Aberrant Behavior Checklist-Community Research Articles

Severe behavior problems in SYNGAP1-related disorder: A summary of 11 consecutive patients in a tertiary care specialty clinic

SYNGAP1-related disorder (SYNGAP1-RD) is a neurodevelopmental disorder that is commonly associated with epilepsy, autism spectrum disorder (ASD), and disruptive behaviors. In this study, behavior problems in 11 consecutive patients with SYNGAP1-RD are described and quantified based on a behavioral screening conducted within the context of a multi-disciplinary tertiary care specialty clinic visit. The behavioral phenotype was then compared to published samples of behavior problems in ASD and other genetic cause of epilepsy occurring in the context of neurodevelopmental disorders using results from the Aberrant Behavior Checklist-Community (ABC-C), an empirically derived outcome measure. We report common antecedent and consequent events surrounding problem behavior across individuals. Additionally, we report on the management approach of caregivers and the impact of problem behaviors on the family. Our results suggest a number of commonalities between behavioral profiles in SYNGAP1-RD with ASD and other genetic causes of developmental and epileptic encephalopathies, and also highlight severe behavior problems as a specific behavioral phenotype of SYNGAP1-RD.

IBehavior-a preliminary proof of concept study of a smartphone-based tool for the assessment of behavior change in neurodevelopmental disabilities.

The purpose of the present study was to describe the content and function of iBehavior, a smartphone-based caregiver-report electronic ecological momentary assessment (eEMA) tool developed to assess and track behavior change in people with intellectual and developmental disabilities (IDDs), and to examine its preliminary validity. Ten parents of children (ages of 5-17 years) with IDDs (n = 7 with fragile X syndrome; n = 3 with Down syndrome) rated their child's behavior (aggression and irritability, avoidant and fearful behavior, restricted and repetitive behavior and interests, and social initiation) using iBehavior once daily for 14 days. At the conclusion of the 14-day observation period, parents completed traditional rating scales as validation measures, as well as a user feedback survey. Across the 140 possible observations, 8 were skipped, leading to a 94% response rate over 10 participants' observation periods. Participants also completed 100% of items for each of their logged observations. Parent ratings using iBehavior showed emerging evidence of convergent validity among domains with traditional rating scales including the Behavior Rating Inventory of Executive Function 2 (BRIEF-2), and Aberrant Behavior Checklist-Community (ABC-C). iBehavior was feasible in the sample, and parent feedback indicated high overall satisfaction. Results of the present pilot study indicate successful implementation and preliminary feasibility and validity of an eEMA tool for use as a behavioral outcome measure in IDDs.

L-carnitine adjunct to risperidone for treatment of autism spectrum disorder-associated behaviors: a randomized, double-blind clinical trial.

Present study was designed to evaluate the efficacy and safety of l-carnitine as an adjuvant agent to risperidone in the treatment of autism spectrum disorder (ASD)-associated behaviors. In this study, 68 children with confirmed ASD were randomly allocated to receive either l-carnitine (150 mg/day) or matched placebo in addition to risperidone. We utilized the Aberrant Behavior Checklist-Community Edition scale (ABC-C) and a checklist of potential adverse effects to assess changes in behavioral status and safety profile at weeks 0, 5 and 10 of the trial. The primary outcome was defined as a change in the irritability subscale score. Sixty patients with similar baseline characteristics completed the trial period. Although scores of ABC-C subscales significantly decreased in both groups over the trial period, the combination of l-carnitine and risperidone resulted in more reduction on the irritability and hyperactivity subscales compared to the combination of risperidone and placebo (P = 0.033 and P < 0.001, respectively). However, changes in lethargy, stereotypic behavior and inappropriate speech subscales were similar between groups. In conclusion, l-carnitine adjuvant to risperidone could improve irritability and hyperactivity features in children with ASD. Results of this study should be considered preliminary and further clinical trials with larger sample sizes and longer follow-up periods are warranted.

Clinical and cost evaluation of two models of specialist intensive support teams for adults with intellectual disabilities who display behaviours that challenge: the IST-ID mixed-methods study.

