Nuklearmedizinische Rezeptordiagnostik bei schizophrenen Patienten unter Therapie mit typischen und atypischen Neuroleptika

Zusammenfassung

Die pharmakologische Therapie von Erkrankungen aus dem schizophrenen Formenkreis erfolgt durch typische und atypische Neuroleptika. Beide Gruppen unterscheiden sich klinisch im Wesentlichen durch die Eigenschaft, extrapyramidal-motorische Nebenwirkungen hervorzurufen. Die Besetzung postsynaptischer Dopamin-D2-Rezeptoren wird als ein wesentlicher Aspekt der antipsychotischen Wirksamkeit der Neuroleptika angesehen. Diese können nuklearmedizinisch durch [I-123]IBZM-SPECT dargestellt werden. Für das typische Neuroleptikum Haloperidol wurde eine dosisabhängige, exponentielle Besetzung der Dopamin-D2-Rezeptoren nachgewiesen. Ab einem Schwellenwert des spezifischen Bindungsindex von 0,4 (Norm: > 0,95) zeigten mit einer Ausnahme alle untersuchten Patienten extrapyramidal-motorische Nebenwirkungen. Auch unter Therapie mit dem atypischen Neuroleptikum Clozapin ergab sich eine exponentielle Dosis-Wirkungsbeziehung mit jedoch einem deutlich flacheren Kurvenverlauf im Vergleich zu Haloperidol. Extrapyramidal-motorische Nebenwirkungen traten bei diesen Patienten nicht auf. Neuere, als atypisch eingestufte Neuroleptika wie Risperidon und Olanzapin zeigten ebenfalls eine exponenzielle Dosis-Wirkungsbeziehung, wobei deren Kurvenverläufe zwischen denen von Haloperidol und Clozapin lagen. Extrapyramidal-motorische Nebenwirkungen traten bei den letzteren Neuroleptika seltener als bei Haloperidol, bei Olanzapin nur bei einem Patienten in unserem eigenen Patientengut auf. Das pharmakologische Profil atypischer Neuroleptika zeichnet sich neben der Bindung an die postsynaptischen Dopamin-D2-Rezeptoren auch durch Bindung an Rezeptoren diverser anderer Neurotransmittersysteme, insbesondere des serotonergen Systems, aus. Somit ist wahrscheinlich, dass die niedrigere Inzidenz für extrapyramidal-motorische Nebenwirkungen bei atypischen Neuroleptika durch eine komplexe Interaktion an verschiedenen Neurotransmittersystemen bedingt ist.

Abstract

Schizophrenic psychosis is typically treated by typical and atypical neuroleptics. Both groups of drugs differ with regard to induction of extrapyramidal side effects. The occupancy of postsynaptic dopaminergic D2 receptors is considered to be an essential aspect of their antipsychotic properties. The dopamine D2 receptor status can be assessed by means of [I-123]IBZM SPECT. Studies on the typical neuroleptic haloperidol revealed an exponential dose response relationship measured by IBZM. Extrapyramidal side effects were presented by all patients below a threshold of the specific binding of IBZM below 0.4 (with one exception, norm value: > 0.95). Also under treatment with the atypical neuroleptic clozapine an exponential dose response relationship was found. However, none of these patients showed extrapyramidal side effects. Recently introduced, new atypical neuroleptics such as risperidone and olanzapine again presented with an exponential relationship between daily dose and IBZM binding. The curves of the latter were in between the curves of haloperidol and clozapine. Extrapyramidal side effects were documented in a less number of patients treated with risperidone as compared to haloperidol, for olanzapine only one patient revealed these findings in our own patient group. The pharmacological profile of atypical neuroleptics shows - in addition to their binding to dopamine receptors - also high affinities to the receptors of other neurotransmitter systems, particularly the serotonergic system. Therefore, the lower incidence of extrapyramidal side effects seen by atypical in comparison to typical neuroleptics is at least in part most likely due to a complex interaction on a variety of neurotransmitter systems.

