CYP1A2 Genetic Polymorphisms are Associated with Early Antidepressant Escitalopram Metabolism and Adverse Reactions

Abstract

Aim: The liver CYP1A2 enzyme may metabolize antidepressant escitalopram (S-CIT) to S-desmethylcitalopram (S-DCIT) and S-didesmethylcitalopram (S-DDCIT). This study tested whether genetic polymorphisms in the CYP1A2 gene are associated with the treatment responses to S-CIT. Materials & methods: Ten SNPs in CYP1A2 were selected and genotyped in 158 patients under S-CIT treatment. The serum levels of S-CIT and its metabolites were measured by HPLC. Results:CYP1A2 SNPs rs2069521, rs2069526, rs4646425 and rs4646427 are significantly associated with the metabolic ratios of S-DDCIT/S-DCIT (p = 0.002, 0.018, 0.008 and 0.004, respectively) at week 2 of treatment. Carriers of the allele types associated with higher S-DDCIT/S-DCIT ratios had more severe side effects. Conclusion: These results suggest that genetic variants in CYP1A2 may be indicators for S-CIT metabolism and that the fast metabolizers may experience more severe adverse reactions in the early stages of S-CIT treatment.

Original submitted 27 December 2012; Revision submitted 15 May 2013

KEYWORDS::

• CYP1A2
• escitalopram
• major depressive disorder
• side effects
• SNP

Acknowledgements

The authors thank R Poland, President of the Research and Education Institute for Texas Health Resources, for his generous donation S-CIT. The authors also thank T-M Hung, Y-C Lin, M-F Lee, M-C Tseng, Y-H Tsai and S-C Ting for interviewing the MDD patients from the five hospitals; S-T Fu for her assistance in preparing the proposal; Y-C Lin for coordinating the DNA samples for genotyping; and the Clinical Trial Information Management System (CTIMeS) at the NHRI for data collection. The authors further thank J-J Chen in the Department of Biochemistry and Molecular Biology, National Taiwan University for assistance with the SNP analysis.

Financial & competing interests disclosure

This study was supported by grants from the National Research Program for Genomic Medicine (NSC 98-3112-B-400-011, NSC 99-3112-B-400-003 and NSC 100-3112-B-400-015), the National Science Council (NSC 97-2314-B-400-001-MY3 and NSC 100-2314-B-400-002-MY3), the National Health Research Institutes, Taiwan (MD-095-PP-01, MD-095-PP-02, MD-097-PP-14, PH-098-PP-41, PH-098-PP-46, PH-098-PP-38, PH-098, 99-PP-42 and PH-100-PP-37) and the Taiwan Psychiatric Research Network (PH-98, 99 and 100-SP-11). C-Y Liu has received grant support from Eli Lilly, Janssen, Wyeth and GlaxoSmithKline, and has participated in speaker bureaus/advisory boards for Eli Lilly, Wyeth, GlaxoSmithKline, Janssen, Organon, Pfizer and Otsuka. WW Shen has lectured for and received honoraria from AstraZeneca, GSK, Jassen, Lilly, Organon, Otsuka, Roche, Wyeth and Pfizer. He has also received research support from GSK, Lilly, Janssen and Lundbeck. L-H Chang has lectured for and received honoraria from GSK, Eli-Lilly, Otsuka, Sanofi-Aventis and Wyeth. 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 Research Program for Genomic Medicine (NSC 98-3112-B-400-011, NSC 99-3112-B-400-003 and NSC 100-3112-B-400-015), the National Science Council (NSC 97-2314-B-400-001-MY3 and NSC 100-2314-B-400-002-MY3), the National Health Research Institutes, Taiwan (MD-095-PP-01, MD-095-PP-02, MD-097-PP-14, PH-098-PP-41, PH-098-PP-46, PH-098-PP-38, PH-098, 99-PP-42 and PH-100-PP-37) and the Taiwan Psychiatric Research Network (PH-98, 99 and 100-SP-11). C-Y Liu has received grant support from Eli Lilly, Janssen, Wyeth and GlaxoSmithKline, and has participated in speaker bureaus/advisory boards for Eli Lilly, Wyeth, GlaxoSmithKline, Janssen, Organon, Pfizer and Otsuka. WW Shen has lectured for and received honoraria from AstraZeneca, GSK, Jassen, Lilly, Organon, Otsuka, Roche, Wyeth and Pfizer. He has also received research support from GSK, Lilly, Janssen and Lundbeck. L-H Chang has lectured for and received honoraria from GSK, Eli-Lilly, Otsuka, Sanofi-Aventis and Wyeth. 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.

Notes on contributors

Hsiang-Wei Kuo

Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan

Shu Chih Liu

Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan

Hsiao-Hui Tsou

Division of Biostatistics & Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan

Sheng-Wen Liu

Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan

Keh-Ming Lin

Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan

Shao-Chun Lu

Institute of Biochemistry & Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan

Mei-Chun Hsiao

Department of Psychiatry, Chang Gung Memorial Hospital & Chang Gung University School of Medicine, Taipei, Taiwan

Chin-Fu Hsiao

Division of Biostatistics & Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan and Division of Clinical Trial Statistics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan

Chia-Yih Liu

Department of Psychiatry, Chang Gung Memorial Hospital & Chang Gung University School of Medicine, Taipei, Taiwan

Chia-Hui Chen

Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan

Department of Psychiatry, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan

Mong-Liang Lu

Department of Psychiatry, Wan Fang Medical Center, affiliated with Department of Psychiatry, College of Medicine, Taipei Medical University, Taipei, Taiwan

Winston W Shen

Department of Psychiatry, Wan Fang Medical Center, affiliated with Department of Psychiatry, College of Medicine, Taipei Medical University, Taipei, Taiwan

Hwa-Sheng Tang

Department of Psychiatry, Songde Branch, Taipei City Hospital, Taipei, Taiwan,

Shen-Ing Liu

Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan

Liang-Huey Chang

Department of Psychiatry, Far Eastern Memorial Hospital, Taipei, Taiwan

Hsiao-Yu Wu

Division of Biostatistics & Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan

Yao-Sheng Chang

Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan

Teng-Kuang Yeh

Institute of Biotechnoloogy & Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan

Andrew CH Chen

Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA

Yu-Li Liu

Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan

Graduate Institute of Drug Safety, School of Pharmacy, China Medical University, Taichung, Taiwan and Department of Psychiatry, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan.