Treating autistic spectrum disorders in children: utility of the cholinesterase inhibitor rivastigmine tartrate

Rivastigmine tartrate is a dual-action cholinesterase inhibitor shown to improve language, cognition, and global functioning in patients with Alzheimer's disease, likely via increased availability of cerebral acetylcholine. Because cholinergic receptor abnormalities can contribute to the neuropathology of autistic spectrum disorders, rivastigmine tartrate could prove to be an effective therapy for affected children. Observations of improved behavior and language output from prior open-label and double-blind treatment of autistic children with donepezil, another cholinesterase inhibitor, prompted this 12-week open-label study with rivastigmine tartrate of 32 autistic patients. Therapeutic indices were the Childhood Autistic Rating Scale, Gardner's Expressive and Receptive One-Word Picture Vocabulary tests, and the Conners' Parent Rating Scale. Testing administered at baseline, 6 weeks, and 12 weeks showed gains in both expressive speech and overall autistic behavior over baseline. These improvements were statistically significant and supported the hypothesis that treatment with cholinergic enhancing drugs in autistic spectrum disorders yields positive therapeutic effects.     

The relationship of depression to social skills and intellectual functioning in mentally retarded adults

ABSTRACT. Ninety-nine mild to severely mentally retarded adults were evaluated on a variety of measures. The battery included the Peabody Picture Vocabulary Test Revised (PPVT), the Psychopathology Instrument for Mentally Retarded Adults, the Social Performance Survey Schedule, Hamilton Rating Scale of Depression, the Beck Depression Inventory and Zung Self-Rating Depression Scale. Depression and social skills measures correlated significantly with each other on self-report and informant reports. Receptive vocabulary did not significantly correlate with depression or social skills measures, irrespective of self or other report format. Additionally, demographic variables such as intellectual level were not significant. The PPVT mean scores differed significantly by level of mental retardation as might be expected. The significance of these data and their implication for further study are reviewed.     

Development and Validation of an Inventory to Assess Mealtime Behavior Problems in Children with Autism

To date, no standardized measures have been developed to evaluate the mealtime behavior of children with autism. The Brief Autism Mealtime Behavior Inventory (BAMBI) was designed to measure mealtime behavior problems observed in children with autism. Caregivers of 40 typically developing children and 68 children with autism completed the BAMBI, the Behavioral Pediatric Feeding Assessment Scale (BPFAS), the Gilliam Autism Rating Scale (GARS), the Youth/Adolescent Questionnaire (YAQ), and a 24-hour recall interview. The BAMBI demonstrated good internal consistency, high test–retest reliability, a clear factor structure, and strong construct and criterion-related validity in the measurement of mealtime behavior problems in children with autism.     

Does Parent Report of Behavior Differ Across ADOS-G Classifications: Analysis of Scores from the CBCL and GARS

Behavior checklists are often utilized to screen for Autism Spectrum Disorders (ASDs) when comprehensive evaluations are unfeasible. The usefulness of two behavioral checklists, the Gilliam Autism Rating Scale (GARS) and Child Behavior Checklist (CBCL), in identifying ASDs was investigated among 109 children with Autism, 32 children with ASD, and 51 Non-Spectrum children based on Autism Diagnostic Observation Schedule-Generic classifications. The GARS did not distinguish children with ASDs from those without. The Withdrawn and Pervasive Developmental Problems subscales of the CBCL were higher among children with Autism than among Non-Spectrum children. These CBCL subscales also had better sensitivity and specificity in identifying children with Autism than the GARS. Results suggest that the CBCL is a useful behavioral checklist for screening ASDs.     

