Skip to main content

Where Do We Stand in the Quest for Neuropsychiatric Biomarkers and Endophenotypes and What Next?

  • Chapter
The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes

Abstract

Although biomarker science is a field that is advancing rapidly in medicine as a whole, neurop-sychiatric disorders are still characterized by an absence of the biomarkers and laboratory tests that will promote new diagnostic and prognostic procedures. Recent advances in genomic, genetic, epige-netic, neuroscience, proteomic and metabolomic knowledge and technologies have opened the way to searching for biomarkers, however, it is still a relatively new field for neuropsychiatry. In addition, candidate endophenotypes, important trait markers widely used for genetic studies, are useful for the development of heritable diagnostic and prognostic biomarkers (endo-phenotype strategy). This chapter provides definitions of biomarkers and endophenotypes, elucidating their types and properties that will make them useful in neuropsychiatric research and practice. Recent results in the schizophrenia and mood disorders literature that illustrate the usefulness of biomarkers and endo-phenotypes are also reviewed. We predict that both biomarker and endophenotypic approaches will open new avenues for practically important applications of genetics, neuroscience and “omics” advantages in neuropsychiatry.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Mueller C, Müller B, Perruchoud AP. Biomarkers: past, present, and future. Swiss Med Wkly. 2008;138:225–229.

    PubMed  Google Scholar 

  2. The National Institute of Mental Health Strategic Plan. NIMH, 2007, p. 37. http://www.nimh.nih.gov/about/ strategic-planning-reports/index.shtml

  3. Harrigan GG. Metabolomics: a ‘systems’ contribution to pharmaceutical discovery and drug development. Drug Discov World. 2006; Available at: http://www.ddw-online.com/data/pdfs/metabolomics.pdf. Accessed June 27, 2007.

  4. Harrison PM, Kumar A, Lang N, et al. A question of size: the eukaryotic proteome and the problems in defining it. Nucleic Acids Res. 2002; 30:1083–1090.

    PubMed  CAS  Google Scholar 

  5. Dettmer K, Hammock BD. Metabolomics — a new exciting field within “omics” sciences. Environ Health Perspect. 2004; 112:A396–A397.

    PubMed  Google Scholar 

  6. Rosenberg RN. Translational research on the way to effective therapy for Alzheimer disease. Arch Gen Psychiatry. 2005; 62:1186–1192.

    PubMed  CAS  Google Scholar 

  7. Hillered L, Vespa PM, Hovda DA. Translational neuro-chemical research in acute human brain injury: the current status and potential future for cerebral microdialysis. J Neurotrauma. 2005; 22:3–41.

    PubMed  Google Scholar 

  8. Henley SM, Bates GP, Tabrizi SJ. Biomarkers for neurode-generative diseases. Curr Opin Neurol. 2005; 18:698–705.

    PubMed  Google Scholar 

  9. Shaw LM, Korecka M, Clark CM, et al. Biomarkers of neu-rodegeneration for diagnosis and monitoring therapeutics. Nat Rev Drug Discov. 2007; 6:295–303.

    PubMed  CAS  Google Scholar 

  10. Phillips ML, Vieta E. Identifying functional neuroimaging biomarkers of bipolar disorder: toward DSM-V. Schizophr Bull. 2007; 33:893–904.

    PubMed  Google Scholar 

  11. Bailey P. Biological markers in Alzheimer's disease. Can J Neurol Sci. 2007; 34 Suppl 1:S72–S76.

    PubMed  Google Scholar 

  12. Schwarz E, Bahn S. The utility of biomarker discovery approaches for the detection of disease mechanisms in psychiatric disorders. Br J Pharmacol. 2008; 153(Suppl 1): S133–S136.

    PubMed  CAS  Google Scholar 

  13. Atkinson AEA. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69:89–95.

    Google Scholar 

  14. Biomarkers Definition Working Group, 1998, Gregory Downing, NIH Initiatives in Surrogate Endpoints and Endpoint Analysis, Non-clinical Studies Subcommittee, Advisory Committee for Pharmaceutical Science presentation, 2000.

    Google Scholar 

  15. Biomarkers Definitions Working Group: Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69:89–95.

    Google Scholar 

  16. Russell K. Biomarkers and surrogate markers: an FDA perspective. NeuroRx. 2004; 1:189–195.

    Google Scholar 

  17. Wagner J, Merck A. Conference on Biomarkers Discovery and Validation, Oct. 14–18, 2004 http://bigdaddy.scripps. edu/darlene/Asilomar/pages/abstracts/jwagner.htm

  18. Huang JT, Leweke FM, Oxley D, et al. Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis. PLoS Med. 2006; 3(11):e428.

    PubMed  Google Scholar 

  19. Sunderland T, Gur RE, Arnold SE. The use of biomarkers in the elderly: current and future challenges. Biol Psychiatry. 2005; 58:272–276.

    PubMed  CAS  Google Scholar 

  20. Alston WP. Traits, consistency, and conceptual alternatives for personality theory. J Theor Soc Behav. 1975; 5:17–48.

    Google Scholar 

  21. Zuckerman M. General and situation-specific traits and states: new approaches to assessment of anxiety and other constructs. In: Zuckerman M, Spielberger CD (eds), Emotion and anxiety: new concepts, methods, and applications. Erlbaum, Hillsdale, NJ; 1976, pp. 133–174.

    Google Scholar 

  22. Zuckerman M. The distinction between trait and state scales is not arbitrary: comment on Allen and Potkay's “on the arbitrary distinction between traits and states.” J Pers Soc Psychol. 1983; 44:1083–1086.

    Google Scholar 

  23. Fridhandler BM. Conceptual note on state, trait, and the state-trait distinction. J Pers Soc Psychol. 1986; 50:169–174.

    Google Scholar 

  24. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003; 1(60):636–645.

