Bhavik Shah

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder

OBJECTIVE To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. METHOD Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. RESULTS When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. CONCLUSIONS Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

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.

Gastrointestinal Symptoms in a Sample of Children with Pervasive Developmental Disorders

Objective To evaluate gastrointestinal (GI) problems in a large, well-characterized sample of children with pervasive developmental disorders (PDDs). Methods One hundred seventy two children entering one of two trials conducted by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network were assessed comprehensively prior to starting treatment and classified with regard to GI symptoms. Results Thirty nine (22.7%) were positive for GI problems, primarily constipation and diarrhea. Those with GI problems were no different from subjects without GI problems in demographic characteristics, measures of adaptive functioning, or autism symptom severity. Compared to children without GI problems, those with GI problems showed greater symptom severity on measures of irritability, anxiety, and social withdrawal. Those with GI problems were also less likely to respond to treatment.

Effects of Short- and Long-Term Risperidone Treatment on Prolactin Levels in Children with Autism

BACKGROUND The effects of short- and long-term risperidone treatment on serum prolactin were assessed in children and adolescents with autism. METHODS Patients with autism (N = 101, 5-17 years of age) were randomized to an 8-week trial of risperidone or placebo and 63 then took part in a 4-month open-label follow-up phase. Serum samples were obtained at Baseline and Week-8 (N = 78), and at 6-month (N = 43) and 22-month (N = 30) follow-up. Serum prolactin was determined by immunoradiometric assay; dopamine type-2 receptor (DRD2) polymorphisms were genotyped. RESULTS Baseline prolactin levels were similar in the risperidone (N = 42) and placebo (N = 36) groups (9.3 +/- 7.5 and 9.3 +/- 7.6 ng/ml, respectively). After 8 weeks of risperidone, prolactin increased to 39.0 +/- 19.2 ng/ml, compared with 10.1 +/- 8.8 ng/ml for placebo (p < .0001). Prolactin levels were also significantly increased at 6 months (32.4 +/- 17.8 ng/ml; N = 43, p < .0001) and at 22 months (N = 30, 25.3 +/- 15.6 ng/ml, p < .0001). Prolactin levels were not associated with adverse effects and DRD2 alleles (Taq1A, -141C Ins/Del, C957T) did not significantly influence baseline levels or risperidone-induced increases in prolactin. CONCLUSIONS Risperidone treatment was associated with two- to four-fold mean increases in serum prolactin in children with autism. Although risperidone-induced increases tended to diminish with time, further research on the consequences of long-term prolactin elevations in children and adolescents is needed.

Psychiatric disorders in Prader-Willi syndrome: epidemiology and management.

Although people with intellectual disabilities are at increased risk for psychiatric disorders, the type and rate of these problems differ between those with different causes for their retardation. In this paper, we review behavioural and psychiatric problems in persons with Prader-Willi syndrome, a disorder caused by a paternally derived deletion at chromosome 15(q11-q13) in about 70% of affected patients, and by maternal uniparental disomy in the majority of the remaining patients.In addition to the syndrome’s characteristic hyperphagia and food seeking, individuals with Prader-Willi syndrome also have increased risks of nonfood, compulsive behaviours. These include skin picking, which is highly prevalent, as well as more variable rates of hoarding, redoing and concerns with symmetry, exactness, cleanliness, ordering and arranging. Relative to others with mental retardation, persons with Prader-Willi syndrome are at a marked increased risk for developing full-blown, obsessive-compulsive disorder. In addition, many people with Prader-Willi syndrome show increased rates of tantrums, oppositionality and aggression. Recent findings suggest that they also have an increased risk of psychotic disorder or affective illness with a psychotic component, especially young adult patients and those with the maternal uniparental disomy as opposed to paternal deletion.Dietary approaches include a reduced-calorie diet and increased physical activity, as well as close supervision around food and keeping food locked away. To date, neither CNS stimulants nor anorectic agents have been effective in treating hyperphagia, in part because hyperphagia in Prader-Willi syndrome is attributed to decreased satiation as opposed to increased hunger.Treatment for compulsivity and maladaptive behaviours include: behavioural programming; a structured, predictable routine; extra help with transitions; family support; and pharmacotherapy.Although formal drug studies have yet to be conducted, SSRIs have been effective in reducing skin picking, compulsivity and aggressive episodes in some individuals with Prader-Willi syndrome. Atypical antipsychotics have also proven helpful in persons with psychotic features or extreme aggression and impulsivity. Largely on the basis of case studies, the risks and benefits of these and other drugs in Prader-Willi syndrome are reviewed. Drug trials that move beyond case studies and that assess the relative efficacy of behavioural treatments alone or in combination with pharmacotherapy are sorely needed.

Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders : An analysis of secondary measures

BACKGROUND Methylphenidate has been shown elsewhere to improve hyperactivity in about half of treated children who have pervasive developmental disorders (PDD) and significant hyperactive-inattentive symptoms. We present secondary analyses to better define the scope of effects of methylphenidate on symptoms that define attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), as well as the core autistic symptom domain of repetitive behavior. METHODS Sixty-six children (mean age 7.5 y) with autistic disorder, Aspergers disorder, and PDD not otherwise specified, were randomized to varying sequences of placebo and three different doses of methylphenidate during a 4-week blinded, crossover study. Methylphenidate doses used approximated .125, .25, and .5 mg/kg per dose, twice daily, with an additional half-dose in the late afternoon. Outcome measures included the Swanson, Nolan, and Pelham Questionnaire revised for DSM-IV (ADHD and ODD scales) and the Childrens Yale-Brown Obsessive Compulsive Scales for PDD. RESULTS Methylphenidate was associated with significant improvement that was most evident at the .25- and .5-mg/kg doses. Hyperactivity and impulsivity improved more than inattention. There were not significant effects on ODD or stereotyped and repetitive behavior. CONCLUSIONS Convergent evidence from different assessments and raters confirms methylphenidates efficacy in relieving ADHD symptoms in some children with PDD. Optimal dose analyses suggested significant interindividual variability in dose response.

Mental Retardation: A Review of the Past 10 Years. Part II

OBJECTIVE To review the literature over the past decade on mental retardation, particularly as regards its definition, prevalence, major causes, and associated mental disorders. METHOD A computerized search was performed for articles published in the past decade, and selected papers were highlighted. RESULTS The study of mental retardation has benefited considerably by advances in medicine generally and by developments in molecular neurobiology in particular. Increasing awareness of psychiatric comorbidity in the context of intellectual disability highlights the need for studies of the phenomenology and treatment of mental disorders in this population. CONCLUSIONS Although the study of developmental disorders has advanced significantly over the past decade, considerable work remains. Mental retardation is a model for the utility of the biopsychosocial approach in medicine.

Extended-Release Guanfacine for Hyperactivity in Children With Autism Spectrum Disorder

OBJECTIVE Hyperactivity, impulsiveness, and distractibility are common problems in children with autism spectrum disorder (ASD). Extended-release guanfacine is approved for children with attention deficit hyperactivity disorder but not well studied in ASD. METHOD In a multisite, randomized clinical trial, extended-release guanfacine was compared with placebo in children with ASD accompanied by hyperactivity, impulsiveness, and distractibility. RESULTS Sixty-two subjects (boys, N=53; girls, N=9; mean age=8.5 years [SD=2.25]) were randomly assigned to guanfacine (N=30) or placebo (N=32) for 8 weeks. The guanfacine group showed a 43.6% decline in scores on the Aberrant Behavior Checklist-hyperactivity subscale (least squares mean from 34.2 to 19.3) compared with a 13.2% decrease in the placebo group (least squares mean from 34.2 to 29.7; effect size=1.67). The rate of positive response (much improved or very much improved on the Clinical Global Impression-Improvement scale) was 50% (15 of 30) for guanfacine compared with 9.4% (3 of 32) for placebo. A brief cognitive battery tapping working memory and motor planning showed no group differences before or after 8 weeks of treatment. The modal dose of guanfacine at week 8 was 3 mg/day (range: 1-4 mg/day), and the modal dose was 3 mg/day (range: 2-4 mg/day) for placebo. Four guanfacine-treated subjects (13.3%) and four placebo subjects (12.5%) exited the study before week 8. The most common adverse events included drowsiness, fatigue, and decreased appetite. There were no significant changes on ECG in either group. For subjects in the guanfacine group, blood pressure declined in the first 4 weeks, with return nearly to baseline by endpoint (week 8). Pulse rate showed a similar pattern but remained lower than baseline at endpoint. CONCLUSIONS Extended-release guanfacine appears to be safe and effective for reducing hyperactivity, impulsiveness, and distractibility in children with ASD.

Eating Themselves to Death: Have “Personal Rights” Gone Too Far in Treating People With Prader-Willi Syndrome?

In contrast to even a decade ago, giant steps have been made toward increased community inclusion, choice, and self-determination for persons with mental retardation. As workers put these goals into practice, they are sometimes faced with uncomfortable exceptions to the rule: persons for whom increased decision-making leads to unhealthy and even life-threatening consequences. Prader-Willi syndrome is one such exception.

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders

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<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH’s efficacy and tolerability.