Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47
https://doi.org/10.1186/s12881-019-0773-3

RESEARCH

Open AccessA pharmacogenetic study of patients withschizophrenia from West Siberia gets
insight into dopaminergic mechanisms ofantipsychotic-induced hyperprolactinemia
Diana Z. Osmanova1,2, Maxim B. Freidin3,4, Olga Yu. Fedorenko1,5, Ivan V. Pozhidaev1,2, Anastasiia S. Boiko1,
Natalia M. Vyalova1, Vladimir V. Tiguntsev1, Elena G. Kornetova1, Anton J. M. Loonen6,7, Arkadiy V. Semke1,
Bob Wilffert6,8, Nikolay A. Bokhan1,2 and Svetlana A. Ivanova1,5*
From 11th International Multiconference “Bioinformatics of Genome Regulation and Structure\Systems Biology” - BGRS\SB2018
Novosibirsk, Russia. 20-25 August 2018

Abstract
Background: Hyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed toblockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland.
Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within
the adenohypophysis. Nevertheless, due to competition for pituitary DRD2s by high dopamine levels may limit
antipsychotic-induced HPRL. Moreover, the activity of prolactin-producing lactotrophs also depends on otherhormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters,
enzymes of neurotransmitter metabolism and other factors. Polymorphic variants in the genes coding for thesereceptors and proteins can have functional significance and influence on the development of hyperprolactinemia.
Methods: A set of 41 SNPs of genes for dopamine receptors DRD1, DRD2, DRD3, DRD4, the dopamine transporter
SLC6A3 and dopamine catabolizing enzymes MAOA and MAOB was investigated in a population of 446 Caucasians(221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) with and without
HPRL who were treated with classical and/or atypical antipsychotic drugs. Additive genetic model was tested andthe analysis was carried out in the total group and in subgroup stratified by the use of risperidone/paliperidone.
Results: One statistically significant association between polymorphic variant rs1799836 of MAOB gene and HPRL in
men was found in the total group. Furthermore, the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be
associated with HPRL in the subgroup of patients using the risperidone/paliperidone, but not with HPRL inducedby other antipsychotic drugs.
(Continued on next page)* Correspondence: ivanovaniipz@gmail.com
1
Mental Health Research Institute, Tomsk National Research Medical Centerof the Russian Academy of Sciences, Aleutskaya str., 4, Tomsk, RussianFederation634014
5
National Research Tomsk Polytechnic University, Lenin Avenue, Tomsk,
Russian Federation30
Full list of author information is available at the end of the article© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

Page 36 of 56(Continued from previous page)

Conclusions: Our results indicate that genetic variants of MAOB and SLC6A3 may have consequences on themodulation of prolactin secretion. A further search for genetic markers associated with the development of
antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.
Keywords: Dopamine receptors genes, Dopamine transporter SLC6A3, Monoamine oxidase (MAO), Antipsychotics,
Hyperprolactinemia

Background
Schizophrenia is a serious polymorphic mental disorder,
characterized by positive (e.g., hallucinations, delusions),
negative (affective flattening, social withdrawal) and cognitive symptoms (disorders of attention, working memory deficits). Treatment of schizophrenic illness usually
involves the long-term usage of antipsychotic drugs [1],which have both therapeutic and side effects, related toantagonism to D2 receptors. One of the common side
effects of these drugs is hyperprolactinemia [2, 3].
HPRL-related phenomena may lead to additional social
stigmatization of the patient with schizophrenia, which
reduces the compliance of patients to therapy and increases the cost of treatment. HPRL has short- andlong-term consequences that can seriously affect qualityof life: menstrual disturbances, galactorrhea, sexual dysfunction, gynecomastia, infertility, and possibly decreased bone mineral density.
Prolactin (PRL) is a polypeptide hormone that contains
199 amino acids and is categorized as part of the growth
hormone family [4]. Prolactin secretion is under a complex neuroendocrine control, in which various agents
participate: neurotransmitters, biologically active neuropeptides, hormones of peripheral endocrine glands. Synthesis and secretion of prolactin are carried out bylactotrophs of the pituitary gland, which constitute an
average of 20–50% of the total cell population of the pituitary cells [5].
Factors involved in the regulation of prolactin secretioncan be divided into two groups: 1. prolactin-inhibiting –dopamine (DA), gamma-aminobutyric acid, gastrin, somatostatin, gonadotropin-binding protein and 2. prolactinstimulating – serotonin, thyrotropin-releasing hormone(TRH), gonadotropin-releasing hormone (TRG), vaso-intestinal peptide, opiates, neurotensin and substance P, oxytocin, angiotensin 2 [6, 7].
Dopamine holds a predominant role in the regulation of prolactin secretion. Dopamine, which is released by tuberoinfundibular neurons, normally acts
at specific receptors on lactotrophes to tonically inhibit prolactin secretion and maintain physiologicallynormal prolactin levels in the blood [8]. These dopamine receptors located on lactotroph membranes belong to the D2 subclass of the dopamine receptor
family [9, 10].

The hypothalamic dopaminergic neurons, which provide DA to the anterior pituitary gland, are themselves
regulated by feedback from PRL through a ‘short-loop
feedback mechanism’. Elevation of serum levels of prolactin increases hypothalamic dopamine synthesis [11] andthe concentration of dopamine in hypothalamic-pituitary
portal blood [12].
All typical antipsychotic medications are associatedwith sustained hyperprolactinemia due to their high affinity for the D2 receptor and their slow dissociationfrom the receptor once bound, but the atypicals clozapine and quetiapine differ quite dramatically in theirpropensity to cause prolonged high prolactin levels, because they are loosely bound to D2 receptors [13]. The
dopamine D2 partial receptor agonist aripiprazole iseven capable to reduce prolactin levels [3].
Another way to explain hyperprolactinemia is the ability of antipsychotic-drugs to cross the blood-brain barrier and to affect the activity of prolactin-inhibiting andprolactin-stimulating factors. This capacity partly depends upon affinity to the drug efflux transporter
P-glycoprotein, which prevents drugs to pass the
blood brain barrier [14, 15]. This may result in relatively accumulation within the pituitary gland in comparison to brain tissue which is protected by theblood brain barrier [16].
PRL elevations with antipsychotic medication generally
are dose dependent. However, antipsychotics having ahigh potential for PRL elevation (amisulpride, sulpriride,
risperidone and paliperidone) can have a profound impact on PRL levels even at relatively low doses, while
PRL levels with antipsychotics having a minimal effecton PRL, in most cases, can remain unchanged (quetiapine) or reduce (aripiprazole) over all dosages. Althoughtolerance and decreases in PRL values after long-term
administration of PRL-elevating antipsychotics canoccur, the elevations, in most cases, remain above theupper limit of normal [3].
In conclusion, antipsychotic drugs may affect prolactin
release directly by blocking dopamine D2 receptors on
lactotrophs, but modulate this activity by affecting dopamine levels within the hypothalamic-pituitary portal
blood. Moreover, antipsychotics can modulate intracerebral mechanisms involved in the regulation of prolactin
release. As the main targets for the therapeutic actions

Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

of neuroleptics in schizophrenia are components of cerebral dopamine and – to a lesser extent – serotonin
neurotransmission, the authors aimed at identifying theassociation of neuroleptic hyperprolactinemia with polymorphism of genes that determine the activity of various
components of dopaminergic transmission – enzymes
that catalyze the synthesis and metabolism of dopamine,
its storage, release into the synaptic cleft and reverse
capture, as well as the structure of its receptors.
According to the literature data genetic variants of
dopaminergic receptors, transporters and enzyme may
have functional consequences on the respond of antipsychotic treatment and development of side effects oftherapy.
In the structure of the dopamine receptor D1 (localized on the postsynaptic membrane), two single nucleotide polymorphisms associated with the risk ofdeveloping schizophrenia have been identified: G198A
and G1263A [17]. These substitutions are synonymous,they do not lead to a change in the amino acid composition of the receptor, but presumably may have an effecton gene expression, particularly on the formation of heterodimeric forms of the dopamine receptor consisting of
the D1 and D2 subunits [18]. In several studies rs4532
polymorphism in DRD1 is considered as a potential
pharmacogenomic marker for treatment response to
antipsychotic drugs [19, 20].
At least 23 single nucleotide polymorphisms within
DRD2 were evaluated to determine whether any of them
controlled DRD2 expression [21]. The polymorphism of
D2 receptors Taq1A, represented by two alleles – A1
and A2 in the region of the promoter that regulates gene
expression, has been studied most. It was found that reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele [22]. The associationof Taq1A polymorphism with schizophrenia was reported [23], it was later shown that A1 allele is associated with a predisposition to the development ofdyskinesias on the background treatment with neuroleptics [24]. The study of this polymorphism is complicatedby the fact that this site is “concurrently” promoted byanother, located next to the gene – ANNK1, which encodes protein kinase RKK2. DRD2/ANKK1 genotypes
are associated with susceptibility to second generation
antipsychotic-induced akathisia [25].
Polymorphism of other subtypes of dopamine receptors of the second type, D3 and D4, also, according to anumber of researchers, is associated with a risk of developing schizophrenia spectrum disorders [26–28]. Thereis evidence that the several polymorphic variants in geneD3 receptor are associated with a risk of developing
schizophrenia [29], as well as with a decrease in the levelof implementation cognitive tasks [30] and antipsychotic
induced tardive dyskinesia [31].

Page 37 of 56

The dopamine transporter gene (SLC6A3) appears to
be one of the most important candidate genes for affecting mental disorders, as it is the target of many psychostimulants that cause symptoms similar to the positive
symptoms of schizophrenia. Controversial information
was obtained by studying the effect of polymorphism in
SLC6A3 on pharmacogenetics of adverse events inschizophrenia treatment [32, 33].
Dopamine can be degraded in several ways, in which
enzymes such as monoamine oxidase (MAO) andcatechol-O-methyltransferase (COMT) play a leadingrole. There are two isoforms of monoamine oxidase –MAOA and MAOB, whose genes are located on the X
chromosome. MAOA catalyzes monoamine neurotransmitters including 5-hydroxytryptamine (5-HT, serotonin), norepinephrine and dopamine, while MAOB
deaminates 2-phenylethylamine and also dopamine [34].
The association of polymorphic variants of the MAOA
gene with features of an alarming series, such as neuroticism and negative affect, is described. Changes in the sequence of nucleotides in the promoter region of the
MAOA gene are associated with a reduced level of expression of this gene and may be associated with an increased level of aggression and impulsivity compared toa typical MAOA promoter that determines the normal
level of expression [35].
There is a series of studies with the search for associations of polymorphisms of the genes of dopamine receptors and metabolizing enzymes in various combinations
and response or side effects to antipsychotic therapy:
DRD2 and dopamine transporter SLC6A3 [36]; DRD1,
DRD2, DRD3 and COMT [37]; DRD1, COMT, DRD2,
and DRD3 [38].

Methods
Based upon reviewing the literature we selected a set of
26 polymorphisms in dopamine receptors genes (DRD1,
DRD2, DRD3, DRD4), 12 polymorphic variants of dopamine transporter SLC6A3, as well as 3 polymorphisms of
monoamine oxidase A and B and here we present new
data on the association between them and HPRL in antipsychotic drug-treated patients with schizophrenia from
West Siberia, Russian Federation.
Patients

The study population was previous described by Ivanova
et al. [39, 40]. The work was carried out in accordancewith The Code of Ethics of the World Medical Association (Declaration of Helsinki 1975, revised in Fortaleza,
Brazil, 2013) for experiments involving humans. The patients in this study were retrieved from three psychiatrichospitals in Tomsk, Kemerovo, and Chita oblasts in Siberia. The inclusion criteria were a clinical diagnosis of
schizophrenia according to ICD-10 (F20), patients aged

Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

Page 38 of 56

18–75 years, Caucasian physical appearance and a signed
informed consent form to participate in the study after approval from the study (protocol N63/7.2014) from the
Local Bioethics Committee of the Mental Health ResearchInstitute. Exclusion criteria for all patients were
non-Caucasian physical appearance (e.g., Mongoloid, Buryats or Khakassians), pregnancy or relevant gynecologicaland endocrine (thyroid) disorders, relevant pharmacological withdrawal symptoms or organic brain disorders(e.g., epilepsy, Parkinson’s disease), the presence of acuteand chronic infectious, inflammatory, autoimmune diseases, as well as persons with active oncological diseases,
accompanied by an increased level of prolactin on the
blood.
The total sample consisted of 446 patients (221 males/
225 females). The women were significantly older (p =2.6e-8, Mann-Whitney test (MWT)) than the men(mean ± SD 45.2 ± 13.9 vs. 37.8 ± 11.9 years). Among thewomen, 86 were > 50 years of age. Women suffered fromthe disease for a significantly longer (p = 0.0002, MWT)
period of time (17.6 ± 12.5 vs. 13.1 ± 10.0 years). The median antipsychotic daily dose was 500 mg CPZeq (quartiles 280; 750) in men and 320 mg CPZeq (quartiles 200;
750) in women (p = 0.0002, MWT).
A total of 227 patients suffered from HPRL (98 males/
129 females) according to the predefined criteria [3, 39].
Demographic and clinical features of patients withschizophrenia with and without hyperprolactinemia arepresented in Table 1.
One hundred ninety-one patients were treated withconventional antipsychotics in oral and/or long-acting
formulations. The most common conventional antipsychotic was haloperidol, which was used in 110 patients,
but other treatments included oral chlorpromazine, chlorprothixene, trifluoperazin, and zuclopenthixol, and/or
long-acting formulations of haloperidol-, zuclopenthixol-,and flupenthixol-decanoate. A total of 176 patients weretreated with atypical antipsychotics: risperidone, clozapine,quetiapine, olanzapine, amisulpride, paliperidone, and sertindole. Different combinations of classical and atypicaldrugs were used by 79 patients. 76 patients were treatedwith risperidone/paliperidone.
To compare antipsychotic medications, all dosages wereconverted into chlorpromazine equivalents (CPZeq) [41].
Blood samples were taken 8 h after overnight fasting intubes containing EDTA for DNA extraction and in tubes

with CAT (clot activator) to obtain serum (BD Vacutainer). Blood with EDTA was stored in several aliquots at-20 °C until DNA isolation. Blood samples with CAT
were centrifuged for 30 min at 1500 rpm at 4 °C to obtain serum.
Hormone analysis

The PRL concentration was measured in serum using the
AccuBind ELISA Microwells kit (Monobind Inc., USA). In
this microplate immunoenzymatic assay, the ELISA has asensitivity of 0.004 ng/well. This is equivalent to a sample
containing 0.150 ng/ml PRL. The upper limits for normal
PRL concentration were set at ≤20 ng/ml for men and ≤25 ng/ml for non-pregnant, non-nursing women [39, 40].
For women of reproductive age, blood was when possibly
taken in the follicular phase of the menstrual cycle. This
corresponds to the criteria for HPRL applied by Kelly et
al. [42] and Peuskens et al. [3].
DNA analysis

DNA was isolated from the leukocytes in whole peripheral blood from patients with mental disorders using thestandard phenol-chloroform method.
Genotyping was carried out for DRD1, DRD2, DRD3,
DRD4, and SLC6A3 genes in the Genome Analysis Facility, Dept. Genetics (Head: Prof. Dr. C. Wijmenga), University Medical Center Groningen on the MassARRAY®
Analyzer 4 (Agena Bioscience™) using the set SEQUENOM Consumables iPLEX Gold 384. DNA sample
preparation for SEQUENOM MassARRAY® Analyzer 4
includes several steps: a standard PCR reaction to obtain
the amplification products, a shrimp alkaline phosphatase (SAP) reaction to neutralize the unincorporated
dNTPs in the amplification products, the PCR iPLEXGold extension reaction, and then placing the samples
on a special chip (SpectroCHIP Array) using NanoDispenser RS1000 prior to loading them into the analyzer. SNPsin MAOA, MAOB genes were genotyped in the Mental
Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, using thefluorogenic 5′-exonuclease TaqMan technology performed on the real-time polymerase chain reaction system“StepOnePlus” (Applied Biosystems, USA).
We selected a set of 26 SNPs from the following dopamine receptors genes: DRD1, DRD2, DRD3, DRD4
(Table 2), 12 polymorphic variants of dopamine transporter

Table 1 Demographic and clinical features of patients with schizophrenia with and without HPRL
FeaturePatients with HPRL, n = 227

Patients without HPRL, n = 219

p-valueAge

49.19 ± 13.19

42.94 ± 13.56

0.031

Male/Female

98/129123/96

0.006

Dose of antipsychotics into chlorpromazine equivalent

400 (225; 750)

400 (280; 750)

0.074

Duration of the disease11.0 (4.0; 22.0)

14.0 (8.0; 22.0)

0.041

Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

Page 39 of 56

Table 2 List of analyzed polymorphic variants of dopamine receptor genes
Gene

SNP

Chromosome

Chromosome position

Alleles

Minor Allele Frequency

DRD1

rs4532

5

174,870,150

T/C

24.4

DRD2

rs6275

11

113,283,477

C/T

47.3

DRD2

rs6277

11

113,283,459

C/T

24.4

DRD2

rs1076560

11

113,283,688

C/A

22.9

DRD2

rs1801028

11

113,283,484

C/G

3.1

DRD2

rs4245147

11

113,318,007

T/C

45.4

DRD2

rs2283265

11

113,285,536

G/T

22.7

DRD2

rs627911

113,281,073

G/C

47.8

DRD2

rs1076562

11

113,296,008

G/A

42.1

DRD2

rs2734842

11

113,280,274

G/C

46.7

DRD2/ANKK1

rs2734849

11

113,270,160

T/C

24.5

DRD3

rs11721264

3

113,879,404

G/A

41.4

DRD3

rs1677703

113,879,562

A/G

42.2

DRD3

rs3773678

3

113,870,078

C/T

32.0

DRD3

rs963468

3

113,862,887

G/A

27.2

DRD3

rs7633291

3

113,887,068

T/G

22.4

DRD3

rs2134655

3

113,858,201

G/A

20.3

DRD3

rs9817063

3

113,847,108

C/T

42.8

DRD3

rs324035

3

113,868,854

C/A

40.2

DRD3

rs1800828

3

113,891,549

G/C

22.2

DRD3

rs167771

3

113,876,275

A/G

41.1

DRD3

rs6280

3

113,890,815

T/C

48.6

DRD3

rs1587756

3

113,902,751

T/C

14.6

DRD4

rs3758653

11

636,399

T/C

24.7

DRD4

rs11246226

11

641,191

A/C

47.7

DRD4

rs936461

11

636,496

G/A

45.7

SLC6A3 and 3 polymorphisms of genes MAOA and MAOB
(Table 3).

All calculations were performed in the R statistical environment using basic R functions and the SNPassoc
package [43].

Statistical analysis

Results
From the list of 38 SNPs studied of dopamine receptor
genes and SLC6A3 genes we excluded 4 SNPs (rs6275,
rs6347, rs2550956, rs11133767) with Hardy-Weinberg
equilibrium p-value < 0.001, thus leaving 34 SNPs forthe analysis of associations with HPRL. In the totalgroup of patients none of the studied genetic markers
localized in autosomal chromosomes are associated with
HPRL (Additional file 1).
Polymorphic variants of monoamine oxidase genes are
localized in the X chromosome. Taking into account the
hemizygotic status of X-chromosomal markers for men,
the analysis of these markers was carried out separately
in men and women. Using the logistic regression analysis with age and CPZeq as covariate we found the association of rs1799836 with HPRL in men (Table 4). Allele

We analyzed associations between the polymorphisms
and HPRL using logistic regression models including
HPRL as a dependent categorical variable and polymorphisms as the predictors. Age, sex, and CPZeq were used
as covariates. Additive genetic model was tested andOdds ratios (OR) along with 95% confidence intervals(CI) were calculated regarding the risk of HPRL for therare allele vs common allele. Prior to the analysis, thepolymorphisms were filtered out in case of minor allele
frequency below 5% or Hardy-Weinberg equilibrium(HWE) p-value below 0.001. HWE was tested using
Fisher’s exact test except for SNPs located in the
X-chromosomal (MAOA, MAOB). The Mann-Whitney
test was used to compare qualitative traits and χ2 test
for categorical traits.

Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

Page 40 of 56

Table 3 List of analyzed polymorphic variants of the dopamine transporter gene and the monoamine oxidase genes
Gene

SNP

Chromosome

Chromosome position

Alleles

Minor Allele Frequency

SLC6A3

rs3756450

5

1,448,148

T/C

34.9

SLC6A3rs2550956

5

1,447,841

T/C

17.3

SLC6A3rs63475

1,411,412

A/G

29.8

SLC6A3

rs2617605

5

1,442,521

A/G

25.6

SLC6A3

rs3863145

5

1,392,711

C/T

16.8

SLC6A3rs250686

5

1,425,159

G/A

40.7

SLC6A3rs464049

5

1,423,905

C/T

39.1

SLC6A3rs4975646

5

1,433,401

G/A

13.4

SLC6A3

rs1048953

5

1,438,174

C/T

14.6

SLC6A3

rs11133767

5

1,401,580

A/G

31.8

SLC6A3rs270485

1,412,645

C/T

32.1

SLC6A3rs40184

5

1,395,077

G/A

41.3

МАОА

rs6323

X

43,591,036

G/T

37.5

МАОА

rs1137070

X

43,603,391

C/T

44.8

МАОB

rs1799836

X

43,627,999

A/G

45.6

and genotype frequencies are shown in Additional file 2.
A protective effect of the rs1799836*A allele against
HPRL development was observed.
Due to the fact that according to literature data, HPRL
is significantly more common in patients receiving risperidone/paliperidone, the next step was the analysis in thesubgroup of patients using the risperidone/paliperidone.
Using logistic regression with age, gender, and CPZeq as
covariates we found that the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be associated with
HPRL in this subgroup of patients (Table 5). Allele andgenotype frequencies are shown in Additional file 3. The
rs40184*A and the rs3863145*C alleles were found to exhibit a protective effect, reducing the risk of hyperprolactinemia in carriers of these genotypes. Notably, the both
SNPs are in some linkage disequilibrium LD, therefore,
their association with the HPRL is bound by the same
Table 4 Analysis of association between HPRL and thepolymorphisms of MAO genes for all patients divided by gender
Gender

SNP

OR

95% CI
Lower bound

95% CI
Upper boundp-value

Femalesrs1799836

0.939

0.644

1.369

0.744

rs1137070

0.757

0.497

1.153

0.195

Males

rs6323

0.786

0.512

1.208

0.273

rs1799836

0.748

0.561

0.998

0.048*

rs1137070

1.279

0.942

1.737

0.115

rs6323

1.315

0.970

1.782

0.078

Logistic regression analysis was used to test additive genetic model for
association between HPRL and the MAO genes polymorphisms in males andfemales separately adjusting for age and CPZeq. OR – odds ratio; CI – lower
and upper bound 95% confidence intervals. ORs are reported for the risk of
HPRL attributable to the rare allele vs common allele*Values are deemed to have significancehaplotype (Additional file 4). Polymorphisms in MAO
genes were not associated with hyperprolactinemia in thestudied subgroup (Additional file 5).

Discussion
We studied the association between polymorphisms ofgenes relevant for dopaminergic neurotransmission suchas receptors, transporter, and enzymes with antipsychotic drug-induced HPRL in white patients withschizophrenia from Siberia. We excluded patients withphysiological or pathological conditions that may affect
PRL secretion and corrected for variables related to PRL
secretion and/or that may determine antipsychotic drugload. The assessment of a possible association is considered the first step in discovering the possible functional
consequences of genetic variations. We distinguished
HPRL for men and women. The studied women weresignificantly older than the men and patients with HPRL
were more often female than those without. Premenopausal women have significantly higher PRL levels thanpostmenopausal female persons, who have not significantly different levels in comparison to men [44–46].
This might be related to modulation of PRL dynamics
by estrogen levels [44]. The gender and age differences
between the patients with and without HPRL may havefalsely decreased the actual prevalence of drug-induced
HPRL in the HPRL group in comparison to non-HPRL
patients. However, when only male patients were studied
significant association was found with one polymorphism rs1799836 of MAOB gene.
MAOB, located adjacent to MAOA on the opposite
strand at chromosome Xp11.23, is involved in the breakdown of dopamine in the brain [34]. MAO-B is widelyOsmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

Page 41 of 56

Table 5 Analysis of association between HPRL and the genetic
polymorphisms in patients from risperidone/paliperidone group
Gene

SNP

OR

95% CI
95% CI
p-value
Lower bound Upper boundDRD1

rs4532

0.522 0.216

1.261

0.148

DRD2

rs1076562

0.490 0.192

1.249

0.135

DRD2

rs4245147

1.148 0.519

2.541

0.733

DRD2

rs2283265

0.900 0.301

2.686

0.850

DRD2

rs2734842

0.472 0.187

1.194

0.113

DRD2

rs62772.081 0.864

5.011

0.102

DRD2

rs62790.434 0.164

1.145

0.092

DRD2

rs1076560

0.969 0.327

2.878

0.955

DRD2/ANKK1 rs2734849

1.833 0.781

4.302

0.164

DRD3

rs11721264 2.042 0.677

6.156

0.205

DRD3

rs2134655

0.659 0.203

2.140

0.488

DRD3

rs963468

0.647 0.251

1.666

0.367

DRD3

rs167771

1.150 0.244

5.414

0.859

DRD3

rs324035

1.719 0.380

7.783

0.482

DRD3

rs167770

1.963 0.622

6.195

0.250

DRD3

rs7633291

2.462 0.640

9.473

0.190

DRD3

rs9817063

1.635 0.626

4.270

0.316

DRD3

rs1587756

2.407 0.489

11.861

0.280

DRD3

rs1800828

2.813 0.739

10.711

0.129

DRD3

rs3773678

1.556 0.326

7.412

0.579

DRD3

rs62802.153 0.668

6.947

0.199

DRD4

rs3758653

1.403 0.410

4.806

0.590

DRD4

rs936461

1.500 0.577

3.895

0.405

DRD4

rs11246226 2.421 0.955

6.142

0.063

SLC6A3rs270481.419 0.660

3.054

0.370

SLC6A3

rs3756450

1.373 0.512

3.684

0.529

SLC6A3rs40184

0.341 0.137

0.852

0.021*SLC6A3rs4975646

0.640 0.258

1.589

0.336

SLC6A3

rs2617605

0.880 0.337

2.299

0.794

SLC6A3rs464049

0.538 0.209

1.384

0.199

SLC6A3

rs1048953

0.823 0.337

2.008

0.668

SLC6A3rs250686

0.563 0.214

1.482

0.245

SLC6A3

rs3863145

0.362 0.135

0.970

0.043*

Logistic regression analysis was used to test an additive genetic model for
association between HPRL and the polymorphisms in adjusting for age, sex
and CPZeq. OR – odds ratio; CI – lower and upper bound 95% confidence
intervals. ORs are reported for the risk of HPRL attributable to the rare allele vscommon allele*Values are deemed to have significance

