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Hyperserotonemia, or elevated levels of whole blood serotonin (WB5-HT), was the first biomarker linked to autism spectrum disorder (ASD). Despite numerous studies investigating the etiology of hyperserotonemia, results have been inconsistent. Recent findings suggest a relationship between the immune system and hyperserotonemia. The current study investigated whether intestinal 5-HT levels, 5-HT gene expression, or intestinal cell types predict WB5-HT. Participants included thirty-one males aged 3-18 who were classified into one of three groups: ASD and functional GI issues, typically developing with GI issues, and typically developing without GI issues. Samples from a lower endoscopy were analyzed to examine the pathways in predicting WB-5HT. Results demonstrated an association between T-Lymphocytes and WB5-HT.

There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults.V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (60 or ≥60), sex, region (North America or rest of world), and age (25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917).Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred.Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures.F Hoffmann-La Roche.

High rates of placebo response are increasingly implicated in failed autism spectrum disorder (ASD) clinical trials. Despite this, there are limited investigations of placebo response in ASD. We sought to identify baseline predictors of placebo response and quantify their influence on clinical scales of interest for three harmonized randomized clinical trials of balovaptan, a V1a receptor antagonist. We employed a two-step approach to identify predictors of placebo response on the Vineland-II two-domain composite (2DC) (primary outcome and a caregiver measure) and Clinical Global Impression (CGI) scale (secondary outcome and a clinician measure). The initial candidate predictor set of variables pertained to participant-level, site-specific, and protocol-related factors. Step 1 aimed to identify influential predictors of placebo response using Least Absolute Shrinkage and Selection Operator (LASSO) regression, while Step 2 quantified the influence of predictors via linear regression. Results were validated through statistical bootstrapping approaches with 500 replications of the analysis dataset. The pooled participant-level dataset included individuals with ASD aged 5 to 62 years (mean age 21 [SD 10]), among which 263 and 172 participants received placebo at Weeks 12 and 24, respectively. Although no influential predictors were identified for CGI, findings for Vineland-II 2DC are robust and informative. Decreased placebo response was predicted by higher baseline Vineland-II 2DC (i.e., more advanced adaptive function), longer trial duration, and European (vs United States) sites, while increased placebo response was predicted by commercial (vs academic) sites, attention deficit hyperactivity disorder and depression. Identification of these factors may be useful in anticipating and mitigating placebo response in drug development efforts in ASD and across developmental and psychiatric conditions.

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess “bridging” collaterals within the globus pallidus (GPe), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches to dissect the roles of bridging collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of pallidostriatal Npas1 neurons. We propose a model by which dSPN GPe collaterals (“striatopallidal Go pathway”) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 signals going back to the striatum.

Williams Syndrome is a rare neurodevelopmental disorder exhibiting cognitive and behavioral abnormalities, including increased social motivation, risk of anxiety and specific phobias along with perturbed motor function. Williams Syndrome is caused by a microdeletion of 26-28 genes on chromosome 7, includingGTF2IRD1, which encodes a transcription factor suggested to play a role in the behavioral profile of Williams Syndrome. Duplications of the full region also lead to frequent autism diagnosis, social phobias, and language delay. Thus, genes in the region appear to regulate social motivation in a dose-sensitive manner. A ‘Complete Deletion’ mouse, heterozygously eliminating the syntenic Williams Syndrome region, has been deeply characterized for cardiac phenotypes, but direct measures of social motivation have not been assessed. Furthermore, the role ofGtf2ird1in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressingGtf2ird1, which can be used both to model duplication of this gene alone and to rescueGtf2ird1expression in the Complete Deletion mice. Using a comprehensive behavioral pipeline and direct measures of social motivation, we provide evidence that the Williams Syndrome Critical Region regulates social motivation along with motor and anxiety phenotypes, but thatGtf2ird1complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However,Gtf2ird1complementation does rescue light-aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.

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.

