Michael G. Aman - US grants

human therapy evaluation; mental disorder chemotherapy; methylphenidate; attention deficit disorder; fenfluramine; mental retardation; cognition; behavior test; drug adverse effect; serotonin; child (0-11); human subject;

[unreadable] DESCRIPTION (provided by applicant): Pervasive Developmental Disorders (PDDs) are serious developmental conditions affecting 6 per 1000 school-age children. We propose a multisite study in which 120 children with PDDs accompanied by highly irritable behavior will be randomly assigned to risperidone only (N=40) or risperidone plus a structured behavior therapy program (N=80) and compared on adaptive and behavioral outcomes after 16 weeks. After an additional eight weeks of stabilization (6 months total), children who show a positive response to the combination of risperidone and behavior therapy (estimated samples size of 60) will be randomized to continued treatment with risperidone or gradual discontinuation. The goal of the discontinuation phase is to examine whether the addition of behavior therapy permits discontinuation of risperidone without relapse. PDD can be a profound disability across social, emotional, and academic domains. Thus, there is a pressing need for new treatments in PDD that are safe and effective. In a previous RUPP Autism Network study, we showed that risperidone was safe and effective for children and adolescents with autism accompanied by tantrums, aggression, and/or self-injury. We also showed that the behavioral symptoms rapidly returned in a high percentage of these pediatric patients when the medication was withdrawn in a placebo-controlled discontinuation study. The present study will extend these findings and will test whether risperidone plus behavior therapy will enhance adaptive functioning in children with PDDs and protect against relapse. Side effects and therapeutic response will be carefully monitored. Subjects will be genotyped in order to evaluate the relationship of specific serotonin receptor genotypes and treatment response. The proposed study will be conducted by a multisite network that has already shown the capacity to collaborate in the design and conduct of clinical trials in the PDD population. Furthermore, this five-site network has established reliability on several measures relevant to the multi-site clinical trials in children with PDD. O.S.U. also plans two pilot studies: (a) a randomized clinical trial in 60 children with PDDs and severe ADHD behavior and (b) a study of ziprasidone in 30 children and adolescents with PDDs and highly irritable behaviors.

children; human therapy evaluation; methylphenidate; pediatric pharmacology; drug screening /evaluation; impulsive behavior; attention deficit disorder; oppositional defiant disorder; dopamine receptor; clinical research; human subject; intelligence tests;

risperidone; antipsychotic agents; saliva; pediatric pharmacology; pharmacokinetics; blood chemistry; drug metabolism; drug screening /evaluation; conduct disorder; preschool child (1-5); middle childhood (6-11); diagnosis design /evaluation; schizophrenia; aggression; autism; liquid chromatography mass spectrometry; human subject; clinical research;

