Evidence of the dual mechanisms of action of venlafaxine

Background: Indirect evidence suggests that the anti-depressant venlafaxine hydrochloride selectively inhibits serotonin (5-MT) 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 presser 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 presser 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 presser response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine. Conclusion: 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.