Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response

Abstract

Introduction Pharmacogenetic testing is proposed to minimize adverse effects when considered in combination with pharmacological knowledge of the drug. As yet, limited studies in clinical settings have investigated the predictive value of pharmacokinetic (pk) gene variation on therapeutic drug levels as a probable mechanism of adverse effects, nor considered the combined effect of pk gene variation and drug level on antidepressant treatment response. Methods Two depression cohorts were investigated for the relationship between pk gene variation and antidepressant serum concentrations of amitriptyline, venlafaxine, mirtazapine and quetiapine, as well as treatment response. For the analysis, 519 patients (49% females; 46.6±14.1 years) were included. Results Serum concentration of amitriptyline was associated with CYP2D6 (higher concentrations in poor metabolizers compared to normal metabolizers), of venlafaxine with CYP2C19 (higher concentrations in intermediate metabolizers compared to rapid/ultrarapid metabolizers) and CYP2D6 (lower metabolite-to-parent ratio in poor compared to intermediate and normal metabolizers, and intermediate compared to normal and ultrarapid metabolizers). Pk gene variation did not affect treatment response. Discussion The present data support previous recommendations to reduce starting doses of amitriptyline and to guide dose-adjustments via therapeutic drug monitoring in CYP2D6 poor metabolizers. In addition, we propose including CYP2C19 in routine testing in venlafaxine-treated patients to improve therapy by raising awareness of the risk of low serum concentrations in CYP2C19 rapid/ultrarapid metabolizers. In summary, pk gene variation can predict serum concentrations, and thus the combination of pharmacogenetic testing and therapeutic drug monitoring is a useful tool in a personalized therapy approach for depression.

ABCB1 Gene Variants and Antidepressant Treatment Outcomes: A Systematic Review and Meta‐Analysis Including Results from the CAN‐BIND‐1 Study

“…In addition to the studies that were included by the 2015 meta-analysis, except for Uhr et al 20 and Dong et al 37 we added new data from the CAN-BIND-1 and IRL-GREY, 30 and from 3 other studies published after 2016. 31,56,57 Our analyses of the other five ABCB1 SNPs (rs1045642, rs2032582, rs2032583, rs2235015, and rs2235040) did not reveal significant associations with any of the examined antidepressant treatment outcome variables in outpatients. These negative findings in outpatients remain consistent with meta-analysis by Breitenstein et al 23 who reported a significant association between rs2032583 and rs2235015 and antidepressant treatment outcomes in inpatients only.…”

“…Identification of data through author collaboration. Three datasets included in the systematic review and meta-analyses which were obtained through author collaborations are: STAR*D (Peters et al 17 ), IRL-GREY, 30 and Scherf-Clavel et al 31 The STAR*D (Sequenced Treatment Alternatives to Relieve Depression: NCT00021528) is a multisite clinical study which included participants diagnosed with MDD and received prospective treatment with citalopram for at least 6 weeks. The IRL-GREY (Incomplete Response in Late-Life Depression: Getting to Remission; NCT00892047) sample consisted of adults ≥ 60 years.…”

“…We included IRL-GREY participants who received open-label venlafaxine for 12 weeks. 30 The cohort study by Scherf-Clavel et al 31 investigated the association between antidepressant treatment outcomes (response and remission) and three ABCB1 SNPs (rs1045642, rs2032582, and rs1128503) in individuals with MDD treated for a duration of 7 weeks. For this study, we included individuals who were treated with mirtazapine, amitriptyline, or venlafaxine.…”

“…The majority of those studies reported nonsignificant findings. 31,40,43,[49][50][51] There were insufficient studies for each antidepressant medication type to conduct a meta-analysis.…”

Quantitative determination of the content of venlafaxine and its active metabolite in human plasma using liquid chromatography-mass spectrometry

“…Периоды полувыведения у венлафаксина (4-14 ч.) и ODV (10-20 часов) сравнительно короткие -меньше интервала дозирования 24 ч, что требует мониторинга их остаточного уровня, влияющего на выраженность антидепрессивного эффекта [7].…”