Download PDF
Pharmacopsychiatry 2004; 37: 103-112
DOI: 10.1055/s-2004-832663
General Concepts
© Georg Thieme Verlag KG Stuttgart · New York

The Etiopathogenesis of Schizophrenias

J. Kornhuber1 , J. Wiltfang1 , S. Bleich1
  • 1Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Friedrich-Alexander Universität zu Erlangen-Nürnberg, Erlangen, Germany
Further Information

Publication History

Publication Date:
16 November 2004 (online)

Also available at
    Permissions and Reprints

There is no generally accepted model explaining the aetiopathogenesis of schizophrenias. In recent years, hypotheses with a focus on single aspects of neurotransmission, single major genetic loci or single brain areas were predominating. Now, these different approaches converge to systemic models including neurotransmission, genetic changes and neurodevelopmental malformation of brain structures. Such systemic models will explain more aspects of schizophrenias than the recent confined hypotheses.

References

  • 1 Adams W, Kendell R E, Hare E H, Munk-Jorgensen P. Epidemiological evidence that maternal influenza contributes to the etiology of schizophrenia.  Br J Psychiatry. 1993;  163 522-534
    PubMedGoogle Scholar
  • 2 Akbarian S, Bunney W E, Potkin S G, Wigal S B, Hagman J O, Sandman C A. Altered distribution of nicotamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development.  Arch Gen Psychiatry. 1996;  50 169-177
    PubMedGoogle Scholar
  • 3 Andreasen N C, Arndt S, Swayze V, Cizadlo T, Flaum M, O'Leary D, Ehrhardt J C, Yuh W T. Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging.  Science. 1994;  266 294-298
    PubMedGoogle Scholar
  • 4 Andreasen N C, Flashman L, Flaum M, Arndt S, Swayze V, O'Leary D S, Ehrhardt J C, Yuh W TC. Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging.  JAMA. 1994;  272 1763-1769
    CrossrefPubMedGoogle Scholar
  • 5 Arnold S E, Hyman B T, Van Hoesen G W, Damasio A R. Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia.  Arch Gen Psychiatry. 1991;  48 625-632
    Google Scholar
  • 6 Barta P E, Pearlson G D, Powers R E, Richards S S, Tune L E. Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia.  Am J Psychiatry. 1990;  147 1457-1462
    PubMedGoogle Scholar
  • 7 Bassett A S, Honer G H. Evidence for anticipation in schizophrenia.  Am J Genet. 1994;  54 314-324
    PubMedGoogle Scholar
  • 8 Beckmann H, Franzek E, Stöber G. Genetic heterogeneity in catatonic schizophrenia: a family study.  Am J Med Genet. 1996;  67 289-300
    CrossrefPubMedGoogle Scholar
  • 9 Beckmann H, Jakob H. Pränatale Entwicklungsstörungen von Hirnstrukturen bei schizophrenen Psychosen.  Nervenarzt. 1994;  65 454-463
    PubMedGoogle Scholar
  • 10 Benes F M. Altered glutamatergic and GABAergic mechanisms in the cingulate cortex of the schizophrenic brain.  Arch Gen Psychiatry. 1995;  52 1015-1018
    PubMedGoogle Scholar
  • 11 Benes F M, McSparran J, Bird E D, SanGiovanni J P, Vincent S L. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients.  Arch Gen Psychiatry. 1991;  48 990-1001
    PubMedGoogle Scholar
  • 12 Benes F M, Sorensen I, Vincent S L, Bird E D, Sathi M. Increased density of glutamate-immunoreactive vertical processes in superficial laminae in cingulate cortex of schizophrenic brain.  Cereb Cortex. 1992;  2 503-512
    PubMedGoogle Scholar
  • 13 Birkmayer W, Danielczyk W, Neumayer E, Riederer P. The balance of biogenic amines as condition for normal behaviour.  J Neural Transm. 1972;  33 163-178
    CrossrefPubMedGoogle Scholar
  • 14 Bissette G, Nemeroff C B. Neurotensin and the mesocorticolimbic dopamine system. In: Kalivas PW, Nemeroff CB, editors The mesocorticolimbic system. Ann NY Acad Sci Vol 537 New York; 1988: 397-404
