Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial.

We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg-1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.

Dietary Supplementation in Children with Autism Spectrum Disorders: Common, Insufficient, and Excessive.

BACKGROUND: Little is known about the effect on dietary adequacy of supplements given to children with autism spectrum disorder (ASD). OBJECTIVE: This cross-sectional study examines dietary supplement use and micronutrient intake in children with ASD. DESIGN: Three-day diet/supplement records and use of a gluten/casein-free diet (GFCF) were documented. Estimates of usual intake of micronutrients from food and supplements were compared with the Dietary Reference Intakes. PARTICIPANTS: Children aged 2 to 11 years (N=288) with ASD from five Autism Treatment Network sites from 2009-2011. MAIN OUTCOME MEASURES: Percentage of children meeting or exceeding upper limits of micronutrient intake with or without supplements and relative to GFCF diet status. STATISTICAL ANALYSIS: Micronutrient intake from food and supplements was compared by Spearman rank correlation. Usual intake was estimated by the National Cancer Institute method adjusted for age, sex, supplement use, and GFCF diet. Adequacy of intake was compared between supplement use status and between food and total intake in supplement users relative to Dietary Reference Intakes limits. RESULTS: Dietary supplements, especially multivitamin/minerals, were used by 56% of children with ASD. The most common micronutrient deficits were not corrected (vitamin D, calcium, potassium, pantothenic acid, and choline) by supplements. Almost one-third of children remained deficient for vitamin D and up to 54% for calcium. Children receiving GFCF diets had similar micronutrient intake but were more likely to use supplements (78% vs 56%; P=0.01). Supplementation led to excess vitamin A, folate, and zinc intake across the sample, vitamin C, and copper among children aged 2 to 3 years, and manganese and copper for children aged 4 to 8 years. CONCLUSIONS: Few children with ASD need most of the micronutrients they are commonly given as supplements, which often leads to excess intake. Even when supplements are used, careful attention should be given to adequacy of vitamin D and calcium intake.

The role of trace elements, thiamin (e) and transketolase in autism and autistic spectrum disorder.

Although there has been much research into autism or autistic spectrum disorder (ASD), there is room for considerable conjecture regarding the etiology of these developmental brain disorders. ASD is marked by a complex interaction between environmental factors and genetic predisposition, including epistasis. This manuscript argues that changes in oxidative metabolism, thiamine homeostasis, heavy metal deposition and cellular immunity have a role in the etiopathogenesis of autism and ASD. Recent findings from our group and others provide evidence for abnormal thiol metabolism, marked by significant alteration in the deposition of several trace heavy metal species. Together with these, we find differences in thiamine homeostasis in ASD patients, which can be corrected by supplementation. We hypothesize that altered thiol metabolism from heavy metal toxicity, one of the key mechanisms for oxidative stress production, may be responsible for the biochemical alterations in transketolase, dysautonomia and abnormal thiamine homeostasis. Although it is unknown why these particular metals accumulate, we suspect that children with ASD and forms of autism may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. We maintain mercury accumulation is evidence of altered clearance. Together with concomitant oxidative stress, these findings may offer an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Regardless of the exact cause, these factors may be more important to the etiology of this symptomatically diverse disease spectrum. Here, we offer insight into new avenues of exploration as well as the development of novel treatment approaches for these growing and devastating diseases.

Core symptoms of autism improved after vitamin D supplementation.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by a complex interaction between genetic and environmental risk factors. Among the environmental factors, vitamin D3 (cholecaliferol) seems to play a significant role in the etiology of ASD because this vitamin is important for brain development. Lower concentrations of vitamin D3 may lead to increased brain size, altered brain shape, and enlarged ventricles, which have been observed in patients with ASD. Vitamin D3 is converted into 25-hydroxyvitamin D3 in the liver. Higher serum concentrations of this steroid may reduce the risk of autism. Importantly, children with ASD are at an increased risk of vitamin D deficiency, possibly due to environmental factors. It has also been suggested that vitamin D3 deficiency may cause ASD symptoms. Here, we report on a 32-month-old boy with ASD and vitamin D3 deficiency. His core symptoms of autism improved significantly after vitamin D3 supplementation. This case suggests that vitamin D3 may play an important role in the etiology of ASD, stressing the importance of clinical assessment of vitamin D3 deficiency and the need for vitamin D3 supplementation in case of deficiency.

Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism.

OBJECTIVE: Preliminary evidence suggests that omega-3 fatty acids may reduce hyperactivity in children with autism spectrum disorder (ASD). We sought to examine the feasibility of a novel, Internet-based clinical trial design to evaluate the efficacy of this supplement. METHOD: E-mail invitations were sent to parents of children aged 5 to 8 years enrolled in the Interactive Autism Network. All study procedures, including screening, informed consent, and collection of outcome measures took place over the Internet. The primary outcome measures were parent- and teacher-rated changes in hyperactivity on the Aberrant Behavior Checklist (ABC-H). RESULTS: During the 6-week recruitment period, 57 children from 28 states satisfied all eligibility criteria and were randomly assigned to 1.3 grams of omega-3 fatty acids or an identical placebo daily for 6 weeks. Outcome assessments were obtained from all 57 participants and 57 teachers, and the study was completed in 3 months. Children in the omega-3 fatty acid group had a greater reduction in hyperactivity (-5.3 points) compared to the placebo group (-2.6 points), but the difference was not statistically significant (1.9-point greater improvement in the omega-3 group, 95% CI = -2.2 to 5.2). Adverse events were rare and not associated with omega-3 fatty acids. Participant feedback was positive. CONCLUSION: Internet-based, randomized controlled trials of therapies in children with ASD are feasible and may lead to marked reductions in the time and cost of completing trials. A larger sample size is required to definitively determine the efficacy of omega-3 fatty acids. Clinical trial registration information-Omega-3 Fatty Acids for Hyperactivity Treatment in Autism Spectrum Disorder; http://clinicaltrials.gov; NCT01694667.

Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep.

Supplemental melatonin has been used to treat sleep onset insomnia in children with autism spectrum disorders (ASD), although the mechanism of action is uncertain. We assessed endogenous and supplemental melatonin profiles in relation to sleep in nine children with ASD. In endogenous samples, maximal melatonin concentration (C(max)) and time to peak concentration (T(max)) were comparable to those previously published in the literature for typically developing children, and dim light melatonin onsets were captured in the majority of children. In treatment samples (supplemental melatonin), melatonin parameters were also comparable to those previously published for typically developing children. Our findings support that children with ASD and insomnia responsive to low dose melatonin treatment have relatively normal profiles of endogenous and supplemental melatonin.

Quality of life in children and adolescents with autism spectrum disorders: what is known about the effects of pharmacotherapy?

A diagnosis of autistic spectrum disorder (ASD), now estimated to affect one in 88 children, requires deficits in social communication and interactions, and restricted interests and/or repetitive behaviors. Almost all children with ASD have deficits in adaptive skills, many have intellectual disability, and others have co-occurring psychiatric disorders or symptoms. Thus, this complex disorder has shown to have a substantial impact on patients' quality of life (QoL) and that of their families. Medication treatment is considered by clinicians and families to address problems with functioning due to psychiatric problems, and, as such, one-third of children and adolescents with ASD take at least one psychotropic medication and many use complementary and alternative medicine. This paper reviews what is known about the benefits and risks of psychotropic medications on the QoL of children with ASD. Although scarce, there are studies of psychiatric medications in autistic patients that include QoL measures, such as the pediatric studies of aripiprazole for irritability and one adult study of oxytocin. The aripiprazole study showed a positive effect on QoL in treated patients, as did the oxytocin study. Several other psychotropic medications are used in the treatment of children with ASD, and although information is available on the risks and benefits of each, we do not have specific data on the QoL impact of these medications. The aripiprazole and oxytocin studies exemplify how researchers can include QoL measures and use this information to guide clinicians. Additionally, we will recommend areas of further study in pharmacotherapy and QoL research in the context of treating children with ASD.

Commentary on the abuse of metal chelation therapy in patients with autism spectrum disorders.

Approximately half a million patients with autism spectrum disorders are subjected to chelation therapy in the US annually. The overwhelming majority of such cases are chelated for non-accepted medical indications. These patients may seek evaluation when a urine sample is assayed after the administration of a chelating agent and the values obtained have been improperly compared to references ranges for non-chelated urines, causing falsely elevated results. Legitimate practitioners confronted with such data must decide, preferably in consultation with the patient or their guardian(s), whether to do further testing using legitimate methodology or to simply dismiss the results of the improper testing. Bayesian principles tell us that further testing is likely to yield results within normal reference ranges. However, under some circumstances, it is useful to do such testing in order to demonstrate that there is no need for chelation therapy. Unnecessary chelation therapy is expensive, can cause significant acute adverse effects, and may be associated with long-term consequences.

Yokukansan (TJ-54) for irritability associated with pervasive developmental disorder in children and adolescents: a 12-week prospective, open-label study.

BACKGROUND: Autistic disorder is a neuropsychiatric syndrome characterized by deficits in social interaction; qualitative impairments in communication; and restricted, repetitive, and stereotyped patterns of behavior, interests, or activities. It is classified as a type of pervasive developmental disorder (PDD). All PDDs have a qualitative impairment in social relatedness. However, many individuals with PDDs have interfering symptoms, including irritability (aggression, self-injurious behavior, and severe tantrums). Behavioral therapy is often helpful in decreasing these behaviors; however, sometimes adjunctive medications are needed, because of the intensity and severity of irritability. Numerous medications have been tested on patients with PDDs. Although many of these medications have been demonstrated to be useful, no clear main treatment for PDD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to their use. Yokukansan (TJ-54), a traditional Japanese medicine, is composed of seven kinds of dried herbs. It is widely prescribed in clinical situations for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous system. Recent studies indicate that TJ-54 may be safe and useful in treating behavioral and psychological symptoms in dementia patients. We aimed at evaluating both the efficacy and the safety of TJ-54 in patients with PDDs. METHODS: This was a 12 week prospective, open-label investigation of TJ-54 in 20 children and adolescents ages 6-17 years diagnosed with PDDs. Primary outcome measures included the Clinical Global Impressions-Improvement of Illness Scale (CGI-I), Children's Global Assessment Score (CGAS), and the Aberrant Behavior Checklist (ABC) irritability subscale. RESULTS: Twenty subjects, ages 6-17 years, received TJ-54 in the dosage range of 2.5-7.5 g/day. The CGI-I was significantly improved from 8 weeks (p<0.001). The mean CGAS was 31.92 at baseline, whereas the mean final score at 12 weeks was 54.52 (p<0.001). The ABC irritability/agitation subscale (subscale 1) was significantly improved from 8 weeks, and the hyperactivity/noncompliance subscale (subscale 4) was significantly improved in 12 weeks. TJ-54 was well tolerated. No subject left the study because of a drug-related adverse event. CONCLUSIONS: These preliminary data suggest that TJ-54 may be effective and well tolerated for the treatment of severe irritability/agitation and hyperactivity/noncompliance in children and adolescents ages 6-17 years with PDD. However, given the characteristics of this trial, the present findings should be taken cautiously, and larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of TJ-54 in this understudied population.

Autism: biomedical complementary treatment approaches.

This article provides a conceptual overview for the use of biomedical complementary and alternative medicine (CAM) treatments for autism spectrum disorders. Pharmaceutical agents with published studies are briefly mentioned; but the focus of the article is on possible biomedical CAM treatments, the rationale for their use, and the current database of mostly preliminary studies regarding their safety and efficacy. Of the more than 50 treatments currently listed here and in use by eager families, 9 are reviewed in more detail because of their promise from preliminary research studies or because of public interest.

An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders.

BACKGROUND: Accumulating evidence suggests an association between autism spectrum disorders (ASD) and inflammation in brain regions related to cognitive function. The natural flavonoid luteolin has antioxidant, anti-inflammatory, mast cell-blocking, and neuroprotective effects. It was shown to improve cognitive performance in a mouse model of ASD, but its effect in humans has not been adequately studied. OBJECTIVES: The goal of this study was to assess the effectiveness and tolerability in white children with ASD of a dietary supplement containing 2 flavonoids (>95% pure), luteolin (100 mg/capsule, from chamomile) and quercetin (70 mg/capsule), and the quercetin glycoside rutin (30 mg/capsule) from the Sophora japonica leaf, formulated in olive kernel oil to increase oral absorption. METHODS: Fifty children (4-10 years old; 42 boys and 8 girls) with ASD were enrolled in a 26-week, prospective, open-label trial at the 2nd University Department of Psychiatry at "Attikon" General Hospital, Athens, Greece. Children were referred for the study by their respective physicians or came from the practice of the senior author. ASD diagnosis by clinical assessment was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, symptom list and corroborated by using the Autism Diagnostic Observation Schedule. The dose of the study formulation used was 1 capsule per 10 kg weight per day with food. The primary outcome measures were the age-equivalent scores in the Vineland Adaptive Behavior Scales domains. Secondary outcomes included the Aberrant Behavior Checklist, the Autism Treatment Evaluation Checklist, and the Clinical Global Impression-Improvement score. Data were measured at baseline, week 18, and week 26. Parents were interviewed for any possible improvements they noticed and instructed to report any unusual adverse events. RESULTS: A total of 40 children completed the protocol. There was a significant improvement in adaptive functioning as measured by using the VABS age-equivalent scores (8.43 months in the communication domain, 7.17 months in daily living skills, and 8 months in the social domain; P < 0.005), as well as in overall behavior as indicated by the reduction (26.6%-34.8%) in Aberrant Behavior Checklist subscale scores. Age, sex, and history of allergies had no effect on the results, whereas the initial level of functioning or difficulty did predict the final outcome in most of the measures used. There was a transient (1-8 weeks) increased irritability in 27 of the 50 participants. CONCLUSIONS: These results are encouraging in that the combination of the flavonoids luteolin and quercetin seemed to be effective in reducing ASD symptoms, with no major adverse effects. ClinicalTrials.gov identifier: NCT01847521.

Effects of Korean red ginseng extracts on neural tube defects and impairment of social interaction induced by prenatal exposure to valproic acid.

Ginseng is one of the most widely used medicinal plants, which belongs to the genus Panax. Compared to uncured white ginseng, red ginseng has been generally regarded to produce superior pharmacological effects with lesser side/adverse effects, which made it popular in a variety of formulation from tea to oriental medicine. Using the prenatal valproic acid (VPA)-injection model of autism spectrum disorder (ASD) in rats, which produces social impairrment and altered seizure susceptibility as in human ASD patients as well as mild neural tube defects like crooked tail phenotype, we examined whether chronic administration of red ginseng extract may rescue the social impairment and crooked tail phenotype in prenatally VPA-exposed rat offspring. VPA-induced impairment in social interactions tested using sociability and social preference paradigms as well as crooked tail phenotypes were significantly improved by administration of Korean red ginseng (KRG) in a dose dependent manner. Rat offspring prenatally exposed to VPA showed higher sensitivity to electric shock seizure and increased locomotor activity in open-field test. KRG treatment reversed abnormal locomotor activity and sensitivity to electric shock to control level. These results suggest that KRG may modulate neurobehavioral and structural organization of nervous system adversely affected by prenatal exposure to VPA.

Yokukansan (TJ-54) for treatment of pervasive developmental disorder not otherwise specified and Asperger's disorder: a 12-week prospective, open-label study.

BACKGROUND: Numerous medications have been tested on patients with pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger's disorder. Although many of these medications have been demonstrated to be useful, no clear primary treatment for PDD-NOS and Asperger's disorder has emerged. Despite the efficacy of some of the medicines, the acceptability and side effects have proven to be barriers to their use. Recent studies indicate that the traditional Japanese herbal medicine yokukansan (TJ-54) may be safe and useful in treating behavioral and psychological symptoms in dementia and some neuropsychiatric disorders. We aimed at evaluating both the efficacy and safety of TJ-54 in patients with well-defined PDD-NOS and Asperger's disorder. METHODS: This was a 12-week prospective, open-label investigation of TJ-54 in 40 children, adolescents, and adults diagnosed with PDD-NOS or Asperger's disorder. Primary outcome measures included the Clinical Global Impressions-Severity of Illness Scale (CGI-S) and the Aberrant Behavior Checklist-Iritability subscale score (ABC-I). RESULTS: Forty subjects, ages 8-40 years (mean 22.7 ± 7.3 years) received a mean final TJ-54 dosage of 6.4 ± 1.3 g/day (range 2.5-7.5 g/day). Full-scale intelligence quotient (IQ) scores ranged from 70 to 110 (mean 88.9 ± 13.2). Thirty-six (90%) of 40 subjects showed fewer interfering symptoms of irritability, including aggression, self-injury, and tantrums, with a final CGI-S of 1 or 2 (normal, not at all ill or borderline mentally ill) and a 80% or greater improvement on the ABC-I. The mean CGI-S score at baseline was 6.8 ± 0.8 whereas scores at end point was 1.9 ± 0.1 (< 0.0001). ABC-I scores ranged from 11 to 29 (mean 17.4 ± 3.66) at baseline, whereas scores at week 12 ranged from 0 to 5 (mean 0.93 ± 0.97) (p <0.0001). TJ-54 was well tolerated. No subject exited the study due to a drug-related adverse event. CONCLUSIONS: These preliminary data suggest that TJ-54 may be effective and well tolerated for treatment of severe irritability, lethargy/withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech in patients with PDD-NOS or Asperger's disorder. However, given the characteristics of this trial, the present findings should be taken cautiously, and larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of TJ-54 in this understudied population.

