Currently no treatments exist for the core symptoms of Autism Spectrum Disorder (ASD). Only two antipsychotics are approved to treat symptoms that often accompany ASD. These drugs are not etiology driven and cause significant adverse effects. Recently an old drug, bumetanide, has been proposed as an etiology driven treatment for ASD. Bumetanide has been used for decades as a diuretic and its safety has been firmly established. Bumetanide has a secondary function. In the brain, bumetanide blocks the NKCC1 cation-chloride co-transporter, a protein that normally becomes inactive after birth allowing chloride levels to decline. Low chloride is necessary for the postnatal brain to develop neuronal inhibition to counterbalance excessive excitation. Interestingly, recent experimental studies have shown that elevated chloride levels due to NKCC1 activity may be a source of hyperexcitability leading to behavioral disturbance in ASD that may be treated by bumetanide. In this capacity, bumetanide could become a rational and safe drug for patients with no therapy at present.
A first trial has tested bumetanide in a modest sample of children with ASD suggested a reduction in symptom severity after 3 months. Replication is warranted in larger samples with endpoints that have been used in other trials. In addition, prognostic markers are needed to select the most responsive patients. Here, we propose to conduct a randomized clinical trial to establish clinical efficacy of bumetanide on autism morbidity in a substantial sample of children and adolescents with ASD. In addition, we aim to develop cognitive and neurophysiological prognostic markers to enhance the rational application of bumetanide in ASD. The strength of our application is that it builds on pre-existing pre-clinical and clinical research as well as on results from our recent pilot studies. With this study, an important step toward implementation of bumetanide as a first rational treatment for ASD may be taken.