A dose-finding study of duloxetine based on serotonin transporter occupancy

Rationale: Positron emission tomography (PET) has been utilized for determining the dosage of antipsychotic drugs. To evaluate the dosage of antidepressants such as selective serotonin reuptake inhibitors, serotonin transporter occupancy (5-HTT) is also a useful index. Objectives: We investigated the degree of 5-HTT occupancy with different doses of the antidepressant duloxetine and the time-course of 5-HTT occupancy using PET. Methods: PET scans with [C-11]DASB were performed before and after a single administration of duloxetine (5-60 mg), and three consecutive scans were performed after a single dose or repeated doses of 60 mg of duloxetine. Results: 5-HTT occupancies by duloxetine were increased by 35.3 to 86.5% with dose and plasma concentration increments. The ED50 value of 5-HTT occupancy was 7.9 mg for dose and 3.7 ng/ml for plasma concentration. In the time-course of 5-HTT occupancy, mean occupancies were 81.8% at 6 h, 71.9% at 25 h, and 44.9% at 53 h after a single administration, and 84.3% at 6 h, 71.9% at 49 h, and 47.1% at 78 h after repeated administrations. Conclusions: Based on 5-HTT occupancy, 40 mg and more of duloxetine was needed to attain 80% occupancy, and 60 mg of duloxetine could maintain a high level of 5-HTT occupancy with a once-a-day administration schedule.