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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.)

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: 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: The authors previously reported on a 2-by-2 randomized clinical trial of individual and combined treatment with atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 5- to 14-year-old children with autism spectrum disorder. In the present report, they describe a 24-week extension of treatment responders and nonresponders., Method: One-hundred seventeen participants from the acute trial (91%) entered the extension; 84 of these were in 2 subgroups: "treatment responders" (n = 43) from all 4 groups in the acute trial, seen monthly for 24 weeks, and "placebo nonresponders" (n = 41), treated with open-label ATX for 10 weeks. Participants originally assigned to PT continued PT during the extension; the remainder served as controls. Primary outcome measurements were the parent-rated Swanson, Nolan and Pelham ADHD scale and the Home Situations Questionnaire., Results: Sixty percent (26 of 43) of treatment responders in the acute trial, including 68% of responders originally assigned to ATX, still met the response criteria at the end of the extension. The response rate of placebo nonresponders treated with 10-week open-label ATX was 37% (15 of 41), similar to the acute trial. Children receiving open-label ATX + PT were significantly more likely to be ADHD responders (53% versus 23%) and noncompliance responders (58% versus 14%) than those receiving open-label ATX alone., Conclusion: Most ATX responders maintained their responses during the extension. PT combined with ATX in the open-label trial appeared to improve ADHD and noncompliance outcomes more than ATX alone. Clinical trial registration information-Atomoxetine, Placebo and Parent Management Training in Autism (Strattera); http://clinicaltrials.gov; NCT00844753., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: This study examined the impact of parent training on adaptive behavior in children with autism spectrum disorder (ASD) and disruptive behavior., Methods: This was a 24-week, 6-site, randomized trial of parent training versus parent education in 180 children with ASD (aged 3-7 years; 158 boys and 22 girls) and moderate or greater behavioral problems. Parent training included specific strategies to manage disruptive behavior over 11 to 13 sessions, 2 telephone boosters, and 2 home visits. Parent education provided useful information about autism but no behavior management strategies over 12 core sessions and 1 home visit. In a previous report, we showed that parent training was superior to parent education in reducing disruptive behavior in young children with ASD. Here, we test whether parent training is superior to parent education in improving daily living skills as measured by the parent-rated Vineland Adaptive Behavior Scales II. The long-term impact of parent training on adaptive functioning is also presented., Results: At week 24, the parent training group showed a 5.7-point improvement from baseline on the Daily Living domain compared to no change in parent education (p = .004; effect size = 0.36). On the Socialization domain, there was a 5.9-point improvement in parent training versus a 3.1-point improvement in parent education (p = .11; effect size = 0.29). Gains in the Communication domain were similar across treatment groups. The gain in Daily Living was greater in children with IQ of >70. However, the interaction of treatment-by-IQ was not significant. Gains in Daily Living at week 24 were maintained upon re-evaluation at 24 weeks posttreatment., Conclusion: These results support the model that reduction in disruptive behavior can lead to improvement in activities of daily living. By contrast, the expected trajectory for adaptive behavior in children with ASD is often flat and predictably declines in children with intellectual disability. In the parent training group, higher-functioning children achieved significant gains in daily living skills. Children with intellectual disability kept pace with time. Clinical trial registration information-Randomized Trial of Parent Training for Young Children With Autism (RUBI); http://clinicaltrials.gov/; NCT01233414., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to evaluate 52-week clinical outcomes of children with co-occurring attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorder, and serious physical aggression who participated in a prospective, longitudinal study that began with a controlled, 9-week clinical trial comparing the relative efficacy of parent training + stimulant medication + placebo (Basic; n = 84) versus parent training + stimulant + risperidone (Augmented; n = 84)., Method: Almost two-thirds (n = 108; 64%) of families in the 9-week study participated in week 52 follow-ups (Basic, n = 55; Augmented, n = 53) and were representative of the initial study sample. The assessment battery included caregiver and clinician ratings and laboratory tests., Results: Only 43% of participants in the Augmented group and 36% in the Basic group still adhered to their assigned regimen (not significant [NS]); 23% of those in the Augmented group and 11% in the Basic group were taking no medication (NS). Both randomized groups improved baseline to follow-up, but the 3 primary parent-reported behavioral outcomes showed no significant between-group differences. Exploratory analyses indicated that participants in the Augmented group (65%) were more likely (p = .02) to have a Clinical Global Impressions (CGI) severity score of 1 to 3 (i.e., normal to mildly ill) at follow-up than those in the Basic group (42%). Parents rated 45% of children as impaired often or very often from ADHD, noncompliant, or aggressive behavior. The Augmented group had elevated prolactin levels, and the Basic group had decreased weight over time. Findings were generally similar whether groups were defined by randomized assignment or follow-up treatment status., Conclusion: Both treatment strategies were associated with clinical improvement at follow-up, and primary behavioral outcomes did not differ significantly. Many children evidenced lingering mental health concerns, suggesting the need for additional research into more effective interventions. Clinical trial registration information-Treatment of Severe Childhood Aggression (the TOSCA Study); http://clinicaltrials.gov/; NCT00796302., (Published by Elsevier Inc.)

