Nordic Journal of Psychiatry

ISSN: 0803-9488 (Print) 1502-4725 (Online) Journal homepage: http://www.tandfonline.com/loi/ipsc20

Homocysteine and MTHFR C677T polymorphism in

children and adolescents with psychotic and mood
disorders
Laura Kevere, Santa Purvina, Daiga Bauze, Marcis Zeibarts, Raisa Andrezina,
Linda Piekuse, Edgars Brekis & Indulis Purvins
To cite this article: Laura Kevere, Santa Purvina, Daiga Bauze, Marcis Zeibarts, Raisa Andrezina,
Linda Piekuse, Edgars Brekis & Indulis Purvins (2014) Homocysteine and MTHFR C677T
polymorphism in children and adolescents with psychotic and mood disorders, Nordic Journal
of Psychiatry, 68:2, 129-136
To link to this article: http://dx.doi.org/10.3109/08039488.2013.782066

Published online: 16 Apr 2013.

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Date: 23 November 2015, At: 07:56

Homocysteine and MTHFR C677T

polymorphism in children and adolescents
with psychotic and mood disorders

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LAURA KEVERE, SANTA PURVINA, DAIGA BAUZE, MARCIS ZEIBARTS,

RAISA ANDREZINA, LINDA PIEKUSE, EDGARS BREKIS, INDULIS PURVINS

Kevere L, Purvina S, Bauze D, Zeibarts M, Andrezina R, Piekuse L, Brekis E, Purvins I.

Homocysteine and MTHFR C677T polymorphism in children and adolescents with psychotic
and mood disorders. Nord J Psychiatry 2014;68:129136.
Background : High level of homocysteine (Hcy) is risk factor of schizophrenia and mood
disorders. Aim: The aim was to detect a serum level of Hcy, examine the associations between
the level of Hcy, methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and
clinical properties for patients with schizophrenia, mood disorders and in a control group.
Material and methods: There were 88 patients with schizophrenia, 28 with affective disorders
and 94 from the control group. The Hamilton Anxiety Scale (HAM-A) was performed to study
anxiety, the Hamilton Depression Scale (HAM-D) to study depression and the Brief Psychiatric
Rating Scale (BPRS) to study severity of schizophrenia. The level of Hcy was stated by
isocratic high-performance liquid chromatography (HPLC) system with fluorometric detection.
DNA isolation from venous blood was performed by the phenolchloroform method. Results:
The levels of B12 vitamin and folic acid were within normal limits for all the patients. The
average level of Hcy was 11.94 5.6 mol/l for patients with schizophrenia and 11.65 3.3
mol/l for patients with affective disorders, vs. 6.80 2.93 mol/l in a control group. The
highest level of Hcy has been observed in patients with an episodicrecurrent course of
schizophrenia, paranoid schizophreniacontinuous, particularly in patients with CT genotype
(r 0.58; P 0.01). In the given diagnostic groups, the highest level of anxiety was observed.
Conclusions: The level of Hcy is higher in the blood of a heterozygotic person who becomes ill
with schizophrenia, and the process of the illness is more serious and with more typical
affective disorders.
Child psychiatry, Homocysteine, Methylenetetrahydrofolate reductase, Mood disorders,
Schizophrenia.
Laura Kevere, 215-27 Maskavas Street, Riga LV-1019, Latvia, E-mail: kevere@gmail.com;
Accepted 23 February 2013.

hree enzymes are directly involved in the homocysteine (Hcy) metabolism: methionine synthase
(MS), betaine homocysteine methyltransferase (BHMT)
and cystathione -synthase (CBS) (1).
Methionine is the immediate precursor of S-adenosylmethionine (SAM), the methyl donor of numerous methylation reactions in the brain, many of which are directly
involved in the synthesis and metabolism of monoamines
such as dopamine, norepinephrine and serotonin (2). This
suggests that the association between the elevated Hcy
and schizophrenia is biologically plausible.
Another way of investigating the association between
Hcy and mental disorders is via the MTHFR gene.
MTHFR converts 5.10-methylene tetrahydrofolate to
5-methyltetrahydrofolate which is needed for the remethylation of Hcy to methionine (3).

