Low Escitalopram Concentrations in Patients with Depression predict Treatment Failure: A Naturalistic Retrospective Study

Abstract

Introduction Cross sectional therapeutic drug monitoring (TDM) data mining introduces new opportunities for the investigation of medication treatment effects to find optimal therapeutic windows. Medication discontinuation has been proven useful as an objective surrogate marker to assess treatment failure. This study aimed to investigate the treatment effects of escitalopram and pharmacokinetic influences on blood levels using retrospectively assessed data from a TDM database. Methods Data was collected from 134 patients longitudinally treated with escitalopram for whom TDM was requested to guide drug therapy. Escitalopram metabolism was estimated by the log-transformed dose-corrected concentrations and compared within subpopulations differing in age, gender, renal function, smoking status, body mass index, and comedication. Results Patients with a depressive episode who were treated with escitalopram and discontinued the treatment within the hospital stay showed lower serum concentrations compared to patients who continued escitalopram treatment with a concentration of 15 ng/mL separating both groups. Variability was high between individuals and factors influencing blood levels, including dose, sex, and age. Comedication that inhibits cytochrome P450 (CYP) 2C19 isoenzymes were further found to influence escitalopram pharmacokinetics independent of dose, age or sex. Discussion Medication switch is a valuable objective surrogate marker to assess treatment effects under real-world conditions. Of note, treatment discontinuation is not always a cause of insufficient response but may also be related to other factors such as medication side effects. TDM might not only be useful in addressing these issues but titrating drug concentrations into the currently recommended reference range for escitalopram will also increase response in non-responders and avoid treatment failure in underdosed patients.

Assessing Pharmacokinetic Correlates of Escitalopram-Related Adverse Drug Reactions

“…Patients in our group had various psychiatric diagnoses, whereas previous studies invariably assessed cohorts of patients with MDD. 16 , 18 , 19 Interestingly, rates of ESC-associated ADRs were more frequent in patients with versus without psychotic disorders (25% vs 7.1%). In this context, it could be speculated (and assuming that patients with psychotic disorders were also receiving antipsychotic treatment) that the interactions of ESC with other medications may explain this pattern.…”

“…Reported ADR rates neither differed between patients with “high” ESC concentrations (>40 ng/mL) versus patients with “low” ESC concentrations (≤40 ng/mL) with 40 ng/mL as the upper threshold of a recently suggested therapeutic reference range for ESC of 20–40 ng/mL by Eichentopf et al 8 nor between patients with ESC concentrations >80 ng/mL versus patients ≤80 ng/mL as the upper threshold of the current therapeutic reference range suggested by Hiemke et al 5 Previous reports have suggested elevated ESC levels in patients with dry mouth, diarrhea, or drowsiness, 18 whereas no pharmacokinetic differences have been reported for other ADRs such as QTc prolongation. 16 Thus, the heterogeneity of the assessed ADRs and their underlying mechanisms may hamper the detection of clear pharmacokinetic patterns directly involved in ESC-associated ADRs. The most reported UKU type (40%) in our retrospective analysis was other ADRs.…”

“…In fact, a previous meta-analysis of TDM studies suggested that the evidence for pharmacokinetic correlates of ESC-associated ADRs is not strong. 8 For instance, Hart et al 16 , 17 did not report any relationship between ESC concentration and QTc in a naturalistic sample. The same research group analyzed ADRs in a naturalistic sample of 300 patients with MDD with information on ADRs being available in 50 (out of 300) patients 17 ; 12 of these 50 patients (24%) reported ESC-associated ADRs with mean drug concentrations of ESC 36.0 ± 33.5 ng/mL and a mean daily dose of 15.6 ± 5.0 mg.…”

Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants

“…65 In addition, 80% of SERT thresholds derived from PET studies are in line with lower efficacy concentrations reported for the drug that predict response to the treatment. [66][67][68] One study demonstrated that treatment response was related to pretreatment SERT binding ratios in the key regions of depression. 20 SNRIs are believed to exert their action by a combination of SERT and NET engagement with varying activities at both transporters, making it more complicated to determine a specific threshold.…”

“…65 In addition, 80% of SERT thresholds derived from PET studies are in line with lower efficacy concentrations reported for the drug that predict response to the treatment. 66–68 One study demonstrated that treatment response was related to pretreatment SERT binding ratios in the key regions of depression. 20…”