Veenstra-VanderWeele Jeremy, Cook Edwin H, King Bryan H, Zarevics Peter, Cherubini Maryann, Walton-Bowen Karen, Bear Mark F, Wang Paul P, Carpenter Randall L
Department of Psychiatry, Columbia University, New York, NY, USA.
Center for Autism and The Developing Brain, New York Presbyterian Hospital, New York, NY, USA.
Neuropsychopharmacology. 2017 Jun;42(7):1390-1398. doi: 10.1038/npp.2016.237. Epub 2016 Oct 17.
Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist arbaclofen improved social avoidance symptoms in FXS. A pilot open-label trial of arbaclofen suggested similar benefits in ASD. We therefore evaluated arbaclofen in a randomized, placebo-controlled, phase 2 study of 150 participants, aged 5-21 years, with ASD. No difference from placebo was detected on the primary outcome measure, the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale. However, a specified secondary analysis found improvement on the clinician-rated Clinical Global Impression of Severity. An exploratory post hoc analysis of participants with a consistent rater across the trial revealed greater improvement in the Vineland Adaptive Behavior Scales II socialization domain in participants receiving arbaclofen. Affect lability (11%) and sedation (9%) were the most common adverse events. In this exploratory study, secondary analyses suggest that arbaclofen may have the potential to improve symptoms in some children with ASD, but further study will be needed to replicate and extend these initial findings.
多项新出现的数据表明，在至少一部分自闭症谱系障碍（ASD）患者中，包括在脆性X综合征（FXS）患者（ASD中最常见的遗传综合征之一）中，神经元兴奋与抑制之间存在失衡。在FXS和ASD的动物模型中，GABA-B激动剂改善了大脑和行为表型，包括社交行为。一项2期随机、安慰剂对照、交叉试验发现，GABA-B激动剂阿巴氯芬改善了FXS患者的社交回避症状。一项阿巴氯芬的开放性试点试验表明，其在ASD中也有类似益处。因此，我们在一项针对150名年龄在5至21岁的ASD患者的随机、安慰剂对照2期研究中评估了阿巴氯芬。在主要结局指标（家长评定的异常行为检查表社交退缩/嗜睡分量表）上未检测到与安慰剂的差异。然而，一项特定的次要分析发现，临床医生评定的临床总体严重程度印象有所改善。对在整个试验中评分者一致的参与者进行的探索性事后分析显示，接受阿巴氯芬的参与者在文兰适应性行为量表II社交领域有更大改善。情感不稳定（11%）和镇静作用（9%）是最常见的不良事件。在这项探索性研究中，次要分析表明，阿巴氯芬可能有改善一些ASD儿童症状的潜力，但需要进一步研究来重复和扩展这些初步发现。