Dopaminrezeptoren - Dopamintransporter - Neuroleptika - Schizophrenie

Dopamine receptors - Dopamine transporter - Neuroleptics - Schizophrenia

Literatur

• 1 Beasley C M, Hamilton S H, Crawford A M, Dellva M A, Tollefson G D, Tran P V, Blin O, Beuzen J N. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial.  Eur Neuropsychopharmacol. 1997;  7 125-137
• 2 Borison R L, Pathiraja A P, Diamond B I, Meibach R C. Risperidone: clinical safety and efficacy in schizophrenia.  Psychopharmacol Bull. 1992;  28 213-218
• 3 Broich K, Alavi A, O'Brien C P, Galloway S, Mozley D. SPECT imaging of D2 receptors with 123 I-IBZM in normal controls with escalating doses of haloperidol.  J Nucl Med. 1992;  33 898
• 4 Brücke T, Podreka I, Angelberger P, Wenger S, Topitz A, Kufferle B, Müller C, Deecke L. Dopamine D₂ receptor imaging with SPECT: studies in different neuropsychiatric disorders.  J Cereb Blood Flow Metab. 1991;  11 220-228
• 5 Brücke T, Roth J, Podreka I, Strobl R, Wenger S, Asenbaum S. Striatal dopamine D₂ receptor blockade by typical and atypical neuroleptics.  Lancet. 1992;  339 497
• 6 Brücke T, Wenger S, Asenbaum S, Fertl E, Pfafflmeyer N, Müller C, Podreka I, Angelberger P. Dopamine D₂ receptor imaging and measurement with SPECT.  Adv Neurol. 1993;  60 494-500
• 7 Bymaster F P, Calligaro D O, Falcone J F, Marsh R D, Moore N A, Tye N C, Seeman P, Wong D T. Radioreceptor binding profile of the atypical antipsychotic olanzapine.  Neuropsychopharmacology. 1996;  14 87-96
• 8 Bymaster F P, Hemrick-Luecke S K, Perry K W, Fuller R W. Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, alpha 1-adrenergic and muscarinic receptors in vivo in rats.  Psychopharmacology. 1996;  124 87-94
• 9 Bymaster F P, Rasmussen K, Calligaro D O, Nelson D L, DeLapp N W, Wong D T, Moore N A. In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug.  J Clin Psychiatry. 1997;  58 28-36
• 10 Cambon H, Baron J C, Boulenger J P, Loc'h C, Zarifian E, Maziere B. In vivo assay for neuroleptic receptor binding in the striatum: positron tomography in humans.  Br J Psychiatry. 1987;  151 824-830
• 11 Casey D E. Will the new antipsychotics bring hope of reducing the risk of developing extrapyramidal syndromes and tardive dyskinesia?.  Int Clin Psychopharmacol. 1997;  12 19-27
• 12 Coward D M, Imperato A, Urwyler S. Biochemical and behavioural properties of clozapine.  Psychopharmacology. 1989;  99 6-12
• 13 Crow T J. Molecular pathology of schizophrenia: more than one disease process?.  Br Med J. 1980;  280 66-68
• 14 Dresel S, Mager T, Rossmuller B, Meisenzahl E, Hahn K, Moller H J, Tatsch K. In vivo effects of olanzapine on striatal dopamine D(2)/D(3) receptor binding in schizophrenic patients: an iodine-123-iodobenzamide single-photon emission tomography study.  Eur J Nucl Med. 1999;  26 862-868
• 15 Dresel S, Tatsch K, Dähne I, Mager T, Scherer J, Hahn K. Iodine-123-iodobenzamide SPECT assessment of dopamine D2 receptor occupancy in risperidone-treated schizophrenic patients.  J Nucl Med. 1998;  39 1138-1142
• 16 Ellenbroek B A, Artz M T, Cools A R. The involvement of dopamine D1 and D2 receptors in the effects of the classical neuroleptic haloperidol and the atypical neuroleptic clozapine.  Eur J Pharmacol. 1991;  196 103-108
• 17 Farde L, Nordström A L, Wiesel F A, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects.  Arch Gen Psychiat. 1992;  49 538-544
• 18 Farde L, Wiesel F -A, Haldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs.  Arch Gen Psychiat. 1988;  45 71-76
• 19 Fulton B, Goa K L. Olanzapine. A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses.  Drugs. 1997;  53 281-298
• 20 Hippius H. The history of clozapine.  Psychopharmacology. 1988;  99 3-5
• 21 Janssen P AJ, Niemeegers C JE, Awouters F, Schellekens K H, Megens A A, Meert T F. Risperidone (R64.766), a new antipsychotic with serotonin S2 and dopamine D2 antagonistic properties.  J Pharmacol Exp Ther. 1988;  244 685-693
