Effexor Confusion in the healthy vs. depressed

I've always seen effexor as a controversial drug. With chemical and pharmacological properties distinct from the SSRI's, there's no doubt that it's effective. Much of the research even demonstrates that it's more effective and faster acting than many other antidepressants. However, a foggy mechanism of action and withdrawal complications have surrounded effexor with a sketchy veil.

Perhaps the biggest controversy regarding Effexor's mechanism of action is its capability to inhibit norepinephrine re-uptake. There's quite a gap in effexor's affinity for the serotonin and norepinephrine re-uptake pump, so its been commonly believed that its norepineprhine action doesn't kick in until the higher dosages. Clinically, most psychiatrists agree with this assessment, citing increased clinical responses as the dose gets above 150mg. Rat studies seem to support effexor's ability to inhibit NE uptake at higher dosages, but the human studies have been lacking.

Just recently a group at McGill published two seperate studies, one on healthy individuals and one on depressed individuals. In depressed individuals, doses of effexor above 225mg showed clear NE uptake inhibition by means of the tyramine pressor test. But in normal individuals, neither a 150mg nor a 300mg dose demonstrated NE uptake inhibition. On the other hand, the relatively selective NE uptake inhibitor desipramine had potent effects in healthy individuals.

So what's going on? Why can high doses of effexor act as an NE re-uptake inhibitor in depressed but not in healthy individuals? Does it have to do with actual physical differences/genetic differences in the NE transporter? Could it have to do with the testing method used and differential blood pressure regulation in the healthy vs. depressed?

Perhaps only time will tell. Until then, the nature of effexor remains quite curious.
Pubmed references: 16690005 and 16690006