Joel Bregman

Diagnosing autism : Analyses of data from the Autism Diagnostic Interview

Results from ROC curves of items from two scales, the Autism Diagnostic Interview (ADI) and Autism Diagnostic Interview-Revised (ADI-R), operationalizing DSM-IV criteria for autism are presented for 319 autistic and 113 other subjects from 8 international autism centers. Analyses indicate that multiple items were necessary to attain adequate sensitivity and specificity if samples with varying levels of language were considered separately. Although considering only current behavior was generally sufficient when a combination cutoff and additive model was employed, predictive power was highest when history was taken into account. A single set of criteria, as operationalized by individually structured questions in the ADI/ADI-R, was effective in differentiating autism from mental handicap and language impairment in subjects with a range of chronological ages and developmental levels.

Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism.

CONTEXT Selective serotonin reuptake inhibitors are widely prescribed for children with autism spectrum disorders. OBJECTIVES To determine the efficacy and safety of citalopram hydrobromide therapy for repetitive behavior in children with autism spectrum disorders. DESIGN National Institutes of Health-sponsored randomized controlled trial. SETTING Six academic centers, including Mount Sinai School of Medicine, North Shore-Long Island Jewish Health System, University of North Carolina at Chapel Hill, University of California at Los Angeles, Yale University, and Dartmouth Medical School. PARTICIPANTS One hundred forty-nine volunteers 5 to 17 years old (mean [SD] age, 9.4 [3.1] years) were randomized to receive citalopram (n = 73) or placebo (n = 76). Participants had autistic spectrum disorders, Asperger disorder, or pervasive developmental disorder, not otherwise specified; had illness severity ratings of at least moderate on the Clinical Global Impressions, Severity of Illness Scale; and scored at least moderate on compulsive behaviors measured with the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. INTERVENTIONS Twelve weeks of citalopram hydrobromide (10 mg/5 mL) or placebo. The mean (SD) maximum dosage of citalopram hydrobromide was 16.5 (6.5) mg/d by mouth (maximum, 20 mg/d). MAIN OUTCOME MEASURES Positive response was defined by a score of much improved or very much improved on the Clinical Global Impressions, Improvement subscale. An important secondary outcome was the score on the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. Adverse events were systematically elicited using the Safety Monitoring Uniform Report Form. RESULTS There was no significant difference in the rate of positive response on the Clinical Global Impressions, Improvement subscale between the citalopram-treated group (32.9%) and the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61-1.51; P > .99). There was no difference in score reduction on the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders from baseline (mean [SD], -2.0 [3.4] points for the citalopram-treated group and -1.9 [2.5] points for the placebo group; P = .81). Citalopram use was significantly more likely to be associated with adverse events, particularly increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus. CONCLUSION Results of this trial do not support the use of citalopram for the treatment of repetitive behavior in children and adolescents with autism spectrum disorders. Trial Registration clinicaltrials.gov Identifier: NCT00086645.

Clomipramine in Autism: Preliminary Evidence of Efficacy

This report provides preliminary evidence for the efficacy of clomipramine in the treatment of young adults with autistic disorder. Four of five outpatients with autistic disorder showed significant improvement in social relatedness, obsessive compulsive symptoms, and aggressive and impulsive behavior with clomipramine treatment. These findings are consistent with previous evidence, suggesting that serotonin neurotransmission may be relevant to the treatment, and possibly the pathophysiology, of some symptoms of autistic disorder.

Exploring the Manifestations of Anxiety in Children with Autism Spectrum Disorders.

This study explores the manifestation and measurement of anxiety symptoms in 415 children with ASDs on a 20-item, parent-rated, DSM-IV referenced anxiety scale. In both high and low-functioning children (IQ above vs. below 70), commonly endorsed items assessed restlessness, tension and sleep difficulties. Items requiring verbal expression of worry by the child were rarely endorsed. Higher anxiety was associated with functional language, IQ above 70 and higher scores on several other behavioral measures. Four underlying factors emerged: Generalized Anxiety, Separation Anxiety, Social Anxiety and Over-arousal. Our findings extend our understanding of anxiety across IQ in ASD and provide guidance for improving anxiety outcome measurement.

Current developments in the understanding of mental retardation. Part II: Psychopathology.

During recent years there has been greater recognition of the impressive degree of psychiatric disturbance that affects those with mental retardation. An increasing number of systematic studies are focusing on the prevalence, risk factors, and clinical characteristics of psychiatric disturbance within this population. In addition, traditional neuropsychiatric assessment and treatment approaches are being evaluated, and new approaches are being developed. Such efforts will undoubtedly improve the ability to effectively diagnose and treat mentally retarded individuals suffering from psychiatric disorders. This paper is the second of two reviews that explore several recent developments in biological, phenomenological, and psychopathological aspects of mental retardation.

Abnormal cingulum bundle development in autism: A probabilistic tractography study

There is now considerable evidence that white matter abnormalities play a role in the neurobiology of autism. Little research has been directed, however, at understanding (a) typical white matter development in autism and how this relates to neurocognitive impairments observed in the disorder. In this study we used probabilistic tractography to identify the cingulum bundle in 21 adolescents and young adults with Autism Spectrum Disorder (ASD), and 21 age- and sex-matched healthy volunteers. We investigated group differences in the relationships between age and fractional anisotropy, a putative measure of white matter integrity, within the cingulum bundle. Moreover, in a preliminary investigation, we examined the relationship between cingulum fractional anisotropy and executive functioning using the Behavior Rating Inventory of Executive Function (BRIEF). The ASD participants demonstrated significantly lower fractional anisotropy within the cingulum bundle compared to the typically developing volunteers. There was a significant group-by-age interaction such that the ASD group did not show the typical age-associated increases in fractional anisotropy observed among healthy individuals. Moreover, lower fractional anisotropy within the cingulum bundle was associated with worse BRIEF behavioral regulation index scores in the ASD group. The current findings implicate a dysregulation in cingulum bundle white matter development occurring in late adolescence and early adulthood in ASD, and suggest that greater disturbances in this trajectory are associated with executive dysfunction in ASD.

Baseline Factors Predicting Placebo Response to Treatment in Children and Adolescents With Autism Spectrum Disorders: A Multisite Randomized Clinical Trial

IMPORTANCE The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population. OBJECTIVE To identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression-Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Childrens Yale-Brown Obsessive-Compulsive Scale. INTERVENTIONS Twelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d). MAIN OUTCOMES AND MEASURES A positive response was defined as having a score of at least much improved on the Clinical Global Impression-Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale-Revised, and the Childrens Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire. RESULTS Several baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders. CONCLUSIONS AND RELEVANCE This analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00086645.

Individual Temperament and Problem Behavior in Children With Autism Spectrum Disorders

Temperament is important for considering differences among diagnostic groups and for understanding individual differences that predict problematic behavior. Temperament characteristics, such as negative affectivity, effortful control, and surgency (highly active and impulsive), are predictive of externalizing behavior in typically developing children, but these links have not been investigated among children with autism spectrum disorder (ASD). In the present study, the authors analyzed differences in temperament between children with ASD and neurotypical children, investigated the range of individual differences within our sample, and examined the relationship between temperament and problem behavior. A few differences in temperament between the ASD sample and reference sample were noted and considerable variability in temperament was observed across children with ASD. High negative affectivity, high surgency, and low effortful control were related to problem behavior as measured by parent questionnaire. The potential utility of temperament assessment in developing new intervention options for addressing problem behavior is discussed.

Current developments in the understanding of mental retardation part I: Biological and phenomenological perspectives

During the past decade, noteworthy advances have taken place within the field of mental retardation. The application of advanced biological techniques in such areas as molecular genetics and neuroimaging has substantially improved our ability to identify the biological factors that underlie the origin and pathogenesis of an increasing number of mental retardation syndromes. Refined genetic and psychosocial assessments have highlighted the impressive degree of heterogeneity that is present within and across many mental retardation syndromes, stimulating increasing interest and study. This, the first of a two-part review, will focus on recent developments in biological and phenomenological aspects of mental retardation.

Design and Subject Characteristics in the Federally-Funded Citalopram Trial in Children with Pervasive Developmental Disorders

The Studies to Advance Autism Research and Treatment Network conducted a randomized trial with citalopram in children with Pervasive developmental disorders (PDDs). We present the rationale, design and sample characteristics of the citalopram trial. Subjects (128 boys, 21 girls) had a mean age of 9.3 (±3.12) years; 132 (88.6%) were diagnosed with autistic disorder (4.7% with Asperger’s Disorder; 6.7% with PDD-not otherwise specified). Less than half of the subjects were intellectually disabled; 117 (78.5%) were rated Moderate or Marked on the Clinical Global Impression for Severity. Study measures were similar to previous Research Units on Pediatric Psychopharmacology trials. Subjects in this trial were slightly older and more likely to have complaints of repetitive behavior than participants in RUPP trials.