Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment

Abstract

Background: Considering the negative impact of anxiety and depression on society and lack of emergence of new antidepressants, it is of paramount importance to utilize the available treatment options in the best manner possible. Escitalopram is a commonly prescribed antidepressant that is predominantly metabolized by the polymorphic CYP2C19 liver enzyme and consequently, CYP2C19 genotype affects escitalopram metabolism. Previous report showed a strong association between CYP2C19 genotype and escitalopram exposure [1]; therefore, CYP2C19 genotype is a potentially clinically relevant feature in escitalopram treatment, since underdosed patients exhibit lower escitalopram treatment effectiveness [2] and since escitalopram adverse drug reactions (ADR) are dose dependent [3]. Objective of this prospective cohort clinical trial is to evaluate the impact of escitalopram dose adjustment based on escitalopram exposure on treatment efficacy and safety.

Methods: In this prospective cohort study patients suffering from depression were assessed for potential clinical benefits of a personalized dosing regimen for escitalopram, which is based on therapeutic drug monitoring of escitalopram plasma level. Treatment effectiveness was evaluated based on Hamilton depression rating scale (HAM-D), which was performed one day prior to escitalopram treatment initiation (Baseline, Visit 0), as well as after four (Visit 1) and eight (Visit 2) weeks of follow-up. Side effect assessment was based on Scandinavian UKU Side effects rating scale, which was performed at V1 and V2. In case of need, dose adjustment was performed at V1 and was guided by the measured steady state drug plasma level using HPLC two weeks after treatment initiation, with the aim to achieve the optimal exposure to escitalopram in every patient at V2. Relative change in HAM-D and UKU scale readouts from V1 to V2, were compared between comparator (dose was adjusted) and control (dose was not adjusted) groups by independent samples t-test and Chi-square test, respectively. The study protocol in full detail is available on clincaltrials.gov [4]

Results: To this day, 25 participants completed the study, and out of these, 19 participants required dose adjustment between visits. There were no statistically significant differences in the change in HAM-D scores from V1 to V2 between groups (p>0.1). In the comparator group, 11/19 patients reported ADRs, compared to 2/6 patients in control group. Appearance of new, or worsening of the existing ADRs between V1 and V2 was reported in 6/19 patients in the comparator group and in 1/6 patients in the control group. There was no statistically significant difference between groups in ADR emergence or worsening (p>0.1)

Conclusion: The dose of escitalopram in 19 participants was augmented, but did not show statistically significant improvement in treatment effectiveness when compared to control group. There was no statistically significant increase in ADR frequencies in the dose augmentation group either, which is in concordance with the hypothesis that dose increase in underdosed patients does not lead to the increase of ADR frequency and severity. Noteworthy, since this report represents interim analysis on a sample which is approximately one fourth of the planned cohort, the conclusions are not yet unequivocal.

References

[1] Jukic, M.M., Haslemo, T., Molden, E., Ingelman-Sundberg, M., 2018. Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure: a retrospective study based on 2,087 patients. The American Journal of Psychiatry 175(5), 463-470. [2] Florio, V., Porcelli, S., Saria, A., Serretti, A., Conca, A., 2017. Escitalopram plasma levels and antidepressant response. European Neuropsychopharmacology 27(9), 940-944. [3] Forest Pharmaceuticals, 2002. Lexapro package insert. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021323s047lbl.pdf [Accessed: May 4, 2022]. [4] Clinical trial protocol for PsyCise-E study. Available from: https://www.clinicaltrials.gov/ct2/show/NCT05210140 [Accessed: May 4, 2022]