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Fortschr Neurol Psychiatr 2005; 73: 32-37
DOI: 10.1055/s-2005-915546
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Pathophysiologische Grundlagen der Schizophrenie und deren Relevanz für die Psychopharmakotherapie

Pathophysiology of Schizophrenia and its Impact on PharmacotherapyC.  G.  Widschwendter1 , W.  W.  Fleischhacker1
  • 1Abteilung für Biologische Psychiatrie, Universitätsklinik für Psychiatrie, Medizinische Universität Innsbruck/Österreich
Prof. Fleischhacker hat finanzielle Forschungsunterstützung und Honorare von folgenden Firmen erhalten: Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Organon, Otsuka, Pfizer, Sanofi-Synthelabo.
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Publication History

Publication Date:
04 November 2005 (online)

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Zusammenfassung

Ungefähr 1 % der Bevölkerung erkrankt an Schizophrenie. Zu den Hauptsymptomen zählen Halluzinationen, Wahn, Denkarmut, emotionaler und sozialer Rückzug sowie kognitive Defizite. Obwohl neuere Antipsychotika mit breiterem Rezeptorprofil umfassendere Therapiemöglichkeiten bieten, wird ein zufriedenstellendes Therapieansprechen bei vielen Patienten nicht erreicht. Trotz intensiver Forschung sind die molekularbiologischen Grundlagen der Schizophrenie nicht genau geklärt. Auch wenn pharmakologische Studien, funktionelle bildgebende Verfahren und Genforschung auf Veränderungen glutamaterger, GABAerger und serotonerger Systeme hinweisen, kommt der Dopaminhypothese in der Therapie nach wie vor eine zentrale Rolle zu. Dieser Artikel gibt einen Überblick über die pathophysiologischen Grundlagen der Schizophrenie, deren Relevanz für die Psychopharmakologie sowie einen Ausblick auf potenziell erfolgversprechende Forschungsansätze.

Abstract

Schizophrenia is a severe psychiatric illness with a lifetime morbidity risk of around 1 %. Symptoms include hallucinations, delusions, poverty of thought and emotion and social withdrawal and cognitive deficits. Although newer antipsychotics affecting multiple neurotransmitter receptors facilitate therapy, many patients still do not achieve full response. Despite intensive study, the molecular etiology of schizophrenia remains enigmatic in many ways. The dopamine hypothesis of schizophrenia still plays an important role, although pharmacological studies, brain imaging analyses and genetic research indicate additional dysfunctions of glutamate, GABA and serotonin transmission. This article reviews the pathophysiological background of the disorder, its implications for pharmacological treatment and possible directions for future research.

