Original articles| Volume 33, ISSUE 4, P227-235, February 15, 1993

Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: A double-blind PET study of schizophrenic patients

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      The relationship between central D2-dopamine receptor occupancy and antipsychotic drug effects was examined in a double-blind study. Raclopride was the compound used to induce a selective occupancy of the D2-dopamine receptors. In addition, 11C-labeled raclopride was the radioligand used to measure occupancy by positron emission tomography (PET). Seventeen schizophrenic patients were randomly assigned to one of three parallel groups treated for 4 weeks with daily doses of 2, 6, or 12 mg of raclopride. D2-receptor occupancy was determined by PET at steady-state conditions in 13 patients who completed the study. A statistically significant relationship was demonstrated between antipsychotic effect and degree of D2-receptor occupancy (p < 0.05). Patients with extrapyramidal side effects had significantly 3igher D2-receptor occupancy than those without (p = 0.02). The finding of a relationship between selective occupancy of the D2-dopamine receptors and clinical effects in schizophrenic patients principally provides new support for the dopamine hypothesis of antipsychotic drug action.


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        • Baldessarini R.J.
        • Cohen B.M.
        • Teicher M.H.
        Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses.
        Arch Gen Psychiatry. 1988; 45: 79-91
        • Barnes T.R.E.
        A rating scale for drug-induced akathisia.
        Br J Psychiatry. 1989; 154: 672-676
        • Baron J.C.
        • Martinot J.L.
        • Cambon H.
        • et al.
        Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: Correlative evaluation by positron emission tomography and plasma prolactin levels.
        Psychopharmacology. 1989; 99: 463-472
        • Bergström M.
        • Boéthius J.
        • Eriksson L.
        • Greitz T.
        • Ribbe T.
        • Widén L.
        Head fixation device for reproducible position alignment in transmission CT and positron emission tomography.
        J Comput Assist Tomogr. 1981; 5: 136-141
        • Bergström M.
        • Litton J.
        • Eriksson L.
        • Bohm C.
        • Blomqvist G.
        Determination of object contour from projections for attenuation correction in cranial positron emission tomography.
        J Comput Assist Tomogr. 1982; 6: 365-372
        • Bishop M.P.
        • Gallant M.
        Observations of placebo response in chronic schizophrenic patients.
        Arch Gen Psychiatry. 1966; 14: 497-503
        • Cambon H.
        • Baron J.C.
        • Boulenger J.P.
        • Loc'h C.
        • Zarifian E.
        • Mazière B.
        In vivo assay for neuroleptic receptor binding in the striatum: Positron tomography in humans.
        Br J Psychiatry. 1987; 151: 824-830
        • Carlsson A.
        Antipsychotic drugs, neurotransmitters, and schizophrenia.
        Am J Psychiatry. 1978; 135: 164-173
        • Creese I.
        • Burt D.R.
        • Snyder S.H.
        Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs.
        Science. 1976; 192: 481-483
        • Dahl S.G.
        Plasma level monitoring of antipsychotic drugs. Clinical utility.
        Clin Pharmacokinet. 1986; 11: 36-61
        • Davis J.M.
        • Schaffer C.B.
        • Killian G.A.
        • Kinard C.
        • Chan C.
        Important issues in the drug treatment of schizophrenia.
        Schizophr Bull. 1980; 6: 70-87
        • Davis K.L.
        • Kahn R.S.
        • Ko G.
        • Davidson M.
        Dopamine in schizophrenia: A review and reconceptualization.
        Am J Psychiatry. 1991; 148: 1474-1486
      1. ECDEU Manual. Assessment Manual for Psychopharmacology. US Dept of Health, Education, and Welfare, Washington, DC1976
        • Farde L.
        Selective D1- and D2-dopamine receptor blockade both induces akathisia in humans—a PET study with [11C]SCH 23390 and [11C]raclopride.
        Psychopharmacology. 1992; 107: 23-29
        • Farde L.
        • von Bahr C.
        Distribution of remoxipride to the human brain and central D2-dopamine receptor binding examined in vivo by PET.
        Acta Psychiatr Scand. 1990; 82: 67-71
        • Farde L.
        • Ehrin E.
        • Eriksson L.
        • et al.
        Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography.
        in: Proc Natl Acad Sci USA. 82. 1985: 3863-3867
        • Farde L.
        • Hall H.
        • Ehrin E.
        • Sedvall G.
        Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET.
        Science. 1986; 231: 258-261
        • 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: 71-76
        • Farde L.
        • Wiesel F.-A.
        • Jansson P.
        • Uppfeldt G.
        • Wahlen A.
        • Sedvall G.
        An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET.
        Psychopharmacology. 1988; 94: 1-7
        • Farde L.
        • Wiesel F.-A.
        • Stone-Elander S.
        • et al.
        D2 dopamine receptors in neuroleptic-naive schizophrenic patients.
        Arch Gen Psychiatry. 1990; 47: 213-219
        • Farde L.
        • Nordström A.-L.
        • Wiesel F.-A.
