Venlafaxine is a dual inhibitor of serotonin (5-HT) and norepinephrine reuptake. The precise dosage at which it begins to efficiently activate the norepinephrine transporter (NET) was unknown. Paroxetine is classified as a selective 5-HT reuptake inhibitor, however it also had modest affinity for NET. Atomoxetine is a NET inhibitor with a little affinity for the 5-HT reuptake transporter (SERT). Potency of Antidepressants to inhibit Serotonin & Norepinephrine Reuptake.

In this trial, 32 patients with major depressive illness were subjected to a forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d. The inhibition of SERT was calculated by depleting whole-blood 5-HT. The reduction of systolic blood pressure caused by intravenous tyramine injections was used to measure NET inhibition. At the start of the study, all three drugs considerably lowered 5-HT levels: venlafaxine and paroxetine by around 60% and atomoxetine by 16%, respectively. The three successive venlafaxine and paroxetine regimens lowered 5-HT levels by more than 90%, whereas the highest dosage of atomoxetine only achieved a 40% reduction. Atomoxetine decreased the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine had no effect.

The findings demonstrated that venlafaxine and paroxetine were both effective SERT inhibitors across their typical therapeutic ranges, however venlafaxine only begins blocking NET at 225 mg/d, and paroxetine stays selective for SERT up to 50 mg/d. Atomoxetine inhibits NET from a low dosage but does not inhibit SERT to a clinically significant level.