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 (K(m)) (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.
Rausch
Jeffrey L
JL
Department of Psychiatry, Veterans Administration Hospital, The Medical College of Georgia, Augusta, Georgia 30912-3800, USA.
Johnson
Maria E
ME
Fei
You-Jun
YJ
Li
Jun Qing
JQ
Shendarkar
Nitin
N
Hobby
Henry Mac
HM
Ganapathy
Vadivel
V
Leibach
Fred H
FH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005473:Fluoxetine / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D011110:Polymorphism, Genetic / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D016896:Treatment Outcome
D002352:Carrier Proteins; D005473:Fluoxetine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human