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Drug Metabol Pers Ther 2016; 31(4): 205212

Dmitriy A. Sychev, Irina S. Burashnikova* and Ruslan E. Kazakov

1846G>A polymorphism of CYP2D6 gene and


extrapyramidal side effects during antipsychotic
therapy among Russians and Tatars: a pilot study
DOI 10.1515/dmpt-2016-0027
Received August 5, 2016; accepted October 20, 2016; previously
published online November 22, 2016

Abstract
Background: ytochrome P450 CYP2D6 activity affects
antipsychotic therapy safety. 1846G>A (CYP2D6*4) polymorphism frequency varies among different ethnic
groups.
Methods: We studied 1846G>A polymorphism in Tatar
and Russian schizophrenic patients taking different antipsychotics and association of 1846G>A polymorphism and
extrapyramidal disorders (EPD) frequency in schizophrenic patients on haloperidol monotherapy in daily
doses up to 20mg.
Results: Heterozygous 1846GA genotype frequency
among Tatars was lower (23.8% vs. 32.4% in Russians),
but the differences did not reach statistical significance.
The 1846A allele frequency among Tatars was also lower
(11.9% vs. 24.3% in Russians), but the difference was not
quite significant (p=0.0592). Average daily haloperidol
dose in the group without EPD was significantly higher
than in the group with EPD (11.354.6 vs. 13.873.3mg,
p=0.0252), but average daily haloperidol dose/weight
ratios in the compared groups had no significant differences. A statistically significant association between
EPD development and heterozygous 1846GA genotype
and 1846A allele carrier frequency was revealed among
all schizophrenic patients and among those of Tatars.
Conclusions: Further well-designed pharmacogenetic
studies in different Russian regions are needed to
improve psychotropic therapy safety and to establish
*Corresponding author: Irina S. Burashnikova, Department of
Clinical Pharmacology and Pharmacotherapy, Kazan State Medical
Academy, Moushtari, 11, Kazan 420012, Russian Federation,
Phone: +79047604240, Fax: +7 843 2730802,
E-mail: irinabis25@mail.ru
Dmitriy A. Sychev: Department of Clinical Pharmacology, Russian
Medical Academy of Postgraduate Education, Moscow, Russian
Federation
Ruslan E. Kazakov: Federal State Budgetary Institution Scientific
Centre for Expert Evaluation of Medicinal Products of the Ministry
of Health of the Russian Federation, Moscow, Russian Federation

evidence-based indications for pharmacogenetic testing


in clinical practice.
Keywords: 1846G>A (CYP2D6*4) polymorphism; antipsychotic; biotransformation; ethnic differences of 1846A
allele carrier frequency; extrapyramidal side effect/
disorder; pharmacogenetics; Russians; schizophrenia;
Tatars.