Objective: We examine weight gain and metabolic consequences of risperidone monotherapy in children with autism spectrum disorder (ASD)., Method: This was a 24-week, multisite, randomized trial of risperidone only versus risperidone plus parent training in 124 children (mean age 6.9 ± 2.35 years; 105 boys and 19 girls) with ASD and serious behavioral problems. We monitored height, weight, waist circumference, and adverse effects during the trial. Fasting blood samples were obtained before treatment and at week 16., Results: In 97 children with a mean of 22.9 ± 2.8 weeks of risperidone exposure, there was a 5.4 ± 3.4 kg weight gain over 24 weeks (p < .0001); waist circumference increased from 60.7 ± 10.4 cm to 66.8 ± 11.3 cm (p < .0001). At baseline, 59 of 97 children (60.8%) were classified as having normal weight; by week 24, only 25 of 85 (29.4%) remained in that group. Growth curve analysis showed a significant change in body mass index (BMI) z scores from pretreatment to week 24 (p < .0001). This effect was significantly greater for children with reported increased appetite in the first 8 weeks. From before treatment to week 16, there were significant increases in glucose (p = .02), hemoglobin A1c (p = .01), insulin (p <.0001), homeostatic model assessment-insulin resistance (HOMA-IR; p < .001), alanine aminotransferase (p = .01), and leptin (p < .0001). Adiponectin declined (p = .003). At baseline, 7 children met conventional criteria for metabolic syndrome; by week 16, 12 additional children were so classified., Conclusion: Rapid weight gain with risperidone treatment may promote the cascade of biochemical indices associated with insulin resistance and metabolic syndrome. Appetite, weight, waist circumference, liver function tests, blood lipids, and glucose warrant monitoring. Clinical trial registration information-Drug and Behavioral Therapy for Children With Pervasive Developmental Disorders; http://clinicaltrials.gov/; NCT00080145., (Published by Elsevier Inc.)