    Google Scholar
  • 15 Bleuler E. Dementia praecox oder Gruppe der Schizophrenien. In: Aschaffenburg G, editor Handbuch der Psychiatrie. Spez. Teil, 4. Abtlg. Leipzig-Wien; Deuticke 1911
    Google Scholar
  • 16 Bogerts B, Ashtari M, Degreef G, Alvir J M, Bilder R M, Lieberman J A. Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia.  Psychiatry Res Neuroimaging. 1990;  35 1-13
    CrossrefPubMedGoogle Scholar
  • 17 Bogerts B, Meertz E, Schönfeldt-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
    Google Scholar
  • 18 Bracha H S, Torrey E F, Bigelow L B, Lohr J B, Linington B B. Subtle signs of prenatal maldevelopment of the hand ectoderm in schizophrenia: a preliminary monozygotic twin study.  Biol Psychiatry. 1991;  30 719-725
    CrossrefPubMedGoogle Scholar
  • 19 Bradbury T N, Miller G A. Season of birth in schizophrenia: a review of evidence, methodology, and etiology.  Psychol Bull. 1985;  98 569-594
    CrossrefPubMedGoogle Scholar
  • 20 Bruton C J, Crow T J, Frith C D, Johnstone E C, Owens D GC, Roberts G W. Schizophrenia and the brain: a prospective clinico-neuropathological study.  Psychol Med. 1990;  20 285-304
    PubMedGoogle Scholar
  • 21 Cantor-Graae E, McNeil T F, Torrey E F, Quinn P, Bowler A, Sjöström K, Rawlings R. Link between pregnancy complications and minor physical anomalies in monozygotic twins discordant for schizophrenia.  Am J Psychiatry. 1994;  151 1188-1193
    PubMedGoogle Scholar
  • 22 Carlsson A. The current status of the dopamine hypothesis of schizophrenia.  Neuropsychopharmacology. 1988;  1 179-186
    CrossrefPubMedGoogle Scholar
  • 23 Carlsson A, Lindquist M. Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain.  Acta Pharmacol Toxicol. 1963;  20 140-144
    Google Scholar
  • 24 Carlsson A, Waters N, Hansson L O. Neurotransmitter aberrations in schizophrenia: new findings In: Fog R, Gerlach J, Hemmingsen R, editors Schizophrenia. An integrated view. Copenhagen; Munksgaard 1995: 332-340 Carlsson M Carlsson A Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice J Neural Transm 1989 77 65 71 Carlsson M Carlsson A Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson's disease Trends Neurosci 1990 13 272 276 Carlsson M Svensson A Carlsson A Synergistic interactions between muscarinic antagonists, adrenergic agonists and NMDA antagonists with respect to locomotor stimulatory effects in monoamine-depleted mice Naunyn Schmiedebergs Arch Pharmacol 1991 343 568 573
    PubMed
  • 28 Carlsson M L. The selective 5-HT2A receptor antagonist MDL 100,907 counteracts the psychomotor stimulation ensuing manipulations with monoaminergic, glutamatergic or muscarinic neurotransmission in the mouse-implications for psychosis.  J Neural Transm Gen Sect. 1995;  100 225-237
    CrossrefPubMedGoogle Scholar
  • 29 Chen H S, Pellegrini J W, Aggarwal S K, Lei S Z, Warach S, Jensen F E, Lipton S A. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity.  J Neurosci. 1992;  12 4427-4436
    PubMedGoogle Scholar
  • 30 Creese I, Burt D R, Snyder S H. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs.  Science. 1976;  192 481-483
    CrossrefPubMedGoogle Scholar
  • 31 Crow T J, Done D J. Prenatal exposure to influenza does not cause schizophrenia.  Br J Psychiatry. 1992;  161 390-393
    PubMedGoogle Scholar
  • 32 Deakin J FW, Slater P, Simpson M D, Gilchrist A C, Skan W J, Royston M C, Reynolds G P, Cross A J. Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia.  J Neurochem. 1989;  52 1781-1786
    CrossrefPubMedGoogle Scholar