    Google Scholar 

  25. Gould TD, Gottesman II. Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav. 2006; 5:113–119.

    PubMed  CAS  Google Scholar 

  26. Adler LE, Freedman R, Ross RG, et al. Elementary pheno-types in the neurobiological and genetic study of schizophrenia. Biol Psychiatry. 1999; 46:8–18.

    PubMed  CAS  Google Scholar 

  27. Jones PB, Tarrant CJ. Developmental precursors and biological markers for schizophrenia and affective disorders: specificity and public health implications. Eur Arch Psychiatry Clin Neurosci. 2000; 250:286–291.

    PubMed  CAS  Google Scholar 

  28. Gould TD, Manji HK. The molecular medicine revolution and psychiatry: bridging the gap between basic neurosci-ence research and clinical psychiatry. J Clin Psychiatry. 2004; 65:598–604.

    PubMed  Google Scholar 

  29. Agarwal DP. The genetics of alcohol metabolism and alcoholism. Indian J Hum Genet. 2001; 1:25–32.

    Google Scholar 

  30. Brittlebank AD, Scott J, Williams JM, Ferrier IN. Autobiographical memory in depression: state or trait marker? Br J Psychiatry. 1993; 162:118–121.

    PubMed  CAS  Google Scholar 

  31. Sharma P, Rao K, Subbakrishna DK. Vulnerability to depression: a study of trait and state factors. Indian J Clin Psychol. 2001; 28:194–203.

    Google Scholar 

  32. Clark L, Goodwin GM. State- and trait-related deficits in sustained attention in bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2004; 254:61–68.

    PubMed  Google Scholar 

  33. Zalla T, Joyce C, Szöke A, et al. Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Res. 2004; 121:207–217.

    PubMed  Google Scholar 

  34. Ilani T, Ben-Shachar D, Strous RD, et al. A peripheral marker for schizophrenia: increased levels of D3 dopamine receptor mRNA in blood lymphocytes. Proc Natl Acad Sci USA. 2001; 98:625–628.

    PubMed  CAS  Google Scholar 

  35. Ritsner M, Modai I, Gibel A, et al. Decreased platelet peripheral-type benzodiazepine receptors in persistently violent schizophrenia patients. J Psychiatr Res. 2003; 37:549–556.

    PubMed  Google Scholar 

  36. Chen Y, Bidwell LC, Norton D. Trait vs. state markers for schizophrenia: identification and characterization through visual processes. Curr Psychiatry Rev. 2006; 2:431–438.

    PubMed  Google Scholar 

  37. van Beveren NJ, van der Spelt JJ, de Haan L, Fekkes D. Schizophrenia-associated neural growth factors in peripheral blood. Eur Neuropsychopharmacol. 2006; 16:469–480.

    PubMed  Google Scholar 

  38. Rao NP, Reddy YC, Kumar KJ, et al. Are neuropsychologi-cal deficits trait markers in OCD? Prog Neuropsychopharmacol Biol Psychiatry. 2008 June 8.

    Google Scholar 

  39. Gasparini L, Racchi M, Binetti G, et al. Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease. FASEB J. 1998; 12:17–34.

    PubMed  CAS  Google Scholar 

  40. Ward M. Biomarkers for Alzheimer's disease. Expert Rev Mol Diagn. 2007; 7:635–646.

    PubMed  CAS  Google Scholar 

  41. Farren CK, Tipton KF. Trait markers for alcoholism: clinical utility. Alcohol 1999; 34:649–665.

    CAS  Google Scholar 

  42. Helander A. Biological markers in alcoholism. J Neural Transm Suppl. 2003; 66:15–32.

    PubMed  CAS  Google Scholar 

  43. Kuusimäki L, Peltonen K, Vainiotalo S. Assessment of environmental tobacco smoke exposure of Finnish restaurant workers, using 3-ethenylpyridine as marker. Indoor Air. 2007; 17:394–403.

    PubMed  Google Scholar 

  44. Okoli CT, Hall LA, Rayens MK, Hahn EJ. Measuring tobacco smoke exposure among smoking and nonsmoking bar and restaurant workers. Biol Res Nurs. 2007; 9:81–89.

    PubMed  CAS  Google Scholar 

  45. Kingsmore SF, Kennedy N, Halliday HL, et al. Identification of diagnostic biomarkers for infection in premature neo-nates. Mol Cell Proteomics. 2008;7:1863 –1875.

    PubMed  CAS  Google Scholar 

  46. Burmeister M, McInnis MG, Zöllner S. Psychiatric genetics: progress amid controversy. Nat Rev Genet. 2008; 9:527–540.

    PubMed  CAS  Google Scholar 

  47. Craddock N, O'Donovan MC, Owen MJ. Genome-wide association studies in psychiatry: lessons from early studies of non-psychiatric and psychiatric phenotypes. Mol Psychiatry. 2008; 13:649–653.

    PubMed  CAS  Google Scholar 

  48. Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet. 2003; 33 Suppl:228–237.

    PubMed  CAS  Google Scholar 

  49. Colburn WA. Biomarkers in drug discovery and development: from target identification through drug marketing. J Clin Pharmacol. 2003; 43:329–341.

    PubMed  Google Scholar 

  50. Bonassi S, Neri M, Puntoni R. Validation of biomarkers as early predictors of disease. Mutat Res./Fund Mol Mech Mutagen. 51. 2001; 480–481:349–358.

    Google Scholar 

  51. Gottesman II, Shields J. Schizophrenia and genetics; a twin study vantage point. Academic, New York. 1972.

    Google Scholar 

  52. Gottesman II, Shields J. Genetic theorizing and schizophrenia. Br J Psychiatry. 1973; 122:15–30.

    PubMed  CAS  Google Scholar 

  53. John B, Lewis KR. Chromosome variability and geographical distribution in insects: chromosome rather than gene variation provide the key to differences among populations. Science. 1966; 152:711–721.