2014 Informa Healthcare

The MTHFR polymorphisms C677T affect nucleotide

synthesis and DNA methylation.
The obtained information points to the fact that a risk
of coming down with psychiatric illness correlates with elevated level of Hcy (4, 5). Men, who have MTHFR C677T
polymorphism for genes, have a greater risk of becoming
ill with schizophrenia than women do; for their part, it is a
greater risk of bipolar affective disorders (BAD) (6).
Hcy has an influence to disturbance origination
through the disordered brain structure development and
functions and/or through placenta vascularization disorders, which reduces oxygen feed for the fetus (7).
The studies indicate that the result of the elevated
Hcy presents conditions of stress in wefts, followed by
hematoencephalytic barrier obstacles permeability increasing for neurotoxic materials (810).
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L KEVERE ET AL.

Hcy was the highest in cases with progression of the

mental disease (1113).
Basing on the above, it is urgent to establish which
mental affections are linked with the changes of Hcy level
in blood plasma, and whether the changes of Hcy concentration depend on a clinical state of affection (affection is
in progress, remission or continuous progredient).
The aim of our study was to gain information and
possible links of serum level of Hcy and MTHFR gene
polymorphism and increased frequency of the CT and
TT genotype for patients with schizophrenia spectrum,
affective spectrum disorders and a control group, as well
as to determine clinical specificity of mentioned groups
and also to set changes of Hcy level in the dynamics for
the patients of the researched groups.

Materials and Methods

The investigation was carried out in the department of
Pharmacology of RSU and in Childrens Psychiatric Hospital. All persons (for children there were one of parent)
signed an informed consent form, issued according to
Riga Stradins University Medical Ethics Committee.
There were the following entry criteria: inclusion criteriaall patients with schizophrenia-spectrum and mood
disorders who were hospitalized in child psychiatry
department and whose parents or guardians gave permission for the child inclusion. Within the period of the
study with such a diagnosis, 170 patients were hospitalized and 116 of them were included in the study. Exclusion criteria-to be eligible for inclusion into this study,
the subjects must not meet any of the following criteria:
patients with serious somatic pathologies (kidney failure,
usage of glucocorticoids), patients with proven genetic
illnesses, non-compliance patients, and in cases if the
parents or the guardians of a juvenile did not agree to
involve a child in the research.
Before the start of the study, each subject (parent/
guardian of the child) was provided with a subject information sheet giving details about the study, procedures
and potential risk involved. They were instructed that
they are free to obtain further information from the investigator at any time and that they are free to withdraw their
childs participation in the study at any time without prejudice. Each potentially eligible subject also was informed
verbally of the studys objectives and study fully. If the
subject agreed with his childs participation in the study,
the parent/guardian was requested to give written informed
consent. The consent form was signed and personally
dated by both the subject and the investigator.
For the study, we have used 116 patients from the
Childrens Psychiatric Hospital and 94 children and
adolescents in the control group. Healthy children from
kindergartens and schools were picked for the control
group.

130

Patients in the study groups were included according

to the diagnosis (ICD-10 Classification of Mental and
Behavioural Disorders: Diagnostic Criteria for Research)
(14) of the current health condition, and after the
patients cognitive processes and thought disorders were
evaluated by the clinical psychologist. Newly diagnosed
patients were in the hospital for at least 1 month (average 24 months), re-hospitalized patients were hospitalized due to exacerbation episode of the illness and
frequently time spent in hospital for these patients was
shorter than when they were hospitalized for first time.
The patients were divided into four diagnostic groups.
The first group (20 patients): paranoid schizophrenia
continuous; the second group (40 patients): paranoid
schizophreniaepisodic with residual symptoms; the
third group (28 patients): simple schizophrenia; the
fourth group (28 patients): patients with affective spectrum disorders (depressive syndrome with anxiety, mixed
affective disorders and depressive syndrome without anxiety) and in the control group94 children and adolescents (the fifth group: intact) (Table 1).
The mean age for patients with schizophrenia spectrum disorders was 15.25 2.6 years (14.05 2.02
years for patients with paranoid schizophreniacontinuous, 16.67 1.03 years for patients with paranoid
schizophreniaepisodic and 14.04 2.50 years for
patients with simple schizophrenia), for patients with
mood disorders 16.54 1.74 years, but for control
group14.76 2.8 years.
The level of vitamin B12 and folic acid in the blood
were analyzed in the Laboratory of NMS. The level of
Hcy in the blood was analyzed in the Research Laboratory of Pharmacology Department of RSU by an isocratic HPLC system with fluorometric detection
(Shimadzu LC-20, model RF-10AxL). The present
method allows a rapid, simple and specific determination
of Hcy using an isocratic HPLC system with fluorometric detection. The HPLC system was a Shimadzu LC-20
Prominence with a fluorescence detector (model RF10AxL, Shimadzu).
Sample preparation and chromatographic separation
were performed according to the recommendations of use
provided with the commercially available Chromsystems
GmbH (Germany) kit for HPLC analyses of Hcy in
plasma.
The reduction step for releasing Hcy from its proteinbound state, protein precipitation and precolumn derivatization followed by HPLC separation and fluorescent
detection is the most widely applied technique.
The level of Hcy was repeatedly set for 43 patients
during time of the study who were re-hospitalized. At
the first time, the level of Hcy was set for a patient when
entering the hospital, before the therapy of drugs,
because this analysis is included in standard diagnostics.
The second analysis was performed after stabilization of
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Relatively stable, often paranoid