Background The identification of reproducible subtypes within autistic populations is a priority research area in the context of neurodevelopment, to pave the way for identification of biomarkers and targeted treatment recommendations. Few previous studies have considered medical comorbidity alongside behavioural, cognitive, and psychiatric data in subgrouping analyses. This study sought to determine whether differing behavioural, cognitive, medical, and psychiatric profiles could be used to distinguish subgroups of children on the autism spectrum in the Australian Autism Biobank (AAB). Methods Latent profile analysis was used to identify subgroups of children on the autism spectrum within the AAB (n = 1151), utilising data on social communication profiles and restricted, repetitive, and stereotyped behaviours (RRBs), in addition to their cognitive, medical, and psychiatric profiles. Results Our study identified four subgroups of children on the autism spectrum with differing profiles of autism traits and associated comorbidities. Two subgroups had more severe clinical and cognitive phenotype, suggesting higher support needs. For the ‘Higher Support Needs with Prominent Language and Cognitive Challenges’ subgroup, social communication, language and cognitive challenges were prominent, with prominent sensory seeking behaviours. The ‘Higher Support Needs with Prominent Medical and Psychiatric and Comorbidity’ subgroup had the highest mean scores of challenges relating to social communication and RRBs, with the highest probability of medical and psychiatric comorbidity, and cognitive scores similar to the overall group mean. Individuals within the ‘Moderate Support Needs with Emotional Challenges’ subgroup, had moderate mean scores of core traits of autism, and the highest probability of depression and/or suicidality. A fourth subgroup contained individuals with fewer challenges across domains (the ‘Fewer Support Needs Group’). Limitations Data utilised to identify subgroups within this study was cross-sectional as longitudinal data was not available. Conclusions Our findings support the holistic appraisal of support needs for children on the autism spectrum, with assessment of the impact of co-occurring medical and psychiatric conditions in addition to core autism traits, adaptive functioning, and cognitive functioning. Replication of our analysis in other cohorts of children on the autism spectrum is warranted, to assess whether the subgroup structure we identified is applicable in a broader context beyond our specific dataset.

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.

Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits. Specific binding to 5-HT1B receptors was measured in OFC and striatum of naive SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.

Abnormal sensory responses are a DSM-5 symptom of autism spectrum disorder (ASD), and research findings demonstrate altered sensory processing in ASD. Beyond difficulties with processing information within single sensory domains, including both hypersensitivity and hyposensitivity, difficulties in multisensory processing are becoming a core issue of focus in ASD. These difficulties may be targeted by treatment approaches such as "sensory integration," which is frequently applied in autism treatment but not yet based on clear evidence. Recently, psychophysical data have emerged to demonstrate multisensory deficits in some children with ASD. Unlike deficits in social communication, which are best understood in humans, sensory and multisensory changes offer a tractable marker of circuit dysfunction that is more easily translated into animal model systems to probe the underlying neurobiological mechanisms. Paralleling experimental paradigms that were previously applied in humans and larger mammals, we and others have demonstrated that multisensory function can also be examined behaviorally in rodents. Here, we review the sensory and multisensory difficulties commonly found in ASD, examining laboratory findings that relate these findings across species. Next, we discuss the known neurobiology of multisensory integration, drawing largely on experimental work in larger mammals, and extensions of these paradigms into rodents. Finally, we describe emerging investigations into multisensory processing in genetic mouse models related to autism risk. By detailing findings from humans to mice, we highlight the advantage of multisensory paradigms that can be easily translated across species, as well as the potential for rodent experimental systems to reveal opportunities for novel treatments. LAY SUMMARY: Sensory and multisensory deficits are commonly found in ASD and may result in cascading effects that impact social communication. By using similar experiments to those in humans, we discuss how studies in animal models may allow an understanding of the brain mechanisms that underlie difficulties in multisensory integration, with the ultimate goal of developing new treatments. Autism Res 2020, 13: 1430-1449. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

* Abbreviations: AIR-P — : Autism Intervention Research Network on Physical Health ASD — : autism spectrum disorder ATN — : Autism Treatment Network ED — : emergency department HRSA — : Health Resources and Services Administration MCHB — : Maternal and Child Health Bureau Children with autism spectrum disorder (ASD) experience significant developmental challenges and complex co-occurring medical and psychiatric conditions,1–3 and they are at risk for considerable unmet health care needs.4–8 As the reported prevalence of ASD continues to rise,9,10 the need for a health care system that is fully equipped to meet the needs of this population is increasingly important. We are pleased to introduce the third supplement to Pediatrics led by the Autism Intervention Research Network on Physical Health (AIR-P) with support from the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA) through the Autism Collaboration, Accountability, Research, Education, and Support Act.11 The 2 previous supplements led by the AIR-P were published in 2012 and 2016, and the work presented in this volume represents significant advances in improving the health and well-being of children with ASD through innovations in research and practice. The articles in this supplement describe infrastructure investments, multiinstitutional collaborations, new models of practice, and original research focused on improving care in multiple locations and contexts for children with ASD and their families. The work reflected in this supplement would not have been possible without considerable federal and private foundation funding. This infrastructure support enabled researchers, clinicians, family members, and key stakeholders to engage in dynamic partnerships to share knowledge and improve systems of care. The supplement begins with an overview of the reach of the HRSA-MCHB Autism and Other Developmental Disabilities Program and its alignment with federal priorities for ASD research.11 The AIR-P represents 1 of 5 autism research networks funded by HRSA and MCHB. In 2008, the … Address correspondence to Evdokia Anagnostou, MD, Holland Bloorview Kids Rehabilitation Hospital, 150 Kilgour Road, Toronto, ON M4G1R8, Canada. Email: eanagnostou{at}hollandbloorview.ca

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.

Child and adolescent psychiatry is among the top 5 medical specialties in the United States with greatest representation of women among active residents (62.5%) and of female physicians among currently practicing physicians (52.7%).1,2 (Note that our use of "gender" (women or men) and "sex" (female or male) parallels use in the referenced publications. We recognize that gender and sex are not interchangeable.) Previous studies have found women faculty physicians to be disadvantaged in attaining higher salaries, National Institutes of Health (NIH) funding, promotion, and tenure-even in majority-women specialties.3,4 Pediatrics, another specialty in which women predominate, has found a disproportionate number of women faculty in junior academic ranks.3 Furthermore, women remain a stark minority in senior-ranking leadership positions.5 To our knowledge, no previous publications have examined the proportion of women physicians at different faculty ranks in US academic child and adolescent psychiatry. In the summer of 2018, we began a search for a named/endowed professor position in child and adolescent psychiatry. Recognizing gender and racial disparities in recruitment, we conducted a comprehensive search for all child and adolescent psychiatry faculty members within the United States. We decided to use the collected data to investigate gender disparities among academic child and adolescent psychiatry physicians. We hypothesized that gender disparities would increase with child and adolescent psychiatry physicians' academic ranks, with greatest disparities among full professors. As separate points of inquiry, we explored gender distribution among division directors and named/endowed faculty.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are separate disorders, with distinct clinical profiles and natural histories. ASD, typically diagnosed in childhood, is characterized by restricted or repetitive interests or behaviors and impaired social communication, and it tends to have a stable course. SCZ, typically diagnosed in adolescence or adulthood, is characterized by hallucinations and delusions, and tends to be associated with declining function. However, youth with ASD are three to six times more likely to develop SCZ than their neurotypical counterparts, and increasingly, research has shown that ASD and SCZ converge at several levels. We conducted a systematic review of studies since 2013 relevant to understanding this convergence, and present here a narrative synthesis of key findings, which we have organized into four broad categories: symptoms and behavior, perception and cognition, biomarkers, and genetic and environmental risk. We then discuss opportunities for future research into the phenomenology and neurobiology of overlap between ASD and SCZ. Understanding this overlap will allow for researchers, and eventually clinicians, to understand the factors that may make a child with ASD vulnerable to developing SCZ. LAY SUMMARY: Autism spectrum disorder and schizophrenia are distinct diagnoses, but people with autism and people with schizophrena share several characteristics. We review recent studies that have examined these areas of overlap, and discuss the kinds of studies we will need to better understand how these disorders are related. Understanding this will be important to help us identify which autistic children are at risk of developing schizophrenia.

