Original ArticleInflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review
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
References (102)
- et al.
Cytokines and chemokines
J Allergy Clin Immunol
(2006) - et al.
Expanding the effector CD4 T-cell repertoire: The Th17 lineage
Curr Opin Immunol
(2006) - et al.
Understanding the IL-23-IL-17 immune pathway
Trends Immunol
(2006) - et al.
The Th2-hypothesis of schizophrenia: A strategy to identify a subgroup of schizophrenia caused by immune mechanisms
Med Hypotheses
(2001) - et al.
T-helper-1 and T-helper-2 responses in psychiatric disorders
Brain Behav Immun
(2001) - et al.
Cytokine production in drug-free and neuroleptic-treated schizophrenic patients
Biol Psychiatry
(1995) - et al.
Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics
Eur Neuropsychopharmacol
(2000) Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration
Schizophr Res
(1999)- et al.
Serum interleukin-6 in schizophrenic patients
Life Sci
(1991) - et al.
Lymphocytes as a neural probe: Potential for studying psychiatric disorders
Prog Neuropsychopharmacol Biol Psychiatry
(2004)
Mechanism of inhibition of tumor necrosis factor production by chlorpromazine and its derivatives in mice
Eur J Pharmacol
In vitro cytokine secretion in individuals with schizophrenia: results, confounding factors, and implications for further research
Brain Behav Immun
Meta-analysis in clinical trials
Control Clin Trials
Serum cytokine concentrations in patients with schizophrenia
Schizophr Res
Cytokines production in chronic schizophrenia patients with or without paranoid behaviour
Prog Neuropsychopharmacol Biol Psychiatry
Cytokine profiles in drug-naive schizophrenic patients
Schizophr Res
Cytokine profiles in schizophrenic patients treated with risperidone: A 3-month follow-up study
Prog Neuropsychopharmacol Biol Psychiatry
Interleukin-1 alpha and interleukin-2 in cerebrospinal fluid of schizophrenic subjects
Prog Neuropsychopharmacol Biol Psychiatry
Decreased interleukin-2 production in schizophrenic patients
Biol Psychiatry
Serum interleukin-6 concentration in schizophrenia: Elevation associated with duration of illness
Psychiatry Res
Abnormalities in serum concentrations of interleukin-2, interferon-alpha and interferon-gamma in schizophrenia not detected
Schizophr Res
Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: Effects of confounding factors and diagnosis
J Psychiatr Res
Decreased interleukin-2 production in Korean schizophrenic patients
Biol Psychiatry
Relationships between interleukins, neurotransmitters and psychopathology in drug-free male schizophrenics
Schizophr Res
Th1, Th2 and Th3 cytokine alteration in schizophrenia
Prog Neuropsychopharmacol Biol Psychiatry
Neuroleptics normalize increased release of interleukin- 1 beta and tumor necrosis factor-alpha from monocytes in schizophrenia
Schizophr Res
The inflammatory response system in treatment-resistant schizophrenia: Increased serum interleukin-6
Schizophr Res
Interleukin-2 and interleukin-6 in schizophrenia and mania: Effects of neuroleptics and mood stabilizers
J Psychiatr Res
In vivo immunomodulatory effects of clozapine in schizophrenia
Schizophr Res
Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor
Schizophr Res
Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: Effects of antipsychotic drugs
Schizophr Res
Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: Effects of clozapine treatment
Psychiatry Res
Elevated circulating levels of IL-6 in schizophrenia
Schizophr Res
Increased production of interleukin-2 (IL-2) but not soluble interleukin-2 receptors (sIL-2R) in unmedicated patients with schizophrenia and schizophreniform disorder
Psychiatry Res
Increased serum soluble interleukin-2 receptors in Caucasian and Korean schizophrenic patients
Biol Psychiatry
Production of cytokines in acute schizophrenic psychosis
Biol Psychiatry
No evidence for autoimmunity in schizophrenia
J Autoimmun
Effect of neuroleptic administration on serum levels of soluble IL-2 receptor-alpha and IL-1 receptor antagonist in schizophrenic patients
Psychiatry Res
Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients
Schizophr Res
Elevated interleukin-6 in schizophrenia
Psychiatry Res
Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: Association with psychopathology
Schizophr Res
Schizophrenia and rheumatoid arthritis: A review
Schizophr Res
A population-based register study of the association between schizophrenia and rheumatoid arthritis
Schizophr Res
In utero infection and adult schizophrenia
Ment Retard Dev Disabil Res Rev
Association of schizophrenia and autoimmune diseases: Linkage of Danish national registers
Am J Psychiatry
Cytokines and the brain: Implications for clinical psychiatry
Am J Psychiatry
Brain-immune system interaction: Relevance to the pathophysiology and treatment of neuropsychiatric disorders
The many worlds of reducing interleukin-1
Arthritis Rheum
Two types of murine helper T cell cloneI. Definition according to profiles of lymphokine activities and secreted proteins
J Immunol
Diversification of T-helper-cell lineages: Finding the family root of IL-17-producing cells
Nat Rev Immunol
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