AUTHOR=van Andel Dorinde M. , Sprengers Jan J. , Keijzer-Veen Mandy G. , Schulp Annelien J. A. , Lillien Marc R. , Scheepers Floortje E. , Bruining Hilgo 

TITLE=Bumetanide for Irritability in Children With Sensory Processing Problems Across Neurodevelopmental Disorders: A Pilot Randomized Controlled Trial

JOURNAL=Frontiers in Psychiatry

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.780281

DOI=10.3389/fpsyt.2022.780281

ISSN=1664-0640

ABSTRACT=Background: Treatment development for neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is impeded by heterogeneity in clinical manifestation and underlying etiologies. Symptom traits such as aberrant sensory reactivity are present across neurodevelopmental disorders and might reflect common mechanistic pathways. Here, we test the effectiveness of repurposing a drug candidate, bumetanide, on irritable behavior in a cross-disorder neurodevelopmental cohort defined by the presence of sensory reactivity problems.

Methods: Participants, aged 5-15 years and IQ≥55, with ASD, ADHD and/or epilepsy and proven aberrant sensory reactivity according to deviant Sensory Profile scores were included. Participants were randomly allocated (1:1) to bumetanide (max 1 mg twice daily) or placebo tablets for 91 days followed by a 28-day wash-out period using permuted block design and minimization. Participants, parents, healthcare providers and outcome assessors were blinded for treatment allocation. Primary outcome was the differences in ABC-irritability  at day 91. Secondary outcomes were differences in SRS-2, RBS-R, SP-NL, BRIEF parent, BRIEF teacher at D91. Differences were analyzed in a modified intention-to-treat sample with linear mixed models and side effects in the intention-to-treat population.

Results: A total of 38 participants (10.1 [SD 3.1] years) were enrolled between June 2017 and June 2019 in the Netherlands. 19 children were allocated to bumetanide and 19 to placebo. 5 patients discontinued (n=3 bumetanide). Bumetanide was superior to placebo on the ABC-irritability (mean difference -4.78, 95%CI: -8.43 to -1.13, p=.0125). No effects were found on secondary endpoints. No wash-out effects were found. Side effects were as expected: hypokalemia (p=0.046) and increased diuresis (p=0.020).

Conclusion: Despite the results being underpowered, this study raises important recommendations for future cross-diagnostic trial designs.

Trial registration: Bumetanide for the Autism Spectrum Clinical Effectiveness Trial (BASCET); EU Clinical Trials Register, 2016-002875-81. Registered 25 October 2016, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002875-81/NL.