  • 33 Deckert J, Gleiter C H. Adenosinergic psychopharmaceuticals: just an extra cup of coffee?.  J Psychopharmacol. 1990;  4 183-187
    PubMedGoogle Scholar
  • 34 Degreef G, Ashtari M, Bogerts B, Bilder R M, Jody D N, Alvir J M, Lieberman J A. Volumes of ventricular system subdivisions measured from magnetic resonance images in first-episode schizophrenic patients.  Arch Gen Psychiatry. 1992;  49 531-537
    Google Scholar
  • 35 DeLisi L E, Hoff A L, Schwartz J E, Shields G W, Halthore S N, Gupta S M, Henn F A, Anand A K. Brain morphology in first-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study [erratum: Biol Psychiatry 1991, 29 : 519].  Biol Psychiatry. 1991;  29 159-175
    PubMedGoogle Scholar
  • 36 Done D J, Crow T J, Johnstone E C, Sacker A. Childhood antecendents of schizophrenia and affective illness: social adjustment at ages 7 and 11.  Br Med J. 1994;  309 699-703
    PubMedGoogle Scholar
  • 37 Farmer A E, McGuffin P, Gottesman I I. Twin concordance and DSM III schizophrenia: scrutinizing the validity of the definition.  Arch Gen Psychiatry. 1987;  44 634-640
    PubMedGoogle Scholar
  • 38 Fish B, Marcus J, Hans S L, Auerbach J G, Perdue S. Infants at risk for schizophrenia: sequelae of a genetic neurointegrative defect. A review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study.  Arch Gen Psychiatry. 1992;  49 221-235
    PubMedGoogle Scholar
  • 39 Franzek E, Beckmann H. Season-of-birth effect reveals the existence of etiologically different groups of schizophrenia.  Biol Psychiatry. 1992;  32 375-378
    CrossrefPubMedGoogle Scholar
  • 40 Franzek E, Beckmann H. Die genetische Heterogenität der Schizophrenie. Ergebnisse einer systematischen Zwillingsstudie.  Nervenarzt. 1996;  67 583-594
    PubMedGoogle Scholar
  • 41 Fritze J. Einführung in die biologische Psychiatrie. Stuttgart New York; Gustav Fischer 1989
    Google Scholar
  • 42 Garbutt J C, van Kammen D P. The interaction between GABA and dopamine: implications for schizophrenia.  Schizophr Bull. 1983;  9 336-353
    PubMedGoogle Scholar
  • 43 Gattaz W F, Gasser T, Beckmann H. Multidimensional analysis of the concentrations of 17 substances in the CSF of schizophrenics and controls.  Biol Psychiatry. 1985;  20 360-366
    CrossrefPubMedGoogle Scholar
  • 44 Geddes J R, Lawrie S M. Obstetric complications and schizophrenia: a meta-analysis.  Br J Psychiatry. 1995;  167 786-793
    CrossrefPubMedGoogle Scholar
  • 45 Goldman-Rakic P S. Glutamate and dopamine interaction in the primate cortex: implications for frontal lobe function and schizophrenia.  Neuropsychopharmacology. 1994;  10 229
    PubMedGoogle Scholar
  • 46 Goldman-Rakic P S. Working memory dysfunction in schizophrenia.  J Neuropsychiatry Clin Neurosci. 1994;  6 348-357
    PubMedGoogle Scholar
  • 47 Gottesman I I. Schizophrenia genesis. New York; W.H. Freeman 1991
    Google Scholar
  • 48 Gottesman I I, Bertelsen A. Confirming unexpressed genotypes for schizophrenia: risks in the offspring of Fischer's Danish identical and fraternal discordant twins.  Arch Gen Psychiatry. 1989;  46 867-872
    PubMedGoogle Scholar
  • 49 Gottesman I I, Shields J. Schizophrenia, the epigenetic puzzle. Cambridge; Cambridge University Press 1982
    Google Scholar
  • 50 Green M F, Satz P, Gaier D J, Ganzell S, Kharabi F. Minor physical abnormalies in schizophrenia.  Schizophr Bull. 1989;  15 91-99
    PubMedGoogle Scholar
  • 51 Griffon N, Sokoloff P, Diaz J, Lévesque D, Sautel F, Schwartz J C, Simon P, Costentin J, Garrido F, Mann A, Wermuth C. The dopamine D3 receptor and schizophrenia: pharmacological, anatomical and genetic approaches.  Eur Neuropsychopharmacol Suppl. 1995;  5 3-9
