Jill A. Hollway

Medication and Parent Training in Children With Pervasive Developmental Disorders and Serious Behavior Problems: Results From a Randomized Clinical Trial

OBJECTIVE Many children with pervasive developmental disorders (PDDs) have serious, functionally impairing behavioral problems. We tested whether combined treatment (COMB) with risperidone and parent training (PT) in behavior management is superior to medication alone (MED) in improving severe behavioral problems in children with PDDs. METHOD This 24-week, three-site, randomized, parallel-groups clinical trial enrolled 124 children, aged 4 through 13 years, with PDDs, accompanied by frequent tantrums, self-injury, and aggression. The children were randomized 3:2 to COMB (n = 75) or MED (n = 49). The participants received risperidone monotherapy from 0.5 to 3.5 mg/day (with switch to aripiprazole if risperidone was ineffective). Parents in the COMB group (n = 75; 60.5%) received a mean of 10.9 PT sessions. The primary measure of compliance was the Home Situations Questionnaire (HSQ) score. RESULTS Primary: intent-to-treat random effects regression showed that COMB was superior to MED on HSQ (p = .006) [effect size at week 24 (d) = 0.34]. The HSQ score declined from 4.31 (± 1.67) to 1.23 (± 1.36) for COMB compared with 4.16 (± 1.47) to 1.68 (± 1.36) for MED. Secondary: groups did not differ on Clinical Global Impressions-Improvement scores at endpoint; compared with MED, COMB showed significant reductions on Aberrant Behavior Checklist Irritability (d = 0.48; p = .01), Stereotypic Behavior (d = 0.23; p = .04), and Hyperactivity/Noncompliance subscales (d = 0.55; p = .04). Final risperidone mean dose for MED was 2.26 mg/day (0.071 mg/kg), compared with 1.98 mg/day for COMB (0.066 mg/kg) (p = .04). CONCLUSIONS Medication plus PT resulted in greater reduction of serious maladaptive behavior than MED in children with PDDs, with a lower risperidone dose.

Parent-defined target symptoms respond to risperidone in RUPP autism study: customer approach to clinical trials.

OBJECTIVE A consumer-oriented efficacy assessment in clinical trials should measure changes in chief complaint and consumer request (symptoms of most concern to patient/caregiver), which may be diluted in change scores of multisymptom scales. METHOD In the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network 8-week double-blind trial of risperidone versus placebo, the chief concerns of parents were collected at 0, 4, and 8 weeks (endpoint), in addition to standardized primary measures. Blinded clinical judges rated change from baseline to 4 and 8 weeks on a 9-point scale (1 = normalized, 5 = unchanged, 9 = disastrous); 94 participants had usable data. RESULTS The most common symptoms identified by parents were tantrums, aggression, and hyperactivity. Interrater reliability was excellent. Mean ratings at endpoint were 2.8 +/- 1.2 on risperidone and 4.5 +/- 1.3 on placebo (p <.001). Ratings were collinear with Clinical Global Impression-Improvement and Aberrant Behavior Checklist Irritability subscale (primary dimensional measure). Effect size d was 1.4, compared to 1.2 on the Aberrant Behavior Checklist Irritability subscale. Effect sizes varied twofold by symptom category, largest for self-injury (2.11) and tantrums (1.95). CONCLUSIONS Risperidone was superior to placebo in reducing symptoms of most concern to parents of autistic children with irritable behavior. Rating individualized participant-chosen target symptoms seems a reliable, sensitive, efficient, and consumer-friendly way to assess treatment effect and might have clinical application.

Validity of the Autism Diagnostic Interview-Revised

The factor structure, internal consistency, and convergent validity of the Autism Diagnostic Interview-Revised (ADI-R) algorithm items were examined in a sample of 226 youngsters with pervasive developmental disabilities. Exploratory factor analyses indicated a three-factor solution closely resembling the original algorithm and explaining 38% of the variance, with one significant discrepancy: Unlike the algorithm, all nonverbal communication items were associated with the Social factor. Internal consistencies of domain scores ranged from .54 to .84. Correlations between ADI-R domain and total scores and instruments assessing adaptive behavior, psychopathology, and autism were examined. They indicated some similarities between constructs, but also that the ADI-R measures autism in a unique fashion.

Sleep Correlates of Pervasive Developmental Disorders: A Review of the Literature.

Sleep disturbance is a significant problem in the general pediatric population, and it occurs even more frequently in children with pervasive developmental disorders (PDDs). Much time and energy have been spent examining the characteristics that predispose children to insomnia and it is likely that equivalent factors influence sleep in PDDs. Though similarly affected, it is the unique set of characteristics incumbent in a diagnosis of PDD that has additive effects and increases the likelihood for developing other predisposing factors and subsequent sleep loss. This review summarized research that has explored the behavioral, cognitive, and emotional correlates of sleep disturbance in children with PDDs. The literature provided 38 sleep studies that used either subjective or objective sleep measures. Of these, 17 met criteria for inclusion. Studies were evaluated for their attempts at matching their study samples and adjusting for possible confounding variables. The results revealed that the combined effects of autism symptom severity, internalizing behavior, and externalizing behavior, were the main predisposing factors for the development of insomnia. Other factors included medical conditions, epilepsy, and medication use (likely a proxy for behavior difficulty and even sleep disorder). A bidirectional theoretical framework for sleep disturbance in children with PDDs has been posited as a conceptual guide for future study. Recommendations for future study designs are included.

