Pharmacogenetics studies in STAR*D: Strengths, limitations, and results

Gonzalo Laje, Roy H. Perlis, A. John Rush, Francis J. McMahon

Research output: Contribution to journalArticle

Abstract

Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder, uniformly treated with citalopram and followed prospectively for up to 12 weeks. This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability. Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment. Variants in HTR2A, GRIK4, and KCNK2 were associated with citalopram treatment outcome. Replication was achieved in markers in the FKBP5 gene. Other findings in PDE11A and BDNF were not successfully replicated, and reports of potential confounders in previous associations with serotonin transporter variation (SLC6A4) were identified. Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response. Adverse events were also tested. Treatment-emergent suicidal ideation was associated with GRIK2, GRIA3, PAPLN, IL28RA, and CREB1. Sexual dysfunction was linked with variation in GRIN3A, GRIA1 GRIA3, and GRIK2. Reported and future findings of pharmacogenetics studies in STAR*D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects. Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments.

Original languageEnglish (US)
Pages (from-to)1446-1457
Number of pages12
JournalPsychiatric Services
Volume60
Issue number11
DOIs
StatePublished - Nov 2009
Externally publishedYes

Fingerprint

Depression
Antidepressive Agents
Citalopram
Therapeutics
Genes
Suicidal Ideation
Serotonin Plasma Membrane Transport Proteins
Pharmacogenetics
Brain-Derived Neurotrophic Factor
Major Depressive Disorder
Pharmacogenomic Testing
Sample Size
Pharmacokinetics
DNA
Research

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Pharmacogenetics studies in STAR*D : Strengths, limitations, and results. / Laje, Gonzalo; Perlis, Roy H.; Rush, A. John; McMahon, Francis J.

In: Psychiatric Services, Vol. 60, No. 11, 11.2009, p. 1446-1457.

Research output: Contribution to journalArticle

Laje, Gonzalo ; Perlis, Roy H. ; Rush, A. John ; McMahon, Francis J. / Pharmacogenetics studies in STAR*D : Strengths, limitations, and results. In: Psychiatric Services. 2009 ; Vol. 60, No. 11. pp. 1446-1457.
@article{a26c8938ffac4f28ac1dd4cd6672a1c8,
title = "Pharmacogenetics studies in STAR*D: Strengths, limitations, and results",
abstract = "Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder, uniformly treated with citalopram and followed prospectively for up to 12 weeks. This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability. Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment. Variants in HTR2A, GRIK4, and KCNK2 were associated with citalopram treatment outcome. Replication was achieved in markers in the FKBP5 gene. Other findings in PDE11A and BDNF were not successfully replicated, and reports of potential confounders in previous associations with serotonin transporter variation (SLC6A4) were identified. Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response. Adverse events were also tested. Treatment-emergent suicidal ideation was associated with GRIK2, GRIA3, PAPLN, IL28RA, and CREB1. Sexual dysfunction was linked with variation in GRIN3A, GRIA1 GRIA3, and GRIK2. Reported and future findings of pharmacogenetics studies in STAR*D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects. Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments.",
author = "Gonzalo Laje and Perlis, {Roy H.} and Rush, {A. John} and McMahon, {Francis J.}",
year = "2009",
month = "11",
doi = "10.1176/appi.ps.60.11.1446",
language = "English (US)",
volume = "60",
pages = "1446--1457",
journal = "Psychiatric Services",
issn = "1075-2730",
publisher = "American Psychiatric Association",
number = "11",

}

TY - JOUR

T1 - Pharmacogenetics studies in STAR*D

T2 - Strengths, limitations, and results

AU - Laje, Gonzalo

AU - Perlis, Roy H.

AU - Rush, A. John

AU - McMahon, Francis J.

PY - 2009/11

Y1 - 2009/11

N2 - Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder, uniformly treated with citalopram and followed prospectively for up to 12 weeks. This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability. Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment. Variants in HTR2A, GRIK4, and KCNK2 were associated with citalopram treatment outcome. Replication was achieved in markers in the FKBP5 gene. Other findings in PDE11A and BDNF were not successfully replicated, and reports of potential confounders in previous associations with serotonin transporter variation (SLC6A4) were identified. Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response. Adverse events were also tested. Treatment-emergent suicidal ideation was associated with GRIK2, GRIA3, PAPLN, IL28RA, and CREB1. Sexual dysfunction was linked with variation in GRIN3A, GRIA1 GRIA3, and GRIK2. Reported and future findings of pharmacogenetics studies in STAR*D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects. Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments.

AB - Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder, uniformly treated with citalopram and followed prospectively for up to 12 weeks. This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability. Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment. Variants in HTR2A, GRIK4, and KCNK2 were associated with citalopram treatment outcome. Replication was achieved in markers in the FKBP5 gene. Other findings in PDE11A and BDNF were not successfully replicated, and reports of potential confounders in previous associations with serotonin transporter variation (SLC6A4) were identified. Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response. Adverse events were also tested. Treatment-emergent suicidal ideation was associated with GRIK2, GRIA3, PAPLN, IL28RA, and CREB1. Sexual dysfunction was linked with variation in GRIN3A, GRIA1 GRIA3, and GRIK2. Reported and future findings of pharmacogenetics studies in STAR*D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects. Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments.

UR - http://www.scopus.com/inward/record.url?scp=70350787070&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350787070&partnerID=8YFLogxK

U2 - 10.1176/appi.ps.60.11.1446

DO - 10.1176/appi.ps.60.11.1446

M3 - Article

C2 - 19880459

AN - SCOPUS:70350787070

VL - 60

SP - 1446

EP - 1457

JO - Psychiatric Services

JF - Psychiatric Services

SN - 1075-2730

IS - 11

ER -