title: Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults.
abstract: OBJECTIVE
  Generalized anxiety disorder (GAD) is common in older adults and can be treated with selective serotonin reuptake inhibitors (SSRIs). Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy: 2 polymorphisms (5-HTTLPR S/L and rs25531 g/a) form a haplotype with the La combination having higher transcription activity than other haplotypes. We hypothesized that GAD patients with no La haplotypes (La⁻) have lower SSRI treatment efficacy than those with 1 to 2 La haplotypes (La+).
  
  
  METHODS
  The study enrolled subjects aged 60 years or older with a principal diagnosis of GAD into a 12-week, randomized trial of escitalopram versus placebo. One hundred fifty subjects were genotyped for the serotonin transporter promoter region haplotype and were divided into La⁻ and La+ genotype groups; the primary analyses were done in European Americans only (n = 125; n = 59 with escitalopram and n = 66 with placebo).
  
  
  RESULTS
  Escitalopram had no efficacy in the La⁻ group versus moderate efficacy in the La+ group. This genetic moderation of SSRI efficacy was due to a higher placebo response in La⁻ subjects, compared with La+ subjects. Drug concentration did not affect the genetic results. Exploratory analyses suggest that La⁻ subjects had greater variability of anxiety symptoms unrelated to treatment.
  
  
  CONCLUSIONS
  The serotonin transporter promoter haplotype is associated with variability in SSRI efficacy for late-life GAD. The variability may result from a genetic effect on anxiety symptom variability unrelated to treatment, rather than a pharmacodynamic effect that has been previously assumed. Further research is needed to understand the pharmacogenetic mechanism of this haplotype.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S Euclid, Box 8134, St Louis, MO 63110, USA. lenzee@wustl.edu
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lenze
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: David
authors.initials: D
authors.lastname: Dixon
authors.forename: Peichang
authors.initials: P
authors.lastname: Shi
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Francis K
authors.initials: FK
authors.lastname: Lotrich
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Rollman
authors.forename: M Katherine
authors.initials: MK
authors.lastname: Shear
authors.forename: Paul A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Carmen
authors.initials: C
authors.lastname: Andreescu
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001008:Anxiety Disorders / Q000188:drug therapy*; D015283:Citalopram / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D015283:Citalopram; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors