Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder

Juárez-Martinez, Erika L.; Sprengers, Jan J.; Cristian, Gianina; Oranje, Bob; Andel, Dorinde M. van; Avramiea, Arthur-Ervin; Simpraga, Sonja; Houtman, Simon J.; Hardstone, Richard; Gerver, Cathalijn; Wilt, Gert Jan van der; Mansvelder, Huibert D.; Eijkemans, Marinus J.C.; Linkenkaer‐Hansen, Klaus; Bruining, Hilgo

doi:10.1016/j.bpsc.2021.08.009

Cited by 25 publications

(21 citation statements)

References 62 publications

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“…For instance, in epilepsy, an increment in alpha power following AEDs (e.g., levetiracetam) has been associated with improvement in neuropsychological tests ( Cho et al, 2012 ; Ricci et al, 2021 ). Similarly, we reported a relationship between increased alpha power and improvement in repetitive behavior after bumetanide in children with ASD ( Juarez-Martinez et al, 2021 ). Interestingly, the EEG effect of bumetanide is contrary to what has been described for other GABAergic drugs (benzodiazepines) in healthy subjects (i.e., a reduction in alpha power) ( Lozano-Soldevilla et al, 2014 ; Lozano-Soldevilla, 2018 ).…”

Section: Discussionmentioning

confidence: 56%

“…f E/I, together with other measures of critical brain dynamics, such as power and long-range temporal correlations (LRTC), have shown sensitivity to E/I changes in disorders such as ASD and epilepsy, and responsive to pharmacological intervention ( Monto et al, 2007 ; Smith et al, 2017 ; Bruining et al, 2020 ). Importantly, using this novel resting-state EEG analysis, we recently confirmed placebo-controlled neurophysiological effects of bumetanide in a cohort with ASD ( Juarez-Martinez et al, 2021 ). Here, we used these measures to investigate network-level E/I imbalances in TSC before and after bumetanide treatment, hypothesizing that TSC would show a reduced inhibitory activity, which could be restored by bumetanide.…”

Section: Introductionmentioning

confidence: 59%

“…Indeed, large variability in LRTC and f E/I have been proposed to contribute to the physiological heterogeneity in ASD ( Bruining et al, 2020 ). Importantly, we reported that baseline EEG features in ASD may have a predictive value for clinical improvement (e.g., after bumetanide treatment) ( Juarez-Martinez et al, 2021 ). Thus, baseline network characteristics in TSC may indicate different “network setpoints” in which bumetanide may induce clinically meaningful effects.…”

Section: Discussionmentioning

confidence: 99%

“…This agent may thus influence E/I-balance regulation via downregulation of intraneuronal chloride concentration, which in turn can shift GABA polarity from depolarizing (with excitatory activity) to hyperpolarizing (inhibitory activity) ( Löscher et al, 2013 ; Ben-Ari, 2017 ; Kharod et al, 2019 ). Through this mechanism, it is hypothesized that bumetanide may be beneficial for neurodevelopmental disorders (e.g., epilepsy, ASD, and TSC) ( Talos et al, 2012 ; Ben-Ari, 2017 ; Kharod et al, 2019 ; van Andel et al, 2020 ; Juarez-Martinez et al, 2021 ). In animal models, it has indeed been shown that bumetanide can reduce the frequency of epileptiform activity ( Dzhala et al, 2008 ; Marguet et al, 2015 ; Auer et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

et al. 2022

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Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide—a chloride-regulating agent—improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8–21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC.Clinical Trial RegistrationEU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

et al. 2022

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“…NKCC1 (Na-K-Cl cotransporter 1) is the primary transporter responsible for regulating (Cl-)i, and its activity controls the level of chloride in neurons, which further affects the post-synaptic effect of GABAergic transmission ( Schulte et al, 2018 ). Bumetanide, a selective NKCC1antagonist ( Ben-Ari, 2017 ; Kharod et al, 2019 ), could restore GABAergic inhibition and weaken behavioral and electrophysiological characteristics in various diseases (e.g., ASD and Fragile X syndrome) by regulating the concentration of neuronal chloride ( Payne et al, 2003 ; He et al, 2014 ; Kaila et al, 2014 ; Tyzio et al, 2014 ; Juarez-Martinez et al, 2021 ). However, there is a lack of reports on the effects of bumetanide on RRBs in animal models.…”

Section: Treatment and Intervention Of Repetitive Restricted Behaviorsmentioning

confidence: 99%

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

2022

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.

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Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: Results from two randomized phase III studies

Fuentes,

Parellada,

Georgoula

et al. 2023

Autism Research

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The efficacy and safety of bumetanide oral solution for the treatment of autism spectrum disorder (ASD) in children and adolescents was evaluated in two international, multi‐center, randomized, double‐blind, placebo‐controlled phase III trials; one enrolled patients aged 7–17 years (SIGN 1 trial) and the other enrolled younger patients aged 2–6 years (SIGN 2). In both studies, patients were randomized to receive bumetanide oral solution twice daily (BID) or placebo BID during a 6‐month double‐blind treatment period. The primary endpoint was change in Childhood Autism Rating Scale 2 (CARS2) total raw score from baseline to Week 26. Key secondary endpoints included changes in Social Responsiveness Scale‐2, Clinical Global Impression Scale, and Vineland Adaptive Behavior Scale. Each study enrolled 211 patients (bumetanide, n = 107; placebo, n = 104). Both studies were terminated early due to absence of any significant difference between bumetanide and placebo in the overall studied populations. In both studies, CARS2 total raw score decreased from baseline to Week 26 in the bumetanide and placebo groups, with no statistically significant difference between groups. No differences were observed between treatment groups for any of the secondary efficacy endpoints in either study. In both studies, treatment‐emergent adverse events that occurred more frequently with bumetanide than placebo included thirst, polyuria, hypokalemia, and dry mouth. These large phase III trials failed to demonstrate a benefit of bumetanide for the treatment of pediatric ASD compared with placebo. Consequently, the sponsor has discontinued the development of bumetanide for the treatment of this condition.Trial registration: https://clinicaltrials.gov: SIGN 1: NCT03715166; SIGN 2: NCT03715153.

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Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder

Cited by 25 publications

References 62 publications

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: Results from two randomized phase III studies

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