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., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: In this study, we aimed to expand on our prior research into the relative efficacy of combining parent training, stimulant medication, and placebo (Basic therapy) versus parent training, stimulant, and risperidone (Augmented therapy) by examining treatment effects for attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms and peer aggression, symptom-induced impairment, and informant discrepancy., Method: Children (6-12 years of age; N = 168) with severe physical aggression, ADHD, and co-occurring ODD/CD received an open trial of parent training and stimulant medication for 3 weeks. Participants failing to show optimal clinical response were randomly assigned to Basic or Augmented therapy for an additional 6 weeks., Results: Compared with Basic therapy, children receiving Augmented therapy experienced greater reduction in parent-rated ODD severity (p = .002, Cohen's d = 0.27) and peer aggression (p = .02, Cohen's d = 0.32) but not ADHD or CD symptoms. Fewer children receiving Augmented (16%) than Basic (40%) therapy were rated by their parents as impaired by ODD symptoms at week 9/endpoint (p = .008). Teacher ratings indicated greater reduction in ADHD severity (p = .02, Cohen's d = 0.61) with Augmented therapy, but not for ODD or CD symptoms or peer aggression. Although both interventions were associated with marked symptom reduction, a relatively large percentage of children were rated as impaired for at least 1 targeted disorder at week 9/endpoint by parents (Basic 47%; Augmented 27%) and teachers (Basic 48%; Augmented 38%)., Conclusion: Augmented therapy was superior to Basic therapy in reducing severity of ADHD and ODD symptoms, peer aggression, and symptom-induced impairment, but clinical improvement was generally context specific, and effect sizes ranged from small to moderate. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov/; NCT00796302., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Repetitive behaviors in autism spectrum disorders (ASD) range from motor stereotypy to immersion in restricted interests. The modified Children's Yale-Brown Obsessive Compulsive Scale for children with autism spectrum disorder (CYBOCS-ASD) includes a Symptom Checklist (behavior present or absent) and 5 severity scales (Time Spent, Interference, Distress, Resistance and Control)., Method: We assembled CYBOCS-ASD data from 3 Research Units on Pediatric Psychopharmacology Autism Network trials to explore the component structure of repetitive behaviors in children with ASD. Raters trained to reliability conducted the CYBOCS-ASD in 272 medication-free subjects. Fifteen Symptom Checklist items were endorsed for less than 5% of the sample and were dropped. Principal component analysis was used to explore the clustering of 23 checklist items. Component scores computed for each subject were correlated with other measures. We also examined the distribution of severity scales., Results: The subjects (229 boys and 43 girls; mean age = 7.8 ± 2.6 years) met criteria for an ASD; half were intellectually disabled. The PCA resulted in a 5-component solution to classify repetitive behaviors (34.4% of the variance): hoarding and ritualistic behavior; sensory and arranging behavior; sameness and self-injurious behavior; stereotypy; restricted interests. Sensory and arranging and stereotypy components were associated with lower adaptive functioning (Pearson r = 0.2-0.3; p < .003). The resistance scale showed little variation, with more than 60% of the sample with the highest score., Conclusions: Rarely endorsed items can be dropped from the Checklist. The resistance item does not appear to be relevant for children with ASD., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Objective: Although combination pharmacotherapy is common in child and adolescent psychiatry, there has been little research evaluating it. The value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression was tested., Method: One hundred sixty-eight children 6 to 12 years old (mean age 8.89 ± 2.01 years) with severe physical aggression were randomized to a 9-week trial of PT, stimulant (STIM), and placebo (Basic treatment; n = 84) or PT, STIM, and risperidone (Augmented treatment; n = 84). All had diagnoses of attention-deficit/hyperactivity disorder and oppositional-defiant disorder (n = 124) or conduct disorder (n = 44). Children received psychostimulant (usually Osmotic Release Oral System methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of week 3, placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (Disruptive-Total subscale was the primary outcome) and Antisocial Behavior Scale; blinded clinicians rated change on the Clinical Global Impressions scale., Results: Compared with Basic treatment (PT + STIM [44.8 ± 14.6 mg/day] + placebo [1.88 mg/day ± 0.72]), Augmented treatment (PT + STIM [46.1 ± 16.8 mg/day] + risperidone [1.65 mg/day ± 0.75]) showed statistically significant improvement on the Nisonger Child Behavior Rating Form Disruptive-Total subscale (treatment-by-time interaction, p = .0016), the Nisonger Child Behavior Rating Form Social Competence subscale (p = .0049), and Antisocial Behavior Scale Reactive Aggression subscale (p = .01). Clinical Global Impressions scores were substantially improved for the 2 groups but did not discriminate between treatments (Clinical Global Impressions-Improvement score ≤2, 70% for Basic treatment versus 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented treatment; other adverse events differed modestly from Basic treatment; weight gain in the Augmented treatment group was minor., Conclusions: Risperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behaviors when added to PT and optimized stimulant treatment. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study), URL: http://clinicaltrials.gov, unique identifier: NCT00796302., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Objective: To follow up on a three-site, 24-week randomized clinical trial (N = 124) comparing antipsychotic medication alone (MED) with antipsychotic medication plus parent training in the behavior management (COMB) of children with autism spectrum disorders and severe behavior problems. The COMB treatment had shown a significant advantage for child behavioral noncompliance (p = .006, d = 0.34), irritability (p = .01, d = 0.48), and hyperactivity/noncompliance (p = .04, d = 0.55) with a lower medication dose., Method: One year after each participant's termination, the authors mailed an assessment packet with a return-addressed envelope; a telephone call alerted the family. Failure to return packets within 1 month elicited another contact and offers to resend., Results: Eighty-seven of 124 families (70.2%) participated in the follow-up. The improvement difference between treatments attenuated from after treatment to follow-up for noncompliance (d = 0.32 to 0.12) and irritability (d = 0.46 to 0.03). The follow-up differences were nonsignificant (the noncompliance difference also was nonsignificant after treatment for these 87 families). Sixty-seven percent of the COMB group and 53% of the MED group were still taking risperidone, the original study medication. Most needed dose adjustments or additional medication, and the COMB group no longer had a significantly lower dose. All COMB families but only 39% of MED families reported seeking parent training after treatment. Improvements in daily living skills during treatment predicted noncompliance improvement at follow-up for the COMB children, but noncompliance deterioration and especially hyperactivity/noncompliance deterioration for the MED children., Conclusions: The study treatment experience/familiarity greatly influenced the follow-up treatment: those who had received parent training reported seeking it, whereas those who had not received it tended not to seek it. The superiority of COMB over MED after treatment attenuated by more than half at follow-up., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Children with Pervasive Developmental Disorders (PDDs) have social interaction deficits, delayed communication, and repetitive behaviors as well as impairments in adaptive functioning. Many children actually show a decline in adaptive skills compared with age mates over time., Method: This 24-week, three-site, controlled clinical trial randomized 124 children (4 through 13 years of age) with PDDs and serious behavioral problems to medication alone (MED; n = 49; risperidone 0.5 to 3.5 mg/day; if ineffective, switch to aripiprazole was permitted) or a combination of medication plus parent training (PT) (COMB; n = 75). Parents of children in COMB received an average of 11.4 PT sessions. Standard scores and Age-Equivalent scores on Vineland Adaptive Behavior Scales were the outcome measures of primary interest., Results: Seventeen subjects did not have a post-randomization Vineland assessment. Thus, we used a mixed model with outcome conditioned on the baseline Vineland scores. Both groups showed improvement over the 24-week trial on all Vineland domains. Compared with MED, Vineland Socialization and Adaptive Composite Standard scores showed greater improvement in the COMB group (p = .01 and .05, and effect sizes = 0.35 and 0.22, respectively). On Age Equivalent scores, Socialization and Communication domains showed greater improvement in COMB versus MED (p = .03 and 0.05, and effect sizes = 0.33 and 0.14, respectively). Using logistic regression, children in the COMB group were twice as likely to make at least 6 months' gain (equal to the passage of time) in the Vineland Communication Age Equivalent score compared with MED (p = .02). After controlling for IQ, this difference was no longer significant., Conclusion: Reduction of serious maladaptive behavior promotes improvement in adaptive behavior. Medication plus PT shows modest additional benefit over medication alone. Clinical trial registration information-RUPP PI PDD: Drug and Behavioral Therapy for Children With Pervasive Developmental Disorders; http://www.clinicaltrials.gov; NCT00080145.

