Summary
Four schizophrenic patients were investigated with dynamic positron emission tomography (PET) using (18F)fluorodeoxyglucose (FDG) and (18F)methylspiperone (MSP) as tracers. Two schizophrenics were on haloperidol therapy at the time of MSP PET. The other two schizophrenics were treated with clozapine, in one of them MSP PET was carried out twice with different daily doses (100 mg and 450 mg respectively). Neuroleptic serum levels were measured in all patients. Results were compared with MSP PET of two drug-free male control subjects and with a previous fluoroethylspiperone (FESP) study of normals. Three hours after tracer injection specific binding of MSP was observed in the striatum in all cases. The striatum to cerebellum ratio was used to estimate the degree of neuroleptic-caused striatal D2 dopamine receptor occupancy. In the haloperidol treated patients MSP binding was significantly decreased, whereas in the clozapine treated patients striatum to cerebellum ratio was normal. Even the increase of clozapine dose in the same patient had no influence on this ratio. Despite the smaller number of patients the study shows for the first time in humans that striatal MSP binding reflects the different D2 dopamine receptor affinities of clozapine and haloperidol.
Similar content being viewed by others
References
AIMS (1976) Abnormal involuntary movement scale. In: Guy W (ed) ECDEU Assessment Manual. Rockville, Maryland, pp 534–537
American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd revised edn (DSM-III-R). Washington, DC
Andersson U, Eckernäs SA, Hartvig P, Ulin J, Langström B, Häggström JE (1990) Striatal binding of11C-NMSP studied with positron emission tomography in patients with persistent tardive dyskinesia: no evidence for altered dopamine D2 receptor binding. J Neural Transm 79: 215–226
Andreasen NC, Carson R, Diksic M, Evans A, Farde L, Gjedde A, Hakim A, Lal S, Nair N, Sedvall G, Tune L, Wong D (1988) Workshop on schizophrenia PET, and dopamine D2 receptors in the human neostriatum. Schizophr Bull 14: 471–484
Baron JC, Martinot JL, Cambon H, Boulenger JP, Poirier MF, Gaillard V, Blin J, Huret JD, Loc'h C, Mazière B (1989) Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology 99: 463–472
Barrio JR, Satyamurthy N, Huang SC, Keen RE, Nissenson CHK, Hoffman JM, Ackermann RF, Bahn MM, Mazziotta JC, Phelps ME (1989) 3-(2′-(18F)fluoroethylspiperone: in vivo biochemical and kinetic characterization in rodents, nonhuman primates, and humans. J Cereb Blood Flow Metab 9: 830–839
Blin J, Baron JC, Cambon H, Bonnet AM, Dubois B, Loc'h C, Mazière B, Agid Y (1989) Striatal dopamine D2 receptors in tardive dyskinesia: PET study. J Neurol Neurosurg Psychiatry 52: 1248–1252
Burt DR, Creese I, Snyder S (1977) Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196: 326–327
Cheng YF, Lundberg T, Bondesson U, Lindström L, Gabrielsson J (1988) Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin Pharmacol 34: 445–449
Coenen HH, Laufer P, Stöcklin G, Wienhard K, Pawlik G, Böcher-Schwarz HG, Heiss WD (1987) 3-N-(2-(18F)-fluoroethyl)-spiperone: a novel ligand for cerebral dopamine receptor studies with PET. Life Sci 40: 81–88
Ereshefsky L, Watanabe MD, Tran-Johnson TK (1989) Drug review: clozapine: an atypical antipsychotic agent. Clin Pharm 8: 691–709
Farde L, Wiesel FA, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45: 71–76
Farde L, Wiesel FA, Stone-Elander S, Halldin C, Nordström AL, Hall H, Sedvall G (1990) D2 dopamine receptors in neuroleptic-naive schizophrenic patients. Arch Gen Psychiatry 47: 213–219
Gerlach J, Casey De, Korsgaard S (1986) Tardive dyskinesia, epidemiology, pathophysiology, and pharmacology. In: Shah NS, Donald AG (eds) Movement disorders. Plenum, New York London, pp 119–147
Hall H, Wedel I, Halldin C, Kopp J, Farde L (1990) Comparison of the in vitro receptor binding properties of N-(3H)raclopride to rat and human brain membranes. J Neurochem 55: 2048–2057
Hamacher K, Nebeling B, Coenen HH, Stöcklin G (1990) (18F)N-methyl-spiperone: direct N.C.A. nucleophilic (18F)fluorination of N-methyl-4-nitrospiperone for remote controlled routine production of N.C.A. (18F)MSP. J Label Comp Radiopharm (in press)
Hartvig P, Eckernäs SA, Ekblom B, Lindström L, Lundqvist H, Axelsson S, Fasth KJ, Gullberg P, Langström B (1988) Receptor binding and selectivity of three11C-labelled dopamine receptor antagonists in the brain of Rhesus monkeys studied with positron emission tomography. Acta Neurol Scand 77: 314–321
Heiss WD, Pawlik G, Herholz K, Wagner R, Göldner H, Wienhard K (1984) Regional kinetic constants and cerebral metabolic rate for glucose in normal human volunteers determined by dynamic PET of (18F)-2-fluoro-2-deoxy-D-glucose. J Cereb Blood Flow Metab 4: 212–223
