Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status

McAllister, Cathy G.; Kammen, Daniël P. van; Rehn, Terri; Miller, Alan L.; Gurklis, John A.; Kelley, Mary E.; Yao, Jeffrey; Peters, Jeffrey L.

doi:10.1176/ajp.152.9.1291

Cited by 178 publications

(21 citation statements)

References 47 publications

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“…Polymorphisms of the IL-1 gene complex have been associated with schizophrenia (Xu and He, 2010) and, specifically, ventricular enlargement (Papiol et al, 2005). High levels of pro-inflammatory cytokines such as IL-1β, IL-6, and IL-2 have also been observed in the CSF of patients with schizophrenia, further supporting this effect (Garver et al, 2003; McAllister et al, 1995; Soderlund et al, 2009). …”

Section: Systemic Inflammation Neuroinflammation and Neuroprogrementioning

confidence: 76%

Viral infection, inflammation and schizophrenia

Kneeland

Fatemi

2013

Progress in Neuro-Psychopharmacology and Biological Psychiatry

129

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Schizophrenia is a severe neurodevelopmental disorder with genetic and environmental etiologies. Prenatal viral/bacterial infections and inflammation play major roles in the genesis of schizophrenia. In this review, we describe a viral model of schizophrenia tested in mice whereby the offspring of mice prenatally infected with influenza at E7, E9, E16, and E18 show significant gene, protein, and brain structural abnormalities postnatally. Similarly, we describe data on rodents exposed to bacterial infection or injected with a synthetic viral mimic (PolyI:C) also demonstrating brain structural and behavioral abnormalities. Moreover, human serologic data has been indispensible in supporting the viral theory of schizophrenia. Individuals born seropositive for bacterial and viral agents are at a significantly elevated risk of developing schizophrenia. While the specific mechanisms of prenatal viral/bacterial infections and brain disorder are unclear, recent findings suggest that the maternal inflammatory response may be associated with fetal brain injury. Preventive and therapeutic treatment options are also proposed. This review presents data related to epidemiology, human serology, and experimental animal models which support the viral model of schizophrenia.

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Section: Systemic Inflammation Neuroinflammation and Neuroprogrementioning

confidence: 76%

Viral infection, inflammation and schizophrenia

Kneeland

Fatemi

2013

Progress in Neuro-Psychopharmacology and Biological Psychiatry

129

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“…Thus, given the efficacy of adjunctive NSAIDs in improving psychopathology in relapsed patients (7-11), these findings support the plausibility of the hypothesis that immune changes are not a merely artifact of increased stress associated with acute psychosis, but may play a role in the pathophysiology of relapse in schizophrenia. In addition to the association between monocytosis and worsening psychosis mentioned above (28), other studies have found that intra-individual changes in other immune parameters, including CSF IL-2 levels and in vitro IL-2 production may predict relapse in some patients (77,78). Further investigation of potential relapse predictive markers is needed.…”

Section: Discussionmentioning

confidence: 92%

Meta-Analysis of Lymphocytes in Schizophrenia: Clinical Status and Antipsychotic Effects

Miller

Gassama

Sebastian

et al. 2013

Biological Psychiatry

200

126

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Background Schizophrenia is associated with immune system dysfunction, including abnormal blood immune cell parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment following an acute exacerbation of psychosis. Methods We identified articles by searching Pub Med, PsychInfo, and ISI, and the reference lists of identified studies. Results Sixteen studies of blood lymphocytes met the inclusion criteria. There was insufficient data for a meta-analysis of the mononuclear phagocytic system. In cross-sectional studies, there was a significant increase in the CD4% and CD56% in acutely relapsed inpatients (AR). Absolute levels of total lymphocytes, CD3, and CD4, and the CD4/CD8 ratio were significantly increased, and the CD3% was significantly decreased in drug-native first-episode psychosis (FEP). In longitudinal studies, the CD4/CD8 ratio appeared to be state-related markers, as it decreased following antipsychotic treatment for acute exacerbations of psychosis. Absolute CD56 levels appeared to be a trait marker, as levels significantly increased following antipsychotic treatment for relapse. Discussion Blood lymphocyte abnormalities in drug-naïve FEP suggest an effect that may be independent of antipsychotic medications. While some parameters (CD4/CD8) may be state markers for acute exacerbations of psychosis, others (CD56) may be trait markers, however more longitudinal studies are needed. Although these findings could provide the basis for future hypothesis testing, a relatively small number of studies and subjects, lack of correlative data with clinical features, and inadequate consideration of potential confounding factors limit the results.

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“…Within schizophrenia, in a study of 36 patients who underwent weekly assessments for 1 year, in vitro IL-2 production plus antihippocampal immunoglobulin G levels from the previous week significantly predicted relapse in three of seven patients (102). Similarly, in a study of 64 male subjects with schizophrenia, increased CSF IL-2 levels following haloper-idol withdrawal were a significant predictor of acute psychotic relapse (78). Our finding of significant alterations in cytokine (and cytokine receptor and antagonist) levels in acute illness exacerbations, measured within days of admission, that start to normalize following antipsychotic treatment support the plausibility of cytokine levels as a putative state-related marker for acute psychosis.…”

Section: Discussionmentioning

confidence: 98%

Meta-Analysis of Cytokine Alterations in Schizophrenia: Clinical Status and Antipsychotic Effects

Miller

Buckley

Seabolt

et al. 2011

Biological Psychiatry

1,487

1,221

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Background Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. Methods We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. Results Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP (p.001 for each) and normalized with antipsychotic treatment (p.001, p.008, and p.005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p.69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls (p.01). Conclusions Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1β, IL-6, and TGF-β) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking.

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Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status

Cited by 178 publications

References 47 publications

Viral infection, inflammation and schizophrenia

Viral infection, inflammation and schizophrenia

Meta-Analysis of Lymphocytes in Schizophrenia: Clinical Status and Antipsychotic Effects

Meta-Analysis of Cytokine Alterations in Schizophrenia: Clinical Status and Antipsychotic Effects

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