Prodromal SchizophreniaBENZOGAPNCT06190483
Investigating the Role of Diazepam on Brain Function and Chemistry in Psychosis Risk
A study testing Diazepam 5 Mg Oral Tablet and Ascorbic Acid 50 Mg Oral Tablet in people with Prodromal Schizophrenia, run by King's College London at 1 site in United Kingdom.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 40 years
- Conditions the study is for
- Prodromal Schizophrenia
- What is being tested?
- Diazepam 5 Mg Oral Tablet and Ascorbic Acid 50 Mg Oral Tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 24 Jul 2019to 24 Mar 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Institute of Psychiatry, Psychology and Neuroscience
London, SE8 5AF
About this study
Official title: 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.
Read the 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.
- Conditions
- Prodromal Schizophrenia
- Being tested
- Diazepam 5 Mg Oral Tablet, Ascorbic Acid 50 Mg Oral Tablet
- Medical subject headings
- Schizotypal Personality Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Diazepam 5 Mg Oral TabletDrug
Also called Diazepam
Single dose given orally (opaque capsule) 60 minutes prior to MRI scan
Ascorbic Acid 50 Mg Oral TabletDrug
Also called Placebo
Single dose given orally (opaque capsule) 60 minutes prior to MRI scan
| Study group | Role | What they receive |
|---|---|---|
| Diazepam/Placebo | Experimental | Participant\'s receive diazepam on 1st MRI scan, and placebo (ascorbic acid) on 2nd MRI scan Receives: Drug: Diazepam 5 Mg Oral Tablet; Drug: Ascorbic Acid 50 Mg Oral Tablet |
| Placebo/Diazepam | Experimental | Participant\'s receive placebo (ascorbic acid) on 1st MRI scan, and diazepam on 2nd MRI scan Receives: Drug: Diazepam 5 Mg Oral Tablet; Drug: Ascorbic Acid 50 Mg Oral Tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
Secondary outcomes (4)
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
Measured: 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
Measured: 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
Measured: 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
Measured: Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jan 2024
- Study start24 Jul 2019
- Primary completion24 Mar 2023
- Study completion24 Mar 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Prodromal SchizophreniaStudies of the same condition, open and under way.
- More trials run by King's College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- King's College London
- Sponsor type
- University, hospital or other
- Collaborators
- Wellcome Trust, The Royal Society
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06190483
- Sponsor's protocol ID
- 18/LO/0618
- Acronym
- BENZOGAP
- Status last verified
- Dec 2023
- First submitted
- 19 Dec 2023
- Last updated
- 5 Jan 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Kiemes A, Livingston NR, Lukow PB, Knight S, Jelen L, Reilly T, Dima A, Nettis MA, Lythgoe DJ, Casetta C, Egerton A, Spencer T, De Micheli A, Fusar-Poli P, Grace AA, Williams SCR, McGuire P, Davies C, Stone JM, Modinos G. Diazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis. Int J Neuropsychopharmacol. 2026 Feb 2;29(2):pyaf078. doi: 10.1093/ijnp/pyaf078.
PubMed 41384764
Study at a glance
From the registry record, last updated by the sponsor on 5 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Benzodiazepine on Corticolimbic Activation, GABA and Glutamate in Subjects at Clinical High Risk of Psychosis
- ClinicalTrials.gov ID
- NCT06190483
- Acronym / sponsor ID
- BENZOGAP / 18/LO/0618
- Conditions
- Prodromal Schizophrenia
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- King's College LondonUniversity, hospital or other
- Collaborators
- Wellcome Trust, The Royal Society
- Study start
- 24 Jul 2019 (actual)
- Primary completion
- 24 Mar 2023 (actual)
- Study completion
- 24 Mar 2023 (actual)
- First posted
- 5 Jan 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Diazepam/Placebo | Experimental | Drug: Diazepam 5 Mg Oral Tablet, Drug: Ascorbic Acid 50 Mg Oral TabletParticipant\'s receive diazepam on 1st MRI scan, and placebo (ascorbic acid) on 2nd MRI scan |
| Placebo/Diazepam | Experimental | Drug: Diazepam 5 Mg Oral Tablet, Drug: Ascorbic Acid 50 Mg Oral TabletParticipant\'s receive placebo (ascorbic acid) on 1st MRI scan, and diazepam on 2nd MRI scan |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (6 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Diazepam 5 Mg Oral TabletAlso: DiazepamSingle dose given orally (opaque capsule) 60 minutes prior to MRI scan | Drug | Diazepam/Placebo, Placebo/Diazepam |
| Ascorbic Acid 50 Mg Oral TabletAlso: PlaceboSingle dose given orally (opaque capsule) 60 minutes prior to MRI scan | Drug | Diazepam/Placebo, Placebo/Diazepam |
Primary outcome
GABA/Glutamate concentrations (Magnetic Resonance Spectroscopy)
Time frame: Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
To evaluate the acute effect of a benzodiazepine drug (diazepam) on GABA and glutamate concentrations in people at clinical high risk of psychosis (CHR).
4 secondary outcomes
Cerebral blood flow (Arterial Spin Labelling)
Time frame: Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
Functional connectivity (Resting State Functional Magnetic Resonance Imaging)
Time frame: 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)
Time frame: 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)
Time frame: Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jan 2024.
- Derived from this study: PubMed 41384764Kiemes A, Livingston NR, Lukow PB, Knight S, Jelen L, Reilly T, Dima A, Nettis MA, Lythgoe DJ, Casetta C, Egerton A, Spencer T, De Micheli A, Fusar-Poli P, Grace AA, Williams SCR, McGuire P, Davies C, Stone JM, Modinos G. Diazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis. Int J Neuropsychopharmacol. 2026 Feb 2;29(2):pyaf078. doi: 10.1093/ijnp/pyaf078.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Diazepam 5 Mg Oral Tablet and Ascorbic Acid 50 Mg Oral Tablet in people with Prodromal Schizophrenia, run by King's College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
GABA/Glutamate concentrations (Magnetic Resonance Spectroscopy) (time frame: Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06190483, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jan 2024.