Escitalopram, citalopram: Are higher doses needed in CYP2C19 ultrarapid metabolizers?
Miguel Ramos, PharmD
Citalopram and escitalopram are selective serotonin reuptake inhibitors commonly used to treat depression, anxiety, and related disorders. Both agents are metabolized primarily by CYP2C19, a polymorphic enzyme known to be associated with interindividual pharmacokinetic (PK) and pharmacodynamic differences. Pharmacogenetic studies of citalopram and escitalopram have resulted in contradictory findings; additional data are needed for clinicians and researchers.
Chang and colleagues conducted a systematic review and meta-analysis to quantify effects of CYP2C19 polymorphisms on escitalopram or citalopram exposure. Investigators included published studies (1993 to 2014) that reported single- or multiple-dose citalopram or escitalopram serum/plasma concentrations or area under the concentration-time curve (AUC) and CYP2C19 genotype or phenotype data. CYP2C19 genotypes were categorized as: CYP2C19 *1 = metabolizer (EM); CYP2C19*17 = ultra-rapid metabolizer (UM); and CYP2C19*2 and *3 = poor metabolizer (PM); diplotypes were assigned accordingly (e.g., CYP2C19 *1/*17 = EM/UM). Included studies must have presented data for CYP2C19*1/*1 metabolizers separately from other genotype categories or included EM or PM phenotype assignment.
A total of 16 studies (n = 987) were included in the analysis. Of these, 3 studies were conducted in Asia and 13 in Europe (11 in Nordic countries). Compared with patients classified as EM/EM genotype, (es)citalopram exposure was 36% and 14% lower in patients categorized as UM/UM and EM/UM, respectively. Conversely, (es)citalopram exposure was increased by 25% in PM/UM, 30% in EM/PM, and 95% in PM/PM, as compared with patients categorized as EM/EM (P < 0.05 for all comparisons).
This is the first systematic meta-analysis of studies that assessed the effect of CYP2C19 genotype variability on levels of escitalopram and citalopram. Authors emphasized findings applicable to the gain-of-function CYP2C19*17 allele. “Homozygous carriers of CYP2C19*17 on average achieved 36% lower exposure to (es)citalopram and may need higher doses to reach an exposure similar to that in subjects homozygous for CYP2C19*1,” authors wrote. However, additional data are needed to support clinical recommendations based on study findings.
Study limitations included pooling data from escitalopram and citalopram studies; possibility of study participants taking interacting drugs that may have affected (es)citalopram levels; and reliance on aggregated group data.
CYP2C19–escitalopram and CYP2C19–citalopram are both identified as gene–drug pairs of interest by the Clinical Pharmacogenetics Implementation Consortium (CPIC). They are classified as CPIC evidence level B and Pharmacogenomics KnowledgeBase (PharmGKB) evidence level 2a. The Dutch Pharmacogenetics Working Group Guideline recommends increasing the dose of (es)citalopram to a maximum of 150% or selecting an alternative drug in patients who are homozygous for the CYP2C19*17 allele, but does not recommend a dose change for other variants.
Chang M et al. Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/ Escitalopram Exposure: A Systematic Review and Meta-Analysis. Clin Pharmacokinet. 2014;53:801–11.
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