The aim of this study was to compare the degree of striatal dopamine D2 receptor availability in patients treated with recommended (5–20 mg, mean dose 11.9 ± 6.3 mg daily) and higher doses (25–40 mg, mean 32.1 ± 5.6 mg daily) of the novel antipsychotic drug olanzapine by means of [123I] IBZM Single photon emission computed tomography (SPECT). The results were compared to those of a group of 10 untreated, healthy, age- and sex-matched controls. The degree of dopamine D2 receptor occupancy in the patient group was correlated with the presence of extrapyramidal symptoms (EPS). A total of 20 patients who met the DSM III R criteria for schizophrenia or schizoaffective disorder received a clinically effective antipsychotic monotherapy with olanzapine. The mean daily dose of olanzapine ranged from 0.05–0.6 mg/kg body weight. The dopamine D2 receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding expressed as the [STR-BKG]/BKG ratio ranged from 0.13–0.61 (healthy controls 0.95). The D2 receptor availability revealed an exponential dose–response relationship (r=–0.85, p< 0.001). The frequency of EPS induced by olanzapine was considerably lower. Only one patient, treated with 40 mg olanzapine, suffered from severe EPS symptoms and had to be given biperiden. There were no significant differences in the presence of EPS symptoms between patients with recommended doses and those with higher doses of olanzapine.
Barnes T, McPhillips M A (1999) Critical analysis and comparison of the side-effect and safety profiles of the new antipsychotics. Br J Psychiatry174 (Suppl. 38): 34–43
2.
Baron J C, Martinot J L, Cambon H, Boulenger J P, Poirier M F, Caillard V, Blin J, Hured J D, Loc'h C, Maziere B (1989) Stiatal dopamine receptor occupancy following withdrawl from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology99: 463–472
3.
Beasley C MJr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S (1996) Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology124: 159–167
4.
Broich K, Grünwald F, Kasper S, Biersack H J, Möller H J (1998) D2-dopamine receptor occupancy measured by IBZM-SPECT in relation to extrapyramidal side effects. Pharmacopsychiatry31: 159–162
5.
Brücke T, Roth J, Podreka I, Strobl R, Wenger S, Asenbaum S (1992) Striatal dopamine D2-receptor blockade by typical and atypical neuroleptics. Lancet339: 497-497
6.
Bymaster F P, Calligaro D O, Falcone J F, Marsh R D, Moore N A, Tye N C, Seeman P, Wong D T (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology14: 87–96
7.
Bymaster F P, Rasmussen K, Calligaro D O (1997) In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug. J Clin Psychiatry58 (Suppl. 10): 28–36
8.
Dresel S, Tatsch K, Dähne I, Mager T, Scherer J, Hahn K (1998) Iodine-123-iodobenzamide SPECT assessment of dopamine D2 receptor occupancy in risperidone-treated schizophrenic patients. J Nucl Med39: 1138–1142
9.
Dresel S, Mager T, Rossmüller B, Meisenzahl E, Hahn K, Möller H J, Tatsch K (1999) In vivo effects of olanzapine on striatal dopamine D2/D3 receptor binding in schizophrenic patients: an iodine-123-iodobenzamide single-photon emission tomography study. Eur J Nucl Med26: 862–868
10.
Farde L, Nordström A L, Wiesel F A, Pauli S, Halldin C, Sedvall G (1992) Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Arch Gen Psychiatry49: 538–544
11.
Janowsky A, Neve K A, Kinsie M J, Taylor B, de Paulis T, Belknap J (1992) Extrastriatal dopamine D2 receptors: distribution, pharmacological characterisation and region specific regulation by clozapine. J Pharmacol Exp Ther261: 1282–1290
12.
Kane J M (1987) Treatment of schizophrenia. Schizophr Bull13: 133–156
13.
Kane J M (1996) Schizophrenia. N Engl J Med334: 34–41
14.
Kapur S, Zipurski R, Roy P, Jones C, Remington G, Reed K, Houle S (1997) The relationship between D2 receptor occupancy and plama levels on low dose oral haloperidol: a PET study. Psychopharmacology131: 148–152
15.
Kapur S, Zipurski R B, Remington G, Jones C, DaSilva J, Wilson A A, Houle S (1998) 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry155: 921–928
16.
Kapur S, Zipursky R B, Remington G (1999) Clinical and theroretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone and olanzapine in schizophrenia. Am J Psychiatry156: 286–293
17.
Kasper S, Tauscher J, Küfferle B, Hesselmann B, Barnas C, Brücke T (1998) IBZM-SPECT imaging of dopamine D2 receptors with typical and atypical antipsychotics. Eur Psychiatry13 (Suppl. 1): 9S–14S
18.
Klemm E, Grünwald F, Kasper S, Menzel C, Broich K, Danos P, Reichmann K, Krappel C, Rieker O, Briele B, Hotze A L, Möller H J, Biersack H J (1996) 123I IBZM SPECT for Imaging of striatal D2 dopamine receptors in 56 schizophrenic patients taking various neuroleptics. Am J Psychiatry153: 183–190
19.
