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Received Date: 29-Oct-2013 Revised date: 02-Dec-2013 Accepted Date: 25-Dec-2013 Category of manuscript: Original Article

Title: Vitamin D Status in Children with Attention Deficit Hyperactivity

Disorder1

Running title: Vitamin D in Attention Deficit Hyperactivity Disorder

Sevil Bilir Goksugur1, MD, Assistant Professor Ali Evren Tufan2, MD, Assistant Professor 3

Murat Semiz , MD, Psychiatrist

[email protected] [email protected]

Cemalettin Gunes4, MD, Pediatrician

[email protected]

Mervan Bekdas1, MD, Assistant Professor

[email protected]

Mehmet Tosun5, MD, Associate Professor Fatih Demircioglu1, MD, Associate Professor

[email protected] [email protected]

1- Department of Pediatrics, Medical Faculty, Abant Izzet Baysal University, Bolu, Turkey 2- Department of Child and Adolescent Psychiatry, Medical Faculty, Abant Izzet Baysal University, Bolu, Turkey 3- Department of Psychiatry, Sivas State Hospital, Sivas, Turkey 4- Department of Pediatrics, Medical Faculty, Duzce University, Duzce, Turkey 5- Department of Biochemistry, Medical Faculty, Abant Izzet Baysal University, Bolu, Turkey

Address correspondence to: Dr. Sevil Bilir Goksugur Abant Izzet Baysal University, Medical Faculty, Department of Pediatrics, 14280 Golkoy – BOLU, TURKEY.

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: doi/10.1111/ped.12286

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Phone: +90 374 2534656 Fax: +90 374 2534615 E-mail: [email protected]

Conflict Of Interest: None of the authors have conflict of interest Number of words = 2.518 Number of text pages = 10 Number of reference pages = 5 Number of tables = 2 Number of figures = 0 Number of legends to figures = 2

Vitamin D Status in Children with Attention Deficit Hyperactivity Disorder

ABSTRACT Background: Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common

psychiatric disorders of the childhood is an early onset, affecting 2-18 % of the children worldwide. Etiopathogenesis of ADHD is obscure. In recent studies, low levels of vitamin D are found in association with many disorders as well as in neuropsychiatric diseases. In this study, we aimed to investigate serum vitamin D levels in pediatric ADHD patients.

Methods: A total of 60 ADHD patients and 30 healthy controls were included in the study. Ages of the both groups were in 7 and 18 years old range. Serum levels of 25-OH-Vitamin D, calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) were investigated.

Results: Serum levels of 25-OH-vitamin D were found to be significantly lower in children

and adolescents with ADHD compared to healthy controls and no significant differences were found between the groups in terms of other variables. 25-OH-vitamin D level in ADHD group and control group was respectively; 20.9±19.4 ng/mL and 34.9±15.4 ng/mL (p=0.001).

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Conclusion: Our results suggest that there is an association between lower 25-OH-vitamin D concentrations and ADHD in childhood and adolescence. Up to our knowledge this is the first

study that investigate the relationship between vitamin D and ADHD in children.

Key words: Vitamin D; Attention Deficit Hyperactivity Disorder; children

INTRODUCTION

Attention deficit hyperactivity disorder (ADHD) is an early onset, chronic, neurodevelopmental disease that is characterized by attention deficit, hyperactivity and impulsivity 1. ADHD affects nearly 2-18 % of children worldwide and is one of the most

common psychiatric disorders of childhood 2. It can affect learning in childhood and cause various psychosocial problems in children and adults 3. The reported prevalence of ADHD in school-age children is 3–5% following the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition-Text Revision (DSM-IV-TR) 4. However, the neurobiology of ADHD is not fully understood. Recent family, adoption, twin and molecular genetic studies

have revealed that genetic factors are predominantly responsible for the development of ADHD 5.

The importance of the neurotransmitters dopamine (DA) and noradrenalin (NA) in attention, concentration, motivation, awareness and other cognitive functions is well known. Since the stimulatory drugs used to treat ADHD affect both the DA and NA systems, many believe that ADHD involves pathology in both of these systems 4, 5. A dopaminergic system disorder in the basal ganglions of children with ADHD was demonstrated using single-photon emission computed tomography (SPECT) 3.

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Vitamin D is a fat-soluble secosteroid, which is essential for intestinal calcium absorption,

serum calcium homeostasis and musculoskeletal development 6. Low serum vitamin D levels

are associated with the development of cardiovascular disease, hypertension, neurodegenerative disease, diabetes mellitus, metabolic syndrome and even cancer 7.

Although the vitamin D receptor and activating enzymes are prominent in the hypothalamus and substantia nigra 8, which are involved in the development of depression 7 and vitamin D has been associated with depressive symptoms and other psychiatric conditions 9, 10, the

precise function of vitamin D in the brain is not fully understood. There are associations between low serum vitamin D levels and depression, mood disorders, premenstrual mood changes, decreased cognitive function and autism spectrum disorder 11-14. There are limited data on the association of hyperactivity and behavioral problems and vitamin D in children 15, 16. To our knowledge, the serum vitamin D levels in ADHD patients have not been determined in a prospective study. Clarifying the role of vitamin D in ADHD might help to understand the pathogenesis of the disease. Therefore, this study investigated the serum of vitamin D3 (25-hydroxy cholecalciferol) levels in adults and children with ADHD.

MATERIALS AND METHODS Study population The medical records of 6074 patients who visited to the outpatient clinic of the Child and Adolescent Psychiatry Department at the study center in between February and August 2013 were screened for their presenting complaints; 332 patients complaining of “inattention” and “hyperactivity” were identified and received initial diagnoses of ADHD or ADHD-NOS (Not Otherwise Specified). After eliminating the patients with incomplete or missing data, 164 patients remained. Patients with ADHD-NOS were also excluded from the study. Ultimately, This article is protected by copyright. All rights reserved.

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78 patients with ADHD (combined, predominantly hyperactive/impulsive and predominantly inattentive subtypes) were selected. The diagnosis of ADHD was made using semi-structured interviews according to the DSMIV-TR criteria. Mental retardation (MR) was ruled out using the Wechsler Intelligence Scale

for Children-Revised where appropriate or in clinical interviews. Patients who were diagnosed at interview with ADHD according to DSM-IV-TR criteria and whose parents and teachers endorsed at least six symptoms of inattention or at least six symptoms of hyperactivity/impulsivity as “frequent” or “very frequent” in the Turgay DSM-IV-Based Child and Adolescent Behavioral Disorders Screening and Rating Scale (T-DSM-IV-S) formed the ADHD group. Patients younger than 7 years or older than 18 years were excluded. In addition, patients with MR, autistic spectrum disorders, psychotic disorders and chronic physical or neurological disorders were excluded. Using the body mass index (BMI), only patients with healthy weights (5th to less than the 85th percentiles) were included in the study.

Thirty healthy controls who were being followed over the same period at the Department of Pediatrics formed the control group. A pediatric evaluation and interview with children and family members helped to rule out psychopathology in this group. Children and adolescents with ADHD were free to continue their treatments during the study period. All of the study procedures were in accordance with the Declaration of Helsinki and local laws and regulations. The Institutional Board of Ethics approved the study protocol and informed consent was obtained from the parents, as well as the assent of the children and adolescents. Eighteen of the patients with ADHD were excluded due to parental refusal to participate or based on the exclusion/inclusion criteria.

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Measures

The height and weight of the patients and controls were measured and the BMI was calculated; venous blood was collected for measuring serum 25-OH-vitamin D, calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) levels.

DSM-IV-Based Child and Adolescent Behavioral Disorders Screening and Rating Scale (T-DSM-IV-S) The T-DSM-IV-S was developed by Turgay and assesses disruptive behavioral changes in children and adolescents based on the diagnostic criteria in DSM-IV17. This scale was adapted to Turkish by Ercan 18. The T-DSM-IV-S is a four-point Likert-type scale. Nine items in this scale assess severe hyperactivity–impulsivity, nine items assess attention-deficit, eight items

assess oppositional behavior and 15 items assess symptoms of conduct disorder. It was completed by the parents in our study.

Wechsler Intelligence Scale for Children-Revised (WISC-R)

The WISC-R was designed to measure the intelligence quotient (IQ) of children between the ages of 6 and 16 and can be completed without reading or writing. Savaşır and Şahin standardized the WISC-R for Turkish children 19.

Laboratory analysis The blood samples were centrifuged to separate serum, which was stored at –80°C. Serum vitamin D levels were determined using an enzyme-linked immunosorbent assay (ELISA; DRG Instruments, Germany). The normal range for the serum vitamin D was accepted as 20–

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100 ng/mL (50–250 nmol/L). The serum Ca, P and ALP levels were measured using photometric methods.

Statistical analysis Parametric data were expressed as the means ± standard deviation and categorical data as percentages. SPSS 16.0 (SPSS, Chicago, IL, USA) was used to perform the statistical analysis. Independent parameters were compared via independent-samples t-tests. The Mann– Whitney U-test was used to test parametric data without a binomial distribution. Categorical data were evaluated using the chi-square test where appropriate. A p-value less than 0.05 was accepted as significant.

RESULTS

Ninety individuals were included in the study. The mean age of the ADHD group (n=60) was 9±2.2 years and 40 (66.7%) were males. The mean age of the control group (n=30) was 10.1±3.3 years and 17 (56.7%) were males. The sociodemographic data of the groups are shown in Table 1. No significant differences were found between the groups in terms of age, gender, weight, height and BMI (all p>0.05).

The mean serum 25-OH-vitamin D level in the ADHD and control groups was 20.9±19.4 and 34.9±15.4 ng/mL, respectively and the difference was significant (p=0.001). Although levels of 25-OH-Vitamin D in ADHD group were statistically lower than the control group, both groups have quite borderline levels. In the ADHD and control group, the mean serum level of calcium was 9.8±0.6 and 9.5±0.8 mg/dL, phosphorus was 5.2±1.2 and 5.1±0.6 mg/dL and alkaline phosphatase was 192.5±58.2

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and 193.1±62.1 U/L, respectively. None of these parameters differed significantly between the groups (all p>0.05) (Table 2). When the ADHD subtypes were evaluated, our patients were mostly the inattentive (n=26, 43.3%) and combined (n=24, 40%) types, with only 10 patients (16.6%) diagnosed as the predominantly hyperactive/impulsive type. No significant differences were found among the ADHD subgroups in terms of serum levels of 25-OH-vitamin D, Ca, P and ALP (all p>0.05).

When the clinical features of ADHD patients were evaluated according to vitamin D levels under and over 20 ng/mL, results were statistically insignificant.

DISCUSSION In this study, the serum vitamin D levels were significantly lower in children and adolescents with ADHD compared to the healthy controls. This is the first report to investigate the association between the plasma vitamin D level and ADHD. Vitamin D is important in cerebral function and might have a role in the etiopathogenesis of ADHD 20. In the early stages of life, vitamin D deficiency might harm neuronal development and function 21. Vitamin D stimulates neurogenesis. Vitamin D regulates the synthesis of neurotrophic factors such as neurotrophin (NT) 3, NT 4, nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF), which are important for cell differentiation and survival 22, 23. Animal studies provide clues to how vitamin D deficiency might increase the risk of ADHD, suggesting that it alters neurotrophic factors and monoamine levels 24, 25, facilitating oxidative stress responses and changing multiple neuroendocrine transmitters 26, 27. Abnormal dopamine regulation in certain areas of the central nervous system might have a

role in the etiology of ADHD 28. Dietary fatty acids alter the regulation of dopamine neurotransmission in rats 29 and the fatty acid desaturase 2 gene is associated with ADHD 30. Bulut et al. also reported that increased oxidative stress might be associated with the

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pathophysiology of ADHD 31. Vitamin D receptors (VDR) and metabolizing enzymes are found in different parts of the brain, including the prefrontal cortex, hippocampus, Brodmanns’s area 32, thalamus, hypothalamus and substantia nigra; areas that might have

causal relationships in the pathophysiology of ADHD 8, 32, 33. In addition, vitamin D insufficiency has detrimental effects on the dopamine pathways associated with brain development 34. Due to the cross-sectional design of our study, we cannot say that low 25OH-vitamin D levels cause ADHD. Nevertheless, our findings suggest that vitamin D

insufficiency plays a role in the etiopathogenesis of ADHD. Clinical trials have examined the associations between vitamin D and mental retardation, depression, autism and behavioral disorders in children and adults 16, 35-37. Smith et al. 37 found that vitamin D insufficiency is common in children with cystic fibrosis. Mostafa et al. 36

suggested that autistic children had significantly lower serum 25-OH-vitamin D levels than

healthy children. In this study, we also found that the serum 25-OH-vitamin D levels were

lower in patients with ADHD than in healthy controls. Tolppanen et al. 16 investigated the association between vitamin D and emotional symptoms, behavioral problems and hyperactivity symptoms and reported that higher serum concentrations of 25 (OH) D3 and 25 (OH) D2 were not associated with a lower risk of behavioral problems, whereas a better vitamin D status, as reflected in the serum 25-OH-vitamin D concentration, was associated with better mental function 16. In that study, the fact that the behavioral problems of the children were evaluated only with a scale, without clinical interviews, might have affected the results negatively. In another study, Llewellyn et al. 13 suggested that low serum 25-OHvitamin D is associated with increased odds of cognitive impairment. Recently, vitamin D deficiency was found to be associated with a number of neuropsychiatric conditions 21. Jorde et al. 38 administered high-dose vitamin D (20,000 and 40,000 IU) for 1

year and found a significant effect of vitamin D on the Beck Depression Inventory score This article is protected by copyright. All rights reserved.

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compared with placebo. In a randomized double-blind controlled trial, combined vitamin D and fluoxetine treatment was found to be superior to fluoxetine only for controlling depressive symptoms in 42 patients with major depression 39. Khoraminya et al. 39 reported that supplemental vitamin D is a safe, effective adjunctive treatment in major depressive disorder. Another randomized controlled trial examined vitamin D supplementation (5000 IU per day for 6 weeks) in healthy young adults (n = 128) 21. Dean et al. 40 indicated that vitamin D supplementation did not influence cognitive or emotional function in healthy young adults;

however; their study population consisted of healthy adults without major psychiatric disorders or cognitive impairment, so their findings might not be applicable to individuals with cognitive or emotional impairment. There are no data on the clinical results of adding vitamin D in the treatment of the children with ADHD; however, our findings and the results of studies of psychiatric disorders with similar mechanisms suggest that vitamin D might be useful for treating the symptoms of attention deficiency. Further studies should examine this topic.

Although we found lower vitamin D levels in children with ADHD, we do not have data about vitamin D levels before diagnosis of ADHD. So it is hard to say, lower vitamin D levels in our study are the cause or result of ADHD. Also it should be remembered that multiple factors affect vitamin D levels, calcium metabolism and brain development such as sunlight exposure, nutrition status and contamination of air, water and foods. Further studies considering these parameters may elucidate complex interactions between vitamin D and ADHD.

No studies have examined the serum Ca and P levels in children with ADHD. A study of children with depressive symptoms found no significant association between the serum Ca and P levels and depression41. We found no significant association between the serum Ca and

P levels and ADHD. The serum Ca and P were measured on a single occasion and this might This article is protected by copyright. All rights reserved.

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not accurately reflect the subjects’ usual status 42. In addition, the serum calcium concentrations are normally maintained within relatively narrow limits in humans 43.

Study strengths and limitations

To our knowledge, this is the first study to analyze the relationship between vitamin D levels and ADHD. However, our study is not without limitations. This work was limited by the small sample size, cross-sectional method and missing data on family psychiatric history, exposure of sunlight and food intake. Also it would be a very good data if 25-OH-vitamin D levels of other siblings of ADHD children would be included.

CONCLUSIONS Our results suggest an association between the 25-OH-vitamin D concentration and ADHD in childhood. Although the nature and direction of the causal relationship between the low serum vitamin D levels and ADHD remain unclear, our study found a noteworthy association. This relationship warrants further investigations to define the exact role of vitamin D in the pathogenesis of ADHD.

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20 Hoang MT, Defina LF, Willis BL, Leonard DS, Weiner MF, Brown ES. Association between low serum 25-hydroxyvitamin D and depression in a large sample of healthy adults: the Cooper Center longitudinal study. Mayo. Clin. Proc. 2011; 86: 1050-5.

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30 Brookes KJ, Chen W, Xu X, Taylor E, Asherson P. Association of fatty acid desaturase genes with attention-deficit/hyperactivity disorder. Biol. Psychiatry. 2006; 60: 1053-61.

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39 Khoraminya N, Tehrani-Doost M, Jazayeri S, Hosseini A, Djazayery A. Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust. N. Z. J. Psychiatry. 2013; 47: 271-5.

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LEGENDS

Table 1. Sociodemographical data of the ADHD patients and control groups. Table 2. The mean serum levels of 25-OH-Vitamin D, Ca, phosphorus and alkaline

phosphatase in the groups.

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Table 1. Sociodemographical data of the ADHD patients and control groups. ADHD group

Control group

9±2.2

10.1±3.3

0.12

0.35

Age (Years)

P value

Gender

Male

40 (66.7%)

17 (56.7%)

Female

20 (33.3%)

13 (43.3%)

Economic status Low

11 (18.3%)

3 (10.0%)

Moderate

35 (58.3%)

19 (63.2%)

High

14 (23.4%)

8 (26.7%)

BMI (kg/m2)

17.73±2.67

0.587

18.06±3.38

0.805

Values are expressed as mean ± standard deviation and numbers (%). ADHD, Attention Deficit Hyperactivity Disorder; BMI, body mass index.

Table 2. The mean serum levels of 25-OH-Vitamin D, calcium, phosphorus and alkaline

phosphatase in the groups.

25-OH Vitamin D (ng/mL)

ADHD group

Control group

p value

20.9±19.4

10.1±3.3

p=0.001*

Calcium (mg/dL)

9.8±0.6

9.5±0.8

p=0.663

Phosphorus (mg/dL)

5.2±1.2

5.1±0.6

p=0.774

192.5±58.1

193.1±62.1

p=0.962

Alkaline phosphatase (U/L)

*P

Vitamin D status in children with attention-deficit-hyperactivity disorder.

Attention-deficit-hyperactivity disorder (ADHD), one of the most common psychiatric disorders of childhood, has an early onset, affecting 2-18% of chi...
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