METHODS
Patients’ data were included retrospectively from the TDM database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, which is a service analysing both serum concentrations of psychotropic drugs and offering CYP genotyping on request from clinicians.CYP2D6 -genotyped patients were included in the study if they had been on vortioxetine treatment during the period January 2013 to June 2020. Exclusion criteria comprised concomitant use of potent CYP2D6 and/or CYP2C19 enzyme inhibitors (bupropion, fluoxetine, levomepromazine, or paroxetine), or CYP3A4 inducers (carbamazepine, phenobarbital, or phenytoin), detected by reviews of the TDM requisitions form, and serum concentrations of vortioxetine below the analytical assay’s lower limit of quantification. Furthermore, patients with missing information on the prescribed vortioxetine daily dose were excluded.
CYP2D6 genotyping was performed using TaqMan®-based real-time PCR assays (Life Technologies, USA) including the following allele variants:CYP2D6*3 (rs35742686 ), CYP2D6*4 (rs3892097 ),CYP2D6*5 (whole gene deletion), CYP2D6*6(rs5030655 ), CYP2D6*9 (rs5030656 ), CYP2D6*10(rs1065852 ), CYP2D6*41 (rs28371725 ), and copy number variation. Based on the CYP2D6 genotype, patients were categorized into CYP2D6 PM, IM, NM or UM categories according to the consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG) [4].
Serum concentration of vortioxetine was determined by an ultra-high-performance LC (UHPLC)-high resolution mass spectrometry (HRMS) method validated for use in clinical practice. The same analytical method was used to detect presence of other antidepressants in serum including amitryptyline, nortryptyline, bupropion, citalopram, escitalopram, fluoxetine, duloxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, clomipramine, trimipramine, mianzerin and mirtazapine.
Longitudinal reviews of serum-detected drugs in the included patients’ TDM profiles were performed to identify cases of treatment switch from vortioxetine treatment to another antidepressant within three months after their last vortioxetine TDM measurement, in line with procedures from recent publications on escitalopram [5] and risperidone [6]. As the timeframe of three months represents a major depressive episode, an event of treatment switch was interpreted as therapeutic failure of vortioxetine, regardless of cause.
When comparing vortioxetine exposure between CYP2D6 phenotype groups, serum concentration measurements of vortioxetine were dose-harmonized and ln-transformed to restore normal distribution. The dose-harmonized, ln-transformed concentrations in each CYP2D6 phenotype group were compared using the one-way analysis of variance (ANOVA) followed by the Tukeypost-hoc tests. Treatment failure rates were compared between CYP2D6 phenotype groups using Fisher’s exact test.
The study was approved by the Regional Ethical Committee of the South-Eastern Health Authority in Norway and the Hospital Investigational Review board.