title: Pharmacogenetic investigation of response to duloxetine treatment in generalized anxiety disorder.
abstract: We examined genetic associations with duloxetine response in generalized anxiety disorder (GAD). Three pooled studies in patients with GAD receiving duloxetine 60-120 mg per day (N=164) or placebo (N=95) were used. Associations between 825 single-nucleotide polymorphisms (SNPs) in 61 candidate genes with change in Hamilton Anxiety Scale scores were examined with set-based testing (adjusted for the number of SNPs within each gene); sets with two-sided adjusted P≤0.05 were examined using repeated measure analysis. Follow-up analysis explored associations of these SNPs with change in Hamilton Rating Scale for Depression-Anxiety Subscale in a 6-week study in duloxetine-treated patients with major depressive disorder (MDD) (N=241). Variants in corticotropin-releasing hormone receptor 1 (CRHR1), dopamine receptor D3 (DRD3), nuclear receptor subfamily group C, member 1 (NR3C1) and phosphodiesterase 1A (PDE1A) were associated with duloxetine response in GAD. Only rs4792888 in CRHR1 showed modest evidence of association with duloxetine response in MDD (P=0.029 in GAD, P=0.054 in MDD). In conclusion, CRHR1 variation merits investigation in pathophysiology of anxiety and its treatment response.
authors.affiliation: Psychiatric Pharmacogenomics Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Perlis
authors.forename: B
authors.initials: B
authors.lastname: Fijal
authors.forename: S
authors.initials: S
authors.lastname: Dharia
authors.forename: J P
authors.initials: JP
authors.lastname: Houston
mesh_terms: D000328:Adult; D001008:Anxiety Disorders / Q000235:genetics* / Q000473:pathology; D054316:Biomarkers, Pharmacological; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D000068736:Duloxetine Hydrochloride; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D013876:Thiophenes / Q000008:administration & dosage*; D000099052:CRF Receptor, Type 1
chemical_list: D054316:Biomarkers, Pharmacological; D018019:Receptors, Corticotropin-Releasing Hormone; D013876:Thiophenes; D000099052:CRF Receptor, Type 1; D000068736:Duloxetine Hydrochloride