    PubMedGoogle Scholar
  • 52 Gross G, Huber G. Sensorische Störungen bei Schizophrenien.  Arch Psychiatr Nervenkr. 1972;  216 119-130
    CrossrefPubMedGoogle Scholar
  • 53 Hansson L O, Waters N, Winblad B, Gottfries C -G, Carlsson A. Evidence for biochemical heterogeneity in schizophrenia: a multivariate study of monoaminergic indices in human post-mortal brain tissue.  J Neural Transm Gen Sect. 1994;  98 217-235
    CrossrefPubMedGoogle Scholar
  • 54 Harrison P J, Owen M J. Genes for schizophrenia? Recent findings and their pathophysiological implications.  Lancet. 2003;  361 417-419
    CrossrefPubMedGoogle Scholar
  • 55 Hodge S E. What association analysis can and cannot tell us about the genetics of complex disease.  Am J Med Genet. 1994;  54 318-323
    PubMedGoogle Scholar
  • 56 Hodge S E, Wickramaratne P. Statistical pitfalls in detecting age-of-onset anticipation: the role of correlation in studying anticipation and detecting ascertainment.  Psychiatr Genet. 1995;  5 43-47
    PubMedGoogle Scholar
  • 57 Hoff A L, Riordan H, O'Donnell D W, Morris L, DeLisi L E. Neuropsychological functioning of first-episode schizophreniform patients.  Am J Psychiatry. 1992;  149 898-903
    PubMedGoogle Scholar
  • 58 Huber G. Die coenästhetische Schizophrenie.  Fortschr Neurol Psychiat. 1957;  25 491-520
    Google Scholar
  • 59 Huber G. Pneumencephalographische und psychopathologische Bilder bei endogenen Psychosen. Berlin Göttingen Heidelberg; Springer 1957
    Google Scholar
  • 60 Hudson C J, Young L T, Li P P, Warsh J J. CNS signal transduction in the pathophysiology and pharmacotherapy of affective disorders and schizophrenia.  Synapse. 1993;  13 278-293
    CrossrefPubMedGoogle Scholar
  • 61 Jacobi W, Winkler H. Encephalographische Studien an chronischen Schizophrenen.  Arch Psychiatr Nervenkr. 1927;  81 299-332
    CrossrefPubMedGoogle Scholar
  • 62 Jakob H, Beckmann H. Prenatal developmental disturbances in the limbic allocortex in schizophrenics.  J Neural Transm. 1986;  65 303-326
    Google Scholar
  • 63 Jaskiw G E, Juliano D M, Goldberg T E, Hertzman M, Urow-Hamell E, Weinberger D R. Cerebral ventricular enlargement in schizophreniform disorder does not progress - a seven year follow-up study.  Schizophr Res. 1994;  14 23-28
    CrossrefPubMedGoogle Scholar
  • 64 Javitt D C, Zukin S R. Recent advances in the phencyclidine model of schizophrenia.  Am J Psychiatry. 1991;  148 1301-1308
    PubMedGoogle Scholar
  • 65 Karson C N, Casanova M F, Kleinman J E, Griffin W ST. Choline acetyltransferase in schizophrenia.  Am J Psychiatry. 1993;  150 454-459
    PubMedGoogle Scholar
  • 66 Kendler K S, Diehl S R. The genetics of schizophrenia: a current, genetic-epidemiologic perspective.  Schizophr Bull. 1993;  19 261-285
    PubMedGoogle Scholar
  • 67 Kim J S, Kornhuber H H, Schmid-Burgk W, Holzmüller B. Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia.  Neurosci Lett. 1980;  20 379-382
    CrossrefPubMedGoogle Scholar
  • 68 Kornhuber H H, Kornhuber J, Kim J S, Kornhuber M E. Zur biochemischen Theorie der Schizophrenie.  Nervenarzt. 1984;  55 602-606
    PubMedGoogle Scholar
  • 69 Kornhuber J, Beckmann H, Riederer P. Die glutamatergen und sigmaergen Systeme bei den Schizophrenien. In: Beckmann H, Osterheider M, editors Neurotransmitter und psychische Erkrankungen. Berlin; Springer Verlag 1991: 147-157
    Google Scholar
  • 70 Kornhuber J, Bormann J, Hübers M, Rusche K, Riederer P. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study.  Eur J Pharmacol Mol Pharmacol Sect. 1991;  206 297-300
    CrossrefPubMedGoogle Scholar
  • 71 Kornhuber J, Bormann J, Retz W, Hübers M, Riederer P. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex.  Eur J Pharmacol. 1989;  166 589-590
    CrossrefPubMedGoogle Scholar
  • 72 Kornhuber J, Herr B, Thome J, Riederer P. The antiparkinsonian drug budipine binds to NMDA and sigma receptors in postmortem human brain tissue.  J Neural Transm Suppl. 1995;  46 131-137
    PubMedGoogle Scholar
  • 73 Kornhuber J, Mack-Burkhardt F, Riederer P, Hebenstreit G F, Reynolds G P, Andrews H B, Beckmann H. [3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients.  J Neural Transm. 1989;  77 231-236
    CrossrefPubMedGoogle Scholar
  • 74 Kornhuber J, Parsons C G, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P. Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies.  J Neural Transm Gen Sect. 1995;  102 237-246
    CrossrefPubMedGoogle Scholar
  • 75 Kornhuber J, Riederer P, Reynolds G P, Beckmann H, Jellinger K, Gabriel E. 3H-Spiperone binding sites in post-mortem brains from schizophrenic patients: relationship to neuroleptic drug treatment, abnormal movements, and positive symptoms.  J Neural Transm. 1989;  75 1-10
    CrossrefPubMedGoogle Scholar
  • 76 Kornhuber J, Weller M. Aktueller Stand der biochemischen Hypothesen zur Pathogenese der Schizophrenien.  Nervenarzt. 1994;  65 741-754
    PubMedGoogle Scholar
  • 77 Kornhuber J, Weller M. Predicting psychotomimetic properties of PCP-like NMDA receptor antagonists. In: Fog R, Gerlach J, Hemmingsen R, Krogsgaard-Larsen P, Thaysen JH, editors Schizophrenia - An integrated view. Alfred Benzon Symposium 38.  Copenhagen; Munksgaard 1995: 314-325
    Google Scholar
  • 78 Kornhuber J, Weller M. Neue therapeutische Möglichkeiten mit niederaffinen NMDA-Rezeptorantagonisten.  Nervenarzt. 1996;  67 77-82
    PubMedGoogle Scholar
  • 79 Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy.  Biol Psychiatry. 1997;  41 135-144
    PubMedGoogle Scholar
  • 80 Kornhuber M E, Kornhuber J, Zettlmeissl H, Kornhuber H H. Phencyclidin und das glutamaterge System. In: Keupp W, editor Biologische Psychiatrie, Forschungsergebnisse Berlin New York; Springer 1986: 176-180
    Google Scholar
  • 81 Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte, Bd. 1-4, 1909-1915. 8th ed Leipzig; Barth 1909
    Google Scholar
  • 82 Kruglyak L, Lander E S. High-resolution genetic mapping of complex traits.  Am J Hum Genet. 1995;  56 1212-1223
    PubMedGoogle Scholar
  • 83 Lesch K P, Stöber G, Balling U, Franzek E, Li S H, Ross C A, Newman M, Beckmann H, Riederer P. Triplet repeats in clinical subtypes of schizophrenia: variation at the DRPLA (B37 CAG repeat) locus is not associated with periodic catatonia.  J Neural Transm Gen Sect. 1994;  98 153-157
    CrossrefPubMedGoogle Scholar
  • 84 Lewis C M, Levinson D F, Wise L H, DeLisi L E, Straub R E, Hovatta I, Williams N M, Schwab S G, Pulver A E, Faraone S V, Brzustowicz L M, Kaufmann C A, Garver D L, Gurling H M, Lindholm E, Coon H, Moises H W, Byerley W, Shaw S H, Mesen A, Sherrington R, O'Neill F A, Walsh D, Kendler K S, Ekelund J, Paunio T, Lonnqvist J, Peltonen L, O'Donovan M C, Owen M J, Wildenauer D B, Maier W, Nestadt G, Blouin J L, Antonarakis S E, Mowry B J, Silverman J M, Crowe R R, Cloninger C R, Tsuang M T, Malaspina D, Harkavy-Friedman J M, Svrakic D M, Bassett A S, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.  Am J Hum Genet. 2003;  73 34-48
    CrossrefPubMedGoogle Scholar
  • 85 Lewis S W, Murray R M. Obstetric complications, neurodevelopmental deviance, and risk of schizophrenia.  J Psychiatr Res. 1987;  21 413-421
    CrossrefPubMedGoogle Scholar
  • 86 Liddle P F, Friston K J, Frith C D, Hirsch S R, Jones T, Frackowiak R S. Patterns of cerebral blood flow in schizophrenia.  Br J Psychiatry. 1992;  160 179-186
