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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.

Significance Autism spectrum disorder (ASD), encompassing impaired communication and social interaction, and repetitive stereotypic behavior and language, affects 1–2% of predominantly male individuals and is an enormous medical and economic problem for which there is no documented, mechanism-based treatment. In a placebo-controlled, randomized, double-blind clinical trial, daily oral administration for 18 wk of the phytochemical sulforaphane (derived from broccoli sprouts) to 29 young men with ASD substantially (and reversibly) improved behavior compared with 15 placebo recipients. Behavior was quantified by both parents/caregivers and physicians by three widely accepted measures. Sulforaphane, which showed negligible toxicity, was selected because it upregulates genes that protect aerobic cells against oxidative stress, inflammation, and DNA-damage, all of which are prominent and possibly mechanistic characteristics of ASD. Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13–27) with moderate to severe ASD received the phytochemical sulforaphane ( n = 29)—derived from broccoli sprout extracts—or indistinguishable placebo ( n = 15). The effects on behavior of daily oral doses of sulforaphane (50–150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC ( P < 0.001, comparing treatments) and 17% for SRS scores ( P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication ( P = 0.015–0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood–brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg −1 per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

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. 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. 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. 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. 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.

Many children with childhood-onset obsessive-compulsive disorder (OCD) fail to respond adequately to standard therapies. Evidence from preclinical and clinical studies suggests that the glutamatergic neurotransmitter system might be an alternative treatment target. This study examined the efficacy of riluzole, a glutamatergic modulator, as an adjunctive therapy for children with treatment-resistant OCD. In a 12-week, double-blind, placebo-controlled study, 60 treatment-resistant children and adolescents (mean age=14.5 ± 2.4 years), with moderate to severe OCD (mean Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS)=28.2 ± 3.7), 17 of whom also had concomitant autism spectrum disorder, were randomized to receive riluzole (final dose of 100 mg/day) or placebo in addition to the existing treatment regimen. Fifty-nine subjects completed the randomized trial. Primary outcome measures were changes on the CY-BOCS, the Clinical Global Impressions Scale, and the Children's Global Assessment Scale. Riluzole was fairly well tolerated, although it was associated with one case of pancreatitis and five instances of slight increases in transaminases. All subjects showed significant reductions in CY-BOCS scores during treatment; however, there was no significant difference between placebo and riluzole on any of the primary or secondary outcome measures. The study failed to demonstrate superiority of riluzole over placebo as an adjunctive treatment for children with childhood-onset OCD. However, future studies may show benefits for less treatment-refractory children with fewer concomitant medications.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and by repetitive behaviors and interests. Irritability/aggression is a significant comorbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability/aggression in children and adolescents with ASD. This was a 12-week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. A total of 55 subjects gavetheir consent and 27 were randomized in a 1 : 1 manner (mean age 9.46±2.46, mean nonverbal IQ 63.3±23.9). Two subjects from the active group and one subject from the placebo group discontinued the study because of either a lack of efficacy or side effects (increased irritability). Primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, which focused on irritability. Overall, 62.5% of divalproex subjects vs 9% of placebo subjects were responders (CGI-irritability OR: 16.7, Fisher's exact p =0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale ( p =0.048). There was a trend for responders to have higher valproate blood levels compared with nonresponders. This study suggests the efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.

This report examined the effect of methylphenidate on social communication and self-regulation in children with pervasive developmental disorders and hyperactivity in a secondary analysis of RUPP Autism Network data. Participants were 33 children (29 boys) between the ages of 5 and 13 years who participated in a four-week crossover trial of placebo and increasing doses of methylphenidate given in random order each for one week. Observational measures of certain aspects of children’s social communication, self-regulation, and affective behavior were obtained each week. A significant positive effect of methylphenidate was seen on children’s use of joint attention initiations, response to bids for joint attention, self-regulation, and regulated affective state. The results go beyond the recent literature and suggest that methylphenidate may have positive effects on social behaviors in children with PDD and hyperactivity.

Objective: The purpose of this study was to examine the behavioral effects of four doses of psychostimulant medication, combining extended-release methylphenidate (MPH) in the morning with immediate-release MPH in the afternoon. Method: The sample comprised 24 children (19 boys; 5 girls) who met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age=8.8 years, SD=1.7; mean intelligence quotient [IQ]=85; SD=16.8). Effects of four dose levels of MPH on parent and teacher behavioral ratings were investigated using a within-subject, crossover, placebo-controlled design. Results: MPH treatment was associated with significant declines in hyperactive and impulsive behavior at both home and school. Parents noted significant declines in inattentive and oppositional behavior, and improvements in social skills. No exacerbation of stereotypies was noted, and side effects were similar to those seen in typically developing children with ADHD. Dose response was primarily linear in the dose range studied. Conclusions: The results of this study suggest that MPH formulations are efficacious and well-tolerated for children with ASD and significant ADHD symptoms.

We conducted a pilot randomized controlled trial to determine the feasibility and initial safety and efficacy of omega-3 fatty acids (1.3 g/day) for the treatment of hyperactivity in 27 children ages 3–8 with autism spectrum disorder (ASD). After 12 weeks, hyperactivity, as measured by the Aberrant Behavior Checklist, improved 2.7 (±4.8) points in the omega-3 group compared to 0.3 (±7.2) points in the placebo group ( p  = 0.40; effect size = 0.38). Correlations were found between decreases in five fatty acid levels and decreases in hyperactivity, and the treatment was well tolerated. Although this pilot study did not find a statistically significant benefit from omega-3 fatty acids, the small sample size does not rule out small to moderate beneficial effects.

Objective: The aim of this study was to investigate the short-term efficacy and safety of methylphenidate (MPH) to treat attention-deficit/hyperactivity disorder (ADHD) symptoms in an understudied population of preschoolers with pervasive developmental disorder (PDD) or intellectual disability (ID). Methods: Fourteen preschoolers with developmental disorders (DD, n = 14; PDD, n = 12; ID, n = 2) underwent MPH titration in a single-blind manner followed by a 4-week double-blind crossover phase. Each child was administered placebo for 2 weeks and “optimal dose” for 2 weeks. The primary outcome measure was the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) ADHD subscale of the Conners' Parent Rating Scale-Revised (CPRS-R-DSM-IV-ADHD). Results: MPH improved parent-rated ADHD symptoms of the preschoolers; 50% were rated as responders. The CPRS-R-DSM-IV-ADHD subscale was significant for the PDD subgroup (p = 0.005, Cohen d = 0.97) and marginally significant for the entire DD sample (p = 0.08, Cohen d = 0.50). Half of the preschoolers experienced side effects with MPH, including reports of increased stereotypic behavior, upset stomach, sleep-related difficulties, and emotional lability. One child discontinued during titration due to side effects. Conclusion: The predominant direction of response in these preschoolers with both ADHD and PDD/ID favored MPH, even though the response was more subtle and variable than in older and typically developing children. Due to high rates of adverse effects, preschoolers should be monitored closely.