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Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.

Objective: Parent and teacher ratings of core attention-deficit/hyperactivity disorder (ADHD) symptoms, as well as behavioral and emotional problems commonly comorbid with ADHD, were compared in children with autism spectrum disorders (ASD).Method: Participants were 86 children (66 boys; mean: age=9.3 years, intelligence quotient [IQ]=84) who met American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for an ASD on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). Parent and teacher behavioral ratings were compared on the Conners' Parent and Teacher Rating Scales (CPRS-R; CTRS-R). The degree to which age, ASD subtype, severity of autistic symptomatology, and medication status mediated this relationship was also examined.Results: Significant positive correlations between parent and teacher ratings suggest that a child's core ADHD symptoms-as well as closely related externalizing symptoms-are perceived similarly by parents and teachers. With the exception of oppositional behavior, there was no significant effect of age, gender, ASD subtype, or autism severity on the relationship between parent and teacher ratings. In general, parents rated children as having more severe symptomatology than did teachers. Patterns of parent and teacher ratings were highly correlated, both for children who were receiving medication, and for children who were not.Conclusions: Parents and teachers perceived core symptoms of ADHD and closely-related externalizing problems in a similar manner, but there is less agreement on ratings of internalizing problems (e.g., anxiety). The clinical implication of these findings is that both parents and teachers provide important behavioral information about children with ASD. However, when a clinician is unable to access teacher ratings (e.g., during school vacations), parent ratings can provide a reasonable estimate of the child's functioning in these domains in school. As such, parent ratings can be reliably used to make initial diagnostic and treatment decisions (e.g., medication treatment) regarding ADHD symptoms in children with ASDs. [ABSTRACT FROM AUTHOR]

Objective: To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient α4β2 nAChRs, excess α7 nAChRs) in brains of patients with autism.Method: Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive.Results: Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense.Conclusion: Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline. [ABSTRACT FROM AUTHOR]

Background Risperidone may be effective in improving tantrums, aggression, or self-injurious behaviour in children with autism, but often leads to weight gain.Method Using a quantitative Food Frequency Questionnaire (FFQ), we prospectively examined the nutritional intake of 20 children with autism participating in a randomised placebo-controlled trial of risperidone for disruptive behaviours.Results At baseline, the mean intakes for macronutrients, vitamins and minerals exceeded Dietary Reference Intakes (DRIs). However there was substantial inter-participant variability, with individual deficiencies (<80% of DRI) in the intake of calcium (9 of 20 participants), pantothenic acid (6 of 20), vitamin D (5 of 20) and vitamin K (8 of 20). For the participants for whom FFQs were available, there was an increase in weight and an increase in vitamin K intake after 2 months of risperidone treatment (n = 9) compared to placebo (n = 8). An additional 4 months of risperidone treatment (n = 8) did not result in significant changes in reported nutritional balance.Conclusion These pilot data suggest that treatment with risperidone did not significantly affect the nutritional balance of this small group of children. [ABSTRACT FROM AUTHOR]

Although atypical antipsychotics generally have a good side effect profile and are clinically very effective, weight gain and associated problems accompany their use. The authors followed up 14 subjects who were in studies of risperidone for management of disruptive behavior disorders. The subjects exited after a mean exposure of 8.9 months because of excessive weight gain, or excessive appetite, or insufficient clinical response. Weight was monitored for the full cohort before risperidone treatment, at termination, and (for various subgroups) at 3, 9-12, and 24 months after termination. Analysis of standardized weight scores in relation to standardized BMI scores suggested marked similarity between them at all time points. Comparison of standardized weights at time of drug termination with 3, 9-12, and 24 months after termination indicated that weight gain during risperidone treatment is reversible (i.e., significantly less weight after risperidone was discontinued) at all time points after termination. Furthermore, standardized weight at 12 and 24 months after discontinuation of risperidone was not distinguishable from standardized weight before risperidone. The prospect of reversibility may provide some comfort for clinicians and parents alike, but far more data are needed before an assumption can be made that this is the case for all children. The authors provide several recommendations for clinicians and researchers working with atypical antipsychotics. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study determined the long-term safety and effectiveness of risperidone in treating severe disruptive behavior in children with subaverage intelligence. METHOD: This 48-week, open-label extension included 107 children ages 5-12 years with severe disruptive behavior disorders (according to DSM-IV criteria and a score of > or = 24 on the conduct problem subscale of the Nisonger Child Behavior Rating Form) and subaverage intelligence (IQ 36-84) who completed at least 2 weeks of a randomized, double-blind, placebo-controlled study of risperidone. All patients received 0.02-0.06 mg/kg/day of oral risperidone; the purpose was to accumulate long-term safety data. Scores on the Nisonger Child Behavior Rating Form were also obtained. RESULTS: The mean risperidone dose was 1.5 mg/day. The most common adverse events reported were somnolence (33%), headache (33%), rhinitis (28%), and weight gain (21%). Somnolence was usually mild and transient. The mean weight increase was 5.5 kg; half was attributable to developmentally expected growth. Transient and asymptomatic increases in prolactin levels were observed. There were no significant changes in Extrapyramidal Symptom Rating Scale scores and no cases of tardive dyskinesia. No clinically relevant changes in ECGs or vital signs were noted. Risperidone was associated with rapid, significant improvement on the conduct problem subscale score of the Nisonger Child Behavior Rating Form in patients previously treated with placebo; improvement was maintained during long-term treatment and in patients previously given risperidone. CONCLUSIONS: Long-term risperidone appears to be generally safe, well tolerated, and effective for treating severely disruptive behaviors in children with subaverage intelligence. [ABSTRACT FROM AUTHOR]

