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.

Guanfacine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Down Syndrome: A Retrospective Chart Review.

Study Design: Retrospective case series. Objectives: The objective of this study was to provide naturalistic data on the use of guanfacine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in a clinically referred sample of youth with Down syndrome (DS). Methods: The medical records of children and adolescents with DS who received guanfacine for the treatment of ADHD from a multidisciplinary neurodevelopmental disorder clinic between September 1, 2011, and September 10, 2021, were reviewed. Demographic and clinical characteristics, guanfacine dose and treatment duration, and adverse effects were recorded. Clinical Global Impression Scale (CGI) scores for ADHD symptom severity (S) and improvement (I) were retrospectively assigned by a child and adolescent psychiatrist based on review of the clinic notes. Response to guanfacine was defined as completion of at least 12 weeks of treatment and a Clinical Global Impression Improvement subscale rating ≤2 (1 = "very much improved" or 2 = "much improved"). Results: Twenty-one patients were eligible for inclusion, of whom 17 (81%) completed at least 12 weeks of guanfacine. Ten of the 21 patients (48%; 95% confidence interval [CI]: 28%-68%) responded to treatment. The median time on guanfacine treatment covered by the clinic notes was 50.4 weeks, with a range of 0.3 weeks to 7.5 years. Thirteen patients (62%) remained on guanfacine at the time of their most recent clinic note. Nine patients had adverse events documented in their clinic notes (43%; 95% CI: 24%-63%), most commonly sleepiness (n = 7) and constipation (n = 2). Conclusion: About half of patients with DS responded to guanfacine for the treatment of ADHD and many tolerated long-term use. Study limitations primarily relate to the retrospective nature of the study and small sample size.

An adapted clinical global Impression of improvement for use in Angelman syndrome: Validation analyses utilizing data from the NEPTUNE study.

PURPOSE: Angelman Syndrome (AS) is a rare, severe neurogenetic disorder that causes symptoms such as intellectual disability and motor impairments and is typically diagnosed in early childhood. The complexity and heterogeneity of AS confound characterization of disease severity and pose unique challenges when determining an individual's response to treatment. There is therefore a substantial unmet need for rating scales specifically designed for complex conditions such as AS. To address this, the Clinical Global Impressions (CGI) scale, which has components for both symptom severity (CGI-S) and improvement (CGI-I) was specifically adapted to measure severity (CGI-S-AS) and improvement (CGI-I-AS) in AS. METHODS: The modified CGI-S/I-AS was used in the NEPTUNE trial of gaboxadol for the treatment of AS. Here we report on the validation of the CGI-I-AS using data from NEPTUNE and discuss insights for its potential use in future trials. RESULTS: Improvements in the CGI-I-AS rating tended to be consistent with changes on other relevant rating scales. Sleep-related symptoms were particularly well represented, while communication-related symptoms were not. CONCLUSIONS: Our validation analysis of the CGI-I-AS demonstrates its usefulness along with possible areas of improvement. The CGI-I-AS is a potential tool for use in other trials of AS drug candidates, and the process for its development can serve as a road map for the development of assessment tools for other neuropsychiatric disorders with similar complexities and heterogeneity.

Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study.

PURPOSE: To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). METHOD: In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least "minimal improvement") and ≤2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range. RESULTS: Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study. CONCLUSIONS: There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants. CLINICALTRIALS: GOV: NCT04106557.

Current and emerging treatment options for Angelman syndrome.

INTRODUCTION: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, limited expressive language, epilepsy, and motor impairment. Angelman syndrome is caused by haploinsufficiency of the UBE3A gene on the maternal copy of chromosome 15. There have been ongoing advances in the understanding of neurological, behavioral, and sleep-based problems and associated treatments for patients with AS. These results along with gene-based therapies entering into clinical development prompted this review. AREAS COVERED: The authors summarize the research basis describing phenomenology of epilepsy and behavioral concerns such as hyperactivity behavior, aggression, self-injury, repetitive behavior, and sleep disorder. The evidence for recent treatment advances in these target symptom domains of concern is reviewed, and the potential for emerging gene therapy treatments is considered. EXPERT OPINION: The prospect for emerging gene therapies means that increasing efforts should be directed toward the early identification of AS implemented equitably. Recent studies emphasize the important role of behavioral therapy in addressing mental health concerns such as aggression and disordered sleep.

Health-related quality of life and medication use among individuals with Angelman syndrome.