Introduction
ytochrome P450 (CYP P450) 2D6 is one of the major CYP
P450 cytochrome isoenzymes, metabolizing most psychotropic drugs and is involved in the metabolism of many
antidepressants and antipsychotics (e.g. haloperidol,
thioridazine, zuclopenthixol, risperidone, aripiprazole
and others). It is also well known that side effects of antipsychotics, especially those affecting the extrapyramidal
system, may reduce patient compliance [1] or require prescribing of correctors (trihexyphenidyl, biperiden, amantadine) and medicines of other anatomical therapeutic
chemical groups, thus increasing the drug load and the
cost of a schizophrenic patients treatment [2]. In this
regard, the search for methods to prevent extrapyramidal side effects, including the possibility of predicting
them with the help of a personalized medicine approach,
remains actual [3].
The activity of CYP P450 cytochrome isoenzymes is
influenced by endogenous factors such as age, gender and
concomitant diseases, as well as external factors, including nutrition and habits (e.g. smoking, alcohol intake),
concomitant therapy and others. Furthermore, biotransformation is under the control of the appropriate genes
and the individuals genetic characteristics manifest
themselves in variations of drug metabolism.
It was established that CYP P450 2D6 functional activity varies considerably among different races and ethnic
groups, which can be explained by its common diversity
with more than 150 genetic polymorphisms [4, 5]. Despite
the fact that a great number of CYP2D6 polymorphisms
have been described to the moment, the frequency of
many of them is relatively low (1%). The most common
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206Sychev etal.: 1846G>A polymorphism and haloperidol extrapyramidal ADRs in Russians and Tatars
variant of the CYP2D6 gene causing an absence of the
enzymatic activity is 1846A (CYP2D6*4) allele (rs3892097)
[6]. It was formed due to single nucleotide replacement
1846G>A in the genomic DNA sequence (NCBI Reference
Sequence: NG_008376.3).
Taking into account a huge number of CYP2D6 gene
polymorphisms with different functional activity, it is
increasingly challenging to translate diplotypes into phenotype [79].
According to recent data by Gaedigk etal. [7], the ratio
of CYP2D6 phenotypes predicted from genotypes in European populations is about 5% poor metabolizer (gPM), 5%
intermediate metabolizer (gIM), 88% normal (or extensive) metabolizer (gNM) and 2% ultrarapid metabolizer
(gUM).
The CYP2D6*4 allele is present in 70%90% of PM
patients [10] with a maximum rate of up to 20%25%
among Caucasians [11]. A minimal rate of the CYP2D6*4
allele and very rare occurrence rate of PMs (0%1%) is
described in Asians [12], for example, among Koreans [13].
To date, a number of studies evaluating the association of CYP2D6 gene polymorphisms and antipsychotic
therapy safety have been conducted. In some of them, the
researchers found no association between the presence of
functionally defective CYP2D6 alleles and extrapyramidal
side effects [14, 15]. However, in other studies, such relationships were found [16, 17].
It was also shown in a study on a Russian population
that CYP2D6*4 allele frequency was similar among schizophrenic and mentally healthy individuals, thus indicating a lack of association between this polymorphism
and schizophrenia [18]. Thus, results of a study assessing
CYP2D6*4 allele frequency conducted on a schizophrenic
population could be extrapolated to the general regional
population and vice versa.
The Tatarstan Republic is a federal region of Russia
located in the Volga Federal District with a population
>3.8 million, including 2 million ethnic Tatars and
1.5 million ethnic Russians [19]. There is currently no
data on 1846G>A polymorphism prevalence among the
healthy population and schizophrenic patients in the
Tatarstan Republic. Furthermore, to date, the potential
association between 1846G>A polymorphism and antipsychotic-induced extrapyramidal side effects has not been
studied in schizophrenic ethnic Tatars.
The objective of this study was to investigate the frequency of 1846G>A polymorphism among Tatars and
Russians (on a sample of schizophrenic patients from
Tatarstan taking different antipsychotics), as well as to
evaluate the association between 1846G>A polymorphism

carriage and development of extrapyramidal disorders


(EPD) during antipsychotic therapy with haloperidol.

Materials and methods


Approval was obtained from the Research Ethics Committee of the
Russian Medical Academy of Postgraduate Education and the study
was performed according to the guidelines of the Declaration of Helsinki. The objectives of the study and its possible complications were
explained to the patients in a manner that they could understand, so
they were mentally capable giving informed consent for participating
in the study.

Study population
To evaluate possible interethnic differences in 1846A allele frequency, 79schizophrenic patients taking different antipsychotics (37
patients of Russian and 42 patients of Tatar ethnicity) were recruited
in accordance with the inclusion criteria (age18years, diagnosed
F20 (Schizophrenia) according to ICD-10 [20] and exclusion criteria (age<18years, pregnancy, inability of blood sampling because of
patients mental state). A flow-chart of the patient cohort is presented
in Figure 1.
To evaluate the association between 1846A allele carriage
and EPD development, two groups of patients were selected from
the original sample: 1) patients with EPD (EPD+) classified on the
extrapyramidal symptom rating scale [21] and 2) patients without
EPD (EPD). The criteria of EPD diagnosis were the presence of acute
motor disorders: akathisia, dystonia, pseudoparkinsonism, dyskinesia or its combinations. Also, because of the data indicating an
important role of CYP2D6 in the metabolism of haloperidol at low
concentrations/doses [22], only patients receiving haloperidol monotherapy in doses 20mg per day were included. Additional exclusion criteria were the concomitant use of drugs affecting CYP P450
2D6 activity (e.g. selective serotonin reuptake inhibitors, carbamazepine), clinical and/or laboratory signs of liver and/or kidney disease
which could independently influence on the risk of EPD development. We compared two groups of patients (n=27) in each with and
without extrapyramidal side effects.
To evaluate the association between 1846A allele carriage and
extrapyramidal side effects of haloperidol in schizophrenic patients
of Tatar ethnicity, we chose among them two groups with extrapyramidal side effects (n=14) and without extrapyramidal side effects
(n=13).

