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.

Clinical Practice Guideline for the Assessment and Treatment of Children and Adolescents With Major and Persistent Depressive Disorders.

OBJECTIVE: To enhance the quality of care and clinical outcomes for children and adolescents with major depressive disorder (MDD) and persistent depressive disorder (PDD). The aims are as follows: (1) to summarize empirically based guidance about the psychosocial and psychopharmacologic treatment of MDD and PDD in children and adolescents; and (2) to summarize expert-based guidance about the assessment of these disorders as an integral part of treatment, and the implementation of empirically based treatments for these disorders in clinical practice. METHOD: Statements about the treatment of MDD and PDD are based upon empirical evidence derived from a critical systematic review of the scientific literature conducted by the Research Triangle Institute International-University of North Carolina at Chapel Hill (RTI-UNC) Evidence-based Practice Center under contract with the Agency for Healthcare Research and Quality (AHRQ). Evidence from meta-analyses published since the AHRQ/RTI-UNC review is also presented to support or refute the AHRQ findings. Guidance about the assessment and clinical implementation of treatments for MDD and PDD is informed by expert opinion and consensus as presented in previously published clinical practice guidelines, chapters in leading textbooks of child and adolescent psychiatry, the DSM-5-TR, and government-affiliated prescription drug information websites. RESULTS: Psychotherapy (specifically, cognitive-behavioral and interpersonal therapies) and selective serotonin reuptake inhibitor (SSRI) medication have some rigorous (randomized controlled trials, meta-analyses) empirical support as treatment options. Because effective treatment outcomes are predicated in part upon accuracy of the diagnosis, depth of the clinical formulation, and breadth of the treatment plan, comprehensive, evidence-based assessment may enhance evidence-based treatment outcomes. CONCLUSION: Disproportionate to the magnitude of the problem, there are significant limitations in the quality and quantity of rigorous empirical support for the etiology, assessment, and treatment of depression in children and adolescents. In the context of a protracted severe shortage of child and adolescent-trained behavioral health specialists, the demonstration of convenient, efficient, cost-effective, and user-friendly delivery mechanisms for safe and effective treatment of MDD and PDD is a key research need. Other research priorities include the sequencing and comparative effectiveness of depression treatments, delineation of treatment mediators and moderators, effective approaches to treatment nonresponders and disorder relapse/recurrence, long-term effects and degree of suicide risk with SSRI use, and the discovery of novel pharmacologic or interventional treatments.

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.).

Psychotropic Medication Prescribing for Youth at a Regional Autism Center.

Objectives: The Seattle Children's Autism Center (SCAC) serves youth throughout Washington state (WA). The authors examined (1) whether the ethnicity and race of patients seen at the SCAC aligned with the demographics reported in the WA census, and (2) whether psychotropic medication prescriptions were associated with patient factors, including age, sex, ethnicity, race, insurance, visit number, and diagnoses. Methods: The authors extracted demographic and prescription data from electronic medical records for all patients (3-21 years) seen at the SCAC in 2018 for psychiatric medication evaluation in the context of autism spectrum disorder (ASD) and/or other related neurodevelopmental disorder (n = 1112), and used binary logistic regression to ascertain the effects of patient factors on psychotropic prescriptions. Results: The SCAC study sample appeared to align well with the WA census. Older age and higher visit number were among the most significant factors associated with psychotropic prescriptions. Psychotropic prescriptions increased with age, across all categories, except attention-deficit/hyperactivity disorder medications. There were no sex differences in prescribing rates. There were differences in prescribing rates by ethnicity and race. There were also increased prescription rates among those with Medicaid insurance. Conclusion: These demographic differences in prescribing for youth with ASD provide more specificity than prior studies about sex, ethnic, racial, and insurance-related differences, and can serve as an impetus to examine the reasons for variance.

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.

Editorial: For Adolescents With Subthreshold Depression, Is an Ounce of Prevention Worth a Pound of Cure?

