TIME-COURSE OF CENTRAL NERVOUS DOPAMINE-D-2 AND 5-HT2 RECEPTOR BLOCKADE AND PLASMA DRUG CONCENTRATIONS AFTER DISCONTINUATION OF QUETIAPINE (SEROQUEL(R)) IN PATIENTS WITH SCHIZOPHRENIA

Quetiapine (Seroquel) is a novel antipsychotic with an atypical profil e 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 block ade of dopamine D-2 and serotonin 5HT(2) receptors of quetiapine using C-11-raclopride and C-11-N-methyl-spiperone as ligands, parallel to m onitoring plasma drug concentrations. It was an open study in 11 schiz ophrenic men using a fixed dose of 450 mg quetiapine. Eight men comple ted 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 D-2 receptors in striatum and 2 h (t(max)) after the last dose, 44% receptor occupancy was calculated. After 26 h it had d ropped to the same level as was found in untreated healthy volunteers. Serotonin 5HT(2) receptor blockade in the frontal cortex was 72% afte r 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 anti psychotic effect without any extrapyramidal side-effects. Out-data sho ws that quetiapine has a relatively low affinity for dopamine D-2 rece ptors, with an occupancy half-life (10 h), which was about twice as lo ng as that for plasma. A more prolonged blockade of the serotonin 5HT( 2) receptors was found in the frontal cortex, with receptor occupancy half-life of 27 h. Compared to clozapine as demonstrated in other stud ies, quetiapine has much the same ratio of D-2/5HT(2) occupancy. This could suggest that the combination of D-2/5HT(2) receptor blockade con tributes to the antipsychotic effect and a low incidence of EPS seen w ith quetiapine in comparative phase three trials. Our results also con firm the clinical data that quetiapine ran be administered twice daily .