Intensive support teams (ISTs) are recommended for individuals with intellectual disabilities who display behaviours that challenge. However, there is currently little evidence about the clinical and cost-effectiveness of IST models operating in England. To investigate the clinical and cost-effectiveness of IST models. We carried out a cohort study to evaluate the clinical and cost-effectiveness of two previously identified IST models (independent and enhanced) in England. Adult participants (n = 226) from 21 ISTs (ten independent and 11 enhanced) were enrolled. The primary outcome was change in challenging behaviour between baseline and 9 months as measured by the Aberrant Behaviour Checklist-Community version 2. We found no statistically significant differences between models for the primary outcome (adjusted β = 4.27; 95% CI -6.34 to 14.87; P = 0.430) or any secondary outcomes. Quality-adjusted life-years (0.0158; 95% CI: -0.0088 to 0.0508) and costs (£3409.95; 95% CI -£9957.92 to £4039.89) of the two models were comparable. The study provides evidence that both models were associated with clinical improvement for similar costs at follow-up. We recommend that the choice of service model should rest with local services. Further research should investigate the critical components of IST care to inform the development of fidelity criteria, and policy makers should consider whether roll out of such teams should be mandated.

The aberrant behavior profile in Indonesian individuals with fragile X syndrome with limited genetic services.

Fragile X syndrome (FXS) is caused by the full mutation in the fragile x messenger ribonucleoprotein 1 (FMR1) gene leading to the absence of the fragile X protein (FXP). Previous studies show that individuals with FXS exhibit changing behavior over time; therefore, this study aimed to elucidate the aberrant behavior profile of FXS individuals. The Aberrant Behavior Checklist-Community (ABC-C) was used to measure the aberrant behavior profile of individuals with FXS, which was rated by the parent/caregiver combined with clinical impression. A total of 58 items were used to assess aberrant behaviors across five subscales. Forty-nine individuals with FXS were included (32 males, 17 females) with a mean age of 32.9 ± 14.62 years in males and 33.4 ± 13.98 years in females. The average score of irritability and hyperactivity was significantly higher in male FXS individuals (5.37 ± 6.231 and 10.28 ± 8.524) than in female individuals (3.24 ± 7.093 and 3.76 ± 3.327) with p = 0.046 and p = 0.001, respectively. Overall irritability in FXS individuals significantly decreased over time (ß = -0.141; p = 0.032). A modest worsening in lethargy/social withdrawal in males across age and a gentle improvement in hyperactivity/noncompliance in male of FXS individuals were observed. FXS males had higher hyperactivity problems than FXS female individuals across age.

A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)

BackgroundFragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy.DesignCONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS.MethodsPatients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-CFXS) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely.ResultsA total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression‐Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%).ConclusionsIn CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe.Trial registrationThe CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).

Intensive support teams for adults with intellectual disabilities displaying challenging behaviour: the IST-ID mixed-methods study

Background National policy recommends intensive support teams for all areas of England for adults with intellectual disabilities who display challenging behaviour. However, to the best of our knowledge, there has not been a systematic evaluation of intensive support teams to date. Objectives Our objectives were to identify and describe the geographical distribution and characteristics of intensive support teams in England; to create a typology of intensive support teams; to investigate clinical and cost outcomes of intensive support team models and factors associated with those outcomes; and to explore professionals’, service users’ and carers’ experiences and describe the wider system context in which they operate. Design This was a two-phase mixed-methods study. In phase 1, a national survey examined the intensive support team models in operation in England. In phase 2, an observational study of adults with intellectual disabilities investigated the clinical effectiveness and cost-effectiveness of the two intensive support team models. Semistructured interviews with intensive support team managers and professionals, carers, and adults with intellectual disabilities explored their experiences of intensive support team care. In parallel, we examined service-level outcomes related to the function of intensive support teams. Setting Phase 1 included 80 intensive support teams serving 242 community intellectual disability services in England. Phase 2 included 21 intensive support teams, half of which were in the enhanced intensive support teams model and half of which were in the independent model. Participants In phase 1, a total of 73 intensive support team managers provided data. In phase 2, a total of 226 participants with intellectual disabilities from 21 intensive support teams (enhanced: teams, n = 11; participants, n = 115; independent: teams, n = 10; participants, n = 111) were enrolled in the study. A total of 42 stakeholders were interviewed. Main outcome measure The main outcome measure was the Aberrant Behaviour Checklist-Community, version 2, total score. Additional data sources were the carer and self-reported questionnaires, qualitative interviews and focus groups. Results Two intensive support team models were identified in England – enhanced and independent. Challenging behaviour at 9 months was reduced in both intensive support team models (β 3.08, 95% confidence interval –7.32 to 13.48; p = 0.561), but the observed Aberrant Behaviour Checklist-Community, version 2, score reduction appeared larger in the independent model than in the enhanced model (21% vs. 13%, respectively). No statistically significant differences were found in the secondary outcomes [Psychiatric Assessment Schedule for Adults with Developmental Disabilities Clinical Interview organic condition (odds ratio 1.09, 95% confidence interval 0.39 to 3.02), affective or neurotic disorder (odds ratio 0.91, 95% confidence interval 0.32 to 2.59), or psychotic disorder score (odds ratio 1.08, 95% confidence interval 0.21 to 5.50); risk score (β 1.12, 95% confidence interval –0.44 to 2.68); or quality of life questionnaire score (β –2.63, 95% confidence interval –5.65 to 0.40)]. Similarly, no differences were observed between models in relation to cost-effectiveness (health and social care costs mean difference £3409.95, 95% confidence interval –£9957.92 to £4039.89; societal costs mean difference –£4712.30, 95% confidence interval –£11,124.85 to £2106.36). The experiences of stakeholders did not differ between the intensive support team models, with carers and adults with intellectual disabilities valuing service accessibility, person-centred care and engagement. All stakeholders reported a range of barriers to intensive support team care. Service-level data and the operational policies from intensive support teams showed variation in organisational function and the roles of intensive support teams. The most commonly delivered intervention was positive behaviour support. Conclusions The study describes the operation of intensive support teams in England and identified two distinct models. We did not find advantages or disadvantages associated with clinical outcomes between models, nor did we find cost differences. On this basis, we recommend that local services decide which model best suits their circumstances. Limitations This was not a randomised controlled trial. It is possible that confounding factors have not been controlled for as there was no matching between intensive support teams. Last, there was no comparison with usual care. Future work There is need to develop model fidelity and investigate clinical effectiveness and cost-effectiveness in a randomised controlled evaluation of intensive support teams against treatment as usual. Study registration This study is registered as ClinicalTrials.gov NCT03586375, Integrated Research Application System (IRAS) 239820 and National Institute for Health and Care Research (NIHR) Central Portfolio Management System (CPMS) 38554. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 33. See the NIHR Journals Library website for further project information.

Long-term follow-up of telehealth-enabled behavioral treatment for challenging behaviors in boys with fragile X syndrome

BackgroundA significant proportion of boys with fragile X syndrome (FXS), the most common known genetic cause of intellectual disability, exhibit challenging behaviors such as aggression and self-injury that can cause significant distress to families. Recent evidence suggests that coaching caregivers to implement functional communication training (FCT) with their child via telehealth can help to ameliorate these behaviors in FXS. In the present study, we followed families who had participated in our previous randomized controlled trial of FCT to evaluate the longer-term effects of FCT on challenging behaviors in this population.MethodsIn study 1, follow-up emails, phone calls, text messages, and letters were sent to caregivers of 48 boys with FXS who had completed our previous study conducted between 2016 and 2019. The main outcome measures administered at follow-up were the Aberrant Behavior Checklist–Community (ABC-C) and the Parenting Stress Index, 4th Edition (PSI-4). In study 2, families who had received FCT treatment but whose child exhibited challenging behaviors daily at follow-up received a 1-h parent training booster session to determine whether the intervention effect could be recovered.ResultsSixteen (66.7%) of 24 families who had received FCT treatment and 18 (75.0%) of 24 families who had received treatment as usual were traced and consented between March and August 2021. The mean follow-up time was 3.1 years (range, 1.4 to 4.2 years). Longitudinal mixed effects analyses indicated that boys who had received FCT were more likely to show improvements on the irritability and lethargy/social withdrawal subscales of the ABC-C over the follow-up interval compared to boys who had continued with treatment as usual. Four of the six boys who had received the booster parent training session via telehealth were reported to exhibit fewer forms of challenging behavior at a 4-week follow-up.ConclusionsEmpowering parents to implement behavior analytic treatments with their child in their own home can have durable effects on maintaining low levels of challenging behaviors in boys with FXS. These data further support the need to implement parent-mediated interventions for challenging behaviors in this population at an early age.Trial registrationClinicalTrials.gov, NCT03510156. Registered 27 April 2018

Agreement between parents' and clinical researchers' ratings of behavioral problems in children with fragile X syndrome and chromosome 15 imprinting disorders

