Variation in catechol-O-methyltransferase is associated with duloxetine response in a clinical trial for major depressive disorder.
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 (experiment wide 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.
Perlis
Roy H
RH
Department of Psychiatry and Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts 02144, USA. rperlis@partners.org
Fijal
Bonnie
B
Adams
David H
DH
Sutton
Virginia K
VK
Trivedi
Madhukar H
MH
Houston
John P
JP
D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D004311:Double-Blind Method; D000068736:Duloxetine Hydrochloride; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome
D002394:Catechol O-Methyltransferase; D000068736:Duloxetine Hydrochloride; D044402:Receptor, Serotonin, 5-HT2A; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes