Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders

Abstract

In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl−)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3–11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2–18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily.

Annual Research Review: The state of autism intervention science: progress, target psychological and biological mechanisms and future prospects

“…More recently, there has been interest in the diuretic Bumetanide, which enhances GABAergic inhibition. In a multi‐centre phase 2 RCT ( n ‐ = 88, aged 2–18 years), Bumetanide use was associated with significant improvement on parent and clinician‐rated autism measures (Lemonnier et al., ); replication is awaited.…”

Tactile hypersensitivity and GABA concentration in the sensorimotor cortex of adults with autism

“…A decreased GABAergic action in ASD could also be induced by a reduced number of GABA receptors in the frontal cortex [Fatemi et al, ], by genetic variations in GABA receptor genes [Shao et al, ; Ma et al, ; Piton et al, ], by disrupted inhibitory action due to altered minicolumn organization [Casanova, Buxhoeveden, Switala, & Roy, ; Casanova, Buxhoeveden, & Gomez, ] or by immature GABA neurons [Ben‐Ari, Khalilov, Kahle, & Cherubini, ]. Interestingly, promoting GABA neuron maturation would reduce symptoms in children with ASD [Lemonnier & Ben‐Ari, ; Du et al, ; Lemonnier et al, ]. Furthermore, increasing GABAergic inhibition in mice models of ASD decreased autistic‐like symptoms [Han, Tai, Jones, Scheuer, & Catterall, ].…”

Enhanced Na+‐K+‐2Cl‐ cotransporter 1 underlies motor dysfunction in huntington's disease

“…Alterations in the level of NKCC1 and the depolarizing GABA action have been linked to a number of neuropsychiatric disorders . Inhibition of NKCC1 has been proposed to serve as a potential treatment for autism, schizophrenia, and seizure in clinical trials and case reports . These reports argue for a critical role of aberrant GABAergic signaling in neurological and psychiatric disorders.…”