Initial conditions of serotonin transporter kinetics and genotype: influence on ssri treatment trial outcome

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.