Robin Libove

All Publications

• A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019; 11 (491)

  View details for DOI 10.1126/scitranslmed.aau7356

  View details for Web of Science ID 000467273900004

• A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Science translational medicine Parker, K. J., Oztan, O. n., Libove, R. A., Mohsin, N. n., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019

  Abstract

  The social impairments of autism spectrum disorder (ASD) have a major impact on quality of life, yet there are no medications that effectively treat these core social behavior deficits. Preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in promoting mammalian social behaviors, may be a possible treatment for ASD. Using a double-blind, randomized, placebo-controlled, parallel study design, we tested the efficacy and tolerability of a 4-week intranasal AVP daily treatment in 30 children with ASD. AVP-treated participants aged 6 to 9.5 years received the maximum daily target dose of 24 International Units (IU); participants aged 9.6 to 12.9 years received the maximum daily target dose of 32 IU. Intranasal AVP treatment compared to placebo enhanced social abilities as assessed by change from baseline in this phase 2 trial's primary outcome measure, the Social Responsiveness Scale, 2nd Edition total score (SRS-2 T score; F1,20 = 9.853; P = 0.0052; ηp2 = 33.0%; Cohen's d = 1.40). AVP treatment also diminished anxiety symptoms and some repetitive behaviors. Most of these findings were more pronounced when we accounted for pretreatment AVP concentrations in blood. AVP was well tolerated with minimal side effects. No AVP-treated participants dropped out of the trial, and there were no differences in the rate of adverse events reported between treatment conditions. Last, no changes from baseline were observed in vital signs, electrocardiogram tracings, height and body weight, or clinical chemistry measurements after 4 weeks of AVP treatment. These preliminary findings suggest that AVP has potential for treating social impairments in children with ASD.

  View details for PubMedID 31043522

• Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124

  Abstract

  Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

  View details for DOI 10.1073/pnas.1705521114

  View details for PubMedID 28696286

  View details for PubMedCentralID PMC5544319

• A Longitudinal Pilot Study of Behavioral Abnormalities in Children with Autism. Journal of psychiatry and psychiatric disorders Libove, R. A., Frazier, T. W., O'Hara, R. n., Phillips, J. M., Jo, B. n., Hardan, A. Y. 2017; 1 (4): 215–23

  Abstract

  This longitudinal investigation examined the development of emotional and behavioral functioning in school-age children with autism. The Child Behavior Checklist was obtained at baseline and after an average interval of 28.5 months from 13 boys with autism and 14 age- and gender-matched controls between the ages of 7 and 12 years at baseline. Children with autism demonstrated clinically significant elevations in several domains including Social, Thought, and Attention Problems. Children with autism exhibited significant improvements over time in Total, Externalizing, Social, and Oppositional Defiant Problems and Aggressive Behavior, while there were no changes over time in the controls. These findings suggest that children with autism may demonstrate improvements over time in some clinical domains such as social and behavioral functioning.

  View details for DOI 10.26502/jppd.2572-519X0022

  View details for PubMedID 32587950

  View details for PubMedCentralID PMC7316392

• Intranasal Vasopressin Treatment Improves Social Abilities in Children With Autism Parker, K., Oztan, O., Libove, R., Sumiyoshi, R., Summers, J., Hinman, K., Fung, L., Motonaga, K., Carson, D., Phillips, J., Garner, J., Hardan, A. NATURE PUBLISHING GROUP. 2016: S341

  View details for Web of Science ID 000440365600575

• Bridging the gap: unveiling key links between autism and anxiety symptoms in autistic children and youth using a network analysis in pooled data from four countries. Child and adolescent mental health Zaidman-Zait, A., Hollocks, M. J., Kerns, C. M., Magiati, I., McVey, A. J., Smith, I. M., Bedford, R., Bennett, T., Duku, E., Georgiades, S., Richard, A., Vaillancourt, T., Zwaigenbaum, L., Hardan, A., Libove, R., Rodgers, J., South, M., Simonoff, E., Van Hecke, A., Uljarević, M., Szatmari, P. 2025

  Abstract

  Autistic children experience significantly higher rates of anxiety compared to nonautistic children. The precise relations between autism characteristics and anxiety symptoms remain unclear in this population. Previous work has explored associations at the domain level, which involve examining broad categories or clusters of symptoms, rather than the relationships between specific symptoms and/or individual characteristics. We addressed this gap by taking a network approach to understand the shared structure of autism characteristics and anxiety symptoms.Data were pooled from five studies from Canada, Singapore, the UK, and the USA, totaling 623 autistic children (17% female sex; aged 6-18 years), for whom the parent-report Spence Children's Anxiety Scale (SCAS-P) was available. We derived two undirected regularized networks, first from the SCAS-P items only, and then by adding autism characteristics pertaining to social communication, highly focused and repetitive behavior, and sensory hypersensitivity. From these models' metrics, we extracted nodes' predictability, key bridging nodes, and community detection.The anxiety-only network was highly connected and consisted of four key clusters: General Anxiety, Social Anxiety, Separation Anxiety, and Panic/Agoraphobia. These broadly aligned with the existing SCAS-P structure based on DSM-IV-TR criteria. In the autism-anxiety network, the structure of anxiety remained mostly stable, with autism features forming their own community. Preference for predictability (i.e., sameness) and sensory hypersensitivity were key nodes that linked autistic features and anxiety symptoms, primarily through generalized anxiety.This study identified some of the key characteristics that bridge the broadly independent structures of autism characteristics and anxiety symptoms. The findings are discussed in the context of guiding the assessment, prevention, and treatment of anxiety in autism.

