Systems Biology in Psychiatric Research: From Complex Data Sets Over Wiring Diagrams to Computer Simulations

Part of the Methods in Molecular Biology book series (MIMB, volume 829)


The classification of psychiatric disorders has always been a problem in clinical settings. The present debate about the major systems in clinical practice, DSM-IV and ICD-10, has resulted in attempts to improve and replace those schemes by some that include more endophenotypic and molecular features. However, these disorders not only require more precise diagnostic tools, but also have to be viewed more extensively in their dynamic behaviors, which require more precise data sets related to their origins and developments. This enormous challenge in brain research has to be approached on different levels of the biological system by new methods, including improvements in electroencephalography, brain imaging, and molecular biology. All these methods entail accumulations of large data sets that become more and more difficult to interpret. In particular, on the molecular level, there is an apparent need to use highly sophisticated computer programs to tackle these problems. Evidently, only interdisciplinary work among mathematicians, physicists, biologists, and clinicians can further improve our understanding of complex diseases of the brain.

Key words

Molecular psychiatry Neurotransmitter Molecular networks Data analysis Modeling Computer simulations 


  1. 1.
    Sadock, B. J., Sadock, V. A. (ed.) (2005) Kaplan`s and Sadock’s Synopsis of Psychiatry. Wolters Kluwer, New York.Google Scholar
  2. 2.
    Puls, I., and Gallinat, J. (2008) The concept of endophenotypes in psychiatric diseases meeting the expectations?, Pharmacopsychiatry 41 Suppl 1, S37–43.PubMedCrossRefGoogle Scholar
  3. 3.
    Tretter, F. Gebicke-Haerter, P. (2010) Neuropsychiatry – Subject, Concepts, Methods and Computational Model, in Systems Biology in Psychiatric Research (Tretter, F., Gebicke-Haerter, P.J., Mendoza, E.R., Winterer, G. eds), pp. 27–80, Wiley-Blackwell, Weinheim.CrossRefGoogle Scholar
  4. 4.
    Jaspers, K. (ed.) (1913, 1997) General Psychopathology - Volumes 1 & 2. Johns Hopkins University Press. Baltimore and London.Google Scholar
  5. 5.
    Tretter, F. (ed.) (2010) Philosophical Aspects of Neuropsychiatry, in Systems Biology in Psychiatric Research (Tretter, F., Gebicke-Haerter, P.J., Mendoza, E.R., Winterer, G. eds), pp. 3–26, Wiley-Blackwell, Weinheim.Google Scholar
  6. 6.
    Taylor MA, Vaidya NA (ed.) (2009) Descriptive Psychopathology. Cambridge University Press, Cambridge Mass.Google Scholar
  7. 7.
    Bennett, M. R. & Hacker, P. M. S. (eds,) (2003) Philosophical Foundations of Neuroscience. Malden (Mass.): Blackwell Publishing.Google Scholar
  8. 8.
    Tretter F., Albus M. (2007) “Computational Neuropsychiatry” of Working Memory Disorders in Schizophrenia: The Network Connectivity in Prefrontal Cortex - Data and Models. Pharmacopsychiatry 40, S2–S16. CrossRefGoogle Scholar
  9. 9.
    Burt, T., Sederer, L., Isgack, WW (eds.) (2002) Outcome Management in Psychiatry: A Critical Review. Washington, DC: American Psychiatry Press.Google Scholar
  10. 10.
    Andreasen, N. (ed.) (2004) Brave New Brain- Conquering Mental Illness in the Era of the Genome. Oxford Univ. Press, New York.Google Scholar
  11. 11.
    Griesinger W (ed.) (1882) Mental Pathology and Therapeutics. William Wood & Co., New York.Google Scholar
  12. 12.
    Vernalaken, I., Gruender, G., Cumming, P. (2010) Progress in Psychopharmacology through Molecular Imaging, in Systems Biology in Psychiatric Research: (Tretter, F., Gebicke-Haerter, P.J., Mendoza, E.R., Winterer, G. eds), pp.189-206Wiley-Blackwell, Weinheim.Google Scholar
  13. 13.
    Michel, Ch. M., Koenig, T., Brandeis, D., Gianotti, L. R. R., Wackermann, J. (eds) (2009) Electrical Neuroimaging. Cambridge University Press, New York.Google Scholar
  14. 14.
