Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder (original) (raw)
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Journal of Affective Disorders, 2014
Objective: Inflammatory cytokines have been suggested to be the trait or state markers of bipolar disorder, but with inconsistent results. This may be related to small sample sizes and poor control of some important confounding factors. Methods: Gender/age-matched outpatients with bipolar disorder and normal controls were enrolled. The clinical symptoms were rated using the Montgomery Åsberg Depression Rating Scale and Young Mania Rating Scale. Inflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1), soluble P-selectin receptor (sP-selectin), and monocyte chemotactic protein-1 (MCP-1), were assessed by enzyme-linked immunosorbent assays. Results: In total, 130 patients with bipolar disorder and 130 normal subjects were enrolled. Among the patients with bipolar disorder, 77 (59.2%) had bipolar I disorder, 53 (40.8%) had bipolar II disorder; 75 (57.7%) were in a euthymic state, 14 (10.8%) were in a manic/hypomanic state, and 41 (31.5%) were in a depressive state. The 130 bipolar patients had significantly higher levels of all cytokines than the normal controls (all po 0.0001). Using multivariate regression analysis with controlling of age, gender, BMI, smoking, duration of illness, and medication grouping, the patients with bipolar II disorder had significantly lower levels of sTNF-R1 than the patients with bipolar I disorder (p¼ 0.038); the patients in a depressive state had significantly lower levels of sTNF-R1 than the patients in manic/hypomanic and euthymic states (p¼ 0.009). Conclusion: The study supported the association of bipolar disorder with inflammatory dysregulation, and sTNF-R1 may be a potential biomarker for staging bipolar disorder.
Cytokine profiles in bipolar affective disorder: Focus on acutely ill patients
Journal of Affective Disorders, 2006
Background: The role of the immune system in mood disorders is predominately supported by studies in unipolar major depression. However activation of the immune system has also been demonstrated in bipolar mania. Our study examines proinflammatory and anti-inflammatory cytokines in both phases of bipolar affective disorder (BPAD). Methods: Plasma concentrations of IL-6, IL-8, IL-10, TNF-a and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in patients with BPAD who were depressed, or manic and in healthy controls. Results: Bipolar depression had significantly higher production of the pro-inflammatory cytokines, IL-8 ( p b 0.001) and TNF-a ( p b 0.05) compared to healthy subjects. The manic group also had increased production of IL-8 ( p b 0.05) and TNF-a ( p b 0.001) as compared to healthy subjects. Anti-inflammatory cytokine levels did not differ across the 3 groups.
Bipolar Disorders, 2014
Research evidence has shown that bipolar disorder (BD) and unipolar depression (UD) are both related to inflammatory dysregulation, but few studies have compared the levels of cytokines between these two disorders. Methods: Study subjects were age-and gender-matched outpatients with BD or UD and normal controls (NC). Severities of depression and mania symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS). Pro-inflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1), soluble p-selectin receptor (sP-selectin), and monocyte chemotactic protein-1 (MCP-1), were assessed in all subjects by enzyme-linked immunosorbent assays. Results: In all, 130 patients with BD, 149 patients with UD, and 130 NC were enrolled in the study; 67.6% were female and the average age was mean AE standard deviation (SD) 43.5 AE 11.8 years. The BD group had a significantly higher smoking rate, more medical comorbidity, higher body mass index (BMI), and higher levels of sIL-2R, sIL-6R, CRP, sTNF-R1, and MCP-1 (all p < 0.01) than the UD and NC groups. When the remitted patients with BD (YMRS scores ≤ 12) were compared with the patients with UD, controlling for age, MADRS score, smoking, medical comorbidity, and BMI in the regression model, the results showed that the BD group had significantly higher levels of sIL-6R (p < 0.001), CRP (p = 0.045), sTNF-R1 (p = 0.036), and MCP-1 (p = 0.001) than the UD group. Conclusions: Higher levels of sIL-6R, CRP, sTNF-R1, and MCP-1 were noted in BD than in UD. These results may suggest a more severe inflammatory dysregulation in BD. Further studies are required to investigate whether these cytokines could be biomarkers for affective disorders.
Immuno- inflammatory markers of bipolar disorder: a review of evidence
Frontiers in Bioscience, 2012
Introduction 3. Immuno-inflammatory markers in bipolar disorder 3.1. Abnormalities of the innate and the adaptative system in bipolar disorder 3.2. C-reactive protein (crp) and bipolar disorder 3.3. Autoimmunity in bipolar disorder 3.4. The contribution of immunogenetics in bipolar disorder 4. The viral hypothesis 4.1. A winter/spring excess of birth in bipolar disorder 4.2. Viruses and bipolar disorder 5. The retroviral hypothesis: a new avenue of research? 6.