BackgroundDespite the increasing number of clinical trials involving children with neurodevelopmental disorders, appropriate and objective outcome measures for behavioral symptoms are still required. AimThis study assessed the agreement between parents' and clinical researchers' ratings of behavioral problem severity in children with fragile X syndrome (FXS) and chromosome 15 imprinting disorders. Methods and ProceduresThe cohort comprised 123 children (64% males), aged 3–17 years, with FXS (n = 79), Prader-Willi (PWS; n = 19), Angelman (AS; n = 15), and Chromosome 15q duplication (n = 10) syndromes. Specific items from the Autism Diagnostic Observation Schedule-Second Edition and Aberrant Behavior Checklist-Community Edition mapping to corresponding behavioral domains were selected ad-hoc, to assess behavioral problems. Outcomes and ResultsInter-rater agreement for the cohort was slight for self-injury (Intraclass Correlation Coefficient (ICC) = 0.12), fair for tantrums/aggression (0.24) and mannerisms/stereotypies (0.25), and moderate for hyperactivity (0.48). When stratified by diagnosis, ICC ranged from poor (0; self-injury, AS and PWS) to substantial (0.48; hyperactivity, females with FXS). Conclusions and ImplicationsThe high level of inter-rater disagreement across most domains suggests that parents' and researchers' assessments led to discrepant appraisal of behavioral problem severity. These findings have implications for treatment targets and outcome measure selection in clinical trials, supporting a multi-informant approach.

Pharmacological approaches in the treatment of autism: a narrative review

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication and social interaction and by the presence of repetitive and restricted behaviors. To review the literature on drug interventions in the treatment of ASD in children and adolescents. Narrative review conducted at a university in São Paulo, Brazil. Search of the literature of studies published from 2005 to 2022, in Portuguese, English and Spanish, in the SciELO, PubMed, SCOPUS, LILACS and TripDatabase databases. Risperidone alone improved stereotyped patterns of behavior. Associations with aripiprazole or galantamine reduced irritability and managing the behavioral symptoms, respectively. Ginkgo biloba, associated to risperidone, led to an improvement in the Aberrant Behavior Checklist-Community (ABC-C) subscales scores. The association with sulforaphane exhibited a greater improvement in irritability and hyperactivity/noncompliance scores. Omega-3s reduced gesture use and hyperactivity. Bumetanide reduced restricted interests and repetitive behavior compared to placebo. Intranasal oxytocin improved social skills. The AB-2004 showed improvement in behavioral endpoints, especially anxiety and irritability. Folinic acid improved verbal communication in non-syndromic ASD children. Prednisolone increased language scores. There is not a drug that treats all of them and the possibility of significant adverse effects must be adjusted according to the symptoms and clinical response.

Variation in Response to Pharmacological Intervention with Risperidone and the Role of Adjuvant Medications in the Treatment of Autism Spectrum Disorders: A Systematic Review and Meta-analysis

Non-genetic traits as predictors of variation in response to pharmacological interventions in ASD need to be identified for better management. This review aims to identify these non-genetic traits and the role of adjuvant medications in ASD. Electronic database searches in PUBMED and Cochrane libraries were conducted using MeSH search terms "Autism" and "Risperidone." Randomized or cross-over trials comparing the efficacy of ‘risperidone plus placebo’ vs. ‘risperidone plus adjuvant medications’ using Aberrant Behavior Checklist-Community Version (ABC-CV) scores in ASD patients of any age group were included in the analysis. The quantity of reduced irritability (ABC-I) sub-score was the primary outcome measure analyzed.In contrast, the reduction in remaining ABC-CV sub-scores at the end of 10 weeks were the secondary outcome measures analyzed. All the outcome measures were estimated by calculating the Mean Difference (MD) values and their 95% Confidence Intervals (CI) by both fixed and random effect models using Revman 5.4.1 software. A total of 13 trials were found to be eligible and included in the quantitative synthesis of efficacy. A small but significant decrease in the ABC irritability sub-score was evident in the ‘risperidone plus adjuvants’ group (MD: -3.19, 95% CI:-3.82, -2.56, N=658). The meta-analysis results attributed the highest decrease in ABC-irritability sub-scores to adjuvant topiramate. There is a possibility of bias and minimal impact of adjuvants in alleviating irritability symptoms of ASD. Baseline severity of irritability symptoms and the dose/medication regimen appear to be possible non-genetic traits responsible for variation in response to pharmacological intervention.

