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.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure.

BACKGROUND: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. METHODS: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. RESULTS: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. CONCLUSIONS: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).

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.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

Importance: Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. Objective: To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. Design, Setting, and Participants: This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Exposures: Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Main Outcomes and Measures: Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. Results: The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. Conclusions and Relevance: The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Buspirone for the treatment of anxiety in Williams syndrome: a retrospective chart review study.

BACKGROUND: Williams syndrome (WS) is a rare genetic disorder associated with a high prevalence of anxiety disorders. Evidence-based pharmacologic treatments for anxiety in WS are lacking. The purpose of this study is to provide naturalistic data on the use of buspirone for the treatment of anxiety in WS. RESEARCH DESIGN AND METHODS: Medical records of 24 individuals with Williams syndrome (ages 7-47 years) and anxiety who received treatment with buspirone were reviewed. Treatment response to buspirone was rated by assigning a retrospective Clinical Global Impression Improvement subscale (CGI-I) score. RESULTS: Twenty-three of 24 (96%) patients completed at least a 16-week treatment course with buspirone. Sixteen patients (67%; 95% CI 47%, 82%) were treatment responders (CGI-I ≤ 2). Only 1 (4%) patient discontinued buspirone due to a treatment-emergent side effect (nausea and vomiting). The most common side effect was nausea (13%). Twenty (84%) patients remained on buspirone at the time of their most recent follow-up visit. CONCLUSIONS: In this retrospective study, the majority of patients responded to a 16-week course of buspirone. Prospective studies are warranted to further assess the efficacy and tolerability of buspirone for anxiety in WS.

Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function.

There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.

Patterns in Medication Use for Treatment of Depression in Autistic Spectrum Disorder.

INTRODUCTION: Depression impacts many individuals with autism spectrum disorder (ASD), carrying increased risk of functional impairment, hospitalization, and suicide. Prescribing medication to target depression in patients with ASD occurs despite limited available systematic data describing medication management of depression in this population. PURPOSE: The purpose of this study is to discover prescribing patterns for individuals with MDD and ASD during this time period (2004-2012) to inform current and future prescribing practices with historical data. METHOD: Drawing from a large clinical database describing the prescribing practices in patients with ASD, we identified 166 individuals with ASD (mean age 14.5 ± 8.3 years old) who received medication targeting symptoms of depression. We report prescribing rates for specific drugs, drug treatment duration, and reasons for drug discontinuation when applicable. RESULTS: Sertraline, mirtazapine, and fluoxetine were the three most commonly prescribed medications to treat comorbid depression for this patient population. Among 241 drug starts, 123 (49%) drug treatments were continued at the final reviewed follow-up visit (average treatment duration of ± 0.72 years). The most common reason for discontinuation across all medications prescribed was loss of or lack of effectiveness. CONCLUSION: This study raises concern that standard of care pharmacological treatments for depression in individuals with ASD may be less effective than in neurotypical populations. There remains a need to develop effective interventions for depression specifically tailored to the needs of individuals with ASD.

Neuroimaging research in Williams syndrome: Beginning to bridge the gap with clinical care.

Williams syndrome (WS) is a genetic disorder affecting multiple organ systems. Cardinal features include cardiovascular disease, distinct facies, and a unique cognitive profile characterized by intellectual disability, hypersociability, and visuospatial weaknesses. Here, we synthesize neuroimaging research in WS with a focus on how the current literature and future work may be leveraged to improve health and quality of life in WS. More than 80 neuroimaging studies in WS have been conducted, the vast majority of which have focused on identifying morphometric brain differences. Aside from decreased volume of the parieto-occipital region and increased cerebellar volume, morphometric findings have been variable across studies. fMRI studies investigating the visuospatial deficit have identified dorsal stream dysfunction and abnormal activation of the hippocampal formation. Minimal work has been done using PET or MRS. Future approaches that conduct neuroimaging in tandem with clinical phenotyping, utilize novel imaging techniques to visualize brain vasculature or provide biochemical and molecular information, and include more homogenous age groups across the lifespan, have significant potential to advance clinical care.

Clozapine for treatment refractory catatonia in individuals with autism spectrum disorder: a retrospective chart review study.

BACKGROUND: Catatonia is increasingly recognized in individuals with autism spectrum disorder (ASD). Empirical data on treating catatonia in this population are limited. The purpose of this study is to provide naturalistic data on the use of clozapine for the treatment of catatonia in patients with ASD. RESEARCH DESIGN AND METHODS: Medical records of 12 individuals with ASD and catatonia who received treatment with clozapine were reviewed. Treatment response to clozapine was rated by assigning a retrospective Clinical Global Impression Improvement scale (CGI-I) score. RESULTS: Mean (SD) and median (IQR) age at initiation of clozapine treatment were 22.1 (7.7) and 20.4 (9.7) years, with a range of 10-39 years. Eleven of the 12 patients had received treatment with lorazepam prior to initiating clozapine and 9 of the 12 patients received concomitant treatment with lorazepam and clozapine. Eleven of the 12 patients (92%; 95% CI: 65%, 99%) responded to clozapine. All 12 patients remained on clozapine at the time of their most recent clinical note. All 12 patients (100%; 95% CI: 76%, 100%) experienced one or more adverse events, the most common of which was sedation (n = 11, 92%). CONCLUSIONS: Overall, clozapine was associated with a high response rate for the treatment of catatonia in patients with ASD. These naturalistic data support the use of clozapine for the treatment of catatonia in patients with ASD for whom lorazepam is either ineffective or partially effective.