Differential effects of early hemisphere damage on lexical comprehension and production

Abstract

The effects of early hemisphere damage on lexical development were investigated in 33 children with unilateral left (n = 21) or right (n = 12) hemisphere damage and 16 normal healthy controls. Single-word naming was assessed using the Expressive One-Word Picture Vocabulary Test (EOW) and lexical comprehension was assessed using the Peabody Picture Vocabulary Test-Revised (PPVT-R). Left lesion subjects (LL) performed comparable to controls in naming, but scored lower than controls on the PPVT-R. Right lesion subjects (RL) scored lower than controls and LL subjects on both the EOW and the PPVT-R. The unexpected superiority of LL in comparison to RL children on the EOW and the PPVT-R argues against a simple left hemisphere dominance for early lexical development. RL subjects' significant comprehension deficits failed to correlate with more general measures of verbal intelligence, supporting a specialized role of the right hemisphere in mediating the acquisition of word meaning.     

Digestive Enzyme Supplementation for Autism Spectrum Disorders: A Double-Blind Randomized Controlled Trial

To examine the effects of a digestive enzyme supplement in improving expressive language, behaviour and other symptoms in children with Autism Spectrum Disorder. Randomized, double-blind placebo-controlled trial using crossover design over 6 months for 43 children, aged 3–8 years. Outcome measurement tools included monthly Global Behaviour Rating Scales, Additional Rating Scales of other symptoms by parents and therapists, and monthly completion of the Rescorla Language Development Survey. Compared with placebo, treatment with enzyme was not associated with clinically significant improvement in behaviour, food variety, gastrointestinal symptoms, sleep quality, engagement with therapist, or the Language Development Survey Vocabulary or Sentence Complexity Scores. A small statistically significant improvement on enzyme therapy was seen for the food variety scores. No clinically significant effect improvement of autism symptoms with enzyme use was shown with this trial, however, possible effects on improvement in food variety warrants further detailed investigation.     

Perspective-taking ability and its relationship to the social behavior of autistic children

A study was undertaken to assess the relationship between perspective-taking ability and the quality of social behavior in autistic children. Sixteen autistic children ranging from 6 to 14 years of age were administered three types of perspective-taking tasks (perceptual, conceptual, and affective), as well as the Peabody Picture Vocabulary Test and the Leiter International Performance Scale. Two measures of social behavior were taken: the Vineland Social Maturity Scale and the Social Behavior Rating Scale, designed for the present study. It was found that perspective-taking ability was significantly correlated with both measures of social skills, whereas receptive vocabulary and nonverbal intelligence were not. These results suggest that the social impairments of autistic children may be related to specific deficits in social cognition.     

Risperidone in children with autism: randomized, placebo-controlled, double-blind study

Some open-label studies suggest that risperidone can be useful in the treatment of certain target symptoms in children with autism. We aimed to study whether the use of risperidone in comparison with placebo improved functioning in children with autism with regard to behavior (aggressiveness, hyperactivity, irritability), social and emotional responsiveness, and communication skills. We conducted a randomized, double-blind, placebo-controlled trial with 40 consecutive children with autism, whose ages ranged from 2 to 9 years, who were receiving either risperidone or placebo given orally at a dose of 1 mg/day for 6 months. Autism symptoms were monitored periodically. The outcome variables were total scores on the Childhood Autism Rating Scale (CARS) and the Children's Global Assessment Scale (CGAS) after 6 months. Of the 40 children enrolled, 39 completed the trial over a period of 18 months; 19 received risperidone, and 20 received placebo. In the risperidone group, 12 of 19 children showed improvement in the total Childhood Autism Rating Scale score and 17 of 19 children in the Children's Global Assessment Scale score compared with 0 of 20 children for the Childhood Autism Rating Scale score and 2 of 20 children for the Children's Global Assessment Scale score in the placebo group (P < .001 and P = .035, respectively). Risperidone also improved social responsiveness and nonverbal communication and reduced the symptoms of hyperactivity and aggression. Risperidone was associated with increased appetite and a mild weight gain, mild sedation in 20%, and transient dyskinesias in three children. Risperidone improved global functioning and social responsiveness while reducing hyperactivity and aggression in children with autism and was well tolerated.     