        • Pauli S.
        • Halldin C.
        • Sedvall G.
        PET-analysis of central D-2 and D2-dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine—relation to extrapyramidal side effects.
        Arch Gen Psychiatry. 1992; 49: 538-544
        • Garver G.
        Neuroleptic drug levels and antipsychotic effects: A difficult correlation: potential advantage of free (or Derivate) versus total plasma levels.
        J Clin Psychopharmacol. 1989; 9: 277-281
        • Greitz T.
        • Bergström M.
        • Boëtius J.
        • Kingsley D.
        • Ribbe T.
        Head fixation system for integration of radiodiagnostic and therapeutic procedures.
        Neuroradiology. 1980; 191: 1-6
        • Halldin C.
        • Farde L.
        • Högberg T.
        • et al.
        A comparative PET-study of five carbon-11 or fluorine-18 labelled salicylamides. Preparation and In vitro dopamine D2 receptor binding.
        Nucl Med Biol. 1991; 18: 871-881
        • Kuchenski R.
        • Segal D.
        Concomitant characterization of behavioral and striatal neurotransmitter response to amphetamine using in vivo microdialysis.
        J Neurosci. 1989; 9: 2051-2065
        • Köhler C.
        • Hall H.
        • Ögren S.
        • Gawell L.
        Specific in vitro and in vivo binding of 3H-raclopride, a potent substituted drug with high affinity for dopamine D-2 receptors in the rat brain.
        Biochem Pharmacol. 1985; 34: 2251-2259
        • Lapierre Y.D.
        • Nair N.P.V.
        • Chouinard G.
        • et al.
        A controlled dose-ranging study of remoxipride and haloperidol in schizophrenia—a Canadian multicenter trial.
        Acta Psychiatr Scand. 1990; 82: 72-76
        • Litton J.
        • Bergström M.
        • Eriksson L.
        • Bohm C.
        • Blomqvist G.
        • Kesselberg M.
        Performance study of the PC-384 positron camera system for emission tomography of the brain.
        J Comput Assist Tomogr. 1984; 8: 74-87
        • Litton J.E.
        • Holte S.
        • Eriksson L.
        Evaluation of the Karolinska new positron camera system: The Scanditronix PC2048-25B.
        IEEE Trans Nucl Sci NS. 1990; 37: 743-748
        • Movin-Osswald G.
        • Nordström A.-L.
        • Hammarlund-Udenaes M.
        • Wahlén A.
        • Farde L.
        Pharmacokinetics of raclopride with different formulations, and its influence on prolactin and side effect in healty male volunteers.
        Clin Pharmacokinet. 1992; 22: 152-161
        • Nordström A.-L.
        • Farde L.
        • Pauli S.
        • Litton J.-E.
        • Halldin C.
        PET analysis of central [11C]raclopride binding in healthy subjects and schizophrenic patients—reliability and age effects.
        Hum Psychopharmacol. 1992; 7: 157-165
        • Nordström A.-L.
        • Farde L.
        • Halldin C.
        Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of naloperidol.
        Psychopharmacology. 1992; 106: 433-438
        • Nordström A.-L.
        • Farde L.
        • Halldin C.
        High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET.
        Psychopharmacology. 1993; (in press)
        • Örgen S.
        • Hall H.
        • Köhler C.
        • Magnusson O.
        • Sjöstrand S.-E.
        The selective dopamine D2 receptor antagonist raclopride discriminates between dopamine-mediated motor functions.
        Psychopharmacology. 1986; 90: 287-294
        • Overall J.E.
        • Gorham D.R.
        The Brief Psychiatric Rating Scale.
        Psychol Rep. 1962; 10: 799-812
        • Ross E.M.
        • Gilman A.G.
        Pharmacodynamics: Mechanisms of drug action and the relationship between drug concentration and effect.
        in: Gilmam A. Goodman L. Rall T. Murad F. The Pharmacological Basis of Therapeutics. Macmillan, New York1985: 35-48
        • Ryan F.
        • Joiner L.
        • Ryan Jr., A.
        The Minitab Handbook. Duxbury Press, Boston1985: 185-190
        • Seeman P.
        Atypical neuroleptics: role of multiple receptors, endogenous dopamine, and receptor linkage.
        Acta Psychiatr Scand. 1989; 82: 14-20
        • Seeman P.
        Elevation of dopamine D2 receptors in schizophrenia is underestimated by radioactive raclopride.
        Arch Gen Psychiatry. 1990; 47: 1170-1172
        • Seeman P.
        • Lee T.
        • Chau-Wong M.
        • Wong K.
        Antipsychotic drug doses and neuroleptic/dopamine receptors.
        Nature. 1976; 261: 179-717
        • Smith M.
        • Wolf A.P.
        • Brodie J.D.
        • et al.
        Serial Math Eq PET studies to measure changes in antipsychotic drug D-2 receptor occupancy in schizophrenic patients.
        Biol Psychiatry. 1988; 23: 653-663
        • 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 for neuroleptics.
        Nature. 1990; 347: 146-151
        • van Rossum J.M.
        The significance of dopamine receptor blockade for the mechanism of action of neuroleptic drugs.
        Arch Int Pharmacodyn Ther. 1966; 160: 492-494
        • Zhang W.
        • Tilson H.
        • Stachowiak M.K.
        • Hong J.S.
        Repeated haloperidol administration changes basal release of striatal dopamine and subsequent response to haloperidol challenge.
        Brain Res. 1989; 484: 389-392