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.

Figure 1

Patient flow in each treatment groups throughout the study. The enrolled and the included patients are noted followed by the four groups who received 0.5, 1.0 and 2 mg twice daily or placebo. Then the number of patients discontinuing the trial because of an adverse event (AE) or loss to follow-up is indicated, followed by the number of patients who completed the trial for each subgroup. One of the three discontinued patients in the placebo group withdrew after the visit on day 90 and was considered as a completer.

Figure 2

Change in the completers of the total CARS score from screening to day 90 after bumetanide (blue bars; n=52) and placebo (orange bars; n=21). All changes were calculated from the initial values for each individual participant at screening. Note a significant amelioration of the CARS scale after the treatment period (>4) is almost entirely restricted to the bumetanide-treated patients (only placebo). CARS, Childhood Autism Rating Scale.

Figure 3

Attenuation in the CARS scale correlates with CGI attenuation. CARS scores and CGI-I values for completers are shown after the end of the trial (D90). Bumetanide treated are in blue circle (N=52) and Placebo in orange triangles (N=21). Note that the much- or very-much-improved children with CGI evaluation were almost entirely restricted to the bumetanide-treated group (only one placebo) and correlated with the most important CARS attenuation (ordinate). CARS, Childhood Autism Rating Scale; CGI-I, Clinical Global Impressions Improvement scale.

Figure 4

Relationship between behavior scales results for treated patients (completers). (a) and (b) Relationship between CARS total score and SRS2 score for patients before (a) and after (b) treatment. CARS <29: mild ASD (blue bubble), 29⩽ CARS <36: moderate ASD (red bubble) and CARS ⩾36: severe ASD (black bubble). ASD, autism spectrum disorder; CARS, Childhood Autism Rating Scale; SRS, Social Responsive Scale.