title: The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia.
abstract: Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p<0.005). While the maximum attainable receptor occupancy Emax approached 100% both in the striatum and cortex, the plasma concentration at 50% of Emax (ED50) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D2/D3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.
authors.affiliation: Department of Psychiatry, University of Mainz, Mainz, Germany. ggruender@ukaachen.de
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
authors.forename: Christian
authors.initials: C
authors.lastname: Landvogt
authors.forename: Ingo
authors.initials: I
authors.lastname: Vernaleken
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Buchholz
authors.forename: Jasmin
authors.initials: J
authors.lastname: Ondracek
authors.forename: Thomas
authors.initials: T
authors.lastname: Siessmeier
authors.forename: Sebastian
authors.initials: S
authors.lastname: Härtter
authors.forename: Mathias
authors.initials: M
authors.lastname: Schreckenberger
authors.forename: Peter
authors.initials: P
authors.lastname: Stoeter
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000494:pharmacology; D001549:Benzamides; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D003024:Clozapine / Q000097:blood* / Q000494:pharmacology; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011759:Pyrrolidines; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D013702:Temporal Lobe / Q000187:drug effects / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D003024:Clozapine; D004298:Dopamine