DNA extraction and genotyping of 1846G>A


polymorphism
Patients venous blood samples were taken in EDTA vials, frozen immediately and then stored at20 C until required. The G1846A mutation
was determined in the Laboratory of Clinical Pharmacology of Scientific Center of Medical Products Expertise (Moscow) via a restriction

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Sychev etal.: 1846G>A polymorphism and haloperidol extrapyramidal ADRs in Russians and Tatars207

All schizophrenic
patients (n = 79)

II

Russians (n = 37)

Tatars (n = 42)

Schizophrenic
patients taking
other antipsychotic
therapy (n = 25)

Patients without EPS


(n = 27)

III

Patients taking
haloperidol in
monotherapy (n = 27)

Patients without EPS


(n = 13)

Patients taking
haloperidol in
monotherapy (n = 54)

Patients with EPS


(n = 27)

Schizophrenic
patients taking
other antipsychotic
therapy (n =15)

Patients with EPS


(n = 14)

Figure 1:Flow chart of schizophrenic patient cohort.

fragment length polymorphism polymerase chain reaction (PCR-RFLP)


assay. Genomic DNA was isolated from peripheral blood samples using
AxyPrep Blood Genomic DNA Midiprep Kit (Axygen Biosciences, USA)
according to the manufacturers instructions. Amplification was carried out with the help of a Tercic amplifier (DNA Technology, Russia)
in 12.5 L reaction mixture containing 100200 ng of DNA solution,
10 pmol of forward primer 3- CGGGAGACCAGGGGGAGCATAGG-5, 10
pmol of reverse primer 3-GACCGTTGGGGCGAAAGGGGGGT-5, 200
mol of each dNTPs, 0.5 U of Taq DNA polymerase (Syntol, Russia),
50mmol of potassium chloride, 10mmol of Tris-HCl (pH 8.5 at 25 )
and 1.7mmol of magnesium chloride.
After an initial denaturation of gDNA at 95 C for 3min, 35 cycles
were performed consisting of denaturation at 95 C for 10s, annealing at 65 C for 40s and extension at 72 C for 15s.
The PCR-product, containing an 358-bp fragment, was digested
with the restriction enzyme endonuclease PspN4I (SibEnzyme, Russia) (restriction site GGNNCC), SE-buffer Y for PspN4I restrictase
(33mmol of Tris-acetate (pH 7.9 at 25 C), 10mmol of magnesium acetate, 66mmol potassium acetate, 1mmol of DTT, SibEnzyme, Russia).

The 1846G allele was identified by the presence of 116 bp, 221 bp
and 22 bp size fragments. Allele 1846 does not have the restriction
site for endonuclease PspN4I and produces only 116 bp and 243 bp
size fragments. Thereafter, the fragments were separated via electrophoresis on an 8% polyacrylamide gel, stained with ethidium bromide and viewed with an ultraviolet transilluminator TFX-20M Gibco
BRL UV Transilluminator (Life Technologies, USA).

Statistical analysis
Statistical analysis of the results was done by nonparametric methods using the Statsoft Statistica V10.0 program (Dell Statistica,
Tulsa, OK, USA). The normality of distributions of samples, which
was evaluated using a W-Shapiro-Wilk test, was taken into account
when choosing a method. Comparisons of the alleles and genotypes
frequencies between Russians and Tatars and between patients
with and without EPD were performed using a 2-test with Yates

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208Sychev etal.: 1846G>A polymorphism and haloperidol extrapyramidal ADRs in Russians and Tatars
Table 1:Baseline characteristics of the study population.
Variable

Number of patients

Age, years, average (SD)

Gender (nSD)
Male, n (%)

Female, n (%)

Ethnicity (nSD)
Tatars, n (%)

Russians, n (%)

CYP2D6 genotype (nSD)


1846GG

1846GA

1846AA

Hardy-Weinberg equilibrium

All schizophrenic
patients

Schizophrenic patients on
haloperidol monotherapy

Schizophrenic patients on haloperidol


monotherapy of Tatar ethnicity

n=79
41.6 (13.46)

n=54
42.98 (13.5)

n=27
42.7 (13.25)

39 (49.4)
40 (50.6)

26 (48.2)
28 (51.8)

13 (48.1)
14 (51.9)

42 (53.2)
37 (46.8)

27 (50.0)
27 (50.0)

27 (100)

34 (62.96)
18 (33.33)
2 (3.7)
2=0.04 (p>0.05)

19 (70.37)
8 (29.63)

2=0.82 (p>0.05)

54 (68.4)

22 (27.8)

3 (3.8)

2=0.16 (p>0.05)

