Effects of Yi-Gan-san on the psychiatric behavior of children and adolescents with Tourette's Syndrome: A randomized, double-blind, controlled preliminary study.

ETHNOPHARMACOLOGICAL RELEVANCE: Gilles de la Tourette's Syndrome (TS) is a childhood-onset disease with clinical features of motor and phonic tics. Yi-Gan-san (YGS) is a traditional Chinese medicine formula that can reduce aggressiveness and agitation and inhibit dopamine function. This study investigated the effects of YGS on the psychiatric behavior of children and adolescents with TS. METHODS: A double-blind, randomized, controlled preliminary study was conducted. A total of 38 patients with TS were assigned to the control group (CG, 19 patients) who received the oral administration of YGS placebo (90% starch and 10% YGS; 2.5 g thrice daily) or to a treatment group (TG, 19 patients) who received YGS for 4 weeks. The primary outcome measure was the change in Yale Global Tic Severity Scale (YGTSS) overall and subscale scores. RESULTS: The intensity score for phonic tics before oral administration of YGS, and after 2 weeks, 3 weeks and 4 weeks was not significantly different between CG and TG groups (2.94 ± 1.14 vs 2.79 ± 1.08, p = .686; 2.29 ± 1.21 vs 1.95 ± 1.08, p = .370; 2.41 ± 1.18 vs 2.05 ± 1.51, p = .435; and 2.29 ± 1.26 vs 1.84 ± 1.42, p = .323, respectively), while the intensity score for phonic tics after 1-week oral administration of YGS in the TG was 1.89 ± 1.10 lower than 3.06 ± 1.39 in the CG (p = .008). CONCLUSION: Oral administration of YGS for 1 week only reduced the intensity of phonic tics compared with oral administration of YGS placebo, suggesting that YGS can reduce their intensity for a short period, and the compliance of oral administration of YGS for 4 weeks can be accepted in children and adolescents with Tourette's Syndrome. However, because this study was preliminary, the selection of an appropriate placebo and dosage and long-term observations are crucial areas for future studies.

Prenatal docosahexaenoic acid supplementation has long-term effects on childhood behavioral and brain responses during performance on an inhibitory task.

Introduction: Offsprings from a prenatal docosahexaenoic acid (DHA) supplementation trial, in which pregnant women were assigned to placebo or 600mg DHA/day, were followed to determine the effect of prenatal DHA supplementation on the behavior and brain function at 5.5 years (n=81 placebo, n=86 supplemented).Methods: Event-related potentials (ERP) were recorded during a visual task requiring a button press (Go) to frequent target stimuli and response inhibition to the rare stimuli (No-Go). Univariate ANOVAs were used to test differences between group and sex for behavioral measures. ERP differences were tested using a three-way mixed-design multivariate analysis of variance (MANOVA).Results: There was a significant sex × group interaction for hit rate and errors of omission; there was no difference between males and females in the placebo group, but DHA males outperformed DHA females. Males overall and the placebo group made more errors requiring response inhibition; DHA females were significantly better than placebo females and DHA males. ERP P2 amplitude was larger in the DHA group. A significant N2 amplitude condition effect was observed in females and DHA group males, but not in placebo group males.Discussion: Prenatal DHA supplementation improved inhibitory performance overall, especially for females in the DHA group, possibly accounting for their conservative behavior during Go trials. Development of brain regions responsible for visual processing may be sensitive to maternal DHA status, evidenced by greater P2 amplitude. Males may benefit more from maternal DHA supplementation, indicated by the N2 condition effect seen only in males in the DHA group.

The Influence of Prenatal DHA Supplementation on Individual Domains of Behavioral Functioning in School-Aged Children: Follow-Up of a Randomized Controlled Trial.

Docosahexaenoic acid (DHA) accumulates in the fetal brain during pregnancy and is thought to have a role in supporting neurodevelopment. We conducted a multicenter, double-blind, randomized controlled trial in women with a singleton pregnancy who were <21 weeks' gestation at trial entry. Women were provided with 800 mg DHA/day or a placebo supplement from trial entry until birth. When children reached seven years of age, we invited parents to complete the Strengths and Difficulties Questionnaire (SDQ), the Behavior Rating Inventory of Executive Function (BRIEF), and the Conners 3rd Edition Attention-Deficit Hyperactivity Disorder (ADHD) Index to assess child behavior and behavioral manifestations of executive dysfunction. There were 543 parent-child pairs (85% of those eligible) that participated in the follow-up. Scores were worse in the DHA group than the placebo group for the BRIEF Global Executive, Behavioral Regulation and Metacognition Indexes, and the Shift, Inhibit, Monitor, Working Memory, and Organization of Materials scales, as well as for the Conners 3 ADHD index, and the SDQ Total Difficulties score, Hyperactivity/Inattention score, and Peer Relationship Problems score. In this healthy, largely term-born sample of children, prenatal DHA supplementation conferred no advantage to childhood behavior, and instead appeared to have an adverse effect on behavioral functioning, as assessed by standardized parental report scales.

The Influence of Omega-3 Long-Chain Polyunsaturated Fatty Acid, Docosahexaenoic Acid, on Child Behavioral Functioning: A Review of Randomized Controlled Trials of DHA Supplementation in Pregnancy, the Neonatal Period and Infancy.

This is a review of randomized controlled trials using docosahexaenoic acid (DHA) interventions in the first 1000 days of life with assessments of behavioral functioning in childhood. Electronic databases were searched for trials with a DHA intervention (compared with a placebo group that received no or less DHA) at any time to either women or infants during the first 1000 days, with a subsequent assessment of child behavior. There were 25 trials involving 10,320 mother-child pairs, and 71 assessments of behavior in 6867 of the children (66.5% of those originally enrolled). From the 71 assessments administered, there were 401 comparisons between a DHA group and a control group, with most reporting a null effect. There were no findings of a positive effect of DHA, and 23 instances where the DHA group had worse scores compared with the control group. There was limited evidence that DHA supplementation had any effect on behavioral development, although two of the largest trials with behavioral measures detected adverse effects. Future trials, and future follow-ups of existing trials, should make an effort to evaluate the effect of DHA intervention on behavioral functioning.

The Effects of an Infant Formula Enriched with Milk Fat Globule Membrane, Long-Chain Polyunsaturated Fatty Acids and Synbiotics on Child Behavior up to 2.5 Years Old: The COGNIS Study.

Although early life nutrition influences brain development and mental health, the long-term effects of supplemented infant formula on children´s behavior remain unclear. We analyzed the effects of a bioactive nutrients-enriched-infant formula on children's behavior up to 2.5 years, compared to a standard infant formula or breastfeeding. Current analysis involved 70 children who were fed a standard infant formula (SF, n = 29) or a bioactive compounds enriched-infant formula (EF, n = 41), during their first 18 months of life, and 33 breastfed (BF) children (reference group) participating in the COGNIS study. Behavioral problems were evaluated using the Child Behavior Checklist at 18 months and 2.5 years. Different statistical analyses were performed using SPSS. EF children aged 2.5 years presented fewer pathological affective problems than SF children. Besides, SF children were classified more frequently as bordering on internalizing problems than BF children. Rates of externalizing problems were increased in SF infants compared to EF and BF infants. Higher maternal IQ was found to have beneficial effects on internalizing and total problem rate in their offspring at 18 months of life; finally, higher maternal educational level was related with fewer ADHD problems in children at 18 months, as well as internalizing, externalizing, total and anxiety problems in children aged 2.5 years. Our analysis suggests that enriched infant formula fed infants seem to show fewer behavioral problems up to 2.5 years compared to a standard infant formula-fed infants. In addition to type of early feeding, maternal IQ and educational level seem to play a key role on children behavioral development.

Influencia de la suplementación con vitamina D, omega 3 o el uso de una dieta libre de gluten y caseína en el comportamiento de niños y niñas con trastorno del espectro autista / Influence of the vitamin D, omega 3 supplementation or the use of a gluten and casein free diet in the behavior of boys and girls with autism spectrum disorder

La prevalencia de trastorno del espectro autista ha ido en aumento, sin embargo, en Chile no existen lineamientos nutricionales acerca del posible tratamiento de la condición. Es por ello que el objetivo de esta revisión fue analizar la evidencia actual en relación al uso de una dieta libre de gluten y caseína, suplementación de vitamina D y omega 3 y su impacto en el comportamiento de niños/as con trastorno del espectro autista. Hay evidencia con resultados en torno a los beneficios de la suplementación con vitamina D debido a su carácter neuroprotector y su función neuromuscular. A su vez, la evidencia con omega 3 (DHA) es estadísticamente significativa para irritabilidad, hiperactividad, letargo, comportamiento estereotipado, conciencia social, comunicación y disminución de la severidad del autismo. Respecto a la dieta libre de gluten y caseína lo observado es que no existe evidencia que respalde los beneficios que esta exclusión entregaría. Aún falta evidencia para declarar un manejo nutricional específico para el tratamiento de los síntomas gastrointestinales y de comportamiento, más allá de la suplementación con aquellos micronutrientes en déficit.

