DISCUSSION
In this retrospective study, we found a significant effect ofCYP2D6 genotype on vortioxetine exposure measured in routine
clinical practice. The systemic exposure of vortioxetine observed in the
CYP2D6 PM group was 3-fold higher than that observed in the NM group,
while the exposure in the IM group was increased 1.5-fold compared to
the NM group. A population pharmacokinetic study of vortioxetine has
previously shown a significant effect of CYP2D6 phenotype on oral
clearance of vortioxetine with average estimated values being 53 L/h for
UMs, 34 L/h for NMs, 27 L/h for IMs and 18 L/h for PM [7].
This is reflected in the vortioxetine drug label, where it is
recommended that CYP2D6 PMs should be treated with a maximum dose of 10
mg vortioxetine per day [8]. The present study confirms
this recommendation based on data from a naturalistic setting, which is
important from a clinical point of view. Although the vortioxetine
exposure for CYP2D6 UMs is expected to be reduced compared to NMs,
clinical studies have shown a significant overlap in exposures between
UMs and NMs and therefore dose adjustment for UMs is not recommended
[3]. This is in line with the results from the current
study where no significant difference in vortioxetine exposure was found
between CYP2D6 UMs and NMs. However, it should be noted that this
finding was based on a limited number of UM patients (N=8).
The current study showed that CYP2D6 PMs and UMs, as compared with NMs,
had an increased frequency of switching to another antidepressant within
the expected time frame of a depressive episode (three months). As PMs
exhibited significantly higher exposures compared to the other CYP2D6
phenotype groups, the increased switch rate in PMs is likely to be
driven by a higher frequency of adverse events caused by
supratherapeutic drug concentrations. By decreasing the dose among the
CYP2D6 PMs, patients could have achieved lower vortioxetine
concentrations, which may have increased the probability of staying
within the therapeutic window and reduced their risk of
concentration-dependent adverse drug reactions. Although no significant
difference in vortioxetine exposure was found between CYP2D6 UMs and
NMs, the median concentration observed among the UMs was lower than 10
ng/mL, which has been reported as the lower limit for efficacy of
vortioxetine [9]. As the UM patients generally had exposure
levels close to the lower limit of the therapeutic window, the increased
frequency of antidepressant switch may be related to insufficient
clinical response. However, these findings are based on a very limited
number of patients and larger studies would be needed to adequately
address this hypothesis.
Overall, the findings from this study are in line with previous reports
on the effect of CYP2D6 and CYP2C19 genotypes on
risperidone and escitalopram treatment outcomes, respectively
[5,6]. In a study of 725 patients treated with risperidone,
CYP2D6 PMs and IMs were found to have a significant increase in serum
levels of risperidone active moiety compared to NMs
(P<0.0001). Furthermore, the incidence of treatment switch
from risperidone to another antipsychotic was significantly increased in
PMs (P=0.015) and UMs (P=0.003) compared to NMs[6].
Similarly, a study of more than 2,000 escitalopram-treated patients
showed a 3.3-fold increase in escitalopram exposure among CYP2C19 PMs
and a 10% reduction in exposure in CYP2C19 UMs compared to NMs.
Paralleled by the differences in exposure, the CYP2C19 PMs and UMs
showed significantly higher frequencies of switching from escitalopram
to another antidepressant compared to CYP2C19 NMs (P<0.001)
[5].
The main limitations of the current study were the limited number of UM
patients and lack of clinical information retrieved from the patients’
medical records due to privacy issues. Although switch of antidepressant
treatment within three months may indicate therapeutic failure, exact
information on treatment outcomes (including the reasons for treatment
switch) was not obtainable from the TDM database. Furthermore, lack of
knowledge on covariates that may affect drug exposure, such as
comedications, renal function and body size represent additional
limitations. However, the use of TDM data also represents several
advantages, e.g. exact information on drug use and replacement (switch),
as the analytical method allows for the detection of serum concentration
levels of multiple antidepressants simultaneously. Furthermore, the
availability of serum concentration levels enables identification and
exclusion of non-compliant patients, where the drug levels are
undetectable.
In conclusion, this study confirms the significant effect ofCYP2D6 genotype on vortioxetine exposure and provides novel data
on the association between CYP2D6 genotype and therapeutic
failure in a naturalistic, clinical setting. Together with previous
studies, these results underline the importance of variability in CYP
metabolism on treatment outcomes of psychiatric medications and support
the value of routine TDM and CYP genotyping in personalised
medicine in psychiatry.