Improved symptoms following bumetanide treatment in children aged 3 to 6 years with autism spectrum disorder via GABAergic mechanisms: a randomized, double-blind, placebo-controlled trial

Abstract

With the drug therapy for the core symptoms of autism spectrum disorder (ASD) currently limited, here we reported a randomised, double-blind, placebo-controlled trial to investigate the efficacy, safety, and potential neural mechanism of bumetanide in children with ASD aged 3 to 6 years old. In this trial, 120 children with ASD were 1:1 randomly assigned to receive 0.5 mg bumetanide or placebo orally twice daily for 3 months. The primary outcome was the score reduction of Childhood Autism Rating Scale (CARS) and the secondary outcomes were the score of Clinical Global Impressions (CGI) Improvement scale (CGI-I) at 3 months and the change from baseline to 3-month in Autism Diagnostic Observation Schedule (ADOS). Magnetic resonance spectroscopy (MRS) was used to measure γ-aminobutyric acid (GABA) and glutamate neurotransmitter concentrations in the insular cortex (IC) before and after the treatment. As compared with the placebo, bumetanide treatment was significantly better in reducing severity. No patient withdrew from the trial due to adverse events. The superiority of bumetanide to placebo in reducing insular GABA, measured using MRS, was demonstrated. The clinical improvement was associated with the decrease in insular GABA in the bumetanide group. In children with predominantly moderate and severe ASD, the treatment of bumetanide at a dose of 0.5 mg twice daily attenuated the core symptoms, as compared with placebo, with few adverse events. The neuroimaging data demonstrated that bumetanide decreased GABA levels in insular cortex, which was associated with symptom reduction.

Treatment Effect of Bumetanide in Children With Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

“…See Figure 2 for the results on the risk of bias of these included studies. Three studies ( 18 , 19 , 25 ) clearly used the method of random sequence generation and were considered to be low risk. Three studies ( 17 , 21 , 26 ) failed to explain their random sequence generation and were rated as unclear risk.…”

“…Their results revealed that bumetanide improved the core symptoms of ASD and had a promising benefit/risk ratio, especially when administered twice per day at a dose of 1.0 mg. Positive results of bumetanide in children with autism have also been reported in one study from Sweden and two studies of the same team from China (19)(20)(21). Moreover, the two Chinese studies tried to assess possible neuropharmacological mechanisms of bumetanide in young children with ASD by magnetic resonance spectroscopy (MRS).…”

“…Regarding the evaluation method pre-and post-bumetanide treatment, MRS was also used in some included RCTs in addition to scales. These studies showed a decreased GABA concentration in the IC after bumetanide treatment in children with ASD (19,21). Unfortunately, a quantitative analysis concerning GABA concentration could not be carried out because of the large heterogeneity.…”

“…For blinding in terms of performance bias, two studies (21,26) did not blind with respect to participants and were considered to be high risk. The other four studies (17)(18)(19)25) had a clear blinding design and were classified as low risk. For blinding in terms of detection bias, four studies were clearly considered to be low risk, and one study was deemed high Means the number risk of bias of each study.…”

“…One study demonstrated that the improvement after bumetanide treatment was related to reduced GABA/Glx (glutamate) ratios in both the insular cortex (IC) and visual cortex (VC) (21). The other study found bumetanide reduced the level of GABA in the IC, which was related to the reduction of symptoms (19). Hadjikhani et al (22) performed an open-label trial pilot study in which they used functional magnetic resonance imaging (MRI) and neuropsychological tests to determine the effect of 10 months of bumetanide treatment in adolescents and young adults with autism.…”