and S. R. Weinberger (2000). Recent advancements in surface-enhanced laser desorption/ionization-time of flightmass spectrometry. Electrophoresis 21(6): 1164–77.PubMedCrossRefGoogle Scholar
  46. Merrell, K., K. Southwick, S. W. Graves, M. S. Esplin, N. E. Lewis and C. D. Thulin (2004). Analysis of low-abundance, low-molecular-weight serum proteins using mass spectrometry. J Biomol Tech 15(4): 238–48.PubMedGoogle Scholar
  47. Morrow, J. D., J. A. Awad, J. A. Oates and L. J. Roberts, II (1992). Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. J Invest Dermatol 98(5): 812–5.PubMedCrossRefGoogle Scholar
  48. O'Hagan, S., W. B. Dunn, J. D. Knowles, D. Broadhurst, R. Williams, J. J. Ashworth, M. Cameron and D. B. Kell (2007). Closed-loop, multiobjective optimization of two-dimensional gas chromatography/mass spectrometry for serum metabolomics. Anal Chem 79(2): 464–76.PubMedCrossRefGoogle Scholar
  49. Old, W. M., K. Meyer-Arendt, L. Aveline-Wolf, K. G. Pierce, A. Mendoza, J. R. Sevinsky, K. A. Resing and N. G. Ahn (2005). Comparison of label-free methods for quantifying human proteins by shotgun proteomics. Mol Cell Proteomics 4(10): 1487–502.PubMedCrossRefGoogle Scholar
  50. Patterson, S. D. and R. H. Aebersold (2003). Proteomics: the first decade and beyond. Nat Genet 33 (Suppl): 311–23.PubMedCrossRefGoogle Scholar
  51. Phizicky, E., P. I. Bastiaens, H. Zhu, M. Snyder and S. Fields (2003). Protein analysis on a proteomic scale. Nature 422(6928): 208–15.PubMedCrossRefGoogle Scholar
  52. Prabakaran, S., M. Wengenroth, H. E. Lockstone, K. Lilley, F. M. Leweke and S. Bahn (2007). 2-D DIGE analysis of liver and red blood cells provides further evidence for oxidative stress in schizophrenia. J Proteome Res 6(1): 141–9.PubMedCrossRefGoogle Scholar
  53. Puri, B. K., T. Easton, I. Das, L. Kidane and A. J. Richardson (2001). The niacin skin flush test in schizophrenia: a replication study. Int J Clin Pract 55(6): 368–70.PubMedGoogle Scholar
  54. Puri, B. K., S. R. Hirsch, T. Easton and A. J. Richardson (2002). A volumetric biochemical niacin flush-based index that noninvasively detects fatty acid deficiency in schizophrenia. Progr Neuro Psychopharmacol Biol Psychiatr 26(1): 49–52.CrossRefGoogle Scholar
  55. Reiner, A., D. Yekutieli and Y. Benjamini (2003). Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics 19(3): 368–75.PubMedCrossRefGoogle Scholar
  56. Rogers, M. A., P. Clarke, J. Noble, N. P. Munro, A. Paul, P. J. Selby and R. E. Banks (2003). Proteomic profiling of urinary proteins in renal cancer by surface enhanced laser desorption ionization and neural-network analysis: identification of key issues affecting potential clinical utility. Cancer Res 63(20): 6971–83.PubMedGoogle Scholar
  57. Schulte, I., H. Tammen, H. Selle and P. Schulz-Knappe (2005). Peptides in body fluids and tissues as markers of disease. Expert Rev Mol Diagn 5(2): 145–57.PubMedCrossRefGoogle Scholar
  58. Seehusen, D. A., M. M. Reeves and D. A. Fomin (2003). Cerebrospinal fluid analysis. Am Fam Physician 68(6): 1103–8.PubMedGoogle Scholar
  59. Shaw, J., R. Rowlinson, J. Nickson, T. Stone, A. Sweet, K. Williams and R. Tonge (2003). Evaluation of saturation labelling two-dimensional difference gel electrophoresis fluorescent dyes. Proteomics 3(7): 1181–95.PubMedCrossRefGoogle Scholar
  60. Steen, H., B. Kuster and M. Mann (2001). Quadrupole time-of-flight versus triple-quadrupole mass spectrometry for the determination of phosphopeptides by precursor ion scanning. J Mass Spectrom 36(7): 782–90.PubMedCrossRefGoogle Scholar
  61. Storey, J. D. (2001). The positive false discovery rate: A Bayesian interpretation and the q-value. Technical Report 2001–12, Department of Statistics, Stanford UniversityGoogle Scholar