    PubMed  Google Scholar 

  54. Cannon TD, Keller MC. Endophenotypes in the genetic analyses of mental disorders. Annu Rev Clin Psychol. 2006; 2:267–290.

    PubMed  Google Scholar 

  55. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsycho-pharmacology. 2004; 29:1765–1781.

    CAS  Google Scholar 

  56. Turetsky BI, Calkins ME, Light GA, et al. Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophr Bull. 2007; 33:69–94.

    PubMed  Google Scholar 

  57. Braff DL, Freedman R, Schork NJ, Gottesman II. Deconstructing schizophrenia: an overview of the use of endophe-notypes in order to understand a complex disorder. Schizophr Bull. 2007; 33:21–32.

    PubMed  Google Scholar 

  58. Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry. 2006; 60:93–105.

    PubMed  Google Scholar 

  59. Chan RC, Gottesman II. Neurological soft signs as candidate endophenotypes for schizophrenia: a shooting star or a Northern star? Neurosci Biobehav Rev. 2008; 32:957–971.

    PubMed  Google Scholar 

  60. Walters JT, Owen MJ. Endophenotypes in psychiatric genetics. Mol Psychiatry. 2007; 12:886–890.

    PubMed  CAS  Google Scholar 

  61. Frederick JA, Iacono WG. Beyond the DSM: defining endophenotypes for genetic studies of substance abuse current psychiatry reports. 2006; 8:144–150.

    Google Scholar 

  62. Leboyer M, Bellivier F, Nosten-Bertrand M, et al. Psychiatric genetics: search for phenotypes. Trends Neurosci. 1998; 21:102–105.

    PubMed  CAS  Google Scholar 

  63. Braff DL, Greenwood TA, Swerdlow NR, et al. Advances in endophenotyping schizophrenia. World Psychiatry. 2008; 7:11–18.

    PubMed  Google Scholar 

  64. Pearlson GD, Folley BS. Endophenotypes, dimensions, risks: is psychosis analogous to common inherited medical illnesses? Clin EEG Neurosci. 2008; 39:73–77.

    PubMed  Google Scholar 

  65. Freedman R, Adler LE, Leonard S. Alternative phenotypes for the complex genetics of schizophrenia. Biol Psychiatry. 1999; 45:551–558.

    PubMed  CAS  Google Scholar 

  66. Skuse DH. Endophenotypes and child psychiatry. Br J Psychiatry. 2001; 178:395–396.

    PubMed  CAS  Google Scholar 

  67. Sporn AL, Greenstein DK, Gogtay N, et al. Progressive brain volume loss during adolescence in childhood-onset schizophrenia. Am J Psychiatry. 2003; 160:2181–2189.

    PubMed  Google Scholar 

  68. Braff DL, Freedman R. Endophenotypes in studies of the genetics of schizophrenia. In: Davis KL, Charney DS, Coyle JT, Nemeroff C (eds) Neuropsychopharmacology: the fifth generation of progress. Lippincott Williams & Wilkens, Philadelphia, PA; 2002, pp. 703–716.

    Google Scholar 

  69. Egan MF, Goldberg TE. Intermediate cognitive phenotypes associated with schizophrenia. Methods Mol Med. 2003; 77:163–197.

    PubMed  Google Scholar 

  70. Lenzenweger MF. Schizophrenia: refining the phenotype, resolving endophenotypes. Behav Res Ther. 1999; 37:281–295.

    PubMed  CAS  Google Scholar 

  71. Gur RE, Calkins ME, Gur RC, et al. The consortium on the genetics of schizophrenia: neurocognitive endophenotypes. Schizophr Bull. 2007; 33:49–68.

    PubMed  Google Scholar 

  72. Glahn DC, Bearden CE, Niendam TA, Escamilla MA. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord. 2004; 6:171–182.

    PubMed  Google Scholar 

  73. Lenox RH, Gould TD, Manji HK. Endophenotypes in bipolar disorder. Am J Med Genet. 2002; 114:391–406.

    PubMed  Google Scholar 

  74. Benes FM. Searching for unique endophenotypes for schizophrenia and bipolar disorder within neural circuits and their molecular regulatory mechanisms. Schizophr Bull. 2007; 33:932–936.

    PubMed  Google Scholar 

  75. Waldman ID. Statistical approaches to complex pheno-types: evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005; 57:1347–1356.

    PubMed  Google Scholar 

  76. Belmonte MK, Cook EH Jr, Anderson GM, et al. Autism as a disorder of neural information processing: directions for research and targets for therapy. Mol Psychiatry. 2004; 9:646–663.

    PubMed  CAS  Google Scholar 

  77. Dick DM, Jones K, Saccone N, et al. Endophenotypes successfully lead to gene identification: results from the collaborative study on the genetics of alcoholism. Behav Genet. 2005; 10:1–15.

    Google Scholar 

  78. Gould TD, Einat H. Animal models of bipolar disorder and mood stabilizer efficacy: a critical need for improvement. Neurosci Biobehav Rev. 2007; 31:825–831.

    PubMed  CAS  Google Scholar 

  79. Harrison-Read PE. Models of mania and antimanic drug actions: progressing the endophenotype approach. J Psycho-pharmacol. 2008 [epub ahead of print].

    Google Scholar 

  80. Flint J, Shifman S. Animal models of psychiatric disease. Curr Opin Genet Dev. 2008 Aug 11 [epub ahead of print].

    Google Scholar 

  81. Cryan JF, Slattery DA. Animal models of mood disorders: recent developments. Curr Opin Psychiatry. 2007; 20:1–7.

    PubMed  Google Scholar 

  82. Powell SB, Geyer MA. Overview of animal models of schizophrenia. Curr Protoc Neurosci. 2007; Chapter 9:Unit 9.24.

    Google Scholar 

  83. Scobioala S, Klocke R, Michel G, et al. Proteomics: state of the art and its application in cardiovascular research. Curr Med Chem. 2004; 11:3203–3218.