delusions, usually accompanied
by hallucinations, particularly of
the auditory variety, and
perceptual disturbances. Volition
and speech, and catatonic
symptoms, are either absent or
relatively inconspicuous
Episodic with progressive or stable
deficit, in the periods of
exacerbation of disease
symptoms like a continuous
course schizophrenia

Disturbances of affect. Affects that is

inappropriate or blunted

Affective disturbances

IQ, intelligence quotient; DRAs, dopamine- receptor antagonists; AEDs, antiepileptic drugs.

Gradual

Clinical characteristic

Cognitive disturbances

Clear consciousness
and intellectual
capacity are usually
maintained although
certain cognitive
deficits may evolve
in the course
of time
Episodic course
Acute
Atypical manic and/or depressive symptoms,
Early onsethave
schizophrenia
anxiety, fears, mixed affective disorders
more significant
deficits in measures
of IQ, memory, and
tests of
perceptuomotor
skills. Disturbances
of working memory
and attention
Simple schizophrenia
Gradual
Simple schizophrenia is
Cold or inappropriate affect, blunting of affect Early onsethave
characterized with an insidious
and loss of volition
more significant
but progressive development of
deficits in measures
oddities of conduct, inability to
of IQ, memory, and
meet the demands of society, and
tests of
decline in total performance. The
perceptuomotor
characteristic negative features of
skills. Disturbances
residual schizophrenia develop
of working memory
without being preceded by any
and attention
overt psychotic symptoms
Affective disorders
Subacute/acute Bipolar affective disorders, current episode mixedthe patient has had at least one Hard to concentrate,
depressive
slow thinking rate
authenticated hypomanic, manic, depressive, or mixed affective episode in the
episode, recurrent
past, and currently exhibits either a mixture or a rapid alteration of manic and
depressive disorders
depressive symptoms.
(with or without
Depressionthe patient suffers from lowering of mood, reduction of energy, and
associated anxiety),
decrease in activity. Capacity for enjoyment, interest, and marked tiredness after
bipolar affective
even minimum effort is common. Sleep is usually disturbed and appetite
disorder (current
diminished. Self-esteem and self-confidence are almost always reduced and, even
episode mixed)
in the mild form, some ideas of guilt or worthlessness are often present. The
lowered mood varies little from day to day, is unresponsive to circumstances and
may be accompanied by so-called somatic symptoms, such as loss of interest
and pleasurable feelings, waking in the morning several hours before the usual
time, depression worst in the morning, marked psychomotor retardation, agitation,
loss of appetite, weight loss, and loss of libido

Continuous course
schizophrenia

Development

Table 1. Clinical characteristic of patients groups (18, 20, 21, 28).

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Prognosis

Bad. Gradual
intellectual skills ,
emotional disorders,
formation of identity
defect

Good, in case of duly

treatment

DRAs monotherapy,
often combinations
with AEDs

Antidepressant /
AEDs

Aggravation
Bad, progressing course
therapycommonly
with defect becoming
2 antipsychotic
deeper, resistance of
medicaments,
therapy, disability
remissions
monotherapy

Often lasting usage of Bad, progressing course

several antipsychotic
with defect becoming
medicine
deeper, resistance of
therapy, disability

Therapy

HOMOCYSTEINE AND PSYCHIATRIC DISORDERS

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L KEVERE ET AL.

the clinical condition, when the patient was discharged.