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.

Diversity of Participants in Williams Syndrome Intervention Studies.

PURPOSE: This study describes participant diversity in Williams syndrome (WS) intervention studies. METHODS: A literature search was conducted to identify prospective treatment studies including participants with WS. Data was extracted on the reporting of and information provided on age, sex, cognitive ability, socioeconomic status, race, and ethnicity. RESULTS: Eleven eligible articles were identified. Reporting rates of demographic factors varied considerably, with the highest rates for age and sex (100%) and the lowest reporting rates for race (18%) and ethnicity (9%). Combining demographic data from the two studies that reported on race and/or ethnicity (n = 33), 88% of participants were White. The combined participant mean age was 20.9 years. CONCLUSION: There is a low frequency of reporting on several demographic factors including socioeconomic status, race, and ethnicity in WS intervention studies. There is a need for increased representation of racial and ethnic minority groups, older participants, and more cognitively impaired patients in WS research.

Clinical Challenges and Solutions in Adapting Cognitive Behavioral Therapy for Anxiety in Adults With Intellectual Disability.

While cognitive behavioral therapy (CBT) is a first-line treatment for anxiety, it is not typically offered to those with intellectual disability (ID). In this article, we provide a historical perspective on the treatment of mental health concerns in adults with ID, describe an adapted CBT treatment for anxiety in adults with Williams syndrome (WS) and mild to moderate ID, and discuss general modifications to CBT for adults with ID. Strategies used to successfully adapt CBT for adults with WS that may generalize for adults with ID more broadly include: (a) using child-based CBT manuals as a framework; (b) involving a caregiver as a therapy partner; (c) incorporating a high level of repetition; (d) simplifying language; (e) slowing the pace of instruction; and (f) incorporating specific examples and adaptations for WS.

Repetitive Thoughts and Behaviors in Autism Spectrum Disorder: A Symptom-Based Framework for Novel Therapeutics.

While the core symptoms of autism spectrum disorder include repetitive thoughts and repetitive behaviors, repetitive phenomena also occur in many other psychiatric disorders. Types of repetitive thoughts include preoccupations, ruminations, obsessions, overvalued ideas, and delusions. Types of repetitive behaviors include tics, stereotypies, compulsions, extrapyramidal symptoms, and automatisms. We provide a description of how to recognize and classify different types of repetitive thoughts and behaviors in autism spectrum disorder, providing clarity on which phenomena should be considered a core feature of autism spectrum disorder and which phenomena are indicative of a comorbid psychiatric disorder. Clinical features that can be used to differentiate types of repetitive thoughts include whether they are distressing and the degree of insight the individual has, while repetitive behaviors can be classified based on whether they are voluntary, goal-directed/purposeful, and rhythmic. We present the psychiatric differential diagnosis of repetitive phenomena within the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) framework. Careful clinical consideration of these transdiagnostic features of repetitive thoughts and behaviors can improve diagnostic accuracy and treatment outcomes, and influence future research.

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.

Adaptive Behavior in Young Autistic Children: Associations with Irritability and ADHD Symptoms.

Attention-deficit/hyperactivity disorder (ADHD) symptoms affect 40-60% of autistic children and have been linked to differences in adaptive behavior. It is unclear whether adaptive behavior in autistic youth is directly impacted by co-occurring ADHD symptoms or by another associated feature of both autism and ADHD, such as increased irritability. The current study examined relationships between irritability, ADHD symptoms, and adaptive behavior in 3- to 7-year-old autistic children. Results suggest that, after adjusting for co-occurring ADHD symptoms, higher levels of irritability are associated with differences in social adaptive behavior specifically. Understanding relationships between irritability, ADHD, and adaptive behavior in autistic children is critical because measures of adaptive behavior, such as the Vineland Scales of Adaptive Functioning, are often used as a proxy for global functioning, as well as for developing intervention plans and measuring outcomes as primary endpoints in clinical trials.

Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children.