    PubMed  CAS  Google Scholar 

  84. Anderson NL, Anderson NG. Proteome and proteomics: new technologies, new concepts, and new words. Electro-phoresis. 1998; 19:1853–1861.

    CAS  Google Scholar 

  85. Liebler DC. Analytical proteomics approaches to analysis of protein modifications: tools for studying proteome-envi-ronment interactions. In Toxicogenomics. Wiley. 2004, pp. 283–297.

    Google Scholar 

  86. Pienaar IS, Daniels WM, Götz J. Neuroproteomics as a promising tool in Parkinson's disease research. J Neural Transm. 2008;115:1413–30.

    PubMed  CAS  Google Scholar 

  87. Sigal A, Milo R, Cohen A, et al. Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins. Nat Methods. 2006; 3:525–531.

    PubMed  CAS  Google Scholar 

  88. Hünnerkopf R, Grassl J, Thome J. Proteomics: biomarker research in psychiatry. Fortschr Neurol Psychiatr. 2007; 75:579–586.

    PubMed  Google Scholar 

  89. Balestrieri ML, Giovane A, Mancini FP, Napoli C. Proteomics and cardiovascular disease: an update. Curr Med Chem. 2008; 15:555–572.

    PubMed  CAS  Google Scholar 

  90. Blake CA. Physiological proteomics: cells, organs, biological fluids, and biomarkers. Exp Biol Med. 2005; 230:785–786.

    CAS  Google Scholar 

  91. Harrigan GG, Goodacre R. (eds), Metabolic profiling: its role in biomarker discovery and gene function analysis. Kluwer, Boston, MA; 2003.

    Google Scholar 

  92. Daviss B. Growing pains for metabolomics. Scientist. 2005; 19:25–28.

    Google Scholar 

  93. Kaddurah-Daouk R. Metabolic profiling of patients with schizophrenia. PLoS Med. 2006; 3(8):e363 doi:10.1371/ journal.pmed.0030363.

    PubMed  Google Scholar 

  94. Goodacre R, Vaidyanathan S, Dunn WB, et al. Metabolomics by numbers: acquiring and understanding global metabolite data. Trends Biotechnol. 2004; 22:245–252.

    PubMed  CAS  Google Scholar 

  95. Griffin JL, Vidal-Puig A. Current challenges in metabolo-mics for diabetes research: a vital functional genomic tool or just a ploy for gaining funding? Physiol Genomics. 2008; 34:1–5.

    PubMed  CAS  Google Scholar 

  96. Kell DB. Metabolomic biomarkers: search, discovery and validation. Expert Rev Mol Diagn. 2007; 7:329–333.

    PubMed  CAS  Google Scholar 

  97. Vangala S, Tonelli A. Biomarkers, metabonomics, and drug development: can inborn errors of metabolism help in understanding drug toxicity?. AAPS J. 2007; 9:E284–E297.

    PubMed  CAS  Google Scholar 

  98. Sabatine MS, Liu E, Morrow DA, et al. Metabolomic iden-tification of novel biomarkers of myocardial ischemia. Circulation. 2005; 112:3868–3875.

    PubMed  CAS  Google Scholar 

  99. Odunsi K, Wollman RM, Ambrosone CM, et al. Detection of epithelial ovarian cancer using 1H-NMR-based metabo-nomics. Int J Cancer. 2005; 113:782–788.

    PubMed  CAS  Google Scholar 

  100. Yang J, Xu G, Hong Q, et al. Discrimination of type 2 diabetic patients from healthy controls by using metabo-nomics method based on their serum fatty acid profiles. J Chromatogr B Analyt Technol Biomed Life Sci. 2004; 813:53–58.

    PubMed  CAS  Google Scholar 

  101. Copolov D, Crook J. Biological markers and schizophrenia. Aust N Z J Psychiatry. 2000; 34 Suppl:S108–S112.

    PubMed  Google Scholar 

  102. Bertram L. Genetic research in schizophrenia: new tools and future perspectives. Schizophr Bull. 2008; 34:806–812.

    PubMed  Google Scholar 

  103. Allen NC, Bagade S, McQueen MB, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008; 40:827–834.

    PubMed  CAS  Google Scholar 

  104. Harms MP, Wang L, Mamah D, et al. Thalamic shape abnormalities in individuals with schizophrenia and their nonpsychotic siblings. J Neurosci. 2007; 27:13835–13842.

    PubMed  CAS  Google Scholar 

  105. Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res. 2001; 49:1–52.

    PubMed  CAS  Google Scholar 

  106. McDonald C, Marshall N, Sham PC, et al. Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives. Am J Psychiatry. 2006; 163:478–487.

    PubMed  Google Scholar 

  107. Makris N, Goldstein JM, Kennedy D, et al. Decreased volume of left and total anterior insular lobule in schizophrenia. Schizophr Res. 2006; 83:155–171.

    PubMed  Google Scholar 

  108. Marcelis M, Suckling J, Woodruff P, et al. Searching for a structural endophenotype in psychosis using computational morphometry. Psychiatry Res. 2003; 122:153–167.

    PubMed  Google Scholar 

  109. Turetsky BI, Moberg PJ, Arnold SE, et al. Low olfactory bulb volume in first-degree relatives of patients with schizophrenia. Am J Psychiatry. 2003; 160:703–708.

    PubMed  Google Scholar 

  110. John JP, Arunachalam V, Ratnam B, Isaac MK. Expanding the schizophrenia phenotype: a composite evaluation of neurodevelopmental markers. Compr Psychiatry. 2008; 49:78–86.

    PubMed  Google Scholar 

  111. Bramon E, McDonald C, Croft RJ, et al. Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study. Neuroimage. 2005; 27:960–968.

