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.).

Prevalence of bias against neurodivergence-related terms in artificial intelligence language models.

Given the increasing role of artificial intelligence (AI) in many decision-making processes, we investigate the presence of AI bias towards terms related to a range of neurodivergent conditions, including autism, ADHD, schizophrenia, and obsessive-compulsive disorder (OCD). We use 11 different language model encoders to test the degree to which words related to neurodiversity are associated with groups of words related to danger, disease, badness, and other negative concepts. For each group of words tested, we report the mean strength of association (Word Embedding Association Test [WEAT] score) averaged over all encoders and find generally high levels of bias. Additionally, we show that bias occurs even when testing words associated with autistic or neurodivergent strengths. For example, embedders had a negative average association between words related to autism and words related to honesty, despite honesty being considered a common strength of autistic individuals. Finally, we introduce a sentence similarity ratio test and demonstrate that many sentences describing types of disabilities, for example, "I have autism" or "I have epilepsy," have even stronger negative associations than control sentences such as "I am a bank robber."

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.

Pragmatic adaptations of telehealth-delivered caregiver coaching for children with autism in the context of COVID-19: Perspectives from the United States and South Africa.

LAY ABSTRACT: COVID-19 caused many autism spectrum disorder caregiver-coaching studies to move to telehealth. Telehealth can increase the diversity of people who take part in research. This matters because most autism spectrum disorder studies have included people who have resources, are White, and live in North America and Europe. When study participants are similar, it is hard to understand which interventions can help different types of people who live in different parts of the world. While telehealth may allow more people to take part in research, it needs to "fit" the local context and consider the "digital divide" because many people around the world have no access to computers and the Internet. This short report describes changes to two research studies that include caregiver coaching based on the Early Start Denver Model in the United States and South Africa. We describe how the local context, including technology and Internet access, guided the telehealth approach. By doing so, we highlight ways to make telehealth available to more people around the world. The pandemic can help us understand how telehealth can "fit" diverse places and support high-quality research. It is important that study changes are tracked and we assess how well the changes work. COVID-19 telehealth changes to caregiver coaching can result in new ways to reach more people around the world.

Meeting the mental health needs of autistic college students: a survey of university and college counseling center clinicians.

OBJECTIVE: University and college counseling centers (UCCCs) are a front-line support for the mental health needs of autistic students, though little is known about clinician attitudes, comfort level, and training in autism. PARTICIPANTS: 89 UCCC clinicians were recruited via email listservs. METHODS: The authors developed a survey which assessed attitudes, comfort level, and training in autism. RESULTS: The majority of clinicians (82.0%, n = 73) had interacted with autistic students in the past year, and reported high levels of comfort with treating anxiety and depression. However, a smaller number reported confidence in their ability to diagnose autism. Training on autism emerged as an important deficit, as 31.5% of the clinicians denied receiving training either in their educational program or the UCCC. CONCLUSIONS: In this pilot study, clinicians reported a discrepancy between self-reported levels of comfort with autistic college students and past training, highlighting continuing education as an important area for future intervention.

Meeting the Mental Health Needs of College Students with ASD: A Survey of University and College Counseling Center Directors.

An increasing number of individuals with Autism Spectrum Disorder (ASD) are enrolling in post-secondary education. Though many students may use services provided by university and college counseling centers (UCCCs), little is known about the landscape of care for students with ASD in this setting. UCCC directors (n = 79) completed an online survey to assess current utilization, clinician experience with ASD, and campus collaborations. While the majority of directors (69.7%) reported an increase in students with ASD requesting mental health services at their centers, the survey identified a discrepancy between their intention to improve services and current reported levels of expertise, training, and resources. Directors identified barriers to improving UCCC services to students with ASD, providing direction for future improvement.

Supporting the needs of college students with autism spectrum disorder.

OBJECTIVE: Young adults with autism spectrum disorder (ASD) are enrolling in colleges at increasing rates. This case highlights the need for college mental health clinicians to be aware of features of ASD in emerging adults. Participants: A case of a young woman with dysphoria and anxiety who also met ASD criteria during a diagnostic evaluation. Methods: The author describes diagnostic criteria for ASD, common psychiatric co-morbidities, and commonly used campus services. Results: The student in this case was diagnosed with ASD during the course of treatment for dysphoria and anxiety. Knowledge of this diagnosis led to better self-understanding and discovery of new supports. Conclusions: College mental health clinicians will increasingly encounter students with ASD whose social and communication challenges impact their success in post-secondary educational environments. Clinicians should be knowledgeable of ASD features, common mental health challenges, and how best to support students.