A review of the literature revealed that there was no adequate assessment instrument available that screens comprehensively for anxiety and depression in persons with mental retardation. The purpose of this research was to develop the Anxiety, Depression, and Mood Scale (ADAMS), an instrument intended to fill this gap. We developed a preliminary rating scale that included 55 symptom items. We examined the factor structure of these items by an exploratory factor analysis of behavior ratings on 265 individuals. A five-factor solution emerged that was both statistically sound and clinically meaningful. These factors were labeled 'Manic/Hyperactive Behavior,' 'Depressed Mood,' 'Social Avoidance,' 'General Anxiety' and 'Compulsive Behavior.' We validated this solution by conducting a confirmatory factor analysis on ratings of 268 additional individuals. Model fit was acceptable. Internal consistency of the subscales and retest reliability for both the total scale and the subscales was high. Interrater reliability was satisfactory. The validity of the ADAMS was assessed with a clinical sample of 129 individuals with mental retardation who were seen in a psychiatric clinic; this provided additional support for the subscales. The ADAMS appears to be a psychometrically sound instrument for screening anxiety, depression and mood disorders among individuals with mental retardation. [ABSTRACT FROM AUTHOR]

We reviewed pharmacological treatments used in children with autism and PDD-NOS who present with hyperactive symptoms. Some 41 studies were identified from the following drug categories: antipsychotics (n = 13), serotonin reuptake inhibitors (n = 3), antianxiety drugs (n = 4), psychostimulants (n = 10), alpha adrenergic agonists (n = 2), opiate blockers (n = 7), and other drugs (n = 2). Empirical evidence for significant reductions in hyperactive symptoms was strongest for the antipsychotics, psychostimulants, and naltrexone. Most studies have focused on the reduction of overactivity, and more emphasis needs to be placed on distractibility and attentional variables. A theoretical model was proposed in which participants' attentional performance may be used to predict clinical response to psychostimulants. More carefully controlled and comprehensive studies of hyperactivity are badly needed in these children. [ABSTRACT FROM AUTHOR]

Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders. [ABSTRACT FROM AUTHOR]

This study assessed the relationship between parent and teacher ratings of hyperactivity and developmental indices (chronological age, IQ, and mental age) in two groups of children. Subjects were drawn separately from two psychiatric clinics: (a) a general clinical sample, largely of normal ability, seen for a multitude of psychiatric and behavioral problems, and (b) a developmental clinic sample, comprising children with cognitive delays and seen for ADHD or the absence of ADHD. The results showed consistent negative correlations between chronological age and severity of hyperactivity symptoms; however, these occurred mainly within the developmental clinic sample. Only 4 of 27 comparisons (15%) between mental age and hyperactivity ratings (all confined to the developmentally delayed sample) showed a significant correlation. When chronological age was first partialled out, the correlations between ratings of hyperactivity and mental age ceased to be significant. Findings suggest that chronological age should be taken into consideration when behavior ratings are used to assess cognitively delayed children for ADHD. However, the results do not support guidelines stating that mental age must be used to determine which norms should be applied when such children are evaluated clinically. [ABSTRACT FROM AUTHOR]

Twenty-eight children took part in a double-blind, placebo-controlled, crossover study of fenfluramine and methylphenidate. Fenfluramine dosage was gradually increased to a standardized dose of 1.5 mg/kg per day, whereas methylphenidate was given in doses of 0.4 mg/kg per day. The children were assessed on laboratory tests of selective and sustained attention, visual matching, and color matching, during which seat activity was monitored automatically. Results showed fenfluramine to be superior to placebo on the memory task, whereas methylphenidate reduced commission errors on a continuous performance test. Methylphenidate caused shorter response times, and fenfluramine caused increases, on two of the tests. Examiner behavior ratings indicated significant improvements with both drugs on the domains of attention, activity level, and mood. These findings, together with those from a companion clinical study, suggest that the drugs may have contrasting mechanisms of action, but both appear to have useful clinical effects in these children. [ABSTRACT FROM AUTHOR]