    PubMed  Google Scholar 

  112. Levy DL, Holzman PS, Matthysse S, et al. Eye tracking and schizophrenia: a selective review. Schizophr Bull. 1994; 20:47–62.

    PubMed  CAS  Google Scholar 

  113. Flechtner KM, Steinacher B, Mackert A. Subthreshold symptoms and vulnerability indicators (e.g., eye tracking dysfunction) in schizophrenia. Compr Psychiatry. 2000; 41(2 Suppl 1):86–89.

    PubMed  CAS  Google Scholar 

  114. Tsuang M. Schizophrenia: genes and environment. Biol Psychiatry. 2000; 47:210–220.

    PubMed  CAS  Google Scholar 

  115. McDowell JE, Brown GG, Paulus M, et al. Neural correlates of refixation saccades and antisaccades in normal and schizophrenia subjects. Biol Psychiatry. 2002; 51:216–223.

    PubMed  Google Scholar 

  116. Iacono WG, Moreau M, Beiser M, et al. Smooth-pursuit eye tracking in first-episode psychotic patients and their relatives. J Abnorm Psychol. 1992; 101:104–116.

    PubMed  CAS  Google Scholar 

  117. Amador XF, Malaspina D, Sackeim HA, et al. Visual fixa-tion and smooth pursuit eye movement abnormalities in patients with schizophrenia and their relatives. J Neuro-psychiatry Clin Neurosci. 1995; 7:197–206.

    CAS  Google Scholar 

  118. Ross RG, Olincy A, Mikulich SK, et al. Admixture analysis of smooth pursuit eye movements in probands with schizophrenia and their relatives suggests gain and leading saccades are potential endophenotypes. Psychophysiology. 2002; 39:809–819.

    PubMed  Google Scholar 

  119. Blackwood D. P300, a state and a trait marker in schizophrenia. Lancet. 2000; 355:771–772.

    PubMed  CAS  Google Scholar 

  120. Cadenhead KS, Swerdlow NR, Shafer KM, et al. Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits. Am J Psychiatry. 2000; 157:1660–1668.

    PubMed  CAS  Google Scholar 

  121. Light GA, Braff DL. Measuring P50 suppression and pre-pulse inhibition in a single recording session. Am J Psychiatry. 2001; 158:2066–2068.

    PubMed  CAS  Google Scholar 

  122. Freedman R, Adams CE, Adler LE, et al. Inhibitory neuro-physiological deficit as a phenotype for genetic investigation of schizophrenia. Am J Med Gen. 2000; 97:58–64.

    CAS  Google Scholar 

  123. Umbricht D, Koller R, Schmid L, et al. How specific are deficits in mismatch negativity generation to schizophrenia? Biol Psychiatry. 2003; 53:1120–1131.

    PubMed  Google Scholar 

  124. Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res. 2005; 76:1–23.

    PubMed  Google Scholar 

  125. Ross RG, Meinlein S, Zerbe GO, et al. Saccadic eye movement task identifies cognitive deficits in children with schizophrenia, but not in unaffected child relatives. J Child Psychol Psychiatry. 2005; 46:1354–1362.

    PubMed  Google Scholar 

  126. Calkins ME, Curtis CE, Iacono WG, Grove WM. Antisaccade performance is impaired in medically and psy-chiatrically healthy biological relatives of schizophrenia patients. Schizophr Res. 2004; 71:167–178.

    PubMed  Google Scholar 

  127. Price GW, Michie PT, Johnston J, et al. A multivariate elec-trophysiological endophenotype, from a unitary cohort, shows greater research utility than any single feature in the Western Australian family study of schizophrenia. Biol Psychiatry. 2006; 60:1–10.

    PubMed  Google Scholar 

  128. Barshtein G, Ponizovsky AM, Nechamkin Y, Ritsner M, et al. Aggregability of red blood cells of schizophrenia patients with negative syndrome is selectively enhanced. Schizophr Bull. 2004; 30:913–922.

    PubMed  Google Scholar 

  129. Moberg PJ, McGue C, Kanes SJ, et al. Phenylthiocarbamide (PTC) perception in patients with schizophrenia and first-degree family members: relationship to clinical symptomatology and psychophysical olfactory performance. Schizophr Res. 2007; 90:221–228.

    PubMed  Google Scholar 

  130. Yeap S, Kelly SP, Sehatpour P, et al. Early visual sensory deficits as endophenotypes for schizophrenia: high-density electrical mapping in clinically unaffected first-degree relatives. Arch Gen Psychiatry. 2006; 63:1180–1188.

    PubMed  Google Scholar 

  131. Craddock RM, Huang JT, Jackson E, et al. Increased alpha defensins as a blood marker for schizophrenia susceptibility. Mol Cell Proteomics. 2008;7:1204–1213.

    PubMed  CAS  Google Scholar 

  132. Suzuki K, Nakamura K, Iwata Y, et al. Decreased expression of reelin receptor VLDLR in peripheral lymphocytes of drug-naive schizophrenic patients. Schizophr Res. 2008; 98:148–156.

    PubMed  Google Scholar 

  133. Morera AL, Henry M, García-Hernández A, Fernández-López L. Acute phase proteins as biological markers of negative psychopathology in paranoid schizophrenia. Actas Esp Psiquiatr. 2007; 35:249–252.

    PubMed  CAS  Google Scholar 

  134. Dickerson F, Stallings C, Origoni A, et al. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res. 2007; 93:261–265.

    PubMed  Google Scholar 

  135. Iwata Y, Suzuki K, Nakamura K, et al. Increased levels of serum soluble L-selectin in unmedicated patients with schizophrenia. Schizophr Res. 2007; 89:154–160.

    PubMed  Google Scholar 

  136. Messamore E. Relationship between the niacin skin flush response and essential fatty acids in schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 2003; 69:413–419.