Combining Lovastatin and Minocycline for the Treatment of Fragile X Syndrome: Results From the LovaMiX Clinical Trial.

Background: Limited success of previous clinical trials for Fragile X syndrome (FXS) has led researchers to consider combining different drugs to correct the pleiotropic consequences caused by the absence of the Fragile X mental retardation protein (FMRP). Here, we report the results of the LovaMiX clinical trial, the first trial for FXS combining two disease-modifying drugs, lovastatin, and minocycline, which have both shown positive effects when used independently.Aim: The main goals of the study were to assess the safety and efficacy of a treatment combining lovastatin and minocycline for patients with FXS.Design: Pilot Phase II open-label clinical trial. Patients with a molecular diagnostic of FXS were first randomized to receive, in two-step titration either lovastatin or minocycline for 8 weeks, followed by dual treatment with lovastatin 40 mg and minocycline 100 mg for 2 weeks. Clinical assessments were performed at the beginning, after 8 weeks of monotherapy, and at week 20 (12 weeks of combined therapy).Outcome Measures: The primary outcome measure was the Aberrant Behavior Checklist-Community (ABC-C) global score. Secondary outcome measures included subscales of the FXS specific ABC-C (ABC-CFX), the Anxiety, Depression, and Mood Scale (ADAMS), the Social Responsiveness Scale (SRS), the Behavior Rating Inventory of Executive Functions (BRIEF), and the Vineland Adaptive Behavior Scale second edition (VABS-II).Results: Twenty-one individuals out of 22 completed the trial. There were no serious adverse events related to the use of either drugs alone or in combination, suggesting good tolerability and safety profile of the combined therapy. Significant improvement was noted on the primary outcome measure with a 40% decrease on ABC-C global score with the combined therapy. Several outcome measures also showed significance.Conclusion: The combination of lovastatin and minocycline is safe in patients for FXS individuals and appears to improve several elements of the behavior. These results set the stage for a larger, placebo-controlled double-blind clinical trial to confirm the beneficial effects of the combined therapy.

LONGER-TERM TOLERABILITY AND EFFICACY OF ZYN002 CANNABIDIOL TRANSDERMAL GEL IN CHILDREN AND ADOLESCENTS WITH AUTISM SPECTRUM DISORDER: AN OPEN-LABEL PHASE 2 STUDY (BRIGHT [ZYN2-CL-030

ZYN002 is a pharmaceutically manufactured transdermal cannabidiol gel. BRIGHT is a single-center, open-label phase 2 study that evaluated the tolerability and efficacy of ZYN002 in children and adolescents aged 3-17 years with autism spectrum disorder (ASD). Data through 14 weeks were previously presented. The objective is to present longer-term data through 38 weeks of treatment with open label ZYN002. Patients with Clinical Global Impression (CGI)–Severity scores ≥4 (moderate or greater) and Aberrant Behavior Checklist-Community (ABC-C) Irritability scores ≥18 were enrolled. Patients received ZYN002 250 or 500 mg/day on top of stable standard of care. Patients demonstrating ≥35% improvement in Irritability at week 14 were allowed to continue treatment. Safety assessments included adverse events (AEs), laboratory tests, and electrocardiograms (ECGs). Thirty-seven patients (mean age: 9.2 years) enrolled; 94% had moderate-to-severe symptoms; the mean baseline ABC-C Irritability score was 30.3. At week 14, significant improvements (p ≤ 0.0053) were observed for each ABC-C subscale, the Parent-Rated Anxiety Scale-ASD (PRAS-ASD) score, the Autism Parenting Stress Index (APSI) score and each Autism Impact Measure (AIM) domain in 28 who completed week 14. 57% of patients were improved (“much/very much improved”) based on CGI-Improvement (CGI-I). Eighteen patients demonstrated ≥35% improvement in Irritability and elected to continue. At week 38, improvements in the ABC-C subscale scores (50% to 61% across domains; p < 0.0001), the PRAS-ASD (42%; p < 0.0001), APSI (40%; p < 0.0001) and the AIM (19% to 36% across domains; p ≤ 0.0008) were maintained. Seventy-seven percent were improved on the CGI-I. Fifty-four percent of patients reported adverse events (AEs); mild (80%) or moderate (20%). Treatment-related AEs were reported in 19% of patients; most were mild and transient. One patient discontinued due to application site reaction. No serious or severe AEs or clinically significant changes in laboratory tests or ECGs were reported. BRIGHT provides initial evidence suggesting a positive risk-benefit profile for ZYN002 when added on top of stable standard of care in children and adolescents with ASD which was maintained over 38 weeks. Further studies are warranted.