Imperato A, Angelucci L (1989) The effects of clozapine and fluperlapine on the in vivo release and metabolism of dopamine in the striatum and in the prefrontal cortex of freely moving rats. Psychopharmacol Bull 25: 383–389
Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenia. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45: 789–796
Klawans HL, Goetz CG, Perlik S (1980) Tardive dyskinesias. Review and update. Am J Psychiatry 137: 900–908
Lane RF, Blaha CD, Rivet JM (1988) Selective inhibition of mesolimbic dopamine release following chronic administration of clozapine, involvement of noradrenergic receptors demonstrated in vivo voltammetry. Brain Res 460: 398–401
Litton J, Bergström M, Eriksson L, Bohm C, Blomqvist G, Kesselberg M (1984) Performance study of the PC-384 positron camera system for the brain. J Comput Assist Tomogr 8: 74–87
Lundberg T, Lindström LH, Hartvig P, Eckernäs SA, Ekblom E, Lundqvist H, Fasth KJ, Gullberg P, Langström B (1989) Striatal and frontal cortex binding of 11-C-labelled clozapine visualized by positron emission tomography (PET) in drug free schizophrenics and healthy volunteers. Psychopharmacology 99: 8–12
Matz R, Rick W, Oh D, Thompson H, Gershon S (1974) Clozapine — a potential antipsychotic agent without extrapyramidal manifestations. Curr Ther Res 16: 687–695
Meltzer HY, Matsubara S, Lee JC (1989) The ratios of serotonine2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol Bull 25: 390–392
Meltzer HY, Stahl SM (1976) The dopamine hypothesis of schizophrenia: a review. Schizophr Bull 2: 19–76
Richelson E (1984) Neuroleptic affinities for human brain receptors and their use in predicting adverse effects. J Clin Psychiatry 45: 331–336
Rupniak NMJ, Mann S, Hall MD, Fleminger S, Kilpatrick G, Jenner P, Marsden CD (1984) Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat. Psychopharmacology 84: 503–511
Rupniak NM, Hall MD, Mann S, Fleminger S, Kilpatrick G, Jenner P, Marsden CD (1985) Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat. Biochem Pharmacol 34: 2755–2763
Sedvall G (1990) PET imaging of dopamine receptors in human basal ganglia: relevance to mental illness. TINS 13: 302–308
Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1: 132–152
Simpson G, Varga E (1974) Clozapine — a new antipsychotic agent. Curr Ther Res 16: 679–686
Smith M, Wolf AP, Brodie JD, Arnett CD, Barouche F, Shiue CY, Fowler JS, Russel JAG, MacGregor RR, Wolkin A, Angrist B, Rotrosen J, Peselow E (1988) Serical (18F)N-ethylspiroperidol PET studies to measure changes in antipsychotic drug D-2 receptor occupancy in schizophrenic patients. Biol Psychiatry 23: 653–663
Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347: 146–151
Stahl SM, Wets KM (1988) Clinical pharmacology of schizophrenia. In: Bebbington P, McGuffin P (eds) Schizophrenia: the major issues. Heinemann Professional Publishing, Halleycourt Jordan Hill Oxford, pp 135–157
Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G (1991) Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature 350: 614–619
Van Tol HHM, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350: 610–614
Wagner HN, Burns HD, Dannals RF, Wong DF, Langstrom B, Duelfer T, Frost JJ, Ravert HT, Links JM, Rosenbloom SB, Lukas SE, Kramer AV, Kuhar MJ (1983) Imaging dopamine receptors in the human brain by positron emission tomography. Science 221: 1264–1266
White JF, Wang RY (1983) Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons. Science 221: 1054–1057
Wienhard K, Coenen HH, Pawlik G, Rudolf J, Laufer P, Jovkar S, Stöcklin G, Heiss WD (1990) PET studies of dopamine receptor distribution using (18F)fluoroethylspiperone: findings in disorders related to the dopaminergic system. J Neural Transm (Gen Sect) 81: 195–213
Wolkin A, Brodie JD, Barouche F, Rotrosen J (1989) Dopamine receptor occupancy and plasma haloperidol levels. Arch Gen Psychiatry 46: 482–483
Wong DF, Wagner HN, Tune LE, Dannals RF, Pearlson SD, Links JM, Tamminga CA, Broussolle EP, Ravert HT, Wilson AA, Toung JKT, Malat J, Williams JA, O'Tuama LA, Snyder SH, Kuhar MJ, Gjedde A (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234: 1558–1563
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Karbe, H., Wienhard, K., Hamacher, K. et al. Positron emission tomography with (18F)methylspiperone demonstrates D2 dopamine receptor binding differences of clozapine and haloperidol. J. Neural Transmission 86, 163–173 (1991). https://doi.org/10.1007/BF01250702
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01250702