CYP1A2 genetic polymorphisms are associated with treatment response to the antidepressant paroxetine.
OBJECTIVE
Paroxetine is a drug of choice in the treatment of major depressive disorder (MDD). Its metabolism has recently been reported to be mediated through the CYP enzymes 1A2 and 2D6. In our current study, we tested whether genetic polymorphisms in CYP1A2 are associated with the treatment efficacy and side effects of paroxetine.


METHODS
A total of 241 MDD patients who had taken paroxetine continually for 8 weeks were recruited, and their steady state paroxetine concentrations were measured at weeks 2, 4 and 8. The genotypes of these patients were then assessed for the presence of nine SNPs, which were selected from either the HapMap Chinese ethnic group, the literature report or through their functional role in the CYP1A2 gene.


RESULTS
The allele types for SNPs rs4646425 (permutation p = 0.03), rs2472304 (permutation p = 0.01) and rs2470890 (permutation p = 0.004) demonstrated significant associations with paroxetine treatment remission at week 8. Response rates in the Hamilton Rating Scale for Depression (HAM-D) and for The Hamilton Rating Scale for Anxiety (HAM-A) were significantly associated with the SNPs rs4646425 (p = 0.0126 and 0.0088 for HAM-D and HAM-A, respectively) and rs4646427 (p = 0.0067 and 0.0196 for HAM-D and HAM-A, respectively). The inducible SNP rs762551 had a significant association with paroxetine dose at week 4 (permutation p = 0.012). We did not find an association between these SNPs and the side effects or serum concentrations of paroxetine.


CONCLUSIONS
Genetic variants in the CYP1A2 region may be indicators of treatment response in MDD patients to paroxetine.
Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
Keh-Ming
KM
Lin
Hsiao-Hui
HH
Tsou
I-Ju
IJ
Tsai
Mei-Chun
MC
Hsiao
Chin-Fu
CF
Hsiao
Chia-Yih
CY
Liu
Winston W
WW
Shen
Hwa-Sheng
HS
Tang
Chun-Kai
CK
Fang
Chi-Shin
CS
Wu
Shao-Chun
SC
Lu
Hsiang-Wei
HW
Kuo
Shu Chih
SC
Liu
Hsiu-Wen
HW
Chan
Ya-Ting
YT
Hsu
Jia-Ni
JN
Tian
Yu-Li
YL
Liu
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D017374:Paroxetine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
D018687:Antidepressive Agents, Second-Generation; D017374:Paroxetine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2