PURPOSE: The primary goal of this analysis is to describe the health-related quality of life (HRQoL), medical history, and medication use among adolescents and adults individuals with Angelman syndrome (AS). METHODS: The analysis uses baseline data collected during the STARS study, a double-blind placebo controlled trial of gaboxadol (OV101) in adolescents and adults with AS. The HRQoL was estimated using EuroQoL 5-Dimension 5-Level (EQ-5D) health questionnaire proxy 1 version, which was completed by the caregivers. EQ-5D consists of two parts, a 5-dimension descriptive and a visual analogue scale (VAS) component. The utility score derived from EQ-5D ranges from 0 to 1 (perfect health) and VAS ranges from 0 to 100 (perfect health). RESULTS: 87 individuals with AS were included in the present analysis. The mean utility score was 0.44 ± 0.20 and VAS score was 84 ± 1.5. The EQ-5D data indicated that the self-care, mobility and daily activities were most impacted. All adolescents (100%) and most adults (93%) had at least moderate problems with self-care activities, such as washing or dressing themselves. More than half (55%) of the adolescents and adults had at least moderate issues with mobility and usual activities. Approximately, 30% of adolescents and adults had moderate to extreme problems with anxiety/depression. High baseline concomitant use of medications was observed across both age groups with an average of 5 medications being used per person. CONCLUSION: This study highlights the impact of AS on HRQoL and medication utilization among adolescents and adults individuals with AS.

Prevalence and factors associated with overweight, obesity, and hypertension in a large clinical sample of adults with autism spectrum disorder.

Adults with autism spectrum disorder (ASD) are at risk for excess bodyweight and hypertension, yet the prevalence of and clinical predictors for these health conditions remain unknown. The objective of this study was to assess the prevalence of overweight, obesity, and hypertension in a large clinical sample of adults with a confirmed diagnosis of ASD and to examine potential clinical predictors. This retrospective chart review study included adult subjects (≥ 20 years) with ASD who had been seen within the past 5 years at a multidisciplinary developmental disorders clinic. Data collected from the electronic health record included age, sex, race and ethnicity, cognitive ability, language ability, body mass index (BMI), hypertension, and use of second generation antipsychotic medications (SGAs). Of 622 adults with a confirmed diagnosis of ASD potentially eligible for the study, 483 (78%) had one or more notes in their records from the past 5 years. Those with recent notes were 23% female, 89% White, and had a mean (SD) age of 28.1 (7.1) years. Overall prevalence estimates for adults represented by this predominantly male, White, and young clinical sample were 28% (95% CI 24%, 32%) for overweight (BMI 25-29.9 kg/m2), 35% (95% CI 31%, 40%) for obesity (≥ 30 kg/m2), and 11% (95% CI 9%, 15%) for hypertension. Controlling for age and sex, intellectual disability (ID) was significantly associated with BMI (p = 0.003) but not hypertension (p = 0.69); those with moderate or more severe ID had a mean BMI that was 2.26 kg/m2 (95% CI 0.96, 3.57) lower than those with no ID. Controlling for age and sex, neither language ability, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) subtype of autism, nor past or current use of SGAs were significantly associated with BMI or hypertension. The study identified a high prevalence of overweight and obesity in adults with ASD consistent with the prevalence of these medical comorbidities in the U.S. population.

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.

Stimulant intolerance in children with Angelman syndrome with hyperactivity: a case series.

OBJECTIVES: Angelman syndrome is a neurogenetic disorder resulting from the loss of expression of the ubiquitin-protein ligase E3A gene on chromosome 15. Problematic behaviors including attention-deficit/hyperactivity disorder (ADHD) symptoms of hyperactivity, impulsivity and inattention are highly prevalent in Angelman syndrome. The efficacy, safety and tolerability of stimulant medications in children with Angelman syndrome for the treatment of ADHD symptoms have not been previously reported. METHODS: We describe three boys with Angelman syndrome who were treated with open-label stimulant medications for ADHD symptoms. RESULTS: Stimulant medications were highly intolerable, and treatment had to be discontinued after limited dosing in all three cases due to marked increases in hyperactivity and impulsivity along with worsened distractibility. CONCLUSION: The findings of this study suggest that stimulant medications may be ineffective and poorly tolerated in children with Angelman syndrome.

A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. METHODS: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. RESULTS: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. CONCLUSION: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

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.

Functional Neurological Symptom Disorder in Williams Syndrome: Case Series and Review of Relevant Literature.

BACKGROUND: Williams syndrome (WS) is a neurodevelopmental disorder associated with several medical and psychiatric comorbidities. OBJECTIVE: To describe the clinical presentation and treatment course of functional neurological symptom disorder (FNSD) in 3 adult patients with WS. METHODS: This report describes the clinical presentation and long-term follow-up of 3 individuals with WS and FNSD who experienced a range of clinical presentations and responses to treatment. The literature on the clinical assessment and treatment of FNSD as it applies to patients with neurodevelopmental disorders is reviewed. RESULTS: FNSD treatment strategies used in the general population were successfully adapted for these 3 patients. Literature on the diagnosis and treatment of FNSD in patients with neurodevelopmental disorders is lacking. CONCLUSIONS: FNSD may be more common in individuals with WS than previously appreciated, and future studies describing the prevalence, clinical presentation, risk factors, and treatment of FNSD in WS are needed.

Brief Report: Suspected Cannabis-Induced Mania and Psychosis in Young Adult Males with Autism Spectrum Disorder.

