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Kraepelin revisited: schizophrenia from degeneration to failed regeneration

Molecular Psychiatry volume 20, pages 671–676 (2015)Cite this article

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Abstract

One hundred years after its conceptual definition as ‘Dementia Praecox’ by Emil Kraepelin, schizophrenia is still a serious psychiatric illness that affects young adults and leads to disability in at least half of patients. The key treatment issue is partial or non-response, especially of negative symptoms. The illness is also associated with different degrees of cognitive dysfunction, particularly in verbal and working memory; the resulting functional impairment may lead to unemployment and an inability to maintain stable relationships. Patients’ cognitive dysfunction led Kraepelin to the assumption that schizophrenia is a form of juvenile dementia caused by a degenerative process of the human brain. Postmortem studies and a plethora of imaging studies do not support the notion of a degenerative process, but such a process is supported by the recently published, largest genome-wide association study on schizophrenia. More than a 100 hits were described, converging on pathways that have a significant role in dopamine metabolism in immune modulation, calcium signalling and synaptic plasticity. This review suggests that research should focus on animal models based on risk genes like transcription factor 4 and study the effects of exposure to environmental stressors relevant for schizophrenia. The use of relevant end points like pre-pulse inhibition or cognitive dysfunction will allow us to gain an understanding of the molecular pathways in schizophrenia and consequently result in improved treatment options, especially for the disabling aspects of this illness.

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References

  1. Kraepelin E . Psychiatrie: ein Lehrbuch für Studirende und Aertze [Psychiatry: A Textbook for Students and Doctors], 6th edn, JA Barth: Lepizig, Germany, 1899.

    Google Scholar 

  2. Alzheimer A . Neuere Arbeiten über die Dementia senilis [recent works on senile dementia]. Monatsschrift für Psychiatrie und Neurologie 1893; 3: 101–115.

    Article  Google Scholar 

  3. Kraepelin E . Lehrbuch der Psychiatrie [Textbook of Psychiatry], 8th edn, JA Barth: Leipzig, Germany, 1913.

    Google Scholar 

  4. Bleuler E . Die schizophrenen Geistesstörungen im Lichte langjähriger Kranken- und Familiengeschichten. Thieme: Stuttgart, Germany, 1908.

    Google Scholar 

  5. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE et al. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl 1992; 20: 1–97.

    Article  CAS  Google Scholar 

  6. Jablensky A . Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Pschiatry Clin Neurosci 2000; 250: 274–285.

    Article  CAS  Google Scholar 

  7. Häfner H, an der Heiden W . Course and outcome of schizophrenia. In: Hirsch R, Weinberger D (eds) Schizophrenia, 2nd edn, Blackwell: Malden, MA, USA, pp 101–139 2003.

    Chapter  Google Scholar 

  8. Marengo J . Classifying the courses of schizophrenia. Schizophr Bull 1994; 20: 519–536.

    Article  CAS  Google Scholar 

  9. Lambert M, Karow A, Leucht S, Schimmelmann BG, Naber D . Remission in schizophrenia: validity, frequency, predictors, and patients' perspective 5 years later. Dialogies Clin Neurosci 2010; 12: 393–407.

    Google Scholar 

  10. Hoff AL, Svetina C, Shields G, Stewart J, DeLisi LE . Ten year longitudinal study of neuropsychological functioning subsequent to a first episode of schizophrenia. Schizophr Res 2005; 78: 27–34.

    Article  Google Scholar 

  11. Green MF . What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153: 321–330.

    Article  CAS  Google Scholar 

  12. Silverstein SM, Schenkel LS, Valone C, Nuernberger SW . Cognitive deficits and psychiatric rehabilitation outcomes in schizophrenia. Psychiatr Q 1998; 69: 169–191.

    Article  CAS  Google Scholar 

  13. Goff DC, Hill M, Barch D . The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav 2010; 99: 245–253.

    Article  Google Scholar 

  14. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421–427.

    Article  Google Scholar 

  15. Walters JT, Rujescu D, Franke B, Giegling I, Vásquez AA, Hargreaves A . The role of the major histocompatibility complex region in cognition and brain structure: a schizophrenia GWAS follow-up. Am J Psychiatry 2013; 170: 877–885.

    Article  Google Scholar 

  16. Corvin A, Morris DW . Genome-wide association studies: findings at the major histocompatibility complex locus in psychosis. Biol Psychiatry 2014; 75: 276–283.