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.

Objective: To evaluate the short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder., Method: Two hundred eighteen children and adolescents (aged 6-17 years) with a diagnosis of autistic disorder, and with behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these symptoms, were randomized 1:1:1:1 to aripiprazole (5, 10, or 15 mg/day) or placebo in this 8-week double-blind, randomized, placebo-controlled, parallel-group study. Efficacy was evaluated using the caregiver-rated Aberrant Behavior Checklist Irritability subscale (primary efficacy measure) and the clinician-rated Clinical Global Impressions-Improvement score. Safety and tolerability were also assessed., Results: At week 8, all aripiprazole doses produced significantly greater improvement than placebo in mean Aberrant Behavior Checklist Irritability subscale scores (5 mg/day, -12.4; 10 mg/day, -13.2; 15 mg/day, -14.4; versus placebo, -8.4; all p < .05). All aripiprazole doses demonstrated significantly greater improvements in mean Clinical Global Impressions-Improvement score than placebo at week 8. Discontinuation rates due to adverse events were as follows: placebo 7.7%, aripiprazole 5 mg/day 9.4%, 10 mg/day 13.6%, and 15 mg/day 7.4%. The most common adverse event leading to discontinuation was sedation. There were two serious adverse events: presyncope (5 mg/day) and aggression (10 mg/day). At week 8, mean weight change (last observation carried forward) was as follows: placebo +0.3 kg, aripiprazole 5 mg/day +1.3 kg, 10 mg/day +1.3 kg, and 15 mg/day +1.5 kg; all p < .05 versus placebo., Conclusions: Aripiprazole was efficacious and generally safe and well tolerated in the treatment of children and adolescents with irritability associated with autistic disorder.

