Evidence of the dual mechanisms of action of venlafaxine.
BACKGROUND
Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake.


METHODS
Healthy male volunteers aged 18 to 45 years received either 75 mg or 375 mg of venlafaxine hydrochloride per day, the 5-HT uptake inhibitor sertraline hydrochloride (50 mg/d), or the NE uptake inhibitor maprotiline hydrochloride (150 mg/d) (n = 8 for each of 4 treatment groups). Changes in platelet 5-HT uptake and the pressor response to intravenous tyramine were assessed following the initial dose and after 1 and 2 weeks of drug administration.


RESULTS
Platelet 5-HT uptake was inhibited by venlafaxine across the dose range and by sertraline but not maprotiline. Inhibition was competitive, related to increases in affinity and not related to capacity. Steady-state drug levels were associated with a 5-HT uptake inhibition of 87% or more in subjects taking venlafaxine or sertraline. The pressor response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine.


CONCLUSIONS
This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.
Harvey
A T
AT
Psychiatric Research Institute and the Department of Psychiatry, University of Kansas School of Medicine, Wichita 67214-2878, USA. aharvey@kumc.edu
Rudolph
R L
RL
Preskorn
S H
SH
D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003511:Cyclohexanols / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008376:Maprotiline / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D020280:Sertraline / Q000493:pharmacokinetics / Q000494:pharmacology; D013599:Systole / Q000187:drug effects; D014439:Tyramine / Q000008:administration & dosage / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride
D018759:Adrenergic Uptake Inhibitors; D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D008376:Maprotiline; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D014439:Tyramine; D000069470:Venlafaxine Hydrochloride