Autism, Psychosis, or Both? Unraveling Complex Patient Presentations.

Autism spectrum disorders (ASDs) and schizophrenia spectrum disorders co-occur at elevated rates. Although these conditions are diagnostically distinct, they share multiple clinical features and genetic risk factors. This article describes the epidemiologic features and clinical manifestations of psychosis in individuals with ASDs, while also discussing shared genetic risk factors and affected brain regions. Components of a diagnostic assessment, including a thorough developmental, behavioral, medical, and psychiatric history, will be reviewed. The authors highlight the manifestations of catatonia in this population and note the shared features between catatonia and ASDs. Finally, treatment approaches and areas for future study are suggested.

Rationale, design, and methods of the Autism Centers of Excellence (ACE) network Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B).

OBJECTIVE: To describe the rationale, design, and methods of the Autism Centers of Excellence (ACE) network Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B). METHOD: This phase 2 clinical trial was designed to evaluate the use of intranasal oxytocin treatment to improve social difficulties in individuals with autism spectrum disorder (ASD). In total, 290 participants ages 3 to 17 years with a DSM-5 diagnosis of ASD were enrolled to receive 24 weeks of treatment with either oxytocin or a matched placebo at one of seven collaborating sites. Participants were subsequently treated with open-label oxytocin for 24 additional weeks. Post-treatment assessments were done approximately 4 weeks after treatment discontinuation. Plasma oxytocin and oxytocin receptor gene (OXTR) methylation level were measured at baseline, and week 8, 24 and 36 to explore potential relationships between these biomarkers and treatment response. RESULTS: This report describes the rationale, design, and methods of the SOARS-B clinical trial. CONCLUSIONS: There is a tremendous unmet need for safe and effective pharmacological treatment options that target the core symptoms of ASD. Several studies support the hypothesis that intranasal oxytocin could improve social orienting and the salience of social rewards in ASD, thereby enhancing reciprocal social behaviors. However, due to conflicting results from a number of pilot studies on the prosocial effects of exogenous oxytocin, this hypothesis remains controversial and inconclusive. SOARS-B is the best powered study to date to address this hypothesis and promises to improve our understanding of the safety and efficacy of intranasal oxytocin in the treatment of social deficits in children with ASD.

Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial.

Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors for premature cardiovascular mortality, are especially frequent in youth, optimal strategies to reduce pediatric antipsychotic-induced overweight/obesity are unclear. The Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) was a randomized, parallel group, 24-week clinical trial which enrolled overweight/obese, psychiatrically stable youth, aged 8-19 years, with a DSM-IV diagnosis of severe mental illness (schizophrenia spectrum disorder, bipolar spectrum disorder or psychotic depression), at four US universities. All of them had developed substantial weight gain following treatment with a second-generation antipsychotic. The centralized, computer-based randomization system assigned participants to unmasked treatment groups: metformin (MET); antipsychotic switch (aripiprazole or, if already exposed to that drug, perphenazine or molindone; SWITCH); or continued baseline antipsychotic (CONTROL). All participants received healthy lifestyle education. The primary outcome was body mass index (BMI) z-score change from baseline, analyzed using estimated least squares means. Altogether, 127 participants were randomized: 49 to MET, 31 to SWITCH, and 47 to CONTROL. BMI z-score decreased significantly with MET (week 24: -0.09±0.03, p=0.002) and SWITCH (week 24: -0.11±0.04, p=0.003), while it increased non-significantly with CONTROL (week 24: +0.04±0.03). On 3-way comparison, BMI z-score changes differed significantly (p=0.001). MET and SWITCH were each superior to CONTROL (p=0.002), with effect sizes of 0.68 and 0.81 respectively, while MET and SWITCH did not differ. More gastrointestinal problems occurred in MET than in SWITCH or CONTROL. The data safety monitoring board closed the perphenazine-SWITCH arm because 35.2% of subjects discontinued treatment due to psychiatric worsening. These data suggest that pediatric antipsychotic-related overweight/obesity can be reduced by adding metformin or switching to a lower risk antipsychotic. Healthy lifestyle education is not sufficient to prevent ongoing BMI z-score increase.

A Review of Methods for Monitoring Adverse Events in Pediatric Psychopharmacology Clinical Trials.

