Abstract
BackgroundA 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.MethodsA 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.DiscussionThis 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 registrationThe 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).
Highlights
A proinflammatory response has been suggested to be involved in the pathophysiology of depression in a subgroup of patients
Study aims The aim of this study is to identify neuroinflammatory alterations that contribute to the development of depression by longitudinal examinations of cerebrospinal fluid (CSF), blood and gut microbiota together with thorough psychopathological and neurological examination leading to a more detailed understanding of the interplay between the immune system and the brain
If all values are observed above the lower limit of quantification (LLOQ), we expect the power for CSF/serum albumin ratio and CSF total protein to be high (95% or higher), whereas the power for immunoglobulin G (IgG) index and CSF total White cell count (WCC) are expected to be low (< 50%) though effect sizes in previous studies are heterogenic
Summary
A proinflammatory response has been suggested to be involved in the pathophysiology of depression in a subgroup of patients. Blood C-reactive protein (CRP) levels have been associated with symptom severity in women [9], and meta-analyses of placebo controlled randomized controlled trials (RCTs) with anti-inflammatory treatment have shown beneficial effects on depression and depressive symptoms [10, 11]. Together, these findings indicate that a proinflammatory or dysfunctional immunological activation can contribute to the development of depression in a subgroup of patients
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