Literatur

  • 1 Andreasen N C. The evolving concept of schizophrenia: from Kraepelin to the present and future.  Schizophr Res. 1997;  28 (2 - 3) 105-109
    CrossrefPubMedGoogle Scholar
  • 2 Meltzer H Y, McGurk S R. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.  Schizophr Bull. 1999;  25 (2) 233-255
    CrossrefPubMedGoogle Scholar
  • 3 Andreasen N C. Pieces of the schizophrenia puzzle fall into place.  Neuron. 1996;  16 (4) 697-700
    CrossrefPubMedGoogle Scholar
  • 4 Harrison P J. The neuropathology of schizophrenia. A critical review of the data and their interpretation.  Brain. 1999;  122 ( Pt 4) 593-624
    CrossrefPubMedGoogle Scholar
  • 5 Os J van. Is there a continuum of psychotic experiences in the general population?.  Epidemiol Psichiatr Soc. 2003;  12 (4) 242-252
    PubMedGoogle Scholar
  • 6 Meltzer H Y, Stahl S M. The dopamine hypothesis of schizophrenia: a review.  Schizophr Bull. 1976;  2 (1) 19-76
    Google Scholar
  • 7 Breier A, Su T P, Saunders R, Carson R E, Kolachana B S, Bartolomeis A de, Weinberger D R, Weisenfeld N, Malhotra A K, Eckelman W C, Pickar D. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method.  Proc Natl Acad Sci USA. 1997;  94 (6) 2569-2574
    CrossrefPubMedGoogle Scholar
  • 8 Laruelle M, Abi-Dargham A. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies.  J Psychopharmacol. 1999;  13 (4) 358-371
    CrossrefPubMedGoogle Scholar
  • 9 Carlsson A. Antipsychotic drugs, neurotransmitters, and schizophrenia.  Am J Psychiatry. 1978;  135 (2) 165-173
    CrossrefPubMedGoogle Scholar
  • 10 Abraham H D, Aldridge A M. Adverse consequences of lysergic acid diethylamide.  Addiction. 1993;  88 (10) 1327-1334
    CrossrefPubMedGoogle Scholar
  • 11 Allen R M, Young S J. Phencyclidine-induced psychosis.  Am J Psychiatry. 1978;  135 (9) 1081-1084
    PubMedGoogle Scholar
  • 12 Krystal J H, Karper L P, Seibyl J P, Freeman G K, Delaney R, Bremner J D, Heninger G R, Bowers Jr M B, Charney D S. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.  Arch Gen Psychiatry. 1994;  51 (3) 199-214
    CrossrefPubMedGoogle Scholar
  • 13 Tamminga C. Glutamatergic aspects of schizophrenia.  Br J Psychiatry Suppl. 1999;  37 12-15
    PubMedGoogle Scholar
  • 14 Lindvall O, Bjorklund A, Skagerberg G. Dopamine-containing neurons in the spinal cord: anatomy and some functional aspects.  Ann Neurol. 1983;  14 (3) 255-260
    CrossrefPubMedGoogle Scholar
  • 15 Pycock C J, Kerwin R W, Carter C J. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats.  Nature. 1980;  286 (5768) 74-76
    PubMedGoogle Scholar
  • 16 Carlsson A. The current status of the dopamine hypothesis of schizophrenia.  Neuropsychopharmacology. 1988;  1 (3) 179-186
    CrossrefPubMedGoogle Scholar
  • 17 Carlsson A, Waters N, Waters S, Carlsson M L. Network interactions in schizophrenia - therapeutic implications.  Brain Res Brain Res Rev. 2000;  31 (2 - 3) 342-349
    CrossrefPubMedGoogle Scholar
  • 18 Weinberger D R. Implications of normal brain development for the pathogenesis of schizophrenia.  Arch Gen Psychiatry. 1987;  44 (7) 660-669
    PubMedGoogle Scholar
  • 19 Davis K L, Kahn R S, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization.  Am J Psychiatry. 1991;  148 (11) 1474-1486
    PubMedGoogle Scholar
  • 20 Goldman-Rakic P S, Selemon L D. Functional and anatomical aspects of prefrontal pathology in schizophrenia.  Schizophr Bull. 1997;  23 (3) 437-458
    PubMedGoogle Scholar
  • 21 Yang C R, Seamans J K, Gorelova N. Developing a neuronal model for the pathophysiology of schizophrenia based on the nature of electrophysiological actions of dopamine in the prefrontal cortex.  Neuropsychopharmacology. 1999;  21 (2) 161-194
    CrossrefPubMedGoogle Scholar
  • 22 Farde L, Wiesel F A, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs.  Arch Gen Psychiatry. 1988;  45 (1) 71-76
    CrossrefPubMedGoogle Scholar
  • 23 Nordstrom A L, Farde L, Wiesel F A, Forslund K, Pauli S, Halldin C, Uppfeldt G. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients.  Biol Psychiatry. 1993;  33 (4) 227-235
    CrossrefPubMedGoogle Scholar
  • 24 Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis.  Am J Psychiatry. 2001;  158 (3) 360-369
    Google Scholar
  • 25 Seeman P. Atypical antipsychotics: mechanism of action.  Can J Psychiatry. 2002;  47 (1) 27-38
    PubMedGoogle Scholar
  • 26 Fleischhacker W W. Aripiprazole. Expert Opinion in Pharmacotherapy 2005