Comparison of Scores on the Checklist for Autism Spectrum Disorder,Childhood Autism Rating Scale,and Gilliam Asperger’s Disorder Scale for Children with Low Functioning Autism,High Functioning Autism,Asperger’s Disorder,ADHD, and Typical Development

Reliability and validity for three autism instruments were compared for 190 children with low functioning autism (LFA), 190 children with high functioning autism or Asperger’s disorder (HFA), 76 children with attention deficit hyperactivity disorder (ADHD), and 64 typical children. The instruments were the Checklist for Autism Spectrum Disorder (designed for children with LFA and HFA), Childhood Autism Rating Scale (CARS) for children with LFA, and Gilliam Asperger’s Disorder Scale (GADS). For children with LFA or ADHD, classification accuracy was 100% for the Checklist and 98% for the CARS clinician scores. For children with HFA or ADHD, classification accuracy was 99% for the Checklist and 93% for the GADS clinician scores. Clinician–parent diagnostic agreement was high (90% Checklist, 90% CARS, and 84% GADS).     

An Assessment of the Pictorial Test of Intelligence for Use with Young Cerebral-palsied Children

In order to determine the concurrent and predictive validity of the Pictorial Test of Intelligence for use with cerebral-palsied children, this test was administered to 46 cerebral-palsied children aged between four and seven years, together with the Columbia Mental Maturity Scale and Peabody Picture Vocabulary Test. The results, compared with a classroom Achievement Rating Scale, showed the Pictorial Test of Intelligence to be superior to the other two tests as a predictor of classroom achievement of the children in this study.     

Abnormal brain protein synthesis in language areas of children with pervasive developmental disorder: a L-[1-11C]-leucine PET study

This study was performed to evaluate the cerebral protein synthesis rate of language brain regions in children with developmental delay with and without pervasive developmental disorder. The authors performed L-[1-(11)C]-leucine positron emission tomography (PET) on 8 developmental delay children with pervasive developmental disorder (mean age, 76.25 months) and 8 developmental delay children without pervasive developmental disorder (mean age, 77.63 months). They found a higher protein synthesis rate in developmental delay children with pervasive developmental disorder in the left posterior middle temporal region (P = .014). There was a significant correlation of the Gilliam Autism Rating Scale autism index score with the protein synthesis rate of the left posterior middle temporal region (r = .496, P = .05). In addition, significant asymmetric protein synthesis (right > left) was observed in developmental delay children without pervasive developmental disorder in the middle frontal and posterior middle temporal regions (P = .03 and P = .04, respectively). In conclusion, abnormal language area protein synthesis in developmentally delayed children may be related to pervasive symptoms.     

Parental Report of Sleep Problems in Children with Autism

This research evaluated parent reports of sleep behaviors of four groups of children: those with Autism or Pervasive Developmental Disorders, those with General Mental Retardation alone, those attending Special Education classes (with no MR diagnosis), and a control group of similar aged children without a developmental diagnosis. Diagnostic classification and demographic information were determined through parent report, report of classroom registration, and the Gilliam Autism Rating Scale (Gilliam, 1995). To evaluate sleeping behavior the study used a 28-item, five-factor scale (Behavioral Evaluation of Disorders of Sleep/BEDS; Schreck, 1997/1998) constructed from the diagnostic criteria for childhood sleep disorders found in the International Classification of Sleep Disorders: Diagnostic and Coding Manual (ICSD, American Sleep Disorders Association, 1990). Findings suggest that reports of parents with children with autistic characteristics exhibit expected quantities of sleep, but parent perception of their sleep difficulties and sleep quality is different for children with autism than for children in all other study groups.     

Behavioral relationship between autism and fragile x syndrome

Previous researchers have reported autistic features in children with fragile X syndrome. We compared 21 children with pervasive developmental disorders (autism group) to 15 with fragile X syndrome on the Childhood Autism Rating Scale and the Reiss Scales for Children's Dual Diagnosis. The 7 children (47%) with fragile X who scored above the Childhood Autism Rating Scale cut-off (fragile X-autism group) were more impaired than the remaining children (fragile X-no autism) on Childhood Autism Rating Scale subscales related to emotion, visual and listening responses, and communication. The autism group's Reiss scores were higher than fragile X-no autism group, but not fragile X-autism group. Although the Childhood Autism Rating Scale identified almost 50% of children with fragile X as having autism, qualitative differences may exist in specific autistic-like behaviors between children with autism and children with fragile X.     

Do Children and Adolescents With ADHD Respond Differently to Atomoxetine?

OBJECTIVE: Controversy exists over changes in tolerability and response to medications across the life span. Here the authors report data contrasting the efficacy and tolerability of atomoxetine between children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD: Data were analyzed for children ages 6-11 (510 atomoxetine, 341 placebo) and adolescents ages 12-17 (107 atomoxetine, 69 placebo) with DSM-IV-defined ADHD enrolled in similarly designed, double-blind, placebo-controlled trials. Efficacy measures included response rates, times to response, and mean changes from baseline to endpoint in the ADHD Rating Scale, Conners' Parent Rating Scale, and Clinical Global Impressions. RESULTS: Adolescents had lower baseline ADHD scores compared with children. There were no statistically significant differences in the overall effects on ADHD symptoms, response rates, or time to response between age groups. Children, but not adolescents, had higher rates of somnolence and headache relative to placebo. No other clinically meaningful treatment differences were seen in adverse event rates, vital signs, weight, height, laboratory values, or ECG between children and adolescents. CONCLUSIONS: Acute atomoxetine treatment appears to be equally effective and tolerated in children and adolescents. These findings suggest that pharmacological differences in tolerability or ADHD symptom response are negligible between children and adolescents.     

Utility of the Gilliam Autism Rating Scale in research and clinical populations

The Gilliam Autism Rating Scale (GARS) was developed as a relatively easy, inexpensive aid in the surveillance and diagnosis of autism. This study examined the validity of the GARS when used with a sample of 119 children with strict DSM-IV diagnoses of autism, ascertained from both clinical and research settings. The GARS consistently underestimated the likelihood that autistic children in this sample would be classified as having autism. The sample mean for the Autism Quotient, a hypothesized index of the likelihood of having autism, was 90.10, significantly below the reference mean of 100. Diagnostic classification according to criteria specified by the GARS resulted in a sensitivity of only .48. Limitations of rating scales in general and of the GARS specifically are discussed. It is recommended that clinicians and researchers using or considering using the GARS for autism diagnosis or ratings of autism severity recognize the need for further research regarding its use.     

A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder

OBJECTIVE: To assess the efficacy of topiramate monotherapy for acute mania in children and adolescents with bipolar disorder type I. METHOD: This double-blind, placebo-controlled study was discontinued early when adult mania trials with topiramate failed to show efficacy. Efficacy end points included the Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale for Children, Children's Depression Rating Scale, Children's Global Assessment Scale, and Clinical Global Impressions-Improvement. RESULTS: Fifty-six children and adolescents (6-17 years) with a diagnosis of bipolar disorder type I received topiramate (n=29, 52%) or placebo (n=27, 48%). The only statistically significant differences in efficacy measures between treatment groups were the difference between slopes of the linear mean profiles of the YMRS (p=.003) using a post hoc repeated measures regression and the change in Brief Psychiatric Rating Scale for Children at day 28 (-14.9 versus-5.9, p=.048) using observed data. Adverse events with topiramate included decreased appetite, nausea, diarrhea, and paresthesia. CONCLUSIONS: Topiramate was well tolerated; however, the results are inconclusive because of premature termination resulting in a limited sample size. Adequately powered controlled trials are necessary to determine whether topiramate has efficacy in reducing symptoms of acute mania in children and adolescents.     

Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study

OBJECTIVE: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD). METHODS: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog). RESULTS: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale.There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. CONCLUSIONS: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.     

Examining the Relationship between Executive Functions and Restricted,Repetitive Symptoms of Autistic Disorder

The executive function theory was utilized to examine the relationship between cognitive process and the restricted, repetitive symptoms of Autistic Disorder (AD). Seventeen adults with AD were compared to 17 nonautistic controls on a new executive function battery (Delis-Kaplin Executive Function Scales). Restricted, repetitive symptoms were measured by a variety of instruments (i.e., the Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, Gilliam Autism Rating Scale, and the Aberrant Behavior Checklist). The study replicated the executive function profile that has been reported in adults with AD. In addition to the replication findings, the study found several executive processes (i.e., cognitive flexibility, working memory, and response inhibition) were highly related to the restrictive, repetitive symptoms of AD; whereas, other executive process (i.e., planning and fluency) were not found to be significantly correlated with restricted, repetitive symptoms. Similarly, we found an executive function model consisting of relative strengths and deficits was the best predictor of restricted, repetitive symptoms of autism. The implications for the executive function theory and how the theory predicts core symptoms of autism are discussed.     

A0001 in Friedreich ataxia: Biochemical characterization and effects in a clinical trial

This study tested the ability of A0001 (α-tocopheryl quinone; EPI-A0001), a potent antioxidant, to improve in vitro measures, glucose metabolism, and neurological function in Friedreich ataxia. We used an in vitro study of protection from cell toxicity followed by a double-blind, randomized, placebo-controlled trial of 2 doses of A0001 in 31 adults with Friedreich ataxia. The primary clinical trial outcome was the Disposition Index, a measure of diabetic tendency, from a frequently sampled intravenous glucose tolerance test, evaluated 4 weeks into therapy. Secondary neurologic measures included the Friedreich Ataxia Rating Scale. A0001 potently inhibited cell death in Friedreich ataxia models in vitro. For the clinical trial, mean guanine-adenine-adenine repeat length was 699, and mean age was 31 years. Four weeks after treatment initiation, differences in changes in the Disposition Index between subjects treated with A0001 and placebo were not statistically significant. In contrast, a dose-dependent improvement in the Friedreich Ataxia Rating Scale score was observed. Patients on placebo improved 2.0 rating scale points, whereas patients on low-dose A0001 improved by 4.9 points (P = .04) and patients on a high dose improved by 6.1 points (P < .01). Although A0001 did not alter the Disposition Index, it caused a dose-dependent improvement in neurologic function, as measured by the Friedreich Ataxia Rating Scale. Longer studies will assess the reproducibility and persistence of neurologic benefit.     

Risperidone monotherapy in preschool children with pervasive developmental disorders

The aim of this preliminary study was to examine the short-term efficacy and safety of the atypical antipsychotic risperidone in preschool autistic children. The sample consisted of 10 subjects (7 males and 3 females) aged 3 9/12 to 6 6/12 years (mean age 4.7 years). A 16-week open-label trial with risperidone monotherapy was initiated at a starting dose of 0.25 mg daily and was increased to a maximum dose of 0.50 mg (0.027 mg/kg daily). Outcome measures were the Childhood Autism Rating Scale, the Children's Psychiatric Rating Scale, Clinical Global Impression (improvement score), and the Children's Global Assessment of Functioning. Two subjects did not complete the trial because of side effects (tachycardia and flushes, fever and hyporexia). After the 16-week treatment, data from the eight children who completed the trial indicated a modest improvement in the Childhood Autism Rating Scale total score, Children's Psychiatric Rating Scale total score, and Children's Global Assessment of Functioning. According to the Clinical Global Impression, the global improvement score for four subjects was much improved or very much improved; the score for the other four children was minimally improved. None of the children exhibited behavioral deterioration. The side effects in the eight children were not severe.