RECONNECT (ZYN2-CL-033): DESIGN OF A PHASE 3 TRIAL OF ZYN002 CANNABIDIOL TRANSDERMAL GEL IN CHILDREN AND ADOLESCENTS WITH FRAGILE X SYNDROME BASED UPON LEARNINGS FROM CONNECT-FX (ZYN2-CL-016)

ZYN002 is a pharmaceutically manufactured transdermal cannabidiol gel in development for the treatment of behavioral symptoms in Fragile X syndrome (FXS). RECONNECT is a pivotal, randomized, double-blind, Phase 3 trial to assess the efficacy and safety of ZYN002 in children/adolescents aged 3 to 17 years with a full FMR1 gene mutation. RECONNECT is designed based on learnings from CONNECT-FX which was completed during the SARS-COV-2 (COVID-19) pandemic in patients with FXS dependent upon caregivers for assessments and support. The results and conduct of CONNECT-FX were reviewed to identify key learnings to design RECONNECT. Lessons learned: 1) treatment response for ZYN002 was greatest in patients with ≥90% methylation of the FMR1 gene; 2) the Aberrant Behavior Checklist–Community FXS Specific (ABC‒CFXS) was determined fit-for-purpose and meaningful within-patient change was determined for the Social Avoidance, Irritability and Socially Unresponsive/Lethargic subscales; 3) the Caregiver Global Impression of Severity/Change (CaGI-S/C) were highly responsive to change, with greatest change on the Social Interactions; 4) a FXS-specific Clinical Global Impression of Severity/Improvement (CGI-S/I) assessment was developed based upon outcomes in response to FDA guidance to use a disease-specific CGI; and 5) virtual visits were successfully incorporated as a result of COVID-19. RECONNECT will randomly assign approximately 200 patients 1:1 to receive 18-weeks of treatment with ZYN002 or placebo. The primary endpoint is change from baseline in the ABC‒CFXS Social Avoidance subscale at week 18 in patients with complete methylation of the FMR1 gene (100% by methylation PCR). Key secondary endpoints include change from baseline in ABC-CFXS Irritability, improvement in CaGI-C Social Interactions and FXS-specific CGI-I, and change from baseline in ABC-CFXS Social Avoidance in the full population (complete and partial methylation). Four of 8 visits will be virtual to reduce family burden. Results from RECONNECT may provide the data needed to support the potential approval of ZYN002 as the first treatment of the behavioral symptoms associated with FXS.

PRO1 Meaningful Change Thresholds for the Aberrant Behavior Checklist-Community Fragile X Syndrome (ABC-CFXS) in Children and Adolescents with FXS

The ABC-C is an observer-reported outcome measure that has been validated in individuals with intellectual disabilities and autism spectrum disorders. An FXS-specific domain structure of the ABC-C (henceforth the ABC-CFXS), which is more representative of the FXS phenotype, has been established. To aid score interpretation, a responder threshold (RT) representing individual patient-level change indicative of treatment benefit was established for three ABC-CFXS subscales (Social Avoidance [SA], Irritability, and Socially Unresponsive/Lethargic [SUL]) measuring the primary and key secondary endpoints in ZYN2-CL-016 (CONNECT-FX), a Phase 3 study of ZYN002 (transdermal cannabidiol) in FXS (NCT03614663). Anchor-based methods supplemented with visual plots were used to estimate the RT for change from Baseline to Week 12 in the three ABC-CFXS subscales. Anchors included domain-specific (DS) Caregiver Global Impression of Severity and Change (CaGI-S/C) items for DS behavioral problems as well as CaGI-S/C items for overall behavior (OB). Higher scores on the ABC-CFXS indicate more severe behavior problems. Identification of the amount of change on the CaGI-S/C representing meaningful change was informed by qualitative interviews with 25 caregivers of children with FXS. Caregivers of children with FXS reported that even small improvements in their child’s behavior would be meaningful. In the analyses (n=193), patients with a 1-category improvement on the CaGI-S DS and OB items had a mean (SD) change of -3.0 (2.96) and -3.6 (2.64), -9.8 (9.65) and -8.9 (9.43), and -5.4 (6.46) and -6.8 (6.92) points on the ABC-CFXS SA, Irritability, and SUL subscales, respectively. A similar pattern of mean change was observed for the CaGI-C DS and OB items. A change from Baseline to Week 12 of 3, 9, and 5 points on the ABC-CFXS SA, Irritability, and SUL subscales can be interpreted as a meaningful change indicative of treatment benefit for an individual patient with FXS.

