Bumetanide attenuates the severity of ASD symptomatology in Tuberous Sclerosis of Bourneville: an open study by Van Andel et al.

In this trial, the authors report that a 3 months open administration of the NKCC1 chloride importer antagonist Bumetanide (0.5-1mg, twice daily) attenuated Autism Spectrum Disorders (ASD) symptomatology in 11 out of 13 patients (8-21 years old). Bumetanide attenuated Irritable Behavior (ABC-I), Social interactions (SRS) and hyperactivity (ABC- hyperactivity subscale), increased the patients’ estimation of quality of life, but did not alter seizure frequency. These results are an additional confirmation of the efficacy of Bumetanide to attenuate ASD. Indeed, in two double-blind phase 2 randomized trials by the company Neurochlore, which used identical conditions and dosage, Lemonnier, Ben-Ari and colleagues reported that bumetanide attenuates ASD symptomatology in over 120 children (Lemonnier et al., 2012 and 2017). These observations have been validated also by several independent trials (Du et al., 2015; Zhang et al., 2020). These results led to the approval by the European Medical Association (EMA) and the FDA of a final phase 3 trial presently being performed by the French pharmaceutic company Servier in partnership with Neurochlore. 

Astonishingly, this open trial stands in contrast with the recent report of the same group where Bumetanide failed to attenuate ASD symptomatology in adolescents with ASD, although the authors stressed that some symptoms might be attenuated in a subset of children (Sprengers et al., 2020).  There are however indications that this failure is due to the trial conditions with a very high level of placebo levels. Whatever the exact explanation, all these results strongly suggest Bumetanide as a promising treatment of ASD symptoms with the same underlying mechanism, namely a reduction of the intracellular neuronal levels of chloride leading to a restoration of GABAergic inhibition that is impacted in ASD. As suggested elsewhere, this shift of GABA polarity is a signature of many developmental and neurodegenerative disorders, which paves the way to treating them with a similar conceptual approach (Ben-Ari 2008; 2015; 2017).

Yehezkel Ben-Ari
CEO Neurochlore, Président du fonds d’action IBEN, grand prix INSERM

References :

  • Van Andel et al (2020): Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open label pilot study. Molecular Autism 11:30.
  • Lemonnier et al., A randomized controlled trial of bumetanide in the treatment of autism in children. Translational Psychiatry, 2012; 2, e202.
  • Lemonnier et al., Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Translational Psychiatry, 2017; 7, e1056.
  • Du et al., A pilot study on the combination of applied behavioral analysis and bumetanide treatment of children with autism; Journal of child and adolescent Psychopharmacology, 2015; (vol 25-7) 585-588.
  • Zhang et al., Symptom improvement in children with Autism Spectrum Disorder following bumetanide administration is associated with decrease GABA/glutamate ratio. Transl Psychiat. 2020; Jan 27, 10:9.
  • Sprengers et al., Bumetanide for Core symptoms of Autism Spectrum Disorders (BAMBI): a Single center, double blinded, participant randomized placebo-Controlled, phase two superiority trial. Journal of the American Academy of Child and Adolescent Psychiatry, 2020; jaac.2020.07.888.
  • Ben-Ari Y. Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders. Trends Neurosci. 2008 Dec;31(12):626-36.
  • Ben-Ari Y. Is birth a critical period in the pathogenesis of autism? Nature Rev Neuroscience, 2015, 16:498-505.
  • Ben-Ari Y. NKCC1 chloride importer antagonists attenuate many neurological and psychiatric disorders. Trends in Neurosc. 2017, 40-9; 536-554. 

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