Initial conditions of serotonin transporter kinetics and genotype: Influence on SSRI treatment trial outcome

Jeffrey L. Rausch, Maria E. Johnson, You Jun Fei, Jun Qing Li, Nitin Shendarkar, Henry Mac Hobby, Vadivel Ganapathy, Fred H. Leibach

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

Background: Fifty-one patients with major depression were classified for 5-HTT promoter region polymorphism and platelet 5-HTT kinetics before treatment with fluoxetine, and then examined for treatment outcome. Methods: Dose was stratified from 1.25 mg to 40 mg per day to allow for the possibility that one genotype could express a lower-dose fluoxetine response. A repeated-measures analysis of variance of 24-item Hamilton depression change through baseline, 1-week placebo lead-in, and 6, 12, and 18 weeks treatment was done to test a genotype effect on outcome. Results: Genotype had a significant effect on outcome (F = 4.7, p < .02), with the initial affinity constant (Km) (F = 11.9, p = .001), and dose (F = 6.0, p < .02) being significant covariates on outcome as well. The gene effect, however, was complex in that the 5-HTT promoter region insertion showed two effects: both a placebo response effect (F = 4, p < .025), and a drug dose response effect (r = .40, p < .01). The long allele group was more responsive to placebo, as well as more responsive to drug dose than was the short allele group. Conclusions: This is the first study to examine the antidepressant dose-response relationship to 5-HTT kinetics and genetics. The findings indicate that both the initial affinity and genotype of 5-HTT may contribute in unique ways to the variation in the outcome of depression treatment trials.

Original languageEnglish (US)
Pages (from-to)723-732
Number of pages10
JournalBiological Psychiatry
Volume51
Issue number9
DOIs
StatePublished - May 1 2002

Fingerprint

Serotonin Plasma Membrane Transport Proteins
Genotype
Fluoxetine
Genetic Promoter Regions
Alleles
Placebos
Placebo Effect
Pharmaceutical Preparations
Antidepressive Agents
Analysis of Variance
Blood Platelets
Therapeutics
Genes

Keywords

  • 5-HT transport kinetics
  • 5-HTT
  • Antidepressants
  • Depression
  • Dose
  • Fluoxetine
  • Genetics
  • SERT
  • SSRI
  • Serotonin
  • Serotonin transporter
  • Treatment response

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Initial conditions of serotonin transporter kinetics and genotype : Influence on SSRI treatment trial outcome. / Rausch, Jeffrey L.; Johnson, Maria E.; Fei, You Jun; Li, Jun Qing; Shendarkar, Nitin; Mac Hobby, Henry; Ganapathy, Vadivel; Leibach, Fred H.

In: Biological Psychiatry, Vol. 51, No. 9, 01.05.2002, p. 723-732.

Research output: Contribution to journalArticle

Rausch, Jeffrey L. ; Johnson, Maria E. ; Fei, You Jun ; Li, Jun Qing ; Shendarkar, Nitin ; Mac Hobby, Henry ; Ganapathy, Vadivel ; Leibach, Fred H. / Initial conditions of serotonin transporter kinetics and genotype : Influence on SSRI treatment trial outcome. In: Biological Psychiatry. 2002 ; Vol. 51, No. 9. pp. 723-732.
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AU - Li, Jun Qing

AU - Shendarkar, Nitin

AU - Mac Hobby, Henry

AU - Ganapathy, Vadivel

AU - Leibach, Fred H.

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AB - Background: Fifty-one patients with major depression were classified for 5-HTT promoter region polymorphism and platelet 5-HTT kinetics before treatment with fluoxetine, and then examined for treatment outcome. Methods: Dose was stratified from 1.25 mg to 40 mg per day to allow for the possibility that one genotype could express a lower-dose fluoxetine response. A repeated-measures analysis of variance of 24-item Hamilton depression change through baseline, 1-week placebo lead-in, and 6, 12, and 18 weeks treatment was done to test a genotype effect on outcome. Results: Genotype had a significant effect on outcome (F = 4.7, p < .02), with the initial affinity constant (Km) (F = 11.9, p = .001), and dose (F = 6.0, p < .02) being significant covariates on outcome as well. The gene effect, however, was complex in that the 5-HTT promoter region insertion showed two effects: both a placebo response effect (F = 4, p < .025), and a drug dose response effect (r = .40, p < .01). The long allele group was more responsive to placebo, as well as more responsive to drug dose than was the short allele group. Conclusions: This is the first study to examine the antidepressant dose-response relationship to 5-HTT kinetics and genetics. The findings indicate that both the initial affinity and genotype of 5-HTT may contribute in unique ways to the variation in the outcome of depression treatment trials.

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KW - Serotonin transporter

KW - Treatment response

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