The SOFIA Study: Negative Multi-center Study of Low Dose Fluoxetine on Repetitive Behaviors in Children and Adolescents with Autistic Disorder.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that reduces obsessive-compulsive symptoms. There is limited evidence supporting its efficacy for repetitive behaviors (RRBs) in autistic spectrum disorder (ASD). We conducted a randomized controlled trial (RCT) of fluoxetine in 158 individuals with ASD (5-17 years). Following 14 treatment weeks (mean dose 11.8 mg/day), no significant differences were noted on the Children's Yale-Brown Obsessive Compulsive Scale; the proportion of responders was similar (fluoxetine: 36%; placebo: 41%). There were similar rates of AEs (e.g., insomnia, diarrhea, vomiting); high rates of activation were reported in both groups (fluoxetine: 42%; placebo: 45%). Overly cautious dosing/duration may have prevented attainment of a therapeutic level. Results are consistent with other SSRI RCTs treating RRBs in ASD.Trial Registration: clinicaltrials.gov Identifier: NCT00515320.

A wide star-black-hole binary system from radial-velocity measurements.

All stellar-mass black holes have hitherto been identified by X-rays emitted from gas that is accreting onto the black hole from a companion star. These systems are all binaries with a black-hole mass that is less than 30 times that of the Sun1-4. Theory predicts, however, that X-ray-emitting systems form a minority of the total population of star-black-hole binaries5,6. When the black hole is not accreting gas, it can be found through radial-velocity measurements of the motion of the companion star. Here we report radial-velocity measurements taken over two years of the Galactic B-type star, LB-1. We find that the motion of the B star and an accompanying Hα emission line require the presence of a dark companion with a mass of [Formula: see text] solar masses, which can only be a black hole. The long orbital period of 78.9 days shows that this is a wide binary system. Gravitational-wave experiments have detected black holes of similar mass, but the formation of such massive ones in a high-metallicity environment would be extremely challenging within current stellar evolution theories.

Neural systems mediating decision-making and response inhibition for social and nonsocial stimuli in autism.

Autism is marked by impairments in social reciprocity and communication, along with restricted, repetitive and stereotyped behaviors. Prior studies have separately investigated social processing and executive function in autism, but little is known about the brain mechanisms of cognitive control for both emotional and nonemotional stimuli. We used functional magnetic resonance imaging to identify differences in neurocircuitry between individuals with high functioning autism (HFA) and neurotypical controls during two versions of a go/no-go task: emotional (fear and happy faces) and nonemotional (English letters). During the letter task, HFA participants showed hypoactivation in the ventral prefrontal cortex. During the emotion task, happy faces elicited activation in the ventral striatum, nucleus accumbens and anterior amygdala in neurotypical, but not HFA, participants. Response inhibition for fear faces compared with happy faces recruited occipitotemporal regions in HFA, but not neurotypical, participants. In a direct contrast of emotional no-go and letter no-go blocks, HFA participants showed hyperactivation in extrastriate cortex and fusiform gyrus. Accuracy for emotional no-go trials was negatively correlated with activation in fusiform gyrus in the HFA group. These results indicate that autism is associated with abnormal processing in socioemotional brain networks, and support the theory that autism is marked by a social motivational deficit.

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.

Puzzling accretion onto a black hole in the ultraluminous X-ray source M 101 ULX-1.

There are two proposed explanations for ultraluminous X-ray sources (ULXs) with luminosities in excess of 10(39) erg s(-1). They could be intermediate-mass black holes (more than 100-1,000 solar masses, M sun symbol) radiating at sub-maximal (sub-Eddington) rates, as in Galactic black-hole X-ray binaries but with larger, cooler accretion disks. Alternatively, they could be stellar-mass black holes radiating at Eddington or super-Eddington rates. On its discovery, M 101 ULX-1 had a luminosity of 3 × 10(39) erg s(-1) and a supersoft thermal disk spectrum with an exceptionally low temperature--uncomplicated by photons energized by a corona of hot electrons--more consistent with the expected appearance of an accreting intermediate-mass black hole. Here we report optical spectroscopic monitoring of M 101 ULX-1. We confirm the previous suggestion that the system contains a Wolf-Rayet star, and reveal that the orbital period is 8.2 days. The black hole has a minimum mass of 5 M sun symbol, and more probably a mass of 20 M sun symbol-30 M sun symbol, but we argue that it is very unlikely to be an intermediate-mass black hole. Therefore, its exceptionally soft spectra at high Eddington ratios violate the expectations for accretion onto stellar-mass black holes. Accretion must occur from captured stellar wind, which has hitherto been thought to be so inefficient that it could not power an ultraluminous source.

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 Children's 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 Children's 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.

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.

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.

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 Children's 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 Children's 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 Children's 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.

Strong association of de novo copy number mutations with autism.

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

Multisystem study of 20 older adults with Williams syndrome.

To address the natural history of Williams syndrome (WS), we performed multisystem assessments on 20 adults with WS over 30 years of age and documented a high frequency of problems in multiple organ systems. The most striking and consistent findings were: abnormal body habitus; mild-moderate high frequency sensorineural hearing loss; cardiovascular disease and hypertension; gastrointestinal symptoms including diverticular disease; diabetes and abnormal glucose tolerance on standard oral glucose tolerance testing; subclinical hypothyroidism; decreased bone mineral density on DEXA scanning; and a high frequency of psychiatric symptoms, most notably anxiety, often requiring multimodal therapy. Review of brain MRI scans did not demonstrate consistent pathology. The adults in our cohort were not living independently and the vast majority were not competitively employed. Our preliminary findings raise concern about the occurrence of mild accelerated aging, which may additionally complicate the long-term natural history of older adults with WS. We provide monitoring guidelines to assist in the comprehensive care of adults with WS.