Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: A randomized, controlled, phase 2 trial – Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, Carpenter RL, Bear MF, Hagerman RJ. Sci Transl Med. 2012 Sep 19;4(152):152ra127. [PMID: 22993294]

While the genes implicated in the development of ASD number in the hundreds, much attention has focused on fragile X syndrome (FXS). FXS, caused by a mutation on a single gene (known as FMR1), is the most common single-gene cause of ASD and of inherited intellectual disability in boys. In FXS, the mutation of FMR1 causes an overabundance of the excitatory neurotransmitter, glutamate, at the synapses between neurons in the brain, interfering with transmission of signals from one brain cell to the next. There has been recent interest in identifying drugs that may alter this signaling pathway, restoring the function of synapses in people with FXS, with the goal of targeting symptoms of FXS for which no direct treatments currently exist, including intellectual disability, irritability, aggression, seizures, and autistic behavior. In this study, researchers conducted a clinical trial evaluating the behavioral effects of a compound known as STX209 (arbaclofen), which stimulates release of an inhibitory neurotransmitter called GABA (gamma aminobutyric acid) in the brain, resulting in reduction of glutamate and improved functioning of synapses. The drug was tested for its efficacy in the treatment of irritable behavior in a group of individuals with FXS (55 male, 8 female) 6 to 39 years old. Based on scientific findings in animals demonstrating that arbaclofen can successfully treat behavioral symptoms in mouse models of FXS, clinical researchers in this study assessed whether arbaclofen can similarly improve symptoms in human FXS patients. Results of this research indicated that while treatment with arbaclofen did not affect behavioral scoring for irritability symptoms or aggression, treated individuals with FXS did exhibit significant improvement in the performance of social functions. Such results suggest that arbaclofen and related compounds may have potential for improving social functioning in individuals with FXS and other related neurodevelopmental disorders associated with social disabilities, like ASD, which may, in turn, improve quality of life.

Early behavioral intervention is associated with normalized brain activity in young children with autism – Dawson G, Jones EJ, Merkle K, Venema K, Lowy R, Faja S, Kamara D, Murias M, Greenson J, Winter J, Smith M, Rogers SJ, Webb SJ. J Am Acad Child Adolesc Psychiatry. 2012 Nov;51(11):1150-9. [PMID: 23101741]

Early Start Denver Model (ESDM) is a developmental, relationship-based early behavioral intervention for children aged 12 to 48 months that incorporates techniques from applied behavior analysis (ABA). ESDM emphasizes social engagement through features such as parent-training, joint activities, imitation skills, and communication development. Previously published randomized clinical trial data indicated that children with ASD who received ESDM for 2 years had improved autism symptoms, IQ, language, and adaptive behaviors.¹ In this study, researchers present additional findings from the same trial in which the relationship between ESDM and functional activity in the brains of children with ASD was evaluated. At the end of the trial, researchers evaluated electrical brain activity recorded in response to social (faces) versus nonsocial (toys) stimuli from 4-year-old children with ASD  who participated in either ESDM or community interventions (referral to local providers in the area). Four-year-old typical children served as a comparison group. Results indicated that when viewing images of faces versus objects, children who received ESDM showed patterns of brain activity that were similar to the typical group, characterized by greater brain activation while viewing the social than the nonsocial stimuli. Furthermore, the improved pattern of brain activity in the ESDM group was also found to be associated specifically with improved social behaviors. In contrast, children in the community intervention group demonstrated the reverse pattern of brain activation, with delayed neural response to social stimuli and increased brain activation during the viewing of object images. The results of this study represent the first demonstration that early behavioral intervention can measurably affect brain activity and related social behaviors, suggesting that the intervention may influence brain development and have the potential to increase positive behavioral outcomes for children with ASD.

Effects of a brief Early Start Denver Model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: A randomized controlled trial – Rogers SJ, Estes A, Lord C, Vismara L, Winter J, Fitzpatrick A, Guo M, Dawson G. J Am Acad Child Adolesc Psychiatry. 2012 Oct;51(10):1052-65. [PMID: 23021480]

Research has shown that early behavioral interventions can improve symptoms in some children with ASD, leading to an emphasis on early diagnosis and treatment. One such intervention is the Early Start Denver Model (ESDM), an intensive early behavioral intervention for children under 3 years old with ASD that combines principles of applied behavior analysis (ABA) therapy with relationship-focused developmental approaches. Previous research indicated that the ESDM intervention provided by trained therapists improved IQ, language, and adaptive behaviors in children with ASD after 15 to 20 hours of therapy per week for 2 years.¹ However, including parents in early interventions has been shown to be important for successful outcomes. Thus, this study was conducted to evaluate the effectiveness of a brief, low-intensity, parent-based ESDM intervention (P-ESDM). This randomized controlled trial of 98 families with children 12 to 24 months of age that were at risk for ASD (based on screenings and clinical assessment) compared one group of children who received the P-ESDM intervention to a group of children who received typical community interventions. To deliver the P-ESDM intervention, parents were trained during a 1-hour session each week with their children where they received instruction and coaching on one of the ten core skills of the ESDM program. The two groups of parents and children were assessed at the beginning of the study and after completion of the 12-week P-ESDM training. At the end of the study, both the P-ESDM and community intervention groups of parents showed improved interaction skills with their children, and both groups of children showed developmental gains and a reduction in core ASD symptoms. However, there was no clear benefit of one intervention over the other, and the authors noted that the study design may have inhibited parents in the P-ESDM group from receiving as much information as the parents in the community intervention group. Children in the community intervention group also received significantly more hours of intervention than children in the P-ESDM group. Notably, however, younger children in both groups made more developmental gains than older children, and a greater number of hours of intervention were associated with improvement in children's behavior. Thus, while parent-implemented interventions have not yet shown the same level of improvement observed in intensive treatment studies, these results provide important evidence about the age and intensity at which interventions could be most effective.