Modulation of the Brain Excitatory/Inhibitory (E/I) Balance Through Neuronal and Glial Systems in Autism Spectrum Disorder (ASD
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- King's College London
- Enrollment
- 87
- Locations
- 1
- Primary Endpoint
- Neurochemical response to GABAergic stimulation.
Study Overview
Brief Summary
This study investigates the brain response to a single acute dose of Arbaclofen, the R-enantiomer of the GABA-B agonist Baclofen, compared to a single dose of placebo in healthy men with and without autism spectrum disorder.
Detailed Description
Previous research suggests that GABAergic drug compounds could shift brain excitation and inhibition (E-I) in the healthy brain and in neurodevelopmental psychiatric conditions, such as autism spectrum disorder (ASD) - where this balance is disrupted. A study by Ajram et al. (2017) has shown an E-I shifted towards more GABA in individuals with ASD, and not in controls, after a single dose of the anti-glutamatergic and pro-GABAergic drug Riluzole. Moreover, brain connectivity patterns in ASD patients where shifted towards the ones observed in the control group. However, it was unclear whether this changes could be driven by GABA receptors, thus more specific probes may help to clarify the mechanism underlying the E-I coordination in ASD. Therefore, this study will use neuroimaging and electrophysiology to investigate the brain E-I coordination in ASD compared to control participants when the system is responding to a single dose of the specific GABA-B (STX209) receptor agonist. 50 adult individuals with ASD and 50 neurotypical adults (25 males and 25 females per group) will be invited to participate. Each participant will receive a single dose of the drug (15mg or 30mg Arbaclofen) or matched placebo). Brain activity and neurochemistry will be investigated using magnetic resonance imaging. Further data will be collected through questionnaires, behavioural tasks, blood samples, and sensory tasks using electroencephalography and retinal imaging.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Double (Participant, Investigator)
Masking Description
Participants and investigators were blinded to the drug condition
Eligibility Criteria
- Ages
- 18 Years to 60 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •ASD participants must pass diagnostic threshold for ASD on the Autism Diagnostic Interview-Revised (if and informant is available)
- •ASD participants must be currently symptomatic on Autism Diagnostic Observation Schedule (ADOS)
- •Age 18-60 years
- •Can give informed consent
- •medication free in the month preceding participation; but regular medication (used in a stable dose over the two months previous to participation) with drug which does not affect glutamate or GABA directly may be permitted
Exclusion Criteria
- •history of psychosis, co-morbid major mental illness, significant physical illness (heart disease, high blood pressure, seizures) habitual substance misuse (including alcohol)
- •ASD caused by a known genetic syndrome e.g. Fragile X or 22q11 deletion syndrome,
- •past/present treatment for epilepsy
- •Change of medication dose/start of a new pharmacological therapy in the month prior to participation
Arms & Interventions
Placebo, Arbaclofen_15, Arbaclofen_30
Dose order: Placebo, Arbaclofen 15mg, Arbaclofen 30mg
Intervention: Arbaclofen_15 (Drug)
Placebo, Arbaclofen_15, Arbaclofen_30
Dose order: Placebo, Arbaclofen 15mg, Arbaclofen 30mg
Intervention: Arbaclofen_30 (Drug)
Placebo, Arbaclofen_15, Arbaclofen_30
Dose order: Placebo, Arbaclofen 15mg, Arbaclofen 30mg
Intervention: Placebo (Drug)
Placebo, Arbaclofen_30, Arbaclofen_15
Dose order: Placebo, Arbaclofen 30mg, Arbaclofen 15 mg
Intervention: Arbaclofen_15 (Drug)
Placebo, Arbaclofen_30, Arbaclofen_15
Dose order: Placebo, Arbaclofen 30mg, Arbaclofen 15 mg
Intervention: Arbaclofen_30 (Drug)
Placebo, Arbaclofen_30, Arbaclofen_15
Dose order: Placebo, Arbaclofen 30mg, Arbaclofen 15 mg
Intervention: Placebo (Drug)
Arbaclofen_30, Placebo, Arbaclofen_15
Dose order: Arbaclofen 30mg, Placebo, Arbaclofen 15mg
Intervention: Arbaclofen_15 (Drug)
Arbaclofen_30, Placebo, Arbaclofen_15
Dose order: Arbaclofen 30mg, Placebo, Arbaclofen 15mg
Intervention: Arbaclofen_30 (Drug)
Arbaclofen_30, Placebo, Arbaclofen_15
Dose order: Arbaclofen 30mg, Placebo, Arbaclofen 15mg
Intervention: Placebo (Drug)
Arbaclofen_15, Placebo, Arbaclofen_30
Dose order: Arbaclofen 15mg, Placebo, Arbaclofen 30mg
Intervention: Arbaclofen_15 (Drug)
Arbaclofen_15, Placebo, Arbaclofen_30
Dose order: Arbaclofen 15mg, Placebo, Arbaclofen 30mg
Intervention: Arbaclofen_30 (Drug)
Arbaclofen_15, Placebo, Arbaclofen_30
Dose order: Arbaclofen 15mg, Placebo, Arbaclofen 30mg
Intervention: Placebo (Drug)
Arbaclofen_15, Arbaclofen_30, Placebo
Dose order: Arbaclofen 15mg, Arbaclofen 30mg, Placebo
Intervention: Arbaclofen_15 (Drug)
Arbaclofen_15, Arbaclofen_30, Placebo
Dose order: Arbaclofen 15mg, Arbaclofen 30mg, Placebo
Intervention: Arbaclofen_30 (Drug)
Arbaclofen_15, Arbaclofen_30, Placebo
Dose order: Arbaclofen 15mg, Arbaclofen 30mg, Placebo
Intervention: Placebo (Drug)
Arbaclofen_30, Arbaclofen_15, Placebo
Dose order: Arbaclofen 30mg, Arbaclofen 15mg, Placebo
Intervention: Arbaclofen_15 (Drug)
Arbaclofen_30, Arbaclofen_15, Placebo
Dose order: Arbaclofen 30mg, Arbaclofen 15mg, Placebo
Intervention: Arbaclofen_30 (Drug)
Arbaclofen_30, Arbaclofen_15, Placebo
Dose order: Arbaclofen 30mg, Arbaclofen 15mg, Placebo
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Neurochemical response to GABAergic stimulation.
Time Frame: Through study completion, an average of 2 years.
Comparing brain excitation-inhibition measures (i.e., glutamate and GABA) when the GABAergic system is activated by a single oral dose of the GABA-B drug Arbaclofen versus the placebo condition.
Secondary Outcomes
- Brain oscillations under sensory stimulation(Through study completion, an average of 2 years.)
- Functional connectivity measures using resting state functional magnetic resonance imaging.(Through study completion, an average of 2 years.)
Investigators
Dr Grainne McAlonan
Deputy head of department
King's College London