Neuroimmunological investigations of cerebrospinal fluid in patients with recent onset depression – a study protocol

Abstract

Background A proinflammatory response has been suggested to be involved in the pathophysiology of depression in a subgroup of patients. However, comprehensive largescale studies on neuroimmunological investigations of the cerebrospinal fluid (CSF) are lacking and no largescale longitudinal CSF studies comparing patients with depression to healthy controls currently exist. Methods A longitudinal case-control study including at least 100 patients with first time depression (ICD-10: F32) within the past year with ongoing symptoms and at least 100 sex and age matched healthy controls with collection of CSF, blood, and fecal samples. All individuals will be evaluated by neurological examination including neurological soft signs, interviewed for psychopathology assessment and have symptomatology evaluated by relevant rating scales. Level of functioning and quality of life will be evaluated by a panel of interview questions and rating scales, and cognitive function assessed by a relevant test battery. In addition, a large number of potential confounders will be registered (BMI, smoking status, current medication etc.). Primary outcomes: CSF white cell count, CSF/serum albumin ratio, CSF total protein levels, IgG index, CSF levels of IL-6 and IL-8, and the prevalence of any CNS-reactive autoantibody in CSF and/or blood. Secondary outcomes: exploratory analyses of a wide range of neuroimmunological markers and specific autoantibodies. Power calculations are computed for all primary outcomes based on previous CSF studies including patients with depression and healthy controls. Discussion This study will represent the hitherto largest investigation of CSF in patients with recent onset depression compared to healthy controls. We expect to elucidate neuroimmunological alterations in individuals with depression and characterize an immunological profile paving the way for the development of effective treatments based on biomarkers. Trial registration The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

Comparisons of 25 cerebrospinal fluid cytokines in a case–control study of 106 patients with recent-onset depression and 106 individually matched healthy subjects

“…This study was designed as a prospective case–control study including 106 patients with first time depression (International Classification of Diseases 10th Revision (ICD-10): F32.0) and 106 individually matched (age and sex) healthy controls. A detailed protocol paper has been published elsewhere prior to data-analyses [ 11 ]. Data on routine measurements have previously been published elsewhere [ 7 ].…”

“…Patients had a first-time diagnosis of depression (according to ICD-10: F32) diagnosed within the past year with ongoing depressive symptoms and were aged between 18 and 50 years. Patients were excluded if they had a previous psychiatric diagnosis within ICD-10 from F20 to F39, contraindications to lumbar puncture, conditions or medication with known substantial impact on the immune system, except psychotropics as needed for the current depression and as specified in the Study Protocol [ 11 ] or conditions other than depressive symptoms with impact on WHO Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview (Version 2.1) [ 12 ]. Individually age and sex matched, mentally and physically healthy controls from the same geographical area were recruited mainly by internet advertisement in the period from September 2018 to July 2021.…”

High‐quality large‐scale longitudinal studies with detailed multimodal immunological phenotyping are warranted to disentangle the involvement of the immune system in psychosis

“…Thus the research area should have a focus on multimodal analyses of immune markers including sampling from multiple tissues as the cerebrospinal fluid, blood and microbiome with longitudinal assessment of the biological markers and the relationship with clinical symptoms in order to identify more stable biomarker panels associated with psychosis that can be used for stratification. 12,13 Preferably, these analyses should be done on crossdisorder cohorts to investigate differences and similarities in the immunological profile between the mental disorders to determine specificity of the findings for the given disorder. Further, this would enable to study associations between immune markers and specific psychiatric symptoms across mental disorders to identify potential crossdisorders subgroups with common biological underpinnings.…”

“…Moreover, cytokine levels display considerable fluctuations, and thus might not be an ideal biomarker to base treatment trials on. Thus the research area should have a focus on multimodal analyses of immune markers including sampling from multiple tissues as the cerebrospinal fluid, blood and microbiome with longitudinal assessment of the biological markers and the relationship with clinical symptoms in order to identify more stable biomarker panels associated with psychosis that can be used for stratification 12,13 . Preferably, these analyses should be done on cross‐disorder cohorts to investigate differences and similarities in the immunological profile between the mental disorders to determine specificity of the findings for the given disorder.…”

“…Further, this would enable to study associations between immune markers and specific psychiatric symptoms across mental disorders to identify potential cross‐disorders subgroups with common biological underpinnings. Examples of this could be specific negative symptoms of schizophrenia and specific depression symptoms as the neurovegative symptoms 12,13 . As psychotic disorders display substantial heterogeneity on symptomatology, clinical course and prognosis, biomarkers as immune markers could show potential for stratification of patients, which is currently used in an increasing number of RCTs testing the clinical utility of different stratification methods for psychotic disorders to improve clinical outcomes and treatment response.…”