    PubMed  CAS  Google Scholar 

  137. Smesny S, Rosburg T, Riemann S, et al. Impaired niacin sensitivity in acute first-episode but not in multi-episode schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 2005; 72:393–402.

    PubMed  CAS  Google Scholar 

  138. Smesny S, Klemm S, Stockebrand M, et al. Endophenotype properties of niacin sensitivity as marker of impaired pros-taglandin signalling in schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 2007; 77:79–85.

    PubMed  CAS  Google Scholar 

  139. Sumiyoshi T, Kurachi M, Kurokawa K, et al. Plasma homo-vanillic acid in the prodromal phase of schizophrenia. Biol Psychiatry. 2000; 47:428–433.

    PubMed  CAS  Google Scholar 

  140. Arranz B, Rosel P, San L, et al. Low baseline serotonin-2A receptors predict clinical response to olanzapine in first-episode schizophrenia patients. Psychiatry Res. 2007; 153:103–109.

    PubMed  CAS  Google Scholar 

  141. Buckley PF, Pillai A, Evans D, et al. Brain derived neuro-tropic factor in first-episode psychosis. Schizophr Res. 2007; 91:1–5.

    PubMed  Google Scholar 

  142. Sachs G, Steger-Wuchse D, Kryspin-Exner I, et al. Facial recognition deficits and cognition in schizophrenia. Schizophr Res. 2004; 68:27–35.

    PubMed  Google Scholar 

  143. Calkins ME, Gur RC, Ragland JD, Gur RE. Face recognition memory deficits and visual object memory performance in patients with schizophrenia and their relatives. Am J Psychiatry. 2005; 162:1963–1966.

    PubMed  Google Scholar 

  144. Leppänen JM, Niehaus DJ, Koen L, et al. Deficits in facial affect recognition in unaffected siblings of Xhosa schizophrenia patients: evidence for a neurocognitive endopheno-type. Schizophr Res. 2008; 99:270–273.

    PubMed  Google Scholar 

  145. Kimhy D, Corcoran C, Harkavy-Friedman JM, et al. Visual form perception: a comparison of individuals at high risk for psychosis, recent onset schizophrenia and chronic schizophrenia. Schizophr Res. 2007 Dec; 97(1–3):25–34.

    PubMed  CAS  Google Scholar 

  146. Chen WJ, Faraone S V. Sustained attention deficits as markers of genetic susceptibility to schizophrenia. Am J Med Genet. 2000; 97:52–57.

    PubMed  CAS  Google Scholar 

  147. Wang Q, Chan R, Sun J, et al. Reaction time of the Continuous Performance Test is an endophenotypic marker for schizophrenia: a study of first-episode neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy population controls. Schizophr Res. 2007; 89:293–298.

    PubMed  CAS  Google Scholar 

  148. Birkett P, Sigmundsson T, Sharma T, et al. Executive function and genetic predisposition to schizophrenia-the Maudsley family study. Am J Med Genet B Neuropsychiatr Genet. 2007; 147B:285–293.

    Google Scholar 

  149. Egan MF, Goldberg TE, Gscheidle T, et al. Relative risk of attention deficits in siblings of patients with schizophrenia. Am J Psychiatry. 2000; 157:1309–1316.

    PubMed  CAS  Google Scholar 

  150. Sitskoorn MM, Aleman A, Ebisch SJ, et al. Cognitive defi-cits in relatives of patients with schizophrenia: a meta-analysis. Schizophr Res. 2004; 71:285–295.

    PubMed  Google Scholar 

  151. Goldberg TE, Torrey EF, Gold JM, et al. Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder. Schizophr Res. 1995; 17:77–84.

    PubMed  CAS  Google Scholar 

  152. Cannon TD, Huttunen MO, Lonnqvist J, et al. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet. 2000; 67:369–382.

    PubMed  CAS  Google Scholar 

  153. Glahn DC, Therman S, Manninen M, et al. Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry. 2003; 53:624–626.

    PubMed  Google Scholar 

  154. Saperstein AM, Fuller RL, Avila MT, et al. Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction. Schizophr Bull. 2006; 32:498–506.

    PubMed  Google Scholar 

  155. Kravariti E, Toulopoulou T, Mapua-Filbey F, et al. Intellectual asymmetry and genetic liability in first-degree relatives of probands with schizophrenia. Br J Psychiatry. 2006;188:186–187.

    PubMed  Google Scholar 

  156. Ritsner M, Susser E. Temperament types are associated with weak self-construct, elevated distress and emotion-oriented coping in schizophrenia: evidence for a complex vulnerability marker? Psychiatry Res. 2004; 128:219–228.

    PubMed  Google Scholar 

  157. Ritsner MS, Ratner Y, Gibel A, Weizman R. Positive family history is associated with persistent elevated emotional distress in schizophrenia: evidence from a 16-month follow-up study. Psychiatry Res. 2007; 153:217–223.

    PubMed  Google Scholar 

  158. Brunelin J, d'Amato T, Brun P, et al. Impaired verbal source monitoring in schizophrenia: an intermediate trait vulnerability marker? Schizophr Res. 2007; 89:287–292.

    PubMed  Google Scholar 

  159. Ladouceur CD, Almeida JR, Birmaher B, et al. Subcortical gray matter volume abnormalities in healthy bipolar offspring: potential neuroanatomical risk marker for bipolar disorder? J Am Acad Child Adolesc Psychiatry. 2008; 47:532 –539.

    PubMed  Google Scholar 

  160. Colla M, Schubert F, Bubner M, et al. Glutamate as a spec-troscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal corti-sol. Mol Psychiatry. 2008 [epub ahead of print].

    Google Scholar 

  161. Thiruvengadam AP, Chandrasekaran K. Evaluating the validity of blood-based membrane potential changes for the identification of bipolar disorder I. J Affect Disord. 2007; 100:75–82.

    PubMed  CAS  Google Scholar 

  162. Srinivasan V, Smits M, Spence W, et al. Melatonin in mood disorders. World J Biol Psychiatry. 2006; 7:138–151.

    PubMed  Google Scholar 

  163. Hantouche EG, Akiskal HS. Toward a definition of a cyclo-thymic behavioral endophenotype: which traits tap the familial diathesis for bipolar II disorder? J Affect Disord. 2006; 96:233–237.

    PubMed  CAS  Google Scholar 

  164. Kemp AH, Hopkinson PJ, Hermens DF, et al. Fronto-temporal alterations within the first 200 ms during an atten-tional task distinguish major depression, non-clinical participants with depressed mood and healthy controls: a potential biomarker? Hum Brain Mapp. 2008 Jan 7 [epub ahead of print].

    Google Scholar 

  165. Politi P, Minoretti P, Piaggi N, et al. Elevated plasma N-terminal ProBNP levels in unmedicated patients with major depressive disorder. Neurosci Lett. 2007; 417:322–325.

    PubMed  CAS  Google Scholar 

  166. Steimer T, Python A, Schulz PE, Aubry JM. Plasma corti-costerone, dexamethasone (DEX) suppression and DEX/ CRH tests in a rat model of genetic vulnerability to depression. Psychoneuroendocrinology. 2007; 32:575–579.

    PubMed  CAS  Google Scholar 

  167. Mannie ZN, Harmer CJ, Cowen PJ. Increased waking salivary cortisol levels in young people at familial risk of depression. Am J Psychiatry. 2007; 164:617–621.

    PubMed  Google Scholar 

  168. Friess E, Schmid D, Modell S, et al. Dex/CRH-test response and sleep in depressed patients and healthy controls with and without vulnerability for affective disorders. J Psychiatr Res. 2008;42:1154 –1162.

    PubMed  Google Scholar 

  169. Gudmundsson P, Skoog I, Waern M, et al. The relationship between cerebrospinal fluid biomarkers and depression in elderly women. Am J Geriatr Psychiatry. 2007; 15:832–838.

    PubMed  Google Scholar 

  170. Mössner R, Mikova O, Koutsilieri E, et al. Consensus paper of the WFSBP Task Force on Biological Markers: biological markers in depression. World J Biol Psychiatry. 2007; 8:141–174.

    PubMed  Google Scholar 

  171. Hines LM, Tabakoff B. WHO/ISBRA study on state and trait markers of alcohol use and dependence investigators. Platelet adenylyl cyclase activity: a biological marker for major depression and recent drug use. Biol Psychiatry. 2005; 58:955–962.

    PubMed  CAS  Google Scholar 

  172. Ising M, Horstmann S, Kloiber S, et al. Combined dexam-ethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential bio-marker? Biol Psychiatry. 2007; 62:47–54.

    PubMed  CAS  Google Scholar 

  173. Stanghellini G, Bertelli M, Raballo A. Typus melancholicus: personality structure and the characteristics of major unipolar depressive episode. J Affect Disord. 2006; 93: 159–167.

    PubMed  Google Scholar 

  174. Modell S, Ising M, Holsboer F, Lauer CJ. The Munich vulnerability study on affective disorders: premorbid poly-somnographic profile of affected high-risk probands. Biol Psychiatry. 2005; 58:694–699.

    PubMed  Google Scholar 

  175. Silk JS, Dahl RE, Ryan ND, et al. Pupillary reactivity to emotional information in child and adolescent depression: links to clinical and ecological measures. Am J Psychiatry. 2007; 164:1873–1880.

    PubMed  Google Scholar 

  176. Clark L, Sarna A, Goodwin GM. Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. Am J Psychiatry. 2005; 162:1980–1982.

    PubMed  Google Scholar 

  177. Kumra S, Sporn A, Hommer DW, et al. Smooth pursuit eye-tracking impairment in childhood-onset psychotic disorders. Am J Psychiatry. 2001; 158:1291–1298.

    PubMed  CAS  Google Scholar 

  178. Kathmann N, Hochrein A, Uwer R, Bondy B. Deficits in gain of smooth pursuit eye movements in schizophrenia and affective disorder patients and their unaffected relatives. Am J Psychiatry. 2003; 160:696–702.

    PubMed  Google Scholar 

  179. Louchart-de la Chapelle S, Nkam I, Houy E, et al. A concordance study of three electrophysiological measures in schizophrenia. Am J Psychiatry. 2005; 162:466–474.

    PubMed  Google Scholar 

  180. Martin LF, Hall MH, Ross RG, et al. Physiology of schizophrenia, bipolar disorder, and schizoaffective disorder. Am J Psychiatry. 2007; 164:1900–1906.

    PubMed  Google Scholar 

  181. de Wilde OM, Bour LJ, Dingemans PM, Koelman JH, Linszen DH. A meta-analysis of P50 studies in patients with schizophrenia and relatives: differences in methodology between research groups. Schizophr Res. 2007; 97: 137–151.

    PubMed  Google Scholar 

  182. Patterson J V, Hetrick WP, Boutros NN, et al. P50 sensory gating ratios in schizophrenics and controls: a review and data analysis. Psychiatry Res. 2008; 158:226–247.

    PubMed  Google Scholar 

  183. Hong LE, Turano KA, O'Neill H, et al. Refining the predictive pursuit endophenotype in schizophrenia. Biol Psychiatry. 2008; 63:458–464.

    PubMed  Google Scholar 

  184. Young AH, Gallagher P, Porter RJ. Elevation of the corti-sol-dehydroepiandrosterone ratio in drug-free depressed patients. Am J Psychiatry. 2002; 159:1237–1239.

    PubMed  Google Scholar 

  185. Ritsner M, Maayan R, Gibel A, et al. Elevation of the cor-tisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur Neuropsychopharmacol. 2004; 14:267–273.