    Koch M. (ed.) (2006) Animal Models of Neuropsychiatric Diseases . Imperial College Press, London. Google Scholar
  15. 15.
    Gallinat J, Obermayer, K, Heinz A (2007) Systems Neurobiology of the Dysfunctional Brain. Pharmacopsychiatry Suppl. 1:S40–S44.CrossRefGoogle Scholar
  16. 16.
    Gebicke-Haerter, P. J. (2008) Systems biology in molecular psychiatry, Pharmacopsychiatry 41 Suppl 1, S19–27.PubMedCrossRefGoogle Scholar
  17. 17.
    Tretter, F., and Gebicke-Haerter, P. J. (2009) Philosophy of neuroscience and options of systems science, Pharmacopsychiatry 42 Suppl 1, S2–S10.PubMedCrossRefGoogle Scholar
  18. 18.
    Meyer-Lindenberg, A., and Weinberger, D. R. (2006) Intermed.iate phenotypes and genetic mechanisms of psychiatric disorders, Nat Rev Neurosci 7 , 818–827. PubMedCrossRefGoogle Scholar
  19. 19.
    Wiener, N. (ed.) (1948) Cybernetics. MIT press, Cambridge, Mass.Google Scholar
  20. 20.
    Bertalanffy, L.V. (ed.) (1968) General System Theory. Braziller, New York.Google Scholar
  21. 21.
    Watts, D. J., and Strogatz, S. H. (1998) Collective dynamics of ‘small-world’ networks, Nature 393, 440–442.PubMedCrossRefGoogle Scholar
  22. 22.
    Strogatz, S.H. (ed.) (2001) Nonlinear Dynamics and Chaos: With Applications to Physics, Biology, Chemistry and Engineering g (Studies in Nonlinearity) . The Perseus Books Group, New York. Google Scholar
  23. 23.
    Periwal V, Szallasi Z, Stelling J. (2006) System modelling in Cellular Biology, in System Modeling in Cellular Biology (Szallasi, Z., Stelling, J. & Periwal, V., ed.), pp. 7–14, The MIT Press, Cambridge, Mass.Google Scholar
  24. 24.
    Quarteroni, A., Formaggia, L., Veneziani, A. (eds) (2006) Complex Systems in Biomed.icine. Springer, Berlin.Google Scholar
  25. 25.
    Stelling, J, Sauer, U. J. Doyle, F J Doyle, J.(2006) Complexity and Robustness of cellular Systems, in System Modeling in Cellular Biology (Szallasi, Z., Stelling, J. & Periwal, V., ed.), pp. 3–18, The MIT Press, Cambridge, Mass.Google Scholar
  26. 26.
    Arbib M A, Grethe JS. (eds) (2001) Computing the Brain: A Guide to Neuroinformatics. Academic Press, San Diego.Google Scholar
  27. 27.
    Arbib MA (ed.) (2002) The Handbook of Brain Theory and Neural Networks. MIT Press: Cambridge, Mass.Google Scholar
  28. 28.
    Dayan, P. Abbott L. (ed.) (2005) Theoretical Neuroscience. Computational and Mathematical Modeling of Neural Systems. MIT Press, Cambridge, Mass.Google Scholar
  29. 29.
    Freeman, W. J. (ed.) (2000). Neurodynamics: An Exploration in Mesoscopic Brain Dynamics. Springer, Berlin.Google Scholar
  30. 30.
    Boccara N (2004) Modeling Complex Systems. Springer, Berlin.Google Scholar
  31. 31.
    Tretter, F. (1989): System-wissenschaft in der Med.izin. Deutsches Ärzteblatt 43, 3198–3209.Google Scholar
  32. 32.
    Ahn, A. C., Tewari, M., Poon, C. S., and Phillips, R. S. (2006) The limits of reductionism in medicine: could systems biology offer an alternative?, PLoS Med. 3, e208.PubMedCrossRefGoogle Scholar
  33. 33.
    Ahn, A. C., Tewari, M., Poon, C. S., and Phillips, R. S. (2006) The clinical applications of a systems approach, PLoS Med. 3, e209.PubMedCrossRefGoogle Scholar
  34. 34.
    Kitano, H. (2002) Systems biology: a brief overview, Science 295, 1662–1664.PubMedCrossRefGoogle Scholar
  35. 35.
    Kitano, H. (2002) Computational systems biology, Nature 420, 206–210. PubMedCrossRefGoogle Scholar
  36. 36.
