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Trial registered on ANZCTR


Registration number
ACTRN12617000086369
Ethics application status
Approved
Date submitted
10/01/2017
Date registered
16/01/2017
Date last updated
16/01/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
A combined PET-fMRI study of frontostriatal dysfunction in first episode psychosis
Scientific title
A combined PET-fMRI study of frontostriatal dysfunction in first episode psychosis
Secondary ID [1] 289975 0
nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Psychosis 299978 0
Condition category
Condition code
Mental Health 299870 299870 0 0
Psychosis and personality disorders
Neurological 301317 301317 0 0
Other neurological disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
1. Baseline
All participants will complete a baseline assessment

a. Patients will complete the following over 2 visits ideally within one week:
i. Clinical assessment (3 hours)
ii. PET-MRI imaging (3 hours)

The same protocol will be used for healthy controls, though the clinical assessment will be briefer, involving some questionnaires and a structured diagnostic interview

a. Healthy control participants will complete the following over 2 visits ideally within one week:
i. Clinical assessment (3 hours)
ii. PET-MRI imaging (3 hours)

2. 12-month follow-up
Patients only will complete a 12-month follow-up assessment, involving:
a. Detailed clinical assessment (3 hours)
No brain imaging is required at 12-month follow-up
Intervention code [1] 295669 0
Diagnosis / Prognosis
Comparator / control treatment
Healthy controls with no personal/family history of neurological/psychiatric illness will be age and gender matched to the patient group.
Control group
Active

Outcomes
Primary outcome [1] 299345 0
Identify specific, neural-circuit-level drivers of variations in striatal FDOPA levels by identifying which specific measure of fMRI functional connectivity makes the strongest unique contribute to the striatal FDOPA signal.

Instrument: PET-MRI scan
Timepoint [1] 299345 0
Baseline
Secondary outcome [1] 330683 0
Compare striatal FDOPA levels between patients and controls.

Instrument: PET-MRI scan
Timepoint [1] 330683 0
Baseline
Secondary outcome [2] 330684 0
Identify which specific circuit-level driver of striatal FDOPA variations different between people with psychosis and healthy controls.

Instrument: PET-MRI scan, clinical assessment
Timepoint [2] 330684 0
Baseline, 12 month follow-up

Eligibility
Key inclusion criteria
Patient Inclusion criteria:

*Experiencing a first episode of psychosis (one or more psychotic symptoms on a daily basis for at least one week) and meeting diagnostic criteria for one of the following DSM-IV disorders: schizophreniform psychosis, schizophrenia, schizoaffective disorder, delusional disorder, brief psychosis, major depressive disorder or bipolar disorder with psychotic features, or psychosis NOS.
*Age range 18-25 years
*Within 3 months of commencing regular antipsychotic treatment; or lifetime cumulative exposure of < 3 months; or no antipsychotic treatment for at least one year
*Ability to provide informed consent as determined either via the clinical opinion of the treating medical physician, or the administration, by one of the research team, of the MacArthur Competence Assessment Tool for Clinical Research.

Healthy Control Participant Inclusion criteria:
* Psychiatrically healthy individual aged 18-25 years
Minimum age
18 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Patient Exclusion criteria:
* Primary diagnosis of Borderline Personality Disorder or Post-Traumatic Stress Disorder
* Intellectual disability
* Colour blindedness
* Diagnosis of substance dependence
* History of neurological disorder, brain injury, or significant loss of consciousness
* MRI/PET contraindications (pregnancy, breastfeeding, metal implants)
* Contraindications for Carbidopa and Entacapone (treatment with MAO inhibitors, blood/needle phobia, glaucoma, malignant melanoma, phaechromocytoma, rhabdomylosis, history of major medical condition such as diabetes, cardiovascular disease, hepatic/renal failure, etc).

Healthy Control Participant Exclusion criteria:
*Personal history of psychiatric or neurologic illness
*First-degree relatives with psychotic illness
*Intellectual disability
*History of neurological disorder, brain injury, or significant loss of consciousness
* MRI/PET contraindications (pregnancy, breastfeeding, metal implants)
* Contraindications for Carbidopa and Entacapone (treatment with MAO inhibitors, blood/needle phobia, glaucoma, malignant melanoma, phaechromocytoma, rhabdomylosis, history of major medical condition such as diabetes, cardiovascular disease, hepatic/renal failure, etc).

