Inflammatory Response In Schizophrenia (IRIS)

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

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Natalizumab; Other: Placebo: normal saline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Tiago Marques, MD, PhD; Phone Number: +44 207 848 0728; Email: tiago.marques@kcl.ac.uk
• Study Contact Backup: Name: Yuya Mizuno, MD, PhD; Phone Number: +44 207 848 0434; Email: yuya.mizuno@kcl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 8AF
    • Institute of Psychiatry, Psychology and Neuroscience, King's College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria:

1. Aged 18-50 years
2. Diagnosis of schizophrenia or other psychotic disorder (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5);
3. Symptomatic, defined as one or more positive symptom >3 AND one or more negative symptom >3 on the Positive and Negative Syndrome Scale (PANSS);
4. No acute relapse and psychiatrically stable for >1 month before screening;

Exclusion criteria:

1. 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).
2. Any absolute contraindications to natalizumab, as per natalizumab SPC
3. Current or recent (last 3 months) infection, or history of significant infection, or an immunocompromised state
4. Previous use of natalizumab or previous use of other monoclonal antibody.
5. Ongoing long-standing use of oral steroids or non-steroidal anti-inflammatory drugs.
6. Pregnancy and/or breast-feeding.
7. Substance dependence/abuse other than to cigarettes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patient Group: Natalizumab; Natalizumab 300mg, intravenous, once monthly, total of 3 doses	Drug: Natalizumab; 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.; Other Names: Tysabri
Placebo Comparator: Patient Group: Placebo; Saline, intravenous, once monthly, total of 3 doses	Other: Placebo: normal saline; Normal saline, intravenous infusion

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: South London and Maudsley NHS Foundation Trust
• Investigators: Principal Investigator: Oliver D Howes, King's College London

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2017
• Primary Completion (Actual): June 15, 2023
• Study Completion (Actual): August 7, 2023

Study Registration Dates

• First Submitted: February 23, 2017
• First Submitted That Met QC Criteria: March 22, 2017
• First Posted (Actual): March 28, 2017

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Immunologic Factors; Natalizumab
• Other Study ID Numbers: 208083

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes