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.

Identifying pediatric emergency department visits for aggression using administrative claims data.

OBJECTIVE: Violence and aggressive behaviors among youth are a leading cause of Emergency Department (ED) mental health (MH) encounters. A consistent method is needed for public health research, to identify ED encounters associated with aggression. The aim of this study was to develop such a screening procedure. DATA SOURCES: Electronic records and administrative claims data related to MH related ED encounters at one of Pediatric Health Information System (PHIS) Children's Hospitals in the United States from January 1, 2019 to December 31, 2019. STUDY DESIGN: The authors selected a combination of ICD-10 codes to screen MH ED encounters for aggression; and then conducted a chart review to compare characteristics of groups that screened positive vs. screened negative, and groups with confirmed vs. without confirmed aggression. DATA EXTRACTION METHOD: Unique ED encounters associated with a MH related ICD-10 code from a one-year period at the study institution were extracted (n = 3092 MH ED encounters). Encounters with any aggression-associated codes were identified as "screen-positive" (N = 349). From the remaining "screen-negative" encounters, 352 unique encounters were randomly selected as a comparison group. Both groups were chart reviewed to investigate the accuracy of the screening method. MAIN FINDING: Chart review confirmed aggression in 287 of 349 screen-positive and 48 of 352 select screen-negative, chart-reviewed encounters. Additional codes were added, with a goal of finding the combination of codes with the highest accuracy. The resulting screen had sensitivity, specificity, positive and negative predictive values of 0.901, 0.817, 0.818, and 0.864, respectively. PRINCIPAL CONCLUSIONS: This paper presents a screening method for identifying ED encounters related to aggression. A replication study will be necessary to validate the method prior to applying to large claims data. If validated, it will support future research on this important population.

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.).

Editors' Note and Special Communication: Research Priorities in Child and Adolescent Mental Health Emerging From the COVID-19 Pandemic.

Over the last year, the coronavirus disease 2019 (COVID-19) pandemic has resulted in profound disruptions across the globe, with school closures, social isolation, job loss, illness, and death affecting the lives of children and families in myriad ways. In an Editors' Note in our June 2020 issue,1 our senior editorial team described this Journal's role in advancing knowledge in child and adolescent mental health during the pandemic and outlined areas we identified as important for science and practice in our field. Since then, the Journal has published articles on the impacts of the pandemic on child and adolescent mental health and service systems,2-5 which are available in a special collection accessible through the Journal's website.6 Alongside many opinion papers, the pace of publication of empirical research in this area is rapidly expanding, covering important issues such as increased frequency of mental health symptoms among children and adolescents3,5,7-10 and changes in patterns of clinical service use such as emergency department visits.11-14 As the Senior Editors prepared that Editors' Note, they were acutely aware that the priorities that they identified were broad and generated by only a small group of scientists and clinicians. Although this had the advantage of enabling us to get this information out to readers quickly, we decided that a more systematic approach to developing recommendations for research priorities would be of greater long-term value. We were particularly influenced by the efforts of the partnership between the UK Academy of Medical Scientists and a UK mental health research charity (MQ: Transforming Mental Health) to detail COVID-19-related research priorities for "Mental Health Science" that was published online by Holmes et al. in The Lancet Psychiatry in April 2020.15 Consistent with its focus on mental health research across the lifespan, several recommendations highlighted child development and children's mental health. However, a more detailed assessment of research priorities related to child and adolescent mental health was beyond the scope of that paper. Furthermore, the publication of that position paper preceded the death of George Floyd at the hands of Minneapolis police on May 25, 2020, which re-energized efforts to acknowledge and to address racism and healthcare disparities in the United States and many other countries. To build upon the JAACAP Editors' Note1 and the work of Holmes et al.,15 we conducted an international survey of professionals-practitioners and researchers-working on child and adolescent development and pediatric mental health to identify concerns about the impact of the pandemic on children, adolescents, and their families, as well as what is helping families navigate these impacts, and the specific research topics that are of greatest importance.

Dr. Liu et al. Reply.

While there is growing acceptance within the field that measurement-based care (MBC) is a valuable and effective care quality improvement strategy, broad and sustained implementation continues to be elusive for most organizations.1 This is partly attributable to the lack of proven implementation strategies for MBC. Although implementation science has made significant progress in recent years,1 more work is needed to identify the most effective and efficient strategies for MBC implementation across a range of service delivery contexts.

Primary Care Management of Children with Attention-Deficit/Hyperactivity Disorder Appears More Assertive Following Brief Psychiatric Intervention Compared with Single Session Consultation.

