T10. BIOMARKERS IN TREATMENT-RESISTANT SCHIZOPHRENIA; THE BITS STUDY (A STUDY PROTOCOL)

BACKGROUND: Approximately 30% of patients diagnosed with schizophrenia do not respond to conventional antipsychotic therapy, however, around 30% of these patients will respond to treatment with clozapine. The remaining clozapine non-respondent patients can be defined as ultra-treatment resistant. Special characteristics (biomarkers) may be found in this subgroup of ultra-treatment resistant patients. Recent evidence points to a central role of altered immunological and anti-inflammatory response in schizophrenia. Studies have found that antipsychotic medication affect the immune system and alter levels of different cytokines, but no clear relation between the effect on cytokine levels and improvement in symptoms has been documented. Also increased permeability of the blood brain barrier (BBB) have been linked to psychosis, and a dysfunctional BBB may lead to structural changes in the white matter and neurochemical changes (glutamatergic abnormalities) in CNS. The longitudinal course of BBB alterations in psychosis and how this may influence changes in neuronal structure and function and relate to fluctuation in symptoms have not been examined. The aim of this study is to establish a database with the purpose of identifying biomarkers for treatment resistant schizophrenia (TRS), containing measures of psychopathology and function, treatment variables, brain imaging data, immunological markers from blood and cerebrospinal fluid, BBB-permeability and genetic material. The database will consist of a group of ultra-treatment resistant patients and a group of patients responding to clozapine matched on sex, age and duration of illness (±3 years). Specific aims: evaluate the permeability of BBB and characterize the immunological profile in blood and CSF; examine the structure of grey and white matter, and the content of glutamate in specific brain areas; characterize the psychopathology and the level of function; collect blood-samples for genetic testing. HYPOTHESIS: Ultra-treatment resistant patients will have an increased inflammatory pattern in blood level cytokines compared to reference levels and clozapine responding patients. Ultra-treatment resistant patients will have increased BBB permeability and altered levels of cytokines in the CSF. Patients with altered CSF level of cytokines will have more pronounced structural and neurochemical brain changes. In some patients, the BBB permeability and the CSF level of cytokines will be altered during the follow up period along with symptom fluctuation and these alterations will correlate with changes in white matter. BBB-permeability and CSF levels of cytokines will be stable in patients stable on clozapine. METHODS: The study is a naturalistic longitudinal study including patients with TRS. We plan a thorough examination twice with a three months interval and ultra-treatment resistant patients will be compared with patients stable on clozapine. Between examinations there will be no planned interference with the antipsychotic treatment, but antipsychotic treatment may be changed during the period in the intention to improve symptoms. The primary longitudinal outcome is comparing changes in BBB-permeability along with symptom-fluctuations. This will be done by comparing changes in qAlb, which is the gold standard technique measuring the CSF:serum albumin ratio (QAlb). RESULTS: The study has been approved by the regional ethical committee and data collection will begin in 2020. DISCUSSION: We expect the obtained results will contribute to a better pathophysiological understanding about illness markers and their progression over time and in relation to functional outcome.