distributed within the brain with moderate levels within
the adenohypophysis – where MAO-A is low – andhypothalamus [47, 48]. A non-coding single nucleotide
polymorphism rs1799836 in intron 13 is associated with
Parkinson’s disease [49, 50], schizophrenia [51] and isalso significantly associated with reduced negative

emotionality [52]. Further, a case-control study by Gasso
et al. indicates that the G allele is a risk factor for developing schizophrenia in a Spanish population [53].
Kang S.G. et al., reported that males schizophrenic patients with MAOA 3-repeat uVNTR and MAOB A644
genotype has higher association with antipsychotic-induced
restless leg syndrome [54].
A. C. Need et al. (2006) studied whether obesity is associated with genetic variants that increase the availability of dopamine. Low activity genotypes at both the
MAOA and MAOB loci – showed a relative risk forobesity of 5.01 [55]. Antipsychotic-induced weight gain,
including as a consequence of increasing the level ofprolactin, can be a particular problem of in schizophrenia treatment, often causing non-compliance and consequent relapse. It is possible that functional variants in
the MAOA and MAOB genes could predispose to
antipsychotic-induced weight gain in patients withschizophrenia.
Our preliminary hypothesis was that genetic variantsof dopamine receptors may have functional consequences on the modulation of PRL secretion and may
play an important role in the development of hyperprolactinemia, but the results of the study indicate that
there is no association in the group of patients.
However we found that rs40184 and rs3863145 of
SLC6A3 gene are associated with risperidone/paliperidone induced HPRL, but not with HPRL induced byother antipsychotic drugs. The solute carrier family 6(neurotransmitter transporter), member 3 (SLC6A3)
gene encodes the dopamine transporter DAT. The difference between risperidone/paliperidone and other antipsychotics might indicate that, although dopaminetransporters are present within the adenohypophysis[56] and may have a role in prolactin secretion [57], thepharmacological mechanism related to this association isless likely on the level of the pituitary gland (which isoutside the blood-brain-barrier) but localized within thebrain itself. Risperidon/paliperidone relatively accumulates within the pituitary gland in comparison to otherantipsychotics [16] and thus can be expected to bind toa higher extend to dopamine D2 receptors there.
The DAT protein is expressed in the membrane of
neurons, where it transports dopamine from the synaptic
cleft back into neurons for reuse. SLC6A3 plays a criticalrole in controlling dopamine transmission (spatial andtemporal domains) through the accumulation of dopamine in extracellular space which is major site of actionof psychostimulant drugs [58–60]. The results of several
studies indicate that altered SLC6A3 functioning maylead to inter-individual variability of response to antipsychotic drug treatment. Sjoholm H. et al. (2004) [61]reported increased number of SLC6A3 binding sites inthe schizophrenia patients who were being treated with

Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

dopamine D2-receptor blocking antipsychotics. Single
locus analysis showed significant association of nine variants from SLC6A3, PIP4K2A and BDNF genes with incomplete antipsychotic response in schizophrenia patientswith high severity [62]. The multifactor-dimensionality reduction approach identified gene-gene interaction among
BDNF_rs7103411-BDNF_rs1491851-SLC6A3_rs40184 inseverely ill incomplete responders [62]. Hence, at least
some intracerebral pharmacological effects of altered
SCL6A3 functioning can be expected and these may also
influence PRL secretion.
Our new data could be taken into account when therapy with risperidone/paliperidone or different antipsychotic therapy is considered regarding the risk ofdeveloping HPRL.

Conclusions
In conclusion, we found an association of
antipsychotic-induced HPRL with rs1799836 of the
MAOB gene in (hemizygous) men and rs40184 andrs3863145 variants in the SLC6A3 gene which codes forthe dopamine transporter in patients using risperidone/
paliperidone. Strength of our study is the relatively large
patient population and careful assessment of hyperprolactinemia. A relative weakness is the sex difference between the HPRL versus non-HPRL groups and therelatively high age of women as this may increase thenumber of post-menopausal women in the HPRL-group.
However, this also makes the associations which we foundmore likely to exist. A further search for genetic markers
associated with the development of antipsychotic-related
hyperprolactinemia in schizophrenic patients is needed.
Additional files

Page 42 of 56

Acknowledgements
This work resulted from a collaboration between the Mental Health ResearchInstitute in Tomsk and the Groningen Research Institute of Pharmacy (GRIP)of the University of Groningen. The Russian part is carried out within theframework of Tomsk Polytechnic University Competitiveness Enhancement
Program.
Funding
This work was in part supported by the Russian Foundation for Basic
Research, grant # 17–29-06035 and by the comprehensive program offundamental scientific research of the SB RAS “Interdisciplinary Integrated
Studies”, project No.30.
Publication cost was covered by the Russian Foundation for Basic Research,
grant # 17–29-06035.
Availability of data and materials
The datasets used and analyzed during the current study are available fromthe corresponding author on reasonable request.
About this supplement
This article has been published as part of BMC Medical Genetics Volume 20
Supplement 1, 2019: Selected articles from BGRS\SB-2018: medical genetics.
The full contents of the supplement are available online at https://
bmcmedgenet.biomedcentral.com/articles/supplements/volume-20supplement-1.
Authors’ contributions
SI and AL instigated, designed, coordinated, and supervised the study. MF
designed and performed the statistical analysis and contributed to writing
the paper. SI wrote the study protocol and selected the SNPs. DO, IP, NV, VT,
EK and OF monitored the study, collected clinical data, and isolated DNA.
DO and IP genotyped the samples and recorded all data in an Excel
database. AB analyzed the prolactin samples. NB and AS supervised theclinical work. SI, AL, and BW supervised the technical work. DO drafted themanuscript. SI and AL supervised the writing. OF, MF, and BW commented
on the manuscript. All authors read the paper and agree with its content. All
authors read and approved the final manuscript.
Ethics approval and consent to participate
This work was performed in accordance with The Code of Ethics of theWorld Medical Association for experiments involving humans (Declaration of
Helsinki 1975, revised in Fortaleza, Brazil, 2013). All participants gave theirsigned informed consent to participate, and the study was approved by the
Local Bioethics Committee of the Mental Health Research Institute (protocol
N63/7.2014).

Additional file 1: Table S1. Logistic regression analysis for HPRL as adependent categorical variable and polymorphisms as the predictors andage, sex, CPZeq as covariates for all patients. (DOC 65 kb)

Consent for publication
Not applicable.

Additional file 2: Table S2. Genotype and allele frequencies for MAO
gene polymorphisms. (DOC 45 kb)

Competing interests
The authors declare that they have no competing interests.