Pediatric psychotropic prescription rates are rising, emphasizing the need for careful monitoring of drug safety in this population. Currently, no standardized assessments are used in clinical trials for adverse event (AE) elicitation focused on long-term drug treatment in pediatric patients. Despite a lack of standardized AE elicitation methods in psychiatric clinical trials, it is clear that psychiatric medications have developmentally dependent AEs that differ from those observed in adults. In this review, we discuss the use of general inquiry elicitation, drug-specific checklists, and systematic elicitation scales for AE reporting in pediatric psychopharmacology trials. The checklists evaluated include the Barkley Side Effect Rating Scales (SERS), the Pittsburg side effect rating scale, and the Systematic Monitoring of Adverse events Related to TreatmentS (SMARTS) checklist. The systematic assessment scales discussed include the Systematic Assessment for Treatment of Emergent Events (SAFTEE) and the Safety Monitoring Uniform Report Form (SMURF). We review the advantages and disadvantages of each method and discuss the need for optimal assessment of AEs. AE instruments that are created and utilized for pediatric psychiatric trials must begin to incorporate symptoms that are relevant to this population and account for the nature of the disorders to better characterize treatment-emergent AEs and monitor long-term safety.

Challenges in the diagnosis and treatment of depression in autism spectrum disorders across the lifespan.

Diagnosis and treatment of comorbid neuropsychiatric illness is often a secondary focus of treatment in individuals with autism spectrum disorder (ASD), given that substantial impairment may be caused by core symptoms of ASD itself. However, psychiatric comorbidities, including depressive disorders, are common and frequently result in additional functional impairment, treatment costs, and burden on caregivers. Clinicians may struggle to appropriately diagnose depression in ASD due to communication deficits, atypical presentation of depression in ASD, and lack of standardized diagnostic tools. Specific risk and resilience factors for depression in ASD across the lifespan, including level of functioning, age, family history, and coping style, have been suggested, but require further study. Treatment with medications or psychotherapy may be beneficial, though more research is required to establish guidelines for management of symptoms. This review will describe typical presentations of depression in individuals with ASD, review current information on the prevalence, assessment, and treatment of comorbid depression in individuals with ASD, and identify important research gaps.

En los sujetos con un trastorno del espectro autista (TEA) el diagnóstico y tratamiento de la enfermedad neuropsiquiátrica comórbida es a menudo un foco secundario de la terapia, dado que el deterioro principal puede estar causado por los síntomas nucleares del TEA propiamente tal. Sin embargo, las comorbilidades psiquiátricas, incluyendo los trastornos depresivos, son comunes y frecuentemente se traducen en adicionales deterioros funcionales, costos del tratamiento y carga para los cuidadores. Los clínicos pueden tener dificultades para diagnosticar adecuadamente la depresión en el TEA debido a los déficits de comunicación, la presentación atípica de la depresión en el TEA y la falta de herramientas diagnósticas estandarizadas. Si bien se han sugerido factores de resiliencia y riesgo específico para la depresión en el TEA a lo largo de la vida como el nivel de funcionamiento, la edad, la historia familiar y el estilo de adaptación, se requiere de más estudio. El tratamiento medicamentoso o la psicoterapia pueden ser útiles, aunque se requiere de más investigación para establecer guías de manejo de los síntomas. Este artícu-lo describe las presentaciones típicas de la depresión en sujetos con TEA, revisa la información actualizada sobre la prevalencia, evaluación y tratamiento de la depresión comórbida en estos individuos e identifica importantes vacíos de la investigación.

Le diagnostic et le traitement des maladies neuropsychiatriques comorbides sont souvent un axe secondaire du traitement des individus ayant un trouble du spectre de l'autisme (TSA), une détérioration importante pouvant être causée par les symptômes de fond du TSA lui-même. Cependant, les comorbidités psychiatriques, dont les troubles dépressifs, sont courantes et entraînent fréquemment un handicap fonctionnel supplémentaire, des coûts pour les traitements et une charge pour les soignants. Il est parfois difficile pour les médecins de diagnostiquer de façon adéquate la dépression dans les TSA à cause des déficits de communication, de la présentation atypique de la dépression et du manque d'outils diagnostiques standardisés. Les risques spécifiques et les facteurs de résilience pour la dépression dans les TSA au long de la vie, y compris le niveau de fonctionnement, l'âge, les antécédents familiaux et le mode d'adaptation ont été suggérés, mais nécessitent d'être étudiés. Des traitements médicamenteux ou psychothérapiques peuvent être bénéfiques, mais il faut d'autres recherches pour établir des recommandations pour la prise en charge des symptômes. Cet article décrira les présentations typiques de la dépression chez les personnes atteintes de TSA, reconsidèrera l'information actuelle sur la prévalence, l'évaluation et le traitement de la dépression comorbide chez les personnes atteintes de TSA et identifiera les lacunes importantes de la recherche.