Although differences in IL-6 amounts were not statistically significant, increased levels in patients were observed compared to healthy volunteers. PubMed and Google Scholar search without restrictions was conducted for articles that reported on cytokine levels in CSF in patients with an SSD compared to healthy controls. Our original data revealed statistically significant increases in levels of interleukin-8 (IL-8) and interleukin-1 beta (IL-1) in the CSF of patients with an SSD compared to healthy volunteers. Our meta-analysis showed statistically significant increases in interleukin-6 (IL-6) and IL-8 in patients compared to healthy volunteers. Effect sizes between treated and untreated patients for IL-6 were of comparable magnitude. However, IL-6 levels were higher in early stage schizophrenia patients compared to chronic schizophrenia patients. Studies with larger sample sizes, comprehensive assessments and ideally in the context of a randomized controlled intervention to minimize the impact of confounding factors are needed to fully understand the role of cytokines and inflammatory markers in the pathophysiology and treatment of schizophrenia. strong class=”kwd-title” Keywords: cytokines, schizophrenia, cerebrospinal fluid, inflammation 1.?Introduction Several lines of evidence suggest that dysfunction in inflammatory processes may be implicated in the pathophysiology of schizophrenia. First, large epidemiological studies have found an association between maternal infections during pregnancy, such as influenza and rubella, and schizophrenia in offspring (Buka et al., 2001; Limosin et al., Reboxetine mesylate 2003). Though the mechanism linking contamination and schizophrenia is Reboxetine mesylate usually uncertain, the leading hypothesis involves the release of maternal cytokines to the fetus via the placenta, leading to abnormal fetal brain development (Brown and Patterson, 2011). Second, recent GWAS studies have consistently shown genome-wide significant associations between schizophrenia and single nucleotide polymorphisms in a large locus on chromosome 6 that includes the major histocompatibility complex, a group of key molecules involved in the inflammatory response (Ripke et al., 2014). A follow-up analysis of this region showed that genetic variation of the complement component 4 (C4) gene, which codes for a protein involved in the classical activation pathway of the complement system, causes greater expression of C4a alleles, and in turn, increased risk for schizophrenia (Sekar et al., 2015). Third, the availability of Food and Drug Administration-approved non-steroidal anti-inflammatory medications like celecoxib and aspirin for the use in pain and other inflammatory conditions has facilitated the investigation of these medications as add-on treatments to antipsychotic medications in schizophrenia, with the effect of modest improvement of psychotic symptoms in individuals with early stage psychosis (Sommer et al., 2014). Further work in support of the hypothesis has been conducted by the examination of peripheral biomarkers of inflammation, such as cytokines, in the blood and cerebrospinal fluid (CSF) of people with schizophrenia (Barak et al., 1995; Coughlin et al., 2016; Garver et al., 2003; Hayes et al., 2014). For example, Miller and colleagues completed a meta-analysis of cytokine alterations in blood and CSF of patients with schizophrenia (Miller et al., 2011). Blood analysis showed increases in IL-1, IL-6 and transforming growth factor- (TGF-) in acute relapsed patients and first episode patients compared Reboxetine mesylate to healthy controls. CSF analysis GLURC showed decreased levels of IL-1 in patients compared to controls and no differences in other cytokines. Comparable results were found by Upthegrove and colleagues, who subsequently completed a meta-analysis focusing on cytokine levels in the blood of medication-naive first-episode individuals and found significant elevation in pro-inflammatory cytokines IL-1, sIL-2r, IL-6, and TNF- (Upthegrove et al., 2014). Despite early results by Miller and colleagues indicating a decrease in IL-1 in CSF, a subsequent meta-analysis by Wang and Miller found increased levels of IL-1, in addition to increased levels of IL-6 and IL-8, in the CSF of patients with schizophrenia (Miller et al., 2011; Wang and Miller, 2018). While several studies have identified cytokine profiles in the blood of patients with schizophrenia spectrum disorders (SSD) compared to healthy controls, fewer studies have been conducted to compare cytokine profiles in CSF. Given that CSF is in direct contact with the brain, it may be that inflammatory abnormalities in brain tissue are more closely reflected in CSF as compared Reboxetine mesylate to peripheral blood. Further, although blood and CSF are both sources of peripheral cytokine levels, the transportation of cytokines across the blood brain barrier is conducted by transporters that are specific for unique families of cytokines and can be affected by a variety of factors like circadian rhythm, brain disease or injury (Banks, 1995; Banks et al., 2009). Although evidence suggests blood brain barrier dysfunction in schizophrenia (Vasic et al., 2012) it is yet unclear how blood brain barrier dysfunction may affect cytokine levels in cerebrospinal fluid compared to peripheral blood. For these reasons, we hypothesized that there is a unique Reboxetine mesylate cytokine profile in CSF that may provide a better understanding of how inflammation affects the central nervous.