Paroxetine and venlafaxine are potent serotonin transporter (SERT) antagonists 
and weaker norepinephrine transporter (NET) antagonists. However, the relative 
magnitude of effect at each of these sites during treatment is unknown. Using a 
novel blood assay that estimates CNS transporter occupancy we estimated the 
relative SERT and NET occupancy of paroxetine and venlafaxine in human subjects 
to assess the relative magnitude of SERT and NET inhibition. Outpatient subjects 
(N=86) meeting criteria for major depression were enrolled in a multicenter, 8 
week, randomized, double-blind, parallel group, antidepressant treatment study. 
Subjects were treated by forced-titration of paroxetine CR (12.5-75 mg/day) or 
venlafaxine XR (75-375 mg/day) over 8 weeks. Blood samples were collected weekly 
to estimate transporter inhibition. Both medications produced dose-dependent 
inhibition of the SERT and NET. Maximal SERT inhibition at week 8 for paroxetine 
and venlafaxine was 90% (SD 7) and 85% (SD 10), respectively. Maximal NET 
inhibition for paroxetine and venlafaxine at week 8 was 36% (SD 19) and 60% (SD 
13), respectively. The adjusted mean change from baseline (mean 28.6) at week 8 
LOCF in MADRS total score was -16.7 (SE 8.59) and -17.3 (SE 8.99) for the 
paroxetine and venlafaxine-treated patients, respectively. The magnitudes of the 
antidepressant effects were not significantly different from each other (95%CI 
-3.42, 4.54, p=0.784). The results clearly demonstrate that paroxetine and 
venlafaxine are potent SERT antagonists and less potent NET antagonists in vivo. 
NET antagonism has been posited to contribute to the antidepressant effects of 
these compounds. The clinical significance of the magnitude of NET antagonism by 
both medications remains unclear at present.