Fortschr Neurol Psychiatr 2005; 73: 38-43
DOI: 10.1055/s-2005-915544
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Biologische Hypothesen zur Schizophrenie: Mögliche Einflüsse von Immunologie und Endokrinologie

Biological Hypotheses of Schizophrenia: Possible Influences of Immunology and EndocrinologyB.  Sperner-Unterweger1
  • 1Abteilung für Biologische Psychiatrie, Univ.-Klinik für Psychiatrie Innsbruck/Österreich (Univ.-Prof. Dr. W. Wolfgang Fleischhacker)
Further Information

Publication History

Publication Date:
04 November 2005 (online)

Zusammenfassung

Bei schizophrenen Patienten sind eine Reihe von biologisch auffälligen Befunden vorhanden, allerdings sind diese Daten sehr heterogen und häufig nicht repliziert. Ein einheitliches Krankheitsbild wird heute nicht mehr angenommen, ebenso wenig wie von einer einzigen Ursache ausgegangen wird, sondern ein Zusammenspiel mehrerer ätiopathologischer Faktoren scheint für die Manifestation der Symptomatik verantwortlich zu sein. Ein integratives Krankheitskonzept bei dem Interaktionen zwischen genetischen Faktoren und umweltbedingten Einflüssen zu einer gestörten neuronalen Entwicklung und in weiterer Folge zu Funktionalitätsveränderungen in den verschiedenen Neurotransmittersystemen führen, scheint der Heterogenität schizophrener Erkrankungen eher zu entsprechen. Der Ausgangspunkt immunologischer Forschung war die Infektionshypothese der Schizophrenie, welche durch die Beobachtung „schizophrenie-ähnlicher” Symptome nach Influenza-Epidemien ausgelöst wurde. Zahlreiche Untersuchungen auf verschiedenste Viren, Antikörper und andere Immunphänomene wurden in dieser Patientengruppe durchgeführt. Obwohl die Befunde nicht einheitlich sind, zeigen Subgruppen schizophrener Patienten ein aktiviertes inflammatorisches Response-System mit Erhöhung der proinflammatorischen Zytokine und der Akut-Phase-Proteine bzw. sind auch Aktivitätsveränderungen im zellulären Immunsystem (IS) beschrieben, wobei eine Verschiebung von primär TH-1 dominierten Funktionen zu einer vermehrten TH-2 Aktivierung festgestellt wurden. Endokrinologisch relevante Faktoren für die Ätiopathogenese schizophrener Erkrankungen betreffen einmal den Einfluss der Sexualhormone, andererseits fokusieren Untersuchungen auf die HPA-Achse und die Bedeutung von Stressauswirkungen zu unterschiedlichen Zeitpunkten auf die Stadien der neuronalen Entwicklung. Veränderungen im IS und in den verschiedenen Hormonsystemen können durch Umweltfaktoren wie Infektionen oder exogene Stresseinwirkungen bedingt sein und infolge der intensiven Vernetzung zwischen ZNS, IS und endokrinem System zu pathologischen Entwicklungen führen, die einem integrativen Krankheitskonzept entsprechen. Relevant für die Manifestation, die Ausprägung und den Verlauf der Erkrankung könnten neben einer genetischen Vulnerabilität, der Zeitpunkt des „primären Insults”, dessen Lokalisation und Schweregrad, sowie eventuelle spätere Kompensations- bzw. Dekompensationsmechanismen sein.

