Investigating the Role of Diazepam on Brain Function and Chemistry in Psychosis Risk
Condition: Prodromal Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional

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.
    

Intervention name(s): Diazepam 5 Mg Oral Tablet; Ascorbic Acid 50 Mg Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): Single dose given orally (opaque capsule) 60 minutes prior to MRI scan; Single dose given orally (opaque capsule) 60 minutes prior to MRI scan
Other intervention name(s): Diazepam; Placebo
Intervention MeSH terms: Ascorbic Acid; Diazepam
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Health Services Research