Modulation of the Brain Excitatory/Inhibitory (E/I) Balance in Autism Spectrum Disorder (ASD)

King's College London

Status: Completed

Conditions: Autism Spectrum Disorder

Treatments: Drug: Arbaclofen_15; Drug: Placebo; Drug: Arbaclofen_30

Study type: Interventional

Funder types: Other

Identifiers

NCT03594552

HR16-17 4081

Details and patient eligibility

About

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.

Full 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.

Enrollment: 87 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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
• IQ>70

Exclusion criteria

• IQ<70
• 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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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87 participants in 6 patient groups

Placebo, Arbaclofen_15, Arbaclofen_30

Experimental group

Description:

Dose order: Placebo, Arbaclofen 15mg, Arbaclofen 30mg

Treatment:

Drug: Arbaclofen_30

Drug: Placebo

Drug: Arbaclofen_15

Placebo, Arbaclofen_30, Arbaclofen_15

Experimental group

Description:

Dose order: Placebo, Arbaclofen 30mg, Arbaclofen 15 mg

Treatment:

Drug: Arbaclofen_30

Drug: Placebo

Drug: Arbaclofen_15

Arbaclofen_30, Placebo, Arbaclofen_15

Experimental group

Description:

Dose order: Arbaclofen 30mg, Placebo, Arbaclofen 15mg

Treatment:

Drug: Arbaclofen_30

Drug: Placebo

Drug: Arbaclofen_15

Arbaclofen_15, Placebo, Arbaclofen_30

Experimental group

Description:

Dose order: Arbaclofen 15mg, Placebo, Arbaclofen 30mg

Treatment:

Drug: Arbaclofen_30

Drug: Placebo

Drug: Arbaclofen_15

Arbaclofen_15, Arbaclofen_30, Placebo

Experimental group

Description:

Dose order: Arbaclofen 15mg, Arbaclofen 30mg, Placebo

Treatment:

Drug: Arbaclofen_30

Drug: Placebo

Drug: Arbaclofen_15

Arbaclofen_30, Arbaclofen_15, Placebo

Experimental group

Description:

Dose order: Arbaclofen 30mg, Arbaclofen 15mg, Placebo

Treatment:

Drug: Arbaclofen_30

Drug: Placebo

Drug: Arbaclofen_15