Table 1 Publication plan

Neuroinflammation study

Primary

Cerebrospinal fluid (CSF) total white cell count (WCC), CSF/serum albumin ratio, CSF total protein, and immunoglobulin G (IgG) index

CSF total WCC is one of the most valuable CSF markers in regards of inflammation [31], but to our knowledge not yet investigated by more precise methods than standard analysis in the context of depression. Standard analysis has the disadvantage that a cell count < 3-5 will not usually be reported leading to interpretation difficulties of small differences in WCC. However, such differences could very well be of importance when investigating low grade inflammation. Increased blood-brain-barrier (BBB) permeability can be related to neuroinflammation [15], and the best marker hereof is CSF/serum albumin ratio [32]. CSF total protein is also increased due to BBB impairment, but is, less specifically however, increased in a broad variety of neurological diseases [33]. IgG index is often used to screen for inflammatory central nervous system (CNS) diseases and reflects intrathecal IgG production [21].

Secondary

CSF WCC differential count, CSF neutrophil/lymphocyte ratio, CSF/serum IgG ratio, and CSF/plasma glucose ratio

Depending on the degree and predominant cell type, CSF pleocytosis is seen in a variety of brain disorders, both infectious and non-infectious [12]. The ratio between neutrophils and lymphocytes is a marker of inflammation and has been found elevated in blood among patients with depression compared to healthy controls [34]. Increased CSF/serum IgG might reflect increased IgG production within tectum [16]. Severe CNS infections can decrease CSF/plasma glucose ratio [12].

CSF cytokine and chemokine profile study

Primary

CSF interleukin (IL-6) and interleukin-8 (IL-8)

The innate immune system is hypothesized to play an important role in the pathophysiology of depression with IL-6 as an important marker of this type of inflammation [3], while IL-8 is mainly involved in diapedeses and chemotaxis of leukocytes [35]. A recent meta-analysis revealed a significant increase in IL-6 and IL-8 in CSF from patients with depression compared to controls, but also revealed how most previous studies had small sample sizes and conflicting results [13].

Secondary

ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12/IL-23p40, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC, TNF-α, TNF-β

To exploratively investigate contrasts between groups, a broad cytokine panel analysis will be carried out.

CNS-reactive autoantibody study

Primary

Any CSF CNS-reactive antibody of either glutamate receptor (type NMDA), glutamate receptor (type AMPA1), glutamate receptor (type AMPA2), CASPR2, LGI1, GABA B receptor or GAD65 in 1) CSF or 2) CSF or blood.

There is a well-established association between autoimmune disorders and depression [4] and also an overlap between the symptomatology of autoimmune and depressive disorders [23]. No previous studies have investigated CNS-reactive autoantibodies in CSF from patients with depression compared to healthy controls [24].

Secondary

Specific CSF CNS-reactive antibodies in CSF and/or blood.

The specific prevalence of the above-mentioned CNS-reactive autoantibodies in CSF and/or blood will provide a thorough characterization of the humoral response towards CNS.