Elsevier

Biological Psychiatry

Volume 63, Issue 8, 15 April 2008, Pages 801-808
Biological Psychiatry

Original Article
Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review

https://doi.org/10.1016/j.biopsych.2007.09.024Get rights and content

Background

Cytokines play an important role in infection and inflammation and are crucial mediators of the cross-talk between the brain and the immune system. Schizophrenia would be associated with an imbalance in inflammatory cytokines, leading to a decrease in Th1 and an increase in Th2 cytokine secretion. However, data published so far have been inconsistent. The primary objective of the present meta-analysis was to verify whether the cytokine imbalance hypothesis of schizophrenia is substantiated by evidence.

Methods

Cross-sectional studies were included if they assessed in vivo plasma or serum cytokine concentrations and/or in vitro secretion of cytokines by peripheral blood leukocytes from schizophrenia patients and healthy volunteers.

Results

Data from 62 studies involving a total sample size of 2298 schizophrenia patients and 1858 healthy volunteers remained for analysis. Ten cytokines were assessed, including the prototypic Th1 and Th2 cytokines gamma interferon (IFN-γ) and interleukin 4 (IL-4) as well as IL-2, soluble IL-2 receptor (sIL-2R), IL-1β, IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha (TNF-α), IL-6, soluble IL-6 receptor (sIL-6R), and IL-10. The results show that an increase occurs in in vivo IL-1RA, sIL-2R, and IL-6 and a decrease occurs in in vitro IL-2 in schizophrenia. No significant effect sizes were obtained for the other cytokines.

Conclusions

These findings provide the first evidence of establishment of an inflammatory syndrome in schizophrenia, which refutes the current hypothesis of a Th2 slant. Caveats are presented to data interpretation, including the role of stress and the effect of weight gain that develops in schizophrenia.

Section snippets

Data Sources

A search of computerized literature databases (PubMed and EMBASE) was conducted, with the following key words: “schizophrenia,” “cytokine,” “interleukin,” “interferon,” and “tumor necrosis factor.” Studies were also identified by cross-referencing of included studies. A consensus has been reached among authors on the studies retained or discarded, on the basis of the following inclusion and exclusion criteria.

Study Selection

Inclusion criteria were: 1) patients with a schizophrenia spectrum disorder:

Study Characteristics

A total of 544 studies were identified; 457 studies were rejected for the following reasons: 1) type of article (e.g., review, letter, case report; 223 studies); 2) methodology (e.g., no control group, immunoglobulin assessment; 92 studies); 3) study population (e.g., depression, bipolar mania, twin subjects; 57 studies); 4) type of study (e.g., immunotherapy, genetic study; 75 studies); 5) cytokines were measured in the cerebrospinal fluid; 4 studies); and 6) foreign language (6 studies).

Discussion

The current meta-analysis was conducted to verify whether the cytokine imbalance and Th2 predominance hypotheses of schizophrenia are substantiated by evidence. The results suggest an increase in in vivo peripheral levels of IL-1RA, sIL-2R, and IL-6 and a decrease in in vitro IL-2 secretion in schizophrenia patients. No significant effect sizes were obtained for IFN-γ, IL-4, IL-1β, TNF-α, sIL-6R, and IL-10. The absence of significant changes of IFN-γ and IL-4 does not support the Th2 shift

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