Globally, depression is among the leading neuropsychiatric disorders of adolescence. Conventional wisdom indicates that an "ounce of prevention is worth a pound of cure," a perspective bolstered by some studies demonstrating that psychological interventions for subthreshold depression reduce acute symptoms and prevent the onset of major depressive disorder (MDD) over short-term follow-up. However, the meta-analysis by Cuijpers et al.,1 the first to pool results from all available relevant studies in the field, provides evidence that would seem to challenge this conventional wisdom. The meta-analysis included 12 randomized controlled trials of children and adolescents. This editorial focuses on the 10 studies with adolescents (age range, 13.5-17.4 years), who were recruited from schools (n = 6), medical settings (n = 3), and mass mailings (n = 1). The youths received short-term psychotherapies ranging from 6 to 16 sessions, primarily cognitive-behavioral therapy or interpersonal therapy, or inactive control/care as usual. Results showed significant short-term benefits in reducing acute depression symptoms, even though effect size was small to medium (number needed to treat = 8.4). At 6-18 months of follow-up, however, the likelihood of meeting full criteria for MDD was not significantly different between the intervention and control conditions. We child and adolescent psychiatrists have difficulty yielding our commitment to conventional wisdom and look for evidence that this meta-analysis is not the last word on the value of early interventions for subthreshold depression to prevent MDD in adolescents.

Clinical Practice Guideline for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders.

Anxiety disorders are among the most common psychiatric disorders in children and adolescents. As reviewed in this guideline, both cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitor (SSRI) medication have considerable empirical support as safe and effective short-term treatments for anxiety in children and adolescents. Serotonin norepinephrine reuptake inhibitor (SNRI) medication has some empirical support as an additional treatment option. In the context of a protracted severe shortage of child and adolescent-trained behavioral health specialists, research demonstrating convenient, efficient, cost-effective, and user-friendly delivery mechanisms for safe and effective treatments for child and adolescent anxiety disorders is an urgent priority. The comparative effectiveness of anxiety treatments, delineation of mediators and moderators of effective anxiety treatments, long-term effects of SSRI and SNRI use in children and adolescents, and additional evaluation of the degree of suicide risk associated with SSRIs and SNRIs remain other key research needs.

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.

Practice Parameter for the Assessment and Treatment of Psychiatric Disorders in Children and Adolescents With Intellectual Disability (Intellectual Developmental Disorder).

Intellectual disability (intellectual developmental disorder) (ID/IDD) is both a psychiatric disorder and a risk factor for co-occurring psychiatric disorders in children and adolescents. DSM-5 introduced important changes in the conceptualization and diagnosis of ID/IDD, and current research studies clarify assessment and treatment of co-occurring psychiatric disorders in this population. Optimal assessment and treatment of psychiatric illness in children and adolescents with ID/IDD includes modifications in diagnostic and treatment techniques, appreciation of variations in the clinical presentation of psychiatric disorders, an understanding of the spectrum of etiologies of behavioral disturbance, and knowledge of psychosocial and medical interventions.

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.

Extended-Release Guanfacine for Hyperactivity in Children With Autism Spectrum Disorder.

OBJECTIVE: Hyperactivity, impulsiveness, and distractibility are common problems in children with autism spectrum disorder (ASD). Extended-release guanfacine is approved for children with attention deficit hyperactivity disorder but not well studied in ASD. METHOD: In a multisite, randomized clinical trial, extended-release guanfacine was compared with placebo in children with ASD accompanied by hyperactivity, impulsiveness, and distractibility. RESULTS: Sixty-two subjects (boys, N=53; girls, N=9; mean age=8.5 years [SD=2.25]) were randomly assigned to guanfacine (N=30) or placebo (N=32) for 8 weeks. The guanfacine group showed a 43.6% decline in scores on the Aberrant Behavior Checklist-hyperactivity subscale (least squares mean from 34.2 to 19.3) compared with a 13.2% decrease in the placebo group (least squares mean from 34.2 to 29.7; effect size=1.67). The rate of positive response (much improved or very much improved on the Clinical Global Impression-Improvement scale) was 50% (15 of 30) for guanfacine compared with 9.4% (3 of 32) for placebo. A brief cognitive battery tapping working memory and motor planning showed no group differences before or after 8 weeks of treatment. The modal dose of guanfacine at week 8 was 3 mg/day (range: 1-4 mg/day), and the modal dose was 3 mg/day (range: 2-4 mg/day) for placebo. Four guanfacine-treated subjects (13.3%) and four placebo subjects (12.5%) exited the study before week 8. The most common adverse events included drowsiness, fatigue, and decreased appetite. There were no significant changes on ECG in either group. For subjects in the guanfacine group, blood pressure declined in the first 4 weeks, with return nearly to baseline by endpoint (week 8). Pulse rate showed a similar pattern but remained lower than baseline at endpoint. CONCLUSIONS: Extended-release guanfacine appears to be safe and effective for reducing hyperactivity, impulsiveness, and distractibility in children with ASD.

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.