Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder.

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

In vivo translocator protein in females with autism spectrum disorder: a pilot study.

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [11C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [11C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [11C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [11C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [11C]PBR28 SUVR across time in both groups. Elevated regional [11C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [11C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.

Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder.

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.

Repetitive Thoughts and Repetitive Behaviors in Williams Syndrome.

The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The parents of 60 subjects with WS completed the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or Children's Y-BOCS, the Yale Global Tic Severity Scale, the Stereotyped Behavior Scale, and the Spence Children's Anxiety Scale-Parent Version. Nineteen males and 41 females participated in the study. Six subjects (10%) had obsessions only, six (10%) had compulsions only, and eleven (18%) had at least one obsession and at least one compulsion. None of the subjects had tics. Fifty subjects (83.3%) endorsed at least one stereotypy. Increased anxiety was associated with increased severity of obsessions, but not severity of compulsions or stereotypies.

A randomized double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in children and adolescents with autism spectrum disorder.

This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5-45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated "much improved" (CGI-I = 2) or "very much improved" (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine's safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Clinical trial registration information: Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders; https://clinicaltrials.gov ; NCT01302964.

Parent Description of Anxiety in Angelman Syndrome.

Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and quantitative assessments were used to evaluate for anxiety in 50 subjects with AS. In-person evaluations assessed behaviors concerning for anxiety and circumstances wherein they occurred. Caregivers completed anxiety and other behavioral rating scales. Caregiver responses were categorized and compared to items from anxiety rating scales. The most common behavioral manifestation of anxiety was "aggression." The most common circumstance was "separation from caregiver/parent." Subjects had elevated scores on anxiety, irritability and hyperactivity scales with lower mean scores among subjects with a maternal deletion. The Pediatric Anxiety Rating Scale best captured behaviors described by caregivers. Existing anxiety scales should be adapted for use in AS.

Beyond the brain: A multi-system inflammatory subtype of autism spectrum disorder.

An immune-mediated subtype of autism spectrum disorder (ASD) has long been hypothesized. This article reviews evidence from family history studies of autoimmunity, immunogenetics, maternal immune activation, neuroinflammation, and systemic inflammation, which suggests immune dysfunction in ASD. Individuals with ASD have higher rates of co-morbid medical illness than the general population. Major medical co-morbidities associated with ASD are discussed by body system. Mechanisms by which FDA-approved and emerging treatments for ASD act upon the immune system are then reviewed. We conclude by proposing the hypothesis of an immune-mediated subtype of ASD which is characterized by systemic, multi-organ inflammation or immune dysregulation with shared mechanisms that drive both the behavioral and physical illnesses associated with ASD. Although gaps in evidence supporting this hypothesis remain, benefits of this conceptualization include framing future research questions that will help define a clinically meaningful subset of patients and focusing clinical interactions on early detection and treatment of high-risk medical illnesses as well as interfering behavioral signs and symptoms across the lifespan.

Accuracy of self-reported history of autoimmune disease: A pilot study.

Research associating the increased prevalence of familial autoimmunity with neuropsychiatric disorders is reliant upon the ascertainment of history of autoimmune diseases from relatives. To characterize the accuracy of self-report, we compared self-reported diagnoses of 18 autoimmune diseases using an online self-report questionnaire to the electronic medical record (EMR) diagnoses in 1,013 adult (age 18-70 years) patients of a primary care clinic. For the 11 diseases meeting our threshold observed prevalence, we estimated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for self-reported diagnoses under the assumption that EMR-based diagnoses were accurate. Six diseases out of 11 had either sensitivity or PPV below 50%, with the lowest PPV for dermatological and endocrinological diseases. Common errors included incorrectly self-reporting type 2 diabetes mellitus (DM), when type 1 DM was indicated by the EMR, and reporting rheumatoid arthritis when osteoarthritis was indicated by the EMR. Results suggest that ascertainment of familial autoimmunity through self-report contributes to inconsistencies and inaccuracies in studies of autoimmune disease history and that future studies would benefit from incorporating EMR review and biological measures.

Brief Report: Major Depressive Disorder with Psychotic Features in Williams Syndrome: A Case Series.

Descriptions of individuals with Williams syndrome (WS) and co-morbid major depressive disorder (MDD) with psychotic features have not appeared in the literature. In addition to reviewing previous reports of psychotic symptoms in persons with WS, this paper introduces clinical histories and therapeutic management strategies for three previously unreported adults with WS diagnosed with co-morbid MDD with psychotic features. Co-morbid medical disorders common in WS are highlighted with regard to safe and appropriate pharmacological treatment. The importance of assessment for co-morbid MDD with psychotic features in individuals with WS is emphasized.

Toward an immune-mediated subtype of autism spectrum disorder.

A role for immunological involvement in autism spectrum disorder (ASD) has long been hypothesized. This review includes four sections describing (1) evidence for a relationship between familial autoimmune disorders and ASD; (2) results from post-mortem and neuroimaging studies that investigated aspects of neuroinflammation in ASD; (3) findings from animal model work in ASD involving inflammatory processes; and (4) outcomes from trials of anti-inflammatory/immune-modulating drugs in ASD that have appeared in the literature. Following each section, ideas are provided for future research, suggesting paths forward in the continuing effort to define the role of immune factors and inflammation in the pathophysiology of a subtype of ASD. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

N-acetylcysteine for neuropsychiatric symptoms in a woman with Williams syndrome.

