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

Ahmed T Ahmed; Joanna M Biernacka; Gregory Jenkins; A John Rush; Gen Shinozaki; Marin Veldic; Simon Kung; William V Bobo; Daniel K Hall-Flavin; Richard M Weinshilboum; Liewei Wang; Mark A Frye

doi:10.1016/j.jad.2018.12.021

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

Journal article

Peer reviewed

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

Ahmed T Ahmed, Joanna M Biernacka, Gregory Jenkins, A John Rush, Gen Shinozaki, Marin Veldic, Simon Kung, William V Bobo, Daniel K Hall-Flavin, Richard M Weinshilboum, …

Journal of affective disorders, Vol.246, pp.62-68

03/01/2019

DOI: 10.1016/j.jad.2018.12.021

PMCID: PMC6501809

PMID: 30578947

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https://www.ncbi.nlm.nih.gov/pmc/articles/6501809View

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Abstract

•This study highlights the association between prospectively confirmed SNRI treatment remission and genetic polymorphisms in CYP2D6, CYP2C19, SLC6A4, and SLC6A2 in MDD patients with prospectively confirmed prior SSRI treatment failure.•Pharmacokinetic and Pharmacodynamic interaction is associated with venlafaxine-XR treatment remission.•These results underscore the multidimensional aspects of precision medicine as an approach to optimize drug treatment of MDD. 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. 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). 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. The primary limitation of this post hoc study was small sample size. 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.

Pharmacodynamic-pharmacokinetic interaction

Remission

Venlafaxine-XR

CYP2D6

SLC6A2

SLC6A4

Details

Title: Subtitle: Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure
Creators: Ahmed T Ahmed - Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, United States
Joanna M Biernacka - Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
Gregory Jenkins - Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
A John Rush - Duke-National University of Singapore, Singapore
Gen Shinozaki - Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
Marin Veldic - Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, United States
Simon Kung - Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, United States
William V Bobo - Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa, United States
Daniel K Hall-Flavin - Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, United States
Richard M Weinshilboum - Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
Liewei Wang - Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
Mark A Frye - Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, United States
Resource Type: Journal article
Publication Details: Journal of affective disorders, Vol.246, pp.62-68
DOI: 10.1016/j.jad.2018.12.021
PMID: 30578947
PMCID: PMC6501809
NLM abbreviation: J Affect Disord
ISSN: 0165-0327
eISSN: 1573-2517
Publisher: Elsevier B.V
Grant note: DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: T32 GM008685; DOI: 10.13039/100000002, name: NIH, award: U19 GM61388, U54 GM114838, NSF164615; DOI: 10.13039/100000002, name: NIH, award: RO1 GM28157, U19 GM61388, U54 GM114838, NSF1624615; DOI: 10.13039/100000002, name: NIH, award: K23 MH107654, NSF 1, 664, 364, UL1 TR000135; DOI: 10.13039/100006108, name: National Center for Advancing Translational Sciences; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: T32 GM008685; DOI: 10.13039/100000002, name: NIH, award: U19 GM61388; DOI: 10.13039/100000002, name: NIH, award: U19 GM61388; DOI: 10.13039/100000002, name: NIH, award: RO1 GM28157
Language: English
Date published: 03/01/2019
Academic Unit: Psychiatry; Iowa Neuroscience Institute; Anesthesia; Neurosurgery
Record Identifier: 9984003452902771

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