1 The efficacy of the antihistamine azatadine maleate at maximum recommended dosage (4 mg/day) for 1 week was assessed relative to placebo in a double-blind crossover study of twenty patients with perennial allergic rhinitis. 2 Sixteen patients reported significant improvement in their clinical symptoms while taking the active drug. 3 The size of skin test weals for both histamine provocation and common inhalant allergens (prick test) diminished significantly after the azatadine treatment. There was no correlation between inhibition of skin reactions and symptom improvement. 4 Eight subjects reported sedative effects attributable to azatadine maleate. Their performance on a choice reaction to placebo occurred in the non-sedated group. [ABSTRACT FROM AUTHOR]

In recent years, there has been a proliferation of instruments for assessing mental health (MH) among autistic people. This study aimed to review the psychometric properties of broadband instruments used to assess MH problems among autistic people. In accordance with the PRISMA guidelines (PROSPERO: CRD42022316571) we searched the APA PsycINFO via Ovid, Ovid MEDLINE, Ovid Embase and the Web of Science via Clarivate databases from 1980 to March 2022, with an updated search in January 2024, to identify very recent empirical studies. Independent reviewers evaluated the titles and abstracts of the retrieved records (n = 11,577) and full-text articles (n = 1000). Data were extracted from eligible studies, and the quality of the included papers was appraised. In all, 164empirical articles reporting on 35 instruments were included. The review showed variable evidence of reliability and validity of the various instruments. Among the instruments reported in more than one study, the Aberrant Behavior Checklist had consistently good or excellent psychometric evidence. The reliability and validity of other instruments, including: the Developmental Behavior Checklist, Emotion Dysregulation Inventory, Eyberg Child Behavior Inventory, Autism Spectrum Disorder-Comorbid for Children Scale, and Psychopathology in Autism Checklist, were less documented. There is a need for a greater evidence-base for MH assessment tools for autistic people., (© 2024. The Author(s).)

There is substantial comorbidity between autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), and there are well-documented executive functioning (EF) deficits in both populations. An important question concerns whether EF deficits in children with ASD are related to severity of ASD, ADHD, or both. We examined ADHD and ASD symptoms in relation to ratings of EF in the home and classroom. The sample comprised 64 children (55 males) diagnosed with ASD (mean age = 9.26 years; mean FSIQ = 92). Analyses indicated that parent and teacher ratings of EF (except Shift and Emotional Control) were consistently related to ADHD symptom severity, but not to ASD severity. Thus, functioning in the domains of Shift and Emotional control appear relatively spared, whereas performance in all other EF was impaired in relation to ADHD symptoms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: In recent years, a number of studies have begun to explore the nature of Attention-Deficit/Hyperactivity Disorder (ADHD) in children with Autism Spectrum Disorder (ASD). In this study, we examined the relationship between both symptoms of ADHD and symptoms of ASD on cognitive task performance in a sample of higher-functioning children and adolescents with ASD. Participants completed cognitive tasks tapping aspects of attention, impulsivity/inhibition, and immediate memory., Aims: We hypothesized that children with ASD who had higher levels of ADHD symptom severity would be at higher risk for poorer sustained attention and selective attention, greater impulsivity/disinhibition, and weaker memory., Methods and Procedures: The sample included 92 children (73 males) diagnosed with ASD (Mean Age = 9.41 years; Mean Full Scale IQ = 84.2)., Outcomes and Results: Using regression analyses, more severe ADHD symptomatology was found to be significantly related to weaker performance on tasks measuring attention, immediate memory, and response inhibition. In contrast, increasing severity of ASD symptomatology was not associated with higher risk of poorer performance on any of the cognitive tasks assessed., Conclusions and Implications: These results suggest that children with ASD who have more severe ADHD symptoms are at higher risk for impairments in tasks assessing attention, immediate memory, and response inhibition-similar to ADHD-related impairments seen in the general pediatric population. As such, clinicians should assess various aspects of cognition in pediatric patients with ASD in order to facilitate optimal interventional and educational planning., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The Aberrant Behavior Checklist (ABC) is a standardized rating scale used for assessing problematic behavior of individuals with developmental disabilities. It has five subscales: Irritability, Social Withdrawal, Stereotypic Behavior, Hyperactivity, and Inappropriate Speech. A previous study in individuals with fragile X syndrome (FXS) reported six factors, with the Social Withdrawal factor bifurcating into Socially Unresponsive and Social Avoidance factors, suggesting a different factor structure in people with FXS. Methods: We assessed the ABC's factor structure (with both exploratory and confirmatory analyses) in 797 people with FXS and we compared these findings with exploratory factors derived from an independent sample of 357 individuals with FXS. In an ancillary analysis, we compared the overlap of the traditional ABC's Social Withdrawal scores with the Social Avoidance scores from the FXS-derived newer scale to determine whether overlap between these was very high and essentially redundant. Finally, we computed norms using both the traditional and the FXS-specific algorithms. Results: In confirmatory factor analyses, the FXS-specific algorithm produced the most consistent factor structure for the sample of 797 participants, but model fit was only marginally better than that derived by the original ABC scoring algorithm. Comparisons of factor structures from separate exploratory analyses revealed no consistent advantage of the FXS algorithm over the traditional algorithm. While a Social Avoidance subscale did emerge in some analyses, in other analyses, this was accompanied by loss of coherence on other domains of interest, such as the Socially Unresponsive/Social Withdrawal subscale. Conclusion: We question whether the newer FXS scoring algorithm contributes data that are consistently helpful in evaluating behavior of people with FXS. In general, we recommend continued use of the original ABC algorithm for scoring behavior of clients with FXS . However, we acknowledge that there may be circumscribed times when the new algorithm may be appropriate for scoring, namely when anxiety and/or social avoidance constructs are the central and unequivocal domains of interest.

