Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue

Background: Increased peripheral inflammation has been consistently reported in patients with major depressive disorder (MDD). However, only few studies have explored markers of central (brain) inflammation in patients with MDD. The aim of this study is to systematically review in vivo and post-mortem markers of central inflammation, including studies examining cerebrospinal fluid (CSF), positron emission tomography, and post-mortem brain tissues in subjects suffering with MDD compared with controls. Methods: PubMed and Medline databases were searched up to December 2018. We included studies measuring cerebrospinal fluid (CSF) cytokines and chemokines, positron emission tomography (PET) studies; and postmortem studies measuring cytokines, chemokines and cell-specific markers of microglia and astrocytes, all in MDD. A meta-analysis was performed only for CSF and PET studies, as studies on post-mortem markers of inflammation had different cell-specific markers and analysed different brain regions. Results: A total of 69 studies met the inclusion criteria. CSF levels of IL-6 and TNF-alpha were higher in patients with MDD compared with controls (standardised mean difference SMD 0.37, 95%CI: 0.17-0.57 and SMD 0.58, 95%CI 0.26-0.90, respectively). CSF levels of IL-6 were increased in suicide attempters regardless of their psychiatric diagnosis. Translocator protein, a PET marker of central inflammation, was elevated in the anterior cingulate cortex and temporal cortex of patients with MDD compared with controls (SMD 0.78, 95%CI: 0.41-1.16 and SMD 052, 95%CI: 0.19-0.85 respectively). Abnormalities in CSF and PET inflammatory markers were not correlated with those in peripheral blood. In post-mortem studies, two studies found increased markers of microglia in MDD brains, while four studies found no MDD related changes. Of the studies investigating expression of cell-specific marker for astrocytes, thirteen studies reported a decreased expression of astrocytes specific markers, two studies reported increased expression of astrocytes specific markers, and eleven studies did not detect any difference. Four out of six studies reported decreased markers of oligodendrocytes in the prefrontal cortex. Post-mortem brain levels of tumor necrosis alpha (TNF-alpha) were also found increased in MDD. Conclusions: Our review suggests the presence of an increase in IL-6 and TNF-alpha levels in CSF and brain parenchyma, in the context of a possible increased microglia activity and reduction of astrocytes and oligodendrocytes markers in MDD. The reduced number of astrocytes may lead to compromised integrity of blood brain barrier with increased monocyte recruitment and infiltration, which is partly supported by post-mortem studies and by PET studies showing an increased TSPO expression in MDD.