Abstract

A great number of studies show biological alterations in patients with schizophrenia, but many of these data are conflicting. Schizophrenia is a vastly heterogeneous disorder, most likely not caused by one etiological factor, but rather due to a complex network of different, interacting pathogenic influences. Variable clinical pictures may reflect different etiological factors. In a comprehensive theory of the origin of schizophrenic disorders, genetic and environmental influences cause changes in neuronal development which result in functional alterations of different neurotransmittersystems. Immunological research in schizophrenia was initially based on the “infection hypothesis” which was triggered by observing schizophrenia-like psychoses after influenza pandemics. Numerous immunological studies focusing on antibodies against specific viruses, unspecific antibodies and different other immune-phenomena were carried out in schizophrenia patients. Although the variability of the results from these studies is strikingly high, subgroups of patients with schizophrenia show an activated inflammatory response system with increased levels of proinflammatory cytokines and acute phase proteins. Furthermore, some investigations find changing activities in the T-cell system with a shift of TH-1 to an increased TH-2 activity. Endocrinological factors which may play a relevant role in the etiopathogenesis of schizophrenia include sex hormones and all changes caused by stress or other influences which are directly related to the HPA-axis. Alterations of the immune and the endocrinological systems might be caused by environmental factors like infections or exogenous stress. Due to the intensive interaction between the central nervous system, the immune system and different hormones the “development of a pathology” like schizophrenia can be seen in an integrative but multifactorial fashion. The clinical manifestation, the severity and the course of the disease might then be modulated by genetic vulnerability, the time of the “primary insult” - which could be an infection, or psychological stress - and its neuronal localisation and intensity. Different compensatory and decompensatory mechanisms in later life very likely play a crucial role for the further course of the disorder.