Additional file 3: Table S3. Genotype and allele frequencies for allpolymorphisms of studied genes in the subgroup of patients using therisperidone/paliperidone. (DOC 275 kb)

Publisher’s Note

Additional file 4: Table S4. Lewontin’s D’ statistics to measure pairwise
linkage disequilibrium between SLC6A3 SNPs. (XLS 40 kb)
Additional file 5: Table S5. Analysis of association between HPRL andpolymorphisms in MAO genes for female/male patients in risperidone/
paliperidone group. (DOC 34 kb)
Abbreviations
CI: Lower and upper bound 95% confidence intervals; COMT: Catechol-Omethyltransferase; CPZeq: Chlorpromazine equivalents; DA: Dopamine;
DRD2s: Dopamine receptor D2; HPRL: Hyperprolactinemia; HWE: HardyWeinberg equilibrium; ICD-10: International Statistical Classification of
Diseases and Related Health Problems 10th Revision; MAO: Monoamineoxidase; MWT: Mann-Whitney test; OR: Odds ratio; PRL: Prolactin; SNP: Single
nucleotide polymorphism; TRG: Gonadotropin-releasing hormone;
TRH: Thyrotropin-releasing hormone

Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
Author details
1
Mental Health Research Institute, Tomsk National Research Medical Centerof the Russian Academy of Sciences, Aleutskaya str., 4, Tomsk, RussianFederation634014. 2National Research Tomsk State University, Lenin Avenue,
Tomsk, Russian Federation36. 3Department of Twin Research and Genetic
Epidemiology, School of Live Course Sciences, King’s College London,
Lambeth Palace Road, London SE1 7EH, UK. 4Research Institute of Medical
Genetics, Tomsk National Research Medical Center of the Russian Academyof Sciences, Naberezhnaya Ushaiki str, Tomsk, Russian Federation10. 5National
Research Tomsk Polytechnic University, Lenin Avenue, Tomsk, RussianFederation30. 6Groningen Research Institute of Pharmacy, PharmacoTherapy,
Epidemiology & Economics, University of Groningen, Antonius Deusinglaan
1, 9713, AV, Groningen, The Netherlands. 7GGZ Westelijk Noord-Brabant,Hoofdlaan 8, 4661 AA Halsteren, The Netherlands. 8University Medical Center

Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

Page 43 of 56

Groningen, Department of Clinical Pharmacy and Pharmacology, Universityof Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.
20.
Published: 9 April 2019
References
1. van Os J, Kapur S. Schizophrenia. Lancet. 2009;374:635–45. https://doi.org/
10.1016/S0140-6736(09)60995-8.
2. Ajmal A, Joffe H, Nachtigall LB. Psychotropic-induced hyperprolactinemia: aclinical review. Psychosomatics. 2014;55:29–36. https://doi.org/10.1016/j.
psym.2013.08.008.
3. Peuskens J, Pani L, Detraux J, De Hert M. The effects of novel and newly
approved antipsychotics on serum prolactin levels: a comprehensive review.
CNS Drugs. 2014;28:421–53. https://doi.org/10.1007/s40263-014-0157-3.
4. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinemia:
mechanisms, clinical features, and management. Drugs. 2004;64:2291–314
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15456328.
5. Bushe CJ, Bradley A, Pendlebury J. A review of hyperprolactinaemia andsevere mental illness: are there implications for clinical biochemistry? Ann
Clin Biochem. 2010;47(Pt 4):292–300. https://doi.org/10.1258/acb.2010.
010025.
6. Majumdar A, Mangal NS. Hyperprolactinemia. J Hum Reprod Sci. 2013;6:
168–75. https://doi.org/10.4103/0974-1208.121400.
7. Grattan DR. 60 YEARS OF NEUROENDOCRINOLOGY: the hypothalamo-prolactin
axis. J Endocrinol. 2015;226:T101–22. https://doi.org/10.1530/JOE-15-0213.
8. Ben-Jonathan N. Dopamine: a prolactin-inhibiting hormone. Endocr Rev.
1985;6:564–89. https://doi.org/10.1210/edrv-6-4-564.
9. Caron MG, Beaulieu M, Raymond V, Gagné B, Drouin J, Lefkowitz RJ, Labrie
F. Dopaminergic receptors in the anterior pituitary gland. Correlation of[3H]dihydroergocryptine binding with the dopaminergic control ofprolactin release. J Biol Chem. 1978;253:2244–53 Available at: http://www.
jbc.org/content/253/7/2244.long.
10. Meador-Woodruff JH, Mansour A, Bunzow JR, Van Tol HHM, Watson SJ,
Civelli O. Distribution of D2 dopamine receptor mRNA in rat brain. Proc Natl
Acad Sci U S A. 1989;86:7625–8 Available at: https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC298119/.
11. Demarest KT, Mckay DW, Riegle GD, Moore KE. Sexual differences intuberoinfundibular dopamine nerve activity induced by neonatal androgen
exposure. Neuroendocrinology. 1981;32:108–13. https://doi.org/10.1159/
000123140.
12. Gudelsky GA, Porter JC. Release of dopamine from tuberoinfundibular
neurons into pituitary stalk blood after prolactin or haloperidol
administration. Endocrinology. 1980;106:526–9. https://doi.org/10.1210/
endo-106-2-526.
13. Seeman P, Tallerico T. Rapid release of antipsychotic drugs from dopamine
D2 receptors: an explanation for low receptor occupancy and early clinicalrelapse upon withdrawal of clozapine or quetiapine. Am J Psychiatry. 1999;
156(6):876–84. https://doi.org/10.1176/ajp.156.6.876.
14. Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on thepenetration of drugs into the brain. Focus on psychotropic drugs. Eur
Neuropsychopharmacol. 2008;18(3):157–69. https://doi.org/10.1016/j.
euroneuro.2007.06.003.
15. Moons T, de Roo M, Claes S, Dom G. Relationship between P-glycoprotein
and second-generation antipsychotics. Pharmacogenomics. 2011;12:1193–
211. https://doi.org/10.2217/pgs.11.55.
16. Ejsing TB, Pedersen AD, Linnet K. P-glycoprotein interaction with risperidone
and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-druginteraction experiments. Hum Psychopharmacol. 2005;20(7):493–500. https://doi.org/10.1002/hup.720.
17. Zhu F, Yan CX, Wang Q, Zhu YS, Zhao Y, Huang J, et al. An association
study between dopamine D1 receptor gene polymorphisms and the risk ofschizophrenia. Brain Res. 2011;1420:106–13. https://doi.org/10.1016/j.brainres.
2011.08.069.
18. Grymek K, Јukasiewicz S, Faron-Gуreckaa A, Tworzydlo M, Polit A,
Dziedzicka-Wasylewska M. Role of silent polymorphisms within the
dopamine D1 receptor associated with schizophrenia on D1-D2 receptor
heterodimerization. Pharmacol Rep. 2009;61(6):1024–33 Available at: http://
www.if-pan.krakow.pl/pjp/pdf/2009/6_1024.pdf.
19. Ota VK, Spíndola LN, Gadelha A, dos Santos Filho AF, Santoro ML,
Christofolini DM, et al. DRD1 rs4532 polymorphism: a potential
pharmacogenomic marker for treatment response to antipsychotic

