Abstract
Bumetanide has been reported to alter synaptic excitation–inhibition (E-I) balance by potentiating the action of γ-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5 mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (γ-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score ≥ 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an increasing global prevalence ranging from 42.6/10,000 in China to 1/58 in the United States[1,2]
If the interaction term was significant for overall symptoms, we further examined the 15 subscales of the Children Autism Rating Scale (CARS) to identify those that were the most affected by the treatment
If a significant association was detected, we further investigated which subscales of the CARS were associated with the change in magnetic resonance spectroscopy (MRS) measurement based on 3000 random permutations
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an increasing global prevalence ranging from 42.6/10,000 in China to 1/58 in the United States[1,2]. Without directly monitoring the neuronal E-I balance, current behavioural interventions for ASD at preschool age are mainly behavioural intervention, including parentsmediate Early Start Denver Model and the Applied Behaviour Analysis[5]. These intervention resources vary greatly between countries and within regions, for example, less well-educated families in Europe may not receive behavioural intervention for ASD children for a year following diagnosis[6]. This failure to receive behavioural treatment is even worse in developing countries[7]. A pharmacological treatment remains an alternative approach, which could be used globally where other behavioural treatments are not readily available
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