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Page 212 Cendrós et al. J Transl Genet Genom 2020;4:210-20 I http://dx.doi.org/10.20517/jtgg.2020.21

duplications, which can have drastic effects on enzymatic activity. The consequences of these variants on
the plasma levels of drugs have been extensively reported [3,10-12] . The contribution of ABCB1 to plasma
levels has been investigated, although there is little evidence that this transporter plays a relevant role [6,12,13] .
However, there are studies that have reported an association between ABCB1 variants and treatment
[14]
response, albeit in moderate sample sizes or healthy volunteers . The number of studies focusing on
pharmacokinetic parameters vastly outnumbers publications evaluating treatment response and side effects.
[15]
Of these, results on clinical outcomes are unclear. For CYP2D6, there are negative reports , although it
has also been reported that improvement of the condition is affected by the metabolizing phenotype [7,16] .
The situation is similar for ABCB1, with some studies having found association [17,18] with antipsychotic
[19]
responses while others have not . There have also been reports of association with genetic variation in
CYPs and ABCB1 with adverse effects [20-23] . These studies focus on particular adverse effects, such as QT
interval prolongation, dyskinesias and prolactinemia. However, no study has evaluated the impact on a
wide spectrum of possible adverse effects.

The objective of this study is to evaluate the contribution of genetic variants in CYPs, and ABCB1 genes on
antipsychotic drug doses, treatment response and induced side effects, in order to select the factors most
predictive of response. To achieve this objective, data regarding efficacy, side-effects, plasma levels and
CYPs and ABCB1 genetic variants were collected in a sample of patients treated with antipsychotics. These
[24]
patients were participants of a previous study investigating the efficiency of a pharmacogenetic algorithm
using the genotype of different CYPs, which concluded that the inclusion of pharmacogenetic information
was beneficial for treatment. However, plasma levels were not investigated other than for assessing
adherence, and neither was drug transport or in-depth analysis of adverse effects.

METHODS
Sample
[24]
Three hundred and eighteen patients from a previous work were included in the study. The gender
distribution was 55% male and 45% female. Mean age was 47 years old. These patients all had a diagnosis
of schizophrenia, schizoaffective or delusional disorder. The most commonly used drug was clozapine
(135 patients) followed by olanzapine (41 patients), paliperidone (39 patients), risperidone (38 patients),
aripiprazole (21 patients), and quetiapine (18 patients); the remaining patients used other drugs. All
patients used a single antipsychotic for the duration of the study. One hundred and thirty of these patients
received a pharmacogenetic intervention consisting of adjustment of their antipsychotic drug dose
according to their CYP genetic profile when required, while the rest received standard treatment. This
cohort is described in Table 1.

Biochemical parameters
The plasma concentrations of both the antipsychotic and its main metabolite were determined at 6 weeks
after starting treatment, when steady state was achieved. Since treatment doses were not modified after
reaching steady state, plasma levels were assumed to be stable for the remainder of the treatment. The
plasma concentration of parent antipsychotic drugs, metabolites and active moiety were measured by a
validated high-performance liquid chromatography (HPLC) method, using ultraviolet visible diode array
detection and solid-phase extraction on cyano cartridges. Compounds were separated on a C8 reversed-
phase column with a gradient of acetonitrile and phosphate buffer 50 mM, pH 3.8 and detected at 210
and 278 nm. To assure high precision and accuracy of the method, an internal standard was included in
the sample preparation and quantitative evaluation. The within- and between day precision expressed as
coefficient of variation (CV)% were < 10%. The quality of analyses was subject to a program of internal
quality control and external quality assessment .
[25]