Importance: Antidepressant use during pregnancy has been associated with neurodevelopmental disorders in children in some studies. However, results may be explained by uncontrolled confounding by parental mental health status, genetics, and environmental factors. Objective: To evaluate the association between antidepressant use in pregnancy and neurodevelopmental outcomes in children. Design, Setting, and Participants: This cohort study of health care utilization data was separated into cohorts of publicly and privately insured pregnant individuals and their children nested in the Medicaid Analytic eXtract (MAX; 2000-2014) and the IBM MarketScan Research Database (MarketScan; 2003-2015). A total of 1.93 million pregnancies in MAX and 1.25 million pregnancies in MarketScan were recorded. Children were followed from birth until outcome diagnosis, disenrollment, death, or end of study (maximum 14 years). Analyses were conducted between August 2020 and July 2021. Exposures: Dispensing of antidepressant medication from gestational week 19 until delivery, the period of synaptogenesis. Main Outcomes and Measures: Neurodevelopmental disorders in children defined using validated algorithms. Early pregnancy exposure was considered in sensitivity analyses, and approaches to confounding adjustment included propensity score fine stratification, discontinuers comparison, and sibling analyses. Results: Among the individuals included in the analysis, there were 145 702 antidepressant-exposed and 3 032 745 unexposed pregnancies; the mean (SD) age among the antidepressant exposed and unexposed was 26.2 (5.7) and 24.3 (5.8) years in MAX and 32.7 (4.6) and 31.9 (4.6) years in MarketScan, respectively; and in MAX, which collected information on race and ethnicity, 72.4% of the antidepressant-exposed and 37.1% of the unexposed individuals were White. Crude results suggested up to a doubling in risk of neurodevelopmental outcomes associated with antidepressant exposure; however, no association was observed in the most fully adjusted analyses. When comparing antidepressant-exposed and unexposed siblings, hazard ratios were 0.97 (95% CI, 0.88-1.06) for any neurodevelopmental disorder, 0.86 (95% CI, 0.60-1.23) for autism spectrum disorder, 0.94 (95% CI, 0.81-1.08) for attention-deficit/hyperactivity disorder, 0.77 (95% CI, 0.42-1.39) for specific learning disorders, 1.01 (95% CI, 0.88-1.16) for developmental speech/language disorder, 0.79 (95% CI, 0.54-1.17) for developmental coordination disorder, 1.00 (95% CI, 0.45-2.22) for intellectual disability, and 0.95 (95% CI, 0.80-1.12) for behavioral disorders. Results were generally consistent for antidepressant classes and drugs and across exposure windows. Conclusions and Relevance: The results of this cohort study suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children. However, given strong crude associations, antidepressant exposure in pregnancy may be an important marker for the need of early screening and intervention.

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.

Association of Antipsychotic Drug Exposure in Pregnancy With Risk of Neurodevelopmental Disorders: A National Birth Cohort Study.

Importance: Although antipsychotic drugs cross the placenta and animal data suggest potential neurotoxic effects, information regarding human neurodevelopmental teratogenicity is limited. Objective: To evaluate whether children prenatally exposed to antipsychotic medication are at an increased risk of neurodevelopmental disorders (NDD). Design, Settings, and Participants: This birth cohort study used data from the Medicaid Analytic eXtract (MAX, 2000-2014) and the IBM Health MarketScan Research Database (MarketScan, 2003-2015) for a nationwide sample of publicly (MAX) and privately (MarketScan) insured mother-child dyads with up to 14 years of follow-up. The MAX cohort consisted of 2 034 883 children who were not prenatally exposed and 9551 who were prenatally exposed to antipsychotic medications; the MarketScan consisted of 1 306 408 and 1221 children, respectively. Hazard ratios were estimated through Cox proportional hazards regression, using propensity score overlap weights for confounding control. Estimates from both cohorts were combined through meta-analysis. Exposures: At least 1 dispensing of a medication during the second half of pregnancy (period of synaptogenesis), assessed for any antipsychotic drug, at the class level (atypical and typical), and for the most commonly used drugs (aripiprazole, olanzapine, quetiapine, risperidone, and haloperidol). Main Outcomes and Measures: Autism spectrum disorder, attention-deficit/hyperactivity disorder, learning disability, speech or language disorder, developmental coordination disorder, intellectual disability, and behavioral disorder, identified using validated algorithms, and the composite outcome of any NDD. Data were analyzed from April 2020 to January 2022. Results: The MAX cohort consisted of 2 034 883 unexposed pregnancies and 9551 pregnancies with 1 or more antipsychotic drug dispensings among women with a mean (SD) age of 26.8 (6.1) years, 204 (2.1%) of whom identified as Asian/Pacific Islander, 2720 (28.5%) as Black, 500 (5.2%) as Hispanic/Latino, and 5356 (56.1%) as White. The MarketScan cohort consisted of 1 306 408 unexposed and 1221 exposed pregnancies among women with a mean (SD) age of 33.1 (5.0) years; race and ethnicity data were not available. Although the unadjusted results were consistent with an approximate 2-fold increased risk for most exposure-outcome contrasts, risks were no longer meaningfully increased after adjustment (eg, pooled unadjusted vs adjusted hazard ratios [95% CI] for any NDD after any antipsychotic exposure: 1.91 [1.79-2.03] vs 1.08 [1.01-1.17]), with the possible exception of aripiprazole (1.36 [1.14-1.63]). Results were consistent across sensitivity analyses. Conclusions and Relevance: The findings of this birth cohort study suggest that the increased risk of NDD seen in children born to women who took antipsychotic drugs late in pregnancy seems to be explained by maternal characteristics and is not causally related with prenatal antipsychotic exposure. This finding highlights the importance of closely monitoring the neurodevelopment of the offspring of women with mental illness to ensure early intervention and support. The potential signal for aripiprazole requires replication in other data before causality can be assumed.

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.