Cytochrome P450 2D6 Phenotype Predicts Antidepressant Efficacy of Venlafaxine: A Secondary Analysis of 4 Studies in Major Depressive Disorder

Introduction: Venlafaxine, a serotonin-norepinephrine reuptake inhibitor antidepressant, is metabolized primarily by the cytochrome P450 2D6 enzyme into O-desmethylvenlafaxine (ODV). The ODV/venlafaxine ratio can be used to distinguish between extensive metabolizers (EMs) and poor metabolizers (PMs).

Objectives: To determine the relative efficacy and tolerability of venlafaxine in EM vs PM patients with major depressive disorder (MDD).

Method: Data from 4 double-blind, placebo-controlled studies of patients with MDD were pooled. Blood samples were analyzed for plasma concentrations of venlafaxine, ODV, total venlafaxine‘ ‰+‘ ‰ODV, and ODV/venlafaxine ratio. Patients were classified as EMs or PMs on the basis of ODV/venlafaxine ratios. Changes from baseline in depression scale scores were compared between EMs and PMs using t tests. Rates of response, remission, discontinuation, and adverse events (AEs) were compared for EMs and PMs using Fisher exact tests.

Results: Compared with PMs, EMs had significantly greater mean changes from baseline on 4 of 5 depression rating scales (all 4 comparisons, P‘ ‰≤‘ ‰.020). A significantly greater percentage of EMs achieved response or remission by most measures compared with PMs (4 of 5 comparisons, P‘ ‰≤‘ ‰.015). Rates of discontinuation and AEs did not differ significantly between EMs and PMs. Since there were no substantial differences between EMs and PMs in terms of venlafaxine dose or tolerability, these factors are not likely to account for the efficacy findings.

Conclusions: Venlafaxine treatment in EMs was associated with greater efficacy in MDD on virtually all measures compared with PMs, with no important tolerability differences.

J Clin Psychiatry

Submitted: October 3, 2008; accepted June 10, 2009.

Online ahead of print: April 6, 2010 (doi:10.4088/JCP.08m04773blu).

Corresponding author: Kasia W. Lobello, MD, Neuroscience, Global Medical Affairs, Wyeth Pharmaceuticals, 500 Arcola Rd, Collegeville, PA 19426 (kasia.lobello@pfizer.com).