    PubMedGoogle Scholar
  • 87 Lieberman J A, Koreen A R. Neurochemistry and neuroendocrinology of schizophrenia: a selective review.  Schizophr Bull. 1993;  19 371-429
    PubMedGoogle Scholar
  • 88 Lohr J B, Flynn K. Minor physical anomalies in schizophrenia and mood disorders.  Schizophr Bull. 1993;  19 551-556
    PubMedGoogle Scholar
  • 89 Maier W, Zobel A, Rietschel M. Genetics of schizophrenia and affective disorders.  Pharmacopsychiatry. 2003;  36(Suppl 3) S195-202
    Article in Thieme ConnectPubMedGoogle Scholar
  • 90 Malmberg A, Jackson D M, Eriksson A, Mohell N. Unique binding characterisitcs of antipsychotic agents interacting with human dopamine D2A, D2B and D3 receptors.  Mol Pharmacol. 1993;  43 749-754
    PubMedGoogle Scholar
  • 91 McGuffin P, Owen M J, Farmer A E. Genetic basis of schizophrenia.  Lancet. 1995;  346 678-682
    CrossrefPubMedGoogle Scholar
  • 92 McGuffin P, Sargeant M, Hett G, Tidmarsh S, Whatley S, Marchbanks R M. Exclusion of a schizophrenia susceptibility gene from the chromosome 5q11-q13 region: new data and a re-analysis of previous reports.  Am J Hum Genet. 1996;  47 524-535
    PubMedGoogle Scholar
  • 93 McNeil T F. Obstetric complications in schizophrenic parents.  Schizophr Res. 1991;  5 89-101
    CrossrefPubMedGoogle Scholar
  • 94 Meadows D e, Meadows D o, Zahn E, Milling P. Die Grenzen des Wachstums. Bericht des Club of Rome zur Lage der Menschheit. Reinbek; Rowohlt 1973
    Google Scholar
  • 95 Mednick S A, Machon R A, Huttunen M O, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic.  Arch Gen Psychiatry. 1988;  45 189-192
    PubMedGoogle Scholar
  • 96 Meltzer H Y, Matsubara S, Lee J -C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonergic2 pKi values.  J Pharmacol Exp Ther. 1989;  251 238-246
    PubMedGoogle Scholar
  • 97 Moises H W, Yang L, Kristbjarnarson H, Wiese C, Byerley W, Macciardi F, Arolt V, Blackwood D, Liu X, Sjogren B ,. et al . An international two-stage genome-wide search for schizophrenia susceptibility genes.  Nat Genet. 1995;  11 321-324
    PubMedGoogle Scholar
  • 98 Murray R M, Lewis S W. Is schizophrenia a neurodevelopmental disorder?.  Br Med J. 1987;  296 681-682
    PubMedGoogle Scholar
  • 99 Nair N PV, Lal S, Bloom D M. Cholecystokinin and schizophrenia. In: van Ree JM, Matthysse S, editors Progress in Brain Research. Vol 65 Amsterdam; Elsevier 1994: 237-258
    Google Scholar
  • 100 O'Callaghan E, Gibson T, Colohan H A, Walshe D, Buckley P, Larkin C, Waddington J L. Season of birth in schizophrenia. Evidence for confinement of an excess of winter births to patients without a family history of mental disorder.  Br J Psychiatry. 1991;  158 764-769
    PubMedGoogle Scholar
  • 101 O'Callaghan E, Larkin C, Kinsella A, Waddington J L. Familial, obstetric, and other clinical correlates of minor physical anomalies in schizophrenia.  Am J Psychiatry. 1991;  148 479-483
    PubMedGoogle Scholar
  • 102 Olney J W, Labruyere J, Price M T. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs.  Science. 1989;  244 1360-1362
    PubMedGoogle Scholar
  • 103 Pakkenberg B. Post-mortem study of chronic schizophrenic brains.  Br J Psychiatry. 1987;  151 744-752
    PubMedGoogle Scholar
  • 104 Parsons C G, Gruner R, Rozental J, Millar J, Lodge D. Patch clamp studies on the kinetic and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan).  Neuropharmacology. 1993;  32 1337-1350
    CrossrefPubMedGoogle Scholar
