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.