Objectives: We examined primary care providers' (PCPs') management of attention-deficit/hyperactivity disorder (ADHD) during and following families' participation in two arms of the Children's ADHD Telemental Health Treatment Study. We hypothesized that more intensive treatment during the trial would show an "after-effect" with more assertive PCPs' management during short term follow-up. Methods: We conducted a pragmatic follow-up of PCPs' management of children with ADHD who had been randomized to two service delivery models. In the Direct Service Model, psychiatrists provided six sessions over 22 weeks of pharmacotherapy followed by behavior training. In the Consultation Model, psychiatrists provided a single-session consultation and made treatment recommendations to PCPs who implemented these recommendations at their discretion for 22 weeks. At the end of the trial, referring PCPs for both service delivery models resumed ADHD treatment for 10 weeks. We performed intent-to-treat analysis using all 223 original participants. We applied linear regression models on continuous outcomes, Poisson regression models on count outcomes, and logistic regression models to binary outcomes. Missing data were addressed through imputations. Results: Participants in the Direct Service Model had more ADHD visits than those in the Consultation Model across the full 32 weeks (mean = 7.05 visits vs. 3.36 visits; adjusted rate ratio = 2.1 [1.85-2.38]; p < 0.0001). During follow-up, participants in the DSM were more likely to be taking ADHD-related medications (82% vs. 61%; adjusted odds ratio = 2.44 [1.24-4.81], p = 0.01). At 32 weeks, participants in the Direct Service Model had higher stimulant dosages (adjusted difference = 5.64 [0.12-11.15] mg; p = 0.046). Conclusion: These results from a pragmatic follow-up of a randomized trial suggest an "after-effect" for brief intensive treatment in the Direct Service Model on the short term follow-up management of ADHD in primary care.

Editorial: A Spoonful of Injury Prevention Makes the ADHD Medicine Go Down.

Unintentional injuries are the leading cause of disability and mortality in youths across the United States1 and globally.2 Attention-deficit/hyperactivity disorder (ADHD) has been associated with an increased rate of unintentional injuries in multiple countries, as reviewed in a recent meta-analysis of studies in youths.3 The study by Ghirardi et al.4 in this issue of the Journal adds to this literature by examining this issue within stratifications of injury and of characteristics of youths with ADHD.4 The authors accessed a very large sample (nearly 2 million youths) drawn from the Truven Health MarketScan Commercial Claims and Encounters databases. They identified all youths in the databases with a diagnosis of ADHD or receiving an ADHD medication prescription from January 1, 2005, to December 31, 2014, who presented to an emergency department with unintentional injuries. To determine the differential rate of unintentional injuries, they used a case-control methodology to compare youths with a diagnosis of ADHD or an ADHD medication with a control group of youths without an ADHD diagnosis or treatment matched on a variety of characteristics. Results of the population comparison not only supported the overall association, but also demonstrated an increased rate of unintentional injuries for both boys and girls and that youths with ADHD had higher rates of traumatic brain injury compared with matched control youths without ADHD.4.

Mind the Gap: Considering Disparities in Implementing Measurement-Based Care.

Synergistic advancements in evidence-based practice, implementation science, health care policy, and health information technology (HIT) have led to increasing efforts to broadly implement measurement-based care (MBC)-the systematic use of repeated outcome measures to monitor treatment progress and support clinical decision making1-in psychiatric services. Much of this work has been done with adult populations, and more efforts are needed for MBC to gain traction in child and adolescent psychiatry. In this Letter to the Editor, we describe a quality improvement (QI) project that leveraged HIT to implement MBC in the child and adolescent psychiatry department of a regional pediatric tertiary-care center and report long-term (5-year) implementation outcomes (ie, adoption and penetration). Although a myriad of implementation strategies was used, here we focus on the most complex strategy-integrating a digital measurement-feedback system (MFS) into standard workflow. Then, we discuss pitfalls and lessons learned with special attention to potential unintended effects of QI efforts on existing health disparities.

The Children's Attention-Deficit Hyperactivity Disorder Telemental Health Treatment Study: Caregiver Outcomes.