    Klipp E, Herwig R, Kowald A, Wielring C, Lehrach H (eds) (2005) Systems Biology in Practice: Concepts, Implementation and Application. Wiley-VCH, Weinheim.Google Scholar
  37. 37.
    Klipp E, Liebermeister, W., Herwig R, Wierling C, Kowald, A, Lehrach H, Herwig R (ed.) (2009) Systems Biology: A textbook. Wiley-VCH, Weinheim.Google Scholar
  38. 38.
    Helms, V. (ed.) (2008): Principles of Computational Cell Biology: From Protein Complexes to Cellular Networks. Wiley-VCH, Weinheim.Google Scholar
  39. 39.
    Noble, D. (2006) Multilevel Modelling in Systems Biology: From Cells to Whole Organs. The Role of Modeling in Systems Biology, in System Modeling in Cellular Biology (Szallasi, Z., Stelling, J. & Periwal, V., ed.), pp. 297–312, The MIT Press, Cambridge, Mass. Google Scholar
  40. 40.
    Noble, D. (2008) Music of Life: Biology beyond Genes. Oxford Univ. Press, New York.Google Scholar
  41. 41.
    Tretter, F., Gallinat, J., Muller, W. E. (2008) Systems biology and psychiatry: the functional architecture of molecular networks in mental disorders- data and models, Pharmacopsychiatry 41 Suppl 1, S1.Google Scholar
  42. 42.
    Tretter, F., Gebicke-Haerter, P. J., Albus, M., an der Heiden, U., and Schwegler, H. (2009) Systems biology and addiction, Pharmacopsychiatry 42 Suppl 1 , S11–31. Google Scholar
  43. 43.
    Matthaeus F., Smith, A., Gebicke-Haerter, P. (2010): Some Useful Mathematical Tools to Transform Microarray Data into Interactive Molecular Networks, in Systems Biology in Psychiatric Research (Tretter, F., Gebicke-Haerter, P.J., Mendoza, E.R., Winterer, G. (eds) pp. 277–300, Wiley-Blackwell, Weinheim.Google Scholar
  44. 44.
    Smith, J., Huett, M-T. (2010) Network Dynamics as an Interface between Modeling and Experiment in Systems Biology, in Systems Biology in Psychiatric Research (Tretter, F., Gebicke-Haerter, P.J., Mendoza, E.R., Winterer, G. (eds) pp 243–270, Wiley-Blackwell, Weinheim.CrossRefGoogle Scholar
  45. 45.
    NIH, National Institute of Health (2007) Systems Biology
  46. 46.
    Reckow, S., Gormanns, P., Holsboer, F., and Turck, C. W. (2008) Psychiatric disorders biomarker identification: from proteomics to systems biology, Pharmacopsychiatry 41 Suppl 1, S70–77.PubMedCrossRefGoogle Scholar
  47. 47.
    Sananbenesi, F., and Fischer, A. (2009) The epigenetic bottleneck of neurodegenerative and psychiatric diseases, Biol Chem 390, 1145–1153.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhubi, A., Veldic, M., Puri, N. V., Kadriu, B., Caruncho, H., Loza, I., Sershen, H., Lajtha, A., Smith, R. C., Guidotti, A., Davis, J. M., and Costa, E. (2009) An upregulation of DNA-methyltransferase 1 and 3a expressed. in telencephalic GABAergic neurons of schizophrenia patients is also detected. in peripheral blood lymphocytes, Schizophr Res 111, 115–122.PubMedCrossRefGoogle Scholar
  49. 49.
    Dahl, C., and Guldberg, P. (2007) A ligation assay for multiplex analysis of CpG methylation using bisulfite-treated. DNA, Nucleic Acids Res 35 , e144. CrossRefGoogle Scholar
  50. 50.
    Shiflet, AB, Shiflet GW (2006) Introduction to Computational Science. Princeton University Press, Princeton.Google Scholar
  51. 51.
    Fishwick P. A. (ed.) (2007) Handbook of Dynamic System Modeling. Chapman & Hall, New York.Google Scholar
  52. 52.
    Szallasi Z, Stelling J, Periwal V (2006) (ed.) System Modeling in Cellular Biology. MIT Press, Cambridge, Mass.Google Scholar
  53. 53.
