Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults

Eric J. Lenze, Alison M. Goate, Petra Nowotny, David Dixon, Peichang Shi, Robert Bies, Francis K. Lotrich, Bruce L. Rollman, M. Katherine Shear, Paul A. Thompson, Carmen Andreescu, Bruce G. Pollock

Research output: Contribution to journalArticle

23 Citations (Scopus)

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+). Method: 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.

Original languageEnglish
Pages (from-to)672-677
Number of pages6
JournalJournal of Clinical Psychopharmacology
Volume30
Issue number6
DOIs
StatePublished - Dec 2010

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Serotonin Plasma Membrane Transport Proteins
Citalopram
Anxiety Disorders
Haplotypes
Serotonin Uptake Inhibitors
Placebos
Genetic Promoter Regions
Anxiety
Pharmacogenetics
Genotype
Therapeutics
Research
Pharmaceutical Preparations
Genes

Keywords

  • anxiety disorders
  • genetics
  • geriatrics
  • SSRI

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults. / Lenze, Eric J.; Goate, Alison M.; Nowotny, Petra; Dixon, David; Shi, Peichang; Bies, Robert; Lotrich, Francis K.; Rollman, Bruce L.; Shear, M. Katherine; Thompson, Paul A.; Andreescu, Carmen; Pollock, Bruce G.

In: Journal of Clinical Psychopharmacology, Vol. 30, No. 6, 12.2010, p. 672-677.

Research output: Contribution to journalArticle

Lenze, EJ, Goate, AM, Nowotny, P, Dixon, D, Shi, P, Bies, R, Lotrich, FK, Rollman, BL, Shear, MK, Thompson, PA, Andreescu, C & Pollock, BG 2010, 'Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults', Journal of Clinical Psychopharmacology, vol. 30, no. 6, pp. 672-677. https://doi.org/10.1097/JCP.0b013e3181fc2bef
Lenze, Eric J. ; Goate, Alison M. ; Nowotny, Petra ; Dixon, David ; Shi, Peichang ; Bies, Robert ; Lotrich, Francis K. ; Rollman, Bruce L. ; Shear, M. Katherine ; Thompson, Paul A. ; Andreescu, Carmen ; Pollock, Bruce G. / Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults. In: Journal of Clinical Psychopharmacology. 2010 ; Vol. 30, No. 6. pp. 672-677.
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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+). Method: 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.",
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AU - Lenze, Eric J.

AU - Goate, Alison M.

AU - Nowotny, Petra

AU - Dixon, David

AU - Shi, Peichang

AU - Bies, Robert

AU - Lotrich, Francis K.

AU - Rollman, Bruce L.

AU - Shear, M. Katherine

AU - Thompson, Paul A.

AU - Andreescu, Carmen

AU - Pollock, Bruce G.

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N2 - 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+). Method: 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.

AB - 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+). Method: 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.

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