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Parents of children with autism spectrum disorder (ASD) face higher levels of caregiver strain compared to parents of children with other disabilities. This study examined child clinical features that predict high levels of caregiver strain for 374 parents of children with ASD. Caregiver strain was measured using the Caregiver Strain Questionnaire (CGSQ) objective, subjective internalized, and subjective externalized subscales. Confirmatory factor analysis indicated an acceptable fit for the original CGSQ three-factor solution. The strongest child predictors across CGSQ subscales were: disruptive behavior for objective strain, autism severity and disruptive behavior for subjective internalized strain, and oppositional behavior and hyperactivity for subjective externalized strain. Individualized interventions that attend to specific elements of parental strain may reduce strain and improve family wellbeing.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that reduces obsessive–compulsive symptoms. There is limited evidence supporting its efficacy for repetitive behaviors (RRBs) in autistic spectrum disorder (ASD). We conducted a randomized controlled trial (RCT) of fluoxetine in 158 individuals with ASD (5–17 years). Following 14 treatment weeks (mean dose 11.8 mg/day), no significant differences were noted on the Children’s Yale-Brown Obsessive Compulsive Scale; the proportion of responders was similar (fluoxetine: 36%; placebo: 41%). There were similar rates of AEs (e.g., insomnia, diarrhea, vomiting); high rates of activation were reported in both groups (fluoxetine: 42%; placebo: 45%). Overly cautious dosing/duration may have prevented attainment of a therapeutic level. Results are consistent with other SSRI RCTs treating RRBs in ASD.Trial Registration: clinicaltrials.gov Identifier: NCT00515320.

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.

Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD.

Background Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials. Discussion points The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results. Conclusion Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.

The estimated prevalence of autism spectrum disorder (ASD) is consistently higher in males than females. Gender differences in ASD have long been debated and are influenced by the historical period and source of the sample. The current study reports gender differences in core symptoms, associated features, and treatment response in 682 youth (585 males, 97 females) with ASD. The sample included participants (mean = 7.4 years; range 3–17 years) from six federally-funded, multisite, randomized clinical trials. These trials collected the same measures of social disability, repetitive behavior, adaptive skills, disruptive behavior, and anxiety pretreatment and used the Improvement scale of the Clinical Global Impression at study endpoint. Exploratory analyses yielded no differences between males and females across numerous pre-treatment measures. The rate of positive response was 49.7% for males and 53.6% for females (Chi square = 0.50; p  = 0.48). In this sample of convenience, youth with ASD clinical characteristics and response to treatment showed no significant gender differences. Highlights This study is the first analysis of gender differences in a large sample of treatment-seeking youth with ASD. Participants included 682 youth with ASD enrolled in six multisite clinical trials. No differences were found between males and females with ASD across pre-treatment characterizing measures.

Severe and persistent mental illnesses in children and adolescents, such as early- onset schizophrenia spectrum (EOSS) disorders and pediatric bipolar disorder (pedBP), are increasingly recognized. Few treatments have demonstrated efficacy in rigorous clinical trials. Enduring response to current medications appears limited. Recently, olanzapine was approved for the treatment of adolescents with schizophrenia or acute manic/mixed episodes in pedBP. PubMed searches were conducted for olanzapine combined with pharmacology, schizophrenia, or bipolar disorder. Searches related to schizophrenia and bipolar disorder were limited to children and adolescents. The bibliographies of the retrieved articles were hand-checked for additional relevant studies. The epidemiology, phenomenology, and treatment of EOSS and pedBP, and olanzapine's pharmacology are reviewed. Studies of olanzapine treatment in youth with EOSS and pedBP are examined. Olanzapine is efficacious for EOSS and pedBP. However, olanzapine is not more efficacious than risperidone, molindone, or haloperidol in EOSS and is less efficacious than clozapine in treatment-resistant EOSS. No comparative trials have been done in pedBP. Olanzapine is associated with weight gain, dyslipidemia, and transaminase elevations in youth. Extrapyramidal symptoms, neuroleptic malignant syndrome, and blood dyscrasias have also been reported but appear rare. The authors conclude that olanzapine should be considered a second-line agent in EOSS and pedBP due to its risks for significant weight gain and lipid dysregulation. Awareness of the consistent weight and metabolic changes observed in olanzapine-treated youth focused attention on the potential long-term risks of atypical antipsychotics in youth.

Pediatric psychotropic prescription rates are rising, emphasizing the need for careful monitoring of drug safety in this population. Currently, no standardized assessments are used in clinical trials for adverse event (AE) elicitation focused on long-term drug treatment in pediatric patients. Despite a lack of standardized AE elicitation methods in psychiatric clinical trials, it is clear that psychiatric medications have developmentally dependent AEs that differ from those observed in adults. In this review, we discuss the use of general inquiry elicitation, drug-specific checklists, and systematic elicitation scales for AE reporting in pediatric psychopharmacology trials. The checklists evaluated include the Barkley Side Effect Rating Scales (SERS), the Pittsburg side effect rating scale, and the Systematic Monitoring of Adverse events Related to TreatmentS (SMARTS) checklist. The systematic assessment scales discussed include the Systematic Assessment for Treatment of Emergent Events (SAFTEE) and the Safety Monitoring Uniform Report Form (SMURF). We review the advantages and disadvantages of each method and discuss the need for optimal assessment of AEs. AE instruments that are created and utilized for pediatric psychiatric trials must begin to incorporate symptoms that are relevant to this population and account for the nature of the disorders to better characterize treatment-emergent AEs and monitor long-term safety.

We sought to test the hypothesis that deficits in grey matter volume are characteristic of psychotic youth with early-onset schizophrenia-spectrum disorders (EOSS) but not of psychotic youth with early-onset mood disorders (EOMD). We used magnetic resonance imaging to examine brain volume in 24 psychotic youth (13male, 11 female) with EOSS (n=12) or EOMD (n=12) and 17 healthy controls (10male, 7 female). We measured the volume of grey and white matter using an automated segmentation program. After adjustment for age and intracranial volume, whole brain volume was lower in the EOSS patients than in the healthy controls (p=0.001) and EOMD patients (p=0.002). The EOSS patients had a deficit in grey matter volume (p=0.005), especially in the frontal (p=0.003) and parietal (p=0.006) lobes, with no significant differences in white matter volume. The main limitations of our study were its small sample size and the inclusion of patients with depression and mania in the affective group. Adolescents with EOSS have grey matter deficits compared with healthy controls and psychotic adolescents with EOMD. Our results suggest that grey matter deficits are not generally associated with psychosis but may be specifically associated with schizophrenia. Larger studies with consistent methods are needed to reconcile the contradictory findings among imaging studies involving psychotic youth.

The presence of attention deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD) is associated with worse cognitive control. Children with ASD and ADHD often respond poorly to medications, thus we need alternative treatments. We examined the feasibility, acceptability, and preliminary efficacy of Project Evo—a digital treatment. Nineteen children with ASD and co-occurring ADHD symptoms completed this app-based treatment that targets multi-tasking through gameplay versus a comparison educational treatment. Children had a high engagement with both treatments, and parents and children reported high acceptability. Within-group analyses suggest the multi-tasking but not the educational treatment may improve cognitive control. This multi-tasking treatment is feasible, acceptable, and possibly efficacious for cognitive control impairments in children with ASD and ADHD.