Genetic Polymorphisms of Cytochrome P450 Enzymes Influence Metabolism of the Antidepressant Escitalopram and Treatment Response

Abstract

Aims: 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. Materials & 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. Conclusion: 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.

KEYWORDS::

• CYP2C19
• CYP2D6
• CYP3A4
• escitalopram
• major depression
• therapeutic drug monitoring

Acknowledgements

We thank Dr Russell Poland for the gift of S -CIT, the president of the Research and Education Institute for Texas Health Resources (TX, USA). We also thank many nurses: Tsui-Mei Hung, Yu-Ching Lin, Miao-Fang Lee, Ming-Chu Tseng, Yu-Hun Tsai and Shu-Chuan Ting for interviewing patients from five hospitals; Szu-Ting Fu for her assistance in preparing the proposal; Yi-Chieh Lin for coordinating DNA samples for genotyping; and Clinical Research Information Management System (CRIMS) at NHRI for the data collection. We also thank Chang Gung Memorial Hospital (Taipei, Taiwan), Mackay Memorial Hospital (Taipei, Taiwan), Far Eastern Memorial Hospital (Taipei, Taiwan), TMU-Wan Fang Hospital (Taipei, Taiwan) and the Songde branch of the Taipei City Hospital (Taipei, Taiwan) for their help.

Financial & competing interests disclosure

This study was supported by grants from the National Science Council, Taiwan (NSC 96-2314-B-400-001, NSC 97-2314-B-400-001-MY3), and the National Health Research Institutes, Taiwan (MD-095-PP-01, MD-095-PP-02, MD-097-PP-14). WW Shen has lectured for and received honoraria from AstraZeneca, GlaxoSmithKline, Jassen, Eli Lilly, Organon, Otsuka, Roche and Wyeth. He has also received research supports from GlaxoSmithKline, Eli Lilly and Janssen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was supported by grants from the National Science Council, Taiwan (NSC 96-2314-B-400-001, NSC 97-2314-B-400-001-MY3), and the National Health Research Institutes, Taiwan (MD-095-PP-01, MD-095-PP-02, MD-097-PP-14). WW Shen has lectured for and received honoraria from AstraZeneca, GlaxoSmithKline, Jassen, Eli Lilly, Organon, Otsuka, Roche and Wyeth. He has also received research supports from GlaxoSmithKline, Eli Lilly and Janssen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.