title: Saturation of striatal D(2) dopamine receptors by clozapine.
abstract: Positron emission tomography (PET) studies have demonstrated low striatal D2 dopamine receptor occupancy in clozapine-treated schizophrenic patients. The aim of this pilot study was to explore if this low receptor occupancy indeed represents partial saturability of striatal D2 dopamine receptors by clozapine. Three anaesthetized Cynomolgus monkeys were examined during one day with PET and [11C]raclopride at baseline and after intravenous injections of clozapine 1.5 mg/kg followed by 18.5 mg/kg. The estimated corresponding human oral doses were approx. 210 mg/d and 2800 mg/d. D2 dopamine receptor occupancy was calculated using an equilibrium-ratio analysis and ranged from 54 to 58% after 1.5 mg/kg and 87 to 89% after the total dose 20 mg/kg. The calculated maximal occupancy was 93%. We conclude that PET-measured D2 dopamine receptor occupancy by clozapine can be described using a model based on the law of mass action, previously validated for conventional antipsychotics. Therefore, sufficiently high doses of clozapine are expected to produce complete striatal D2 dopamine receptor occupancy. The findings further support our previous findings of low D2 dopamine receptor occupancy in patients treated with standard doses of clozapine.
authors.affiliation: Karolinska Institute, Department of Clinical Neuroscience, Stockholm, Sweden. svante.nyberg@cns.ki.se
authors.forename: Svante
authors.initials: S
authors.lastname: Nyberg
authors.forename: Yuan-Hwa
authors.initials: YH
authors.lastname: Chou
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000465:Algorithms; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D003024:Clozapine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D010865:Pilot Projects; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D014055:Tomography, Emission-Computed
chemical_list: D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D003024:Clozapine