GABA Pathways in Autism Spectrum Disorder (ASD)

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

This study investigates the brain response to a single acute dose of a GABAa receptor acting drug (Benzodiazepine or positive allosteric modulator) compared to a single dose of placebo in adults with and without autism spectrum disorder.

Study Overview

• Status: Completed
• Conditions: Autism Spectrum Disorder
• Intervention / Treatment: Drug: AZD7325_10; Drug: AZD7325_20; Drug: Placebo; Drug: Clobazam

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 a GABA-A acting drug.

Please note, when first registered we had access to the specific GABA-A (AZD7325) receptor positive allosteric modulator. Following a pause in the study over the Covid pandemic this compound was not longer available. Therefore, we have updated the protocol and instead are using clobazam, a GABA-A/benzodiazepine receptor agonist. We have also now expanded the information about measures acquired in this study.

Up to 50 adult individuals with ASD and 50 neurotypical adults (25 males and 25 females per group) will be invited to participate. Prior to the pandemic, each participant received a single dose of the drug (10mg or 20mg AZD7325) or matched placebo. Following ethics amendment post pandemic, AZD7325 will no longer be used and participants will receive 5mg of clobazam or placebo.

Brain activity and neurochemistry will be investigated using magnetic resonance imaging, EEG and psychophysics. Further data will be collected through questionnaires, behavioural tasks, blood samples, and retinal physiology.

Our study is defined as a Basic Science study in human participants. It does not address safety or clinical efficacy and the UK Medicines and Health Regulatory Authority (MHRA) has confirmed that our protocol is therefore not a clinical trial of an Investigational Medicinal Product (IMP) as defined by the EU Directive 2001/20/EC

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London
    • London, London, United Kingdom, SE5 8AF
      • King's College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria

For all participants:

1. Calendar age above 18 years.
2. Able to give informed consent.
3. Not pregnant or breastfeeding.
4. Ideally prescription medication free during the 2-week period preceding a study visit. However, occasional use of over-the-counter medication (e.g. painkillers) on an as needed basis (and not on the day of study visit) may be permitted. In addition, regular prescription medication (use of a stable dose over the two months preceding participation) with a drug that does not affect glutamate or GABA directly may be permitted. Also permitted is topical medication without systemic exposure.

For individuals with ASD:

1. Diagnosis of ASD confirmed on the Autism Diagnostic Interview-Revised (ADI-R) if a relative is available and/or on the Autism Diagnostic Observation Schedule (ADOS-2).

For all relatives:

1. Aged under 18 years.
2. Does not know the participant personally at present or in their childhood.

Exclusion Criteria:

For all participants

1. History of allergy/idiosyncrasy to AZD7325 or chemically related compounds or excipients which may be employed in the study or to any other drug used in the past.
2. Subject has taken systemically (po, iv) any potent or moderate CYP3A4 or CYP2C9 inhibitor or inducer, 1 month prior to screening (topical or inhaled are permitted) such as: aprepitant, barbiturates, carbamazepine, clarithromycin, erythromycin, cyclosporine, diltiazem, efavirenz, fluconazole, HIV protease inhibitors, glucocorticoids, itraconazole (oral/IV), ketoconazole, nefazodone, nevirapine, phenytoin, pioglitazone, primidone, rifabutin, rifampicin, telithromycin, St. John's wort, verapamil.
3. Clinically relevant history or presence of any medical disorder, potentially interfering with this study.
4. Clinically relevant abnormality at screening as judged by the investigator.
5. History of or current abuse of drugs (including prescription medication) or alcohol or solvents.
6. Participation in a research study involving a pharmacological probe or drug trial within last month or more than four in the previous 12 months
7. Subjects with a history of epilepsy, seizures or episodes of unexplained and unprovoked loss of consciousness.
8. Anyone with a history or examination which indicates laboratory testing is needed will be excluded from the study.
9. Intelligence Quotient below 70.

Reproductive safety: Male study participants who are sexually active should avoid procreation for 1 week after study drug administration. Avoidance of procreation can be through use of a highly effective contraception method by the study participant or by the partner. In this case, effective means of contraception are defined as tubal occlusion, copper banded intrauterine device, levonorgestrel medicated intra uterine system (e.g., Mirena), medroxyprogesterone injections (e.g. Depo-Provera), etonogestrel implants (e.g., Implanon, Norplan), normal and low dose combined oral contraceptive pills, norelgestromin / EE transdermal system, intravaginal device (e.g., EE and etonogestrel) and desogestrel (Cerazette).