The prevalence rate of autism spectrum disorder has been increasing, however, in Chile there are no nutritional guidelines about the possible treatment of the condition. That is the reason why the aim of this review is to analyze the current evidence regarding the use of a gluten and casein free diet, vitamin D and omega 3 supplementation and its impact in the behavior of children's with spectrum disorder autistic. There is evidence based on significant results regarding the benefits of vitamin D supplementation due to its neuroprotective character and neuromuscular function. At the same time the omega 3 evidence is statistically significant in the diminution of irritability hyperactivity, lethargy, stereotypical behavior, severity of autism and increase of social consciousness and communication. Regarding the gluten-free and casein-free diet, what was observed is that there is no evidence to support the benefits that this exclusion would provide. The evidence has not been conclusive to declare a specific nutritional management for the treatment of gastrointestinal and behavioral symptoms, beyond supplementation with those micronutrients in deficit.

Controlled Antenatal Thyroid Screening II: Effect of Treating Maternal Suboptimal Thyroid Function on Child Behavior.

CONTEXT & OBJECTIVES: The Controlled Antenatal Thyroid Screening (CATS) study was the first randomized controlled trial to investigate effects of treating suboptimal gestational thyroid function (SGTF) on child cognition. Since observational studies indicated that SGTF may also increase symptoms of autism and attention-deficit/hyperactivity disorder (ADHD), the CATS cohort was used to investigate whether treatment of mothers affected their children's behavior. DESIGN & PARTICIPANTS: Mothers (N = 475) completed 3 questionnaires: the Strengths and Difficulties Questionnaire (SDQ), the Child ADHD Questionnaire, and the Social Communication Questionnaire (SCQ, used as a screen for autism spectrum disorder [ASD]), about their children (mean age 9.5 years). Group comparisons of total scores, numbers of children above clinical thresholds, and association between high maternal free thyroxine (FT4) (> 97.5th percentile of the UK cohort, "overtreated") and child neurodevelopment were reported. RESULTS: There were no differences in total scores between normal gestational thyroid function (GTF) (n = 246), treated (n = 125), and untreated (n = 104) SGTF groups. More children of treated mothers scored above clinical thresholds, particularly the overtreated. Scores were above thresholds in SDQ conduct (22% vs 7%), SCQ total scores (7% vs 1%), and ADHD hyperactivity (17% vs 5%) when comparing overtreated (n = 40) and untreated (N = 100), respectively. We identified significantly higher mean scores for SDQ conduct (adjusted mean difference [AMD] 0.74; 95% confidence interval [CI], 0.021-1.431; P = 0.040, effect size 0.018) and ADHD hyperactivity (AMD 1.60, 95% CI, 0.361-2.633; P = 0.003, effect size 0.028) comparing overtreated with normal-GTF children. CONCLUSIONS: There was no overall association between SGTF and offspring ADHD, ASD, or behavior questionnaire scores. However, children of "overtreated" mothers displayed significantly more ADHD symptoms and behavioral difficulties than those of normal-GTF mothers. Thyroxine supplementation during pregnancy requires monitoring to avoid overtreatment.

Safety, effectiveness, and economic evaluation of an herbal medicine, Ukgansangajinpibanha granule, in children with autism spectrum disorder: a study protocol for a prospective, multicenter, randomized, double-blinded, placebo-controlled, parallel-group clinical trial.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by continuous impairment in communication and social interaction and by limited and repetitive behaviors, interests, or activities. Behavioral, educational, and pharmaceutical interventions have been shown to reduce behavioral disabilities, improve verbal/non-verbal communication, and help patients acquire self-reliance skills. However, there has been a lack of systematic verification and consensus regarding the treatment of the core symptoms of ASD because of its unclear etiology. Ukgansangajinpibanha (UGSJB), a legitimately prescribed herbal medicine for nervousness, insomnia, night crying, and malnutrition in South Korea and Japan, has been used for angry, sensitive, nervous, and unsettled children with ASD. METHODS/DESIGN: This trial is a prospective, multicenter, randomized, double-blinded, placebo-controlled, parallel-group, clinical trial. The 4- to 6-year-old children with ASD will be randomly assigned to following groups: 1. A UGSJB granule with acupuncture, twice daily (n = 120) 2. A placebo group with acupuncture, twice daily (n = 120). The following outcome measures will be used: behavior by the Childhood Autism Rating Scale, Autism Behavior Checklist, and Aberrant Behavior Checklist; social maturity by the Social Maturity Scale; quality of life by the Child Health Questionnaire and EuroQoL Five-dimension Five-level Youth; and parental stress by the Parenting Stress Index at baseline and at 6, 12, and 24 weeks after the beginning of treatment. In addition, to evaluate safety, we will investigate the adverse reactions that may be caused by UGSJB granule. Finally, we will make an economic evaluation of UGSJB for the treatment of ASD. DISCUSSION: We prepared a well-designed clinical trial to investigate the safety and effectiveness of UGSJB on ASD symptoms compared with placebo treatment. The results from this study will provide clinical evidence on the safety, effectiveness, and economic value of UGSJB combined with acupuncture in children with ASD. TRIAL REGISTRATION: Clinical Research Information Service: KCT0003007 (registered on April 5, 2018).

The Kansas University DHA Outcomes Study (KUDOS) clinical trial: long-term behavioral follow-up of the effects of prenatal DHA supplementation.

BACKGROUND: Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid that has been linked to improved vision and cognition in postnatal feeding studies and has been consistently associated with reduction of early preterm birth in prenatal supplementation trials. This is a report of the first long-term follow-up of infants from mothers receiving prenatal DHA supplementation in a US cohort. OBJECTIVE: Our objective was to evaluate the efficacy of the prenatal supplementation on both global and granular longitudinal assessments of cognitive and behavioral development. METHODS: In a randomized double-blind clinical trial, mothers received either 600 mg/d of DHA or a placebo beginning at 14.5 weeks of gestation and capsules were provided until delivery. Children from those pregnancies were followed by cognitive and behavioral assessments administered from 10 mo through 6 y of age. From 301 mothers in the initial study, ∼200 infants completed the longitudinal schedule. RESULTS: Although this intervention had been shown to reduce high-risk pregnancies and improve visual attention in infants during the first year, only a few positive long-term effects of prenatal DHA supplementation emerged from analyses of this follow-up. Increases in maternal blood DHA during pregnancy were related to verbal and full scale intelligence quotient (IQ) scores at 5 and 6 y, but these effects disappeared after controlling for SES. Maternal blood DHA concentrations at delivery were unrelated to outcomes, although maternal DHA at enrollment was related to productive vocabulary at 18 mo. CONCLUSIONS: Although prenatal DHA supplementation substantially reduced early preterm birth and improved visual attention in infancy in this sample, no consistent long-term benefits were observed into childhood. Increases in maternal blood DHA concentration in pregnancy were related to higher IQs but this effect was confounded with SES and disappeared when SES was statistically controlled. This trial was registered at http://www.clinicaltrials.gov as NCT00266825 and NCT02487771.

Randomized open-label trial of docosahexaenoic acid-enriched fish oil and fish meal on cognitive and behavioral functioning in Omani children.

OBJECTIVE: This study aimed to examine the effect of docosahexaenoic acid (DHA)-enriched fish oil supplement and meal of grilled fish on cognitive and behavioral functioning manifested as attention-deficit/hyperactivity disorder in primary school students 9 to 10 y of age in Muscat, Oman. METHODS: This randomized open-label trial involved two types of interventions: fish oil supplement or one serving (100 g) of grilled fish per day (Sunday through Friday) for 12 weeks. Red cell total lipid DHA levels were assessed. The Verbal Fluency Test, Buschke Selective Reminding Test, and Trail Making Test were used to measure cognitive functioning. Behavioral functioning was assessed using a standardized Arabic version of the National Initiative for Children's Health Quality Vanderbilt Assessment Scales. All measurements were carried out before and after intervention. RESULTS: DHA levels increased by 72% and 64% in the fish oil (mean, 3.6%-6.2%) and fish-meal (mean, 3.4%-5.6%) groups, respectively (P = 0.000). The Trail Making Test was the only cognitive test that demonstrated marked differences between groups: Median interquartile range difference between pre- and postintervention in the Trail Making Part B score was 61.5 (SE, 19.3, 103.2) in the fish oil versus fish-meal group, 24.5 (SE, -15.2, 74.7, P = 0.005). The Vanderbilt Assessment Scales also showed significant differences between groups (P < 0.001). CONCLUSION: This study contributed to available evidence on the cognitive and behavioral benefits of DHA in healthy school children. Expanding the food fortification program with DHA-enriched fish oil should be considered as part of broader policy to improve child health.

Behavioral and cognitive effects of docosahexaenoic acid in drug-naïve children with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial.

This study aimed to investigate the efficacy of docosahexaenoic acid (DHA) dietary supplementation on behavior and cognition in school-aged, drug-naïve children with attention-deficit/hyperactivity disorder (ADHD). A total of 50 participants with ADHD aged 7 to 14 were enrolled in a 6-month randomized, placebo-controlled clinical trial and received either DHA or placebo. The primary outcome measure was the change in the ADHD rating scale IV Parent Version-Investigator (ADHD-RS-IV) after 4 and 6 months. Secondary outcome measures included Conners Parent Rating Scale-revised, other behavioral rating scales including quality of life and global functioning, and computerized cognitive tasks. Baseline assessment also addressed the blood fatty acids profile. No superiority of DHA supplement to placebo was observed on ADHD-RS-IV, the a priori primary outcome. DHA supplementation showed a significant, nonetheless quite small, effect on children's psychosocial functioning, emotional problems, and focused attention. Neither major nor minor adverse events were reported throughout the trial. This study shows that 6-month DHA supplementation has no beneficial effect on the symptoms of ADHD in school-aged, drug-naïve children with an established diagnosis of ADHD. Nevertheless, the 6 months treatment with supplemental DHA appears to have small positive effects on other behavioral and cognitive difficulties, which, in light of the absence of side-effects, could be reasonably followed up in future intervention studies. ( https://clinicaltrials.gov/ct2/show/NCT01796262 : The Effects of DHA on Attention Deficit and Hyperactivity Disorder (DADA)).

Using acute tryptophan depletion to investigate predictors of treatment response in adolescents with major depressive disorder: study protocol for a randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are amongst the most prescribed antidepressants for adolescents with depressive symptoms and major depressive disorder. However, SSRIs have significant shortcomings as a first-line treatment considering that not all patients respond to these antidepressants. Amongst paediatric populations, meta-analyses indicate that up to approximately 40% of patients do not respond, and for those who do show benefit, there is substantial heterogeneity in response onset. The neurotransmitter serotonin (5-HT) plays a role in the clinical effectiveness and mechanisms of action of SSRIs. However, the exact and complete mechanism of action and reasons for the low response rate to SSRIs in some adolescent populations remains unknown. METHODS: To examine SSRI response and the role of 5-HT, this study will employ a randomised double-blind within subject, repeated measures design, recruiting adolescent patients with major depressive disorder. Participants will be subjected to acute tryptophan depletion (ATD) and the balanced control condition on two separate study days within a first study phase (Phase A), and the order in which these conditions (ATD/balanced control condition) occur will be random. This phase will be followed by Phase B, where participants will receive open label pharmacological treatment as usual with the SSRI fluoxetine and followed-up over a 12-week period. DISCUSSION: ATD is a neurodietary method typically used to investigate the impact of lowered brain 5-HT synthesis on mood and behaviour. The major hypothesis of this study is that ATD will be negatively associated with mood and cognitive functioning, therefore reflecting individual serotonergic sensitivity and related depressive symptoms. Additionally, we expect the aforementioned effects of ATD administration on mood to predict clinical improvement with regard to overall depressive symptomatology 12 weeks into SSRI treatment. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001561471 . Registered on 11 November 2016.

Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children.

The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes. An AOP provides the mechanistic detail required to support chemical safety assessment, the development of alternative methods and the implementation of an integrated testing strategy. An example of the AOP relevant to developmental neurotoxicity (DNT) is described here following the requirements of information defined by the OECD Users' Handbook Supplement to the Guidance Document for developing and assessing AOPs. In this AOP, the binding of an antagonist to glutamate receptor N-methyl-d-aspartate (NMDAR) receptor is defined as MIE. This MIE triggers a cascade of cellular KEs including reduction of intracellular calcium levels, reduction of brain derived neurotrophic factor release, neuronal cell death, decreased glutamate presynaptic release and aberrant dendritic morphology. At organ level, the above mentioned KEs lead to decreased synaptogenesis and decreased neuronal network formation and function causing learning and memory deficit at organism level, which is defined as the AO. There are in vitro, in vivo and epidemiological data that support the described KEs and their causative relationships rendering this AOP relevant to DNT evaluation in the context of regulatory purposes.

Pyridoxine Add-On Treatment for the Control of Behavioral Adverse Effects Induced by Levetiracetam in Children: A Case-Control Prospective Study.

BACKGROUND: Few studies on adult and pediatric patients have shown pyridoxine efficacy as additional therapy for those receiving levetiracetam (LEV) to prevent and mitigate behavioral adverse effects (BAEs). OBJECTIVE: The aim of our study was to analyze the safety and efficacy of pyridoxine supplementation in the prevention of LEV adverse effects, including suicidal ideation. METHODS: This randomized, case-control trial included patients receiving LEV as monotherapy treatment. Patients were subdivided into 2 groups, according to whether they were treated with LEV only (group 1) or LEV with supplemental pyridoxine (group 2). RESULTS: In both cohorts, the most frequent BAEs were irritability/aggression followed by depression and confusion. Those patients (92%) who initiated pyridoxine after 1 month of LEV treatment did not need to change or suspend LEV ( P < 0.001), and BAE improved after 9.06 ± 3.05 days of pyridoxine supplementation. None of the patients complained of symptoms of pyridoxine toxicity, and no new adverse effects of LEV off-label were reported. CONCLUSIONS: In our study, we found pyridoxine to be safe and effective in controlling LEV-induced BAEs in children.

Effects of prenatal iron status on child neurodevelopment and behavior: A systematic review.

Iron deficiency and iron-deficiency anemia are the main worldwide nutritional disorders. A good level of prenatal iron is essential for the correct child neurodevelopment but this association has been poorly investigated. To gather the scientific evidence on the relation between prenatal iron status and child neurodevelopment. To emphasize the importance of personalize the dose and type of supplementation. Wide search strategy was performed in electronic databases for English language articles with no limitations as regards the language or date of publication. Additional studies were selected by hand search. The inclusion criteria were pregnant women without high-risk pregnancy and their children as study population and neurodevelopment as the main outcome. Six RCTs and 13 observational studies were included. The majority concluded that deficit or excess iron during pregnancy injures the mental and psychomotor development of child. Other authors found no association of low iron level with troubles in neurodevelopment, recommended multi-micronutrients instead of iron alone and/or showed inconsistent results. Both iron deficiency as its excess are harmful for the child neurodevelopment. The prenatal iron supplementation should be adjusted for each woman, taking into account the iron stores, some genetic mutation and other health habits.

Effect of vitamin A supplementation on gut microbiota in children with autism spectrum disorders - a pilot study.

BACKGROUND: Dysbiosis of gut microbiota are commonly reported in autism spectrum disorder (ASD) and may contribute to behavioral impairment. Vitamin A (VA) plays a role in regulation of gut microbiota. This study was performed to investigate the role of VA in the changes of gut microbiota and changes of autism functions in children with ASD. RESULTS: Sixty four, aged 1 to 8 years old children with ASD completed a 6-month follow-up study with VA intervention. High-performance liquid chromatography was used to assess plasma retinol levels. The Autism Behaviour Checklist (ABC), Childhood Autism Rating Scale (CARS) and Social Responsiveness Scale (SRS) were used to assess autism symptoms. CD38 and acid-related orphan receptor alpha (RORA) mRNA levels were used to assess autism-related biochemical indicators' changes. Evaluations of plasma retinol, ABC, CARS, SRS, CD38 and RORA mRNA levels were performed before and after 6 months of intervention in the 64 children. Illumina MiSeq for 16S rRNA genes was used to compare the differences in gut microbiota before and after 6 months of treatment in the subset 20 of the 64 children. After 6 months of intervention, plasma retinol, CD38 and RORA mRNA levels significantly increased (all P < 0.05); the scores of ABC, CARS and SRS scales showed no significant differences (all P > 0.05) in the 64 children. Meanwhile, the proportion of Bacteroidetes/Bacteroidales significantly increased and the proportion of Bifidobacterium significantly decreased in the subgroup of 20 (all false discovery rate (FDR) q < 0.05). CONCLUSIONS: Bacteroidetes/Bacteroidales were the key taxa related to VA. Moreover, VA played a role in the changes in autism biomarkers. It remains unclear whether the VA concentration is associated with autism symptoms. TRIAL REGISTRATION: The study protocol was peer reviewed and approved by the institutional review board of Children's Hospital, Chongqing Medical University in 2013 and retrospectively registered in Chinese Clinical Trial Registry (ChiCTR) on November 6, 2014 (TRN: ChiCTR-ROC-14005442 ).

