Venlafaxine Efficacy Varies With CYP2D6 Phenotype in Patients Treated for Depression

Kasia Lobello, MD; Christine Guico-Pabia, MD, MPH, MBA; Qin Jiang, MS; Alice Nichols, PhD; and Sheldon Preskorn, MD
Wyeth Research, Collegeville, Pennsylvania (Drs Lobello, Guico-Pabia, and Nichols, and Mr Jiang), and Clinical Research Institute, Wichita, Kansas (Dr Preskorn)

This poster presentation was supported by Wyeth Research.

Background: Venlafaxine (VEN) is primarily metabolized by CYP2D6 into O-desmethylvenlafaxine (ODV). Individuals can be broadly classified as poor metabolizers (PMs) or extensive metabolizers (EMs) based on CYP2D6 activity. This analysis evaluates using plasma ODV to VEN ratio (ODV/VEN) following VEN administration to determine CYP2D6 metabolizer phenotype, and examines the relative efficacy of VEN in patients with major depressive disorder (MDD) classified as EMs versus PMs based on ODV/VEN.

Methods: The relationship between ODV/VEN and CYP2D6 metabolizer status was assessed using data from two studies: in one, 13 healthy adults were genotyped as EMs or PMs; in the second, 15 healthy adults were phenotyped based on dextromethorphan metabolism. Participants were administered VEN (75–150 mg/d), blood samples were taken (30 min–120 hr after administration), and plasma ODV/VEN was calculated for each time point to generate decision rules for distinguishing EMs from PMs. Using these rules, data from four other double-blind, placebo-controlled efficacy studies of patients with MDD were pooled to assess VEN efficacy in EMs and PMs versus placebo. In those studies, blood samples were taken; plasma concentrations of VEN and ODV were determined in order to calculate ODV/VEN. Depression rating scale scores and remission rates (17-item Hamilton Rating Scale for Depression [HAMD-17] score =7) were compared for EMs and PMs, classified based on ODV/VEN, versus placebo using T-tests and the Fisher exact test, respectively.

Results: In all healthy individuals previously genotyped or phenotyped as EMs (n=15), ODV/VEN was >1 and ODV/VEN was =1 for all PMs (n=13) from four hours after dosing. VEN-treated MDD patients, both EMs (n=415) and PMs (n=49), had significantly improved depression rating scale scores compared with placebo-treated patients (n=372; p=0.04). Compared with PMs, VEN-treated EMs had significantly greater change from baseline on four of five depression rating scales (p=0.020). For EMs, but not PMs, remission rate (EM, 41.4%; PM, 28.6%; placebo, 20.8%) and distribution of percent improvement in HAMD-17 scores (post-hoc analysis using Cochran-Mantel-Haenszel test) were significantly different from placebo (p<0.001). Discontinuation rates did not differ significantly between EMs and PMs.

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

References
Hermann M, Hendset M, Fosaas K, et al. Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4, or *5 allele. Eur J Clin Pharmacol. 2008;64(5):483–487.

Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit. 2000;22(2):202–208.

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