Effects of Cytochrome P450 (CYP) 2C19 Genotypes on Steady-State Plasma Concentrations of Escitalopram and its Desmethyl Metabolite in Japanese Patients With Depression

Abstract

Background:Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression.Methods:Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods.Results:There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram.Conclusions:These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy

“…Six studies showed an association between ESC BL and CYP2C19 metabolism ( 25 – 29 , 32 ). Four studies showed an increase in ESC BL (dose-corrected and non-dose-corrected) of up to 90% and 470% in patients carrying heterozygous and homozygous non-functioning CYP2C19 alleles (either *2, *3, or *4 alleles), respectively ( 25 – 28 ).…”

“…Six studies examined the effect of age on ESC BL ( 21 – 23 , 29 , 31 , 32 ), four of which found an association ( 21 , 22 , 29 , 32 ), while two did not ( 23 , 31 ). In one study, older age correlated with higher ESC dose-normalized BL ( 22 ).…”

“…One study compared the C/D ratio in elderly (>65 years) with younger (<65 years) patients, which was increased by an average of 40% in the elderly (not significant for CYP2C19 low metabolizers) ( 32 ). Analysis of covariance in one study showed a correlation of CYP2C19 genotypes and age with the steady-state ESC BL ( 29 ). A linear regression analysis from another study showed no influence of age on the ESC BL ( 23 ).…”

“…Two studies reported median and interquartile blood levels from responders treated with oral ESC under flexible dosing ( 11 , 13 ). Interquartile ranges (median) of responders were 21–44 ( 29 ) ng/ml ( n = 360), and 24–54 ( 36 ) ng/ml ( n = 34), respectively.…”

Factors associated with fluoxetine and norfluoxetine plasma concentrations and clinical response in Mexican patients with mental disorders

“…This study has some limitations that need to be recognized. First, the sample size is smaller than previously SSRI studies published 35,36 ; nevertheless, considering the outpatient condition of the patients included, the sample size resulted adequate compared to similar antidepressants studies 13,37 . Second, the outpatient setting condition did not guarantee medication adherence due to the unsupervised administration of the drugs and there is knowledge that factors like difficulty in accepting the need for long‐term treatment and preference for the psychological management, make frequent high non‐adherence rates in psychiatric clinical practice 38 .…”