  • 105 Parsons C G, Quack G, Bresink I, Baran L, Przegalinski E, Kostowski W, Krzascik P, Hartmann S, Danysz W. Comparison of the potency, kinetics and voltage-dependency of open channel blockade for a series of uncompetitive NMDA antagonists in vitro with anticonvulsive and motor impairment activity in vivo.  Neuropharmacology. 1995;  34 1239-1258
    CrossrefPubMedGoogle Scholar
  • 106 Porenta G, Riederer P. Some aspects of modeling neuronal interactions in the basal ganglia. In: Trappl R, editor Cybernetics and systems '86. D. Reidel Publishing Company 1986: 351-358
    Google Scholar
  • 107 Pulver A E, Lasseter V K, Kasch L, Wolyniec P, Nestadt G, Blovin J L, Kimberland M, Babb R, Vourlis S, Chen H ,. et al . Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility.  Am J Med Genet. 1995;  60 252-260
    CrossrefPubMedGoogle Scholar
  • 108 Reading P J. Frontal lobe dysfunction in schizophrenia and Parkinson's disease - a meeting point of neurology, psychology and psychiatry: a discussion paper.  J R Soc Med. 1991;  84 349-353
    PubMedGoogle Scholar
  • 109 Reveley A M, Reveley M A, Clifford C A, Murray R M. Cerebral ventricular size in twins discordant for schizophrenia.  Lancet. 1982;  ii 540-541
    PubMedGoogle Scholar
  • 110 Reynolds G P. Beyond the dopamine hypothesis. The neurochemical pathology of schizophrenia.  Br J Psychiatry. 1989;  155 305-316
    PubMedGoogle Scholar
  • 111 Reynolds G P. Dopamine D4 receptors in schizophrenia [letter]?.  J Neurochem. 1996;  66 881-883
    PubMedGoogle Scholar
  • 112 Reynolds G P, Mason S L. Are striatal dopamine D4 receptors increased in schizophrenia?.  J Neurochem. 1994;  63 1576-1577
    PubMedGoogle Scholar
  • 113 Ross C A, Pearlson G D. Schizophrenia, the heteromodal association neocortex and development: potential for a neurogenetic approach.  Trends Neurosci. 1996;  19 171-176
    CrossrefPubMedGoogle Scholar
  • 114 Saykin A J, Shtasel D L, Gur R E, Kester D B, Mozley L H, Stafiniak P, Gur R C. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia.  Arch Gen Psychiatry. 1994;  51 124-131
    CrossrefPubMedGoogle Scholar
  • 115 Scheibel A B, Kovelman J A. Disorientation of the hippocampal pyramidal cell and its processes in the schizophrenic patient.  Biol Psychiatry. 1981;  16 101-102
    PubMedGoogle Scholar
  • 116 Schwab S G, Albus M, Hallmayer J, Honig S, Borrmann M, Lichtermann D, Ebstein R P, Ackenheil M, Lerer B, Risch N ,. et al . Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.  Nat Genet. 1995;  11 325-327
    PubMedGoogle Scholar
  • 117 Schwab S G, Lerer B, Albus M, Maier W, Hallmayer J, Fimmers R, Lichtermann D, Minges J, Bondy B, Ackenheil M, Altmark D, Hasib D, Gur E, Ebstein R P, Wildenauer D B. Potential linkage for schizophrenia an chromosome 22q12-q13: a replication study.  Am J Med Genet. 1995;  60 436-443
    CrossrefPubMedGoogle Scholar
  • 118 Schwartz J C, Diaz J, Lévesque D, Pilon C, Dimitriadou V, Griffon N, Lammers C, Martres M P, Sokoloff P. The D2-like subfamily of dopamine receptors. In: Fog R, Gerlach J, Hemmingsen R, editors Schizophrenia. An integrated view. Copenhagen; Munksgaard 1995: 251-262
    Google Scholar
  • 119 Seeman P, Guan H -G, Van Tol H HM. Dopamine D4 receptors elevated in schizophrenia.  Nature. 1993;  365 441-445
    CrossrefPubMedGoogle Scholar
  • 120 Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors.  Nature. 1976;  261 717-719
    Google Scholar
  • 121 Shenton M E, Kikinis R, Jolesz F A, Pollak S D, LeMay M, Wible C G, Hokama H, Martin J, Metcalf D, Coleman M ,. et al . Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study.  N Engl J Med. 1992;  327 604-612
    PubMedGoogle Scholar