Table 2:Frequency of genotypes and alleles of the CYP2D6 gene by polymorphic marker 1846G>A in Tatar and Russian schizophrenic
patients.
Genotype CYP2D6*4

Tatars (n=42)
n

1846GG
1846GA
1846AA

Russians (n=37)
n

p-Value

32
10
0

76.2
23.8

22
12
3

59.5
32.4
8.1

0.147
0.456
0.098

Hardy-Weinberg equilibrium
1846G

1846A

74
10

2=0.77 (p>0.05)
88.1
11.9

56
18

2=0.52 (p>0.05)
75.7
24.3

0.059
0.059

correction for continuity or two-tailed Fishers exact test. Comparisons of qualitative characteristics were performed using Fishers
two-tailed 2-test. The differences were considered statistically significant at p<0.05 (with a statistical power >80%). Hardy-Weinberg
equilibrium analysis was performed using online calculator [23].

Results
Of a total of 79 schizophrenic patients, 39 (49.4%) were
male and 40 (50.6%) female. Of these, 42 (53.2%) patients
classified themselves as being of Tatar and 37 (46.8%)
patients of Russian ethnicity. Baseline characteristics of
the study sub-populations are shown in Table 1.
The 1846GG, 1846GA and 1846AA genotypes frequency ratio in all groups of patients corresponded to
the Hardy-Weinberg distribution, because the difference
between numbers of observed and expected individuals
with these genotypes is not significant (Tables 1 and 2).
That allowed us to conclude that the samples were representative and the results reliable.

At first, we compared 1846A allele frequency among


Tatars and Russians (Table 2). Heterozygous 1846GA genotype carrier frequency among Tatars was lower (23.8%
vs. 32.4% in Russians), but the differences did not reach
statistical significance. The 1846A allele frequency among
Tatars was also lower (11.9% vs. 24.3% in Russians), but the
difference was not quite significant (p=0.059) (Table2).
Thereafter, we chose patients receiving haloperidol at
doses up to 20 mg per day (n=54; Figure 1) and divided
them into two groups with and without extrapyramidal side
effects (n=27 in each group). Baseline characteristics of the
compared EPD+ and EPD groups are shown in Table 3.
Gender, ethnic composition and mean ages of the
patients in EPD+ and EPD groups were comparable.
Average daily haloperidol dose in the EPD group was
significantly higher (11.354.6 mg vs. 13.873.3 mg,
p=0.025), but average daily haloperidol dose/weight
ratios in the EPD+ and EPD groups were not statistically,
significantly different (Table 3).
Analysis of the heterozygous 1846A allele carriers
frequency between EPD+ and EPD groups revealed

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Sychev etal.: 1846G>A polymorphism and haloperidol extrapyramidal ADRs in Russians and Tatars209
Table 3:Baseline characteristics of the schizophrenic patients with and without extrapyramidal side effects on haloperidol monotherapy.
Variable

EPD+

EPD

p-Value

Number of patients
Age, years, average (SD)
Weight, kg, average (SD)
Daily haloperidol dose, mg, average (SD)
Daily haloperidol dose/weight, mg/kg, average (SD)
Gender
Male, n (%)
Female, n (%)
Ethnicity
Tatars, n (%)
Russians, n (%)

n=27
43.6 (13.5)
74.1 (18.1)
11.35 (4.6)
0.16 (0.08)

n=27
42.33 (13.42)
73.3 (16.2)
13.87 (3.3)
0.19 (0.05)

0.72
0.88
0.025
0.16

14 (51.9)
13 (48.1)

14 (51.9)
13 (48.1)

1.000
1.000

14 (51.9)
13 (48.1)

13 (48.1)
14 (51.9)

1.000
1.000

Table 4:Frequency of genotypes and alleles of the CYP2D6 gene by polymorphic marker 1846G>A in schizophrenic patients receiving haloperidol monotherapy with and without extrapyramidal side effects.
CYP2D6 genotype

1846GG
1846GA
1846AA

Hardy-Weinberg equilibrium
1846G

1846A

EPD+(n=27)

12
14
1

44.4
51.9
3.7

38
16

2=1.6 (p>0.05)
70.4
29.6

significant differences (51.9% vs. 14.8%, p=0.008). In the


EPD group, homozygous 1846G allele carriers frequency
was significantly higher (81.5% vs. 44.4%, p=0.01)
(Table4). The 1846A allele frequency in the EPD+ group
was also significantly higher than in the EPD group
(29.6% vs. 11.1%, p=0.03).
After that, we selected only persons of Tatar ethnicity treated with haloperidol and divided them into two
groups of those with extrapyramidal side effects (n=14)
and without extrapyramidal side effects (n=13). Baseline
characteristics of compared groups are shown in Table 5.
Mean ages of the patients of Tatar ethnicity in the
EPD+ and EPD groups were comparable. There were a
few more men in the EPD+ group, but the differences were
not significant (Table 5).
Analysis of the 1846A allele frequency among EPD+
and EPD patients of Tatar ethnicity revealed that there
were no patients with the 1846AA genotype in this group.
Heterozygous 1846GA genotype was detected only in Tatar
patients with extrapyramidal side effects, with significant
differences in frequency between EPD+ and EPD groups
(57.1% vs. 0%, respectively, p=0.002) (See Table 6). The
1846A allele frequency was significantly higher in the

p-Value

EPD(n=27)

22
4
1

81.5
14.8
3.7

0.01
0.008
1.509

2=1.69 (p>0.05)
48
88.9
6
11.1

0.03
0.03

EPD+ group than in the EPD group (28.6% vs. 0%,


p=0.005) (Table 6).

Discussion
The patients in our study were on different antipsychotics such as haloperidol, risperidone, paliperidone, quetiapine and others. Despite the CYP P450 2D6 involvement in
the biotransformation of many antipsychotics, there is a
difference in the pharmacological activity of the metabolites of these various drugs. For example, risperidone is
hydroxylated by CYP P450 2D6 to an active metabolite
9-OH-risperidone [24]. CYP P450 2D6 inhibitors reduce
9-OH-risperidone concentration and increase the blood
concentration of risperidone [25], but the total active
concentration of the metabolites remains stable [26].
Therefore, the influence of 1846A allele carriage on EPD
development during risperidone therapy is less predictable. Thus, in the study [27], EPD frequency during risperidone therapy was lower in poor metabolizers (50%)
than in the other phenotypic groups (78%). Haloperidol

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210Sychev etal.: 1846G>A polymorphism and haloperidol extrapyramidal ADRs in Russians and Tatars
Table 5:Baseline characteristics of the schizophrenic patients of Tatar ethnicity on haloperidol monotherapy with and without extrapyramidal side effects.
Variable

EPD+

Number of patients
Age, years, average (SD)

Gender
Male, n (%)

Female, n (%)

Weight, kg, average (SD)

Daily haloperidol dose, mg, average (SD)

Daily haloperidol dose/weight, mg/kg, average (SD)

EPD

p-Value

n=14
39.3 (14.15)

n=13
41.6 (12.49)

0.65

9 (64.3)

5 (35.7)

69.36 (11.55)
11.68 (6.85)
0.174 (0.07)

4 (30.8)
9 (69.2)
69.23 (16.55)
12.27 (7.0)
0.179 (0.05)

0.13
0.13
0.98
0.695
0.85

Table 6:Frequency of genotypes and alleles of the CYP2D6 gene by polymorphic marker 1846G>A in schizophrenic patients of Tatar ethnicity receiving haloperidol monotherapy with and without extrapyramidal side effects.
CYP2D6 genotype

1846GG
1846GA
1846AA

Hardy-Weinberg equilibrium
1846G

1846A

EPD+

EPD
n

p-Value

6
8

42.9
57.1

13
0

100
0

0.002
0.002

20
8

2=2.24 (p>0.05)
71.4
28.6

26
0

100
0

0.005
0.005

is metabolized by the CYP P450 2D6 isoenzyme to inactive


metabolites [28] and a decrease in CYP P450 2D6 activity,
including that due to 1846G>A polymorphism, may lead
to an increased haloperidol blood level and an increase in
the frequency of extrapyramidal side effects.
Some potential limitations of our cohort study should
be recognized. The numbers of patients were relatively
small due to inclusion only of schizophrenic in-patients
who gave informed consent. This could have influenced
the significance values of the differences between the
ethnic groups compared. Also, very few in-patients receive
haloperidol alone and require active antipsychotic polytherapy for treating schizophrenia during hospitalization
in the acute state of the disease. Despite the fact that we
restricted the upper haloperidol daily dose threshold to
20 mg, and mean doses in compared groups were not
significantly different, the actual haloperidol daily doses
received in different patients varied over wide ranges.
We did not investigate the severity of extrapyramidal
side effects, but only established their presence and evaluated them only once (cross-sectional assessment) during
at least 1week of haloperidol treatment. We also did not
assess the disease severity and duration of antipsychotic
treatment, both of which could elevate the risks for developing extrapyramidal side effects.

