Author’s Accepted Manuscript

Vitamin B12, folic acid, homocysteine and vitamin

D levels in children and adolescents with obsessive
compulsive disorder

Erman Esnafoğlu, Elif Yaman

www.elsevier.com/locate/psychres

PII: S0165-1781(16)31441-X
DOI: http://dx.doi.org/10.1016/j.psychres.2017.04.032
Reference: PSY10458
To appear in: Psychiatry Research
Received date: 25 August 2016
Revised date: 14 April 2017
Accepted date: 20 April 2017
Cite this article as: Erman Esnafoğlu and Elif Yaman, Vitamin B12, folic acid,
homocysteine and vitamin D levels in children and adolescents with obsessive
compulsive disorder, Psychiatry Research,
http://dx.doi.org/10.1016/j.psychres.2017.04.032
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 Vitamin B12, folic acid, homocysteine and vitamin D levels in children and

adolescents with obsessive compulsive disorder

Erman Esnafoğlua, Elif Yamanb

a
Department of Child and Adolescent Psychiatry, Training and Research

Hospital, Faculty of Medicine, Ordu University, Ordu, Turkey

b
Department of Pediatry, Training and Research Hospital, Faculty of Medicine,

Ordu University, Ordu, Turkey

Abstract

Obsessive compulsive disorder (OCD) is a complex disorder with a poorly

understood aetiopathogenesis. One carbon metabolism that includes vitamin B12,

folic acid and homocysteine has been investigated in many psychiatric disorders like

OCD. In recent years, vitamin D has also been considered to contribute to many of

these psychiatric disorders. In this study we investigated whether vitamin B12,

homocysteine and vitamin D play a role in the aetiology of paediatric OCD. With this

aim we compared 52 children and adolescent OCD patients with 30 healthy controls.

The participants were tested for vitamin B12, folic acid, homocysteine and vitamin D

levels and were evaluated with a sociodemographic form, state-trait anxiety inventory

1 and 2, Kovacs Depression Inventory and Yale-Brown Obsessive Compulsive Scale

(Y-BOCS). As a result we found significantly lower levels of vitamin B12 and vitamin

D and higher levels of homocysteine in the patient group compared to control group

(p values for all three scores were <0.001), whereas there was no significant

difference between groups in terms of folate levels (p=0.083). This demonstrates that
one carbon metabolism and vitamin D deficiency can play a role in the aetiology of

OCD.

Keywords: obsessive compulsive disorder, vitamin B12, folate, homocysteine,

vitamin D, aetiopathogenesis,

1. Introduction

Obsessive compulsive disorder (OCD) is a psychiatric disorder characterized

by obsessions (all kinds of images and impulses that are involuntary and persistent)

and compulsions (repetitive involuntary behaviours that are performed to clear the

mind of the obsessive thoughts and to eliminate the stress caused by them)

(American Psychiatry Association, 2013). Epidemiological studies have

demonstrated the prevalence of OCD in children and adolescents as 0.25-4%

(Douglass et al., 1995; Flament, 1990; Heyman et al., 2001; Jaisoorya et al.,

2015; Zohar et al., 1992). Adolescents with OCD have greater psychological distress

and poorer academic performance together with higher rates of suicidal thoughts,

suicide attempts, attention deficit and hyperactivity, sexual abuse and tobacco use

(Jaisoorya et al., 2015). OCD is a complex psychiatric disorder that may occur due

to genetics (Pauls, 2010), alterations in frontostriatal connections (Pauls et al.,

2014), psychosocial experiences, perinatal injuries, toxic pathogens, stress and

traumatic events and environmental factors like infections, particularly streptococcal

infections (Grisham et al., 2008).

Vitamin B12, folic acid and homocysteine levels were shown to be associated

with certain neuropsychiatric disorders and vitamin B12, folate deficiency and high

levels of homocysteine were shown to have an impact on brain functions and cause
non-specific psychiatric symptoms. Many studies found high levels of homocysteine,

low levels of vitamin B12 and/ or folic acid in patients with schizophrenia

(Haidemenos et al., 2007; Kim and Moon 2010; Mabrouk et al., 2011;

Muntjewerff et al., 2006, Zhang et al., 2016), autism (Al-Farsi et al., 2013; Ali et

al., 2011; Puig-Alcaraz et al., 2015; Tu et al., 2013; Zhang et al., 2016) and

depression (Tiemeier et al., 2002; Tolmunen et al., 2004). In a study involving

children and adolescents high levels of homocysteine were shown to be associated

with schizophrenia and mood disorders (Kevere et al., 2012). In a few studies on

adult patients with OCD, there is some evidence of increased homocysteine, deficient

levels of folic acid and vitamin B12 in adult patients with OCD (Atmaca et al., 2005;

Türksoy et al., 2014). Also cases of OCD that are due to a vitamin B12 deficiency

have been reported (Sharma and Biswas, 2012; Valizadeh and Valizadeh, 2011).

Circulating levels of homocysteine are accepted as a sensitive marker of folic acid

and vitamin B12 (Folstein et al., 2007; Klee, 2000; Nilsson et al., 1999).

Vitamin D is another vitamin that has been investigated in the aetiology of

psychiatric disorders. Vitamin D deficiency has been suggested to play an important

role in the aetiology of schizophrenia and autism (Crews et al., 2013; Feng et al.,

2016; McGrath et al., 2010; Saad et al., 2015; Valipour et al., 2014; Wang et al.,

2016). Vitamin D deficiency can also contribute to development of depression and

anxiety disorders (Anglin et al., 2013; Berk et al., 2007; Bertone-Johnson, 2009;

Bicikova et al., 2015; Milaneschi et al., 2013). In the last few years, many reports

demonstrating an important role for vitamin D in brain development and functions and

aetiopathogenesis of neuropsychiatric disorders have been published (Eyles et al.

2012; Harms et al., 2011; McCann and Ames, 2008).

 To the best of our knowledge the role of one carbon mechanism and vitamin D

deficiency in children and adolescents with OCD has not yet been investigated. For

this reason we aimed to investigate serum vitamin B12, folic acid homocysteine and

vitamin D levels in children and adolescents in this study.

2. Materials and Methods

All subjects were patients who attended the outpatient clinic for children and

adolescent psychiatry at Ordu University Research and Training Hospital.

Participants in the patient group were diagnosed according to DSM V criteria. Healthy

control subjects were chosen from patients with minor issues that were admitted to

the outpatient clinic for consultancy. All participants completed a sociodemographic

form, Yale-Brown Obsessive Compulsive scale, KOVAKS depression scale, STAI-1

and STAI-2 anxiety scales. Psychometric tests were administered by expert

psychologists blind to the study. Besides routine laboratory tests (thyroid function

tests, hemogram, routine biochemistry), vitamin B12, folic acid, homocysteine and

vitamin D levels were measured. Blood samples were collected from all participants

between 08:00 and 11:00 in the morning under sterile conditions. To obtain more

accurate results those participants who had used a nutritional support product in the

last year and who were vegetarians were not included in the study. Additionally,

those with infection, psychotic disorders, and subjects with diagnosis of mental

retardation and developmental disorder were excluded from the study. This study

was approved by the ethics committee of Ordu University School of Medicine.

Informed consent was obtained from all participants and their families.

2.1. Sociodemographic form

 Sociodemographic form includes age, residential address, beginning of the

illness, comorbidities, other psychiatric conditions, being vegetarian or not, drug

history and intake of any dietary supplements in the last year.

2.2. Yale-Brown Obsessive Compulsive Scale (Y-BOCS):

This scale was developed to evaluate the degree of severity of the OCD,

independent of the various types of obsessions and compulsions (Goodman et al.,

1989). On this scale, 10 parameters are scored between 0 (no symptoms) and 4

(extreme symptoms). Turkish validity and reliability studies of the scale, which is

accepted as a reliable and valid tool for evaluating the severity of OCD, were

performed by Karamustafalioglu et al. (1993). On this scale, scores from 8 to 15

indicate mild disease, scores from 16 to 23 indicate moderate disease, and scores

above 24 indicate severe disease. Y-BOCS was administered by an interviewer in

the present study.

2.3. Children’s Depression Inventory (CDI)

This inventory was developed by M. Kovacs with the hypothesis that ‘child

depression exists, it can be observed and measured, it’s characteristics resemble

adult depression (Kovacs, 1985). The validity of this questionnaire for Turkish

speaking children and adolescents aged 6-17 was demonstrated by Öy et al. in 1991

(Öy, 1991). The depression scale for children can be applied to children aged 6-17

years. It consists of 27 items in total. The cut off value was determined as 19. The

scale is completed by the child himself/herself or it is read to the child. The child is

asked to choose the most representative option from three available sentences

considering his/her situation in the last 2 weeks. Given answers were scored
between 0 and 2 points. The highest possible total score is 54. The total score

increases with the severity of the disease.

2.4. State-Trait Anxiety Inventory - STAI-I, STAI-II

This item was developed by C.D. Spielberger in 1970 (Spielberger, 1970).

The Turkish validation study of this form was performed by Öner and Le in 1985

(Öner, 1985). The questionnaire has 2 sub-domains each of which has 20 items:

Situational Anxiety Scale and Continuous Anxiety Scale. The Situational Anxiety

Scale determines how a subject feels under a certain condition at a certain time and

it is scored by choosing either ‘nothing’, ’a little bit’, ‘a lot’ or ‘completely’ to reflect the

severity of the feeling, thought or behaviour. The Continuous Anxiety Scale evaluates

how the subject feels irrespective of the situations or circumstances. The

questionnaire contains direct or inverted statements. The total score obtained from 2

subscales changes between 20 and 80. A higher score shows a higher level of

anxiety. The cut off value for each sub domain is 45.

2.5. Vitamin B12, folic acid, homocysteine and vitamin D measurements

Briefly, 1 ml of venous blood sample was collected in anticoagulant-free tubes

(BD Vacutainer Blood Collection Tube) after overnight fasting. Serum was isolated by

centrifugation at 3000 rpm for 10 min at room temperature (NF 1200R, Nuve®). Then

25-OH Vitamin D levels were measured using the chemiluminescent micro particle

immunoassay ARCHI-TECT 25-OH Vitamin D assay and read in an Architect i1000

analyser (Abbott Laboratories, Abbot Park, Illinois, USA). Vitamin B12 was measured

by chemiluminescent micro particle Intrinsic Factor ARCHI-TECT B12 assay with

commercial kits supplied by Abbott Laboratory. Folate was measured by

chemiluminescent micro particle Folate binding protein ARCHI-TECT Folate assay

with commercial kits supplied by Abbott Laboratory. Homocysteine measured by

chemiluminescent immunassay method using kits supplied by Abbott Laboratory.

2.6. Statistical Analysis

According to the completed power analysis, with type 1 error rate 0.05 and

0.80 power ratio, for a 50 pg/ml difference in vitamin B12 values to be significant, the

minimum subject number in each group was calculated as 65. Data analysis was

performed using SPSS 22.0 software. Descriptive statistics were stated as mean ±

standard deviation (SD) for continuous variables and as percentage (%) for

categorical variables. To evaluate whether or not there was a significant difference

between the groups, the Student’s t-test and the Mann Whitney U-test were applied.

The normal distribution of the data was checked using Shapiro-Wilk test. Direct

relationships between continuous variables were examined with Pearson and

Spearman correlation tests. Categorical data comparisons were made using the Chi-

Square test. A value of p<0.05 was accepted as statistically significant.

3. Results

This study involves 52 OCD patients and 30 healthy controls. Fifty percent of

patient group were boys (n=26) and 50% were girls (n=26). The mean age was

14.7±2.3 SD years. Fifty-three percent of the control group were girls (n=16) and

46.7% were boys (n=14). The mean age of the control group was 14.2±2.6 years

(Table 1). None of the subjects were taking nutritional support like any medication or

neuro-nutraceuticals.
 There was no significant difference between patient and control groups in

terms of age and gender distribution (p: 0.821 and 0.364, respectively). There was a

significant difference in Y-BOCS, Kovacs CDI and STAI-2 scores (p values for all

three scores were <0.001). There was no significant difference between STAI-1

scores of the groups (p: 0.057). For all subjects there was a positive correlation

identified between Y-BOCS points and Kovacs CDI, STAI-1 and STAI-2 values

(r:0.546; p<0.001 and r:0.301; p:0.006 and r:0.507; p<0.001, respectively).

There was a statistically significant difference between the vitamin B12,

homocysteine and Vitamin D levels of the groups (p values for all three scores were

<0.001). There was no significant difference between the groups in terms of folic acid

levels (p: 0.083) (Table 1; Figure 1).

Table 1: Group characteristics and vitamin levels

Patient group Control group p value
(n: 52) (n:30)
*
Gender (Female/Male) 26/26 16/14 0.821
**
Age 14.7±2.3 14.2±2.6 0.364
**
Y-BOCS 19.9±7.4 1.3±1.3 < 0.001
**
STAI-1 43.07±14.1 36.83±13.9 0.057
**
STAI-2 50.8±13.8 39.4±10.3 < 0.001
**
CDI 20.1±8.0 9.5±5.9 <0.001
**
Vitamin B12 (pg/ml) 243.6±105.3 355.6±115.6 <0.001
**
Folic acid (ng/ml) 5.4±2.0 6.2±2.3 <0. 083
**
Homocysteine (umol/L) 15.1±5.6 10.2±2.6 <0.001
**
25-OH Vitamin D 16.1±6.8 29.4±12.1 <0.001
(ng/ml)
Note:
*
Chi-square p value;
**
variables are designated as mean±SD and Student’s t test p value

Y-BOCS: Yale-Brown Obsessive Compulsive Scale; CDI: Children’s Depression Inventory; STAI-1
and 2: State-Trait Anxiety Inventory 1 and 2

Figure 1: Distribution of vitamin B12, folic acid, homocysteine and vitamin D between
the groups The upper and lower edges of the boxes show the 25th and 75th
percentile values, horizontal lines in the box are median value, asterix (*) are extreme
values and circle (o) are outliers. The vertical lines extending from the boxes extend
to larger and smaller values that are not outliers.
 The correlation analysis between groups demonstrated a statistically

significant positive correlation between age and homocysteine levels (r: 0.320, p:

0.003). Yale-Brown score and depression scale score, STAI-1 and STAI-2 scores

were positively correlated (r: 0.550, p<0.001; r: 0.322, p: 0.003; r: 0.499, p< 0.001,
respectively) when all subjects were evaluated. There was no correlation between

folic acid, homocysteine levels and Y-BCOS score (r:-0.141, p: 0.207 and r: 0.093, p:

0.404 respectively). There was a significant negative correlation between vitamin

B12, vitamin D levels and Y-BOCS score (r:-0.260, p: 0.018 and r:-0.545, p<0.001

respectively) (Figure 2). When the patient group is investigated, there was no

significant correlation identified between Y-BOCS score and vitamin D (r:-0.241;

p:0.086), but there was a significant correlation identified with vitamin B12, folic acid

and homocysteine levels (r:0.314; p:0.023; r:0.278; p:0.046 and r:-0.599; p<0.001,

respectively). Additionally there was a statistically significant negative correlation

identified between vitamin B12 and folic acid and homocysteine (r:-0.401; p<0.001

and r:-0.315; p:0.023, respectively). When the healthy control group is assessed,

there was no significant correlation found between Y-BOCS and all vitamin values.

Additionally when the presence and degree of insight among OCD patients

was evaluated, there was no significant difference or correlations identified with

vitamin B12, folic acid, vitamin D and homocysteine.

Figure 2: Scattergram of Y-COBS score with vitamin B12 and vitamin D distribution
4. Discussion

In this study the OCD group were found to have higher points on anxiety and

depression scales. Obsessions in OCD patients lead to nearly constant fear,

repulsion, anxiety and the need for repetition. The result is that OCD commonly

occurs with other psychiatric disorders. It is proposed that 80% of OCD children have

another axis I disorder (Friedlander and Desrocher, 2006; Pinto et al., 2006). Of

these the most common appear to be other anxiety disorders at rates of 50% and

depressive disorders at rates of 40% (Pinto et al., 2006; Shafran, 2001). In this

study in accordance with the data, OCD patients obtained clearly high points on the

CDI depression scale and the STAI-2 showing continuous anxiety and there was a

clear positive correlation identified.

Although vitamin B12, folic acid and homocysteine levels in adults with OCD

have been studied, no such research on children and adolescents with OCD has

been performed up to now. To the best of our knowledge vitamin D levels have never

been investigated in any patients with OCD. The findings of this study demonstrated

that vitamin B12 and vitamin D levels were significantly lower in patients compared to

healthy controls, whereas homocysteine was higher in the patient group. There was

no significant difference between groups in terms of folic acid levels. These findings

are in line with similar studies conducted in adults. In the study of Atmaca et al.

(2005), folic acid levels in OCD patients were low whereas homocysteine levels were

high. Türksoy et al. (2014) found low vitamin B12 levels, high homocysteine levels

and indifferent folic acid levels in patients with OCD. Hermesh et al. (1988) reported

more frequent vitamin B12 deficiency in patients with OCD. There are studies in the

literature reporting OCD symptoms in patients with vitamin B12 deficiency (Sharma

and Biswas, 2012; Valizadeh and Valizadeh, 2011). When evaluated together all

these findings suggest that one carbon metabolism, which involves vitamin B12, folic

acid and homocysteine, may contribute to the aetiology of OCD. One carbon

metabolism maintains the methylation processes of neurotransmitters, proteins, and

neural membrane phospholipids and is required for DNA synthesis (Bottiglieri,

2005). These metabolic pathways may play a central role in the occurrence of

neuropsychiatric symptoms (Coşar at al., 2014). Folic acid and vitamin B12

deficiencies cause a decrease in methylation reactions that leads to a decrease in

neurotransmitter levels and as a result intracellular biochemical pathways are

adversely effected (Bottiglieri, 2005). Besides, a significant increase in

homocysteine levels may occur which may be toxic. Increased levels of

homocysteine cause DNA damage, mitochondrial dysfunction and stress in

endoplasmic reticulum and also increases influx of calcium into the cell by activating

NMDA receptors. Apoptotic signals are activated and intracellular oxidative stress

increases (Bhatia and Singh , 2015; Bottiglieri, 2005; Coşar at al., 2014; Ho at al.,

2002; Mattson and Shea, 2003; Stranger et al., 2009).

Vitamin D plays important roles in development and normal functioning of the

brain by regulating proliferation, differentiation, neurotransmission, myelinisation,

neuron protection and neuroplasticity. Besides this, it also has functions such as DNA

stabilization, suppression of autoimmunity, anti-inflammatory effects, mitochondrial

protection and protection against oxidative stress (Cannell, 2013a, 2013b; Kinney at

al., 2011). For this reason it has been argued that vitamin D can play a role in normal

functioning of central nervous system and it’s diseases (Eyles at al., 2012; Harms at

al., 2011). Additionally Vitamin D affects brain serotonin concentrations by regulating

tryptophan hydroxylase gene expression which is a rate limiting step in serotonin

synthesis. There is a dysregulation of brain serotoninergic neurotransmission in some

psychiatric disorders like OCD (Kaneko at al., 2015; Patrick and Ames, 2014;

Patrick and Ames, 2015). Therefore vitamin D may contribute to OCD development

via the serotonin system. Closest to OCD, vitamin D has been investigated in anxiety
disorders and it was found to be significantly lower in patients with anxiety disorders

compared to control subjects (Bicikova at al., 2015). As a result of this study vitamin

D levels were found to be lower in OCD patients with a negative correlation to the

severity of the disease.

There are some limitations to this study. Firstly increasing the number of

subjects may allow the opportunity to make a more accurate assessment. The

subject number in our study is low compared to the results of power analysis.

Additionally the dietetic situation of subjects and seasonal effects on vitamin values

should be noted. Additionally, due to reasons such as OCD patients making changes

to their eating habits linked to symptoms and reduced exposure to ultraviolet sunlight

required for vitamin D synthesis, these factors should be taken into consideration

when evaluating the cause-effect relationship.

5. Conclusion

This study has demonstrated that there is a significant decrease in vitamin

B12 and vitamin D and a significant increase in homocysteine in children and

adolescents with OCD. Vitamin D deficiency may be a risk factor for development of

OCD. Clinicians should be vigilant about one carbon metabolism and vitamin D levels

in patients with OCD. The role of one carbon metabolism and vitamin D in the

development of OCD symptoms should be researched in more advanced studies and

limitations should be researched with more subjects. Further research on the benefits

of vitamin B12, folic acid and vitamin D supplementation is needed.

Conflict of interest
 The authors declare no conflict of interest. The authors declare that this study

has received no financial support.

Acknowledgments

We wish to thank all children and adolescents and their families who

participated in the study and Prof.Dr. Suna Taneli for guidance and inspiration.

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Highlights

 OCD is a frequent disorder in children and adolescents that has a poorly

understood aetiopathogenesis

 One carbon metabolism that includes vitamin B12, folic acid and

homocysteine can play a role in the aetiopathogenesis of OCD.

 It has been suggested that Vitamin D can play a role in the aetiopathogenesis

of many psychiatric disorders.

 Findings of this study demonstrated lower levels of vitamin B12 and higher

levels of homocysteine in OCD patients which suggests that they can play a

role in aetiopathogenesis of OCD.

 Vitamin D levels were found to be lower in OCD patients and had a negative

correlation with disease severity, so it may contribute to OCD

aetiopathogenesis.