[Useful pharmacologic treatment in impaired social interaction in autism spectrum disorders].

It is important to note that risperidone solution, intranasal administration of oxytocin, and dietary supplementation with large doses of arachidonic acid added to docosahexaenoic acid (DHA) have been reported to improve impaired social interaction. In addition, atypical antipsychotics aripiprazole and SSRI fluvoxamine were useful in treating some aspects of social relatedness or the core deficits of communication and socialization. The evaluation of treatments for ASD should be directed at neurobiological targets known to be important in the brain's response to abnormal developmental trajectories or toward enhancing plasticity during the highly sensitive period in gene-environment interaction (epigenetic mechanism). Recent epidemiological studies have indicated that at least one in every 100 people has some form of ASD. Environmental chemicals can affect the development of the brain. Further studies will be required to address the effect of environmental chemicals.

A case series of a luteolin formulation (NeuroProtek®) in children with autism spectrum disorders.

There has been an impressive, little understood increase in cases of autism spectrum disorders (ASD). The lack of any distinctive pathogenetic mechanism has hampered the development of any effective treatments. Increasing evidence indicates oxidative stress, brain inflammation, gastrointestinal (GI) dysfunction and allergic symptoms may be present in ASD patients. The flavone luteolin has anti-oxidant, anti-flammatory, anti-allergy and neuroprotective properties. Given these findings, a dietary supplement was developed with a unique mixture of luteolin with the related flavonoids quercetin and rutin in a liposomal formulation of olive kernel oil (OKO), which increases their absorption. Results are presented for children with ASD (n=37, 4-14 years old) who had not obtained any benefit from multiple other regimens and who used this formulation for at least 4 months. GI and allergy symptoms improved in about 75 percent of children, eye contact and attention in 50 percent, social interaction in 25 percent and resumption of speech in about 10 percent. There were no adverse effects. Even though these results represent an uncontrolled open case series, they are encouraging because they suggest good tolerability and potential effectiveness.

[Comprehensive models of treatment in individuals with autism spectrum disorders]. / Modelos de intervencion global en personas con trastorno del espectro autista.

INTRODUCTION. The steady increase in the number of children with autism spectrum disorders, has led to a better social awareness but also to a higher demand for specific interventions. This has questioned what the most appropriate and effective procedures for detection, diagnosis and treatment are. AIM. To review different approaches and classifications of interventions with individuals with autism spectrum disorders based on scientific evidence. DEVELOPMENT. According to the latest revisions, there are three types of classifications to categorize evidence-based interventions: practice-based intervention, comprehensive models of treatment and drug treatments. There are difficulties in comparing results of different methods of intervention, however, some common elements to prove their effectiveness have been identified. CONCLUSIONS. All intervention models should include functional communication skills, meaningful learning, carried out in various contexts, addressing challenging behaviors through positive behavioral support, promoting activities with peers and emphasize the role of parents in the planning and implementation of the objectives.

A double-blind placebo controlled trial of Ginkgo biloba added to risperidone in patients with autistic disorders.

Ginkgo biloba has been reported to affect the neurotransmitter system and to have antioxidant properties that could impact the pathogenesis of Autism Spectrum Disorder. Based on these studies, we decided to assess the effectiveness of Ginkgo biloba extract (Ginko T.D., Tolidaru, Iran) as an adjunctive agent to risperidone in the treatment of autism. Forty-seven outpatients with a DSM-IV-TR diagnosis of autism ages between 4 and 12 years were assigned to this double blinded clinical trial and were randomly divided into two groups. One group received risperidone plus Ginko T.D and the other received risperidone plus placebo. The dose of risperidone was 1-3 mg/day and the dose of Ginko T.D. was 80 mg/day for patients under 30 kg and 120 mg/day for patients above 30 kg. Patients were assessed using Aberrant Behavior Checklist-Community (ABC-C) rating scale and the side effect check list every 2 weeks until the endpoint. None of the 5 subscales of ABC-C rating scale showed significant differences between the two groups. Incidents of side effects were not significantly different between the two groups. Adding Ginkgo biloba to risperidone did not affect the treatment outcome of ADs. Nevertheless, further observations are needed to confirm this result.

Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in individuals with autism spectrum disorders: a double-blind, placebo-controlled, randomized trial.

Autism spectrum disorders are a neurodevelopmental disorders with reduced cortical functional connectivity relating to social cognition. Polyunsaturated fatty acids arachidonic acid (ARA) and docosahexaenoic acid (DHA) may have key role in brain network maturation. In particularly, ARA is important in signal transduction related to neuronal maturation. Supplementation with larger ARA doses added to DHA may therefore mitigate social impairment. In a 16-week, double-blind, randomized, placebo-controlled trial, we evaluated the efficacy of supplementation with large doses of ARA added to DHA (n = 7) or placebo (n = 6) in 13 participants (mean age, 14.6 [SD, 5.9] years). To examine underlying mechanisms underlying the effect of our supplementation regimen, we examined plasma levels of antioxidants transferrin and superoxide dismutase, which are useful markers of signal transduction. The outcome measures were the Social Responsiveness Scale and the Aberrant Behavior Checklist-Community. Repeated-measures analysis of variance revealed that our supplementation regimen significantly improved Aberrant Behavior Checklist-Community-measured social withdrawal and Social Responsiveness Scale-measured communication. Treatment effect sizes were more favorable for the treatment group compared with the placebo group (communication: treatment groups, 0.87 vs, placebo, 0.44; social withdrawal: treatment groups, 0.88, vs placebo, 0.54). There was a significant difference in the change in plasma transferrin levels and a trend toward a significant difference in the change in plasma superoxide dismutase levels between the 2 groups. This preliminary study suggests that supplementation with larger ARA doses added to DHA improves impaired social interaction in individuals with autism spectrum disorder by up-regulating signal transduction.

A clinical trial of glutathione supplementation in autism spectrum disorders.

BACKGROUND: Recent evidence shows that subjects diagnosed with an autism spectrum disorder (ASD) have significantly lower levels of glutathione than typically developing children. The purpose of this study was to examine the use of two commonly used glutathione supplements in subjects diagnosed with an ASD to determine their efficacy in increasing blood glutathione levels in subjects diagnosed with an ASD. MATERIAL/METHODS: The study was an eight-week, open-label trial using oral lipoceutical glutathione (n=13) or transdermal glutathione (n=13) in children, 3-13 years of age, with a diagnosis of an ASD. Subjects underwent pre- and post-treatment lab testing to evaluate plasma reduced glutathione, oxidized glutathione, cysteine, taurine, free and total sulfate, and whole-blood glutathione levels. RESULTS: The oral treatment group showed significant increases in plasma reduced glutathione, but not whole-blood glutathione levels following supplementation. Both the oral and transdermal treatment groups showed significant increases in plasma sulfate, cysteine, and taurine following supplementation. CONCLUSIONS: The results suggest that oral and transdermal glutathione supplementation may have some benefit in improving some of the transsulfuration metabolites. Future studies among subjects diagnosed with an ASD should further explore the pharmacokinetics of glutathione supplementation and evaluate the potential effects of glutathione supplementation upon clinical symptoms.

[Therapeutic effects of larger doses of arachidonic acid added to DHA on social impairment and its relation to alterations of polyunsaturated fatty acids in individuals with autism spectrum disorders].

The polyunsaturated fatty acids (PUFAs), arachidonic acid (ARA) and docosahexaenoic acid (DHA) may play key roles in brain network maturation. ARA plays an important role in signal transduction related to neuronal maturation. This study aims to evaluate the efficacy of supplementing with larger doses of ARA added to DHA in a double-blind, placebo-controlled 16-week trial. To confirm findings observed in the placebo-controlled trial, an additional 16-week open-label study was further conducted. To examine the relationship between the efficacy of the supplementation regimen and alterations in PUFAs levels, we examined plasma levels of PUFAs. We used the Social Responsiveness Scale (SRS) and the Aberrant Behavior Checklist-Community (ABC) to estimate psychotic symptoms. Repeated measures ANOVA revealed that this supplementation significantly improved SRS-measured communication as well as ABC-measured social withdrawal during the placebo-controlled trial. The treatment effect sizes were more favorable for the treatment group compared with the placebo group (communication: 0.87 vs. 0.44; social withdrawal: 0.88 vs. 0.54). At the end of the placebo-controlled trial, there was a significant difference in the change in plasma ARA levels from the baseline and a trend towards a significant difference in plasma ARA levels between the two groups. The open-label study was not powered to detect significant improvements in the outcome measures or significant differences in plasma ARA levels. The present clinical trials suggest that supplementation with larger ARA doses added to DHA improves social impairment in individuals with ASD via ARA-induced upregulation of neuronal functioning.