ST1 Caregiver-Perceived Behavioral Challenges in Fragile X Syndrome (FXS) and Their Measurement Using the Aberrant Behavior Checklist-Community FXS Specific (ABC-CFXS)

Fragile X Syndrome (FXS) is a rare X-linked condition associated with physical and behavioral manifestations. Qualitative research was conducted with both the caregivers of children with FXS participating in ZYN2-CL-016 (CONNECT-FX), a phase 3 study of ZYN002 (transdermal cannabidiol) versus placebo (NCT03614663), as well as in the real-world setting. The objective was to establish the content validity of the ABC-CFXS to support the use of the Social Avoidance [SA], Irritability, and Socially Unresponsive/Lethargic [SUL] subscales to measure change in FXS behavioral problems.

The safety and efficacy of metformin in fragile X syndrome: An open-label study

Fragile X syndrome (FXS) is a rare genetic disorder characterized by a deficit of the fragile X mental retardation protein (FMRP), encoded by the fragile X mental retardation gene (FMR1) on the X chromosome. It has been hypothesized that the absence of FRMP leads to higher levels of Insulin-like Growth Factor 1 (IGF-1) in the brain, possibly contributing to the intellectual impairment characteristic of the disorder. Preclinical studies have shown that metformin downregulates the insulin/IGF-1 signaling pathway, corrects dendritic defects, and improves repetitive behavior in Fmr1 knockout mice. Here, we conducted an open-label study to evaluate: (1) the safety of metformin in normoglycemic individuals with FXS; and (2) the efficacy of metformin to improve aberrant behavior, attention, and to modulate cortical functioning. Fifteen patients with FXS, aged from 17 to 44, received 500 mg of metformin twice/daily over a 9-week treatment period. The primary outcome measures were: (1) the incidence of adverse events (AE); (2) the decrease in IGF-1 levels; and (3) the global score of the Aberrant Behavior Checklist-Community, Fragile X. The secondary outcomes were: (1) the Test of Attentional Performance for children (KiTAP); and (2) the Transcranial Magnetic Stimulation (TMS) parameters measuring cortical excitability. The metformin treatment was well tolerated, with no significant related AE. The TMS data showed an increase in corticospinal inhibition mediated by GABAA and GABAB mechanisms. This study demonstrates the safety of metformin in normoglycemic patients with FXS, and suggests the potential of this medication in modifying GABA-mediated inhibition, a hallmark of FXS pathophysiology. Implications for future clinical trials are discussed.

Comparison of aberrant behavior profiles across different severity levels of autism symptoms among Thai children aged 2-9 years with autistic spectrum disorder

Background: The incidence of autism spectrum disorder (ASD) has been increasing steadily, thus posing a substantial public health concern in Thailand and globally. Individuals with ASD, who frequently experience challenges related to their behavior and emotions, have neurodevelopmental disorders. The Aberrant Behavior Checklist (ABC) represents one available tool for addressing these issues. Objectives: This study aimed to explore and compare aberrant behavior profiles across different severity levels of autism among Thai children aged 2-9 years with ASD. Materials and methods: The participants comprised 71 parents and young children with ASD, recruited online, particularly from an online Facebook community of parents from diverse regions of Thailand. A convenience sampling method was employed for selecting the participants. The research tools consisted of 3 parts for collecting data. Demographic data were used for collecting such information about the participants. A Thai version of the Autism Treatment Evaluation Checklist (ThaiATEC) was utilized to measure autism symptom severity, and the Aberrant Behavior Checklist-Community (ABC-C) Thai Version was used for evaluating behavioral problems from caregiver administration. Results: A total of 71 ASD participants were identified, of which 5, 15, and 51 displayed mild, moderate, and severe symptoms of ASD, respectively. The mean scores of aberrant behaviors, as assessed by the ABC-C Thai version, showed an increase across all four subscales and the total score in response to the severity levels of ASD symptoms. The study findings, including reported correlations between aberrant behaviors and severity levels of autism symptoms, revealed predominantly high correlation coefficients (rs ranging from 0.27 to 0.93). Furthermore, a positive correlation was identified between the four subscales of the Thai-ATEC assessment and the five subscales of the ABC-C Thai version, highlighting their interrelated nature. For more detailed analysis, the ASD participants were categorized into two groups: a “mild-moderate” group consisting of 20 participants and a “severe” group comprising 51 participants. Subsequently, a comparison was made between the mean scores of the ABC-C subscales and total scores. The results of this comparison demonstrated significant distinction in all five subscales and the total score of the ABC-C Thai version between the “mild-moderate” and “severe” groups of ASD participants. These findings shed light on the notable differences in aberrant behavior profiles between individuals with varying levels of autism symptom severity. Conclusion: The aberrant behaviors increased in response to severe symptoms of ASD. This might be useful for clinical purposes, and assessing aberrant behaviors may help understand behavioral problems and severity levels of ASD and tailoring occupational therapy interventions.

