A Randomized Controlled Trial With Rituximab for Psychotic Disorder in Adults

Study Overview
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Brief Summary
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Immunological factors are assumed to be determinants for some psychiatric disorders, thus anti-inflammatory drugs may be helpful. However, studies on such treatments are scarce. An inflammatory modulating drug rituximab, cluster of differentiation antigen 20 antibodies (anti-CD20 antibodies), is a standard treatment for e.g. multiple sclerosis. The investigators aim to test rituximab in a randomised placebo-controlled double-blinded, add-on treatment trial in 120 participants (18-55 years) with schizophrenia spectrum disorder. Sampling from blood for analyses of inflammatory mediators are investigated at gene and protein levels and resting state functional magnetic resonance imaging (rsfMRI) and lumbar puncture are optional. Biomarkers will be investigated in relation to treatment response. Family member(s) to the patient and the patient (separate) will be asked to participate in a qualitative interview by an independent researcher after 3 months.

Detailed Description
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Immunological factors are assumed to be determinants for some psychiatric disorders, thus anti-inflammatory drugs may be helpful. However, studies on such treatments are scarce. Rituximab (anti-CD20 antibodies), a standard treatment for multiple sclerosis in Sweden, is an inflammatory modulating drug. In a small open pilot trial, markedly ill, treatment-resistant participants with schizophrenia spectrum disorder were treated with a single- dose rituximab (1000 mg), as add-on treatment to antipsychotics in Örebro, Sweden (2019-2022). Large improvements in all types of psychotic symptoms were evident, with long-lasting effects and few side-effects in most of the participants. This is a proof-of-concept study based on our earlier findings. The investigators will conduct a multicenter, placebo-controlled, double-blinded, add-on intervention study for 120 participants with schizophrenia spectrum disorder (18-55 years). Sampling from blood for analyses of inflammatory mediators are investigated at gene and protein levels and rsfMRI and lumbar puncture are optional at baseline and endpoints. Biomarkers will be investigated in relation to treatment response. Participants are assessed at five time-points; week 0, 2, 7, 12 (endpoint I) and 24 (endpoint II). Research questions: I Does the addition of rituximab to standard psychiatric treatment improve psychotic symptoms in SSD? II Does overall disability improve with the addition of rituximab? III Are clinical or biological markers related to treatment response? IV Is rituximab safe and well tolerated by participants with SSD? In addition family member(s) to the patient will be asked to participate in a qualitative interview by a researcher after 3 months on changes in the patient's mood and anxiety level, general functioning, behaviours, energy level, psychotic symptoms, motivation, emotional reciprocity and insight to enable a qualitative analysis. We will also ask them about their general thoughts on the study. In addition we will interview the patient after 3 months using qualitative methods. We also aim study changes in negative symptoms with the Motivation and pleasure- self report (MAP-SR) in addition to the Positive and Negative Syndrome Scale (PANSS) scale and Self-evaluation of Negative Symptoms (SNS). Childhood onset neuropsychiatric symptoms will be investigated retrospectively by the use of Five-to-Fifteen Brief (FTF-Brief).

Official Title
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A Randomized Controlled Trial With Rituximab for Psychotic Disorder in Adults

Conditions
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Schizophrenia Spectrum and Other Psychotic Disorders

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ages 18 to 55 years duration of illness exceeding 1 year diagnosed with Schizophrenia spectrum disorder (SSD) according to The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). if female and with any risk for pregnancy, willing to use contraceptives or abstinence if normal and preferred lifestyle. participants should be judged by the investigator to be lucid and oriented to person, place, time, and situation when giving the informed consent. insufficiently recovered from previous antipsychotic treatments. a minimum score of 4 (moderately ill) in Clinical global impression - severity (CGI-S) at baseline. Exclusion Criteria: pregnancy or breast-feeding weight below 40 kg clinically relevant ongoing infection at the discretion of the physician chronic infections positive test for hepatitis B, hepatitis C, HIV, or tuberculosis malignancy currently or within 2 years prior to inclusion current severe heart failure (NYHA grade IV) or any other severe heart disease (e.g. or history of cardiac arrhythmia or myocardial infarction) any change of antipsychotic medication within the previous 4 weeks unable to make an informed decision to consent to the trial ongoing clozapine treatment ongoing immunomodulatory treatment treatments with monoclonal antibodies within 1 year before the inclusion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A proof-of-concept study: a multicenter, placebo-controlled, double-blinded, add-on intervention study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>Rituximab 1000 mg, infusion | Drug: Rituximab<br>* Infusion<br>* Other names: Saline;|
| Placebo Comparator: Placebo<br>Saline infusion | Drug: Rituximab<br>* Infusion<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in psychotic symptoms | Change in scores in the measure for psychotic symptoms the Positive and Negative Syndrome Scale (PANSS) | Baseline up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in functioning | Measuring overall disability with Personal and Social Performance Scale (PSP) | Baseline up to week 12 and 24 | 
| Proportion of responders to treatment, rated as much or very much improved with CGI-I | Improvement according to clinical rated Clinical Global Impression-Improvement (CGI-I) | Baseline up to week 12 and 24 | 
| Improvement since baseline | Improvement according to clinical rated Clinical Global Impression-Improvement (CGI-I) | Baseline up to week 12 and 24 | 
| Change in severity since baseline | Improvement according to clinical rated Clinical Global Impression-Severity (CGI-S) | Baseline up to week 12 and 24 | 
| Improvement in psychotic symptoms since baseline | Change in scores in the measure for psychotic symptoms the Positive and Negative Syndrome Scale (PANSS). | Baseline up to week 24 | 
| Change in self-rated overall health | Differences in patient self-rated health (VAS-health) | Baseline up to week 12 and 24 | 
| Patient-rated improvement | Patient's Global Evaluation of improvement (PGE) corresponding to the CGI-I scores | Baseline up to week 12 and 24 | 
| Inflammatory markers in blood and/or cerebro spinal fluid (CSF) | Baseline levels of inflammatory markers in relation to treatment response (optional) | Baseline up to week 12 and 24 | 
| Safety and tolerability of rituximab | Open questions and a questionnaire (AAR-Revised) | Baseline up to week 12 and 24 | 
| fMRI | Change in brain morphology and/or activity in fMRI (optional) | Baseline up to week 12 and 24 | 
| Patient-rated change in psychiatric symptoms | Mental health symptom domains (Level 1 Cross-cutting symptom measure of global symptom severity) in relationship to response. | Baseline up to week 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RCT, immunomodulatory treatment, psychosis, rituximab, CD20 antibodies