Repeated amphetamine treatment results in locomotor sensitization, a phenomenon that may relate to the development of psychosis and addiction. Evidence suggests that interactions between dopaminergic and glutamatergic systems are involved in amphetamine sensitization. We previously demonstrated that the neuronal excitatory amino acid transporter (Slc1a1/EAAT3) produces bidirectional, expression-dependent effects on the response to acute amphetamine. Here, using mice with decreased or increased expression of EAAT3, we found that chronic alterations in EAAT3 expression do not significantly impact amphetamine-induced locomotor sensitization. Compensation by other glutamate transporters cannot be ruled out in this important neuroadaptive phenomenon.

Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control sample (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this 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.)

Few studies have followed young people with autism spectrum disorder (shortened to "autism" herein) over time, and all previous longitudinal studies have used clinical or center-based samples,1,2 leaving considerable uncertainty about the course of autism in the general population. In this issue, Simonoff and colleagues3 describe the first longitudinal study within a population-based sample, the Special Needs and Autism Project (SNAP) cohort. By assessing adolescents and young adults with autism at 3 time points over 11 years, from approximately 12 to 23 years of age, the authors profiled the trajectories of both cognitive and autism symptoms. Despite little change in caregiver-rated autism symptoms over this time period, they found that full-scale IQ (FSIQ) showed a moderate increase, with some hints of factors that may predict greater improvement.

Background Impaired face emotion recognition (FER) and abnormal motion processing are core features in schizophrenia (SZ) and autism spectrum disorder (ASD) that have been linked to atypical activity within the visual cortex. Despite overlaps, only a few studies have directly explored convergent versus divergent neural mechanisms of altered visual processing in ASD and SZ. We employed a multimodal imaging approach to evaluate FER and motion perception in relation to functioning of subcortical and cortical visual regions. Methods Subjects were 20 high-functioning adults with ASD, 19 patients with SZ, and 17 control participants. Behavioral measures of coherent motion sensitivity and FER along with electrophysiological and functional magnetic resonance imaging measures of visual pattern and motion processing were obtained. Resting-state functional magnetic resonance imaging was used to assess the relationship between corticocortical and thalamocortical connectivity and atypical visual processing. Results SZ and ASD participants had intercorrelated deficits in FER and motion sensitivity. In both groups, reduced motion sensitivity was associated with reduced functional magnetic resonance imaging activation in the occipitotemporal cortex and lower delta-band electroencephalogram power. In ASD, FER deficits correlated with hyperactivation of dorsal stream regions and increased evoked theta power. Activation of the pulvinar correlated with abnormal alpha-band modulation in SZ and ASD with under- and overmodulation, respectively, predicting increased clinical symptoms in both groups. Conclusions SZ and ASD participants showed equivalent deficits in FER and motion sensitivity but markedly different profiles of physiological dysfunction. The specific pattern of deficits observed in each group may help guide development of treatments designed to downregulate versus upregulate visual processing within the respective clinical groups.

