Biomarkers in Clozapine-responding Schizophrenia

Study Overview
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Brief Summary
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The outline of the current project is to establish a cohort of patients with treatment refractory schizophrenia eligible for clozapine, to identify clinical and biological characteristics of clozapine responding patients. Patients will be offered treatment with clozapine according to national clinical guidelines. Before clozapine is initiated, patients will be offered a thoroughly neurobiological examination, and re-examination will be carried out after 12 weeks of treatment. The primary focus of the examinations will be immunological markers and autoantibodies in the blood and cerebrospinal fluid, permeability of the blood-brain barrier and magnetic resonance imaging of structural, neurochemical and functional brain changes.

Detailed Description
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Patients will be examined before and after 12 weeks of treatment with clozapine Examinations at baseline and follow up will be: Clinical ratings Blood inflammatory markers Inflammatory markers in cerebro spinal fluid MRI : examination of grey & white matter, glutamate and GABA in Anterior Cingulate cortex and glutamate in thalamus, selected cognitive measures

Official Title
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Biomarkers in Clozapine-responding Schizophrenia

Conditions
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Schizophrenia, Psychosis

Intervention / Treatment
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* Drug: Clozapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: According to ICD-10 fulfill diagnostic criteria for schizophrenia (F20.x), chronical paranoid psychoses (F22), Schizoaffective psychoses (F25) or other non-organic psychoses (F28/F29); Age 18-65 years; Legally competent; Stabil antipsychotic treatment during last month Being treatment refractory according to TRIPP-guidelines (Howes et al. 2017) defined as having tried at least two antipsychotic drugs in sufficient dosage (≥600 mg chlorpromazine equivalent) for a sufficient time (≥ 6 weeks) without sufficient symptom improvement (still a moderate level of positive symptoms). Recreational use of substances is allowed as long as it does not interfere with compliance Fertile females must use safe contraception (spiral or any hormonal contraception). Exclusion Criteria: Involuntarily psychiatric admittance during the study Substance abuse that interfere with compliance Pregnancy (will be verified by urine-HCG-test in fertile females) Toxic or idiosyncratic agranulocytosis in the past Reduced bone marrow function according to blood samples According to information from patient and available files, noUncontrolled Current uncontrolled epilepsy Current circulatory collapse and / or CNS depression for any cause Current severe kidney, heart or liver disease Current paralytic ileus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: To compare biomarkers between clozapine responders and non-responder before and after 12 weeks of treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: clozapine treatment<br>Open label clozapine will be given to all participants in clinical doses adjusted to sideeffects and clinical effect | Drug: Clozapine<br>* clinical doses adjusted to sideeffects and clinical effect<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Qalb | Quotient albumin (Qabl) in cerebrospinal fluid (CSF) compared to plasma | Baseline | 
| Change in Qalb | Change in quotient albumin in cerebrospinal fluid compared to plasma | Baseline and after 12 weeks | 
| Change in IL-6 and TGF-beta | Change in interleukin 6 (IL-6) and transcription growth factor beta (TGF-beta) | Baseline and after 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FA, MD, AD and RD | Change in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) | Baseline and after 12 weeks | 
| Change in cortical thickness as measured with FreeSurfer | Change in cortical thickness as measured with FreeSurfer | Baseline and after 12 weeks | 
| Change in glutamate in ACC and thalamus measured with MTI | Change in glutamate in anterior cingulate cortex (ACC) and thalamus measured with magnetic transfer imaging (MTI) | Baseline and after 12 weeks |