Treatment of Inattention, Overactivity, and Impulsiveness in Autism Spectrum Disorders

We reviewed the recent literature on medicines used to manage inattention, impulsiveness, and overactivity in children with pervasive developmental disorders (autistic disorder, pervasive developmental disorder not otherwise specified, Aspergers disorder) using computer searches of pharmacologic studies. A substantial number of reports were identified and summarized. The literature tends to be dominated by uncontrolled studies, although the number of controlled trials is growing. Findings are described for psychostimulants, noradrenergic reuptake inhibitors, antipsychotics, alpha adrenergic agonists, antidepressants, anxiolytics, cholinesterase inhibitors, N-methyl-D-aspartate receptor blockers, and antiepileptic mood stabilizers. Evidence for a positive effect is strongest for psychostimulants, noradrenergic reuptake inhibitors, antipsychotics, and alpha adrenergic agonists. Evidence for efficacy seems weakest for newer antidepressants, anxiolytics, and mood stabilizers.

Cognitive Effects of Risperidone in Children with Autism and Irritable Behavior

OBJECTIVE The objective of this research was to explore the effects of risperidone on cognitive processes in children with autism and irritable behavior. METHOD Thirty-eight children, ages 5-17 years with autism and severe behavioral disturbance, were randomly assigned to risperidone (0.5 to 3.5 mg/day) or placebo for 8 weeks. This sample of 38 was a subset of 101 subjects who participated in the clinical trial; 63 were unable to perform the cognitive tasks. A double-blind placebo-controlled parallel groups design was used. Dependent measures included tests of sustained attention, verbal learning, hand-eye coordination, and spatial memory assessed before, during, and after the 8-week treatment. Changes in performance were compared by repeated measures ANOVA. RESULTS Twenty-nine boys and 9 girls with autism and severe behavioral disturbance and a mental age >or=18 months completed the cognitive part of the study. No decline in performance occurred with risperidone. Performance on a cancellation task (number of correct detections) and a verbal learning task (word recognition) was better on risperidone than on placebo (without correction for multiplicity). Equivocal improvement also occurred on a spatial memory task. There were no significant differences between treatment conditions on the Purdue Pegboard (hand-eye coordination) task or the Analog Classroom Task (timed math test). CONCLUSION Risperidone given to children with autism at doses up to 3.5 mg for up to 8 weeks appears to have no detrimental effect on cognitive performance.

Pharmacological treatment of sleep disturbance in developmental disabilities: a review of the literature.

Sleep disturbance is a common problem in children with developmental disabilities. Effective pharmacologic interventions are needed to ameliorate sleep problems that persist when behavior therapy alone is insufficient. The aim of the present study was to provide an overview of the quantity and quality of pharmacologic research targeting sleep in children with developmental disabilities. Efficacy studies of medications most likely to be prescribed to children are reviewed in detail. Medline and PsychInfo searches were performed to identify relevant clinical trials and case reports, published between 1975 and 2009. Key search terms included sleep, children, antihistamines, alpha adrenergic agonists, antidepressants, antipsychotics, melatonin, ramelteon, benzodiazepines, and nonbenzodiazepines. The literature search identified 58 articles that met the inclusion criteria. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy and safety of currently prescribed pediatric sleep medicines. Melatonin appears to be the most widely assessed agent and safest choice for children with developmental disabilities. Trazodone, mirtazapine, and ramelteon hold promise but require further study.

Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

OBJECTIVE Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance. METHOD In a 3-site, 10-week, double-blind, 2 × 2 trial of ATX and PT, 128 children (ages 5-14 years) with ASD and ADHD symptoms were randomized to ATX, ATX+PT, placebo+PT, or placebo. ATX was adjusted to optimal dose (capped at 1.8 mg/kg/day) over 6 weeks and maintained for 4 additional weeks. Nine PT sessions were provided. Primary outcome measures were the parent-rated DSM ADHD symptoms on the Swanson, Nolan and Pelham (SNAP) scale and Home Situations Questionnaire (HSQ). RESULTS On the SNAP, ATX, ATX+PT and placebo+PT were each superior to placebo (effect sizes 0.57-0.98; p values of .0005, .0004, and .025, respectively). For noncompliance, ATX and ATX+PT were superior to placebo (effect sizes 0.47-0.64; p values .03 and .0028, respectively). ATX was associated with decreased appetite but was otherwise well tolerated. CONCLUSION Both ATX and PT resulted in significant improvement on ADHD symptoms, whereas ATX (both alone and combined with PT) was associated with significant decreases on measures of noncompliance. ATX appears to have a better side effects profile than psychostimulants in the population with ASD. CLINICAL TRIAL REGISTRATION INFORMATION Atomoxetine, Placebo and Parent Management Training in Autism; http://clinicaltrials.gov/; NCT00844753.

Correlates and Risk Markers for Sleep Disturbance in Participants of the Autism Treatment Network

We explored possible cognitive, behavioral, emotional, and physiological risk markers for sleep disturbance in children with autism spectrum disorders. Data from 1,583 children in the Autism Treatment Network were analyzed. Approximately 45 potential predictors were analyzed using hierarchical regression modeling. As medication could confound findings, it was included in the analyses as a covariate. Results revealed that anxiety, autism symptom severity, sensory sensitivities, and GI problems were associated with sleep disturbance. IQ positively predicted sleep disturbance, and children with Asperger’s Disorder were more vulnerable than others. The amount of variance in sleep outcomes explained by predictor variables was modest (i.e., R2 from .104 to .201). Predictor variables were evaluated in the context of a bidirectional theoretical framework.

Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial

IMPORTANCE Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use. OBJECTIVE To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years. DESIGN, SETTING, AND PARTICIPANTS A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication. RESULTS Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005). CONCLUSIONS AND RELEVANCE Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01825798.