The Children's Attention-deficit Hyperactivity Disorder (ADHD) Telemental Health Treatment Study (CATTS) tested the hypotheses that children and caregivers who received guideline-based treatment delivered through a hybrid telehealth service delivery model would experience greater improvements in outcomes than children and caregivers receiving treatment via a comparison delivery model. Here, we present caregiver outcomes. 88 primary care providers (PCPs) in seven geographically underserved communities referred 223 children (ages 5.5 - 12.9 years) to the randomized controlled trial. Over 22 weeks, children randomized to the CATTS service delivery model received six sessions of telepsychiatry and six sessions of caregiver behavior management training provided in person by community therapists who were trained and supervised remotely. Children randomized to the comparison Augmented Primary Care (APC) service model received management in primary care augmented by a single telepsychiatry consultation. Caregiver outcomes included changes in distress, as measured by the Patient Health Questionnaire (PHQ-9), Parenting Stress Index (PSI), Caregiver Strain Questionnaire (CSQ) and Family Empowerment Scale (FES). Caregivers completed five assessments. Multilevel mixed effects regression modeling tested for differences between the two service delivery models in caregiver outcomes from baseline to 25 weeks. Compared to caregivers of children in the APC model, caregivers of children in the CATTS service model showed statistically significantly greater improvements on the PHQ-9 (ß = -1.41, 95 % CI = [-2.74, -0.08], p < .05), PSI (ß = -4.59, 95 % CI = [-7.87, - 1.31], p < .001), CSQ (ß = -5.41, 95 % CI = [- 8.58, -2.24], p < .001) and FES (ß = 6.69, 95 % CI = [2.32, 11.06], p < .01). Improvement in child ADHD symptoms mediated improved caregiver scores on the PSI and CSQ. Improvement in child ODD behaviors mediated caregiver CSQ scores. The CATTS trial supports the effectiveness of a hybrid telehealth service delivery model for reducing distress in caregivers of children with ADHD and suggests a mechanism through which the service model affected caregiver distress.

Telepsychiatrists' Medication Treatment Strategies in the Children's Attention-Deficit/Hyperactivity Disorder Telemental Health Treatment Study.

OBJECTIVE: The purpose of this study was to examine the prescribing strategies that telepsychiatrists used to provide pharmacologic treatment in the Children's Attention-Deficit/Hyperactivity Disorder (ADHD) Telemental Health Treatment Study (CATTS). METHODS: CATTS was a randomized controlled trial that demonstrated the superiority of a telehealth service delivery model for the treatment of ADHD with combined pharmacotherapy and behavior training (n=111), compared with management in primary care augmented with a telepsychiatry consultation (n=112). A diagnosis of ADHD was established with the Computerized Diagnostic Interview Schedule for Children (CDISC), and comorbidity for oppositional defiant disorder (ODD) and anxiety disorders (AD) was established using the CDISC and the Child Behavior Checklist. Telepsychiatrists used the Texas Children's Medication Algorithm Project (TCMAP) for ADHD to guide pharmacotherapy and the treat-to-target model to encourage their assertive medication management to a predetermined goal of 50% reduction in ADHD-related symptoms. We assessed whether telepsychiatrists' decision making about making medication changes was associated with baseline ADHD symptom severity, comorbidity, and attainment of the treat-to-target goal. RESULTS: Telepsychiatrists showed high fidelity (91%) to their chosen algorithms in medication management. At the end of the trial, the CATTS intervention showed 46.0% attainment of the treat-to-target goal compared with 13.6% for the augmented primary care condition, and significantly greater attainment of the goal by comorbidity status for the ADHD with one and ADHD with two comorbidities groups. Telepsychiatrists' were more likely to decide to make medication adjustments for youth with higher baseline ADHD severity and the presence of disorders comorbid with ADHD. Multiple mixed methods regression analyses controlling for baseline ADHD severity and comorbidity status indicated that the telepsychiatrists also based their decision making session to session on attainment of the treat-to-target goal. CONCLUSIONS: Telepsychiatry is an effective service delivery model for providing pharmacotherapy for ADHD, and the CATTS telepsychiatrists showed high fidelity to evidence-based protocols.

ASD: Psychopharmacologic Treatments and Neurophysiologic Underpinnings.

Autism Spectrum Disorder encompasses a range of neurodevelopmental disorders characterized by early deficits in social communication in addition to restricted and repetitive behaviors. Symptoms are increasingly understood to be associated with abnormalities in the coordination of neuronal assemblies responsible for processing information essential for early adaptive behaviors. Pharmacologic treatments carry evidence for clinically significant benefit of multiple impairing symptoms of ASD, yet these benefits are limited and range across a broad spectrum of medication classes, making it difficult to characterize associated neurochemical impairments. Increasing prevalence of both ASD and its pharmacologic management calls for greater understanding of the neurophysiologic basis of the disorder. This paper reviews underlying alterations in local brain regions and coordination of brain activation patterns during both resting state and task-related processes. We propose that new pharmacologic treatments may focus on realigning trajectories of network specialization across development by working in combination with behavioral treatments to enhance social and emotional learning by bolstering the impact of experience-induced plasticity on neuronal network connectivity.

What clinical differences distinguish depressed teens with and without comorbid externalizing problems?