    Article  CAS  Google Scholar 

  17. McAllister AK . Major histocompatibility complex I in brain development and schizophrenia. Biol Psychiatry 2014; 75: 262–268.

    Article  CAS  Google Scholar 

  18. Pribiag H, Stellwagen D . Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology 2014; 78: 13–22.

    Article  CAS  Google Scholar 

  19. Haijma SV, Van Haren N, Cahn W, Koolschijn PC, Hulshoff Pol HE, Kahn RS . Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr Bull 2013; 39: 1129–1138.

    Article  Google Scholar 

  20. Ellison-Wright I, Bullmore E . Anatomy of bipolardisorder and schizophrenia: a meta-analysis. Schizophr Res 2010; 117: 1–12.

    Article  Google Scholar 

  21. De Peri L, Crescini A, Deste G, Fusar-Poli P, Sacchetti E, Vita A . Brain structural abnormalities at the onset of schizophrenia and bipolar disorder: a meta-analysis of controlled magnetic resonance imaging studies. Curr Pharm Des 2012; 18: 486–494.

    Article  CAS  Google Scholar 

  22. Ellison-Wright I, Bullmore E . Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 2009; 108: 3–10.

    Article  Google Scholar 

  23. Hasan A, Wobrock T, Falkai P, Schneider-Axmann T, Guse B, Backens M et al. Hippocampal integrity and neurocognition in first-episode schizophrenia: a multidimensional study. World J Biol Psychiatry 2014; 15: 188–199.

    Article  Google Scholar 

  24. Kühn S, Gallinat J . Resting-state brain activity in schizophrenia and major depression: a quantitative meta-analysis. Schizophr Bull 2013; 39: 358–365.

    Article  Google Scholar 

  25. Adriano F, Caltagirone C, Spalletta G . Hippocampal volume reduction in first-episode and chornic schizophrenia: a review and meta-analysis. Neuroscientist 2012; 18: 180–200.

    Article  Google Scholar 

  26. Shepherd AM, Laurens KR, Matheson SL, Carr VJ, Green MJ . Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia. Neurosci Biobehav Rev 2012; 36: 1342–1356.

    Article  Google Scholar 

  27. Bogerts B, Falkai P, Haupts M, Greve B, Ernst S, Tapernon-Franz U et al. Post-mortem volume measurements of limbic system and basal ganglia structures in chronic schizophrenics. Initial results from a new brain collection. Schizophr Res 1990; 3: 295–301.

    Article  CAS  Google Scholar 

  28. Bogerts B, Meertz E, Schonfeldt-Bausch R . Basal ganglia and limbic system pathology in schizophrenia. A morphometric study of brain volume and shrinkage. Arch Gen Psychiatry 1985; 42: 784–791.

    Article  CAS  Google Scholar 

  29. Wood SJ, Kennedy D, Phillips LJ, Seal ML, Yücel M, Nelson B . Hippocampal pathology in individuals at ultra-high risk for psychosis: a multi-modal magnetic resonance study. Neuroimage 2010; 52: 62–68.

    Article  CAS  Google Scholar 

  30. Schmitt A, Steyskal C, Bernstein HG, Schneider-Axmann T, Parlapani E, Schaeffer EL et al. Stereologic investigation of the posterior part of the hippocampus in schizophrenia. Acta Neuropathol 2009; 117: 395–407.

    Article  Google Scholar 

  31. Falkai P, Bogerts B . Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci 1986; 236: 154–161.

    Article  CAS  Google Scholar 

  32. Stocum DL . Regenerative Biology and Medicine. Academic Press: San Diego, CA, USA, 2010.

    Google Scholar 

  33. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch K-P . Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 2006; 11: 514–522.

    Article  CAS  Google Scholar 

  34. Toro CT, Deakin JFW . Adult neurogenesis and schizophrenia: a window on abnormal early brain development. Schizophr Res 2007; 90: 1–14.

    Article  CAS  Google Scholar 

  35. Schmitt A, Hasan A, Gruber O, Falkai P . Schizophrenia as a disorder of disconnectivity. Eur Arch Psychiatry Clin Neurosci 2011; 261: S150–S154.

    Article  Google Scholar 

  36. Morrison BM, Lee Y, Rothstein JD . Oligodendroglia: metabolic supporters of axons. Trends Cell Biol 2013; 23: 644–651.