Literatur

  • 1 Horn J D van, McManus I C. Ventricular enlargement in schizophrenia. A meta-analysis of studies of the ventricle: brain ratio (VBR).  Br J Psychiatry. 1992;  160 687-697
  • 2 Wright I C, Rabe-Hasketh S, Woodruff P WR, David A S, Murray R M, Bullmore E T. Meta-analysis of regional brain volumes in schizophrenia.  Am J Psychiatry. 2000;  157 16-25
  • 3 Akbarian S, Bunney W E Jr, Potkin S G, Wigal S B, Hagman J O, Sandman C A, Jones E G. Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development.  Arch Gen Psychiatry. 1993;  50 169-177
  • 4 Spence S A, Hirsch S R, Brooks D J, Grasby P M. Prefrontal cortex activity in people with schizophrenia and control subjects. Evidence from positron emission tomography for remission of “hypofrontality” with recovery from acute schizophrenia.  Br J Psychiatry. 1998;  172 316-323
  • 5 Curtis V A, Bullmore E T, Brammer M J, Wright I C, Williams S C, Morris R G, Sharma T S, Murray R M, McGuire P K. Attenuated frontal activation during a verbal fluency task in patients with schizophrenia.  Am J Psychiatry. 1998;  155 1056-1063
  • 6 Bilder R M, Goldman R S, Robinson D, Reiter G, Bell L, Bates J A, Pappadopulos E, Willson D F, Alvir J M, Woerner M G, Geisler S, Kane J M, Lieberman J A. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates.  Am J Psychiatry. 2000;  157 549-559
  • 7 Hofbauer B. Infecto psychica.  Österr Med Wschr. 1846;  39 1183
  • 8 Bruce L C, Peebles A MS. Quantitative and qualitative leucocyte counts in various forms of mental disease.  J Ment Sci. 1904;  50 409-417
  • 9 King D J, Cooper S J, Earle J. et al . A survey of serum antibodies to eight common viruses in psychiatry patients.  Br J Psychiatry. 1985;  147 137-144
  • 10 Karlsson H, Bachmann S, Schröder J. et al . Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia.  PNAS. 2001;  98 4634-4639
  • 11 DeLisi L E. Is there a viral or immune dysfunction etiology to schizophrenia? Re-evaluation a decade later.  Schizophr Res. 1996;  22 1-4
  • 12 Watson S, Kucala T, Tilleskjor C. Schizophrenic births seasonality in relation to the incidence of infectious diseases and temperature extremes.  Arch Gen Psychiatry. 1984;  41 85
  • 13 Mednick S A, Huttunen M O, Machon R A. Prenatal influenza infections and adult schizophrenia.  Schizophr Bull. 1994;  20 263-267
  • 14 Torrey E F, Yolken R H. Familial and genetic mechanisms in schizophrenia.  Brain Res Rev. 2000;  31 (2 - 3) 113-117
  • 15 Heath R G, Krupp I M. Schizophrenia as an immunologic disorder. I. Demonstration of antibrain globulins by fluorescent antibody techniques.  Arch Gen Psychiatry. 1967;  16 1-9
  • 16 DeLisi L E, Weber R J, Pert C B. Are there antibodies against brain in sera from schizophrenic patient? Review and prospectus.  Biol Psychiatry. 1985;  20 110-115
  • 17 Schwarz M J, Riedel M, Gruber R, Muller N, Ackenheil M. Autoantibodies against 60-kDa heat shock protein in schizophrenia.  Eur Arch Psychiatry Clin Neurosci. 1998;  248 282-288
  • 18 Leykin I, Spivak B, Weizman A, Ackenheil M. Elevated cellular immune response to human heat-shock protein-60 in schizophrenic patients.  Eur Arch Psychiatr Clin Neurosci. 1999;  249 238-246
  • 19 Schwarz M J, Riedel M, Gruber R, Ackenheil M, Muller N. Antibodies to heat shock proteins in schizophrenic patients: Implications for the mechanism of the disease.  Am J Psychiatry. 1999;  156 1103-1104
  • 20 Muller N, Riedel M, Hadjamu M, Schwarz M J, Ackenheil M, Gruber R. Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood-brain barrier permeability in schizophrenia.  Am J Psychiatry. 1999;  156 634-636
  • 21 Amason B WG. Autoimmune diseases of the central and peripheral nervous systems. In: Rose NR, Mackay IR (Hrsg). The autoimmune diseases. San Diego: Academic Press 1998: 571-602
  • 22 Knight J, Knight A, Ungvari G. Can autoimmune mechanisms account for the genetic predisposition to schizophrenia?.  Br J Psychiatry. 1992;  160 533-540
  • 23 Murray R M, Jones P, O'Callaghan E. Genes, viruses and neurodevelopmental schizophrenia.  Arch Gen Psychiatry. 1987;  44 660-669
  • 24 Arolt V, Rothermundt M, Wandinger K P, Kirchner H. Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment.  Mol Psychiatry. 2000;  5 150-158
  • 25 Zhang X Y, Zhou D F, Zhang P Y, Wu G Y, Cao L Y, Shen Y C. Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology.  Schizophr Res. 2002;  57 247-258
  • 26 Sperner-Unterweger B, Whithworth A, Kemmler G, Hilbe W, Thaler J, Weiss G, Fleischhacker W W. T-cell subsets in schizophrenia: a comparison between drug-naïve first episode patients and chronic schizophrenic patients.  Schizophr Res. 1999;  38 61-70
  • 27 Akiyama K. Serum levels of soluble IL-2 receptor α, IL-6 and IL-1 receptor antagonist in schizohrenia before and during neuroleptic administration.  Schizophr Res. 1999;  37 97-106
