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Divalproex sodium vs placebo for the treatment of irritability in children and adolescents with autism spectrum disorders.

ABSTRACT: 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.

SUBMITTER: Hollander E

PROVIDER: S-EPMC2846602 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVES:Our clinical experience with low dose loxapine (5-15?mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation. METHODS:We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores >14. Loxapine was dosed flexibly up to 15?mg daily, starting with 5?mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped. RESULTS:Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5?mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was -31%, p=0.01. Mean body mass index (BMI)-Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly (p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype. CONCLUSIONS:Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study.

Project description:ImportanceThe finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population.ObjectiveTo identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders.Design, setting, and participantsRandomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression-Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Children's Yale-Brown Obsessive-Compulsive Scale.InterventionsTwelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d).Main outcomes and measuresA positive response was defined as having a score of at least much improved on the Clinical Global Impression-Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale-Revised, and the Children's Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire.ResultsSeveral baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders.Conclusions and relevanceThis analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders.Trial registrationclinicaltrials.gov Identifier: NCT00086645.

Project description:Flourishing is an indicator of positive mental health and is important for children's development and well-being. We used variables from the National Survey of Children's Health 2016 as indicators of flourishing (difficulty making friends, is bullied, bullies others, shares ideas with family, argues, finishes tasks, does all homework, shows curiosity, stays calm, and cares about doing well in school) to compare differences in parent perceptions of their children with and without autism spectrum disorder (ASD). We anticipate that these findings will help identify intervention targets to support the well-being of individuals with ASD. Children between 6 and 17 years of age, without intellectual disability, brain injury, cerebral palsy, or Down syndrome were included. Total participants were 34,171 controls (male/female = 17,116/17,155) and 812 with ASD (male/female = 668/144). Factor analysis resulted in three-factor structures (social competence, behavioral control, and school motivation) with good model fit (root mean square error of approximation = 0.08, comparative fit index = 0.92, Tucker-Lewis index = 0.89). The multivariate regression model and propensity score with inverse probability of treatment weighting (PS-IPTW) method revealed that children with ASD had lower scores in the social competence and behavioral control factors compared to the control group (all P < 0.05). However, no significant differences were found in the school motivation factor between the two groups (P > 0.05) in both multivariate regression model and PS-IPTW method. Findings suggest that social competence and behavioral control are indicators of flourishing and are important intervention targets to increase flourishing among children with ASD. Autism Res 2019, 12: 952-966. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Flourishing is an indicator of positive mental health and is important for children's development and well-being. We used variables from The National Survey of Children's Health 2016 to examine differences in parent perceptions of the indicators of flourishing (difficulty making friends, is bullied, bullies others, shares ideas with family, argues, finishes tasks, does all homework, shows curiosity, stays calm, and cares about doing well in school) between children with and without autism spectrum disorders (ASD). We anticipate that this information will help to identify therapeutic targets to support the well-being of individuals with ASD. Children between 6 and 17 years old, without intellectual disability (ID), brain injury (BI), cerebral palsy (CP), or Down syndrome (DS) were included. From the total (N = 50,212), we excluded children under age 6 (n = 14,494), those who once, but do not currently have ASD (n = 81), and those with ID (n = 432), BI (n = 170), CP (n = 35), and DS (n = 17), resulting in 34,983 records used. Total participants, age 6-17 years, were 34,171 controls (male/female = 17,116/17,155) and 812 with ASD (male/female = 668/144). Factor analysis resulted in the identification of three flourishing categories among the indicator variables (social competence, behavioral control, and school motivation). Children with ASD had lower scores in the social competence and behavioral control factors compared to the control group. However, there were no significant differences in the school motivation factor between the two groups. Findings suggest that social competence and behavioral control are indicators of flourishing and are important intervention targets to increase flourishing among children with ASD.

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Divalproex sodium vs placebo for the treatment of irritability in children and adolescents with autism spectrum disorders.

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