    Article  CAS  Google Scholar 

  37. Sawada K, Barr AM, Nakamura M, Arima K, Young CE, Dwork AJ . Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Arch Gen Psychiatry 2005; 62: 263–272.

    Article  CAS  Google Scholar 

  38. Schmitt A, Leonardi-Essmann F, Durrenberger PF, Wichert SP, Spanagel R, Arzberger T et al. Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients. Eur Arch Psychiatry Clin Neurosci 2012; 262: 565–577.

    Article  Google Scholar 

  39. Anderson KK, Voineskos A, Mulsant BH, George TP, McKenzie KJ . The role of untreated psychosis in neurodegeneration: a review of hypothesized mechanosms of neurotoxicity in first-episode psychosis. Can J Psychiatry 2014; 59: 513–517.

    Article  Google Scholar 

  40. Pino O, Guilera G, Gómez-Benito J, Najas-Garcia A, Rufián S, Rojo E . Neurodevelopment of neurodegeneration: reviews of theories of schizophrenia. Actas Esp Psiquiatr 2014; 42: 185–195.

    PubMed  Google Scholar 

  41. Brzózka MM, Radyushkin R, Wichert SP, Ehrenreich H, Rossner MJ . Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the forebrain. Biol Psychiatry 2010; 68: 33–40.

    Article  Google Scholar 

  42. Brzózka MM, Rossner MJ . Deficits in trace fear memory in a mouse model of the schizophrenia risk gene TCF4. Behav Brain Res 2013; 237: 348–356.

    Article  Google Scholar 

  43. Quednow BB, Brzozka MM, Rossner MJ . Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective. Cell Mol Life Sci 2014; 71: 2815–2835.

    Article  CAS  Google Scholar 

  44. Wirgenes KV, Sonderby IE, Haukvik UK, Mattingsdal M, Tesil M, Athanasiu L et al. TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. Transl Psychiatry 2012; 2: e112.

    Article  CAS  Google Scholar 

  45. Brennand KJ, Simone A, Jou J, Belboin-Burkhart C, Tran N, Sangar S et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011; 473: 221–225.

    Article  CAS  Google Scholar 

  46. Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM et al. An in vivo correlated of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA 2007; 104: 5638–5643.

    Article  CAS  Google Scholar 

  47. Erickson KI, Voss MW, Prakash RS, Basek C, Szabo A, Chaddock L et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA 2011; 108: 3017–3022.

    Article  CAS  Google Scholar 

  48. Biedermann S, Fuss J, Zheng L, Sartorius A, Falfan-Melgoza C, Demirakca T et al. In vivo voxel based morphometry: detection of increased hippocampal volume and decreased glutamate levels in exercising mice. Neuroimage 2012; 61: 1206–1212.

    Article  Google Scholar 

  49. van Praag H, Christie BR, Sejnowski TJ, Gage FH . Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 1999; 96: 13427–13431.

    Article  CAS  Google Scholar 

  50. Naylor AS, Bull C, Nilsson MKL, Zhu C, Björk-Eriksson T, Eriksson PS et al. Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young muse brain. Proc Natl Acad Sci USA 2008; 105: 14632–14637.

    Article  CAS  Google Scholar 

  51. Morroni F, Kitazawa M, Drago D, Cheng D, Medeiros R, LaFerla FM . Repeated physical training and environmental enrichment induce neurogenesis and synaptogenesis following neuronal injury in an inducable mouse model. J Behav Brain Sci 2011; 1: 199–209.

    Article  Google Scholar 

  52. Hasan A, Wobrock T, Rajji T, Malchow B, Daskalakis ZJ . Modulating neural plasticity with non-invasive brain stimulation in schizophrenia. Eur Arch Psychiatry Clin Neurosci 2013; 263: 621–631.

    Article  Google Scholar 

  53. Frantseva MV, Fitzgerald PB, Chen R, Möller B, Daigle M, Daskalakis ZJ . Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning. Cereb Cortex 2008; 18: 990–996.

    Article  Google Scholar 

  54. Daskalakis ZJ, Christensen BK, Fitzgerald PB, Chen R . Dysfunctional neural plasticity in patients with schizophrenia. Arch Gen Psychiatry 2008; 65: 378–385.

