Adjuvant Effects of Vitamin A and Vitamin D Supplementation on Treatment of Children With ADHD

Adjuvant Effects of Vitamin A and Vitamin D Supplementation on Treatment of Children With ADHD:A Randomized, Double Blind, Placebo-controlled, Multicentric Trial.

Around 7.2% of children around the world are suffering from ADHD. On account of current medical treatment, a high remission rate can be reached for ADHD. Nevertheless, patients have to face a number of side effects associated with the treatment. It was informed that patients of ADHD have a tendency to vitamin A and vitamin D deficiency. The aim of the study is to determine the effect of vitamin A and vitamin D supplementation as adjunctive therapy to methylphenidate on symptoms of ADHD. 504 subjects aged 6-12 years with a diagnosis of ADHD based on DSM-5 criteria are randomly assigned into three groups to receive vitamin A 6000 IU/day and vitamin D 2100 IU/day, or vitamin D 2100 IU/day or placebo adding to methylphenidate for 8 weeks. Symptoms severity is assessed by Vanderbilt Assessment Scales and Questionnaire - Children with Difficulties at weeks 0, 4, and 8. Serum levels of retinol and 25(OH)D are measured at baseline and after 8 weeks. All the other sociodemographic data are assessed. The study can give more references on the application of vitamin A and vitamin D in addition to methylphenidate to ADHD. Future research is needed to clarify mechanism of vitamin A and vitamin D on ADHD.

Procedures The patients showed deficiency or insufficiency in vitamin A (≤1.05 umol/ L) and vitamin D (≤50 nmol/L) are stratified by gender and randomly assigned in double-blind fashion in a 1:1:1 ratio to the vitamin AD supplementation group, vitamin D supplementation group or the placebo group. The participants will be given the related interventions. Placebo constituents by oily liquids without vitamin A and vitamin D. Placebo, vitamin AD and vitamin D are identical in the appearance to guarantee blind. These patients will be followed up at weeks 4 and 8 to evaluate the changes of ADHD symptoms after adding the adjunctive therapy to methylphenidate. And serum concentration of retinol and 25(OH)D are measured at weeks 8. Accordingly, the placebo group and vitamin D group will be prescribed with vitamin A and vitamin D supplementation on the grounds of retinol and 25 (OH)D concentration after the study. Demographic questionnaire and clinical data The demographic questionnaire is completed by the child's primary caregiver, detailing child's name, gender, date of birth, height, weight, blood pressure, heart rate ; supplementation of vitamin A/D products or vitamin A/D-containing products. Clinical data will be ascertained from the medical records, including information about DSM-5 diagnosis, disease classification, current treatment, and comorbid conditions. Sample size This study is a randomized double-blind controlled trial. Intervention groups are vitamin AD group and vitamin D group, control group is placebo group. The primary outcome index is changes in ADHD symptoms evaluated by Vanderbilt Assessment Scales and Questionnaire - Children with Difficulties (QCD) in the last 4 weeks or 8 weeks. The second outcome is the serum concentration of vitamin A and vitamin D. Conner's Parent Rating Scale (CPRS) was considered as the main outcome in the previous literature, the mean ± SD of ADHD index was 55.84 ± 10.2, 56.79 ± 9.6 for vitamin D + methylphenidate(n = 25), placebo + methylphenidate (n = 29) respectively. The investigators cautiously presume that the mean ± SD for vitamin AD + methylphenidate is 54 ± 9.88. Considering 0.05 of the alpha and 0.80 of power, a sample of 453 subjects divided among 3 groups are calculated by PASS 2020. And 504 subjects are enrolled in the study based on the dropout rate of 10%. Statistical analysis All the data are analyzed using SPSS 19.0. The normality of variables are assessed by Kolmogorov Smirnov test. Comparison of parametric and nonparametric variables between groups are examined by F test and Kruskal-Wallis test, respectively. Paired t-test and Wilcoxon signed-rank test are used to investigate within-group differences. Confounding factors are adjusted by the analysis of covariance. Bias control the investigators will describe both responders and non-responders on demographic questionnaire and clinical data in detail to assess the selection bias. And in order to decrease the dropout rate, the investigators will contact with the patient's parents about compliance to therapy by Wechat, E-mail, sometimes telephone contact is necessary. Ethical matters and data protection The patients participated in the study will sign the informed consent (obtained from the guardian). And this study was approved by the local ethics committee . Patient's name will be abbreviated and the research data will be assigned a code then to provide to the researcher. The authorization from parents on the patient's health information remains valid until the study is completed. After that, researchers will delete private information from the study record.

The patients showed deficiency or insufficiency in vitamin A (≤1.05 umol/ L) and vitamin D (≤50 nmol/L) are randomly assigned in double-blind fashion in a 1:1:1 ratio to the vitamin AD supplementation group, vitamin D supplementation group or the placebo group. Vitamin AD supplementation group will be administrated vitamin AD capsules (3 capsules/time, once a day for 8 weeks), which contain vitamin A (2000 IU/capsule) and vitamin D (700 IU/capsule). Vitamin D supplementation group will be administrated vitamin D capsules (400 IU/capsule, 6 capsules/time, once a day for 2 weeks, then change to 5 capsules/time, once a day for 6 weeks). The placebo capsules given to the placebo group (3 capsules/time, once a day for 8 weeks), consists of oily liquids which do not contain vitamin A and vitamin D, and were produced in strict accordance with China's drug management and packaging requirements for placebo by Shandong DYNE Marine Biopharmaceutical Co., Ltd in China.

The participants and care providers don't know which group they are enrolled in. And the investigators just play a roll in recruiting the patients, inform the patients about the study, and then randomly assign the patients in a 1:1:1 ratio to the A group, B group or C group. The drugs are dispensed by staff who was not involved in the process of evaluation, diagnosis and treatment. The staff will take notes about the patients' basic information and medication records. After the study, the staff will give the unblinded results to to investigators and outcomes assessor. The investigators will provide the compensatory therapy for the patients. The outcomes assessor will do the statistic analysis.

The patients aged 6-12 with a diagnose of ADHD of this group is deficient or insufficient in vitamin A and vitamin D. They will receive vitamin A 6000 IU/day and vitamin D 2100 IU/day supplementation in addition to methylphenidate for 8 weeks.

The patients aged 6-12 with a diagnose of ADHD of this group is deficient or insufficient in vitamin A and vitamin D. They will receive vitamin D 2100 IU/day supplementation in addition to methylphenidate for 8 weeks. After the study, vitamin D group will be administrated with vitamin A on the basis of serum retinol concentration after the study.

The patients aged 6-12 with a diagnose of ADHD of this group is deficient or insufficient in vitamin A and vitamin D. They will receive placebo once a day in addition to methylphenidate for 8 weeks. After the study, the placebo group will be prescribed with vitamin A and vitamin D supplementation on the grounds of retinol and 25 (OH)D concentration.

Placebo, vitamin AD and vitamin D are identical in the appearance to guarantee blind. The patients need to administrate 3 capsules once a day for 8 weeks.

A vitamin AD capsule contains vitamin A 2000 IU and vitamin D 700 IU. The patients need to administrate 3 capsules once a day for 8 weeks.

A vitamin D capsule contains vitamin D 400 IU. The patients need to asministrate 6 capsules/time, once a day for 2 weeks, then change to 5 capsules/time, once a day for 6 weeks.

The changes in ADHD clinical symptoms-Predominantly Inattentive subtype estimated by Chinese version of Vanderbilt parent assessment scale

The Vanderbilt parent assessment scale is designed to measure the severity of ADHD symptoms for children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 49-56 are performance measures. The symptom measures in the scale, scored 0 to 3. A positive response in symptom assessment part is a 2 or 3 (often, very often). The performance measures in the scale, scored 1 to 5, with 4 and 5 being somewhat of a problem/problematic. The scoring standard for Predominantly Inattentive subtype: Must score a 2 or 3 on 6 out of 9 items on questions 1-9 AND Score a 4 or 5 on any of the Performance questions 49-56. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-Predominantly Inattentive subtype estimated by Chinese version of Vanderbilt teacher assessment scale

The Vanderbilt teacher assessment scale is designed to measure the severity of ADHD symptoms for children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 36-43 are performance measures. The symptom measures in the scale, scored 0 to 3. A positive response in symptom assessment part is a 2 or 3 (often, very often). The performance measures in the scale, scored 1 to 5, with 4 and 5 being somewhat of a problem/problematic. The scoring standard for Predominantly Inattentive subtype: Must score a 2 or 3 on 6 out of 9 items on questions 1-9 AND Score a 4 or 5 on any of the Performance questions 36-43. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-Predominantly Hyperactive/Impulsive subtype estimated by Chinese version of Vanderbilt parent assessment scale

The Vanderbilt parent assessment scale is designed to measure the severity of ADHD symptoms for children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 49-56 are performance measures. The symptom measures in the scale, scored 0 to 3. A positive response in symptom assessment part is a 2 or 3 (often, very often). The performance measures in the scale, scored 1 to 5, with 4 and 5 being somewhat of a problem/problematic. The scoring standard for Predominantly Hyperactive/Impulsive subtype: Must score a 2 or 3 on 6 out of 9 items on questions 10-18 AND Score a 4 or 5 on any of the Performance questions 49-56. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-Predominantly Hyperactive/Impulsive subtype estimated by Chinese version of Vanderbilt teacher assessment scale

The Vanderbilt teacher assessment scale is designed to measure the severity of ADHD symptoms for children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 36-43 are performance measures. The symptom measures in the scale, scored 0 to 3. A positive response in symptom assessment part is a 2 or 3 (often, very often). The performance measures in the scale, scored 1 to 5, with 4 and 5 being somewhat of a problem/problematic. The scoring standard for Predominantly Hyperactive/Impulsive subtype: Must score a 2 or 3 on 6 out of 9 items on questions 10-18 AND Score a 4 or 5 on any of the Performance questions 36-43. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-ADHD Combined Inattention/Hyperactivity estimated by Chinese version of Vanderbilt parent assessment scale

The Vanderbilt parent assessment scale is designed to measure the severity of ADHD symptoms for children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 49-56 are performance measures. The symptom measures in the scale, scored 0 to 3. A positive response in symptom assessment part is a 2 or 3 (often, very often). The performance measures in the scale, scored 1 to 5, with 4 and 5 being somewhat of a problem/problematic. The scoring standard for ADHD Combined Inattention/Hyperactivity: Must score a 2 or 3 on 6 out of 9 items not only on questions 1-9 but also on questions 10-18. AND Score a 4 or 5 on any of the Performance questions 49-56. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-ADHD Combined Inattention/Hyperactivity estimated by Chinese version of Vanderbilt teacher assessment scale

The Vanderbilt teacher assessment scale is designed to measure the severity of ADHD symptoms for children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 36-43 are performance measures. The symptom measures in the scale, scored 0 to 3. A positive response in symptom assessment part is a 2 or 3 (often, very often). The performance measures in the scale, scored 1 to 5, with 4 and 5 being somewhat of a problem/problematic. The scoring standard for ADHD Combined Inattention/Hyperactivity: Must score a 2 or 3 on 6 out of 9 items not only on questions 1-9 but also on questions 10-18. AND Score a 4 or 5 on any of the Performance questions 36-43. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-Predominantly Inattentive subtype estimated by Chinese version of Vanderbilt parent follow-up assessment

The Vanderbilt parent follow-up assessment is designed to track treatment effect over time for ADHD children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 19-26 are performance measures. The symptom measures in the scale, scored 0 to 3 (Never, Occasionally, Often, Very Often). The performance measures in the scale, scored 1 to 5 (Excellent, Above Average, Average, Somewhat of a Problem, Performance Problematic). The scoring standard for Predominantly Inattentive subtype: 1) Calculate Total Symptom Score for questions 1-18. 2) Calculate Average Performance Score for questions 19-26. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-Predominantly Inattentive subtype estimated by Chinese version of Vanderbilt teacher follow-up assessment

The Vanderbilt teacher follow-up assessment is designed to track treatment effect over time for ADHD children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 19-26 are performance measures. The symptom measures in the scale, scored 0 to 3 (Never, Occasionally, Often, Very Often). The performance measures in the scale, scored 1 to 5 (Excellent, Above Average, Average, Somewhat of a Problem, Performance Problematic). The scoring standard for Predominantly Inattentive subtype: 1) Calculate Total Symptom Score for questions 1-18. 2) Calculate Average Performance Score for questions 19-26. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-Predominantly Hyperactive/Impulsive subtype estimated by Chinese version of Vanderbilt parent follow-up assessment

The Vanderbilt parent follow-up assessment is designed to track treatment effect over time for ADHD children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 19-26 are performance measures. The symptom measures in the scale, scored 0 to 3 (Never, Occasionally, Often, Very Often). The performance measures in the scale, scored 1 to 5 (Excellent, Above Average, Average, Somewhat of a Problem, Performance Problematic). The scoring standard for Predominantly Hyperactive/Impulsive subtype: 1) Calculate Total Symptom Score for questions 1-18. 2) Calculate Average Performance Score for questions 19-26. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-Predominantly Hyperactive/Impulsive subtype estimated by Chinese version of Vanderbilt teacher follow-up assessment

The Vanderbilt teacher follow-up assessment is designed to track treatment effect over time for ADHD children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 19-26 are performance measures. The symptom measures in the scale, scored 0 to 3 (Never, Occasionally, Often, Very Often). The performance measures in the scale, scored 1 to 5 (Excellent, Above Average, Average, Somewhat of a Problem, Performance Problematic). The scoring standard for Predominantly Hyperactive/Impulsive subtype: 1) Calculate Total Symptom Score for questions 1-18. 2) Calculate Average Performance Score for questions 19-26. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-ADHD Combined Inattention/Hyperactivity estimated by Chinese version of Vanderbilt parent follow-up assessment

The Vanderbilt parent follow-up assessment is designed to track treatment effect over time for ADHD children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 19-26 are performance measures. The symptom measures in the scale, scored 0 to 3 (Never, Occasionally, Often, Very Often). The performance measures in the scale, scored 1 to 5 (Excellent, Above Average, Average, Somewhat of a Problem, Performance Problematic). The scoring standard for ADHD Combined Inattention/Hyperactivity: 1) Calculate Total Symptom Score for questions 1-18. 2) Calculate Average Performance Score for questions 19-26. The higher scores mean a worse outcome.

The changes in ADHD clinical symptoms-ADHD Combined Inattention/Hyperactivity estimated by Chinese version of Vanderbilt teacher follow-up assessment

The Vanderbilt teacher follow-up assessment is designed to track treatment effect over time for ADHD children aged 6 to 12. It has 2 components: symptom assessment and impairment in performance. The symptom assessment screens for symptoms relevant to inattentive (items 1-9) and hyperactive (items 10-18) ADHD. The items 19-26 are performance measures. The symptom measures in the scale, scored 0 to 3 (Never, Occasionally, Often, Very Often). The performance measures in the scale, scored 1 to 5 (Excellent, Above Average, Average, Somewhat of a Problem, Performance Problematic). The scoring standard for ADHD Combined Inattention/Hyperactivity: 1) Calculate Total Symptom Score for questions 1-18. 2) Calculate Average Performance Score for questions 19-26. The higher scores mean a worse outcome.

The Questionnaire - Children with Difficulties (QCD) measures the daily-life problems in children aged 6-18 years during the special time of the day, including in the morning, during school, after school, in the evening, and overall difficulties over the entire day and night. It has been proved the Chinese version of QCD has good validity and reliability. Filled in by the parents, the scale consists of 20 questions with regard to ADHD-related difficulties. Each question is scored on a four-point scale: 0 = completely disagree, 1 = somewhat (partially) agree, 2 = mostly agree, and 3 = completely agree. Score of 30 - 35 is considered as cut-off value for functional impairment and score of less than 30 is considered as functional impairment (Full marks: 57). The lower scores indicate lower life functioning and more difficulty in children's daily activities.

Vitamin A state is measured by the serum concentration of retinol through high performance liquid chromatography (HPLC) from 2 milliliter of venous blood. The vitamin A status is categorized based on serum retinol: <0.35 µmol/L is considered very deficient, 0.35-0.7 µmol/L deficient, 0.7-1.05 µmol/L marginal, 1.05-2.56 µmol/L adequate, and >2.56 µmol/L toxic. Too low or too high concentrations are harmful

Vitamin D state is measured by the serum concentration of 25OHD through high performance liquid chromatography (HPLC) from 2 milliliter of venous blood. The values of serum vitamin D level are classified into 4 categories: <30 nmol/L is regarded as deficiency, 30-50 nmol/L insufficiency, 50-250 nmol/L normal, and >250 nmol/L toxic . Too low or too high concentrations are harmful。

Inclusion Criteria: Diagnose of ADHD according to DSM-5 Aged 6-12 years Intelligence quotient (IQ) ≥70 Receiving methylphenidate (trade name Concerta) 18-54 mg/day once a day (began with 18 mg/day for a week and titrated gradually to the optimum dose not more than 54 mg/day). Exclusion Criteria: Inconsistent or changing dose of methylphenidate during the participation period Use of anticonvulsant drugs or hydrocortisone Suffering from other neurological disorders and mental diseases now or in the past, such as convulsions, anxiety and depression Suffer from metabolic disorders such as cholestasis, liver dysfunction, pancreatic insufficiency, measles, diarrhea, respiratory illness, severe inflammation or malnutrition, etc. Use of vitamins and vitamin-containing products IQ≤70 The serum concentration of vitamin A >1.05 umol/L and/ or vitamin D >50 nmol/L

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