Evidence of the Dual Mechanisms of Action of Venlafaxine

Abstract

VENLAFAXINE hydrochloride¹ is an antidepressant with a mechanism of action that is believed to involve inhibition of the uptake pumps for serotonin (5-HT) and norepinephrine (NE)² with inhibition of NE uptake particularly relevant at higher doses. Preclinically, noradrenergic neurons had a biphasic dose-dependent response to venlafaxine,² and high doses caused rapid desensitization of β-adrenergic receptors,³ reminiscent of that achieved when a selective serotonin reuptake inhibitor (SSRI) is combined with desipramine hydrochloride.⁴ Clinically, venlafaxine hydrochloride, 375 mg/d led to a more rapid onset of antidepressant efficacy than did 75 mg/d.⁵ Furthermore, venlafaxine has an ascending dose–antidepressant response curve⁶ inconsistent with a single, saturable mechanism of action. Finally, the adverse effect profile of venlafaxine hydrochloride at 75 mg/d is typical of an SSRI (nausea, vomiting, gastrointestinal disturbances, and sexual dysfunction), but at higher doses, patients also experience effects similar to those of an NE uptake inhibitor (increased sweating, dry mouth, increased heart rate, and increased blood pressure). Although this pharmacological profile is consistent with the putative dual mechanisms of action of venlafaxine, this characteristic has not been directly examined in humans. Evidence that both mechanisms contribute to the action of venlafaxine would support short-term 5-HT and NE potentiation as separate routes to antidepressant efficacy.