An interventional study of Diazepam 5 Mg Oral Tablet and Ascorbic Acid 50 Mg Oral Tablet in Prodromal Schizophrenia, sponsored by King's College London. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 40 Years. Per ClinicalTrials.gov, last updated 2024-01-05.
Sponsored by King's College London · Not applicable, Interventional, and Health services research
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.
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.
3,472 studies on the registry are indexed under Schizophrenia; 472 are open to participants now.
This study's enrollment of 24 is below the median of 70 across 2,873 interventional studies indexed under Schizophrenia.
Browse Schizophrenia studies →King's College London is the lead sponsor of 507 studies on the registry; 125 are open to participants now.
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Participant\'s receive diazepam on 1st MRI scan, and placebo (ascorbic acid) on 2nd MRI scan
Drug: Diazepam 5 Mg Oral Tablet · Drug: Ascorbic Acid 50 Mg Oral Tablet
Participant\'s receive placebo (ascorbic acid) on 1st MRI scan, and diazepam on 2nd MRI scan
Drug: Diazepam 5 Mg Oral Tablet · Drug: Ascorbic Acid 50 Mg Oral Tablet
Single dose given orally (opaque capsule) 60 minutes prior to MRI scan
Also known as: Diazepam
Single dose given orally (opaque capsule) 60 minutes prior to MRI scan
Also known as: Placebo
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).
Time frame: Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
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
Time frame: 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
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)
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
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)
To determine if neural response during working memory is normalised in subjects at CHR under the diazepam condition compared to placebo
Time frame: Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment)
Plan to share: No
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This study is completed, as verified in Dec 2023. You cannot join it, but the record below documents what was studied.
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King's College London