TY - JOUR

T1 - Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders

T2 - a systematic review and meta-analysis

AU - Orlovska-Waast, Sonja

AU - Köhler-Forsberg, Ole

AU - Brix, Sophie Wiben

AU - Nordentoft, Merete

AU - Kondziella, Daniel

AU - Krogh, Jesper

AU - Benros, Michael Eriksen

N1 - Correction to: Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. DOI: 10.1038/s41380-019-0381-9

PY - 2019

Y1 - 2019

N2 - Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942–2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.62; 95% CI 0.24–1.00) and affective disorders (4 studies [302 patients]; SMD = 0.43; 95% CI 0.25–0.61, I2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.38; 95% CI 0.12–0.65, I2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.77; 95% CI 0.36–1.18, I2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.60; 95% CI 0.23–0.98), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = −0.62; 95%CI −1.13 to −0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.38; 95% CI 0.02–0.74; I2 = 64%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17–0.75, I2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2–6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.

AB - Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942–2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.62; 95% CI 0.24–1.00) and affective disorders (4 studies [302 patients]; SMD = 0.43; 95% CI 0.25–0.61, I2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.38; 95% CI 0.12–0.65, I2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.77; 95% CI 0.36–1.18, I2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.60; 95% CI 0.23–0.98), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = −0.62; 95%CI −1.13 to −0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.38; 95% CI 0.02–0.74; I2 = 64%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17–0.75, I2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2–6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.

UR - https://www.nature.com/articles/s41380-019-0381-9

U2 - 10.1038/s41380-018-0220-4

DO - 10.1038/s41380-018-0220-4

M3 - Review

C2 - 30116031

AN - SCOPUS:85052542563

VL - 24

SP - 869

EP - 887

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 6

ER -