Objective: To examine the effectiveness of four doses of psychostimulant medication, combining extended-release methylphenidate (ER-MPH) in the morning with immediate-release MPH (IR-MPH) in the afternoon, on cognitive task performance. Method: The sample comprised 24 children (19 boys and 5 girls) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-R and the Autism Diagnostic Observation Schedule , 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 = 85; SD = 16.8). Effects of placebo and three dose levels of ER-MPH (containing 0.21, 0.35, and 0.48 mg/kg equivalent of IR-MPH) on cognitive task performance were compared using a within-subject, crossover, placebo-controlled design. Each of the four MPH dosing regimens (placebo, low-dose MPH, medium-dose MPH, and high-dose MPH) was administered for 1 week; the dosing order was counterbalanced across children. Results: MPH treatment was associated with significant performance gains on cognitive tasks tapping sustained attention, selective attention, and impulsivity/inhibition. Dose/response was generally linear in the dose range studied, with no evidence of deterioration in performance at higher MPH doses in the dose range studied. Conclusion: The results of this study suggest that MPH formulations are associated with significant improvements on cognitive task performance in children with ASD and ADHD.

There is a need for measures to track symptom change in autism spectrum disorder (ASD). We conducted a validation study on a revised version of the Autism Behavior Inventory (ABI), and a short form (ABI-S). Caregivers of individuals (6-54 years) with confirmed diagnoses of ASD (N = 144) completed the ABI and other rating scales at 4 time points. Scale consistency for each domain, 3-5 day test-retest reliability, and construct validity, determined by comparison to pre-specified scales, were all good. Change in the ABI was congruent with changes in other instruments. Collectively, results suggest incipient suitability of the ABI as a measure of changes in core and associated symptoms of ASD.Trial Registration NCT02299700.

Objective: Study goals were to (1) provide a rationale for developing a composite primary outcome score that includes symptom severity for attention-deficit/hyperactivity disorder (ADHD) and emotional dysregulation, plus symptom-induced impairment; (2) demonstrate weighting methods to calculate the composite score using a sample of children diagnosed with ADHD and aggression; and (3) identify the optimal weighting method most sensitive to change, as measured by effect sizes. Methods: We conducted secondary data analyses from the previously conducted Treatment of Severe Childhood Aggression (TOSCA) study. Children aged 6-12 years were recruited through academic medical centers or community referrals. The composite primary outcome comprised the ADHD, oppositional defiant disorder, disruptive mood dysregulation disorder, and peer conflict subscales from the Child and Adolescent Symptom Inventory (CASI), a DSM ( Diagnostic and Statistical Manual )-referenced rating scale of symptom severity and symptom-induced impairment. Five weighting methods were tested based on input from senior statisticians. Results: The composite score demonstrated a larger (Cohen's d ) effect size than the individual CASI subscales, irrespective of the weighting method (10%-55% larger). Across all weighting methods, effect sizes were similar and substantial: approximately a two-standard deviation symptom reduction (range: -1.97 to -2.04), highest for equal item and equal subscale weighting, was demonstrated, from baseline to week 9, among all TOSCA participants. The composite score showed a medium positive correlation with the Clinical Global Impressions-Severity scores, 0.46-0.47 for all weighting methods. Conclusions: A composite score that included severity and impairment ratings of ADHD and emotional dysregulation demonstrated a more robust pre-post change than individual subscales. This composite may be a more useful indicator of clinically relevant improvement in heterogeneous samples with ADHD than single subscales, avoiding some of the statistical limitations associated with multiple comparisons. Among the five similar weighting methods, the two best appear to be the equal item and equal subscale weighting methods.

