@article{d8ad46bae673483d991fe26c6a691e9a,
title = "Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure",
abstract = " 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-C 16 ). 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. ",
keywords = "CYP2D6, Pharmacodynamic-pharmacokinetic interaction, Remission, SLC6A2, SLC6A4, Venlafaxine-XR",
author = "Ahmed, {Ahmed T.} and Biernacka, {Joanna M.} and Gregory Jenkins and Rush, {A. John} and Gen Shinozaki and Marin Veldic and Simon Kung and Bobo, {William V.} and Hall-Flavin, {Daniel K.} and Weinshilboum, {Richard M.} and Liewei Wang and Frye, {Mark A.}",
note = "Funding Information: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding: Dr Ahmed Research reported in this publication was supported by National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685 . Funding Information: Dr. Frye has received grant support from AssureRx Health Inc, Myriad, Pfizer Inc, NIMH (R01 MH079261), the National Institute on Alcohol Abuse and Alcoholism (P20AA017830) in the National Institutes of Health at the US Department of Health and Human Services, and the Mayo Foundation. He has been a consultant (for Mayo) to Janssen Global Services, LLC; Mitsubishi Tanabe Pharma Corp; Myriad Genetics, Inc; Sunovion Pharmaceuticals, Inc; and Teva Pharmaceutical Industries Ltd. He has received continuing medical education, travel, and presentation support from American Physician Institute and CME Outfitters. Funding Information: Dr. Liewei Wang was supported by NIH grants U19 GM61388 , U54 GM114838 and NSF164615 . Dr. Wang is a cofounder and stockholder in OneOme. Funding Information: Dr. Weinshilboum was supported by NIH grants RO1 GM28157 , U19 GM61388 , U54 GM114838 and NSF1624615 . Dr. Weinshilboum is a cofounder and stockholder in OneOme. Funding Information: Dr. Gen Shinozaki is supported by NIH grant K23 MH107654 , and NSF 1,664,364 . Dr. Shinozaki is a cofounder and president of Predelix Medical LLC. Funding Information: The authors of this paper would like to recognize the vision and original contributions to this research of the late Dr. David Mrazek. This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCAT) as part of Ahmed T Ahmed master's degree thesis. ",
year = "2019",
month = mar,
day = "1",
doi = "10.1016/j.jad.2018.12.021",
language = "English (US)",
volume = "246",
pages = "62--68",
journal = "Journal of Affective Disorders",
issn = "0165-0327",
publisher = "Elsevier",
}