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.

Antidepressant Tolerability in Pediatric Anxiety and Obsessive-Compulsive Disorders: A Bayesian Hierarchical Modeling Meta-analysis

“…20,23,44 The prior meta-analysis that evaluated activation and used a similar definition examined antidepressants in aggregate (ie, SSRIs and SNRIs), thus potentially obscuring SSRI-specific activation. 2 Additionally, SSRI-related activation in pediatric patients is correlated with dose 34 and blood level in several studies; however, the relationship between dose and exposure (eg, blood level) 20 as well as other factors that increase the risk of activation (eg, age) is complex. In the Child/ Adolescent Anxiety Multimodal Study, 1 activation-related AEs were more common in sertraline-treated children compared with adolescents (disinhibition: 5.8% versus 0%; increased motor activity: 4.1% versus 0.8%; restless/fidgety: 2.8% versus 1.6%; significance thresholds for individual events not reported).…”

“…Also, in children and adolescents treated with escitalopram or citalopram, the number of activation symptoms that patients exhibited (insomnia, irritability, hyperactivity, and impulsivity) was related to the CYP2C19 metabolizer status, with slower metabolizers experiencing more activation symptoms than faster metabolizers (p ¼ .019) in addition to the maximum dose of escitalopram or citalopram (p < .001). 34 Gastrointestinal symptoms have been associated with SSRI/SNRI treatment in pediatric patients 23 but are also influenced by the presence and severity of anxiety disorders. 52 However, in general, gastrointestinal symptoms improve with active treatment, whether psychopharmacologic or psychotherapeutic.…”

“…For example, "activation" consisted of activation then restlessness then impulsivity then irritability. 20,34 "Abdominal pain" was the preferred AE term; however, if this was not reported, the frequency of "abdominal discomfort" was used, and if neither was reported, the frequency of "gastric distress" was used. Establishing this hierarchy of preferred terms for our AE analysis a priori decreased the likelihood of inflation and reporting bias and is consistent with approaches used in meta-analyses of the efficacy of these medications in pediatric anxiety disorders.…”

Clinical Utilization of Pharmacogenetics in Psychiatry – Perspectives of Pharmacists, Genetic Counselors, Implementation Science, Clinicians, and Industry

“…It is critical that PGx testing be utilized as a guide rather than a replacement for clinical judgment. Further, accumulating data suggest that PGx testing may be utilized to guide dosing, particularly with regard to enhancing tolerability [126]. However, with the exception of FDA guidelines for many psychotropic medications and CPIC guidelines for several additional medications, PGx-driven titration strategies are lacking [127].…”

CYP2C19-Guided Escitalopram and Sertraline Dosing in Pediatric Patients: A Pharmacokinetic Modeling Study

“…For example, in sertraline-treated children and adolescents (N = 90), higher plasma concentrations were associated with more antidepressant-related side effects (Taurines et al 2013), and activation is associated with plasma fluvoxamine concentrations in anxious youth (Reinblatt et al 2009). More recently, a retrospective study of escitalopram/citalopram tolerability (N = 248) showed CYP2C19 metabolizer status significantly influenced weight gain, activation, and insomnia (Aldrich et al 2019), suggesting that side effects were related to CYP2C19-related differences in exposure rather than differences in dosing (despite no observed differences in dosing across phenotypes). Taken together, these findings suggest that plasma SSRI concentrations might be related to side effect burden and potentially efficacy.…”