Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects

Duloxetine is a dual inhibitor of norepinephrine (NE) and serotonin (5-MT) uptake. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidep ressant. Tile aim of this study was to assess thr effects of duloxetine on the 5-HT arm NE reuptake processes in healthy human volunteers. Twenty-seve n healthy young males without a history of psychiatric disorder were random ly assigned to four groups, each group receiving one of the following daily drug regimens: placebo, clomipramine (a potent 5-HT/NE reuptake blocker) 1 00 mg/day, duloxetine 20 mg/day, or duloxetine 60 mg/day. In order to asses s tile NE reuptake process, the pressor response to intravenous tyramine (4 and 6 mg) teas measured. Determination of the whole blood 5-HT con tent se as used to evaluate the 5-HT reuptake blockade. These measurements were per formed at baseline and repeated after 7 and 14 days of drug intake. Both du loxetine, at doses of 20 to 60 mg/day, and clomipramine significantly inter fered with the 5-HT reuptake process, as demonstrated by marked decreases i n blood 5-HT concentrations. However, tile same doses of duloxetine, unlike clomipramine,failed to impede the usual increase in blood pressure that fo llows a tyramine intravenous infusion, indicating that clomipramine but not duloxetine blocked NE reuptake. At doses tested in a population of healthy volunteers, duloxetine acted as a selective 5-HT reuptake inhibitor, havin g no clear effect on tile NE reuptake process. Nevertheless, given that the highest dose of duloxetine increased supine systolic blood pressure, it is possible that if represents the threshold regimen for NE reuptake inhibiti on. (C) 2001 American College of Neuropsychopharmacology. Published by Else vier Science Inc.