Objective: To explore blinded observational outcomes in the Treatment of Severe Childhood Aggression (TOSCA) study. Methods: During a 9-week acute trial, children with severe physical aggression and attention-deficit/hyperactivity disorder received parent training + titrated psychostimulant for 3 weeks, and those who failed to show an optimal response during Week 4 through Week 6 received in addition either randomly assigned placebo (Basic treatment) or titrated risperidone (Augmented treatment). Child and parent behaviors were videotaped in a Standardized Observation Analogue Procedure (SOAP) designed to elicit problems and strengths in child and parent interactions. SOAPs were collected at baseline and Week 9 and 52 follow-up. Results: During the acute 9-week trial, augmented treatment was associated with better outcomes than basic treatment for 3 of 13 measures: increased Child Compliance ( p  = 0.004; significant after correction for multiple tests), greater use of positive Parent Reinforcement ( p  = 0.03), and more Shared Enjoyment ( p  = 0.04). At follow-up, when medication was no longer by randomized assignment, parents used more Alpha Commands and displayed fewer Parent Negative Behaviors, and the dyads showed more Shared Enjoyment regardless of original randomization. Thus, there were better parent-child interactions with Augmented treatment, and interactions improved overall at follow-up regardless of original treatment assignment. Conclusions: The SOAP demonstrated sensitivity to behavior changes between short-term treatments for a few (but not most) measures. The acute treatment differences for Child Compliance and Child Negative Behavior are generally consistent with the moderate superiority of Augmented over Basic treatment previously reported for the primary study outcome.

Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

Objective: Anxiety is common in youth with autism spectrum disorder (ASD). There is no accepted outcome measure for anxiety in this population., Method: Following a series of focus groups with parents of youth with ASD, we generated 72 items (scored 0-3). Parents of 990 youth with ASD (aged 5-17 years; 80.8% male) completed an online survey. Factor analysis and item response theory analyses reduced the content to a single factor with 25 items. Youth with at least mild anxiety (n = 116; aged 5-17 years; 79.3% male) participated in a comprehensive clinical assessment to evaluate the validity and reliability of the 25-item Parent-Rated Anxiety Scale for ASD (PRAS-ASD)., Results: In the online sample, the mean PRAS-ASD score was 29.04 ± 14.9 (range, 0-75). The coefficient α was 0.93. The item response theory results indicated excellent reliability across a wide range of scores with low standard errors. In the clinical sample (n = 116), the PRAS-ASD mean was 31.0 ± 15.6 (range, 1-65). Pearson correlations with parent ratings of ASD symptom severity, repetitive behavior, and disruptive behavior ranged 0.33 to 0.66, supporting divergent validity of the PRAS-ASD. Pearson correlation with a parent-rated measure of anxiety used in the general pediatric population of 0.83 supported convergent validity. A total of 40 participants (32 boys, 8 girls; mean age, 11.9 ± 3.4 years) returned at time 2 (mean, 12.2 days) and time 3 (mean, 24.2 days). Intraclass correlation showed test-retest reliabilities of 0.88 and 0.86 at time 2 and time 3, respectively., Conclusion: The 25-item PRAS-ASD is a reliable and valid scale for measuring anxiety in youth with ASD., (Copyright © 2019 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: We recently found that metformin attenuated weight gain due to mixed dopamine and serotonin receptor antagonists, commonly termed atypical antipsychotics, in children and adolescents with autism spectrum disorder (ASD). Previous studies have found that genetic variation predicts response to metformin in diabetes. In this study, we aimed to assess whether response to metformin for weight gain in this population is associated with variants in five genes previously implicated in metformin response in diabetes. Methods: Youth with ASD who experienced significant weight gain while taking mixed receptor antagonist medications were randomly assigned to metformin or placebo for 16 weeks, followed by open-label metformin treatment for 16 weeks. In the 53 participants with available DNA samples, we used a linear, mixed model analysis to assess response in the first 16 weeks of metformin treatment, whether in the randomized or open-label period, based upon genotypes at polymorphisms in five genes previously associated with metformin response in diabetes: ATM , SLC2A2 , MATE1 , MATE2 , and OCT1 . Results: In the primary analysis, both ATM and OCT1 showed significant effects of genotype on change in body mass index z -scores, the primary outcome measure, during the first 16 weeks of treatment with metformin. No other polymorphism showed a significant difference. Conclusion: As has been shown for metformin treatment in diabetes, genetic variation may predict response to metformin for weight gain in youth with ASD treated with mixed receptor antagonists. Further work is needed to replicate these findings and evaluate whether they can be used prospectively to improve outcomes.

