Bumetanide for autism: more eye contact, less amygdala activation.
Hadjikhani Nouchine,Åsberg Johnels Jakob,Lassalle Amandine,Zürcher Nicole R,Hippolyte Loyse,Gillberg Christopher,Lemonnier Eric,Ben-Ari Yehezkel
We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli. In keeping with clinical trials, our data support the Excitatory/Inhibitory dysfunction hypothesis in autism, and indicate that bumetanide may improve specific aspects of social processing in autism. Future double-blind placebo controlled studies with larger cohorts of participants will help clarify the mechanisms of bumetanide action in autism.
Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Design of Two Phase III Studies (SIGN Trials).
Crutel Véronique,Lambert Estelle,Penelaud Pierre-François,Albarrán Severo Cristina,Fuentes Joaquin,Rosier Antoine,Hervás Amaia,Marret Stéphane,Oliveira Guiomar,Parellada Mara,Kyaga Simon,Gouttefangeas Sylvie,Bertrand Marianne,Ravel Denis,Falissard Bruno
Journal of autism and developmental disorders
There are currently no approved pharmacological treatments to improve social reciprocity and limit repetitive and rigid behaviors in autism spectrum disorder (ASD). We describe the design of two Phase III studies evaluating the efficacy/safety of bumetanide oral liquid formulation in ASD. These are international, multicenter, randomized, double-blind, placebo-controlled studies in children and adolescents with ASD aged 7 to 17 years (n = 200; study 1), or younger children with ASD aged 2 to 6 years (n = 200; study 2). The primary endpoint of each is change in Childhood Autism Rating Scale 2 total raw score after 6 months. These studies could contribute to the first pharmacological treatment to improve social reciprocity and limit repetitive and rigid behaviors in children and adolescents with ASD.
Treatment outcomes of bumetanide continuous infusion: A systematic review and meta-analysis.
Hansrivijit Panupong,Techorueangwiwat Chol,Khanal Resha,Dimech Christina T,Thongprayoon Charat,Cheungpasitporn Wisit
Nephrology (Carlton, Vic.)
The clinical use of continuous bumetanide infusion for acute heart failure and volume overload is common. However, there is not enough supporting evidence for the use of continuous bumetanide infusion. Thus, we conducted this systematic review and meta-analysis aiming to describe the treatment outcomes of continuous bumetanide infusion. We searched Ovid MEDLINE, EMBASE and the Cochrane Library for eligible publications. Inclusion criteria were patients age ≥18 years with bumetanide infusion for heart failure, acute kidney injury (AKI) or volume overload. From 1564 citations, three studies (n = 94 patients) were included in the systematic review and meta-analysis. The mean dose of bumetanide was 1.08 ± 0.43 mg/hour with a mean treatment duration of 45.09 ± 10.12 hours. Mean urine output in response to continuous bumetanide infusion was 1.88 mL/kg/hour (95% confidence interval [CI], 1.72-2.05). The incidence of AKI with continuous bumetanide infusion was 24.7% (95% CI, 8.2-54.6). By using Pearson's correlation coefficient, increasing doses of bumetanide were correlated with increased urine output (P = .026) and increased incidence of AKI (P < .01). There was no correlation between increasing urine output and the incidence of AKI (P = .739). In conclusion, with available evidence, continuous bumetanide infusion may be used in the treatment of acute heart failure or volume overload with close monitoring for new-onset or worsening AKI.
Bumetanide for autism: Open-label trial in six children.
Fernell Elisabeth,Gustafsson Peik,Gillberg Christopher
Acta paediatrica (Oslo, Norway : 1992)
AIM:Bumetanide, a diuretic agent, that reduces intracellular chloride-thereby reinforcing GABAergic inhibition-has been reported to improve core symptoms of autism in children. Given the positive results reported from French trials of bumetanide in children with autism, we decided to evaluate its effects in a small-scale pilot study, in advance of a larger randomised controlled study (RCT). METHODS:This was an open-label three-month trial of bumetanide on six children (five boys), aged 3-14 years with autism. Ratings according to the Parental Satisfaction Survey (PASS) were used after four and twelve weeks to assess symptom change. Blood electrolyte status was monitored. RESULTS:Improvement in the PASS domain "Communicative and cognitive abilities" was marked or very marked in four children, and two had some improvements. Few negative side effects were reported. CONCLUSION:Our small cohort responded well to bumetanide, particularly with regard to "Communicative and cognitive abilities". Taken with the evidence from larger-scale RCTs, we suggest that bumetanide should be considered for inclusion in ethically approved treatment/management trials for children with autism, subject to rigorous follow-up in large-scale RCTs.
Bumetanide for Core Symptoms of Autism Spectrum Disorder (BAMBI): A Single Center, Double-Blinded, Participant-Randomized, Placebo-Controlled, Phase-2 Superiority Trial.
Sprengers Jan J,van Andel Dorinde M,Zuithoff Nicolaas P A,Keijzer-Veen Mandy G,Schulp Annelien J A,Scheepers Floortje E,Lilien Marc R,Oranje Bob,Bruining Hilgo
Journal of the American Academy of Child and Adolescent Psychiatry
OBJECTIVE:Recent trials have indicated positive effects of bumetanide in autism spectrum disorder (ASD). We tested efficacy of bumetanide on core symptom domains using a single center, parallel-group, participant-randomized, double-blind, placebo-controlled phase-2 superiority trial in a tertiary hospital in the Netherlands. METHOD:Unmedicated children aged 7 to 15 years with ASD and IQ ≥55 were block-randomized 1:1 to oral-solution bumetanide versus placebo, titrated to a maximum of 1.0 mg twice daily for 91 days (D91), followed by a 28-day wash-out period. The primary outcome was difference in Social Responsiveness Scale-2 (SRS-2) total score at D91, analyzed by modified intention-to-treat with linear mixed models. RESULTS:A total of 92 participants (mean age 10.5 [SD 2.4] years) enrolled between June 2016 and December 2018. In all, 47 children were allocated to bumetanide and 45 to placebo. Two participants dropped out per treatment arm. After 91 days, bumetanide was not superior to placebo on the primary outcome, the SRS-2 (mean difference -3.16, 95% CI = -9.68 to 3.37, p = .338). A superior effect was found on one of the secondary outcomes, the Repetitive Behavior Scale-Revised (mean difference -4.16, 95% CI = -8.06 to -0.25, p = .0375), but not on the Sensory Profile (mean difference 5.64, 95% CI = -11.30 to 22.57, p = .508) or the Aberrant Behavior Checklist Irritability Subscale (mean difference -0.65, 95% CI = -2.83 to 1.52, p = .552). No significant wash-out effect was observed. Significant adverse effects were predominantly diuretic effects (orthostatic hypotension (17 [36%] versus 5 [11%], p = .007); hypokalemia (24 [51%] versus 0 [0%], p < .0001), the occurrence of which did not statistically influence treatment outcome. CONCLUSION:The trial outcome was negative in terms of no superior effect on the primary outcome. The secondary outcomes suggest efficacy on repetitive behavior symptoms for a subset of patients. CLINICAL TRIAL REGISTRATION INFORMATION:Bumetanide in Autism Medication and Biomarker Study (BAMBI); https://www.clinicaltrialsregister.eu/; 2014-001560-35.