  62. Tavares, H., J. Yacubian, L. L. Talib, N. R. Barbosa and W. F. Gattaz (2003). Increased phospholipase A2 activity in schizophrenia with absent response to niacin. Schizophr Res 61(1): 1–6.PubMedCrossRefGoogle Scholar
  63. Tonge, R., J. Shaw, B. Middleton, R. Rowlinson, S. Rayner, J. Young, F. Pognan, E. Hawkins, I. Currie and M. Davison (2001). Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology. Proteomics 1(3): 377–96.PubMedCrossRefGoogle Scholar
  64. Tosato, S., P. Dazzan and D. Collier (2005). Association between the neuregulin 1 gene and schizophrenia: a systematic review. Schizophr Bull 31(3): 613–7.PubMedCrossRefGoogle Scholar
  65. Tosic, M., J. Ott, S. Barral, P. Bovet, P. Deppen, F. Gheorghita, M. L. Matthey, J. Parnas, M. Preisig, M. Saraga, A. Solida, S. Timm, A. G. Wang, T. Werge, M. Cuenod and K. Q. Do (2006). Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet 79(3): 586–92.PubMedCrossRefGoogle Scholar
  66. Tsang, T. M., J. T. Huang, E. Holmes and S. Bahn (2006). Metabolic profiling of plasma from discordant schizophrenia twins: correlation between lipid signals and global functioning in female schizophrenia patients. J Proteome Res 5(4): 756–60.PubMedCrossRefGoogle Scholar
  67. Villar[AU3]-Garea, A., M. Griese and A. Imhof (2006). Biomarker discovery from body fluids using mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci.Google Scholar
  68. Vitzthum, F., F. Behrens, N. L. Anderson and J. H. Shaw (2005). Proteomics: from basic research to diagnostic application. A review of requirements & needs. J Proteome Res 4(4): 1086–97.PubMedCrossRefGoogle Scholar
  69. Vong, R., P. Geladi, S. Wold and K. Esbensen (1988). Source contributions to ambient aerosol calculated by discriminant partial least squares regression (PLS). J. Chemometrics 2: 281–6.CrossRefGoogle Scholar
  70. Wan, C., Y. La, H. Zhu, Y. Yang, L. Jiang, Y. Chen, G. Feng, H. Li, H. Sang, X. Hao, G. Zhang and L. He (2007). Abnormal changes of plasma acute phase proteins in schizophrenia and the relation between schizophrenia and haptoglobin (Hp) gene. Amino Acids 32(1): 101–8.PubMedCrossRefGoogle Scholar
  71. Wan, C., Y. Yang, H. Li, Y. La, H. Zhu, L. Jiang, Y. Chen, G. Feng and L. He (2006). Dysregulation of retinoid transporters expression in body fluids of schizophrenia patients. J Proteome Res 5(11): 3213–6.PubMedCrossRefGoogle Scholar
  72. Wang, W., H. Zhou, H. Lin, S. Roy, T. A. Shaler, L. R. Hill, S. Norton, P. Kumar, M. Anderle and C. H. Becker (2003). Quantification of proteins and metabolites by mass spectrometry without isotopic labeling or spiked standards. Anal Chem 75(18): 4818–26.PubMedCrossRefGoogle Scholar
  73. Xiao, Z., D. Prieto, T. P. Conrads, T. D. Veenstra and H. J. Issaq (2005). Proteomic patterns: their potential for disease diagnosis. Mol Cell Endocrinol 230(1–2): 95–106.PubMedCrossRefGoogle Scholar
  74. Zhang, B., N. C. VerBerkmoes, M. A. Langston, E. Uberbacher, R. L. Hettich and N. F. Samatova (2006). Detecting differential and correlated protein expression in label-free shotgun proteomics. J Proteome Res 5(11): 2909–18.PubMedCrossRefGoogle Scholar
  75. Zhang, X. Y., D. F. Zhou, L. Y. Cao, P. Y. Zhang and G. Y. Wu (2002). Decreased production of interleukin-2 (IL-2), IL-2 secreting cells and CD4+ cells in medication-free patients with schizophrenia. J Psychiatr Res 36(5): 331–6.PubMedCrossRefGoogle Scholar
  76. Zieske, L. R. (2006). A perspective on the use of iTRAQ reagent technology for protein complex and profiling studies. J Exp Bot 57(7): 1501–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Institute of BiotechnologyUniversity of CambridgeCambridgeUnited Kingdom

Personalised recommendations