Objective: We explored patterns of concomitant psychiatric disorders in a large sample of treatment-seeking children and adolescents with autism spectrum disorder (ASD)., Methods: Participants were 658 children with ASD (age 3-17 years; mean = 7.2 years) in one of six federally-funded multisite randomized clinical trials (RCT) between 1999 and 2014. All children were referred for hyperactivity or irritability. Study designs varied, but all used the Child and Adolescent Symptom Inventory or Early Childhood Inventory to assess Attention Deficit Hyperactivity Disorder (ADHD), Oppositional-Defiant Disorder (ODD), Conduct Disorder (CD), Anxiety Disorders, and Mood Disorders. In addition, several measures in common were used to assess demographic and clinical characteristics., Results: Of the 658 children, 73% were Caucasian and 59% had an IQ >70. The rates of concomitant disorders across studies were: ADHD 81%, ODD 46%, CD 12%, any anxiety disorder 42%, and any mood disorder 8%. Two or more psychiatric disorders were identified in 66% of the sample. Of those who met criteria for ADHD, 50% also met criteria for ODD and 46% for any anxiety disorder. Associations between types of concomitant disorders and a number of demographic and clinical characteristics are presented., Conclusion: In this well-characterized sample of treatment-seeking children with ASD, rates of concomitant psychiatric disorders were high and the presence of two or more co-occurring disorders was common. Findings highlight the importance of improving diagnostic practice in ASD and understanding possible mechanisms of comorbidity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 ( TPH2 ), dopamine beta hydroxylase ( DBH ), and dopamine transporter ( DAT, SLC6A3 )., Method: We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites., Results: There was no association between CYP2D6 metabolizer status and atomoxetine response. TPH2 rs7305115 genotype was associated with ADI-R Restrictive/Repetitive Behavior score ( p =0.03). DBH rs1611115 genotype was associated with ADI-R Social score ( p =0.002) and Restrictive/Repetitive Behavior score ( p =0.04). The DAT intron 8 5/6 repeat was associated with ADHD symptoms (ABC Hyperactivity p =0.01 and SNAP ADHD p =0.03), replicating a previous finding., Conclusions: We find associations between ASD phenotypes and regulatory variants in catecholamine biosynthesis genes. This work may help guide future genetics studies related to ASD., Competing Interests: Authors’ Conflicts of Interest Dr. Elizabeth Barrie declares that she has no conflict of interest. Ms. Emily Hansen-Kiss, LGC declares that she has no conflict of interest.

Objective: To examine status of children with autism spectrum disorder (ASD) 10 months after a 34-week clinical trial of atomoxetine (ATX) and parent training (PT)., Methods: In a 2 × 2 design, 128 children with ASD and attention-deficit/hyperactivity disorder (ADHD) were randomly assigned ATX, PT+placebo, PT+ATX, or placebo alone. PT was weekly for 10 weeks, and then monthly. ATX/placebo was titrated over 6 weeks [≤1.8 mg/kg/d], and then maintained until week 10. Responders continued to week 34 or nonresponse. Placebo nonresponders had a 10-week ATX open trial; ATX nonresponders were treated clinically. All continued to week 34. With no further treatment from the study, all were invited to follow-up (FU) at 1.5 years postbaseline; 94 (73%) participated. Changes from Week 34 to FU and from baseline to FU were tested by one-way analysis of variance or chi-squared test. PT versus no PT was tested by chi-squared test, Fisher's exact test, Welch's t-test, Student's t-test, and Mann-Whitney's U test., Results: For the whole sample, the primary outcomes (parent-rated ADHD on the Swanson, Nolan, and Pelham [SNAP] scale and noncompliance on the Home Situations Questionnaire [HSQ]) deteriorated mildly from week 34 to FU, but were still substantially better than baseline (SNAP: t = 12.177, df = 93, p < 0.001; HSQ: t = 8.999, df = 93, p < 0.001). On the SNAP, 61% improved ≥30% from baseline (67% did at week 34); on noncompliance, 56% improved ≥30% from baseline (77% did at week 34). Outcomes with PT were not significantly better than without PT (SNAP p = 0.30; HSQ p = 0.27). Originally assigned treatment groups did not differ significantly. Only 34% still took ATX; 27% were taking stimulants; and 25% took no medication., Conclusions: The majority retained their 34-week end-of-study improvement 10 months later, even though most participants stopped ATX. For some children, ATX continuation may not be necessary for continued benefit or other drugs may be necessary. Cautious individual clinical experimentation may be justified. Twelve sessions of PT made little long-term difference. ClinicalTrials.gov Identifier: Atomoxetine, Placebo and Parent Management Training in Autism (Strattera) (NCT00844753).

Objectives: Studies in humans and rodents suggest that metformin, a medicine typically used to treat type 2 diabetes, may have beneficial effects on memory. We sought to determine whether metformin improved spatial or verbal memory in children with autism spectrum disorder (ASD) and overweight associated with atypical antipsychotic use., Methods: We studied the effects of metformin (Riomet ® ) concentrate on spatial and verbal memory in 51 youth with ASD, ages 6 through 17 years, who were taking atypical antipsychotic medications, had gained significant weight, and were enrolled in a trial of metformin for weight management. Phase 1 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group comparison of metformin (500-850 mg given twice a day) versus placebo. During Phase 2, all participants took open-label metformin from week 17 through week 32. We assessed spatial and verbal memory using the Neuropsychological Assessment 2nd Edition (NEPSY-II) and a modified children's verbal learning task., Results: No measures differed between participants randomized to metformin versus placebo, at either 16 or 32 weeks, after adjustment for multiple comparisons. Sixteen-week change in memory for spatial location on the NEPSY-II was nominally better among participants randomized to placebo. However, patterns of treatment response across all measures revealed no systematic differences in performance, suggesting that metformin had no effect on spatial or verbal memory in these children., Conclusions: Although further study is needed to support these null effects, the overall impression is that metformin does not affect memory in overweight youth with ASD who were taking atypical antipsychotic medications.