Objectives: We recently found that metformin attenuated weight gain due to mixed dopamine and serotonin receptor antagonists, commonly termed atypical antipsychotics, in children and adolescents with autism spectrum disorder (ASD). Previous studies have found that genetic variation predicts response to metformin in diabetes. In this study, we aimed to assess whether response to metformin for weight gain in this population is associated with variants in five genes previously implicated in metformin response in diabetes. Methods: Youth with ASD who experienced significant weight gain while taking mixed receptor antagonist medications were randomly assigned to metformin or placebo for 16 weeks, followed by open-label metformin treatment for 16 weeks. In the 53 participants with available DNA samples, we used a linear, mixed model analysis to assess response in the first 16 weeks of metformin treatment, whether in the randomized or open-label period, based upon genotypes at polymorphisms in five genes previously associated with metformin response in diabetes: ATM, SLC2A2, MATE1, MATE2, and OCT1. Results: In the primary analysis, both ATM and OCT1 showed significant effects of genotype on change in body mass index z-scores, the primary outcome measure, during the first 16 weeks of treatment with metformin. No other polymorphism showed a significant difference. Conclusion: As has been shown for metformin treatment in diabetes, genetic variation may predict response to metformin for weight gain in youth with ASD treated with mixed receptor antagonists. Further work is needed to replicate these findings and evaluate whether they can be used prospectively to improve outcomes.

The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2+/- mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors. However, KCC2+/- mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild-type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2+/- mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism-like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism-related behavioral phenotypes. Autism Research 2019, 12: 732-743. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism-related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism-like behaviors.

Elevated whole blood serotonin (WB5-HT) is a well-replicated biomarker in autism spectrum disorder (ASD). Decreased platelet serotonin receptor 5-HT2A binding has been reported in ASD. WB5-HT levels and platelet 5-HT2A specific binding were obtained from 110 individuals with ASD and 18 controls. Individuals with ASD had significantly higher WB5-HT levels than controls. There was no difference in the platelet 5-HT2A specific binding between groups. Multiple regression analyses revealed that platelet 5-HT2A binding significantly predicted WB5-HT in the control sample but not in the ASD sample. These results indicate that the relationship between WB5-HT and platelet 5-HT2A binding differs depending on ASD diagnosis, suggesting differences in platelet 5-HT system regulation in ASD.

Plasma membrane neurotransmitter transporters maintain extracellular concentrations of neurotransmitters by facilitating transport into the cytosol. This regulation of extracellular neurotransmitters limits binding to receptors and activation of downstream signaling pathways. In addition to this critical function, transporters modulate neuronal activity via direct gating of transporter-associated ion channels and indirectly through trafficking of transporters to and from the plasma membrane. These functions are dependent on diverse expression patterns and levels of the transporters throughout the brain. This diversity is highlighted within the excitatory amino acid transporter family, which consists of five excitatory amino acid transporters found in the mammalian central nervous system (CNS). EAAT1 (GLAST) and EAAT2 (GLT-1) are primarily expressed in astrocytes while EAAT3 expression is mainly observed in many neurons throughout the brain (Holmseth et al., 2012). In contrast, EAAT4 is most prominently expressed in cerebellar Purkinje neurons and EAAT5 is exclusively found in the retina. In general, the astroglial transporters are highly expressed in the brain; EAAT2 is the most abundant, followed by EAAT1 with approximately a 4-fold lower expression (Holmseth et al., 2012). High expression levels of these glial transporters are consistent with their role in glutamate clearance (Lehre and Danbolt, 1998; Rothstein et al., 1996; Tanaka et al., 1997). The role of the neuronal transporter EAAT3 in brain has been more difficult to elucidate. Levels of EAAT3 are approximately 100-fold lower than EAAT2 (Holmseth et al., 2012) but EAAT3 expression is observed throughout the CNS, with enriched expression in the cerebral cortex, hippocampus, cerebellum and basal ganglia (Rothstein et al., 1994; Shashidharan et al., 1997). Given the lack of selective EAAT3 inhibitors, studies have relied on EAAT3 transporters expressed in various cells and endogenous transporters expressed in cultured hippocampal neurons (Diamond and Jahr, 1997; Grewer et al., 2000; Wadiche et al., 1995b), as well as EAAT3 knockout mice (Scimemi et al., 2009) to dertmine the physiological functions of EAAT3. These studies determined that the time course of glutamate in the synaptic cleft is a function of the binding of glutamate to EAATs and that transport of glutamate does not significantly contribute to the amplitude or kinetics of synaptic responses due to the relatively slow transport cycle (Diamond and Jahr, 1997; Tong and Jahr, 1994; Wadiche and von Gersdorff, 2006). Interestingly, EAAT3 knockout mice exhibit few behavioral deficits (Peghini et al., 1997), and antisense oligonucleotide knockdown in the striatum results in minimal elevation of extracellular glutamate levels or neurodegeneration, in contrast to knockdown of EAATs 1 and 2 (Rothstein et al., 1996). The lack of neurodegeneration is particularly surprising given that EAAT3 also serves as a cysteine transporter (Aoyama et al., 2006; Watts et al., 2014; Zerangue and Kavanaugh, 1996). Cysteine is the rate-limiting substrate for the synthesis of the antioxidant glutathione and its extracellular depletion is hypothesized to contribute to neurodegeneration. EAAT3 is also the dominant glutamate transporter in the intestines and provides nutrient absorption from the diet (Hu et al., 2018), but knockout animals appear to grow at a comparable rate to their litter mates (Peghini et al., 1997). The most remarkable initial observation from EAAT3 knockout mice was aminoaciduria due to the absence of EAAT3 in the kidneys (Peghini et al., 1997). The reported lack of overt behavioral abnormalities in the EAAT3 knockout mice suggest that either EAAT3 is not integral to regulation of glutamatergic signaling in the brain or that substantial developmental compensatory changes are induced in these mice. Human genetic studies and constitutive deletion mouse models have now provided evidence that EAAT3 has important roles in regulating neuronal signaling.

