title: Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study.
abstract: Selective action at limbic cortical dopamine D2-like receptors is a putative mechanism of atypical antipsychotic efficacy with few extrapyramidal side effects. Although risperidone is an atypical antipsychotic with high affinity for D2 receptors, low-dose risperidone treatment is effective without inducing extrapyramidal symptoms. The objective was to test the hypothesis that treatment with low-dose risperidone results in 'limbic selective' D2/D3 receptor blockade in vivo. Dynamic single photon emission tomography (SPET) sequences were obtained over 5 hours after injection of [123I]-epidepride (approximately 150 MBq), using a high-resolution triple-headed brain scanner (Marconi Prism 3000XP). Kinetic modelling was performed using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a normal volunteer control group (n = 5). Six patients treated with low-dose risperidone (mean = 2.6 mg) showed moderate levels of D2/D3 occupancy in striatum (49.9%), but higher levels of D2/D3 occupancy in thalamus (70.8%) and temporal cortex (75.2%). Occupancy values in striatum were significantly different from thalamus (F (1,4) = 26.3, p < 0.01) and from temporal cortex (F (1,4) = 53.4, p < 0.01). This is the first study to evaluate striatal and extrastriatal occupancy of risperidone. Low dose treatment with risperidone achieves a similar selectivity of limbic cortical over striatal D2/D3 receptor blockade to that of atypical antipsychotics with lower D2/D3 affinity such as clozapine, olanzapine and quetiapine. This finding is consistent with the relevance of 'limbic selective' D2/D3 receptor occupancy to the therapeutic efficacy of atypical antipsychotic drugs.
authors.affiliation: Section of Neurochemical Imaging, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, UK. r.bressan@iop.kcl.ac.uk
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Bressan
authors.forename: Kjell
authors.initials: K
authors.lastname: Erlandsson
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Jones
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Mulligan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ell
authors.forename: Lyn S
authors.initials: LS
authors.lastname: Pilowsky
mesh_terms: D000328:Adult; D000465:Algorithms; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008032:Limbic System / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008297:Male; D011759:Pyrrolidines / Q000138:chemical synthesis; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D018967:Risperidone / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; C493593:DRD3 protein, human; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C063525:epidepride; D018967:Risperidone