  • 28 Maes M, Bocchio Chiavetto L, Bignotti S, BattisaTura G J, Pioli R, Boin F, Kenis G, Bosmans E, Jongh R de, Altamura C A. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor.  Schizophr Res. 2002;  54 281-291
  • 29 Kowalski J, Blada P, Kucia K, Madej A, Herman Z S. Neuroleptics normalize increased relase of interleukin-1β and tumor necrosis factor-α from monocytes in schizophrenia.  Schizophr Res. 2001;  50 169-175
  • 30 Gaughran F, O'Neill E, Cole M, Collins K, Daly R J, Shanahan F. Increased soluble interleukin-2 receptor levels in schizophrenia.  Schizophr Res. 1998;  29 263-267
  • 31 Mehler M F, Kessler J A. Hematolymphopoetic and inflammatory cytokines in neural development.  Trends Neurosci. 1997;  20 357-365
  • 32 Licinio J, Seibyl J P, Altemus M, Charney D S, Krystal J H. Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients.  Am J Psychiatry. 1993;  150 1408-1410
  • 33 Marx C E, Jarskog F, Lauder J M, Lieberman J A, Gilmore J H. Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia.  Biol Psychiatry. 2001;  50 743-749
  • 34 Muller N, Riedel M, Scheppack C, Brandstatter B, Sokullu S, Krampe K, Ulmschneider M, Engel R R, Moller H J, Schwarz M J. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.  Am J Psychiatry. 2002;  159 1029-1034
  • 35 Levine J, Susnovski M, Handzel Z T, Leykin I, Shinitzky M. Treatment of schizophrenia with an immunosupressant.  Lancet. 1994;  34 59-60
  • 36 Zhang X Y, Zhou D F, Cao L Y, Zhang P Y, Wu G Y, Shen Y C. Changes in serum interleukin-2, -6 and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia.  J Clin Psychiatry. 2004;  65 940-947
  • 37 Chiavetto L B, Boin F, Zanardini R, Popoli M, Michelato A, Bignotti S, Tura G B, Gennarelli M. Association between promoter polymorphic haplotypes of interleukin-10 gene and schizophrenia.  Biol Psychiatry. 2002;  51 480-484
  • 38 Hinze-Selch D, Pollmächer T. In vitro cytokine secretion in individuals with schizophrenia: Results, confounding factors and implications for further research.  Brain Behav Immunity. 2001;  15 282-318
  • 39 Lammers C H, Garcia-Borreguero D, Schmieder J, Gotthardt U, Dettling M, Holsboer F, Heuser I J. Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: II.  Biol Psychiatry. 1995;  38 803-807
  • 40 Altamura C, Guercetti G, Percudani M. Dexamethasone suppression test in positive and negative schizophrenia.  Psychiatry Res. 1989;  30 69-75
  • 41 Newcomer J W, Faustman W O, Whiteford H A, Moses J A Jr, Csernansky J G. Symptomatology and cognitive impairment associate independently with post-dexamethasone cortisol concentrations in unmedicated schizophrenic patients.  Biol Psychiatry. 1991;  29 855-864
  • 42 Koenig J I, Kirkpatrick B, Lee P. Glucocorticoid hormones and early brain development in schizophrenia.  Neuropsychopharmacol. 2002;  27 309-318
  • 43 Kinnunen A K, Koenig J I, Bilbe G. Repeated variable prenatal stress alters pre- and postsynaptic gene expression in the rat frontal pole.  J Neurochemistry. 2003;  86 736-748
  • 44 Bhatnagar S, Lee T M, Vining C. Prenatal stress differentially affects habituation of corticosterone responses to repeated stress in adult male and female rats.  Horm Behav. 2005;  47 430-438
  • 45 Hummer M, Huber J. Hyperprolactinaemia and antipsychotic therapy in schizophrenia.  Curr Med Res Opin. 2004;  20 189-197
  • 46 Halbreich U, Kahn L S. Hormonal aspects of schizophrenias: an overview.  Psychoneuroendocrinology. 2003;  28 1-16
  • 47 Kelly D L, Conley R R. Thyroid function in treatment-resistant schizophrenia patients treated with quetiapine, risperidone, or fluphenazine.  J Clin Psychiatry. 2005;  66 80-84
  • 48 Häfner H. Gender differences in schizophrenia.  Psychoneuroendocrinology. 2003;  28 17-54
  • 49 Huber T J, Tettenborn C, Leifke E, Emrich H M. Sex hormones in psychotic men.  Psychoneuroendocrinology. 2005;  30 111-114
  • 50 Bergemann N, Mundt C, Parzer P, Pakrasi M, Eckstein-Mannsperger U, Haisch S, Salbach B, Klinga K, Runnebaum B, Resch F. Estrogen as an adjuvant therapy to antipsychotics does not prevent relapse in women suffering from schizophrenia: results of a placebo-controlled double-blind study.  Schizophr Res. 2005;  74 125-134
  • 51 Stevens J R. Schizophrenia: Reproductive hormones and the brain.  Am J Psychiatry. 2002;  159 713-719
  • 52 Goyal R O, Sagar R, Ammini A C, Khurana M L, Alias A G. Negative correlation between negative symptoms of schizophrenia and testosterone levels.  Ann N Y Acad Sci. 2004;  1032 291-294

Barbara Sperner-Unterweger

Univ.-Klinik für Psychiatrie Innsbruck · Abteilung für Biologische Psychiatrie

Anichstraße 35

6020 Innsbruck

Österreich

Email: barbara.sperner-unterweger@uibk.ac.at