Letter to the Editor: The Impact of Adherence and CYP2C19 Phenotype on Escitalopram Exposure in Adolescents

To the Editor:

In adolescents, variability in escitalopram pharmacokinetics is linked to CYP2C19 activity (Bousman et al., 2023; Jukić et al., 2018), and CYP2C19 metabolism correlates with peak drug concentrations, area under the curve, and clearance (Strawn et al., 2023; Strawn et al., 2020). However, the ramifications of inconsistent adherence on escitalopram pharmacokinetics in adolescents across CYP2C19 phenotypes have not been explored. With this in mind, we present four adolescents enrolled in an NIH-funded, IRB-approved prospective trial of forced-flexibly dosed escitalopram in adolescents with generalized anxiety disorder (GAD) (Strawn et al., 2020). Escitalopram was initiated at 5 mg daily for 2 days, titrated to 10 mg for 5 days, and then titrated to 15 mg; at week 4 or 6, it could be further titrated to 20 mg. Using pharmacokinetic parameters that account for differences in CYP2C19 phenotypes and previously reported pediatric pharmacokinetic data for escitalopram (Strawn et al., 2023), we modeled escitalopram exposure, in four patients with varying degrees of adherence during an 8-week study and compared these effects across CYP2C19 phenotypes.

Patient A is a 14-year-old girl (CYP2C19 normal metabolizer, *1/*1, Tanner stage 3, height 162 cm and weight 55.8 kg) who meets DSM-IV-TR criteria for GAD (primary), panic disorder with agoraphobia (baseline pediatric anxiety rating scale [PARS] score: 15). She missed about one dose of escitalopram every 2 weeks, although before her week 8 visit, she missed four doses. She experienced shakiness, shortness of breath, myalgia, and abdominal pain during this period. Regular adherence eliminated these withdrawal symptoms, and her plasma escitalopram concentrations contemporaneously returned to steady state. Her PARS score was 9 at week 8 and missed doses reduced escitalopram concentrations by ∼60% (Fig. 1A).

FIG. 1.

Concentration time curves in four escitalopram-treated adolescents with GAD. Patient A is a CYP2C19 normal metabolizer (A), Patient B is a CYP2C19 rapid metabolizer (B), while Patients C and D are intermediate metabolizers (C, D). Escitalopram was initiated at 5 mg daily and titrated to 10 mg daily after 2 days and then 15 mg daily with the option to increase to 20 mg daily at either week 4 or 6. The dot reflects pharmacokinetic sampling. The gray dotted lines indicate the escitalopram therapeutic reference range for adults (Hiemke et al., 2018), and asterisks represent missed doses. GAD, generalized anxiety disorder.

Patient B is a 16-year-old girl (CYP2C19 rapid metabolizer, *1/*17, Tanner stage 4, height 151 cm and weight 47.9 kg) who meets DSM-IV-TR criteria for social anxiety disorder, GAD, panic disorder with agoraphobia (baseline PARS score: 22). She worried about the future, academic success, being on time, not making mistakes, her family and relationships, and her anxiety was difficult to control. She had significant improvement (week 8 PARS score: 7). However, in the fourth week of treatment, she missed six doses of medication, and by the eighth week, she missed two more. Missed doses reduced plasma escitalopram concentrations by 92% (Fig. 1B).

Patient C is a 16-year-old boy (CYP2C19 intermediate metabolizer, *1/*2, Tanner stage 4, height 174 cm and weight 55.5 kg) who meets DSM-IV-TR criteria for generalized and social anxiety disorders (baseline PARS score: 15). He had minimal response over the course of the study with his week 8 PARS score being 16 and missed several doses of medication during the trial, but not more than 1 day consecutively (Fig. 1C). Missed doses corresponded with ∼a 54% reduction in escitalopram concentrations.

Patient D is a 16-year-old girl (CYP2C19 intermediate metabolizer, *1/*2, Tanner stage 5, height 164 cm and weight 79.2 kg) with GAD, social and separation anxiety disorders, and dysthymia (baseline PARS score: 20). Despite external psychosocial struggles, her core anxiety symptoms improved (week 8 PARS score: 13); however, she missed several doses (Fig. 1D), which reduced escitalopram concentrations by ∼35%.

Marked adherence-related fluctuations in escitalopram concentrations reported herein underscore the need for clinicians to consider medication adherence and its interplay with pharmacokinetic genes. The reduction in escitalopram concentrations associated with missed doses ranged from 35% to 54% in intermediate metabolizers to more than 90% in rapid metabolizers because of significantly shorter half-life with faster metabolism. Peak concentrations varied widely across CYP2C19 metabolizer groups. Thus, across CYP2C19 phenotypes, differences in adherence patterns produce strikingly variable effects on escitalopram exposure, which may alter the treatment trajectory (Strawn et al., 2020).

The nexus between adherence, plasma concentrations, and pharmacogenetics may underlie differences in tolerability, withdrawal symptoms (Strawn et al., 2023), and response frequently observed in selective serotonin reuptake inhibitor (SSRI)-treated youth. This highlights the potential role of pharmacogenetic testing in understanding adherence-related fluctuations in antidepressant concentrations. Moreover, even in the absence of therapeutic drug monitoring, understanding the pharmacogenetic makeup of a patient can be clinically salient information for the counseling of a patient and their family. The impact of variation in metabolism, in the context of partial adherence, on SSRI withdrawal symptoms or discontinuation strategies may be helpful for clinicians' discussions with parents, patients, and caregivers.

Disclosures

J.R.S. has received research support from the National Institutes of Health, the Yung Family Foundation, and PCORI. He has received material support from Myriad. He is an Associate Editor for Current Psychiatry and receives royalties from UpToDate, Springer, and Cambridge. He has provided CME lectures for the Neuroscience Education Institute, the American Academy of Child & Adolescent Psychiatry, and the American Academy of Pediatrics. He has consulted to FDA, Cerevel, Intracellular Therapeutics, and Otsuka. L.B.R. has received research support from the National Institutes of Health and has served as a consultant and received research support from BTG Specialty Pharmaceuticals. The other authors report no conflicts of interest.