The repeated analyses were performed in the following
way: the first group (nine patients): paranoid schizophreniacontinuous; the second group (seven patients): paranoid schizophreniaepisodic; the third group (nine
patients): simple schizophrenia; the fourth group (eight
patients): patients with affective spectrum disorders and
in the control group10 children and adolescents.
Genetic studies involving also DNA isolations were
done in Riga Stradins University Scientific Laboratory of
Molecular Genetics.
DNA isolation from venous blood was made by the
use of standard phenolchloroform method (15). The
MTHFR C677T (rs1801133) polymorphism was analyzed
by the restriction fragment length polymorphism
polymerase chain reaction (RFLPPCR) adapted method
(16). PCR was performed in a total volume of 20 l,
containing 2 l 10 Taq Buffer with (NH4)2SO4 (Fermentas), 1.6 l 25 mM MgCl2, 0.5 l 10 mM deoxyribonucleotide triphosphate (dNTP), 2.5 U recombinant
Taq polymerase (Fermentas) and 5 l of the following
10 pmol primers: MTHFR-PF 5TGAAGGAGAAAG
GTGTCTGCGGGA3, MTHFR-P5 AGGACGGTGCGG
TGAGAGTG3. The reaction was carried out in a T
professional Thermocycler (Biometra). Following denaturation at 95C for 3 min, 30 cycles at 94, 65 and
72 for 1 min each were performed. A final extension
step at 72C for 10 min concluded the reaction. The
198-bp PCR product (4 l) was digested with restriction

enzyme HinfI (Fermentas) at 37C for 18 h. HinfI can

recognize the cytosine to timine substitution and
formed 176- and 22-bp-long fragments. The HinfI
treated PCR fragments were analyzed by 6% polyacrylamide gel electrophoresis at 180 V for 40 min,
stained with ethidium bromide and visualized under
UV light. For some of DNA samples, there was used
direct sequencing (ABI Prism 300 Genetic analyzer,
using Big Dye v.3.1. kit (Applied Biosystems)). In all
cases, the genotypes corresponded to those after RFLP
analysis.
The level of the clinical condition of schizophrenia
patients was evaluated by using the Brief Psychiatric Rating Scale (BPRS) (17), but for the patients with depression the Hamilton Depression Rating Scale (HAM-D)
was used (18). The anxiety level of the patients was set
by the Hamilton Anxiety Scale (HAM-A) (19).

Statistical analysis
There have been used several methods and statistical
indicators for statistics processingaverage value, average standard deviation and average standard errors.
Validity in difference in the average measurements of
two groups was estimated according to the Student t-test,
significance level P 0.05.
The data were obtained using STATA Data Analyses
Tool: Regression Statistics, a two sample t-test with
equal variances, Bartletts test for equal variances and the
Bonferroni test.

Fig. 1. The mean level of homocysteine (Hcy, mol/l) in patients with affective disorders and schizophrenia spectrum disorders.

132

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Results
The level of vitamin B12 and folic acid has been found
according to the norm for all patients.
It has been found that the highest level of Hcy in the
group of schizophrenia spectrum disorders was observed
in patients with paranoid schizophreniacontinuous
(12.76 5.25 mol/l) and episodicrecurrent process of
disease (11.30 7.75 mol/l) (r 0.56; P 0.01). For
the group with the affective disorders, the highest level
was observed in patients of anxiety with depressive
symptoms and patients with mixed affective disorders
(r 0.58; P 0.01). The lowest level of Hcy was
observed in patients with simple schizophrenia and
depression without anxiety (8.47 3.26 and 9.25 mol/l,
respectively) (Figure 1).
In the genetic research, the patients were divided into
three groups, depending on the existing genotype for T
allele: CC, CT and TT. Genetic analyses were performed

for all patients. There were 80 patients with CC genotype, 92 patients with CT genotype and only eight with
TT genotype.
For the patients with paranoid schizophrenia of continuous process and episodic process, the Hcy level was
stated statistically credibly higher if they had CT genotype, not CC genotype. The patients with paranoid
schizophrenia of continuous process had an Hcy level of
10.03 3.42 with the CC genotype and 16.36 2.99
with CT genotype. The patients with schizophrenia of
episodic process had an average Hcy level of 10.08 4.4
with the CC genotype and 14.76 5.54 with the CT
genotype. The genotype did not influence the level of
Hcy in the other groups of patients (Figure 2).
The indices of the HAM-A scale were higher for the
patients with paranoid schizophreniacontinuous (20
values), episodicrecurrent process of schizophrenia (15
values), depressive symptoms with anxiety (16 values)

Fig. 2. The mean level of homocysteine (Hcy, mol/l) in patients with affective disorders and schizophrenia spectrum disorders depending
on MTHFR C677T polymorphism.
NORD J PSYCHIATRYVOL 68 NO 22014

133

L KEVERE ET AL.