  View details for DOI 10.1111/camh.70026

  View details for PubMedID 40891268

• Randomized Controlled Trial of Developmental Reciprocity Treatment in Young Children with Autism. Journal of autism and developmental disorders Gengoux, G. W., Paszek, K., Millan, M. E., Gong, J., Goodman, R., Guillory, S., Baldi, G., Libove, R., Phillips, J. M., Hardan, A. Y. 2025

  Abstract

  Developmental social pragmatic interventions for autism spectrum disorder (ASD) focus on development of strong interpersonal relationships by encouraging social communication during joint play routines. The goal of the current investigation was to conduct a randomized controlled 24-week pilot trial to examine the efficacy of a Developmental Reciprocity Treatment package (DRT-P), a developmentally-based intervention that includes both parent training and direct treatment with the child, compared to a delayed treatment group (DTG). Thirty-seven children aged 2-5 years with ASD and language delay were randomized. 83% of parents in DRT-P met fidelity of implementation criteria by 24 weeks. Controlling for fidelity, participants in DRT-P showed significantly greater improvement on the Social Responsiveness Scale Total Score (F = 5.00; p = 0.034) and the Clinical Global Impressions Improvement scale; however no significant group differences were observed on the Brief Observation of Social Communication Change, Vineland Adaptive Behavior Scales, or the MacArthur-Bates Communicative Development Inventories. Findings suggest DRT is a promising intervention for improving some aspects of social functioning in young children with ASD. Future research exploring how behavioral and developmental interventions can be optimally combined to target core social difficulties along with adaptive and functional communication skills is expected to be beneficial.

  View details for DOI 10.1007/s10803-025-06904-x

  View details for PubMedID 40488923

• Using Language Environment Analysis System (LENA) in Natural Settings to Characterize Outcomes of Pivotal Response Treatment. Journal of autism and developmental disorders Ferguson, E. F., Steele, M., Schuck, R. K., Millan, M. E., Libove, R. A., Phillips, J. M., Gengoux, G. W., Hardan, A. Y. 2025

  Abstract

  Despite the importance of monitoring changes in expressive language in early intervention, existing approaches to language assessment are often costly, time-intensive, and capture limited variability in autistic children. The Language ENvironmental Analysis (LENA) system has thus received considerable attention as an automated approach that may hold promise for capturing fine-grained changes in language development in a more efficient and cost-effective manner. However, evaluations of the utility of the LENA system for tracking response to early intervention in unstructured contexts are currently limited.This study aimed to build on prior research through evaluating the use of LENA in the context of a well-defined clinical sample from a randomized controlled trial (RCT) of Pivotal Response Treatment (PRT) that demonstrated expressive language gains across standardized and manually-coded measures.Exploration of automatically-derived LENA metrics (i.e., child vocalizations, conversational turns) revealed no significant association with standardized language assessments (i.e., Mullen expressive language subscale, MacArthur Bates Communicative Development Inventory, Vineland-II expressive language subscale). Furthermore, relative to the delayed treatment group, children participating in PRT did not show significantly greater improvement in the number of vocalizations or conversational turns during naturalistic, daylong LENA recordings collected in home settings from baseline to post-intervention.Implications and future directions for natural language sampling and the measurement of expressive language in early intervention are discussed.

  View details for DOI 10.1007/s10803-025-06740-z

  View details for PubMedID 40024967

  View details for PubMedCentralID 8862714

• Understanding the heterogeneity of anxiety in autistic youth: A person-centered approach. Autism research : official journal of the International Society for Autism Research Spackman, E., Lerh, J. W., Rodgers, J., Hollocks, M. J., South, M., McConachie, H., Ozsivadjian, A., Vaughan Van Hecke, A., Libove, R., Hardan, A. Y., Leekam, S. R., Simonoff, E., Frazier, T. W., Alvares, G. A., Schwartzman, J. M., Magiati, I., Uljarevic, M. 2022

  Abstract

  The present study aimed to examine anxiety profiles among children and adolescents on the autism spectrum. It further aimed to characterize the association between the identified anxiety profiles and key clinical and developmental variables. The Spence Children's Anxiety Scale-Parent Version (SCAS-P) data from a large international pooled sample of 870 caregivers of autistic children and adolescents (Mage =11.6years, SDage =2.77; 107 females) was used. Latent profile analysis identified a three-anxiety profile solution exhibiting high entropy (0.80) and high latent profile probabilities, with good classification accuracy. Identified profiles fell along the severity spectrum and were named as the mild (n=498), moderate (n=272) and severe (n=100) anxiety profiles. There were no statistically significant differences between the three anxiety profiles in terms of sex distribution. Participants in the mild profile were significantly younger than those in the severe profile, had significantly fewer social communication difficulties than youth in the moderate anxiety profile group and had significantly fewer restricted and repetitive behaviors and lower cognitive functioning scores compared to participants in moderate and severe anxiety profiles. This is the first study to move beyond identifying associations and group-level differences to exploring and identifying characteristics of anxiety-based subgroups at an individual level that differ on key clinical and developmental variables. The subgroups identified in this study are a preliminary, yet important, first step towards informing future assessment and individualized interventions aiming to support young people on the autism spectrum to reduce and manage anxiety. LAY SUMMARY: This study tried to understand if there are subgroups of autistic young people who may have similar anxiety profiles. We found that we could meaningfully group young people into three groups based on how severe the anxiety symptoms their caregivers reported were: a group with low levels of anxiety, those with moderate anxiety, and those with more severe anxiety. We also found that the young people in the mild group were younger, had fewer autism traits and lower levels of intellectual functioning than young people in the other two groups.

  View details for DOI 10.1002/aur.2744

  View details for PubMedID 35642170

• Characterizing Emotion Recognition and Theory of Mind Performance Profiles in Unaffected Siblings of Autistic Children FRONTIERS IN PSYCHOLOGY Uljarevic, M., Bott, N. T., Libove, R. A., Phillips, J. M., Parker, K. J., Hardan, A. Y. 2022; 12: 736324

  Abstract

  Emotion recognition skills and the ability to understand the mental states of others are crucial for normal social functioning. Conversely, delays and impairments in these processes can have a profound impact on capability to engage in, maintain, and effectively regulate social interactions. Therefore, this study aimed to compare the performance of 42 autistic children (Mage = 8.25 years, SD = 2.22), 45 unaffected siblings (Mage = 8.65 years, SD = 2.40), and 41 typically developing (TD) controls (Mage = 8.56 years, SD = 2.35) on the Affect Recognition (AR) and Theory of Mind (TOM) subtests of the Developmental Neuropsychological Assessment Battery. There were no significant differences between siblings and TD controls. Autistic children showed significantly poorer performance on AR when compared to TD controls and on TOM when compared to both TD controls and unaffected siblings. An additional comparison of ASD, unaffected sibling and TD control subsamples, matched on full-scale IQ, revealed no group differences for either AR or TOM. AR and TOM processes have received less research attention in siblings of autistic children and remain less well characterized. Therefore, despite limitations, findings reported here contribute to our growing understanding of AR and TOM abilities in siblings of autistic children and highlight important future research directions.

  View details for DOI 10.3389/fpsyg.2021.736324

  View details for Web of Science ID 000766850000001

  View details for PubMedID 35283803

  View details for PubMedCentralID PMC8907847

• A case-control study of visual, auditory and audio-visual sensory interactions in children with autism spectrum disorder. Journal of vision Norcia, A. M., Lee, A., Meredith, W. J., Kohler, P. J., Pei, F., Ghassan, S. A., Libove, R. A., Phillips, J. M., Hardan, A. Y. 2021; 21 (4): 5

  Abstract

  To assess the relative integrity of early visual and auditory processes in autism spectrum disorder (ASD), we used frequency-tagged visual and auditory stimulation and high-density electroencephalogram recordings of unimodal and dual-modality responses in a case-control design. To test for the specificity of effects on ASD, we recorded from a smaller group of children with attention-deficit hyperactivity disorder (ADHD). Horizontal 3 cycle per degree (cpd) gratings were presented at 5 Hz, and a random stream of /ba/, /da/, /ga/ syllables was presented at 6 Hz. Grating contrast response functions were measured unimodally and in the presence of a 64-dB auditory input. Auditory response functions were measured unimodally and in the presence of a 40% contrast grating. Children with ASD (n = 34) and ADHD (n = 13) showed a common lack of audio-visual interaction compared to typically developing children (n = 40) when measured at the first harmonic of the visual stimulus frequency. Both patient groups also showed depressed first harmonic responses at low contrast, but the ADHD group had consistently higher first-harmonic responses at high contrast. Children with ASD had a preferential loss of second-harmonic (transient) responses. The alteredtransient responses in ASD are likely to arise very early in the visual pathway and could thus have downstream consequences for many other visual mechanisms and processes. The alteration in audio-visual interaction could be a signature of a comorbid phenotype shared by ASD and ADHD, possibly due to alterations in attentional selection systems.

  View details for DOI 10.1167/jov.21.4.5

  View details for PubMedID 33830169

• Psychiatric Characteristics Across Individuals With PTEN Mutations. Frontiers in psychiatry Steele, M., Uljarevic, M., Rached, G., Frazier, T. W., Phillips, J. M., Libove, R. A., Busch, R. M., Klaas, P., Martinez-Agosto, J. A., Srivastava, S., Eng, C., Sahin, M., Hardan, A. Y. 2021; 12: 672070

  Abstract

  Germline heterozygous PTEN mutations have been associated with high prevalence of autism spectrum disorder (ASD) and elevated rates and severity of broadly defined behavioral problems. However, limited progress has been made toward understanding whether PTEN mutation is associated with specific psychiatric co-morbidity profiles when compared to idiopathic ASD. The current study aimed to utilize a cross-measure approach to compare concurrent psychiatric characteristics across children and adolescents with PTEN mutation with (PTEN-ASD; n = 38) and without ASD (PTEN-No ASD; n = 23), and ASD with macrocephaly but no PTEN mutation (macro-ASD; n = 25) using the Child Behavior Checklist (CBCL) and the Aberrant Behavior Checklist (ABC). There were significant group effects for the CBCL Internalizing and Externalizing broad symptom score, the majority of specific CBCL syndrome scores, and all ABC subscale scores. Post-hoc comparisons revealed greater behavioral symptoms in the ASD groups (PTEN-ASD and macro-ASD) compared to the PTEN-no ASD group on nearly all subtest scores examined. There were no statistically significant differences between the PTEN-ASD and macro-ASD groups; however, there was a trend for the macro-ASD group showing higher levels of aggressive behaviors. Our findings provide evidence of specific behavior profiles across PTEN-No ASD, PTEN-ASD, and macro-ASD groups and highlight the importance of early identification of behavioral vulnerabilities in individuals with PTEN mutations in order to provide access to appropriate evidence-based interventions.

  View details for DOI 10.3389/fpsyt.2021.672070

  View details for PubMedID 34489750

• SUPPORTING WORKING PARENTS IN AN ACADEMIC PSYCHIATRY DEPARTMENT DURING THE COVID-19 PANDEMIC: THE VIRTUAL CHILD ENGAGEMENT PROGRAM White, D., Aufderheide, C., Figueroa, J., Meza, E., Bundang, M., Libove, R., Gengoux, G., Hardan, A. ELSEVIER SCIENCE INC. 2021: S207

  View details for DOI 10.1016/j.jaac.2021.09.237

  View details for Web of Science ID 000707082801083

• Complex Interplay Between Cognitive Ability and Social Motivation in Predicting Social Skill: A Unique Role for Social Motivation in Children With Autism AUTISM RESEARCH Itskovich, E., Zyga, O., Libove, R. A., Phillips, J. M., Garner, J. P., Parker, K. J. 2020

  View details for DOI 10.1002/aur.2409

  View details for Web of Science ID 000578768000001

• Complex Interplay Between Cognitive Ability and Social Motivation in Predicting Social Skill: A Unique Role for Social Motivation in Children With Autism. Autism research : official journal of the International Society for Autism Research Itskovich, E., Zyga, O., Libove, R. A., Phillips, J. M., Garner, J. P., Parker, K. J. 2020

  Abstract

  Impairment in social interaction is a core feature of autism spectrum disorder (ASD), but the factors which contribute to this social skill deficiency are poorly understood. Previous research has shown that cognitive ability can impact social skill development in ASD. Yet, children with ASD whose cognitive abilities are in the normal range nevertheless demonstrate deficits in social skill. More recently, the social motivation theory of ASD has emerged as a framework by which to understand how failure to seek social experiences may lead to social skill deficits. This study was designed to better understand the relationships between cognitive ability, social motivation, and social skill in a well-characterized cohort of children with ASD (n = 79), their unaffected siblings (n = 50), and unrelated neurotypical controls (n = 60). The following instruments were used: The Stanford-Binet intelligence quotient (IQ), the Social Responsiveness Scale's Social Motivation Subscale, and the Vineland Adaptive Behavior Scales' Socialization Standard Score. We found that lower cognitive ability contributed to diminished social skill, but did so universally in all children. In contrast, social motivation strongly predicted social skill only in children with ASD, such that those with the lowest social motivation exhibited the greatest social skill impairment. Notably, this relationship was observed across a large range of intellectual ability but was most pronounced in those with IQs ≥ 80. These findings establish a unique link between social motivation and social skill in ASD and support the hypothesis that low social motivation may impair social skill acquisition in this disorder, particularly in children without intellectual disability. LAY SUMMARY: The relationships between cognitive ability, social motivation, and social skill are poorly understood. Here we report that cognitive ability predicts social skill in all children, whereas social motivation predicts social skill only in children with autism. These results establish a unique link between social motivation and social skill in autism, and suggest that low social motivation may impair social skill acquisition in this disorder, particularly in those without intellectual disability.

  View details for DOI 10.1002/aur.2409

  View details for PubMedID 33280272

• Exploring Social Subtypes in Autism Spectrum Disorder: A Preliminary Study. Autism research : official journal of the International Society for Autism Research Uljarevic, M., Phillips, J. M., Schuck, R. K., Schapp, S., Solomon, E. M., Salzman, E., Allerhand, L., Libove, R. A., Frazier, T. W., Hardan, A. Y. 2020

  Abstract

  Impairments in social functioning are considered a hallmark diagnostic feature of autism spectrum disorder (ASD). Yet, individuals diagnosed with ASD vary widely with respect to specific presentation, severity, and course across different dimensions of this complex symptom domain. The aim of this investigation was to utilize the Stanford Social Dimensions Scale (SSDS), a newly developed quantitative measure providing parental perspective on their child's social abilities, in order to explore the existence of homogeneous subgroups of ASD individuals who share unique profiles across specific dimensions of the social domain. Parents of 164 individuals with ASD (35 females, 129 males; meanage = 7.54years, SD = 3.85) completed the SSDS, the Social Responsiveness Scale (SRS-2) and the Child Behavior Checklist (CBCL). Data on children's verbal and nonverbal intellectual functioning (FSIQ) were also collected. The Latent Profile Analysis was used to classify participants according to the pattern of SSDS subscale scores (Social Motivation, Social Affiliation, Expressive Social Communication, Social Recognition, and Unusual Approach). Five profiles were identified. Profiles did not differ in terms of chronological age nor gender distribution but showed distinct patterns of strengths and weaknesses across different social components rather than simply reflecting a severity gradient. Profiles were further differentiated in terms of cognitive ability, as well as ASD and internalizing symptom severity. The implications of current findings and the necessary further steps toward identifying subgroups of individuals with ASD who share particular constellation of strengths and weaknesses across key social domains as a way of informing personalized interventions are discussed. Autism Res 2020. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) vary greatly in terms of their social abilities and social motivation. However, researchers lack measures that can fully assess different components of social functioning. This paper provides initial evidence for capturing subgroups of individuals with ASD with specific strengths and weakness across different aspects of social functioning.