Objective: To determine whether impulsive aggression (IA) is a meaningful clinical construct and to ascertain whether it is sufficiently similar across diagnostic categories, such that parallel studies across disorders might constitute appropriate evidence for pursuing indications. If so, how should IA be assessed, pharmacological studies designed, and ethical issues addressed?, Method: Experts from key stakeholder communities, including academic clinicians, researchers, practicing clinicians, U.S. Food and Drug Administration, National Institute of Mental Health, industry sponsors, and patient and family advocates, met for a 2-day consensus conference on November 4 and 5, 2004. After evaluating summary presentations on current research evidence, participants were assigned to three workgroups, examined core issues, and generated consensus guidelines in their areas. Workgroup recommendations were discussed by the whole group to reach consensus, and then further iterated and condensed into this report postconference by the authors., Results: Conference participants agreed that IA is a substantial public health and clinical concern, constitutes a key therapeutic target across multiple disorders, and can be measured with sufficient precision that pharmacological studies are warranted. Additional areas of consensus concerned types of measures, optimal study designs, and ethical imperatives., Conclusion: Derived from scientific evidence and clinical experience, these consensus-driven recommendations can guide the design of future studies.

Objective: To explore placebo-controlled efficacy and safety of atomoxetine (ATX) for attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorders (ASD)., Method: Children ages 5 to 15 with ASD and prominent ADHD symptoms were randomly assigned to order in a crossover of clinically titrated ATX and placebo, 6 weeks each, separated by 1-week washout. Slopes for each condition were compared by paired t test., Results: In 2004-2005, 12 boys and 4 girls (7 with autistic disorder, 1 Asperger's, 8 pervasive developmental disorder not otherwise specified) all completed at least 3 weeks of each condition. On the primary outcome, the Hyperactivity subscale of the Aberrant Behavior Checklist, ATX was superior to placebo (p =.043, effect size d = 0.90). It was also superior on a 0 to 3 rating of nine DSM-IV ADHD hyperactive/impulsive symptoms (p =.005, d = 1.27), but missed significance on nine inattentive symptoms (p =.053, d= 0.89). Nine subjects responded to ATX, four to placebo (25% improvement on the Hyperactivity subscale plus Clinical Global Impressions-Improvement of 1-2. One was rehospitalized for recurrent violence on ATX. Adverse events were otherwise tolerable, with no tendency to stereotypy., Conclusions: ATX appears safe and effective for treating hyperactivity in some children with autism spectrum disorders. The effect appears as large as in a multisite methylphenidate trial in the same population, with fewer intolerable side effects. Further study in autism spectrum disorders is indicated.

Objective: To examine the psychometric properties of the Children's Yale-Brown Obsessive Compulsive Scales (CYBOCS) modified for pervasive developmental disorders (PDDs)., Method: Raters from five Research Units on Pediatric Psychopharmacology (RUPP) Autism Network were trained to reliability. The modified scale (CYBOCS-PDD), which contains only the five Compulsion severity items (range 0-20), was administered to 172 medication-free children (mean 8.2 +/- 2.6 years) with PDD (autistic disorder, n = 152; Asperger's disorder, n = 6; PDD not otherwise specified, n = 14) participating in RUPP clinical trials. Reliability was assessed by intraclass correlation coefficient (ICC) and internal consistency by Cronbach's alpha coefficient. Correlations with ratings of repetitive behavior and disruptive behavior were examined for validity., Results: Eleven raters showed excellent reliability (ICC = 0.97). The mean CYBOCS score was 14.4 (+/- 3.86) with excellent internal consistency (alpha = .85). Correlations with other measures of repetitive behavior ranged from r = 0.11 to r = 0.28 and were similar to correlations with measures of irritability (r = 0.24) and hyperactivity (r = 0.25). Children with higher scores on the CYBOCS-PDD had higher levels of maladaptive behaviors and lower adaptive functioning., Conclusions: The five-item CYBOCS-PDD is reliable, distinct from other measures of repetitive behavior, and sensitive to change.

