Elevated Interleukin-6 in the Cerebrospinal Fluid of a Previously Delineated Schizophrenia Subtype

Garver, David L.; Tamas, Rebecca L.; Holcomb, Jennifer

doi:10.1038/sj.npp.1300217

Cited by 133 publications

(73 citation statements)

References 36 publications

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“…Similar increases in inflammatory cytokines and acute-phase reactants have also been reported in patients with bipolar disorder and schizophrenia, including meta-analyses (Goldsmith et al, 2016b;Miller et al, 2011;Potvin et al, 2008). Increased inflammatory cytokine concentrations in the cerebrospinal fluid (CSF) of patients with unipolar and bipolar depression, and schizophrenia have also been observed (Garver et al, 2003;Levine et al, 1999;Schwieler et al, 2015;Soderlund et al, 2011;Soderlund et al, 2009). In MDD, CSF cytokines have been shown to be associated with the severity of depression or with the change in symptoms in response to successful treatment (Levine et al, 1999;Lindqvist et al, 2009;Martinez et al, 2012).…”

Section: Increased Inflammation In Psychiatric Disordersmentioning

confidence: 66%

“…In MDD, CSF cytokines have been shown to be associated with the severity of depression or with the change in symptoms in response to successful treatment (Levine et al, 1999;Lindqvist et al, 2009;Martinez et al, 2012). In schizophrenia, increased cytokines have been associated with delayed treatment response (Garver et al, 2003), and in bipolar disorder, they are higher in patients that have had more recent manic or hypomanic episodes (Soderlund et al, 2011).…”

Section: Increased Inflammation In Psychiatric Disordersmentioning

confidence: 99%

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Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Felger

Treadway

2016

Neuropsychopharmacol

301

237

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Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation.

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Section: Increased Inflammation In Psychiatric Disordersmentioning

confidence: 66%

Section: Increased Inflammation In Psychiatric Disordersmentioning

confidence: 99%

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Felger

Treadway

2016

Neuropsychopharmacol

301

237

View full text Add to dashboard Cite

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“…A combination of genetic and environmental factors resulting in some immune dysregulation in general and the lack of the CMV IgG antibodies in particular could be the most plausible speculations. While there are no specific research results supporting this finding in existing literature, the activation of the immune system and prolonged neuroinflammation are well established phenomena implicated in the etiopathogenesis and symptomatology of schizophrenia (Lin et al, 1998;Nikkila et al, 1999;Kim et al, 2000;Theodoropoulou et al, 2001;Ebrinc et al, 2002;Patterson, 2002;Zhang et al, 2002;Garver et al, 2003;Zhang et al, 2004;Coelho et al, 2008;Potvin et al, 2008;Doorduin et al, 2009;Kim et al, 2009;Song et al, 2009;Drexhage et al, 2010;Romero et al, 2010;Drexhage et al, 2011;Weigelt et al, 2011;Beumer et al, 2012;Brito-Melo et al, 2012). Other mechanisms could also be considered.…”

Section: Discussionmentioning

confidence: 83%

Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel

Li¹,

Weber²,

Fisher³

et al. 2013

Schizophrenia Research

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a b s t r a c t a r t i c l e i n f oIntroduction: Multiple studies have documented immune activation in many individuals with schizophrenia suggesting that antigens capable of generating a prolonged immune response may be important environmental factors in many cases of this disorder. While existing studies have found single-agent associations of antibodies to food and neurotropic infectious agents with schizophrenia, a simultaneous examination of multiple agents may shed light on agent interactions or possible etiopathogenic pathways. Methods: We used traditional regression and novel statistical techniques to examine associations of single and combined infectious and food antigens with schizophrenia. We tested 6106 serum samples from 855 cases and 1165 matched controls. Results: Higher antibody levels to casein were borderline significant in the prediction of schizophrenia (HR = 1.08, p = 0.06). Study participants with higher cytomegalovirus (CMV) IgG antibody levels had a reduced risk of developing schizophrenia (HR = 0.90; p = 0.02). While IgG antibodies to gliadin, Toxoplasma gondii, vaccinia, measles, and human herpesvirus-6 (HHV-6) showed no significant independent associations with schizophrenia, the increase in antibody levels to several combinations of agents, to include casein, measles, CMV, T. gondii and vaccinia, was predictive of an 18-34% increase in the risk of developing schizophrenia. Conclusion: Certain patterns of antibodies, involving some agents, were predictive of developing schizophrenia, with the magnitude of association rising when the level of antibodies increased to two or more agents. A heightened antibody response to a combination of several infectious/food antigens might be an indicator of an altered immune response to antigenic stimuli.Published by Elsevier B.V.

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“…13 A few studies have also shown that CSF IL 6 is elevated in patients with chronic schizophrenia. 14,15 Al though evidence of immune activation in schizophrenia is emerging, its functional relationship to aberrant brain neuro transmission and behaviour has been unclear. Activation of the kynurenine (KYN) pathway has been suggested as a mech anism serving to transfer information from the immune sys tem of the brain to neurons.…”

Section: Introductionmentioning

confidence: 99%

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Schwieler

Larsson

Skogh

et al. 2015

jpn

180

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IntroductionThe role of immune activation in schizophrenia has received increasing interest in recent years. Epidemiological studies have shown that infections and autoimmune diseases are clin ic ally important risk factors for the development of schizo phrenia. [1][2][3] Furthermore, a recent study integrating results from a meta analysis of genome wide association studies in schizophrenia found that the most significant changes were observed in genetic loci related to the immune system. 4 Also, patients with schizophrenia show microglial activation, as re vealed by positron emission tomography. 5,6 Further, postmor tem studies using messenger RNA (mRNA) expression or im munohistochemical detection have shown increased levels of immune related compounds. 7-9 A number of investigations have focused on cytokines, but these studies have not yielded a unanimous picture, possibly because of a number of con founding factors, such as smoking and dietary habits, body mass index (BMI), type and duration of antipsychotic treat ment and drug abuse -all factors potentially affecting the Background: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. Methods: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were ana lyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. Results: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. Limitations: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. Conclusion: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-d-aspartate receptor antagonist KYNA in patients with schizophrenia.

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Elevated Interleukin-6 in the Cerebrospinal Fluid of a Previously Delineated Schizophrenia Subtype

Cited by 133 publications

References 36 publications

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

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