Inflammatory Response In Schizophrenia

Study Overview
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Brief Summary
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Schizophrenia affects a significant proportion of the population and current levels of understanding of the illness is inadequate to treat it effectively. Converging lines of evidence suggest that neuroinflammation occurs in schizophrenia, and specifically over-activity of brain-resident immune cells called microglia. It is however unclear whether activated microglia play a primary role in schizophrenia, or whether this is a secondary phenomenon of no pathophysiological significance. The investigators therefore plan to test the effect of a monoclonal antibody (natalizumab) on psychotic symptoms in a cohort of first episode psychosis patients.

Detailed Description
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One of the key aims of the study is to determine if there is a relationship between change in imaging inflammation markers from baseline to follow-up and changes in other markers of inflammation over the same period. In September 2021, an open label arm for natalizumab was added to the study. The relationship between changes in imaging inflammation markers and changes in other markers of inflammation will be analysed within subjects including all patients who received natalizumab.

Official Title
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The Role of Inflammation in Brain and Cognitive Function in Mental Disorders

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Natalizumab
* Other: Placebo: normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Aged 18-50 years Diagnosis of schizophrenia or other psychotic disorder (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5); Symptomatic, defined as one or more positive symptom >3 AND one or more negative symptom >3 on the Positive and Negative Syndrome Scale (PANSS); No acute relapse and psychiatrically stable for >1 month before screening; Exclusion criteria: History of significant co-morbid CNS disorder (including significant head trauma or significant loss of consciousness, Parkinson's Disease, Epilepsy, Alzheimer's Dementia, Huntington's Disease). Any absolute contraindications to natalizumab, as per natalizumab SPC Current or recent (last 3 months) infection, or history of significant infection, or an immunocompromised state Previous use of natalizumab or previous use of other monoclonal antibody. Ongoing long-standing use of oral steroids or non-steroidal anti-inflammatory drugs. Pregnancy and/or breast-feeding. Substance dependence/abuse other than to cigarettes.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an experimental medicine study, the purpose of which is provide a mechanistic understanding of neuroinflammation in schizophrenia by investigating response to natalizumab (phase 1b).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient Group: Natalizumab<br>Natalizumab 300mg, intravenous, once monthly, total of 3 doses | Drug: Natalizumab<br>* Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin, currently licensed for the treatment of multiple sclerosis and Crohn's disease.<br>* Other names: Tysabri;|
| Placebo Comparator: Patient Group: Placebo<br>Saline, intravenous, once monthly, total of 3 doses | Other: Placebo: normal saline<br>* Normal saline, intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Translocator Protein (TSPO) availability pre- and post-natalizumab or placebo administration | TSPO availability assessed using Positron Emission Tomography (PET) | Baseline TSPO availability will be assessed at day -14 prior to first administration of natalizumab/placebo (day zero). TSPO availability will be re-assessed post administration of natalizumab/placebo at day +57(+14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of TSPO availability with brain functional measures at baseline. | Both TSPO availability (as measured using PET imaging) and brain functional measures (as measured using functional magnetic resonance imaging and magnetic resonance spectroscopy) will be measured simultaneously using a combined PET/MRI scanner. | Baseline combined PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero) | 
| Correlation of cerebrospinal fluid (CSF) inflammatory markers with brain functional measures at baseline. | Brain functional measures assessed using functional magnetic resonance imaging and magnetic resonance spectroscopy. CSF inflammatory markers: measurements of cytokine concentrations (e.g. C-reactive protein, Interleukin-6) | Baseline PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero). CSF collection will be performed between the time points day -14 to day -1 prior to administration of natalizumab/placebo (day zero). | 
| Correlation of blood inflammatory markers with brain functional measures at baseline. | Brain functional measures assessed using functional magnetic resonance imaging and magnetic resonance spectroscopy. Blood inflammatory markers: measurements of cytokine concentrations (e.g. C-reactive protein, Interleukin-6) | Baseline PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero). Blood collection will be performed between the time points day -14 to day -1 prior to administration of natalizumab/placebo (day zero). | 
| Longitudinal change in TSPO availability correlated with longitudinal change in brain functional measures. | Both TSPO availability (as measured using PET imaging) and brain functional measures (as measured using functional magnetic resonance imaging and magnetic resonance spectroscopy) will be measured simultaneously using a combined PET/MRI scanner. There will be two separate scans - before and after administration of natalizumab/placebo. | Baseline combined PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero). Repeat combined PET/MRI scan will be performed at day +57(+14 days). |