Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response.
OBJECTIVE
The antidepressant escitalopram (S-CIT) is metabolized by the cytochrome-P450 (CYP) enzymes CYP 2D6, 2C19 and 3A4. This study evaluated the impact of CYP2D6, 2C19 and 3A4 genetic polymorphisms on plasma concentrations of S-CIT and patient treatment response.


METHODS
A total of 100 patients diagnosed with major depressive disorder were recruited to the study and their depression symptoms were assessed using the Hamilton Depression Rating Scale. The genetic polymorphisms *4, *5 and *10 on CYP2D6, *2, *3 and *17 on CYP2C19, and *18 on CYP3A4 were selected based on their function and respective allele frequencies in Asian populations. Polymorphisms were analyzed using the SNPstream genotyping system, PCR and direct sequencing methods. The steady-state serum concentrations of S-CIT and its metabolites S-desmethylcitalopram and S-didesmethylcitalopram were analyzed by HPLC. According to semiquantitative gene dose (SGD) and gene dose (GD) models for allele combinations of these polymorphisms, CYP2D6 was clustered into intermediate (0.5, 1 and 1.5 SGD) and extensive (2 SGD) metabolizers, while CYP2C19 was clustered into poor (0 GD) and extensive (1 and 2 GDs) metabolizers.


RESULTS
The group of patients with intermediate CYP2D6 metabolism (0.5 SGD) had a significantly higher frequency of remitters from major depressive disorder during the 8-week treatment (p = 0.0001). Furthermore, CYP2C19 poor metabolizers had significantly higher S-CIT serum levels than did extensive metabolizers at weeks 2, 4 and 8 (p < 0.05). The allele frequencies in CYP3A4*18 and CYP2C19*17 were too low to permit further subgroup analyses.


CONCLUSIONS
Our results suggest that the genetic polymorphisms in CYP2C19 may be influencing S-CIT serum concentrations, and that specific CYP2D6 polymorphisms may be predicting patient treatment outcomes based on gene dosage analyses.
Tsai
Ming-Hsien
MH
Division of Mental Health & Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan.
Lin
Keh-Ming
KM
Hsiao
Mei-Chun
MC
Shen
Winston W
WW
Lu
Mong-Liang
ML
Tang
Hwa-Sheng
HS
Fang
Chun-Kai
CK
Wu
Chi-Shin
CS
Lu
Shao-Chun
SC
Liu
Shu Chih
SC
Chen
Chun-Yu
CY
Liu
Yu-Li
YL
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D015283:Citalopram / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D016896:Treatment Outcome
D018687:Antidepressive Agents, Second-Generation; D015415:Biomarkers; D015283:Citalopram; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human