OBJECTIVE: This study examined differences in co-occurring symptoms, psychosocial correlates, health care utilization and functional impairment in youth who screened positive for depression, stratified by whether or not they also self-reported externalizing problems. METHODS: The AdoleSCent Health Study examined a random sample of youth ages 13-17 enrolled in a health care system. A total of 2291 youth (60.7% of the eligible sample) completed a brief depression screen: the two-item Patient Health Questionnaire. The current analyses focus on a subset of youth (n=113) who had a follow-up interview and screened positive for possible depression on the Patient Health Questionnaire 9 using a cutoff score of 11 or higher [1]. Youth were categorized as having externalizing behavior if their score was ≥ 7 on the Pediatric Symptom Checklist (PSC) externalizing scale [2,3]. χ(2) tests and Wilcoxon rank sum tests were used to compare groups. RESULTS: Differences between groups included that youth with depression and externalizing symptoms had a higher rate of obesity and had higher self-reported functional impairment than youth with depression symptoms alone. CONCLUSIONS: Adding screening for externalizing problems to existing recommendations for depression screening may help primary care providers to identify a high-risk depressed group of youth for referral to mental health services.

Healthcare costs associated with mild traumatic brain injury and psychological distress in children and adolescents.

PRIMARY OBJECTIVE: Comparison of healthcare costs for youth with mild traumatic brain injuries (TBIs) to costs in a matched cohort of children without TBI in the 3 years following injury. RESEARCH DESIGN: This study used a prospective cohort design with 3-year follow-up. Costs were examined using the well-established two-step model and controlling for potential confounding variables. METHODS AND PROCEDURES: Four-hundred and ninety subjects from a large health maintenance organization, 14 years old or younger, who sustained a mild TBI in 1993, were identified using computerized records. For each youth with mild TBI, three control subjects were selected (n = 1470), matched on age, sex and enrolment at the time of injury. EXPERIMENTAL INTERVENTIONS: Not applicable. MAIN OUTCOMES AND RESULTS: TBI exposure was associated with an increase in the proportion of subjects who had non-zero medical costs in all categories examined and a 75% increase in mean total costs. Presence of psychological distress was also associated with increased proportion of subjects with costs in all categories examined and was associated with an approximate doubling of mean total costs. CONCLUSIONS: Mild TBI and psychological distress were each associated with significant increases in healthcare costs in an HMO setting.

Social competence and social support as mediators between comorbid depressive and conduct problems and functional outcomes in middle school children.

This study examined the roles of social competence and social support as potential mediators of the association between psychopathology and functional outcomes in a middle school sample (n=521). Participants were stratified into four psychopathology risk groups (depression only, conduct problems only, comorbid depression and conduct problems, low symptoms) based on screening during early 6th grade. Functional outcomes were 6th grade point average (GPA) and parent rating of global adaptive functioning in their 7th grade student. Low levels of social competence were found to mediate the association between symptoms and both lower grades and global functioning for adolescents with depressive symptoms alone and with comorbid symptoms, but not for those with conduct problems alone. Lack of social support mediated the association between psychiatric symptoms and lower grades for adolescents with depression alone and comorbid symptoms, but not for those with conduct problems alone. These findings suggest that intervention to improve social competence and social support may enhance functional outcomes, especially for youth with depressive symptoms or comorbid depressive and conduct symptoms.

Agreement between parents and children regarding anxiety and depression diagnoses in children with asthma.

This study examined parent-child agreement regarding anxiety and depressive disorders in youth with asthma and evaluated key demographic and health differences associated with parent-child agreement. Of 756 outpatient youth with asthma, 122 (16.0%) were diagnosed with a DSM-IV anxiety or depression disorder using the Diagnostic Interview Schedule for Children (C-DISC). Parents reported on internalizing symptoms using the Child Behavior Checklist (CBCL). Logistic regression analyses were used to examine factors related to parent- and child-reported symptom agreement. Low rates of agreement (48.9%) between youth and parents regarding diagnosis of a DSM-IV anxiety or depressive disorder were found among youth with asthma. Increased agreement was associated with higher externalizing behavior score on the CBCL and more anxiety and depressive symptoms on the C-DISC. Children without behavioral problems and with less severe anxiety and depression were recognized significantly less often by their parents.

Friendship interactions in children with and without depressive symptoms: observation of emotion during game-playing interactions and post-game evaluations.

This observational study supplements the strong and consistent link found between childhood depression and deficits in interpersonal functioning by examining the relationship between a high versus low score on the Children's Depression Inventory (CDI) and children's emotions when interacting with their best friends. High-CDI and low-CDI target children (n=86) were paired for videotaped game-playing with self-reported best friends. Researchers found that although high-CDI target children were not distinguishable from low-CDI peers in their displays of positive and negative emotion. However, the partners of high-CDI target children displayed significantly more negative emotion during the competitive task and significantly less positive emotion during the cooperative task than did partners of low-CDI target children. In addition, high-CDI target children and their partners reported less enjoyment of their interactions than low-CDI target children and their partners. This combination of findings suggests that depressive symptoms were associated with a relative lack of success achieving an optimal friendship interaction even under highly favorable conditions.