Overweight and obesity are common in pediatric populations. Children with autism spectrum disorder and disruptive behavior may be at higher risk. This study examined whether children with autism spectrum disorder and disruptive behavior are more likely to be overweight or obese than matched controls. Baseline data from medication-free children with autism spectrum disorder who participated in trials conducted by the Research Units on Pediatric Psychopharmacology Autism Network (N = 276) were compared to 544 control children from the National Health and Nutrition Examination Survey database matched on age, sex, race, parent education, and era of data collection. The mean age of the children with autism spectrum disorder was 7.9 ± 2.6 years; 84.4% were males. In the autism spectrum disorder group, the prevalence was 42.4% for overweight and 21.4% for obesity compared to 26.1% for overweight and 12.0% for obesity among controls (p < 0.001 for each contrast). Within the autism spectrum disorder sample, obesity was associated with minority status and lower daily living skills. These findings suggest that children with autism spectrum disorder and disruptive behavior are at increased risk for obesity and underscore the need for weight management interventions in this population.

We previously reported a 2 × 2 randomized clinical trial of atomoxetine (ATX) and parent training (PT) for attention deficit hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 children with autism spectrum disorder, ages 5-14 years. Children were randomized to one of four conditions: ATX alone, placebo alone, ATX + PT, or PT + placebo. Both ATX and PT improved some indices of ADHD and behavioral compliance. In this report, we describe parent stress over time and across conditions. All four treatments improved parent self-rated stress from baseline to week 10. However, there were no statistically significant differences between treatment groups. Significantly more improvement in parent stress scores was observed for clinical responders than non-responders. ClinicalTrials.gov Title: Atomoxetine, Placebo and Parent Management Training in Autism (Strattera) ClinicalTrials.gov Identifier: NCT00844753.

Objective: Sleep disturbance is often a problem for children with either autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD). Psychostimulant medications used to treat ADHD symptoms can exacerbate this problem. For children with ASD and ADHD, atomoxetine (ATX) is a viable alternative to psychostimulants. We investigated the effects of ATX and a manualized parent training (PT) program targeting noncompliance, on the sleep quality of children with ASD and ADHD., Methods: Participants in a randomized clinical trial were treated with ATX + PT, ATX alone, PT alone, or placebo (PBO) alone, for 10 weeks. Fifty-four of 128 (42%) caregivers completed the Children's Sleep Habits Questionnaire (CSHQ) at baseline and endpoint. Analysis of covariance was used to investigate possible differences between treatment groups., Results: There were no significant differences between treatment groups, including PBO on the CSHQ 33-Item total score, total hours of sleep per day, and total minutes awake after sleep onset at the study endpoint., Conclusion: ATX appears sleep neutral. Clinicians who treat ADHD symptoms in children and adolescents with ASD may prefer ATX over psychostimulants when sleep disturbance is an issue.

Background: The behavioural challenges and medical conditions associated with fragile X syndrome (FXS) can lead to increased need for medications., Method: This longitudinal study examined the use of prescription medications for psychotropic and non-psychotropic purposes by adolescents and adults with FXS drawn from a North American community sample (N = 105). Odds and probabilities of continuing or discontinuing medication were calculated. Predictors of medication use were calculated., Results: More than two-thirds took psychotropic medication, and about one-quarter took non-psychotropic medication. Over a 3-year period, those who initially took prescription medications were considerably more likely to remain on medications than to stop. Individuals with more autism symptoms, more behavioural problems, a mental health diagnosis, and greater family income were significantly more likely to use psychotropic medication 3 years later. Individuals who had more health problems, a mental health diagnosis, and were female were more likely to use non-psychotropic medication over this time period., Conclusions: Findings highlight the elevated and ongoing use of medication by individuals with FXS. Implications for social and behavioural research on FXS are discussed., (© 2017 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

Objective: The Treatment of Severe Childhood Aggression (TOSCA) project examined augmentation of stimulant treatment and parent training (PT) with risperidone for severe physical aggression. This article summarizes the clinical implications; reanalyzes the data to examine the utility of 4 criteria for deciding to augment; and presents a treatment algorithm., Method: The newly analyzed 4 criteria for augmenting after 3 weeks of stimulant and PT treatment consisted of not meeting a Clinical Global Impressions-Improvement (CGI-I) score of 1 and a normal score (≤15) on the Nisonger Child Behavior Rating Form Disruptive-Total (D-Total); a CGI-I score of 1 or 2 plus 25% improvement in D-Total score; a D-Total score no higher than 15; and a CGI-Severity score of 3 (mild) or better. Effect sizes were calculated. Prior TOSCA publications were reviewed for clinically relevant findings., Results: All 4 criteria resulted in medium or better effect sizes (d = 0.59-0.72) when comparing risperidone with placebo. Providing risperidone to children who did not reach a CGI-I score of 1 plus a D-Total score no higher than 15 resulted in the greatest benefit. In addition, a review of clinically relevant data suggests that stimulant plus PT shows further improvement after 3 weeks even without augmentation., Conclusion: For those children who did not attain a CGI-I score of 1 and a D-total score no higher than 15, adding risperidone maximized the number of children benefitting from treatment and the average amount of benefit. Unless clinical circumstances dictate otherwise, practitioners should delay an antipsychotic drug for at least 1 month after the optimal stimulant dose is achieved and PT has commenced. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov; NCT00796302., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Autism Behavior Inventory (ABI) is a new measure for assessing changes in core and associated symptoms of autism spectrum disorder (ASD) in participants (ages: 3 years-adulthood) diagnosed with ASD. It is a web-based tool with five domains (two ASD core domains: social communication, restrictive and repetitive behaviors; three associated domains: mental health, self-regulation, and challenging behavior). This study describes design, development, and initial psychometric properties of the ABI., Methods: ABI items were generated following review of existing measures and inputs from expert clinicians. Initial ABI scale contained 161 items that were reduced to fit a factor analytic model, retaining items of adequate reliability. Two versions of the scale, ABI-full (ABI-F; 93 items) and ABI-short version (ABI-S; 36 items), were developed and evaluated for psychometric properties, including validity comparisons with commonly used measures. Both scales were administered to parents and healthcare professionals (HCPs) involved with study participants., Results: Test-retest reliability (intraclass correlation coefficient [ICC] = 0.79) for parent ratings on ABI was robust and compared favorably to existing scales. Test-retest correlations for HCP ratings were generally lower versus parent ratings. ABI core domains and comparison measures strongly correlated (r ≥ 0.70), demonstrating good concurrent validity., Conclusions: Overall, ABI demonstrates promise as a tool for measuring change in core symptoms of autism in ASD clinical studies, with further validation required.

Objective: A previous study reported on a 16-week placebo-controlled, randomized clinical trial (RCT) of metformin for weight stabilization in 61 children and adolescents 6 to 17 years old with autism spectrum disorder who were prescribed atypical antipsychotics. The present study describes the results of a 16-week open-label extension., Method: Fifty-two participants from the acute trial (85%) entered the extension; 22 had been on metformin during the initial RCT and 30 had been on placebo. Participants were re-titrated to 500 mg twice a day (6- to 9-year-olds) or 850 mg twice a day (10- to 17-year-olds) during the open-label extension. Primary outcome measure was change in body mass index (BMI) z-score after 16 weeks; secondary outcomes were change in additional body composition and metabolic parameters., Results: After 16 weeks of open-label treatment, participants initially taking placebo during the RCT had lower BMI z-scores (mean 16-week change -0.10, p = .004). Statistically significant improvements also were noted in secondary body composition measures (weight z-score and BMI and weight percentile) but not in metabolic variables. Participants who initially had been taking metformin during the 16-week RCT maintained prior decreases in BMI z-scores but did not have additional weight loss. Three participants discontinued treatment because of an adverse event. No significant changes were noted on metabolic measures, although the decrease in hemoglobin A 1c was large (∼1 mmol) and consistent across the acute and open-label phases., Conclusion: Metformin can be effective for decreasing weight gain associated with atypical antipsychotic use and maintaining prior improvement in children and adolescents with autism spectrum disorder. Clinical trial registration information-Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD); http://clinicaltrials.gov/; NCT01825798., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Attention-deficit/hyperactivity disorder (ADHD) symptoms, including inattention and over activity, occur in approximately one-third of children with autism spectrum disorder (ASD). We describe the rate and duration of adverse events in a randomized controlled trial of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance in children with ASD., Methods: We conducted a 10-week, double-blind, 2 × 2 trial of ATX and PT with 128 children (ages 5-14) randomized to ATX alone, ATX+PT, placebo+PT, or placebo alone. For 6 weeks, ATX (or placebo) doses were clinically adjusted to a maximum of 1.8 mg/(kg·day) and maintained for an additional 4 weeks. An average of seven PT sessions were conducted in the two PT arms. Adverse events (AEs) were assessed through parent ratings of common symptoms on a seven-point Likert severity scale and through direct interviews with study medical staff., Results: ATX was associated with decreased appetite and fatigue, but was otherwise well tolerated. Most reported AEs lasted 4 weeks or less. Unlike reports with typically developing (TD) children, there were no concerns with QTc changes or suicidal ideation., Conclusions: This study extends the findings of previous studies of ATX in ASD by documenting that the type of AEs was similar to that of TD children, with no significant safety concerns.