    Google Scholar
  • 27 Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E. SB 242 084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system.  Neuropharmacology. 1999;  38 (8) 1195-1205
    CrossrefPubMedGoogle Scholar
  • 28 Gobert A, Rivet J M, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas J P, Cistarelli L, Melon C, Millan M J. Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat.  Synapse. 2000;  36 (3) 205-221
    CrossrefPubMedGoogle Scholar
  • 29 Celada P, Puig M V, Casanovas J M, Guillazo G, Artigas F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors.  J Neurosci. 2001;  21 (24) 9917-9929
    PubMedGoogle Scholar
  • 30 Ichikawa J, Meltzer H Y. R(+)-8-OH-DPAT, a serotonin(1A) receptor agonist, potentiated S(-)-sulpiride-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens but not striatum.  J Pharmacol Exp Ther. 1999;  291 (3) 1227-1232
    PubMedGoogle Scholar
  • 31 Kane J M, Carson W H, Saha A R, McQuade R D, Ingenito G G, Zimbroff D L, Ali M W. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder.  J Clin Psychiatry. 2002;  63 (9) 763-771
    CrossrefPubMedGoogle Scholar
  • 32 Schotte A, Janssen P F, Gommeren W, Luyten W H, Gompel P van, Lesage A S, Loore K de, Leysen J E. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding.  Psychopharmacology. 1996;  124 (1 - 2) 57-73
    CrossrefPubMedGoogle Scholar
  • 33 Richelson E. Neuroleptic affinities for human brain receptors and their use in predicting adverse effects.  J Clin Psychiatry. 1984;  45 (8) 331-336
    PubMedGoogle Scholar
  • 34 Westenberg H G. Pharmacology of antidepressants: selectivity or multiplicity?.  J Clin Psychiatry. 1999;  60 Suppl 17 : 4 - 8 discussion 46-48
    PubMedGoogle Scholar
  • 35 Hertel P, Fagerquist M V, Svensson T H. Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade.  Science. 1999;  286 (5437) 105-107
    CrossrefPubMedGoogle Scholar
  • 36 Bolden C, Cusack B, Richelson E. Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells.  J Pharmacol Exp Ther. 1992;  260 (2) 576-580
    PubMedGoogle Scholar
  • 37 Felder C C, Porter A C, Skillman T L, Zhang L, Bymaster F P, Nathanson N M, Hamilton S E, Gomeza J, Wess J, McKinzie D L. Elucidating the role of muscarinic receptors in psychosis.  Life Sci. 2001;  68 (22 - 23) 2605-2613
    CrossrefPubMedGoogle Scholar
  • 38 Parada M A, Hernandez L, Puig de Parada M, Rada P, Murzi E. Selective action of acute systemic clozapine on acetylcholine release in the rat prefrontal cortex by reference to the nucleus accumbens and striatum.  J Pharmacol Exp Ther. 1997;  281 (1) 582-588
    PubMedGoogle Scholar
  • 39 Ichikawa J, Dai J, O'Laughlin I A, Fowler W L, Meltzer H Y. Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum.  Neuropsychopharmacology. 2002;  26 (3) 325-339
    CrossrefPubMedGoogle Scholar
  • 40 Fleischhacker W W. New developments in the pharmacotherapy of schizophrenia.  J Neural Transm Suppl. 2003;  64 105-117
    PubMedGoogle Scholar
  • 41 Gorelick D A, Balster R L. Phencyclidine (PCP). In: Bloom FE, Kupfer DJ (Hrsg.). Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press 1995: 1767-1776
    Google Scholar
  • 42 Baranano D E, Ferris C D, Snyder S H. Atypical neural messengers.  Trends Neurosci. 2001;  24 (2) 99-106
    CrossrefPubMedGoogle Scholar
  • 43 Goff D C, Coyle J T. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.  Am J Psychiatry. 2001;  158 (9) 1367-1377
    CrossrefPubMedGoogle Scholar
  • 44 Goff D C, Herz L, Posever T, Shih V, Tsai G, Henderson D C, Freudenreich O, Evins A E, Yovel I, Zhang H, Schoenfeld D. A six-month, placebo-controlled trial of D: -cycloserine co-administered with conventional antipsychotics in schizophrenia patients.  Psychopharmacology. 2005;  179 (1) 144-150
    CrossrefPubMedGoogle Scholar
  • 45 Seeman M V. The role of estrogen in schizophrenia.  J Psychiatry Neurosci. 1996;  21 (2) 123-127
    PubMedGoogle Scholar
  • 46 Riecher-Rössler A. Estrogens and the gonadal axis. Implications for women with schizophrenia.  Nervenarzt. 2003;  74 (5) 398-405
    CrossrefPubMedGoogle Scholar

Univ.-Prof. Dr. W. Wolfgang Fleischhacker

Leiter der Abteilung für Biologische Psychiatrie · Universitätsklinik für Psychiatrie · Medizinische Universität Innsbruck

Anichstraße 35

6020 Innsbruck

Österreich

Email: wolfgang.fleischhacker@uibk.ac.at

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