Prodromal Schizophrenia
Conditions
Brief 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.
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.
Interventions
DRUGDiazepam 5 Mg Oral Tablet
Single dose given orally (opaque capsule) 60 minutes prior to MRI scan
DRUGAscorbic Acid 50 Mg Oral Tablet
Single dose given orally (opaque capsule) 60 minutes prior to MRI scan
Sponsors
Wellcome Trust
The Royal Society
King's College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GABA/Glutamate concentrations (Magnetic Resonance Spectroscopy) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cerebral blood flow (Arterial Spin Labelling) | Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment) | To determine if hippocampal cerebral blood flow is normalised in subjects at CHR under the diazepam condition compared to placebo |
| Functional connectivity (Resting State Functional Magnetic Resonance Imaging) | Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment) | To determine if hippocampal resting functional connectivity is normalised in subjects at CHR under the diazepam condition compared to placebo |
| Neural response to emotional stimuli (Task Based Functional Magnetic Resonance Imaging) | Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment) | 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 |
| Neural response during working memory (Task Based Functional Magnetic Resonance Imaging) | Assessed at 1st and 2nd MRI scan (~2 and ~6 weeks, respectively, after enrolment) | To determine if neural response during working memory is normalised in subjects at CHR under the diazepam condition compared to placebo |
Countries
United Kingdom
Outcome results
None listed