In this study we only determined the 1846G>A as a


CYP2D6 polymorphism most commonly found in Europeans. Data regarding 1846A (CYP2D6*4) allele frequency
among Tatars and Russians vary considerably depending on the region studied. According to a Russian study
in an Astrakhan population cohort [29], the frequency of
1846GG/1846GA+1846AA genotypes in Russian and Tatar
populations was 78%/22% and 68%/32%, respectively.
Another Russian study in the Bashkortostan Republic
revealed that the non-functional CYP2D6*4 allele frequency
was 17.2% in Russians, 9.5% in Tatars and 7.1% in Bashkirs
[30]. Therefore, our data on 1846A allele frequency in Tatars
and Russians more closely resemble that of our Bashkirian
colleagues, probably due to geographical proximity and
historical relationship. This finding justifies the need for
pharmacogenetic studies in each Russian region to determine the frequency of the most important polymorphisms.
From data from previous studies achieved in different
European groups, the most common loss-of-function polymorphisms other than CYP2D6*4 that can predict most
of the PM phenotypes in the white Caucasian population
were CYP2D6*3, CYP2D6*5, CYP2D6*6, CYP2D6*7 and
CYP2D6*9 [7, 3134].
Most pharmacogenetic studies in different Russian
populations estimated CYP2D6*3 allele frequency to lie
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Sychev etal.: 1846G>A polymorphism and haloperidol extrapyramidal ADRs in Russians and Tatars211

within 0.4%2.86% [3540]. Gaikovitch et al. [37] also


determined CYP2D6*5 and CYP2D6*6 alleles frequency
and found it to be 2.4% and 1.2%, respectively. Thus, the
total frequency of CYP2D6*3, CYP2D6*5 and CYP2D6*6
allele in Russians is approximately in the order of 5%6%.
We could not find data regarding CYP2D6*3, CYP2D6*5,
CYP2D6*6 polymorphism frequency among Tatars.
However, as we cannot completely exclude the influence
of these polymorphisms on EPD frequency, we envisage
studying these variants in our future investigations.
Additionally, we also did not assess other genetic
factors that could have an influence on the risk of haloperidol extrapyramidal side effects (e.g. polymorphisms
of other genes affecting drug metabolism (CYP1A1/2,
CYP3A4/5), dopamine DRD2 and DRD3 receptors and
transporter, MDR1 that codes for a P-glycoprotein).
At the same time, we demonstrated a statistically significant association between EPD development and heterozygous 1846GA genotype and 1846A allele frequency
among all schizophrenic patients and among those of Tatar
ethnicity. This fact strongly supports the feasibility of determining the foregoing polymorphism before prescribing
haloperidol therapy to prevent extrapyramidal side effects.

Conclusions
The 1846A allele frequency in Tatars was lower (11.9%)
than in Russians (24.3%), but the difference was not statistically significant. However, a statistically significant
association between the development of EPD during haloperidol monotherapy and heterozygous 1846GA genotype
and 1846A allele frequency was revealed among all schizophrenic patients and among those of Tatar ethnicity.
More pharmacogenetic studies are needed to assess
the association of different polymorphisms, in particular of 1846G>A, and their effect on drug therapy. This
will provide a better understanding of these links and
hopefully lead to improved therapeutic approaches to
eliminate, or at least ameliorate them, e.g. via personalized therapy. Considering ethnic genetic peculiarities, it
is necessary to initiate well-designed research projects in
different regions of Russia to exclude the influence of nongenetic factors in an attempt to clarify the role of genotyping indications in routine clinical practice.
Acknowledgments: This project forms part of the PhD
thesis in Clinical Pharmacology at Kazan State Medical
Academy, of I.S.B. The authors would like to thank the
following: The Republican Clinical Psychiatric Hospital

administration for their local support and the staff of the


Republican Clinical Psychiatric Hospital who volunteered
to take the blood samples.
Author contributions: All the authors have accepted
responsibility for the entire content of this submitted
manuscript and approved submission. I.S.B. conceived
the idea of this study, participated in its design, collected the data, performed the analysis and wrote the
initial draft of the manuscript. D.A.S. participated in the
conception and design of the study, contributed to the
analysis and helped to prepare the draft manuscript.
R.E.K. participated in the conception and design of the
study, performed genotyping and helped to prepare the
draft manuscript.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played
no role in the study design; in the collection, analysis, and
interpretation of data; in the writing of the report; or in the
decision to submit the report for publication.

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