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

drugs. Schizophr Res. 2012;142(1–3):206–8. https://doi.org/10.1016/j.
schres.2012.08.003.
De Matos LP, Santana CV, Souza RP. Meta-analysis of dopamine receptor D1
rs4532 polymorphism and susceptibility to antipsychotic treatment
response. Psychiatry Res. 2015;229(1–2):586–8. https://doi.org/10.1016/j.
psychres.2015.07.054.
Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, et al.
Polymorphisms in human dopamine D2 receptor gene affect gene
expression, splicing, and neuronal activity during working memory. Proc
Natl Acad Sci U S A. 2007;104:20552–7. https://doi.org/10.1073/pnas.
0707106104.
Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK, et al. D2
dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine
D2 receptor binding in the human striatum associated with the A1 allele.
Pharmacogenetics. 1997;7:479–84 Available at: https://www.ncbi.nlm.nih.
gov/pubmed/9429233.
Dubertret C, Gouya L, Hanoun N, Deybach JC, Ades J, Hamon M, Gorwood
P. The 3′ region of the DRD2 gene is involved in genetic susceptibility toschizophrenia. Schizophr Res. 2004;67:75–85. https://doi.org/10.1016/S09209964(03)00220-2.
Alenius M, Wadelius M, Dahl ML, Hartvig P, Lindstrom L, HammarlundUdenaes M. Gene polymorphism influencing treatment response inpsychotic patients in a naturalistic setting. J Psychiatr Res. 2008;42(11):884–
93. https://doi.org/10.1016/j.jpsychires.2007.10.007.
Lawford BR, Barnes M, Swagell CD, Connor JP, Burton SC, Heslop K, et al.
DRD2/ANKK1 Taq1A (rs1800497 C>T) genotypes are associated withsusceptibility to second generation antipsychotic-induced akathisia.
Schizophr Bull. 2013;39(4):848–56. https://doi.org/10.1177/
0269881112463469.
Ettinger U, Joober RDE, Guzman R, O’Driscoll GA. Schizotypy, attention
deficit hyperactivity disorder, and dopamine genes. Psychiatry Clin Neurosci.
2006;60(6):764–7. https://doi.org/10.1111/j.1440-1819.2006.01594.x.
Talkowski ME, Mansour H, Chowdari KV, Wood J, Butler A, Varma PG, et al.
Novel, replicated associations between dopamine D3 receptor gene
polymorphisms and schizophrenia in two independent samples. Biol
Psychiatry. 2006;60:570–7. https://doi.org/10.1016/j.biopsych.2006.04.012.
Talkowski ME, Kirov G, Bamne M, Georgieva L, Torres G, Mansour H, et al. A
network of dopaminergic gene variations implicated as risk factors forschizophrenia. Hum Mol Genet. 2008;17(5):747–58. https://doi.org/10.1093/
hmg/ddm347.
Zhang F, Fan H, Xu Y, Zhang K, Huang X, Zhu Y, et al. Converging evidence
implicates the dopamine D3 receptor gene in vulnerability to schizophrenia.
Am J Med Genet Part B. 2011;156:613–9. https://doi.org/10.1002/ajmg.b.
31203.
Bombin I, Arango C, Mayoral M, Castro-Fornieles J, Gonzalez-Pinto A,
Gonzalez-Gomez C, et al. DRD3, but not COMT or DRD2, genotype affects
executive functions in healthy and first-episode psychosis adolescents. Am J
Med Genet Part B. 2008;147B(6):873–9. https://doi.org/10.1002/ajmg.b.30710.
Al Hadithy AF, Ivanova SA, Pechlivanoglou P, Semke A, Fedorenko O,
Kornetova E, et al. Tardive dyskinesia and DRD3, HTR2A and HTR2C gene
polymorphisms in Russian psychiatric inpatients from Siberia. Prog NeuroPsychopharmacol Biol Psychiatry. 2009;33(3):475–81. https://doi.org/10.1016/
j.pnpbp.2009.01.010.
Xu M, Xing Q, Li S, Zheng Y, Wu S, Gao R, et al. Pharmacogenetic effects of
dopamine transporter gene polymorphisms on response to chlorpromazine
and clozapine and on extrapyramidal syndrome in schizophrenia. Prog
Neuro-Psychopharmacol Biol Psychiatry. 2010;34(6):1026–32. https://doi.org/
10.1016/j.pnpbp.2010.05.017.
Tybura P, Trześniowska-Drukała B, Bienkowski P, Beszlej A, Frydecka D,
Mierzejewski P, et al. Pharmacogenetics of adverse events in schizophrenia
treatment: comparison study of ziprasidone, olanzapine and perazine. Psychiatry
Res. 2014;219(2):261–7. https://doi.org/10.1016/j.psychres.2014.05.039.
Finberg JP. Update on the pharmacology of selective inhibitors of MAO-A
and MAO-B: focus on modulation of CNS monoamine neurotransmitter
release. Pharmacol Ther. 2014;143(2):133–52. https://doi.org/10.1016/j.
pharmthera.2014.02.010.
Manuck SB, Flory JD, Ferrell RE, Mann JJ, Muldoon MF. A regulatory
polymorphism of the monoamine oxidase a gene may be associated withvariability in aggression, impulsivity, and central nervous systemserotonergic responsivity. Psychiatry Res. 2000;95:9–23. https://doi.org/10.
1016/S0165-1781(00)00162-1.

