Influence of CYP2C19 Metabolizer Status on Escitalopram/Citalopram Tolerability and Response in Youth With Anxiety and Depressive Disorders

Abstract

In pediatric patients, the selective serotonin reuptake inhibitors (SSRIs) escitalopram and citalopram (es/citalopram) are commonly prescribed for anxiety and depressive disorders. However, pharmacogenetic studies examining CYP2C19 metabolizer status and es/citalopram treatment outcomes have largely focused on adults. We report a retrospective study of electronic medical record data from 263 youth < 19 years of age with anxiety and/or depressive disorders prescribed escitalopram or citalopram who underwent routine clinical CYP2C19 genotyping. Slower CYP2C19 metabolizers experienced more untoward effects than faster metabolizers (p = 0.015), including activation symptoms (p = 0.029) and had more rapid weight gain (p = 0.018). A larger proportion of slower metabolizers discontinued treatment with es/citalopram than normal metabolizers (p = 0.007). Meanwhile, faster metabolizers responded more quickly to es/citalopram (p = 0.005) and trended toward less time spent in subsequent hospitalizations (p = 0.06). These results highlight a disparity in treatment outcomes with es/citalopram treatment in youth with anxiety and/or depressive disorders when standardized dosing strategies were used without consideration of CYP2C19 metabolizer status. Larger, prospective trials are warranted to assess whether tailored dosing of es/citalopram based on CYP2C19 metabolizer status improves treatment outcomes in this patient population.

Keywords: CYP2C19; SSRI (selective serotonin reuptake inhibitor); antidepressant; anxiety disorders; citalopram; depressive disorder; escitalopram; pharmacogenetics.

FIGURE 1

(A) Total number of side effects experienced during treatment with escitalopram or citalopram (es/citalopram) by 248 patients included in the tolerability analysis. CYP2C19 metabolizer status is associated with the total number of side effects experienced (p = 0.015). The association with CYP2C19 metabolizer status remained significant (p = 0.019) in a multivariate regression model that accounted for es/citalopram dose and concomitant medications. Mean and standard deviation are indicated by the bar and whiskers. (B) Discontinuation rates by CYP2C19 metabolizer status in the tolerability analysis with a documented reason for discontinuation of es/citalopram in the electronic medical record. PMs and IMs were significantly more likely to discontinue es/citalopram relative to NMs (p = 0.007, χ²), while RMs and UMs were not (p = 0.20, χ²). PM, poor metabolizer; IM, intermediate metabolizer; NM, normal metabolizer; RM, rapid metabolizer; UM, ultrarapid metabolizer; n, number.

FIGURE 2

(A) Cumulative days in the inpatient psychiatric unit (over the entire follow-up period after the initial hospitalization) correlated with the total number of side effects in a linear model (regression line in black p = 2 × 10^-10). (B) Cumulative days patients were admitted to the inpatient psychiatric unit during treatment with es/citalopram after the initial hospitalization by CYP2C19 metabolizer status, p = 0.076. Mean and standard deviation are indicated by the bar and whiskers. PM, poor metabolizer; IM, intermediate metabolizer; NM, normal metabolizer; RM, rapid metabolizer; UM, ultrarapid metabolizer; n, number.

FIGURE 3

(A) Time to first weight gain concern during es/citalopram treatment is associated with CYP2C19 metabolizer status (p = 0.018, log-rank test for trend). B, Number of activation side effects during es/citalopram treatment is associated with CYP2C19 metabolizer status (p = 0.029, one-way ANOVA with test for trend). Median and interquartile range are indicated by the bar and whiskers. PM, poor metabolizer; IM, intermediate metabolizer; NM, normal metabolizer; RM, rapid metabolizer; UM, ultrarapid metabolizer; n, number.

FIGURE 4

(A) Percentages of patients in the response analysis who achieved or did not achieve a response while prescribed es/citalopram (p = 0.12, χ²). (B) Time to response was associated with CYP2C19 metabolizer status (p = 0.005, log-rank test for trend). (C) Time to response dose among patients who achieved a response was not different by CYP2C19 metabolizer status (p = 0.27, log-rank test for trend). (D) Response dose was not associated with CYP2C19 metabolizer status (p = 0.67, one-way ANOVA with test for trend). Mean and standard deviation are indicated by the bar and whiskers. PM, poor metabolizer; IM, intermediate metabolizer; NM, normal metabolizer; RM, rapid metabolizer; UM, ultrarapid metabolizer; n, number.