  View details for DOI 10.1002/aur.2294

  View details for PubMedID 32187854

• Anxiety in young people with autism spectrum disorder: Common and autism-related anxiety experiences and their associations with individual characteristics. Autism : the international journal of research and practice Lau, B. Y., Leong, R., Uljarevic, M., Lerh, J. W., Rodgers, J., Hollocks, M. J., South, M., McConachie, H., Ozsivadjian, A., Van Hecke, A., Libove, R., Hardan, A., Leekam, S., Simonoff, E., Magiati, I. 2019: 1362361319886246

  Abstract

  Anxiety is common in autism spectrum disorder. Many anxiety symptoms in autism spectrum disorder are consistent with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) anxiety disorders (termed "common" anxieties), but others may be qualitatively different, likely relating to autism spectrum disorder traits (herein termed "autism-related" anxieties). To date, few studies have examined both "common" and "autism-related" anxiety experiences in autism spectrum disorder. We explored caregiver-reported Spence Children's Anxiety Scale-Parent version data from a multi-site (United Kingdom, Singapore, and United States) pooled database of 870 6- to 18-year-old participants with autism spectrum disorder, of whom 287 provided at least one written response to the optional open-ended Spence Children's Anxiety Scale-Parent item 39 ("Is there anything else your child is afraid of?"). Responses were thematically coded to explore (a) common and autism-related anxiety presentations and (b) their relationship with young people's characteristics. Nearly half of the responses were autism-related anxieties (mostly sensory, uncommon, or idiosyncratic specific phobias and worries about change and unpredictability). The other half described additional common anxieties not covered in the original measure (mostly social, weather and environmental disasters, and animals). Caregivers of participants who were more severely affected by autism spectrum disorder symptoms reported more autism-related, as compared to common, additional anxieties. Implications for the assessment and understanding of anxiety in autism are discussed.

  View details for DOI 10.1177/1362361319886246

  View details for PubMedID 31852214

• A Pivotal Response Treatment Package for Children With Autism Spectrum Disorder: An RCT. Pediatrics Gengoux, G. W., Abrams, D. A., Schuck, R., Millan, M. E., Libove, R., Ardel, C. M., Phillips, J. M., Fox, M., Frazier, T. W., Hardan, A. Y. 2019

  Abstract

  OBJECTIVES: Our aim was to conduct a randomized controlled trial to evaluate a pivotal response treatment package (PRT-P) consisting of parent training and clinician-delivered in-home intervention on the communication skills of children with autism spectrum disorder.METHODS: Forty-eight children with autism spectrum disorder and significant language delay between 2 and 5 years old were randomly assigned to PRT-P (n = 24) or the delayed treatment group (n = 24) for 24 weeks. The effect of treatment on child communication skills was assessed via behavioral coding of parent-child interactions, standardized parent-report measures, and blinded clinician ratings.RESULTS: Analysis of child utterances during the structured laboratory observation revealed that, compared with the delayed treatment group, children in PRT-P demonstrated greater improvement in frequency of functional utterances (F1,41 = 6.07; P = .026; d = 0.61). The majority of parents in the PRT-P group (91%) were able to implement pivotal response treatment (PRT) with fidelity within 24 weeks. Children receiving PRT-P also demonstrated greater improvement on the Brief Observation of Social Communication Change, on the Clinical Global Impressions Improvement subscale, and in number of words used on a parent-report questionnaire.CONCLUSIONS: This is the first 24-week randomized controlled trial in which community treatment is compared with the combination of parent training and clinician-delivered PRT. PRT-P was effective for improving child social communication skills and for teaching parents to implement PRT. Additional research will be needed to understand the optimal combination of treatment settings, intensity, and duration, and to identify child and parent characteristics associated with treatment response.

  View details for DOI 10.1542/peds.2019-0178

  View details for PubMedID 31387868

• Blood oxytocin concentration positively predicts contagious yawning behavior in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research Mariscal, M. G., Oztan, O., Rose, S. M., Libove, R. A., Jackson, L. P., Sumiyoshi, R. D., Trujillo, T. H., Carson, D. S., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2019

  Abstract

  Research suggests that children with autism spectrum disorder (ASD) may have reduced empathy, as measured by an impaired contagious yawn response, compared to typically developing (TD) children. Other research has failed to replicate this finding, instead attributing this phenomenon to group differences in attention paid to yawn stimuli. A third possibility is that only a subgroup of children with ASD exhibits the impaired contagious yawn response, and that it can be identified biologically. Here we quantified blood concentrations of the "social" neuropeptide oxytocin (OXT) and evaluated yawning behavior and attention rates during a laboratory task in children with ASD (N=34) and TD children (N=30) aged 6-12years. No group difference in contagious yawning behavior was found. However, a blood OXT concentration*group (ASD vs. TD) interaction positively predicted contagious yawning behavior (F1,50 =7.4987; P=0.0085). Specifically, blood OXT concentration was positively related to contagious yawning behavior in children with ASD, but not in TD children. This finding was not due to delayed perception of yawn stimuli and was observed whether attention paid to test stimuli and clinical symptom severity were included in the analysis or not. These findings suggest that only a biologically defined subset of children with ASD exhibits reduced empathy, as measured by the impaired contagious yawn response, and that prior conflicting reports of this behavioral phenomenon may be attributable, at least in part, to variable mean OXT concentrations across different ASD study cohorts. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism may contagiously yawn (i.e., yawn in response to another's yawn) less often than people without autism. We find that people with autism who have lower levels of blood oxytocin (OXT), a hormone involved in social behavior and empathy, show decreased contagious yawning, but those who have higher blood OXT levels do not differ in contagious yawning from controls. This suggests that decreased contagious yawning may only occur in a biologically defined subset of people with autism.

  View details for DOI 10.1002/aur.2135

  View details for PubMedID 31132232

• Effects of a parent-implemented Developmental Reciprocity Treatment Program for children with autism spectrum disorder AUTISM Gengoux, G. W., Schapp, S., Burton, S., Ardel, C. M., Libove, R. A., Baldi, G., Berquist, K. L., Phillips, J. M., Hardan, A. Y. 2019; 23 (3): 713–25

  View details for DOI 10.1177/1362361318775538

  View details for Web of Science ID 000464503900017

• Development of the Stanford Social Dimensions Scale: initial validation in autism spectrum disorder and in neurotypicals. Molecular autism Phillips, J. M., Uljarević, M. n., Schuck, R. K., Schapp, S. n., Solomon, E. M., Salzman, E. n., Allerhand, L. n., Libove, R. A., Frazier, T. W., Hardan, A. Y. 2019; 10: 48

  Abstract

  The aim of this paper was to provide an initial validation of a newly developed parent questionnaire-the Stanford Social Dimensions Scale (SSDS), designed to capture individual differences across several key social dimensions including social motivation in children and adolescents with and without psychiatric disorders.The initial validation sample was comprised of parents of 175 individuals with autism spectrum disorder (ASD) (35 females, 140 males; Mage = 7.19 years, SDage = 3.96) and the replication sample consisted of 624 parents of children who were either typically developing or presented with a range of neurodevelopmental and neuropsychiatric disorders (302 females, 322 males; Mage = 11.49 years, SDage = 4.48). Parents from both samples completed the SSDS and the Social Responsiveness Scale (SRS-2).Exploratory Structural Equation Modeling indicated that a 5-factor model provided adequate to excellent fit to the data in the initial ASD sample (comparative fit index [CFI] = .940, Tucker-Lewis Index [TLI] = .919, root mean square error of approximation [RMSEA] = .048, standardized root mean square residual [SRMR] = .038). The identified factors were interpreted as Social Motivation, Social Affiliation, Expressive Social Communication, Social Recognition, and Unusual Approach. This factor structure was further confirmed in Sample 2 (CFI = 946, TLI = .930, RMSEA = .044, SRMR = .026). Internal consistency for all subscales was in the good to excellent range across both samples as indicated by Composite Reliability scores of ≥ .72. Convergent and divergent validity was strong as indexed by the pattern of correlations with relevant SRS-2 and Child Behavior Checklist domains and with verbal and non-verbal intellectual functioning scores in Sample 1 and with the Need to Belong Scale and Child Social Preference Scale scores in Sample 2. Across both samples, females had higher social motivation and expressive social communication scores. Discriminant validity was strong given that across all SSDS subscales, the ASD sample had significantly higher impairment than both the typically developing group and the group with other clinical conditions, which in turn, had significantly higher impairment than the typically developing group.Our findings provide initial validation of a new scale designed to comprehensively capture individual differences in social motivation and other key social dimensions in ASD.

  View details for DOI 10.1186/s13229-019-0298-9

  View details for PubMedID 31890146

  View details for PubMedCentralID PMC6921422

• Effects of a parent-implemented Developmental Reciprocity Treatment Program for children with autism spectrum disorder. Autism : the international journal of research and practice Gengoux, G. W., Schapp, S., Burton, S., Ardel, C. M., Libove, R. A., Baldi, G., Berquist, K. L., Phillips, J. M., Hardan, A. Y. 2018: 1362361318775538

  Abstract

  Developmental approaches to autism treatment aim to establish strong interpersonal relationships through joint play. These approaches have emerging empirical support; however, there is a need for further research documenting the procedures and demonstrating their effectiveness. This pilot study evaluated changes in parent behavior and child autism symptoms following a 12-week Developmental Reciprocity Treatment parent-training program. A total of 22 children with autism spectrum disorder between 2 and 6years (mean age=44.6months, standard deviation=12.7) and a primary caregiver participated in 12 weekly sessions of Developmental Reciprocity Treatment parent training, covering topics including introduction to developmental approaches, supporting attention and motivation, sensory regulation and sensory-social routines, imitation/building nonverbal communication, functional language development, and turn taking. Results indicated improvement in aspects of parent empowerment and social quality of life. Improvement in core autism symptoms was observed on the Social Responsiveness Scale total score (F(1,19): 5.550, p=0.029), MacArthur-Bates Communicative Development Inventories number of words produced out of 680 (F(1,18): 18.104, p=0.000), and two subscales of the Repetitive Behavior Scale, Revised (compulsive, p=0.046 and restricted, p=0.025). No differences in sensory sensitivity were observed on the Short Sensory Profile. Findings from this pilot study indicate that Developmental Reciprocity Treatment shows promise and suggest the need for future controlled trials of this developmentally based intervention.

  View details for PubMedID 29775078

• Plasma anandamide concentrations are lower in children with autism spectrum disorder MOLECULAR AUTISM Karhson, D. S., Krasinska, K. M., Dallaire, J., Libove, R. A., Phillips, J. M., Chien, A. S., Garner, J. P., Hardan, A. Y., Parker, K. J. 2018; 9: 18

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N = 112).Anandamide concentrations significantly differentiated ASD cases (N = 59) from controls (N = 53), such that children with lower anandamide concentrations were more likely to have ASD (p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p = 0.034).These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.

  View details for PubMedID 29564080

• The measurement properties of the spence children's anxiety scale-parent version in a large international pooled sample of young people with autism spectrum disorder. Autism research Magiati, I., Lerh, J. W., Hollocks, M. J., Uljarevic, M., Rodgers, J., McConachie, H., Ozsivadjian, A., South, M., Van Hecke, A., Hardan, A., Libove, R., Leekam, S., Simonoff, E. 2017

  Abstract

  Anxiety-related difficulties are common in ASD, but measuring anxiety reliably and validly is challenging. Despite an increasing number of studies, there is no clear agreement on which existing anxiety measure is more psychometrically sound and what is the factor structure of anxiety in ASD. The present study examined the internal consistency, convergent, divergent, and discriminant validity, as well as the factor structure of the Spence Children's Anxiety Scale-Parent Version (SCAS-P), in a large international pooled sample of 870 caregivers of youth with ASD from 12 studies in the United Kingdom, United States, and Singapore who completed the SCAS-P. Most were community recruited, while the majority had at least one measure of ASD symptomatology and either cognitive or adaptive functioning measures completed. Existing SCAS-P total scale and subscales had excellent internal consistency and good convergent, divergent and discriminant validity similar to or better than SCAS-P properties reported in typically developing children, except for the poorer internal consistency of the physical injury subscale. Confirmatory Factor Analysis (CFA) of the existing SCAS-P six-correlated factor structure was a poor fit for this pooled database. Principal component analysis using half of the pooled sample identified a 30-item five correlated factor structure, but a CFA of this PCA-derived structure in the second half of this pooled sample revealed a poor fit, although the PCA-derived SCAS-P scale and subscales had stronger validity and better internal consistency than the original SCAS-P. The study's limitations, the use of the SCAS-P to screen for DSM-derived anxiety problems in ASD and future research directions are discussed. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1809

  View details for PubMedID 28574646

• Biomarker discovery for disease status and symptom severity in children with autism. Psychoneuroendocrinology Oztan, O. n., Jackson, L. P., Libove, R. A., Sumiyoshi, R. D., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2017; 89: 39–45

  Abstract

  Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.

  View details for PubMedID 29309996

• Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124

  Abstract

  Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

  View details for DOI 10.1073/pnas.1705521114

  View details for PubMedCentralID PMC5544319

• Pregnenolone in the Treatment of Irritability in Autism Spectrum Disorder: A Post-Hoc Metabolomic Analysis Fung, L., Sun, W., Libove, R., Tanaka, S., Kwa, L., Philips, J., Haddad, F., Rajadas, J., Hardan, A. NATURE PUBLISHING GROUP. 2015: S188

  View details for Web of Science ID 000366597700336

• A randomized controlled trial of Pivotal Response Treatment Group for parents of children with autism. Journal of child psychology and psychiatry, and allied disciplines Hardan, A. Y., Gengoux, G. W., Berquist, K. L., Libove, R. A., Ardel, C. M., Phillips, J., Frazier, T. W., Minjarez, M. B. 2015; 56 (8): 884-892

  Abstract

  With rates of autism diagnosis continuing to rise, there is an urgent need for effective and efficient service delivery models. Pivotal Response Treatment (PRT) is considered an established treatment for autism spectrum disorder (ASD); however, there have been few well-controlled studies with adequate sample size. The aim of this study was to conduct a randomized controlled trial to evaluate PRT parent training group (PRTG) for targeting language deficits in young children with ASD.Fifty-three children with autism and significant language delay between 2 and 6 years old were randomized to PRTG (N = 27) or psychoeducation group (PEG; N = 26) for 12 weeks. The PRTG taught parents behavioral techniques to facilitate language development. The PEG taught general information about ASD (clinical trial NCT01881750; http://www.clinicaltrials.gov).Analysis of child utterances during the structured laboratory observation (primary outcome) indicated that, compared with children in the PEG, children in the PRTG demonstrated greater improvement in frequency of utterances (F(2, 43) = 3.53, p = .038, d = 0.42). Results indicated that parents were able to learn PRT in a group format, as the majority of parents in the PRTG (84%) met fidelity of implementation criteria after 12 weeks. Children also demonstrated greater improvement in adaptive communication skills (Vineland-II) following PRTG and baseline Mullen visual reception scores predicted treatment response to PRTG.This is the first randomized controlled trial of group-delivered PRT and one of the largest experimental investigations of the PRT model to date. The findings suggest that specific instruction in PRT results in greater skill acquisition for both parents and children, especially in functional and adaptive communication skills. Further research in PRT is warranted to replicate the observed results and address other core ASD symptoms.

  View details for DOI 10.1111/jcpp.12354

  View details for PubMedID 25346345

• Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism PLOS ONE Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

  Abstract

  Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

  View details for DOI 10.1371/journal.pone.0132224

  View details for Web of Science ID 000358597100030

  View details for PubMedCentralID PMC4511760

• Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism. PloS one Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

  Abstract

  Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

  View details for DOI 10.1371/journal.pone.0132224

  View details for PubMedID 26200852

• Brief Report: An Open-Label Study of the Neurosteroid Pregnenolone in Adults with Autism Spectrum Disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

  Abstract

  The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

  View details for DOI 10.1007/s10803-014-2144-4

  View details for Web of Science ID 000343724000027

• Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Journal of autism and developmental disorders Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

  Abstract

  The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

  View details for DOI 10.1007/s10803-014-2144-4

  View details for PubMedID 24849255

• Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Parker, K. J., Garner, J. P., Libove, R. A., Hyde, S. A., Hornbeak, K. B., Carson, D. S., Liao, C., Phillips, J. M., Hallmayer, J. F., Hardan, A. Y. 2014; 111 (33): 12258-12263

  Abstract

  The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.