Williams syndrome is a relatively rare genetic disorder caused by the hemizygous microdeletion of a region in chromosome 7q11.23. Individuals with Williams syndrome typically present with a highly social, overfriendly, and empathic personality. Comorbid medical and neuropsychiatric disorders are common. Reports of effective pharmacological treatment of associated neuropsychiatric disorders are limited. The authors describe the successful treatment of interfering anger, aggression, and hair-pulling with N-acetylcysteine in a 19-year-old woman with Williams syndrome. The neuropsychiatric symptoms emerged 1 week following an upper gastrointestinal endoscopy, for which fentanyl, midazolam, and propofol were used as anesthetics. The patient's treatment course and hypothesized mechanisms underlying the clinical presentation and symptom resolution are described.

Paliperidone for irritability in adolescents and young adults with autistic disorder.

RATIONALE: Individuals with autistic disorder (autism) frequently exhibit significant irritability marked by severe tantrums, aggression, and self-injury. Despite advances in the treatment of this symptom domain in autism, there remains an ongoing need for more effective and better tolerated pharmacotherapies. OBJECTIVES: The aim of this study is to determine the effectiveness and tolerability of paliperidone for irritability in autism. METHODS: This is a prospective, 8-week open-label study of paliperidone in 25 adolescents and young adults with autism. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) Scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Concomitant medications (except antipsychotics) were permitted if dosages were stable for ≥2 months. RESULTS: Twenty-one (84 %) of 25 subjects ages 12-21 years (mean 15.3 years) responded to paliperidone, based on a CGI-I Scale score of 1 or 2 (very much or much improved) and ≥25 % improvement on the ABC-I. The mean final dosage of paliperidone was 7.1 mg/day (range 3-12 mg/day). Two subjects discontinued paliperidone prior to study completion (moderate sedation, n = 1; nonresponse, n = 1). Mild-to-moderate extrapyramidal symptoms were recorded in four subjects. A mean weight gain of 2.2 ± 2.6 kg (range -3.6 to +7.9 kg) was recorded. Mean age- and sex-normed body mass index increased from 23.6 to 24.2 (p ≤ 0.001). Mean serum prolactin increased from 5.3 to 41.4 ng/mL (p ≤ 0.0001). CONCLUSIONS: Paliperidone treatment was associated with significant improvement in irritability and was generally well tolerated. Larger scale, placebo-controlled studies are needed to elucidate the efficacy and tolerability of paliperidone in this population.

A prospective open-label study of aripiprazole in fragile X syndrome.

RATIONALE: Fragile X syndrome (FXS) is the most common inherited form of developmental disability and most common single gene cause of autism. Persons with FXS frequently exhibit irritable behavior marked by aggression, self-injury, and severe tantrums. Despite frequent clinical use of atypical antipsychotic drugs to target this behavioral cluster, no systematic trials to date have assessed the efficacy and safety of these drugs in persons with FXS. METHODS: We conducted a prospective open-label 12-week trial of aripiprazole in 12 persons aged 6-25 years (mean age, 14.3 years) with FXS who were free of concomitant psychoactive drugs. RESULTS: Aripiprazole use (mean dose, 9.8 mg/day) was associated with treatment response (defined by a Clinical Global Impressions-Improvement scale score of much improved or very much improved and a ≥ 25% improvement on the Aberrant Behavior Checklist-Irritability subscale) in 10 of 12 (87%) persons. Two individuals (13%) discontinued aripiprazole prior to study completion due to adverse events. One discontinuation was due to akathisia, mild drooling, and mild tiredness and the other due to moderate tiredness and moderate drooling. No significant changes in vital signs including weight or laboratory measures occurred during treatment with aripiprazole. CONCLUSIONS: Aripiprazole was generally safe and well tolerated and was associated with significant improvement in irritable behavior. Given these findings, a double-blind, placebo-controlled study of aripiprazole in FXS is warranted.

An open-label naturalistic pilot study of acamprosate in youth with autistic disorder.

To date, placebo-controlled drug trials targeting the core social impairment of autistic disorder (autism) have had uniformly negative results. Given this, the search for new potentially novel agents targeting the core social impairment of autism continues. Acamprosate is U.S. Food and Drug Administration-approved drug to treat alcohol dependence. The drug likely impacts both gamma-aminobutyric acid and glutamate neurotransmission. This study describes our initial open-label experience with acamprosate targeting social impairment in youth with autism. In this naturalistic report, five of six youth (mean age, 9.5 years) were judged treatment responders to acamprosate (mean dose 1,110 mg/day) over 10 to 30 weeks (mean duration, 20 weeks) of treatment. Acamprosate was well tolerated with only mild gastrointestinal adverse effects noted in three (50%) subjects.

Brief report: acamprosate in fragile X syndrome.

Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). We report on the first trial of acamprosate, a drug with putative mGluR5 antagonism, in three adults with FXS and autism. Medical records describing open-label treatment with acamprosate in 3 patients with FXS and a comorbid diagnosis of autistic disorder were reviewed. In all three patients, acamprosate was associated with improved linguistic communication. Three patients received acamprosate over a mean 21.3 weeks of treatment. All patients showed global clinical benefit as rated with the Clinical Global Impressions-Improvement scale. Marked communication improvement was unexpected and has potential implications for the treatment of FXS, as well as idiopathic autism.

Open-label memantine in fragile X syndrome.

Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). The purpose of this pilot study was to examine the effectiveness and tolerability of memantine for a number of target symptoms associated with FXS. Medical records describing open-label treatment with memantine in 6 patients with FXS and a comorbid diagnosis of PDD were reviewed. Six patients received memantine over a mean 34.7 weeks of treatment. Four of 6 (67%) patients showed global clinical benefit on ratings with the CGI-I. Symptom specific rating scales, however, showed no statistically significant improvement. Two patient developed treatment-limiting irritability on memantine. Memantine was modestly effective in several patients with FXS. Further systematic study is warranted.