Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration.

We believe there are serious problems with a recently published and highly publicized paper entitled "Serotonin reduction in post-acute sequelae of viral infection." The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the "Discussion" section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, "Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment", it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs' effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.

Forebrain EAAT3 Overexpression Increases Susceptibility to Amphetamine-Induced Repetitive Behaviors.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the SLC1A1 gene with OCD. The most common of these OCD-associated polymorphisms increases the expression of the encoded protein, excitatory amino acid transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of Slc1a1 in forebrain neurons. The mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and Slc1a1-overexpressing (OE) mice, but Slc1a1-OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in Slc1a1-OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in Slc1a1-OE mice were driven by cFos expression specifically in D1 neurons, as Slc1a1-OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in Slc1a1-OE mice.

A non-canonical striatopallidal Go pathway that supports motor control.

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 axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe 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 Npas1 neurons. We propose a model by which dSPN GPe axon collaterals (striatopallidal Go pathway) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 neurons.

Effects of AFQ056 on language learning in fragile X syndrome.

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

Repeated chemogenetic activation of dopaminergic neurons induces reversible changes in baseline and amphetamine-induced behaviors.

RATIONALE: Repeated chemogenetic stimulation is often employed to study circuit function and behavior. Chronic or repeated agonist administration can result in homeostatic changes, but this has not been extensively studied with designer receptors exclusively activated by designer drugs (DREADDs). OBJECTIVES: We sought to evaluate the impact of repeated DREADD activation of dopaminergic (DA) neurons on basal behavior, amphetamine response, and spike firing. We hypothesized that repeated DREADD activation would mimic compensatory effects that we observed with genetic manipulations of DA neurons. METHODS: Excitatory hM3D(Gq) DREADDs were virally expressed in adult TH-Cre and WT mice. In a longitudinal design, clozapine N-oxide (CNO, 1.0 mg/kg) was administered repeatedly. We evaluated basal and CNO- or amphetamine (AMPH)-induced locomotion and stereotypy. DA neuronal activity was assessed using in vivo single-unit recordings. RESULTS: Acute CNO administration increased locomotion, but basal locomotion decreased after repeated CNO exposure in TH-CrehM3Dq mice relative to littermate controls. Further, after repeated CNO administration, AMPH-induced hyperlocomotion and stereotypy were diminished in TH-CrehM3Dq mice relative to controls. Repeated CNO administration reduced DA neuronal firing in TH-CrehM3Dq mice relative to controls. A two-month CNO washout period rescued the decreases in basal locomotion and AMPH response. CONCLUSIONS: We found that repeated DREADD activation of DA neurons evokes homeostatic changes that should be factored into the interpretation of chronic DREADD applications and their impact on circuit function and behavior. These effects are likely to also be seen in other neuronal systems and underscore the importance of studying neuroadaptive changes with chronic or repeated DREADD activation.

Circuits underlying social function and dysfunction.

Substantial advances have been made toward understanding the genetic and environmental risk factors for autism, a neurodevelopmental disorder with social impairment as a core feature. In combination with optogenetic and chemogenetic tools to manipulate neural circuits in vivo, it is now possible to use model systems to test how specific neural circuits underlie social function and dysfunction. Here, we review the literature that has identified circuits associated with social interest (sociability), social reward, social memory, dominance, and aggression, and we outline a preliminary roadmap of the neural circuits driving these social behaviors. We highlight the neural circuitry underlying each behavioral domain, as well as develop an interactive map of how these circuits overlap across domains. We find that some of the circuits underlying social behavior are general and are involved in the control of multiple behavioral aspects, whereas other circuits appear to be specialized for specific aspects of social behavior. Our overlapping circuit map therefore helps to delineate the circuits involved in the various domains of social behavior and to identify gaps in knowledge.

Extensive characterization of a Williams syndrome murine model shows Gtf2ird1-mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior.

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, including GTF2IRD1, 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 of Gtf2ird1 in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressing Gtf2ird1, which can be used both to model duplication of this gene alone and to rescue Gtf2ird1 expression 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 that Gtf2ird1 complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However, Gtf2ird1 complementation does rescue light-aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.

Candidate biomarkers in psychiatric disorders: state of the field.