[unreadable] DESCRIPTION (provided by applicant): Disruptive behavior disorders (DBDs; conduct disorder and oppositional-defiant disorder) with severe aggression constitute a public health problem for which evidence-based treatment options are limited. Increasing numbers of youth with aggression are being treated with atypical antipsychotics without good evidence of safety or incremental advantage over safer stimulants. This double-blind, placebo-controlled, parallel groups study will compare the effectiveness of (a) parent training in behavior management (PMT) + placebo (PBO), (b) PMT + d-methylphenidate (d-MPH), and (c) PMT + d-MPH + risperidone (RIS) in children with severe aggression, primary DBDs, and comorbid ADHD. Participants must exhibit a clear history and current pattern of serious physical aggression (i.e., moderate or higher scores on the Modified Overt Aggression Scale (OAS-M), a Clinical Global Impressions (CGI) Scale Severity score of 4 or higher for aggression), and high scores on the on the Disruptive-Total of the Nisonger Child Behavior Rating Form (NCBRF) . The primary aims are to determine (a) if PMT + d-MPH are superior to PMT+ PBO and (b) if PMT + d-MPH + RIS are superior to PMT + d-MPH and to PMT + PBO. Secondary aims include determining whether type of aggression (reactive vs. proactive) moderates treatment response. Design: Two hundred sixteen children across 4 sites (Case Western Reserve, Ohio State, Pittsburgh, & Stony Brook) will be randomized to 9 weeks double-blind of PMT + PBO (n=72), PMT + MPH (n=72), or PMT + MPH + RIS (n=72). All groups will receive a 12-session course of carefully monitored, empirically-based PMT. Responders will be followed on their assigned treatments in a 12-week Extension, and all participants will be assessed at one year after baseline. Clinical change will be measured by (a) parent ratings on the NCBRF & ADHD Symptom Checklist (CL) ; (b) teacher ratings on the ADHD Symptom CL; (c) clinician interview of the child with OAS-M; (d) clinician CGI-Improvement score (CGI-I); and direct observations of child-parent behavior. The primary outcome measure is the NCBRF Disruptive Total score; secondary outcomes are CGI-I, response rate (NCBRF reduction of at least 25%, plus CGI-I score of 1 or 2), other NCBRF and ADHD Symptom Checklist subscales, and cognitive tests. Baseline score on the Antisocial Behavior Scale will assess type of aggression (reactive or proactive) as a potential moderator. AEs and tolerability will also be assessed. This study will assess the use of placebo, d-methylphenidate (Focalin), and d-methylphenidate plus risperidone (an atypical antipsychotic drug; brand name Risperdal) against the back-drop of behavior therapy which will be taught to the parents of participants. The participants will be children ages 6 to 12 years, inclusive, who have been diagnosed with a disruptive behavior disorder plus ADHD and who display significant aggressive behavior. Given the increasing rates and severity of violence in our society, this investigation will help to determine if drug therapy, combined with parent-provided behavior therapy, can reduce child aggression. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): There have been relatively few randomized clinical trials of pharmacology for attention-deficit/hyperactivity (ADHD) in children with Autism Spectrum Disorders (ASD). Studies involving stimulant medications have generally found poorer response rates and higher rates of intolerable side effects than in typically developing children with ADHD. Atomoxetine (Strattera) was approved by the FDA in January 2003 for treatment of ADHD. A nonstimulant, it inhibits the presynaptic norephinephrine transporter. There have been only four studies (three open and one small double-blind) examining this medication in children with ASD. Behavioral treatments, such as training parents in the use of behavioral interventions (PMT), are also standard treatments for ADHD in typically developing children. While PMT also has long been used in ASD, it has rarely been studied in combination with psychopharmacologic treatment in this population. This proposal addresses four objectives: a) to conduct a double-blind, placebo-controlled, 10-week parallel-group comparison of atomoxetine (ATX) versus placebo on i) clinician- and parent-rated behavior, ii) direct observations of behavior, iii) cognitive/performance measures of attention, and iv) adverse events in 156 children with ASD (78 treated with ATX, 78 with placebo); b) to conduct a 10-week parallel-group comparison of PMT versus no-PMT on behavioral measures of compliance in 156 children with ASD (78 with PMT, 78 without PMT) c) to conduct a 10-week parallel-group comparison of combined (ATX plus PMT) vs. single treatment (PMT alone) on measures of compliance in 156 children with ASD; and d) to compare the long-term maintenance of efficacy, safety, and tolerability of ATX and PMT via an open-label 6-month extension trial of responders. Medication doses will be titrated against benefit and side effects over the first 6 weeks (ATX to a cap of 1.8 mg/kg/day). PMT will be 10 sessions, 1-1.5 hr. each, modeled on the RUPP Autism Network PMT. Data analyses will capitalize on the power of a 2 x 2 analysis where appropriate. Children with ASD have been neglected in pharmacological research, placing an enormous burden on health care and educational systems. This trial has the potential to provide answers regarding optimal treatment (both psychosocial and pharmacological) for a sizeable subgroup of children with ASD who experience symptoms of over activity and inattention. [unreadable] [unreadable] [unreadable]

0-11 years old; 4H-Pyrido(1,2-a)pyrimidin-4-one, 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl)-6 ,7,8,9-tetrahydro-2-methyl-; Active Follow-up; Adaptive Behaviors; Aggression; Aggressive behavior; Behavior Conditioning Therapy; Behavior Modification; Behavior Therapy; Behavior Treatment; Behavior or Life Style Modifications; Behavioral Conditioning Therapy; Behavioral Modification; Behavioral Therapy; Behavioral Treatment; Behaviors, Adaptive; CRISP; Child; Child Youth; Children (0-21); Clinical Trials; Clinical Trials, Unspecified; Compliant Behaviors; Computer Retrieval of Information on Scientific Projects Database; Conditioning Therapy; Controlled Clinical Trials, Randomized; Daily; Deliberate Self-Harm; Drugs; Funding; Grant; Human, Child; Institution; Investigators; Life; Life Style Modification; Measures; Medication; NIH; National Institutes of Health; National Institutes of Health (U.S.); Parents; Pharmaceutic Preparations; Pharmaceutical Preparations; Randomized Controlled Clinical Trials; Rate; Relapse; Research; Research Personnel; Research Resources; Researchers; Resources; Risperidone; Self-Injurious Behavior; Source; Training; United States National Institutes of Health; Week; adaptation behavior; adaptive behavior; behavior intervention; behavioral intervention; children; clinical investigation; deliberate self harm; discontinuation study; discontinuation trial; drug/agent; follow-up; intentional self harm; intentional self injury; randomized trial; resperidone; self harm; self injury; skills; treatment effect; youngster