Objective: To evaluate the impact of risperidone on adaptive behavior in children with autistic disorder who have serious behavior problems and to examine different methods of scoring the Vineland Adaptive Behavior Scales to measure change., Method: Forty-eight children (5 years to 16 years, 5 months) who showed behavioral improvement during acute treatment with risperidone were followed for 6 months and assessed with the Vineland Scales., Results: Raw scores, age-equivalents, and special norm percentile scores all showed significant increases in adaptive behavior in the areas of communication, daily living skills, and socialization (p <.01). During a period of 6 to 8 months, children gained an average of 7.8 age-equivalent months in the area of socialization, a > 6% improvement beyond what would be expected based on baseline growth rates., Conclusions: Although limited by the absence of a control group, these results suggest that risperidone may improve adaptive skills in children with autistic disorder accompanied by serious behavioral problems. Vineland age-equivalent scores appear to be most useful in assessing change with treatment over time.

Objective: Parental permission is required for child research, but parents' understanding of research aims and procedures has not been well documented. Parental research knowledge was assessed during a clinical trial in autism., Method: Parents of 101 children (age 5-17 years) with autism participating in a placebo-controlled trial of risperidone were given a questionnaire at the end of the study., Results: Of the 95 parents completing the questionnaire, 99% knew of possible placebo assignment and that testing the medication efficacy was the main purpose of the investigators; 96% to 98% knew that research involved both risks and potential benefits, identified the study medication, and knew of their right to withdraw at any time; 90% to 95% knew of the medication's main side effects; 87% reported having been informed of possible alternatives to research participation; and 72% were aware that treatment was randomly assigned (whereas 27% reported that treatment was chosen based on individual needs to ensure best care). Parents with a college degree were more likely to recognize the random nature of treatment assignment., Conclusions: Overall, parents were highly knowledgeable of the main research components. About one fourth, however, seemed unaware that treatment was randomly determined and not personalized, suggesting that therapeutic misconception may affect some otherwise well-informed parents.

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.

Objective: To survey the prevalence and patterns of psychotropic and anticonvulsant medication and vitamin treatments in patients with autism., Method: Caregivers of 1,595 index cases were sent survey questionnaires by mail, and repeat questionnaires were sent twice if no reply was received., Results: A total of 838 care providers (53%) responded to the survey. In all, 33.8% of the sample was taking some psychotropic drug or vitamin for autism or associated behavioral/psychiatric problems. A total of 19.2% reported having epilepsy, but only 13.2% were taking anticonvulsant drugs. More than 50% of the sample was taking some psychotropic, antiepileptic, vitamin, or "medical" agent. Of the agents taken, care providers were most satisfied with anticonvulsants, antidepressants, and stimulants. The use of each drug group was analyzed with respect to subject and demographic variables to evaluate medication patterns within this population., Conclusion: As in the often related clinical population of mental retardation, psychotropic medication appears to be heavily used in patients with autism.

Objective: To assess the social importance and personal benefit attached to involvement in drug research for participating families., Method: Parents of children with mental retardation or borderline IQ who took part in two drug studies were surveyed by mail 4 weeks after their involvement. The questionnaire addressed the acceptability of study procedures and satisfaction with study outcomes ("social validity")., Results: Forty (63.5%) of 63 families responded to the survey. In all, 83% felt that their questions were satisfactorily answered regarding the role of medication for their children, and 88% were satisfied with the individual conclusions reached regarding pharmacotherapy for their children. Virtually all parents believed that the study assessments used were important, and 88% indicated that they would join the study again if faced with the same choices., Conclusions: These parents appear to have found the research experience to be of practical benefit to them, and they were generally positive about their experiences. As this seems to be the only published study of the social or perceived validity of drug research, more surveys of this type are needed to assess consumer reactions to a broader array of research experiences.