• 22 Janssen P AJ, Niemegeers C JE, Awouters F, Schellekens K KHL, Megens A AHP, Meert T F. Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties.  J Pharmacol Exp Ther. 1988;  244 685
• 23 Kapur S, Remington G, Zipursky R B, Wilson A A, Houle S. The D2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study.  Life Sci. 1995;  57 103-107
• 24 Kerwin R. Olanzapine.  Lancet. 1997;  350 594
• 25 Kerwin R W, Busatto G F, Pilowsky L S, Ell P J, Costa D C, Verhoeff N PLG. Dopamine D2 receptor occupany in vivo and response to the new antipsychotic risperidone.  Br J Psychiatry. 1993;  163 833-834
• 26 Leysen J E, Janssen P M, Schotte A, Luyten W H, Megens A A. Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors.  Psychopharmacology. 1993;  112 40-54
• 27 Meltzer H Y. New drugs for the treatment of schizophrenia.  Psychiatr Clin N Am. 1993;  16 365-385
• 28 Meltzer H Y, Fibiger H C. Olanzapine: a new typical antipsychotic drug.  Neuropsychopharmacology. 1996;  14 83-85
• 29 Meltzer H Y, Matsubara S, Lee J C. The ratios of serotonin 2 and dopamine 2 affinities differentiate atypical and typical antipsychotic drugs.  Psychopharmacol Bull. 1989;  25 390-392
• 30 Nyberg S, Farde L, Eriksson L, Halldin C, Eriksson B. 5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone.  Psychopharmacology. 1993;  110 265-272
• 31 Nyberg S, Farde L, Halldin C. A PET study of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects.  Neuropsychopharmacology. 1997;  16 1-7
• 32 Pilowsky L S, Busatto G F, Taylor M, Costa D C, Sharma T, Sigmundsson T, Ell P J, Nohria V, Kerwin R W. Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine - a I-123-IBZM single photon emission tomography (SPET) study.  Psychopharmacology. 1996;  124 148-153
• 33 Pilowsky L S, Costa D C, Ell P J, Murray R M, Verhoeff N PLG, Kerwin R W. Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia.  Lancet. 1992;  340 199-202
• 34 Pilowsky L S, O'Connell P, Davies N, Busatto G F, Costa D C, Murray R M, Ell P J, Kerwin R W. In vivo effects on striatal dopamine D2 receptor binding by the novel atypical antipsychotic drug sertindole - a I-123-IBZM single photon emission tomography (SPET) study.  Psychopharmacology. 1997;  130 152-158
• 35 Scherer J, Tatsch K, Albus M, Schwarz J, Mager T, Oertel W H. D2-dopamine-receptor occupancy during treatment with haloperidol decanoate.  Eur Arch Psychiatry Clin Neurosci. 1997;  247 104-106
• 36 Scherer J, Tatsch K, Schwarz J, Oertel W, Kirsch C -M, Albus M. Striatal D2 dopamine receptor occupancy during treatment with typical and atypical neuroleptics.  Biol Psychiatry. 1994;  36 627-629
• 37 Scherer J, Tatsch K, Schwarz J, Oertel W H, Konjarczyk M, Albus M. D2-dopamine receptor occupancy differs between patients with and without extrapyramidal side effects.  Acta-Psychiatr-Scand. 1994;  90 266-268
• 38 Sokoloff P, Giros B, Martres M -P, Bouthenet M -L, Schwartz J -C. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target of neuroleptics.  Nature. 1990;  347 146-151
• 39 Sunahara R K, Guan H -C, O’Dowd B F, Seeman P, Laurier L G, Ng G, George S R, Torchia J, Van Tol H HM, Niznik H B. Cloning of the gene for the human dopamine D5 receptor with higher affinity for dopamine than D1.  Nature. 1991;  350 614-619
• 40 Tamminga C A, Lahti A C. The new generation of antipsychotic drugs.  Int Clin Psychopharmacol. 1996;  11 73-76
• 41 Tran P V, Dellva M A, Tollefson G D, Beasley CM J r, Potvin J H, Kiesler G M. Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia.  published erratum appears in J Clin Psychiatry. 1997;  58 205-211
• 42 Van Tol H HM, Bunzow J R, Guan H C, Sunahara R K, Seeman P, Niznik H B, Civelli O. Cloning of the gene for the human D4 receptor with high affinity for the antipsychotic clozapine.  Nature. 1991;  350 610-614