    Conrad E.D., Tyson J. J. (2006) Modeling Molecular Interaction Networks with Nonlinear Ordinary Differential Equations., in System Modeling in Cellular Biology. (Szallasi Z, S. J., Periwal V, ed.), pp. 97–124, MIT Press, Cambridge, Mass.Google Scholar
  54. 54.
    Paulsson, J., Elf, J. (2006) Modeling Molecular of Intracellular Kinetics, in System Modelling in Cellular Biology (Szallasi Z, P. V., Stelling ed.), pp. 149–176 Cambridge Ma.Google Scholar
  55. 55.
    Kell, D. B., Knowles, J.D. (2006) The Role of Modeling in Systems Biology in System Modeling in Cellular Biology (Szallasi, Z., Stelling, J. & Periwal, V., ed.), pp. 3–18, The MIT Press, Cambridge, Mass.Google Scholar
  56. 56.
    Tretter, F., and Scherer, J. (2006) Schizophrenia, neurobiology and the methodology of systemic modeling, Pharmacopsychiatry 39 Suppl 1, S26–35.PubMedCrossRefGoogle Scholar
  57. 57.
    Voit, E. O., Qi, Z., and Miller, G. W. (2008) Steps of modeling complex biological systems, Pharmacopsychiatry 41 Suppl 1, S78–84.PubMedCrossRefGoogle Scholar
  58. 58.
    Finney A., Hucka M., Borstewin J., Keating SM., Shapiro BE., Matthews J Kovitz Bl., Schilstra MJ., Funahashi A., Doyle J., Kitano H. (2006) Software Infrastructure for Effective Communication and reuse of Computational Models, in System Modeling in Cellular Biology (Szallasi, Z., Stelling, J. & Periwal, V., ed.), pp. 297–312, The MIT Press, Cambridge, Mass. Google Scholar
  59. 59.
    Kitano H. (ed.) (2001) Foundations of Systems Biology. MIT Press, Cambridge, Mass.Google Scholar
  60. 60.
    Tretter, F., and Albus, M. (2008) Systems biology and psychiatry - modeling molecular and cellular networks of mental disorders, Pharmacopsychiatry 41, Suppl 1, S2–S18.Google Scholar
  61. 61.
    ed.elman G M, T. G., (ed.) (2000) A Universe Of Consciousness How Matter Becomes Imagination, Basic Books, New York.Google Scholar
  62. 62.
    ed.elman G M, T. G. (2000) A Universe Of Consciousness How Matter Becomes Imagination,, Basic Books, New York.Google Scholar
  63. 63.
    Carlsson, A. (1988) The current status of the dopamine hypothesis of schizophrenia, Neuropsychopharmacology 1, 179–186.PubMedCrossRefGoogle Scholar
  64. 64.
    Carlsson, A. (2006) The neurochemical circuitry of schizophrenia, Pharmacopsychiatry 39 Suppl 1 , S10–14. PubMedCrossRefGoogle Scholar
  65. 65.
    Tretter F, Müller W, Carlsson A (2006). Systems Science, Computational Science and Neurobiology of Schizophrenia. Pharmacopsychiatry 39, 1–2.Google Scholar
  66. 66.
    Berns, G. S., and Sejnowski, T. J. (1998) A computational model of how the basal ganglia produce sequences, J Cogn Neurosci 10, 108–121.PubMedCrossRefGoogle Scholar
  67. 67.
    Winterer, G. (2006) Cortical microcircuits in schizophrenia--the dopamine hypothesis revisited., Pharmacopsychiatry 39 Suppl 1, S68–71.Google Scholar
  68. 68.
    Goldman-Rakic, P. S. (1999) The physiological approach: functional architecture of working memory and disordered. cognition in schizophrenia, Biol Psychiatry 46, 650–661.PubMedCrossRefGoogle Scholar
  69. 69.
    Goldman-Rakic, P. S., Muly, E. C., 3rd, and Williams, G. V. (2000) D(1) receptors in prefrontal cells and circuits, Brain Res Brain Res Rev 31, 295–301.PubMedCrossRefGoogle Scholar
  70. 70.
    Durstewitz, D., Seamans, J. K., and Sejnowski, T. J. (2000) Neurocomputational models of working memory, Nat Neurosci 3 Suppl, 1184–1191.PubMedCrossRefGoogle Scholar
  71. 71.
