Pharmacodynamics and Pharmacokinetics of Citalopram and Escitalopram

Summary

This study is one component of a larger U01 grant that was submitted in August, 2004 to the NIGMS as part of the Pharmacogenomic Research Network. This study will enroll 1200 patients over 4 years. It is known that functionally significant genetic polymorphisms for the cytochrome P450 (CYPs) can contribute to individual differences in response to specific selective serotonin reuptake inhibitors (SSRIs). However, a better understanding of the pharmacogenomics of both PK and PD for SSRI antidepressants will inform clinical practice. Therefore, we propose to evaluate the contribution of pharmacogenomics to variation in response to the highly specific SSRIs citalopram (a racemic mixture) and escitalopram (a chiral compound containing the active S-isomer of citalopram ) by correlating both PK and PD variation for these agents with intragene haplotypes in genes encoding proteins involved in citalopram metabolism, as well as central nervous system (CNS) pathways for monoamine neurotransmitter biosynthesis, metabolism, storage, release, reuptake, and receptors. In the future this "candidate pathway" intragene haplotype genotyping strategy will also be complemented by the application of genome-wide screens performed with DNA from subjects with extreme phenotypes for response to citalopram. Phenotypes to be measured before and after the initiation of citalopram or escitalopram therapy will include determinations of serum citalopram and metabolite concentrations, treatment response as measured by Hamilton Rating Scale for Depression indices, and number and severity of side effects as determined by structured questionnaires. The hypothesis to be tested is that inherited variation in citalopram metabolism and transport (PK) and/or PD variation as a result of inherited variation in monoamine neurotransmitter biosynthesis, metabolism, reuptake, storage, receptors or signaling contribute to individual variation in citalopram antidepressant efficacy and/or side effects.

Timeline

Start

2005-03

Primary completion

2013-05

Completion

2013-05

Publications

• Liu D, Ray B, Neavin DR, Zhang J, Athreya AP, Biernacka JM, Bobo WV, Hall-Flavin DK, Skime MK, Zhu H, Jenkins GD, Batzler A, Kalari KR, Boakye-Agyeman F, Matson WR, Bhasin SS, Mushiroda T, Nakamura Y, Kubo M, Iyer RK, Wang L, Frye MA, Kaddurah-Daouk R, Weinshilboum RM. Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics. Transl Psychiatry. 2018 Jan 10;8(1):10. doi: 10.1038/s41398-017-0056-8.
• Mrazek DA, Biernacka JM, McAlpine DE, Benitez J, Karpyak VM, Williams MD, Hall-Flavin DK, Netzel PJ, Passov V, Rohland BM, Shinozaki G, Hoberg AA, Snyder KA, Drews MS, Skime MK, Sagen JA, Schaid DJ, Weinshilboum R, Katzelnick DJ. Treatment outcomes of depression: the pharmacogenomic research network antidepressant medication pharmacogenomic study. J Clin Psychopharmacol. 2014 Jun;34(3):313-7. doi: 10.1097/JCP.0000000000000099.
• Ji Y, Biernacka J, Snyder K, Drews M, Pelleymounter LL, Colby C, Wang L, Mrazek DA, Weinshilboum RM. Catechol O-methyltransferase pharmacogenomics and selective serotonin reuptake inhibitor response. Pharmacogenomics J. 2012 Feb;12(1):78-85. doi: 10.1038/tpj.2010.69. Epub 2010 Sep 28.

Drugs

Indications