Effect of Pycnogenol® on attention-deficit hyperactivity disorder (ADHD): study protocol for a randomised controlled trial.

BACKGROUND: Methylphenidate (MPH), the first choice medication for attention-deficit hyperactivity disorder (ADHD), is associated with serious adverse effects like arrhythmia. Evidence on the association of ADHD with immune and oxidant-antioxidant imbalances offers potential for antioxidant and/or immunomodulatory nutritional supplements as ADHD therapy. One small randomised trial in ADHD suggests, despite various limitations, therapeutic benefit from Pycnogenol®, a herbal, polyphenol-rich extract. METHODS: This phase III trial is a 10-week, randomised, double-blind, placebo and active treatment controlled multicentre trial with three parallel treatment arms to compare the effect of Pycnogenol® to MPH and placebo on the behaviour of 144 paediatric ADHD and attention-deficit disorder (ADD) patients. Evaluations of behaviour (measured by the ADHD-Rating Scale (primary endpoint) and the Social-emotional Questionnaire (SEQ)), immunity (plasma cytokine and antibody levels, white blood cell counts and faecal microbial composition), oxidative stress (erythrocyte glutathione, plasma lipid-soluble vitamins and malondialdehyde and urinary 8-OHdG levels, as well as antioxidant enzyme activity and gene expression), serum zinc and neuropeptide Y level, urinary catecholamines and physical complaints (Physical Complaints Questionnaire) will be performed in week 10 and compared to baseline. Acceptability evaluations will be based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account. DISCUSSION: This trial takes into account comorbid behavioural and physical symptoms, as well as a broad range of innovative immune and oxidative biomarkers, expected to provide fundamental knowledge on ADHD aetiology and therapy. Research on microbiota in ADHD is novel. Moreover, the active control arm is rather unseen in research on nutritional supplements, but of great importance, as patients and parents are often concerned with the side effects of MPH. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT02700685 . Registered on 18 January 2016. EudraCT 2016-000215-32 . Registered on 4 October 2016.

Clinical improvement following vitamin D3 supplementation in Autism Spectrum Disorder.

OBJECTIVE: High prevalence of vitamin D deficiency was previously reported in children with Autism Spectrum Disorder (ASD), but little is known about the efficacy of vitamin D3 treatment in ASD, although data from pilot studies seem promising. We hypothesized that serum vitamin D levels are reduced in ASD and correlate with the severity of disease. Also, we hypothesized that vitamin D3 treatment may be beneficial for a considerable portion of children with ASD. METHODS: In total, 215 children with ASD and 285 healthy control children were recruited in our study. Thirty seven of 215 ASD children received vitamin D3 treatment. The Autism Behaviour Checklist (ABC) and the Childhood Autism Rating Scale (CARS) were used to assess autism symptoms. High-performance liquid chromatography was used to assess the serum 25-hydroxyvitamin D [25(OH) D] level. Evaluations of ABC, CARS, and serum 25(OH) D levels were performed before and after 3 months of treatment. RESULTS: Serum levels of 25(OH) D were significantly lower in ASD children than typically developing children. Levels of serum 25(OH) D were negatively correlated with ABC total scores and language subscale scores. After vitamin D3 supplementation, symptom scores were significantly reduced on the CARS and ABC. In addition, the data also suggest that treatment effects were more pronounced in younger children with ASD. CONCLUSION: Vitamin D deficiency might contribute to the aetiology of ASD. Supplementation of vitamin D3, which is a safe and cost-effective form of treatment, may significantly improve the outcome of some children with ASD, especially younger children (identifier ChiCTR-CCC-13004498). CLINICAL TRIAL REGISTRATION: The trial 'Association of Polymorphisms of Vitamin D Metabolism-Related Genes With Autism and the Treatment of Autism with Vitamin D' has been registered at www.chictr.org/cn/proj/show.aspx? proj=6135 (identifier ChiCTR-CCC-13004498).