Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure

Background: The purpose of this study was to identify specific pharmacokinetic (PK) and pharmacodynamics (PD) factors that affect the likelihood of treatment remission with a serotonin norepinephrine reuptake inhibitor (SNRI) in depressed patients whose initial selective serotonin reuptake inhibitor (SSRI) failed. Methods: Multiple logistic regression modeling of PK and PD variation hypothesized to contribute to SNRI (i.e. duloxetine or venlafaxine) treatment remission in prior SSRI (i.e. citalopram or escitalopram) failure was conducted on 139 subjects from the Pharmacogenomics Research Network (PGRN) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies. Depressive symptoms were assessed with the Quick Inventory of Depressive Symptomatology Clinician-rated (QIDS-C₁₆). Results: Venlafaxine-XR remission was associated with a significant interaction between CYP2D6 ultra-rapid metabolizer (URM) phenotype and SLC6A4 5-HTTLPR L/L genotype. A similar significant interaction effect was observed between CYP2D6 URM and SLC6A2 G1287A GA genotype. Stratifying by transporter genotypes, venlafaxine-XR remission was associated with CYP2D6 URM in patients with SLC6A4 L/L (p = 0.001) and SLC6A2 G1287A GA genotypes. Limitations: The primary limitation of this post hoc study was small sample size. Conclusion: Our results suggest that CYP2D6 ultra-rapid metabolizer status contributes to venlafaxine-XR treatment remission in MDD patients; in particular, there is a PK-PD interaction with treatment remission associated with CYP2D6 URM phenotype and SLC6A4 5-HTTLPR L/L or SLC6A2 G1287A G/A genotype, respectively. These preliminary data are encouraging and support larger pharmacogenomics studies differentiating treatment response to mechanistically different antidepressants in addition to further PK-PD interactive analyses.