Osmanova et al. BMC Medical Genetics 2019, 20(Suppl 1):47

36. Zivković M, Mihaljević-Peles A, Bozina N, Sagud M, Nikolac-Perkovic M,
Vuksan-Cusa B, et al. The association study of polymorphisms in DAT, DRD2,
and COMT genes and acute extrapyramidal adverse effects in maleschizophrenic patients treated with haloperidol. J Clin Psychopharmacol.
2013;33(5):593–9. https://doi.org/10.1097/JCP.0b013e31829abec9.
37. Terzić T, Kastelic M, Dolžan V, Plesničar BK. Genetic polymorphisms in
dopaminergic system and treatment-resistant schizophrenia. Psychiatr
Danub. 2016;28(2):127–31 Available at: http://www.psychiatria-danubina.
com/UserDocsImages/pdf/dnb_vol28_no2/dnb_vol28_no2_127.pdf.
38. Han J, Li Y, Wang X. Potential link between genetic polymorphisms ofcatechol-O-methyltransferase and dopamine receptors and treatment
efficacy of risperidone on schizophrenia. Neuropsychiatr Dis Treat. 2017;13:
2935–43. https://doi.org/10.2147/NDT.S148824 eCollection 2017.
39. Ivanova SA, Osmanova DZ, Boiko AS, Pozhidaev IV, Freidin MB, Fedorenko
OY, et al. Prolactin gene polymorphism (-1149 G/T) is associated withhyperprolactinemia in patients with schizophrenia treated with
antipsychotics. Schizophr Res. 2017;182:110–4. https://doi.org/10.1016/j.
schres.2016.10.029.
40. Ivanova SA, Osmanova DZ, Freidin MB, Fedorenko OY, Boiko AS, Pozhidaev
IV, et al. Identification of 5-hydroxytryptamine receptor gene
polymorphisms modulating hyperprolactinaemia in antipsychotic drugtreated patients with schizophrenia. World J Biol Psychiatry. 2017;18(3):239–
46. https://doi.org/10.1080/15622975.2016.1224926.
41. Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC. Antipsychotic dose
equivalents and dose-years: a standardized method for comparing exposure
to different drugs. Biol Psychiatry. 2010;67(3):255–62. https://doi.org/10.1016/
j.biopsych.2009.08.040.
42. Kelly DL, Wehring HJ, Earl AK, Sullivan KM, Dickerson FB, Feldman S, et al.
Treating symptomatic hyperprolactinemia in women with schizophrenia:
presentation of the ongoing DAAMSEL clinical trial (dopamine partial
agonist, aripiprazole, for the Management of Symptomatic ELevated prolactin).
BMC Psychiatry. 2013;13:214. https://doi.org/10.1186/1471-244X-13-214.
43. Gonzalez JR, Armengol L, Guino E, Sole X, Moreno V. SNPassoc: SNPs-based
whole genome association studies. R package version 1.9–2. 2014, Available
at: https://CRAN.R-project.org/package=SNPassoc
44. Katznelson L, Riskind PN, Saxe VC, Klibanski A. Prolactin pulsatile
characteristics in postmenopausal women. J Clin Endocrinol Metab. 1998;83:
761–4. https://doi.org/10.1210/jcem.83.3.4675.
45. Maddox PR, Jones DL, Mansel RE. Basal prolactin and total lactogenic
hormone levels by microbioassay and immunoassay in normal human sera.
Acta Endocrinol (Copenh). 1991;125:621–7 Available at: https://www.ncbi.
nlm.nih.gov/pubmed/1789057.
46. Tanner MJ, Hadlow NC, Wardrop R. Variation of female prolactin levels withmenopausal status and phase of menstrual cycle. Aust NZJ Obstet
Gynaecol. 2011;51:321–4. https://doi.org/10.1111/j.1479-828X.2011.01321.x.
47. Saura J, Kettler R, Da Prada M, Richards JG. Quantitative enzyme
radioautography with 3H-Ro 41-1049 and 3H-Ro 19-6327 in vitro:
localization and abundance of MAO-A and MAO-B in rat CNS, peripheralorgans, and human brain. J Neurosci. 1992;12(5):1977–99. https://doi.org/10.
1523/JNEUROSCI.12-05-01977.1992.
48. Saura J, Bleuel Z, Ulrich J, Mendelowitsch A, Chen K, Shih JC, et al. Molecular
neuroanatomy of human monoamine oxidases a and B revealed by quantitative
enzyme radioautography and in situ hybridization histochemistry. Neuroscience.
1996;70(3):755–74. https://doi.org/10.1016/S0306-4522(96)83013-2.
49. Kurth JH, Kurth MC, Poduslo SE, Schwankhaus JD. Association of a
monoamine oxidase B allele with Parkinson's disease. Ann Neurol. 1993;33:
368–72. https://doi.org/10.1002/ana.410330406.
50. Liu JJ, Wang W, Meng M, Liang CS, Zhang JW. Association between
monoamine oxidase B A644G polymorphism and Parkinson's disease risk: ameta-analysis in the Chinese population. Genet Mol Res. 2016;15(2). https://doi.org/10.4238/gmr.15028349.
51. Yi-Liang W, Li C-X, Li S-B, Liu Y, Lan H. Association study of monoamineoxidase A/B genes and schizophrenia in Han Chinese. Behav Brain Funct.
2011;7:42. https://doi.org/10.1186/1744-9081-7-42.
52. Dlugos AM, Palmer AA, de Wit H. Negative emotionality: monoamineoxidase B gene variants modulate personality traits in healthy humans. J
Neural Transm. 2009;116:1323–34. https://doi.org/10.1007/s00702-009-0281-2.
53. Gasso P, Bernardo M, Mas S, Crescenti A, Garcia C, Parellada E, et al.
Association of a/G polymorphism in intron 13 of the monoamine oxidase B
gene with schizophrenia in a Spanish population. Neuropsychobiology.
2008;58:65–70. https://doi.org/10.1159/000159774.

Page 44 of 56

54. Kang SG, Park YM, Choi JE, Lim SW, Lee HJ, Lee SH, et al. Association study
between antipsychotic-induced restless legs syndrome and polymorphismsof monoamine oxidase genes in schizophrenia. Hum Psychopharmacol.
2010;25(5):397–403. https://doi.org/10.1002/hup.1130.
55. Need AC, Ahmadi KR, Spector TD, Goldstein DB. Obesity is associated withgenetic variants that Alter dopamine availability. Ann Hum Genet. 2006;70:
293–303. https://doi.org/10.1111/j.1529-8817.2005.00228.x.
56. Mitsuma T, Rhue H, Hirooka Y, Kayama M, Wago T, Takagi J, et al.
Distribution of dopamine transporter in the rat: an Immunohistochemical
study. Endocr Regul. 1998;32(2):71–5 Available at: https://www.sav.sk/
journals/endo/full/er0298b.pdf.
57. Demaria JE, Nagy GM, Lerant AA, Fekete MI, Levenson CW, Freeman ME.
Dopamine transporters participate in the physiological regulation ofprolactin. Endocrinology. 2000;141(1):366–74. https://doi.org/10.1210/endo.
141.1.7281.
58. Bannon MJ, Michelhaugh SK, Wang J, Sacchetti P. The human dopaminetransporter gene: gene organization, transcriptional regulation, and potential
involvement in neuropsychiatric disorders. Eur Neuropsychopharmacol. 2001;
11:449–55. https://doi.org/10.1016/S0924-977X(01)00122-5.
59. Riddle EL, Fleckenstein AE, Hanson GR. Role of monoamine transporters inmediating psychostimulant effects. AAPS J. 2005;7:E847–51. https://doi.org/
10.1208/aapsj070481.
60. Sotnikova TD, Beaulieu JM, Gainetdinov RR, Caron MG. Molecular biology,
pharmacology and functional role of the plasma membrane dopaminetransporter. CNS Neurol Disord Drug Targets. 2006;5:45–56. https://doi.org/
10.2174/187152706784111579.
61. Sjoholm H, Bratlid T, Sundsfjord J. 123I-beta-CIT SPECT demonstrates
increased presynaptic dopamine transporter binding sites in basal ganglia
in vivo in schizophrenia. Psychopharmacology (Berl). 2004;173:27–31.
https://doi.org/10.1007/s00213-003-1700-y.
62. Kaur H, Jajodia A, Grover S, Baghel R, Gupta M, Jain S, et al. Genetic
variations of PIP4K2A confer vulnerability to poor antipsychotic response in
severely ill schizophrenia patients. PLoS One. 2014;9(7):e102556. https://doi.
org/10.1371/journal.pone.0102556 eCollection 2014.