    Brunel, N., and Wang, X. J. (2001) Effects of neuromodulation in a cortical network model of object working memory dominated. by recurrent inhibition, J Comput Neurosci 11, 63–85.PubMedCrossRefGoogle Scholar
  72. 72.
    Wang, X. J., Tegner, J., Constantinidis, C., and Goldman-Rakic, P. S. (2004) Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory, Proc Natl Acad Sci U S A 101, 1368–1373.PubMedCrossRefGoogle Scholar
  73. 73.
    Wang, X. J. (2006) Toward a prefrontal microcircuit model for cognitive deficits in schizophrenia, Pharmacopsychiatry 39 Suppl 1, S80–87.PubMedCrossRefGoogle Scholar
  74. 74.
    Seamans, J. K., Durstewitz, D., Christie, B. R., Stevens, C. F., and Sejnowski, T. J. (2001) Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons, Proc Natl Acad Sci U S A 98, 301–306.PubMedCrossRefGoogle Scholar
  75. 75.
    Winterer, G., and Weinberger, D. R. (2004) Genes, dopamine and cortical signal-to-noise ratio in schizophrenia, Trends Neurosci 27, 683–690.PubMedCrossRefGoogle Scholar
  76. 76.
    Abbott, L. F., and Regehr, W. G. (2004) Synaptic computation, Nature 431, 796–803.PubMedCrossRefGoogle Scholar
  77. 77.
    Grant, S. G. (2003) Systems biology in neuroscience: bridging genes to cognition, Curr Opin Neurobiol 13, 577–582.PubMedCrossRefGoogle Scholar
  78. 78.
    Pocklington, A. J., Cumiskey, M., Armstrong, J. D., and Grant, S. G. (2006) The proteomes of neurotransmitter receptor complexes form modular networks with distributed. functionality underlying plasticity and behaviour, Mol Syst Biol 2, 2006 0023.PubMedGoogle Scholar
  79. 79.
    Qi, Z., Miller, G. W., and Voit, E. O. (2010) Computational modeling of synaptic neurotransmission as a tool for assessing dopamine hypotheses of schizophrenia, Pharmacopsychiatry 43 Suppl 1, S50–60.PubMedCrossRefGoogle Scholar
  80. 80.
    Best, J., Reed., M., and Nijhout, H. F. (2010) Models of dopaminergic and serotonergic signaling, Pharmacopsychiatry 43 Suppl 1, S61–66.Google Scholar
  81. 81.
    Tretter, F. (2010) Mental illness, synapses and the brain--behavioral disorders by a system of molecules within a system of neurons?, Pharmacopsychiatry 43 Suppl 1, S9–S20.PubMedCrossRefGoogle Scholar
  82. 82.
    Fernandez, E., Schiappa, R., Girault, J. A., and Le Novere, N. (2006) DARPP-32 is a robust integrator of dopamine and glutamate signals, PLoS Comput Biol 2, e176.PubMedCrossRefGoogle Scholar
  83. 83.
    Lindskog, M., Kim, M., Wikstrom, M. A., Blackwell, K. T., and Kotaleski, J. H. (2006) Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation, PLoS Comput Biol 2, e119.PubMedCrossRefGoogle Scholar
  84. 84.
    Lindskog, M. (2008) Modelling of DARPP-32 regulation to understand intracellular signaling in psychiatric disease, Pharmacopsychiatry 41, Suppl 1, S99–S104.Google Scholar
  85. 85.
    Aghajanian, G. K., and Marek, G. J. (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanisms, Brain Res Brain Res Rev 31, 302–312.PubMedCrossRefGoogle Scholar
  86. 86.
    Moghaddam, B., and Homayoun, H. (2008) Divergent plasticity of prefrontal cortex networks, Neuropsychopharmacology 33, 42–55.PubMedCrossRefGoogle Scholar
  87. 87.
    Moghaddam, B. (2003) Bringing order to the glutamate chaos in schizophrenia, Neuron 40, 881–884.PubMedCrossRefGoogle Scholar
  88. 88.
    Benes, F. M. (2009) Neural circuitry models of schizophrenia: is it dopamine, GABA, glutamate, or something else?, Biol Psychiatry 65, 1003–1005.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Kompetenzzentrum Sucht, Isar-Amper-Klinikum gemeinnützigeGmbH, Klinikum München-OstHaarGermany
  2. 2.Department of PsychopharmacologyCentral Institute for Mental HealthMannheimGermany

Personalised recommendations