title: Paradoxical Benzodiazepine Response: A Rationale for Bumetanide in Neurodevelopmental Disorders?
abstract: The diuretic agent bumetanide has recently been put forward as a novel, promising treatment of behavioral symptoms in autism spectrum disorder (ASD) and related conditions. Bumetanide can decrease neuronal chloride concentrations and may thereby reinstate γ-aminobutyric acid (GABA)-ergic inhibition in patients with neurodevelopmental disorders. However, strategies to select appropriate candidates for bumetanide treatment are lacking. We hypothesized that a paradoxical response to GABA-enforcing agents such as benzodiazepines may predict the efficacy of bumetanide treatment in neurodevelopmental disorders. We describe a case of a 10-year-old girl with ASD, epilepsy, cortical dysplasia, and a 15q11.2 duplication who had exhibited marked behavioral arousal after previous treatment with clobazam, a benzodiazepine. We hypothesized that this response indicated the presence of depolarizing excitatory GABA and started bumetanide treatment with monitoring of behavior, cognition, and EEG. The treatment resulted in a marked clinical improvement in sensory behaviors, rigidity, and memory performance, which was substantiated by questionnaires and cognitive assessments. At baseline, the girl's EEG showed a depression in absolute α power, an electrographic sign previously related to ASD, which was normalized with bumetanide treatment. The effects of bumetanide on cognition and EEG seemed to mirror the "nonparadoxical" responses to benzodiazepines in healthy subjects. In addition, temporal lobe epilepsy and cortical dysplasia have both been linked to disturbed chloride homeostasis and seem to support our assumption that the observed paradoxical response was due to GABA-mediated excitation. This case highlights that a paradoxical behavioral response to GABA-enforcing drugs may constitute a framework for targeted treatment with bumetanide.
authors.affiliation: Departments of Translational Neuroscience, Psychiatry, and h.bruining@umcutrecht.nl.
authors.forename: Hilgo
authors.initials: H
authors.lastname: Bruining
authors.affiliation: Psychiatry, and.
authors.forename: Laurien
authors.initials: L
authors.lastname: Passtoors
authors.affiliation: Mediterranean Institute of Neurobiology (INMED), INSERM, Marseille, France;
authors.forename: Natalia
authors.initials: N
authors.lastname: Goriounova
authors.affiliation: Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, Netherlands;
authors.forename: Floor
authors.initials: F
authors.lastname: Jansen
authors.affiliation: Research Institute of Child Development and Education, University of Amsterdam, Amsterdam, Netherlands; and.
authors.forename: Britt
authors.initials: B
authors.lastname: Hakvoort
authors.affiliation: Psychiatry, and.
authors.forename: Maretha
authors.initials: M
authors.lastname: de Jonge
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Netherlands.
authors.forename: Simon-Shlomo
authors.initials: SS
authors.lastname: Poil
mesh_terms: D001569:Benzodiazepines / Q000627:therapeutic use*; D002034:Bumetanide / Q000627:therapeutic use*; D002648:Child; D002658:Developmental Disabilities / Q000150:complications / Q000188:drug therapy*; D005260:Female; D006801:Humans; D009422:Nervous System Diseases / Q000150:complications / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D002034:Bumetanide; D001569:Benzodiazepines