There are no approved medications for the core symptoms of autism spectrum disorder (ASD), socialization and communication difficulties.To evaluate the efficacy and safety of balovaptan, an oral selective vasopressin 1a receptor antagonist, compared with placebo in children and adolescents with ASD.The aV1ation study was a randomized, double-blind, 24-week, parallel-group, placebo-controlled phase 2 trial. Between November 22, 2016, and September 3, 2019, individuals were screened and randomly assigned to treatment groups. The primary efficacy analysis population comprised participants taking age-adjusted balovaptan equivalent to a 10-mg adult dose and participants from the concurrently randomized placebo group. This multicenter trial took place across 41 sites in the US. Participants were aged 5 to 17 years with diagnosed ASD and an IQ of 70 or greater. Data were analyzed from April 8 to November 16, 2020.Participants were randomly assigned to daily 4-mg or 10-mg adult-equivalent balovaptan or placebo, until the 4-mg group was discontinued.The primary end point was change from baseline on the Vineland-II two-domain composite (2DC; socialization and communication domains) score at week 24.Between November 2016 and September 2019, a total of 599 individuals were screened and 339 participants were randomly assigned to receive 4-mg balovaptan adult-equivalent dose (91 [26.8%]), 10-mg balovaptan adult-equivalent dose (126 [37.2%]), or placebo (122 [36.0%]). Primary analysis included 86 participants assigned to receive 10-mg balovaptan adult-equivalent dose and 81 assigned to receive placebo (mean [SD] age, 12.1 [3.4] years; 139 male participants [83.2%]). No statistically significant differences were observed between the balovaptan and placebo groups in change from baseline on the Vineland-II 2DC score at week 24 (difference in adjusted least-squares mean, -0.16; 90% CI, -2.56 to 2.23; P = .91). No improvements for balovaptan vs placebo were observed at week 24 for any secondary end points. Balovaptan was well tolerated with no emerging safety concerns. Similar proportions of participants reported adverse events (balovaptan, 66 of 86 [76.7%] vs placebo, 61 of 81 [75.3%]) and serious adverse events (balovaptan, 1 of 86 [1.2%] vs placebo, 4 of 81 [4.9%]).In this randomized clinical trial, balovaptan did not demonstrate efficacy in improvement of socialization and communication in this population with pediatric ASD. Balovaptan was well tolerated in children 5 years or older. Further development of robust, sensitive, and objective outcome measures may help to improve future studies in the assessment of therapies targeting communication and socialization in pediatric ASD.ClinicalTrials.gov Identifier: NCT02901431.

Emotional dysregulation and irritability are common in individuals with autism spectrum disorder (ASD). We conducted the first meta-analysis assessing the efficacy of a broad range of pharmacological interventions for emotional dysregulation and irritability in ASD and predictors of response.Following a preregistered protocol (PROSPERO: CRD42021235779), we systematically searched multiple databases until January 1, 2021. We included placebo-controlled randomized controlled trials (RCTs) and evaluated the efficacy of pharmacological interventions and predictors of response for emotional dysregulation and irritability. We assessed heterogeneity using Q statistics and publication bias. We conducted subanalyses and meta-regressions to identify predictors of response. The primary effect size was the standardized mean difference. Quality of studies was assessed using the Cochrane Risk of Bias Tool (RoB2).A total of 2,856 individuals with ASD in 45 studies were included, among which 26.7% of RCTs had a high risk of bias. Compared to placebo, antipsychotics (standardized mean difference = 1.028, 95% CI = 0.824-1.232) and medications used to treat attention-deficit/hyperactivity disorder (ADHD) (0.471, 0.061-0.881) were significantly better than placebo in improving emotional dysregulation and irritability, whereas evidence of efficacy was not found for other drug classes (p.05). Within individual medications, evidence of efficacy was found for aripiprazole (1.179, 0.838-1.520) and risperidone (1.074, 0.818-1.331). Increased rates of comorbid epilepsy (β = -0.049, p = .026) were associated with a lower efficacy.Some pharmacological interventions (particularly risperidone and aripiprazole) have proved efficacy for short-term treatment of emotional dysregulation and irritability in ASD and should be considered within a multimodal treatment plan, taking into account also the tolerability profile and families' preferences.

Obsessive-compulsive disorder (OCD) is a disabling condition that often begins in childhood. Genetic studies in OCD have pointed to SLC1A1, which encodes the neuronal glutamate transporter EAAT3, with evidence suggesting that increased expression contributes to risk. In mice, midbrain Slc1a1 expression supports repetitive behavior in response to dopaminergic agonists, aligning with neuroimaging and pharmacologic challenge studies that have implicated the dopaminergic system in OCD. These findings suggest that Slc1a1 may contribute to compulsive behavior through altered dopaminergic transmission; however, this theory has not been mechanistically tested. To examine the developmental impact of Slc1a1 overexpression on compulsive-like behaviors, we, therefore, generated a novel mouse model to perform targeted, reversible overexpression of Slc1a1 in dopaminergic neurons. Mice with life-long overexpression of Slc1a1 showed a significant increase in amphetamine (AMPH)-induced stereotypy and hyperlocomotion. Single-unit recordings demonstrated that Slc1a1 overexpression was associated with increased firing of dopaminergic neurons. Furthermore, dLight1.1 fiber photometry showed that these behavioral abnormalities were associated with increased dorsal striatum dopamine release. In contrast, no impact of overexpression was observed on anxiety-like behaviors or SKF-38393-induced grooming. Importantly, overexpression solely in adulthood failed to recapitulate these behavioral phenotypes, suggesting that overexpression during development is necessary to generate AMPH-induced phenotypes. However, doxycycline-induced reversal of Slc1a1/EAAT3 overexpression in adulthood normalized both the increased dopaminergic firing and AMPH-induced responses. These data indicate that the pathologic effects of Slc1a1/EAAT3 overexpression on dopaminergic neurotransmission and AMPH-induced stereotyped behavior are developmentally mediated, and support normalization of EAAT3 activity as a potential treatment target for basal ganglia-mediated repetitive behaviors.