Table 2. The mean level of homocysteine (Hcy, mol/l), MTHFR

C677T gene polymorphism and indices of diagnostic scales in
patients with affective disorders, schizophrenia spectrum disorders
and in control group.
Patients group
Continuous course
schizophrenia
Episodic course schizophrenia
Simple schizophrenia

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Affective disorders
Control group

Genotype Hcy (mol/l) BPRS HAM-A

CC

9.03

40

12

CT
CC
CT
CC
CT
CC
CT
CC
CT

17.6
10.27
14.01
7.26
8.96
11.47
11.71
6.35
7.62

90
45
86
20
28

28
14
26
10
12
18
19

BPRS, Brief Psychiatric Rating Scale; HAM-A, Hamilton Anxiety Scale.

and mixed affective disorders (14 values). Significantly

lower levels of anxiety were observed for the patients
with simple schizophrenia (11 values). More scores on
the HAM-A scale were for patients with schizophrenia
spectrum disorders and CT genotype. For the patients
with affective spectrum disorders, the values of the
HAM-A were high, but independent of genotype.
The HAM-D score number was higher in patients who
showed depression with anxiety (average 22 values) and
mixed affective disorders (average 18 values), but for
patients with depression without anxiety, the scale score
number was lower (average 15 values). There was no relation among score numbers and any genotype observed.
The values of BPRS scale were higher for the patients
with paranoid schizophreniacontinuous (65 values) and
for patients with an episodicrecurrent process of schizophrenia (66 values), especially if they have a CT genotype (Table 2).
In the repeated analyses of Hcy level, a significant
increase of Hcy level was found for the patient with
paranoid schizophrenia of continuous process (r 0.82;
P 0.01), as well as for the patients with schizophrenia
of episodic process and affective disorders.

Discussion
If schizophrenia is beginning in the childhood and adolescence, it has been consistently associated with a range
of early neurodevelopmental abnormalities and psychological factors (20).
The studies carried out now have not yet convincingly
demonstrated the role of Hcy in the pathogenesis of mental
disorders. The results of these studies reflect a partial, episodic and sometimes even weak clinical correlation between
hyperhomocysteinemia and psychiatric diseases (21, 22).
The studies being conducted simultaneously or repeatedly
do not always show a confirmation in this correlation.

134

It is established that an increased Hcy level is commonly linked with MTHFR gene TT genotype (23, 24).
It results in brain development disordersthe brain
becomes more sensitive to exotoxin and produces a
predisposition for schizophrenia development in latter
periods (25).
Two common single MTHFR nucleotide polymorphisms have been reported: a CT transition at nucleotide 766 in exon 4 (rs1801133) and an AC
transversion in exon 7 at position 1298 (rs1801131).
Both of these polymorphisms are functional and result in
diminished enzyme activity. For the C677T polymorphism, homozygote variants have 30% enzyme activity
in comparison with homozygotes for the wild-type C
allele, while heterozygotes retain 65% of wild-type
MTHFR enzyme activity (26, 27). The consequences of
the C677T polymorphism have been demonstrated in
population studies, where the lower levels of the red
blood cell folate, plasma folate and vitamin B12 have
been reported among healthy persons with genotype 677
TT compared with persons of other genotypes (28).
There was an increased risk of schizophrenia among
homozygote variants (TT) (reliability of statistical data
is low) in one study. Subjects with schizophrenia showed
a significantly increased frequency of the T allele. A
cumulative meta-analysis showed that a moderate and
significant association between schizophrenia and
MTHFR C677T has remained over time. However, no
association between MTHFR C677T and anxiety disorders was found (29).
For the present, there are practically no studies about
hyperhomocysteinemia linked with psychic disorders in
children and adolescent psychiatry. There are some separate research studies on the connection of Hcy level and
affection in the case of schizophrenia in adolescents
using numerically small groups of patients (aged 1421
years). It is seen that Hcy level is higher for patients
with schizophrenia than for healthy patients from the
control group. However, this concurrence is observed
only in boys (30).
Up to now, there are no data for research on changes
of Hcy level during the illness, depending on the clinical
condition of the patients.
According to Hcy level differences between the diagnostic groups of our study, we have to consider that its
level depends on the clinical features of the illness. Hcy
level is higher for the patients with an acute start of
the illness, and it characterizes affective saturation and a
more serious general psychic and somatic condition. In
those diagnostic groups were patients with continuous
paranoid schizophrenia, with an average Hcy level of
12.76 5.25 mol/l and episodic paranoid schizophrenia
and schizoaffective disorders with the average Hcy level in
blood plasma of 11.30 7.75 mol/l. The increased Hcy
level during aggravation of the illness could be connected
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HOMOCYSTEINE AND PSYCHIATRIC DISORDERS