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Case control
Timing
Prospective
Statistical methods / analysis
Patlak graphical analysis will be used to compute 18F-DOPA influx rate constants (Ki values)
fMRI data will be processed and analysed. Specifically, six spherical seed regions will be placed in the dorsal and ventral striatum to extract representing time courses of activity fluctuations in each sub-region. These time courses will be entered as covariates along with other signals modeling various noise sources in the data into a general linear model. This model will be fitted to each individual’s functional data on a voxel-wise basis to identify regions showing significant functional connectivity with each striatal area. Group differences in striatal functional connectivity will be compared using two-sample t-tests. Effective connectivity within these networks will be modeled using dynamic causal modeling (DCM) an established fMRI procedure for inferring causal influences between neural systems.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
17/12/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 294530 0
Government body
Name [1] 294530 0
NHMRC
Country [1] 294530 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Rd, Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 293393 0
None
Name [1] 293393 0
Address [1] 293393 0
Country [1] 293393 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295763 0
Melbourne Health HREC
Ethics committee address [1] 295763 0
Ethics committee country [1] 295763 0
Australia
Date submitted for ethics approval [1] 295763 0
Approval date [1] 295763 0
15/08/2014
Ethics approval number [1] 295763 0
2014.047

Summary
Brief summary
Psychosis is a debilitating neuropsychiatric syndrome characterized by delusions, hallucinations, disorganized thinking and cognitive and emotional disturbances. It is a defining characteristic of schizophrenia, and occurs frequently in other major mental illnesses such as depression and bipolar disorder. All current treatments for psychosis modulate levels of the neurotransmitter dopamine (DA), and it is thought that DA dysregulation within circuits linking frontal brain regions with a set of subcortical nuclei called the striatum (the so called frontostriatal circuits) is a final common pathway for the emergence of psychotic symptoms. Precisely how this dysregulation arises however, remains a mystery.
This study will be the first to combine Positron Emission Technology (PET) measures of striatal DA function with functional Magnetic Resonance Imaging (fMRI) measures of frontostriatal connectivity to investigate the way in which altered subcortical dopamine may give rise to, or arise from, aberrant frontostriatal connectivity.
The project has three specific aims:
1. characterise the direct relationship between PET markers of striatal DA function and fMRI measures of frontostriatal functional dysconnectivity;
2. determine whether striatal DA abnormalities are a cause or consequence of frontostriatal dysconnectivity; and
3. investigate the potential of these two phenotypes as clinical biomarkers by determining whether they can predict patients’ 12month clinical outcome.
We will recruit 50 First Episode Psychosis (FEP) patients and 50 healthy controls to take part in the study. All participants will complete a clinical and brain imaging assessment at baseline. The brain imaging assessment will involve MRI and PET.
FEP patients will additionally complete a clinical assessment after a 12 month
followup period. No brain imaging will be conducted at this time. No followup of controls will be performed.
During the followup period, the research staff will maintain regular contact with the patients' clinical team. Information on treatments will be acquired, enabling us to account for variations in treatment protocols in our analyses.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68398 0
A/Prof Alex Fornito
Address 68398 0
Monash Biomedical Imaging
770 Blackburn Rd, Clayton VIC 3168
Country 68398 0
Australia
Phone 68398 0
+61 3 99029796
Fax 68398 0
Email 68398 0
[email protected]
Contact person for public queries
Name 68399 0
Ms Amy Finlay
Address 68399 0
Monash Biomedical Imaging
770 Blackburn Rd, Clayton VIC 3168
Country 68399 0
Australia
Phone 68399 0
+61 3 9902 9803
Fax 68399 0
Email 68399 0
[email protected]
Contact person for scientific queries
Name 68400 0
A/Prof Alex Fornito
Address 68400 0
Monash Biomedical Imaging
770 Blackburn Rd, Clayton VIC 3168
Country 68400 0
Australia
Phone 68400 0
+61 3 99029796
Fax 68400 0
Email 68400 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



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