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

Abstract

Background: The therapeutic effect of bumetanide on autism spectrum disorder (ASD) seems to be controversial. To obtain better evidence on the efficacy of bumetanide, a systematic review and meta-analysis were performed.Methods: Randomized, placebo-controlled trials (RCTs) of bumetanide treatment in children with ASD were identified through systematic review from database inception to January 17, 2021. Subsequently, a meta-analysis was carried out to examine the effect of bumetanide on the severity of symptoms of ASD as assessed by the Childhood Autism Rating Scale (CARS) and Social Responsive Scale (SRS); core symptoms according to criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 of the American Psychiatric Association [social affect (SA), restricted, repetitive patterns of behavior, interests, or activities (RRB) and sensory symptoms]; and the therapeutic effect as assessed by Clinical Global Impressions-Efficacy (CGI-E).Results: In total, six RCTs involving 496 participants with ASD were identified in our study. The results showed that bumetanide could significantly improve the severity of the ASD symptoms measured by CARS and SRS. There was also evidence that bumetanide had positive effect on the core symptoms of ASD such as the SA and RRB, but there was no statistically significant effect on sensory symptoms. A significant positive effect on CGI-E scores in ASD patients was also observed.Conclusion: Our meta-analysis provided some support that bumetanide could improve the symptoms of children with ASD. However, additional large-scale longitudinal studies that provide clearer information and better control for confounding factors are needed to confirm our findings.

Delaying the GABA shift indirectly affects membrane properties in the developing hippocampus

“…There is accumulating evidence that the developmental GABA shift is often delayed in NDD patients (Talos et al, 2012; Duarte et al, 2013; Merner et al, 2015; Tang et al, 2016; Ruffolo et al, 2018; Wang et al, 2021; Birey et al, 2022) and in NDD animal models (He et al, 2014; Tyzio et al, 2014; Deidda et al, 2015b; Banerjee et al, 2016; Corradini et al, 2017; Fernandez et al, 2018; Roux et al, 2018; Lozovaya et al, 2019; Bertoni et al, 2021). Here, we used organotypic hippocampal cultures to examine the consequences of a delayed GABA shift for the developing CA1 network using the specific KCC2 blocker VU0463271 (VU).…”

A bibliometrics analysis and visualization of autism spectrum disorder

“…In 2010, Lemonnier and Ben-Ari ( 72 ) reported for the first time that bumetanide could reduce autism behavior in ASD children without adverse reactions. Although a number of randomized controlled trials (RCTs) about bumetanide in recent 10 years are contradictory, a meta-analysis shows that bumetanide can significantly improve the severity of ASD symptoms including the social effect, and the repetitive patterns of behavior, interests, or activities ( 73 ). Although there were adverse reactions such as mild polyuria/polyuria and mild hypokalemia, which could be relieved without additional treatment.…”

Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling

“…In the circulation, however, loop diuretics are mostly bound to albumin ( 14 , 15 ), which may explain why these drugs are less effective in reaching peripheral tissues and inhibiting NKCC1. Regardless of this limitation, Bu has been shown to attenuate the severity of neurodevelopmental disorders such as autism spectrum disorders ( 16 , 17 ) and Fragile X ( 18 ). However, the molecular mechanisms underlying drug inhibition of the NKCC cotransporters remain elusive despite decades of clinical use of these drugs.…”