  View details for DOI 10.1073/pnas.1402236111

  View details for Web of Science ID 000340438800080

  View details for PubMedID 25092315

• Plasma Vasopressin Levels Positively Predict Social Cognition in Children with Autism Spectrum Disorder but not in Siblings of Probands or Healthy Controls Carson, D. S., Howerton, C. L., Garner, J. P., Libove, R. A., Hyde, S. A., Phillips, J. M., Hardan, A. Y., Parker, K. J. ELSEVIER SCIENCE INC. 2014: 255S–256S

  View details for Web of Science ID 000334101801368

• A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Fung, L. K., Libove, R. A., Obukhanych, T. V., Nair, S., Herzenberg, L. A., Frazier, T. W., Tirouvanziam, R. 2012; 71 (11): 956-961

  Abstract

  An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism.This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale.Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96).Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

  View details for DOI 10.1016/j.biopsych.2012.01.014

  View details for Web of Science ID 000303814800007

  View details for PubMedID 22342106

• A Retrospective Review of the Effectiveness of Aripiprazole in the Treatment of Sensory Abnormalities in Autism JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Fung, L. K., Chahal, L., Libove, R. A., Bivas, R., Hardan, A. Y. 2012; 22 (3): 245-248

  Abstract

  Although sensory deficits are frequently observed in autistic individuals, pharmacologic interventions targeting these abnormalities are lacking. The goal of this investigation was to assess the effectiveness of aripiprazole in targeting sensory deficits in children and adolescents with autism. Using an outpatient clinic registry for pervasive developmental disorder, 13 individuals who had received aripiprazole for treating disruptive behaviors and had completed behavioral rating scales (aberrant behavior checklist [ABC] and sensory profile questionnaire [SPQ]) were identified. Mean treatment duration was 24.4 weeks with a mean final aripiprazole dosage of 10.8 mg. Aripiprazole yielded improvements in the total ABC and in several items of the SPQ including registration, inattention/distractibility, auditory processing, and modulation of visual input affecting emotional responses and activity level, suggesting that aripiprazole might be beneficial in targeting sensory abnormalities in autism.

  View details for DOI 10.1089/cap.2010.0103

  View details for Web of Science ID 000305337300009

  View details for PubMedID 22537360

• Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Tirouvanziam, R., Obukhanych, T. V., Laval, J., Aronov, P. A., Libove, R., Banerjee, A. G., Parker, K. J., O'Hara, R., Herzenberg, L. A., Herzenberg, L. A., Hardan, A. Y. 2012; 42 (5): 827-836

  Abstract

  The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.

  View details for DOI 10.1007/s10803-011-1314-x

  View details for Web of Science ID 000302771500017

  View details for PubMedID 21713591

• Dorsolateral Prefrontal Cortex Magnetic Resonance Imaging Measurements and Cognitive Performance in Autism JOURNAL OF CHILD NEUROLOGY Griebling, J., Minshew, N. J., Bodner, K., Libove, R., Bansal, R., Konasale, P., Keshavan, M. S., Hardan, A. 2010; 25 (7): 856-863

  Abstract

  This study examined the relationships between volumetric measurements of frontal lobe structures and performance on executive function tasks in individuals with autism. Magnetic resonance imaging (MRI) scans were obtained from 38 individuals with autism and 40 matched controls between the ages of 8 and 45 years. Executive function was assessed using neuropsychological measures including the Wisconsin Card Sorting Test and Tower of Hanoi. Differences in performance on the neuropsychological tests were found between the 2 groups. However, no differences in dorsolateral prefrontal cortex volumes were observed between groups. No correlations between volumetric measurements and performance on the neuropsychological tests were found. Findings from this study suggest that executive function deficits observed in autism are related to functional but not anatomical abnormalities of the frontal lobe. The absence of correlations suggests that executive dysfunction is not the result of focal brain alterations but, rather, is the result of a distributed neural network dysfunction.

  View details for DOI 10.1177/0883073809351313

  View details for Web of Science ID 000279409100008

  View details for PubMedID 20097663

  View details for PubMedCentralID PMC3428128

• A Preliminary Longitudinal Magnetic Resonance Imaging Study of Brain Volume and Cortical Thickness in Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Libove, R. A., Keshavan, M. S., Melhem, N. M., Minshew, N. J. 2009; 66 (4): 320-326

  Abstract

  Autism is a developmental neurobiologic disorder associated with structural and functional abnormalities in several brain regions including the cerebral cortex. This longitudinal study examined developmental changes in brain volume and cortical thickness (CT) using magnetic resonance imaging (MRI) in children with autism.MRI scans and behavioral measures were obtained at baseline and after a 30-month interval in a sample of male subjects with autism (n = 18) and healthy age-, and sex-matched control subjects (n = 16) between ages 8 and 12 years at baseline.No differences in brain volumes were observed between the autism and control subjects at baseline or follow-up. However, differences in total gray matter volumes were observed over time with significantly greater decreases in the autism group compared with control subjects. Differences in CT were observed over time with greater decreases in the autism group compared with control subjects in several brain regions including the frontal lobe. When accounting for multiple comparisons, differences between the two groups became nonsignificant except for changes in occipital CT. Furthermore, associations were observed between several clinical features and changes in CT with greater thinning of the cortex being correlated with more severe symptomatology.Findings from this study provide preliminary evidence for age-related changes in gray matter volume and CT in children with autism that are associated with symptoms severity. Future longitudinal studies of larger sample sizes are needed to evaluate developmental changes and examine the relationships between structural abnormalities and clinical expressions of the disorder.

  View details for DOI 10.1016/j.biopsych.2009.04.024

  View details for Web of Science ID 000268840200005

  View details for PubMedID 19520362

  View details for PubMedCentralID PMC2905654