    Article  Google Scholar 

  55. Hasan A, Nitsche MA, Rein B, Schneider-Axmann T, Guse B, Gruber O et al. Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation. Behav Brain Res 2011; 224: 15–22.

    Article  Google Scholar 

  56. Fitzgerald PB, Brown TL, Marston NA, Oxley T, De Castella A, Daskalakis ZJ et al. Reduced plastic brain responses in schizophrenia: a transcranial magnetic stimulation study. Schizophr Res 2004; 71: 17–26.

    Article  Google Scholar 

  57. Hasan A, Nitsche MA, Herrmann M, Schneider-Axmann T, Marshall L, Gruber O et al. Impaired long-term depression in schizophrenia: a cathodal tDCS pilot study. Brain Stimul 2012; 5: 475–483.

    Article  Google Scholar 

  58. Strube W, Nitsche MA, Wobrock T, Bunse T, Rein B, Herrmann M et al. BDNF-Val66Met-polymorphism imoact on cortical plasticity in schizophrenia patients: a proof-of-concept study. Int J Neuropsychopharmacol 2014; 18, e-pub ahead of print 31 October 2014; doi:10.1093/ijnp/pyu040.

  59. Pajonk FG, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry 2010; 67: 133–143.

    Article  Google Scholar 

  60. Schmitt A, Malchow B, Hasan A, Falkai P . The impact of environmental factors in severe psychiatric disorders. Front Neurosci 2014; 8: 19.

    Article  Google Scholar 

  61. Hasan A, Mitchell A, Schneider A, Halene T, Akbarian S . Epigenetic dysregulation in schizophrenia: molecular and clinical aspects of histone deacetylase inhibitors. Eur Arch Psychiatry Clin Neurosci 2013; 263: 273–284.

    Article  Google Scholar 

  62. Wright C, Turner JA, Calhoun VD, Perrone-Bizzozero N . Potential impact of miR-137 and its targets in schizophrenia. Front Genet 2013; 4: 58.

    Article  Google Scholar 

  63. Peter CJ, Akbarian S . Balancing histone methylation activities in psychiatric disorders. Trends Mol Med 2011; 17: 372–379.

    Article  CAS  Google Scholar 

  64. Chase KA, Gavin DP, Guidotti A, Sharma RP . Histone methylation at H3K9: evidence for a restrictive epigenome in schizophrenia. Schizophr Res 2013; 149: 15–20.

    Article  Google Scholar 

  65. Kato T, Iwamoto K . Comprehensive DNA methylation and hydroxymethylation analysis in the human brain and its implication in mental disorders. Neuropharmacology 2014; 80: 133–139.

    Article  CAS  Google Scholar 

  66. Wockner LF, Noble EP, Lawford BR, Young RM, Morris CP, Whitehall VL et al. Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Transl Psychiatry 2014; 4: e339.

    Article  CAS  Google Scholar 

  67. Fischer A, Sananbenesi F, Mungenast A, Tsai L-H . Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 2010; 31: 605–617.

    Article  CAS  Google Scholar 

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Acknowledgements

This work is supported by the Deutsche Forschungsgemeinschaft via the Clinical Research Group 241 ‘Genotype–phenotype relationships and neurobiology of the longitudinal course of psychosis’ (http://www.kfo241.de; grant number FA 241/16-1, SCHU 1603/5-1 and RO 4076/1-1). The authors thank Jacquie Klesing, Board-certified Editor in the Life Sciences, for editing assistance with the manuscript.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy,

    P Falkai, M J Rossner, A Hasan, M M Brzózka, B Malchow & A Schmitt

  2. Ludwig-Maximilians-University, Munich, Germany

    P Falkai, M J Rossner, A Hasan, M M Brzózka, B Malchow & A Schmitt

  3. Max-Planck-Institute of Experimental Medicine, Goettingen, Germany

    M J Rossner

  4. Institute for Psychiatric Phenomics and Genomics,

    T G Schulze

  5. Ludwig-Maximilians-University, Munich, Germany

    T G Schulze

  6. Department of Psychiatry,

    W G Honer

  7. University of British Columbia, Canada

    W G Honer

  8. Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil

    A Schmitt

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Correspondence to P Falkai.

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Falkai, P., Rossner, M., Schulze, T. et al. Kraepelin revisited: schizophrenia from degeneration to failed regeneration. Mol Psychiatry 20, 671–676 (2015). https://doi.org/10.1038/mp.2015.35

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