title: Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel) in patients with schizophrenia.
abstract: Quetiapine (Seroquel) is a novel antipsychotic with an atypical profile in animal models and a relatively short plasma half-life of 2.5 5 h. In the present study, we used PET to compare the time course of blockade of dopamine D2 and serotonin 5HT2 receptors of quetiapine using C11-raclopride and C11-N-methyl-spiperone as ligands, parallel to monitoring plasma drug concentrations. It was an open study in 11 schizophrenic men using a fixed dose of 450 mg quetiapine. Eight men completed the 29 days treatment, followed by four PET scans performed over a 26-h period after withdrawal of the compound. Quetiapine was shown to bind to dopamine D2 receptors in striatum and 2 h (t[max]) after the last dose, 44% receptor occupancy was calculated. After 26 h it had dropped to the same level as was found in untreated healthy volunteers. Serotonin 5HT2 receptor blockade in the frontal cortex was 72% after 2 h, which declined to 50% after 26 h. The terminal plasma half-life of quetiapine was 5.3 h. Clinically, our eight patients had good antipsychotic effect without any extrapyramidal side-effects. Our data shows that quetiapine has a relatively low affinity for dopamine D2 receptors, with an occupancy half-life (10 h), which was about twice as long as that for plasma. A more prolonged blockade of the serotonin 5HT2 receptors was found in the frontal cortex, with receptor occupancy half-life of 27 h. Compared to clozapine, as demonstrated in other studies, quetiapine has much the same ratio of D2/5HT2 occupancy. This could suggest that the combination of D2/5HT2 receptor blockade contributes to the antipsychotic effect and a low incidence of EPS seen with quetiapine in comparative phase three trials. Our results also confirm the clinical data that quetiapine can be administered twice daily.
authors.affiliation: Psychiatric Research Unit, Västerås Central Hospital, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Gefvert
authors.forename: M
authors.initials: M
authors.lastname: Bergström
authors.forename: B
authors.initials: B
authors.lastname: Långström
authors.forename: T
authors.initials: T
authors.lastname: Lundberg
authors.forename: L
authors.initials: L
authors.lastname: Lindström
authors.forename: R
authors.initials: R
authors.lastname: Yates
mesh_terms: D000328:Adult; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003987:Dibenzothiazepines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D000069348:Quetiapine Fumarate; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012457:Salicylamides; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D003987:Dibenzothiazepines; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012457:Salicylamides; D000069348:Quetiapine Fumarate; D020891:Raclopride