    PubMed  CAS  Google Scholar 

  186. Ritsner M, Gibel A, Maayan R, et al. A. State and trait related predictors of serum cortisol to DHEA(S) molar ratios and hormone concentrations in schizophrenia patients. Eur Neuropsychopharmacol. 2007; 17:257–264.

    PubMed  CAS  Google Scholar 

  187. Gallagher P, Watson S, Smith MS, et al. Plasma cortisol-dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder. Schizophr Res. 2007; 90:258–265.

    PubMed  Google Scholar 

  188. Lakhan SE. Schizophrenia proteomics: biomarkers on the path to laboratory medicine? Diagn Pathol. 2006; 1:11 doi:10.1186/1746-1596-1-11.

    PubMed  Google Scholar 

  189. Rozen S, Cudkowicz ME, Bogdanov M, et al. Metabolomic analysis and signature in motor neuron disease. Metabolomic. 2005; 2:101–108.

    Google Scholar 

  190. Underwood BR, Broadhurst D, Dunn WB, et al. Huntington disease patients and transgenic mice have similar pro-cata-bolic serum metabolite profiles. Brain. 2006; 129:877–886.

    PubMed  Google Scholar 

  191. Bogdanov M, Matson WR, Wang L, et al. Metabolomic profiling to develop blood biomarkers for Parkinson's disease. Brain. 2008; 131:389–396.

    PubMed  Google Scholar 

  192. Holmes E, Tsang TM, Huang JT, et al. Metabolomic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Med. 2006; 3:e327.

    PubMed  Google Scholar 

  193. Marcotte ER, Srivastava LK, Quirion R. cDNA microarray and proteomic approaches in the study of brain diseases: focus on schizophrenia and Alzheimer's disease. Pharmacol Ther. 2003; 100:63–74.

    PubMed  CAS  Google Scholar 

  194. Vercauteren FG, Bergeron JJ, Vandesande F, et al. Proteomic approaches in brain research and neuropharmacology. Eur J Pharmacol. 2004; 500:385–398.

    PubMed  CAS  Google Scholar 

  195. Schmidt O, Schulenborg T, Meyer HE, et al. How proteom-ics reveals potential biomarkers in brain diseases. Expert Rev Proteomics. 2005; 2:901–913.

    PubMed  CAS  Google Scholar 

  196. Fountoulakis M, Kossida S. Proteomics-driven progress in neurodegeneration research. Electrophoresis 2006; 27: 1556–1573.

    PubMed  CAS  Google Scholar 

  197. Kobeissy FH, Sadasivan S, Liu J, et al. Psychiatric research: psychoproteomics, degradomics and systems biology. Expert Rev Proteomics. 2008; 5:293–314.

    PubMed  CAS  Google Scholar 

  198. Brunner J, Bronisch T, Uhr M, et al. Proteomic analysis of the CSF in unmedicated patients with major depressive disorder reveals alterations in suicide attempters. Eur Arch Psychiatry Clin Neurosci. 2005; 255:438–440.

    PubMed  Google Scholar 

  199. Beasley CL, Pennington K, Behan A, et al. Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: evidence for disease-associated changes. Proteomics. 2006; 6:3414–3425.

    PubMed  CAS  Google Scholar 

  200. Novikova SI, He F, Cutrufello NJ, Lidow MS. Identification of protein biomarkers for schizophrenia and bipolar disorder in the postmortem prefrontal cortex using SELDI-TOF-MS ProteinChip profiling combined with MALDI-TOF-PSD-MS analysis. Neurobiol Dis. 2006; 23:61–76.

    PubMed  CAS  Google Scholar 

  201. Levin Y, Schwarz E, Wang L, et al. Label-free LC-MS/ MS quantitative proteomics for large-scale biomarker discovery in complex samples. J Sep Sci. 2007; 30: 2198–2203.

    PubMed  CAS  Google Scholar 

  202. Prabakaran S, Wengenroth M, Lockstone HE, et al. 2-D DIGE analysis of liver and red blood cells provides further evidence for oxidative stress in schizophrenia. J Proteome Res. 2007; 6:141–149.

    PubMed  CAS  Google Scholar 

  203. Hirano M, Rakwal R, Shibato J, et al. Proteomics- and transcriptomics-based screening of differentially expressed proteins and genes in brain of Wig rat: a model for attention deficit hyperactivity disorder (ADHD) research. J Proteome Res. 2008; 7:2471–2489.

    PubMed  CAS  Google Scholar 

  204. Kety SS. Biochemical theories of schizophrenia. II. Science. 1959; 129:1590–1596.

    PubMed  CAS  Google Scholar 

  205. Saccuzzo DP, Braff DL. Information-processing abnormalities: trait- and state-dependent components. Schizophr Bull. 1986; 12:447–459.

    PubMed  CAS  Google Scholar 

  206. Insel TR, Quirion R. Psychiatry as a clinical neuroscience discipline. JAMA. 2005; 294:2221–2224.

    PubMed  CAS  Google Scholar 

  207. Colburn WA, Lee JW. Biomarkers, validation and pharma-cokinetic-pharmacodynamic modelling. Clin Pharmacokinet. 2003; 42:997–1022.

    PubMed  CAS  Google Scholar 

  208. Kuhlmann J, Wensing G. The applications of biomark-ers in early clinical drug development to improve decision- making processes. Curr Clin Pharmacol. 2006; 1:185–191.

    PubMed  CAS  Google Scholar 

  209. Flint J, Munafò MR. The endophenotype concept in psychiatric genetics. Psychol Med. 2007; 37:163–180.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Ritsner, M.S., Gottesman, I.I. (2009). Where Do We Stand in the Quest for Neuropsychiatric Biomarkers and Endophenotypes and What Next?. In: Ritsner, M.S. (eds) The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-9464-4_1

Download citation

Publish with us

Policies and ethics