Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study

Neuropsychopharmacology. 2008 Nov;33(12):2810-9. doi: 10.1038/npp.2008.6. Epub 2008 Feb 20.

Abstract

Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C(16)) score < or =5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical p<0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n=225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain Chemistry / genetics*
  • Citalopram / pharmacology
  • DNA Mutational Analysis
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / genetics*
  • Depressive Disorder / metabolism
  • Drug Resistance / genetics*
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Potassium Channels, Tandem Pore Domain / genetics*
  • Rodentia / genetics
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Young Adult

Substances

  • Antidepressive Agents
  • Potassium Channels, Tandem Pore Domain
  • Serotonin Uptake Inhibitors
  • potassium channel protein TREK-1
  • Citalopram