Pregnancy or breastfeeding (is a routine exclusion for research MRI scanning). Female study participants must be willing to use one form of highly effective non-hormonal contraception for one week after study drug administration. This would include a vasectomised partner (sole partner), tubal occlusion, intrauterine system [IUS]/hormonal coil or copper containing intrauterine device or copper containing IUD, or true abstinence (when this is in line with the preferred and usual lifestyle of the subject). Women should have been stable on their chosen method of birth control for a minimum of 2 months before entering the study. Participants must agree to undergo a pregnancy test prior to each administration of study drug.

For individuals with ASD:

1. ASD caused by a known genetic syndrome, e.g. Fragile X, 22q11 deletion syndrome.
2. Currently treated for epilepsy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: AZD7325; Prepandemic. Single Dose of Placebo or AZD7325 10mg or AZD7325 20mg random order on visits separated by 1 week	Drug: AZD7325_10; Single oral dose (10mg); Drug: AZD7325_20; Single oral dose (20mg); Drug: Placebo; Single oral dose placebo (capsule)
Other: Clobazam; Post pandemic: Single Dose Placebo or 5mg Clobazam random order on visits separated by 1 week	Drug: Placebo; Single oral dose placebo (capsule); Drug: Clobazam; Single dose (5mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain activation and connectivity response to GABAergic stimulation as assessed by functional magnetic resonance imaging.	Comparing whole brain blood-oxygen-level-dependent (BOLD) activation (institutional units) during the resting state in cases and controls when a single oral dose of GABA-A receptor acting compound administered versus the placebo condition.	Data collected on up to 3 visit days per participant. Completed within up to 1 year.
Brain electrophysiological activity task-free electroencephalography (EEG)	Case-control comparison of task-free Electroencephalogram (EEG) during placebo and when GABA-A compound administered. Analyses approaches will include examining power and phase information across different frequencies and aperiodic signal analysis (1/f like); and evaluation of power spectrum and functional connectivity across source localisations.	Data collected on up to 3 visit days per participant. Completed within up to 1 year
Brain oscillations under sensory stimulation	Brain oscillations (spectral perturbations) and event-related potentials will be recorded during sensory stimulation - auditory (odd-ball) and visual (contrast saturation, face perception/N170) tasks using electroencephalography during placebo and when GABA-A compound administered.	Data collected on up to 3 visit days per participant. Completed within up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional connectivity measures using resting state functional magnetic resonance imaging.	Maps of functional connectivity will be obtained for each condition and compared between adults with and without ASD.	Through study completion, an average of 2 years.
Brain oscillations under sensory stimulation	Brain oscillations and event-related potentials will be recorded during sensory stimulation using high density electroencephalography.	Through study completion, an average of 2 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain excitation and inhibition response to GABAergic stimulation as assessed by magnetic resonance spectroscopy.	Quantification and case-control comparison of brain metabolites relevant to regulation of excitation and inhibition (focus on Glx, GABA, GSH) using proton magnetic resonance spectroscopy when 'at rest' (placebo) and when activated by GABA-A compound.	Data collected on up to 3 visit days per participant. Completed within up to 1 year
Tactile perception	Case-control comparison of tactile discrimination during placebo and when GABA-A compound administered.	Data collected on up to 3 visit days per participant. Completed within up to 1 year
Electroretinogram	Case-control comparison of ERG acquired with hand held device during placebo and when GABA-A compound administered. three stimulus protocols: i) the standard white flash; ii) the standard 30-Hz flickering protocol; iii) the photonic negative response (PhNR) protocol.	Data collected on up to 3 visit days per participant. Completed within up to 1 year

Collaborators and Investigators

• Sponsor: King's College London
• Investigators: Principal Investigator: Grainne McAlonan, PhD, King's College London, UK

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2018
• Primary Completion (Actual): June 27, 2025
• Study Completion (Actual): June 27, 2025

Study Registration Dates

• First Submitted: September 18, 2018
• First Submitted That Met QC Criteria: September 18, 2018
• First Posted (Actual): September 19, 2018

Study Record Updates

• Last Update Posted (Estimated): August 26, 2025
• Last Update Submitted That Met QC Criteria: August 19, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Autism Spectrum Disorder; GABA; E-I balance; pharmacological imaging; AZD7325
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Substandard Drugs; Pharmaceutical Preparations; Benzazepines; Benzodiazepines; Clobazam; Counterfeit Drugs
• Other Study ID Numbers: REC 18/WM/0208

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No