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Abstract

Objective:

The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.

Method:

The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology–Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.

Results:

The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.

Conclusions:

The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 751 - 759
PubMed: 25815420

History

Received: 29 May 2014
Revision received: 28 September 2014
Revision received: 26 December 2014
Accepted: 11 January 2015
Published online: 27 March 2015
Published in print: August 01, 2015

Authors

Details

Alan F. Schatzberg, M.D.
From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford; the Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), VA Palo Alto Health Care System, Palo Alto, Calif.; and Brain Resource, Ltd., Sydney, Australia; and Brain Resource, Inc., San Francisco.
Charles DeBattista, M.D.
From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford; the Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), VA Palo Alto Health Care System, Palo Alto, Calif.; and Brain Resource, Ltd., Sydney, Australia; and Brain Resource, Inc., San Francisco.
Laura C. Lazzeroni, Ph.D.
From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford; the Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), VA Palo Alto Health Care System, Palo Alto, Calif.; and Brain Resource, Ltd., Sydney, Australia; and Brain Resource, Inc., San Francisco.
Amit Etkin, M.D., Ph.D.
From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford; the Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), VA Palo Alto Health Care System, Palo Alto, Calif.; and Brain Resource, Ltd., Sydney, Australia; and Brain Resource, Inc., San Francisco.
Greer M. Murphy, Jr., M.D., Ph.D.
From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford; the Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), VA Palo Alto Health Care System, Palo Alto, Calif.; and Brain Resource, Ltd., Sydney, Australia; and Brain Resource, Inc., San Francisco.
Leanne M. Williams, Ph.D.
From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford; the Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), VA Palo Alto Health Care System, Palo Alto, Calif.; and Brain Resource, Ltd., Sydney, Australia; and Brain Resource, Inc., San Francisco.

Notes

Address correspondence to Dr. Williams ([email protected]) or Dr. Schatzberg ([email protected]).

Funding Information

Supported by Brain Resource, Ltd.Dr. Schatzberg has served as a consultant to Bay City Capital, BrainCells, CeNeRx, Cervel, Depomed, Eli Lilly, Forum, Genentech, Gilead, Jazz, Lundbeck/Takeda, McKinsey, Merck, MSI, Neuronetics, Novadel, One-Carbon, PharmaNeuroBoost, Sunovion, Synosia, and Xhale; he has received honoraria from Merck; he has equity in Amnestix, BrainCells, CeNeRx, Corcept (co-founder), Delpor, Forest, Merck, Neurocrine, Novadel, Pfizer, PharmaNeuroBoost, Somaxon, Synosis, Titan, and Xhale; and he receives royalties from Stanford University for patents on mifepristone use and the pharmacogenetics of antidepressant response. Dr. DeBattista has received research funding from Assurex, Brain Resource, Janssen, Takeda, and Roche and has served as a consultant for Genentech and Pfizer. Dr. Lazzeroni is named as an inventor on a genetics patent application filed by Stanford University. Dr. Etkin has received research funding from Brain Resource, Ltd. Dr. Murphy is named as an inventor on a patent application on genetic markers for antidepressant response filed by Stanford University; his contribution to the present work was done as a paid consultant for Brain Resource, Ltd., and was not part of his Stanford duties and responsibilities. Dr. Williams has received fees as a consultant for Brain Resource, Ltd., and has been a stockholder in Brain Resource, Ltd.

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