Lidow M S, Goldman-Rakic P S (1994) A common action of clozapine, haloperidol and remoxipride on D1- and D2-dopaminergic receptors in the primate cerebral cortex. Proc Acad Sci USA91: 4353–4356
20.
Meltzer H Y (1995) The concept of atypical antipsychotics. In den Boer J A, Westenberg H G M, van Praag H M (eds), Advances in the neurobiology of schizophrenia, vol. 1, pp. 265–273. Wiley & Sons, Chichester
21.
Nordström A L, Farde L, Wiesel F-A, Forslund K, Pauli S, Halldin C, Uppfeldt G (1993) Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry33: 227–235
22.
Nordström A L, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G (1995) D1, D2 and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry152: 1444–1449
23.
Nordstrom A L, Nyberg S, Olsson H, Farde L (1998) Positron emission tomography finding of a high striatal D2 receptor occupancy in olanzapine-treated patients. Arch Gen Psychiatry55: 283–284
24.
Nyberg S, Nakashima Y, Nordström A L, Halldin C, Farde L (1996) Positron emission tomography of in-vivo binding characteristics of atypical antipsychotic drugs. Reviews of D2 and 5HT2 receptor occupancy studies and clinical response. Br J Psychiatry168 (Suppl. 29): 40–44
25.
Nyberg S, Farde L, Halladin C (1997) A PET of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects. Neuropsychopharmacology16: 1–7
26.
Pilowsky L S, Costa D C, Ell P J (1992) Clozapine, single photon emission tomography and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet340: 199–202
27.
Pilowsky L S, Costa D C, Ell P J, Verhoeff N P, Murray R M, Kerwin R W (1994) D2 dopamine receptor binding in the basal ganglia of antipsychotic-free schizophrenic patients. An 1231-IBZM single photon emission computerised tomography study. Br J Psychiatary164: 16–26
28.
Pilowsky L S, Busatto G F, Taylor M, Costa D C, Sharma T, Sigmundsson T, Ell P J, Nohria V, Kerwin R W (1996) Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine – a 123I IBZM single photon emission tomography (SPECT) study. Psychopharmacology124: 148–153
29.
Remington G, Kapur S (1999) D2 and 5-HT2 receptor effects of antipsychotics: bridging basic and clinical findings using PET. J Clin Psychiatry60 (Suppl. 10): 10–19
30.
Scherer J, Tatsch K, Schwarz J, Oertel W H, Konjarczyk M, Albus M (1994a) D2-dopamine receptor occupancy differs between patients with and without extrapyramidal side effects. Acta Psychiatr Scand90: 266–268
31.
Scherer J, Tatsch K, Schwarz J, Oertel W, Kirsch M C, Albus M (1994b) Striatal D2-dopamine receptor occupancy during treatment with typical and atypical neuroleptics. Biol Psychiatry36: 627–629
32.
Sheitman B B, Lindgren J C, Early J, Sved M (1997) High-dose olanzapine for treatment-refractory schizophrenia (letter). Am J Psychiatry154: 1626-1626
33.
Seeman P, Van Tol H H (1995) Deriving the therapeutic concentrations for clozapine and haloperidol: the apparent dissociation constant of a neuroleptic at the D2 or D4 receptor varies with the affinity of the competing radioligand. Eur J Phramacol291: 59–66
34.
Seeman P, Tallerico T (1998) Antipsychotic drugs which elict little or no parkinsonism bind more looseley than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry3: 123–134
35.
Tatsch K, Schwarz J, Oertel W H, Kirsh, C M (1992) Dopamine D2 receptor imaging with 123I IBZM SPECT to differentiate idiopathic parkinson syndroms. J Nuclear Med33: 917–918
36.
Tauscher J, Küfferle B, Asenbaum S, Brücke T, Kasper S (1997) Previous treatment as a confounding variable in studies with novel antipsychotics: two cases of high dopamine-2 receptor occupancy with quetiapine. Psychopharmacology133: 102–105
37.
Tauscher J, Küfferle B, Asenbaum S, Fischer P, Pezawas L, Barnas C, Tauscher-Wisniewski S, Brücke T, Kasper S (1999) In vivo 123I IBZM SPECT imaging of striatal dopamine-2 receptor occupancy in schizophrenic patients treated with olanzapine in comparison to clozapine and haloperidol. Psychopharmacol141: 175–181
38.
Tollefson G D, Sanger T M (1997a) Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry154: 466–474
39.
Tollefson G D, Beasley C M, Tran P V, Street J S, Krueger J A, Tamura R N, Graffeo K A, Thieme M E (1997b) Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry154: 457–465
40.
Tran P V, Dellva M A, Tollefson G D, Beasley C M Jr, Potvin J H, Kiesler G M (1997) Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia [published erratum appears in J Clin Psychiatry (1997) 58: 275]. J Clin Psychiatry58: 205–211