Folinic Acid as Adjunctive Therapy in Treatment of Inappropriate Speech in Children with Autism: A Double-Blind and Placebo-Controlled Randomized Trial

This is a double-blind, placebo-controlled randomized trial to investigate the potential therapeutic effects of folinic acid/placebo as an adjuvant to risperidone on inappropriate speech and other behavioral symptoms of autism spectrum disorder (ASD). Fifty-five ASD children (age (mean ± standard deviation) = 13.40 ± 2.00; male/female: 35/20) were evaluated for behavioral symptoms at baseline, week 5, and week 10 using the aberrant behavior checklist-community (ABC-C). Folinic acid dosage was 2mg/kg up to 50mg per day for the entire course of the study. The repeated measures analysis showed significant effect for time × treatment interaction on inappropriate speech (F = 3.51; df = 1.61; P = 0.044), stereotypic behavior (F = 4.02; df = 1.37; P = 0.036), and hyperactivity/noncompliance (F = 6.79; df = 1.66; P = 0.003) subscale scores. In contrast, no significant effect for time × treatment interaction was found on lethargy/social withdrawal (F = 1.06; df = 1.57; P = 0.336) and irritability (F = 2.86; df = 1.91; P = 0.064) subscale scores. Our study provided preliminary evidence suggesting that folinic acid could be recommended as a beneficial complementary supplement for alleviating speech and behavioral symptoms in children with ASD.Clinical trial registeration: This trial was registered in the Iranian Registry of Clinical Trials ( www.irct.ir ; No. IRCT20090117001556N114).

Does Pregnenolone Adjunct to Risperidone Ameliorate Irritable Behavior in Adolescents With Autism Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial?

Pregnenolone is a neurosteroid with modulatory effects on γ-aminobutyric acid neurotransmission. Here, we aimed to evaluate the effectiveness and safety of pregnenolone add-on to risperidone in adolescents with autism spectrum disorders (ASD). Sixty-four ASD patients were randomly allocated to receive either pregnenolone (n = 32) or matching placebo (n = 32) in addition to risperidone. The Aberrant Behavior Checklist-Community Edition scale was used to evaluate the behavioral status of patients at baseline, week 5, and the trial end point. The change in score of irritability subscale was the primary outcome. Frequency of adverse effects due to trial medications was compared between the treatment groups. Fifty-nine patients completed the trial (30 in pregnenolone and 29 in the placebo arm). Baseline characteristics of both treatment groups were similar (P > 0.05). Repeated measures analysis was suggestive of greater exhibited improvement for the pregnenolone group on irritability, stereotypy, and hyperactivity subscales of the Aberrant Behavior Checklist-Community Edition over the trial period (F = 3.84, df = 1.96, P = 0.025; F = 4.29, df = 1.39, P = 0.029; F = 6.55, df = 1.67, P = 0.004, respectively). Nonetheless, the alterations in lethargy and inappropriate speech domains scores were similar for both arms (F = 0.93, df = 1.49, P = 0.375; F = 1.10, df = 1.60, P = 0.325, respectively). There was no significant difference in frequency as well as severity of adverse effects between the 2 groups. Pregnenolone adjunct to risperidone could attenuate core features associated with ASD.