Open-label study to evaluate VMAT2 inhibition in psychosis
Research type
Research Study
Full title
An Open-label Positron Emission Tomography Study to Evaluate the Effects of Vesicular Monoamine Transporter 2 Receptor (VMAT2) Blockade on the Dopamine Neurotransmitter System in Subjects with Positive Symptoms and a Diagnosis of Schizophrenia or Schizoaffective Disorder
IRAS ID
300422
Contact name
Oliver D Howes
Contact email
Sponsor organisation
Neurocrine Biosciences Inc.
Duration of Study in the UK
2 years, 0 months, 1 days
Research summary
Antipsychotic treatment is inadequate for many patients with schizophrenia or schizoaffective disorder. The mechanism underlying persistent symptoms despite antipsychotic treatment is unknown, but several lines of evidence implicate the dopamine system. This study will investigate the role of the dopamine system in treatment-resistant psychosis by measuring dopamine synthesis capacity and levels of vesicular monoamine transporter 2 (VMAT2) in healthy volunteers and in patients with schizophrenia or schizoaffective disorder with ongoing positive symptoms of psychosis. This will help identify new approaches to treat ongoing positive symptoms of psychosis despite antipsychotic treatment for patients with schizophrenia or schizoaffective disorder.
The study addresses two questions:
1. Are VMAT2 levels and dopamine synthesis capacity elevated in patients relative to healthy controls?
2. Does VMAT2 inhibition lead to a reduction in dopamine synthesis capacity and is this related to the degree of VMAT2 inhibition?The first question will be answered by a cross-sectional case-control study, with [F18]-AV-133 and [18F]-DOPA uptake compared between patients and healthy volunteers. The second by a nested longitudinal observational study of the effect of VMAT2 inhibition on dopamine synthesis capacity in patients alone.
Healthy volunteers aged 21-85 will undergo assessments to determine eligibility, including: a brain magnetic resonance imaging (MRI) to exclude pre-existing neurological disease; CYP2D6 genotyping; and psychiatric assessments. There will be two PET imaging visits using [18F]DOPA and [18F]AV-133 tracers to measure dopamine synthesis capacity and VMAT2 levels.
Patients will undergo the same baseline clinical assessments and imaging as healthy volunteers. Eligible candidates with ongoing positive symptoms will enter the longitudinal arm and take a VMAT2 inhibitor (valbenazine) orally for up to 45 days. Following this the PET imaging measures will be repeated and the valbenazine stopped. There will be a follow-up visit to undertake safety assessments one week later.
Duration:up to 8weeks for healthy volunteers and 16weeks for patient participants.
REC name
South Central - Hampshire B Research Ethics Committee
REC reference
21/SC/0233
Date of REC Opinion
4 Oct 2021
REC opinion
Further Information Unfavourable Opinion