The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post-traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety. This review highlights a critical gap in the biomarker validation process. An enormous societal investment over the past 50 years has identified numerous candidate biomarkers. However, to date, the overwhelming majority of these measures have not been proven sufficiently reliable, valid and useful to be adopted clinically. It is time to consider whether strategic investments might break this impasse, focusing on a limited number of promising candidates to advance through a process of definitive testing for a specific indication. Some promising candidates for definitive testing include the N170 signal, an event-related brain potential measured using electroencephalography, for subgroup identification within autism spectrum disorder; striatal resting-state functional magnetic resonance imaging (fMRI) measures, such as the striatal connectivity index (SCI) and the functional striatal abnormalities (FSA) index, for prediction of treatment response in schizophrenia; error-related negativity (ERN), an electrophysiological index, for prediction of first onset of generalized anxiety disorder, and resting-state and structural brain connectomic measures for prediction of treatment response in social anxiety disorder. Alternate forms of classification may be useful for conceptualizing and testing potential biomarkers. Collaborative efforts allowing the inclusion of biosystems beyond genetics and neuroimaging are needed, and online remote acquisition of selected measures in a naturalistic setting using mobile health tools may significantly advance the field. Setting specific benchmarks for well-defined target application, along with development of appropriate funding and partnership mechanisms, would also be crucial. Finally, it should never be forgotten that, for a biomarker to be actionable, it will need to be clinically predictive at the individual level and viable in clinical settings.

Editorial: Failing in our Responsibility to Address Obesity Caused by Psychotropic Medications.

Obesity is the most common pediatric chronic disease, affecting close to 14.4 million children and adolescents in the US, according to a recent estimate.1 Despite a significant increase in systematic research and clinical focus in this area, the problem is estimated to worsen in the next 20 years, with estimates predicting that about 57% of children and adolescents between 2 and 19 years of age will be obese by 2050.2 Obesity is defined as a body mass index (BMI) at or greater than the 95th percentile for children and teens of the same age and sex. Because of changes in weight and height with age, and their relation to body fat percentage, BMI levels among children and teens are expressed relative to those of other children of the same sex and age. These percentiles are calculated from the Centers for Disease Control and Prevention (CDC) growth charts, which were based on national survey data collected from 1963-1965 to 1988-1994 (CDC.gov healthy weight webpage). Mental health providers, especially child and adolescent psychiatrists, have an important role in assessing, treating, and even preventing obesity, but current data indicate that we are failing in this responsibility. This is particularly relevant in the context of metabolic side effects of psychotropic agents.

Translational Neuroscience Approaches to Understanding Autism.

While autism spectrum disorder affects nearly 2% of children in the United States, little is known with certainty concerning the etiologies and brain systems involved. This is due, in part, to the substantial heterogeneity in the presentation of the core symptoms of autism as well as the great number of co-occurring conditions that are common in autistic individuals. Understanding the neurobiology of autism is further hampered by the limited availability of postmortem brain tissue to determine the cellular and molecular alterations that take place in the autistic brain. Animal models therefore provide great translational value in helping to define the neural systems that constitute the social brain and mediate repetitive behaviors or interests. If they are based on genetic or environmental factors that contribute to autism, organisms from flies to nonhuman primates may serve as models of the neural structure or function of the autistic brain. Ultimately, successful models can also be employed to test the safety and effectiveness of potential therapeutics. This is an overview of the major animal species that are currently used as models of autism, including an appraisal of the advantages and limitations of each.

Predictors of placebo response in three large clinical trials of the V1a receptor antagonist balovaptan in autism spectrum disorder.

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.

A non-canonical striatopallidal "Go" pathway that supports motor control.

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.

Identification of subgroups of children in the Australian Autism Biobank using latent class analysis.

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.

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.

Extensive characterization of a Williams Syndrome murine model shows Gtf2ird1 -mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior.

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, including GTF2IRD1 , 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 of Gtf2ird1 in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressing Gtf2ird1 , which can be used both to model duplication of this gene alone and to rescue Gtf2ird1 expression 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 that Gtf2ird1 complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However, Gtf2ird1 complementation does rescue light-aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.

Systematic Review and Meta-analysis: Efficacy of Pharmacological Interventions for Irritability and Emotional Dysregulation in Autism Spectrum Disorder and Predictors of Response.

OBJECTIVE: 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. METHOD: 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). RESULTS: 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 (ß = -0.049, p = .026) were associated with a lower efficacy. CONCLUSION: 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.

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

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

Intact amphetamine-induced behavioral sensitization in mice with increased or decreased neuronal glutamate transporter SLC1A1/EAAT3.

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.

Balovaptan vs Placebo for Social Communication in Childhood Autism Spectrum Disorder: A Randomized Clinical Trial.

Importance: There are no approved medications for the core symptoms of autism spectrum disorder (ASD), socialization and communication difficulties. Objective: To evaluate the efficacy and safety of balovaptan, an oral selective vasopressin 1a receptor antagonist, compared with placebo in children and adolescents with ASD. Design, Setting, and Participants: 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. Interventions: Participants were randomly assigned to daily 4-mg or 10-mg adult-equivalent balovaptan or placebo, until the 4-mg group was discontinued. Main Outcomes and Measures: The primary end point was change from baseline on the Vineland-II two-domain composite (2DC; socialization and communication domains) score at week 24. Results: 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%]). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT02901431.