Investigating the Role of Diazepam on Brain Function and Chemistry in Psychosis Risk (BENZOGAP)

Effect of Benzodiazepine on Corticolimbic Activation, GABA and Glutamate in Subjects at Clinical High Risk of Psychosis

This study will investigate whether a single dose of diazepam (5mg) compared to placebo can modulate brain chemistry (GABA/glutamate levels) and function (blood flow, neural response and connectivity during tasks and at-rest) in 24 individuals at clinical high-risk for psychosis.

Study Overview

• Status: Completed
• Conditions: Prodromal Schizophrenia
• Intervention / Treatment: Drug: Diazepam 5 Mg Oral Tablet; Drug: Ascorbic Acid 50 Mg Oral Tablet

Detailed Description

The pathophysiology of psychosis involves elevated subcortical dopamine function, but the factors driving this are still unclear. Evidence from a neurodevelopmental animal model of psychosis suggests that this arises through a pathway linking psychosocial stress, corticolimbic hyperresponsivity, and GABA/glutamate imbalance. In response to stress/negative emotion, amygdala hyperresponsivity decreases GABA interneuron function in the hippocampus through strong direct projections. Decreased hippocampal GABA function leads to disinhibition of hippocampal pyramidal cells, elevating local activity and glutamate levels. Increased output from the hippocampus to the striatum elevates dopamine release in the striatum, and increases the firing of dopaminergic neurons in the midbrain. These neurobiological effects are associated with cognitive (e.g., working memory) and emotional deficits (e.g., increased anxiety). Moreover, peripubertal (premorbid) administration of benzodiazepines at anxiolytic doses to this animal of psychosis is shown to normalise hippocampal activity, thereby preventing the emergence of striatal hyperdopaminergia and associated behavioural abnormalities in adulthood. Collectively, these findings indicate that GABA dysfunction and emotional hyperresponsivity may play a critical role in the development of psychosis in humans, and suggest that clinical interventions targeting this pathway have the potential to reduce the risk of developing the disorder.

This study will use multimodal neuroimaging (MRS, ASL, rs-fMRI, tb-fMRI) to assess whether the acute administration of a benzodiazepine can modulate the pathway linking corticolimbic response and GABA/glutamate levels in people in the premorbid stage of psychosis (at "clinical high risk", CHR). Using a randomised, double-blind, placebo-controlled, crossover design, 24 CHR-P participants will undergo two MRI sessions, once under an acute oral dose of diazepam (5 mg; generic) and once under oral placebo (50 mg ascorbic acid), with a minimum 3-week washout period between visits.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE8 5AF
    • Institute of Psychiatry, Psychology and Neuroscience

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age range 18-40 years
• Capacity to consent to participation in the study
• Inclusion into one of three groups as assessed by the CAARMS: i) genetic vulnerability group, ii) attenuated psychosis group, iii) brief intermittent psychosis symptoms group. This instrument has been modified to additionally allow the scoring of the SIPS v.520. The scoring of the SIPS v.5 is included for comparative purposes and does not constitute inclusion criteria.
• Inclusion based on meeting criteria for "basic symptoms" which are assessed using the Schizophrenia Proneness Instrument (SPI-A)21

Exclusion Criteria:

• History of neurological disorders
• Current exposure to any drug with potential GABAergic or glutamatergic effects other than antipsychotics, mood stabilisers, antidepressants. This includes opiates, psychostimulants, benzodiazepines, atomoxetine, memantine, ketamine, cough medication containing dextromethorphan
• Current or past exposure to any antipsychotic medication
• Pregnancy/breastfeeding
• Contra-indication to MRI scanning (e.g., metal in body, such as pacemakers or implants, claustrophobia)
• IQ < 70 as determined with the shortened version of the Wechsler Adult Intelligence Scale III (WAIS-III)22

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Diazepam/Placebo; Participant's receive diazepam on 1st MRI scan, and placebo (ascorbic acid) on 2nd MRI scan	Drug: Diazepam 5 Mg Oral Tablet; Single dose given orally (opaque capsule) 60 minutes prior to MRI scan; Other Names: Diazepam; Drug: Ascorbic Acid 50 Mg Oral Tablet; Single dose given orally (opaque capsule) 60 minutes prior to MRI scan; Other Names: Placebo
Experimental: Placebo/Diazepam; Participant's receive placebo (ascorbic acid) on 1st MRI scan, and diazepam on 2nd MRI scan	Drug: Diazepam 5 Mg Oral Tablet; Single dose given orally (opaque capsule) 60 minutes prior to MRI scan; Other Names: Diazepam; Drug: Ascorbic Acid 50 Mg Oral Tablet; Single dose given orally (opaque capsule) 60 minutes prior to MRI scan; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GABA/Glutamate concentrations (Magnetic Resonance Spectroscopy)	To evaluate the acute effect of a benzodiazepine drug (diazepam) on GABA and glutamate concentrations in people at clinical high risk of psychosis (CHR).	Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral blood flow (Arterial Spin Labelling)	To determine if hippocampal cerebral blood flow is normalised in subjects at CHR under the diazepam condition compared to placebo	Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
Functional connectivity (Resting State Functional Magnetic Resonance Imaging)	To determine if hippocampal resting functional connectivity is normalised in subjects at CHR under the diazepam condition compared to placebo	Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
Neural response to emotional stimuli (Task Based Functional Magnetic Resonance Imaging)	To determine if neural response to emotional stimuli and during working memory is normalised in subjects at CHR under the diazepam condition compared to placebo	Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
Neural response during working memory (Task Based Functional Magnetic Resonance Imaging)	To determine if neural response during working memory is normalised in subjects at CHR under the diazepam condition compared to placebo	Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: Wellcome Trust; The Royal Society

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2019
• Primary Completion (Actual): March 24, 2023
• Study Completion (Actual): March 24, 2023

Study Registration Dates

• First Submitted: December 19, 2023
• First Submitted That Met QC Criteria: December 19, 2023
• First Posted (Actual): January 5, 2024

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antiemetics; Gastrointestinal Agents; Protective Agents; Micronutrients; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Vitamins; Antioxidants; Neuromuscular Agents; Muscle Relaxants, Central; Diazepam; Ascorbic Acid
• Other Study ID Numbers: 18/LO/0618

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