Each of 28 nonautistic children with attention-deficit hyperactivity disorder and mental retardation received placebo, methylphenidate (0.4 mg/kg/day), and fenfluramine (gradually increased to 1.5 mg/kg/day) for 4 weeks each in a double-blind, crossover design. Teacher ratings indicated significant improvements with both active drugs on subscales designated as Conduct Problem, Hyperactivity, and Irritability, but methylphenidate alone produced improvements on an Inattention subscale. Parent ratings indicated significant improvements with both drugs on subscales labeled Hyperactivity, Motor Excess, and Conduct Problem. Fenfluramine alone caused improved parent ratings on Irritability and Inappropriate Speech, and on Conners' Abbreviated Symptom Questionnaire. Unlike a previous study, subgroup analyses failed to show a significantly better clinical response to methylphenidate for subjects with higher mental ages, although children with higher IQs responded better than those with IQs less than 45. The active drugs had contrasting effects on heart rate and blood pressure. Fenfluramine caused significant weight reductions relative to both placebo and methylphenidate. These findings suggest that both methylphenidate and fenfluramine have useful, but somewhat different, clinical effects in certain children with attention-deficit hyperactivity disorder and mental retardation.

Twenty-seven children (or smaller subgroups depending upon task difficulty and subject ability) with subaverage IQs took part in a double-blind, placebo-controlled, cross-over study of methylphenidate (0.4 mg/kg/day) and thioridazine (1.75 mg/kg/day). The children were tested for IQ performance, breadth of attention, and performance on a series of electronically controlled cognitive-motor tests. Methylphenidate improved accuracy on a memory task, reduced omission errors on an attentional task, and reduced seat movements on two tasks. Thioridazine failed to have any deleterious effects on IQ performance when subjects received reinforcers for correct answers. Thioridazine at the given dose did not adversely affect performance on any of the cognitive-motor performance tests. Methylphenidate appears likely to enhance sustained attention and motivation in appropriately selected children with mild developmental delays, whereas thioridazine at this modest dose does not appear to impair performance on most psychomotor tests.

Thirty children with subaverage IQs and psychiatric diagnoses of attention deficit disorder and/or or conduct disorder took part in a double-blind study of placebo, methylphenidate, and thioridazine, which were given for 3 weeks each. The results showed a consistent and highly significant effect of methylphenidate in reducing teacher ratings of problem behavior. Parent ratings showed no behavioral effects for the group as a whole. An attentional model of stimulant drug response was used to divide subjects according to a cognitive maturity domain presumed to reflect selective attention. When divided according to breadth of attention, mental age, and IQ level, higher functioning subjects were found to show a generally favorable response to methylphenidate on both teacher and parent rating scales, whereas children of low functional level typically showed an adverse or indifferent response. The present data suggest that mental age and IQ may be important determinants of drug response; below a given level, there was a greatly reduced likelihood of responding positively. Clinical response to thioridazine was substantially less than the response to methylphenidate, with significant improvements confined to conduct and hyperactivity problems on teacher ratings.

Fenfluramine, a serotonin reducing agent, has been the subject of intense research effort in recent years. A variety of biochemical studies summarized suggest that some autistic children and many nonautistic severely retarded individuals have elevated blood serotonin concentrations. The research on fenfluramine's clinical efficacy is thoroughly reviewed from a methodological perspective. All studies assessing the drug's effects on blood serotonin have observed reductions in whole blood serotonin to about 50% of baseline concentrations. Although there were early reports of drug enhancement of IQ, there is no good evidence that this is the case. However, there are data to suggest that fenfluramine may enhance social relatedness, reduce stereotypic behavior, lessen overactivity, and improve attention span in some autistic children, although these results do not appear consistently across studies. The animal literature on the neurotoxicity of fenfluramine is reviewed, and a number of limitations in this research are identified that raise questions about its relevance to the pharmacotherapy of children.