  • 122 Sherrington R, Brynjolfsson B, Petursson H, Potter M, Dudleston K, Barraclough B, Wasmuth J, Dobbs M, Gurling H. Localization of a susceptibility locus for schizophrenia on chromosome 5.  Nature. 1988;  336 164-167
    CrossrefPubMedGoogle Scholar
  • 123 Stöber G, Franzek E, Beckmann H. Obstetric complications in distinct schizophrenic subgroups.  Eur Psychiatry. 1993;  8 293-299
    PubMedGoogle Scholar
  • 124 Stöber G, Franzek E, Beckmann H. Schwangerschaftsinfektionen bei Müttern von chronisch Schizophrenen. Die Bedeutung einer differenzierten Nosologie.  Nervenarzt. 1994;  65 175-182
    PubMedGoogle Scholar
  • 125 Stöber G, Franzek E, Lesch K P, Beckmann H. Periodic catatonia: a schizophrenic subtype with major gene effect and anticipation.  Eur Arch Psychiatry Clin Neurosci. 1995;  245 135-141
    PubMedGoogle Scholar
  • 126 Straub R E, MacLean C J, O'Neill F A, Burke J, Murphy B, Duke F, Shinkwin R, Webb B T, Zhang J, Walsh D ,. et al . A potential vulnerability locus for schizophrenia on chromosome 6p24 - 22: evidence for genetic heterogeneity.  Nat Genet. 1995;  11 287-293
    PubMedGoogle Scholar
  • 127 Suddath R L, Christison G W, Torrey E F, Weinberger D R. Cerebral anatomical abnormalities in monozygotic twins discordant for schizophrenia.  N Engl J Med. 1990;  322 789-794
    PubMedGoogle Scholar
  • 128 Svensson A, Carlsson M L, Carlsson A. Interaction between glutamatergic and dopaminergic tone in the nulcleus accumbens of mice: evidence for a dual glutamatergic function with respect to psychomotor control.  J Neural Transm. 1992;  88 235-240
    CrossrefPubMedGoogle Scholar
  • 129 Tandon R, Greden J F. Cholinergic hyperactivity and negative schizophrenic symptoms. A model of cholinergic/dopaminergic interactions in schizophrenia.  Arch Gen Psychiatry. 1989;  46 745-753
    CrossrefPubMedGoogle Scholar
  • 130 Thomson G. Identifying complex disease genes: progress and paradigms.  Nat Genet. 1994;  8 108-110
    PubMedGoogle Scholar
  • 131 Vita A, Sacchetti E, Valvassori G, Cazzullo C L. Brain morphology in schizophrenia: a 2- to 5-year follow-up study.  Acta Psychiatr Scand. 1988;  78 618-621
    PubMedGoogle Scholar
  • 132 Waddington J L. Schizophrenia: developmental neuroscience and pathobiology.  Lancet. 1993;  341 531-536
    CrossrefPubMedGoogle Scholar
  • 133 Walker J M, Bowen W D, Walker F O, Matsumoto R R, De Costa B, Rice K C. Sigma receptors: biology and function.  Pharmacol Rev. 1990;  42 355-402
    PubMedGoogle Scholar
  • 134 Warren S T. The expanding world of trinucleotide repeats.  Science. 1996;  271 1374-1375
    PubMedGoogle Scholar
  • 135 Weinberger D R. Implications of normal brain development for the pathogenesis of schizophrenia.  Arch Gen Psychiatry. 1987;  44 660-669
    PubMedGoogle Scholar
  • 136 Weinberger D R. Schizophrenia and the frontal lobe.  Trends Neurosci. 1988;  11 367-370
    CrossrefPubMedGoogle Scholar
  • 137 Wiegant V M, Ronken E, Kovács G, de Wied D. Endorphins and schizophrenia.  Prog Brain Res. 1992;  93 433-453
    PubMedGoogle Scholar
  • 138 Winn P. Schizophrenia search moves to the prefrontal cortex.  Trends Neurosci. 1994;  17 265-268
    CrossrefPubMedGoogle Scholar
  • 139 Zipursky R B, Marsh L, Lim K O, DeMent S, Shear P K, Sullivan E V, Murphy G M, Csernansky J G, Pfefferbaum A. Volumetric MRI assessment of temporal lobe structures in schizophrenia.  Biol Psychiatry. 1994;  35 501-516
    CrossrefPubMedGoogle Scholar

Prof. Dr. med. Johannes Kornhuber

Friedrich-Alexander Universität zu Erlangen-Nürnberg

Klinik mit Poliklinik für Psychiatrie und Psychotherapie

Schwabachanlage 6-10

91054 Erlangen

Phone: +49 9131 85 34160

Fax: +9131 85 34862

Email: Johannes.Kornhuber@psych.imed.uni-erlangen.de