There is increasing interest in investigating cannabis for behavioral symptoms in individuals with autism spectrum disorder (ASD). The potential role of dysregulated cannabinoid signaling contributing to the pathophysiology of ASD is an area of active investigation. Results from retrospective and uncontrolled trials of cannabis in subjects with ASD have been published, reporting both potential benefits and adverse effects. Here, we describe the clinical course of three young adult males with ASD who developed mania or psychosis after the consistent use of cannabidiol and delta-9-tetrahydrocannabinol. Caution should be utilized with cannabis use in individuals with ASD until large-scale, replicated randomized controlled trials demonstrating efficacy, safety and tolerability have been published.

Development of an adapted Clinical Global Impression scale for use in Angelman syndrome.

BACKGROUND: The Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales are widely accepted tools that measure overall disease severity and change, synthesizing the clinician's impression of the global state of an individual. Frequently employed in clinical trials for neuropsychiatric disorders, the CGI scales are typically used in conjunction with disease-specific rating scales. When no disease-specific rating scale is available, the CGI scales can be adapted to reflect the specific symptom domains that are relevant to the disorder. Angelman syndrome (AS) is a rare, clinically heterogeneous condition for which there is no disease-specific rating scale. This paper describes efforts to develop standardized, adapted CGI scales specific to AS for use in clinical trials. METHODS: In order to develop adapted CGI scales specific to AS, we (1) reviewed literature and interviewed caregivers and clinicians to determine the most impactful symptoms, (2) engaged expert panels to define and operationalize the symptom domains identified, (3) developed detailed rating anchors for each domain and for global severity and improvement ratings, (4) reviewed the anchors with expert clinicians and established minimally clinically meaningful change for each symptom domain, and (5) generated mock patient vignettes to test the reliability of the resulting scales and to standardize rater training. This systematic approach to developing, validating, and training raters on a standardized, adapted CGI scale specifically for AS is described herein. RESULTS: The resulting CGI-S/I-AS scales capture six critical domains (behavior, gross and fine motor function, expressive and receptive communication, and sleep) defined by caregivers and expert clinicians as the most challenging for patients with AS and their families. CONCLUSIONS: Rigorous training and careful calibration for clinicians will allow the CGI-S/-I-AS scales to be reliable in the context of randomized controlled trials. The CGI-S/-I-AS scales are being utilized in a Phase 3 trial of gaboxadol for the treatment of AS.

Characterization of sleep habits and medication outcomes for sleep disturbance in children and adults with Angelman syndrome.

The objectives of this study were to characterize the sleep habits of 50 clinically referred individuals with Angelman syndrome (AS) and to retrospectively compare the effectiveness/tolerability of the three most commonly prescribed sleep medications in the sample. An experienced physician assigned a Clinical Global Impressions-Severity scale (CGI-S) score for each subject's AS-specific symptoms. Caregivers completed the Child Sleep Habits Questionnaire (CSHQ; screen for sleep problems in school-aged [4-10 years] children), a screening assessment for sleep problems. Caregivers provided information about medication trials targeting disturbed sleep, with the physician assigning a CGI-Improvement scale (CGI-I) score for each trial. Linear regression showed significant negative association between age and CSHQ score. In their lifetime, 72% of participants had taken a medication for sleep, most commonly melatonin, clonidine and trazodone. The majority continued these for 6 months or longer. With these medications, many demonstrated significant improvement in sleep disturbances, with no difference in odds of improvement between medications. Disturbed sleep was common in this cohort and significantly worse in younger-aged participants. The majority received at least one medication trial for disturbed sleep and each of the most commonly prescribed medication was effective for a substantial percentage of participants. Most participants remained on medication for at least 6 months, suggesting favorable tolerability.

Psychiatric Assessment of Social Impairment Across the Lifespan.

Although autism spectrum disorder (ASD) is the prototypical psychiatric disorder of social impairment, several if not most psychiatric disorders are characterized by prominent impairments in social functioning. A challenge in clinically assessing and describing social impairment is that it has been variably defined and can be difficult to measure. In this article we consider the psychiatric differential diagnosis of social impairment within the DSM-5 framework. We describe the features of social impairment in 13 DSM-5 disorders from a developmental perspective and highlight diagnostic factors that differentiate among the disorders, including the main features of social impairment, verbal communication, nonverbal communication, course of social impairment, social cognition, and key features of accompanying neuropsychiatric symptoms. We conclude by describing an approach for assessing social impairment across the lifespan.

Buspirone for the Treatment of Generalized Anxiety Disorder in Williams Syndrome: A Case Series.

Co-morbid anxiety disorders, including generalized anxiety disorder (GAD), are highly prevalent among individuals with Williams syndrome (WS). However, reports of the pharmacologic treatment of only a limited number of previous anxiety disorders in WS have appeared in the literature. Here, we review the case histories of three adolescents/young adults with WS and the treatment course of co-morbid GAD with buspirone. Treatment with buspirone was well-tolerated and resulted in sustained response in all three cases. Common medical disorders in WS are highlighted with regards to safe and appropriate pharmacologic treatment of GAD. Buspirone's generally benign side effect profile is a major benefit of its use for treating GAD in individuals with WS.

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.