A randomised controlled trial of bumetanide in the treatment of autism in children

Abstract

Gamma aminobutyric acid (GABA)-mediated synapses and the oscillations they orchestrate are altered in autism. GABA-acting benzodiazepines exert in some patients with autism paradoxical effects, raising the possibility that like in epilepsies, GABA excites neurons because of elevated intracellular concentrations of chloride. Following a successful pilot study,(1) we have now performed a double-blind clinical trial using the diuretic, chloride-importer antagonist bumetanide that reduces intracellular chloride reinforcing GABAergic inhibition. Sixty children with autism or Asperger syndrome (3-11 years old) received for 3 months placebo or bumetanide (1 mg daily), followed by 1-month wash out. Determination of the severity of autism was made with video films at day 0 (D0) and D90 by blind, independent evaluators. Bumetanide reduced significantly the Childhood Autism Rating Scale (CARS) (D90-D0; P<0.004 treated vs placebo), Clinical Global Impressions (P<0.017 treated vs placebo) and Autism Diagnostic Observation Schedule values when the most severe cases (CARS values above the mean ± s.d.; n=9) were removed (Wilcoxon test: P-value=0.031; Student's t-test: P-value=0.017). Side effects were restricted to an occasional mild hypokalaemia (3.0-3.5 mM l(-1) K(+)) that was treated with supplemental potassium. In a companion study, chronic bumetanide treatment significantly improved accuracy in facial emotional labelling, and increased brain activation in areas involved in social and emotional perception (Hadjikhani et al., submitted). Therefore, bumetanide is a promising novel therapeutic agent to treat autism. Larger trials are warranted to better determine the population best suited for this treatment.

Trial registration: ClinicalTrials.gov NCT01078714.

Figure 1

Schematic diagram of the protocol used. A total of 60 children were recruited for the trial, 6 withdrew for various reasons (see text) and the remaining 54 completed treatments and assessment. The video film was not available for one child and thus ADOS could not be performed. Tests included CARS at D0, 90 and 120 after 1-month wash out, CGI at D0, 90 and 120, and ADOS at D0 and 90.

Figure 2

All the values obtained with CARS are depicted. Note the significant differences between placebo and bumetanide treated patients and a partial return to pretreatment values after 1-month wash-out period. The number of items >3 was also significantly reduced as shown at the right side of the figure (number corresponding to D0, D90 and D120; ***p<0.005 for D90 and **p<0.05 for D120).

Figure 3

Top figure: Boxplot of ADOS total scores gains between the beginning and the end of the trial (90 days later) for patient receiving placebo (left panel) and treatment (right panel). Bottom: Boxplot of ADOS total scores gains but excluding patients with ‘above normal' CARS scores (that is, above mean±s.d.)—between the beginning and the end of the trial (90 days later) for patient receiving placebo (left panel) and treatment (right panel).