with a stress in the condition of acute psychosis and in

such way causing different neurodegenerative impacts
and clinical worsening.
For patients who have the MTHFR gene C677T polymorphism in heterozygotic form, a more serious illness
pace has been observedthere are more characteristic
forms of less favorable process schizophrenia (continuous pace or episodic with a progress). The illness is a
more serious condition in general patients (both somatic
and psychic). The patients have more often partial remissionspositive symptoms do not disappear completely
and strong negative symptoms remain during remissions,
which significantly impair the patients social functioning
(this is the reason why many patients in the remission
phase continue receiving polypharmacotherapy and stay
in care centers). After mutation of the MTHFR gene
C677T for heterozygotic patients show resistance to therapy; they received bigger doses of medicine than patients
with the CC genotype did. Patients with the CT genotype showed more side-effects (changes of QT interval,
side-effects of endocrine and extrapyramidal system).
Currently, it is not possible to say precisely what
causes more side-effects for the patients with the CT
genotypeextreme sensitivity, bigger doses of medicine
or both. However, we can conclude that the patients with
the CT genotype have to use medicine more carefully,
and it is necessary to follow the somatic condition of the
patients to discover and treat the possible side-effects.

Conclusions
The data from this research testify that the level of Hcy
is significantly higher for the patients with paranoid
schizophrenia of continuous and episodic process, compared with the level of Hcy of the patients of the control
group.
We found that the level of Hcy is connected also with
the level of affectednessif the clinical process is with
the marked affective expression, the level of Hcy is
higher.
It was proved in the research that the level of Hcy is
connected with the existence of CT genotype of the
MTHFR genethe level of Hcy was higher for the
patients with the CT genotype.
We concluded that clinical process of schizophrenia is
of less favorable gait for patients with an increased level
of Hcy.
Data from the research show the connection between
the MTHFR C677T polymorphism, the level of Hcy, illness with schizophrenia and its process. After evaluation
of these results, we can conclude that the level of Hcy is
higher for a person with the heterozygotic gene, who
becomes ill with schizophrenia, as well as for the process of the illness, is less favorable and with more
marked affective expression.
NORD J PSYCHIATRYVOL 68 NO 22014

Declaration of interest: The authors report no conflicts of

interest. The authors alone are responsible for the content
and writing of the paper.
The authors declare that they have no competing
interests and did not apply for or receive any funding for
this work.

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Laura Kevere, Department of Psychiatry, Riga Stradins University,
Riga, Latvia.
Santa Purvina, Department of Internal Diseases, Riga Stradins
University, Riga, Latvia.
Daiga Bauze, BKUS Gailezers, Childrens Psychiatric Hospital, Riga,
Latvia.
Marcis Zeibarts, Department of Internal Diseases, Riga Stradins
University, Riga, Latvia.
Raisa Andrezina, Department of Psychiatry, Riga Stradins University,
Riga, Latvia.
Linda Piekuse, Scientific Laboratory of Molecular Genetics, Riga
Stradins University, Riga, Latvia.
Edgars Brekis, Department of Mathematical Economics, Faculty of
Economics and Management, University of Latvia, Riga, Latvia.
Indulis Purvins, Department of Internal Diseases, Riga Stradins
University, Riga, Latvia.

NORD J PSYCHIATRYVOL 68 NO 22014