Variation in Catechol-O-Methyltransferase Is Associated with Duloxetine Response in a Clinical Trial for Major Depressive Disorder

Roy H. Perlis, Bonnie Fijal, David H. Adams, Virginia K. Sutton, Madhukar H. Trivedi, John P. Houston

Research output: Contribution to journalArticle

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Abstract

Background: The study objective was to evaluate variations in genes implicated in antidepressant mechanism of action for association with response to duloxetine treatment in major depressive disorder (MDD). Methods: We assessed response over 6 weeks in 250 duloxetine-treated Caucasian patients in a randomized, double-blind study of patients with MDD. Single nucleotide polymorphisms (SNPs) were genotyped in 19 candidate genes selected based on evidence for involvement in antidepressant mechanism of action. Primary analysis examined baseline to end point reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score, using a set-based test for association for each gene. Follow-up analyses examined individual SNPs within any significant gene for association with reduction in HAMD17 and 30-item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C-30). Results: After correction for multiple comparisons, only COMT was associated with change in HAMD17 (experimentwide p = .018). Peak association was detected with rs165599 (p = .006), which accounted for approximately 3% of variance in HAMD17 change and >4% of variance in IDS-C-30 change (p = .001). The least-squared mean change (SE) in HAMD17 score by rs165599 genotype was -10.8 (1.2), -8.7 (.6), and -6.5 (.7) for patients with GG, GA, and AA genotypes, respectively. For SNPs in serotonin 2A receptor (HTR2A) previously associated with citalopram response, including rs7997012, no significant evidence of association with duloxetine response was identified. Conclusions: Single nucleotide polymorphisms in COMT were associated with symptom change in duloxetine-treated patients with MDD. If replicated, the magnitude of the COMT genotype effect is of clinical relevance.

Original languageEnglish (US)
Pages (from-to)785-791
Number of pages7
JournalBiological Psychiatry
Volume65
Issue number9
DOIs
StatePublished - May 1 2009

Fingerprint

Catechol O-Methyltransferase
Major Depressive Disorder
Single Nucleotide Polymorphism
Clinical Trials
Genotype
Antidepressive Agents
Genes
Receptor, Serotonin, 5-HT2A
Citalopram
Double-Blind Method
Depression
Equipment and Supplies
Duloxetine Hydrochloride
IDS 30
Therapeutics

Keywords

  • Antidepressant
  • genetic association
  • genomics
  • response
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Variation in Catechol-O-Methyltransferase Is Associated with Duloxetine Response in a Clinical Trial for Major Depressive Disorder. / Perlis, Roy H.; Fijal, Bonnie; Adams, David H.; Sutton, Virginia K.; Trivedi, Madhukar H.; Houston, John P.

In: Biological Psychiatry, Vol. 65, No. 9, 01.05.2009, p. 785-791.

Research output: Contribution to journalArticle

Perlis, Roy H. ; Fijal, Bonnie ; Adams, David H. ; Sutton, Virginia K. ; Trivedi, Madhukar H. ; Houston, John P. / Variation in Catechol-O-Methyltransferase Is Associated with Duloxetine Response in a Clinical Trial for Major Depressive Disorder. In: Biological Psychiatry. 2009 ; Vol. 65, No. 9. pp. 785-791.
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AU - Perlis, Roy H.

AU - Fijal, Bonnie

AU - Adams, David H.

AU - Sutton, Virginia K.

AU - Trivedi, Madhukar H.

AU - Houston, John P.

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AB - Background: The study objective was to evaluate variations in genes implicated in antidepressant mechanism of action for association with response to duloxetine treatment in major depressive disorder (MDD). Methods: We assessed response over 6 weeks in 250 duloxetine-treated Caucasian patients in a randomized, double-blind study of patients with MDD. Single nucleotide polymorphisms (SNPs) were genotyped in 19 candidate genes selected based on evidence for involvement in antidepressant mechanism of action. Primary analysis examined baseline to end point reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score, using a set-based test for association for each gene. Follow-up analyses examined individual SNPs within any significant gene for association with reduction in HAMD17 and 30-item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C-30). Results: After correction for multiple comparisons, only COMT was associated with change in HAMD17 (experimentwide p = .018). Peak association was detected with rs165599 (p = .006), which accounted for approximately 3% of variance in HAMD17 change and >4% of variance in IDS-C-30 change (p = .001). The least-squared mean change (SE) in HAMD17 score by rs165599 genotype was -10.8 (1.2), -8.7 (.6), and -6.5 (.7) for patients with GG, GA, and AA genotypes, respectively. For SNPs in serotonin 2A receptor (HTR2A) previously associated with citalopram response, including rs7997012, no significant evidence of association with duloxetine response was identified. Conclusions: Single nucleotide polymorphisms in COMT were associated with symptom change in duloxetine-treated patients with MDD. If replicated, the magnitude of the COMT genotype effect is of clinical relevance.

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