title: CYP2C19 variation, not citalopram dose nor serum level, is associated with QTc prolongation.
abstract: Recently, a FDA Safety Communication warned of a dose-dependent risk for QTc prolongation with citalopram, which is metabolized by CYP2C19 of the cytochrome P450 system. We investigate associations between citalopram and escitalopram dose, serum concentration, CYP2C19 phenotype, and QTc. We undertook a retrospective chart review of citalopram or escitalopram patients with the inclusion criteria of consistent medication dose, CYP2C19 phenotype (extensive metabolizers [EM], intermediate metabolizers [IM], poor metabolizers [PM]), and QTc interval on ECG. We further identified 42 citalopram users with citalopram serum concentration measurements and ECG. Regression and one-way ANOVA were used to examine the relationship between citalopram dose, citalopram serum concentration, CYP2C19 phenotype, and QTc interval. Of 75 citalopram patients, the EM group had significantly shorter QTc intervals than a combined IM+PM group (427.1±23.6 ms vs. 440.1±26.6 ms, one-tailed t-test, p=0.029). In the 80 escitalopram cohort, there was no significant difference in QTc between phenotype groups. There was no statistical correlation between citalopram (p=0.62) or escitalopram (p=0.30) dose and QTc. QTc was not associated with citalopram serum level (p=0.45). In contrast to the FDA warning, this study found no association between citalopram/escitalopram dose and QTc. However, PM of the drug tended to have longer QTc intervals. Our findings suggest cytochrome P450 genotyping in select patients may be helpful to guide medication optimization while limiting harmful effects.
authors.affiliation: Mayo Medical School, Mayo Clinic, Rochester, MN, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Kumar
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Kung
authors.affiliation: Department of Psychiatry, University of Iowa, Iowa City, IA, USA gen-shinozaki@uiowa.edu.
authors.forename: Gen
authors.initials: G
authors.lastname: Shinozaki
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000097:blood* / Q000139:chemically induced; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D015283:Citalopram / Q000009:adverse effects* / Q000097:blood; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006329:Heart Conduction System / Q000002:abnormalities*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012189:Retrospective Studies; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000097:blood
chemical_list: D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human
keywords: CYP2C19; Citalopram; QTc interval prolongation; escitalopram; serum level