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 D Veldic, Simon Kung, William V Bobo, Daniel K. Hall-Flavin, Richard M Weinshilboum, Liewei M Wang, Mark A Frye

Research output: Contribution to journalArticle

3 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)62-68
Number of pages7
JournalJournal of Affective Disorders
Volume246
DOIs
StatePublished - Mar 1 2019

Fingerprint

Citalopram
Major Depressive Disorder
Cytochrome P-450 CYP2D6
Treatment Failure
Pharmacokinetics
Genotype
Serotonin Uptake Inhibitors
Therapeutics
Depression
Phenotype
Pharmacogenetics
Sample Size
Antidepressive Agents
Venlafaxine Hydrochloride
Logistic Models
Equipment and Supplies
Research

Keywords

  • CYP2D6
  • Pharmacodynamic-pharmacokinetic interaction
  • Remission
  • SLC6A2
  • SLC6A4
  • Venlafaxine-XR

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health

Cite this

@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-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.",
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 Veldic, {Marin D} and Simon Kung and Bobo, {William V} and Hall-Flavin, {Daniel K.} and Weinshilboum, {Richard M} and Wang, {Liewei M} and Frye, {Mark A}",
year = "2019",
month = "3",
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",

}

TY - JOUR

T1 - Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure

AU - Ahmed, Ahmed T.

AU - Biernacka, Joanna M

AU - Jenkins, Gregory

AU - Rush, A. John

AU - Shinozaki, Gen

AU - Veldic, Marin D

AU - Kung, Simon

AU - Bobo, William V

AU - Hall-Flavin, Daniel K.

AU - Weinshilboum, Richard M

AU - Wang, Liewei M

AU - Frye, Mark A

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

KW - CYP2D6

KW - Pharmacodynamic-pharmacokinetic interaction

KW - Remission

KW - SLC6A2

KW - SLC6A4

KW - Venlafaxine-XR

UR - http://www.scopus.com/inward/record.url?scp=85058654979&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058654979&partnerID=8YFLogxK

U2 - 10.1016/j.jad.2018.12.021

DO - 10.1016/j.jad.2018.12.021

M3 - Article

C2 - 30578947

AN - SCOPUS:85058654979

VL - 246

SP - 62

EP - 68

JO - Journal of Affective Disorders

JF - Journal of Affective Disorders

SN - 0165-0327

ER -