A prescription drug that is used to treat edema (fluid build up in the body) also improves some of the symptoms of autism spectrum disorder (ASD) in young children, without causing significant side effects, according to the results of a clinical trial. The study, by researchers in the U.K. and China, demonstrated for the first time that the drug, bumetanide, improves ASD symptoms in children aged 3–6 years, by decreasing the ratio of the neurotransmitter γ-aminobutyric acid (GABA), to that of glutamate in certain regions of the brain. GABA and glutamate are known to be important for brain plasticity and promoting learning. Reporting their results in Translational Psychiatry, the researchers say the relative concentration of GABA to glutamate could represent a useful biomarker of treatment efficacy.

“This study is important and exciting because it means that there is a drug that can improve social learning and reduce ASD symptoms during the time when the brains of these children are still developing,” said research lead Barbara Sahakian, PhD, DSc, a professor in the department of psychiatry at the University of Cambridge in the U.K. “We know that GABA and glutamate are key chemicals in the brain for plasticity and learning and so these children should have an opportunity for better quality of life and wellbeing.” Sahakian and colleagues described the trial in a paper titled, “Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios.”

ASD is a neurodevelopmental disorder estimated to affect one in 160 children worldwide. It is characterized by impairments in social communication, which can manifest as difficulties understanding emotions, and with problems in nonverbal communication, such as eye contact and smiling. Individuals with ASD may have restricted interests, show repetitive behavior, and struggle to develop, maintain, and understand social relationships. While people with mild ASD may live independently, those with more severe ASD may need life-long care and support. ASD can be reliably diagnosed at age 24 months or even as early as 18 months of age, the researchers noted.

Although the biological mechanisms underlying ASD remain largely unknown, previous research has suggested that the disorder may result from changes in brain development early in life, and in particular to activity of the neurotransmitter GABA. In the adult brain, GABA is inhibitory, and so switches nerve cells “off.” However, during fetal and early postnatal development GABA is mostly excitatory, triggering nerve cells to fire, and playing a key role in nerve cell development and maturation. Alterations in the GABA-switch (from excitatory to inhibitory; E-I) that cause an E-I imbalance can delay the development of functional maturity in neural circuits. This has consequences for network activity, and implies that intervention at an early age may help to reduce some of the symptoms associated with ASD.

“E-I imbalance has been posited to be the neurobiology of autistic sensory impairment,” the researchers noted. “Although the molecular and neural mechanisms underlying ASD remain largely unknown, a previous study suggested that ASD may result from alteration in brain development during early life, such as the E-I imbalance in the autistic brain can affect the sensory, memory, and emotional systems indicating the necessity of early intervention.”

Current treatments for ASD at preschool age are mainly focused on behavioral interventions, such as using play and joint activities between parents and their child to boost language, social, and cognitive skills. However, with limited resources there is an inequality in access to these treatments across the globe, particularly in developing countries. “Therefore, a pharmacological treatment remains an alternative approach, which could be used globally where other behavioral treatments are not readily available,” the team noted.

Risperidone and aripiprazole are currently the only two FDA-approved drugs for treating ASD, but as the researchers pointed out, they don’t address core ASD symptoms, and can have considerable adverse side effects. “Therefore, there is a need for treatment strategies focused on the atypical early development of the autistic brain that can mitigate ASD symptoms, including impairments in social and emotional cognition.”

Previous studies in rats, and small clinical trials involving children with ASD have suggested that bumetanide could help reduce symptoms of ASD. However, the authors noted, “No studies to date have directly tested whether bumetanide regulates E-I balance by facilitating the GABA switch in autistic brain, especially in young children with ASD.” To address this question, the collaborating researchers at multiple institutions in the U.K. and China designed and carried out a clinical trial in children diagnosed with ASD, through which they used the brain imaging technique, magnetic resonance spectroscopy (MRS), to assess whether bumetanide therapy could regulate GABA/glutamate ratios in the brain, and reduce the severity of autistic symptoms.

The team recruited 83 children in China, who were aged three years to six years, and who had no access to behavioral therapy. The children were divided into two groups. The treatment group of 42 children received 0.5 mg of bumetanide twice a day for three months, while a control group of 41 children received no treatment. For their primary outcome, the researchers assessed symptoms using the Childhood Autism Rating Scale (CARS), which is used to rate behavior such as imitation, emotional response, and verbal and nonverbal communication. Children scoring above 30 on the scale are considered to have ASD.

Secondary outcomes were assessed using the Clinical Global Impression (CGI) scale to evaluate the degree of improvement in symptoms relative to baseline, and to assess clinical efficacy of bumetanide in terms of both treatment effect and side effects. MRS was used to measure inhibitory (GABA) and excitatory (glutamate; Glx) neurotransmitter concentrations in the visual cortex (VC) region of the brain, which is responsible for integrating and processing visual information, and the insular cortex (IC), which plays a role in emotions, empathy, and self-awareness.

The results confirmed that before bumetanide therapy, both groups of children had similar CARS scores. However, after three months of bumetanide therapy, the mean CARS scores of the treated children dropped to 34.51, compared with a mean control group score of 37.27. Importantly, the treatment group showed a significant reduction in the number of items on the CARS assigned a score greater than or equal to three, with the average number of 3.52 items in the treatment group compared to 5.49 items in the control group. The MRS results showed that in both the VC and IC areas of the brain, the ratio of GABA to glutamate decreased over the three-month period in the treatment group.

The study’s clinical lead, Fei Li MD, from Xinhua Hospital, Jiao Tong University School of Medicine, commented, “I have many children with autism spectrum disorder under my care, but as psychological treatment resources are not available in many places, we are unable to offer them treatment. An effective and safe treatment will be very good news for them. The mother of a four-year-old boy living in a rural area outside Shanghai who received the treatment told me that he was now better at making eye contact with family members and relatives and was able to participate more in activities. In the future, we hope to be able to ensure all families, regardless of where they are living, can receive treatment for their child.”

Ching-Po Lin, PhD, of National Yang-Ming University, added, “This is the first demonstration that bumetanide improves brain function and reduces symptoms by reducing the amount of the brain chemical GABA. Understanding this mechanism is a major step towards developing new and more effective drug treatments.”

The discovery that bumetanide changes the relative concentrations of GABA to glutamate suggests that the neurotransmitter ratios could represent a useful biomarker of drug effectiveness. “In summary, the results of this study demonstrate that bumetanide has clinical potential for the treatment of ASD, with few side effects; and that the GABA/Glx ratio in the IC is a useful neuroimaging biomarker for monitoring the response to treatment.”

They acknowledged that their study did have some limitations, and also cautioned that further research in greater numbers of patients will be needed to confirm the effectiveness of bumetanide as a treatment for ASD. “ … although the results of our study are promising, a double-blind, randomized clinical trial with a larger population is required to confirm the efficacy of bumetanide treatment for ASD,” they wrote.

Qiang Luo, PhD, from Fudan University, concluded, “These findings are very promising and suggest we will be able to use the biomarker measure to identify which children with ASD will benefit most from bumetanide. Further studies in a larger number of children will hopefully confirm whether bumetanide is an effective treatment for children with autism spectrum disorder.”