Cytokine levels in euthymic bipolar patients
Journal of affective …, 2010
Background: The pathophysiology of bipolar disorder is not thoroughly understood. Several studies have investigated the possible role of cytokines in psychiatric disorders, based on their role in neuro-immune modulation; however, findings in studies on bipolar disorder remain limited and contradictory, and most studies have focused on either manic or depressive episodes. These studies suggest that both manic and depressive episodes could be pro-inflammatory states. The present study aimed to determine whether there are enduring differences in cytokine levelsunrelated to the effects of medication-between euthymic bipolar patients and healthy controls. Methods: The study included 31 euthymic bipolar patients-16 medication-free (MF) and 15 on lithium monotherapy (LM) and 16 healthy volunteers in whom serum cytokine levels were measured. The 3 groups were homogenous in terms of age, gender, and ethnicity. IFN-γ, TNF-α, IL-2, IL-4, IL-5, and IL-10 levels were measured in all groups using flow cytometry. Results: There were no differences in cytokine levels between MF euthymic bipolar patients and healthy controls. TNF-α and IL-4 levels in LM euthymic bipolar patients were higher than in both the MF euthymic bipolar patients and controls. Limitations: The small and strictly selected study sample could limit the generalizability of the findings. Conclusions: Cytokine production in MF euthymic bipolar patients was similar to that in healthy controls. The present study shows that the pro-inflammatory state resolves in euthymia and that lithium had an influence on the cytokine profile, which could create a confounding factor while investigating disease-related immunopathology of bipolar disorder.
Immunologic variables in acute mania of bipolar disorder
Journal of Neuroimmunology, 2004
Macrophages, lymphocytes and their products, may be involved in the pathophysiology of psychiatric disorders. The cell-mediated immune activation response of manic patients during pre-medication and medication stages remains unclear. The purpose of this case-control study was to investigate the plasma levels of immunologic variables, including interleukin (IL)-1 receptor antagonist (IL-1RA), soluble CD 4 (sCD4) and sCD8, and TH1 (interferon [IFN]-g and IL-2) and TH2 (IL-4 and IL-10) cytokines in patients with pre-medicated, medicated bipolar mania. The study subjects, aged 16-44 years, were physically healthy patients with Young Mania Rating Scale (YMRS) scores z 26, and normal controls, aged 19-40 years, were matched for sex. The immune variables were measured in acute mania and in consequent remission (YMRS scores V 12) among bipolar patients. The plasma levels of IL-1RA, sCD4, and sCD8 were found significantly increased in pre-medicated acute manic patients as compared to normal controls. But only IL-1RA and sCD8 were found different in remitted bipolar patients as compared to normal controls. For TH1 cytokines, culture supernatant level of IFN-g was found significantly lower in manic patients of both acute and remission stages as compared to normal controls. No significant difference was found in IL-2 level in premedicated acute manic patients compared to controls. For TH2 cytokines, no significant differences in IL-4 and IL-10 levels were observed. We showed that cell-mediated immune response was activated in patients with bipolar disorder during the pre-medication, medication, and the remission stages. Our study findings suggest that the immune-modulation in patients with bipolar disorder may be abnormal.
Revista Brasileira de Psiquiatria, 2011
Objective: Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. Method: Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. Results: IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. Discussion: These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response. Resumo Objetivo: Pesquisas sugerem as citocinas como potenciais mediadores da interação entre os sistemas imune e neuroendócrino, e que existe um estado pró-inflamatório associado com transtorno bipolar e esquizofrenia. O objetivo deste estudo é comparar os níveis de citocinas entre os dois distúrbios. Método: Vinte pacientes com transtorno bipolar eutímicos, 53 pacientes com esquizofrenia crônica estabilizados e 80 controles saudáveis foram recrutados. Todos os indivíduos eram não-fumantes e não-obesos. As citocinas TNF-α, IL-6 e IL-10 foram examinadas por ELISA sanduíche. Resultados: A IL-6 estava aumentada nos pacientes com esquizofrenia quando comparados aos controles (p < 0,0001) e aos pacientes bipolares eutímicos (p < 0,0001). Os níveis de IL-6 não foram diferentes nos controles em comparação com pacientes com transtorno bipolar eutímicos (p = 0,357). Os níveis de IL-10 foram menores nos controles quando comparados aos pacientes com esquizofrenia (p = 0,001) ou aos bipolares (p = 0,004). Não houve diferença significativa nos níveis séricos de TNF-α entre os grupos (p = 0,284). A separação por sexo não mostrou diferenças significativas e não houve correlação entre a dose de antipsicóticos e os níveis de citocinas em pacientes com esquizofrenia. Discussão: Estes resultados evidenciam uma ativação imune crônica na esquizofrenia. O transtorno bipolar parece apresentar um aumento da atividade inflamatória relacionado ao episódio de humor. Níveis maiores de IL-10 no transtorno bipolar e esquizofrenia sugerem diferentes padrões de equilíbrio inflamatório entre esses dois transtornos. Resultados fornecem apoio adicional para a investigação de citocinas como possíveis biomarcadores para a atividade da doença ou resposta ao tratamento. Descritores: Transtorno bipolar; Esquizofrenia; Interleucina-6; Interleucina-10; Fator de necrose tumoral alfa Revista Brasileira de Psiquiatria • vol 33 • nº 3 • set2011 • 268 Kunz M et al. 269 • Revista Brasileira de Psiquiatria • vol 33 • nº 3 • set2011
Bipolar disorders, 2015
Abnormalities of protein levels of proinflammatory cytokines and their soluble receptors have been reported in plasma of patients with bipolar disorder (BP). In this study, we tested the hypothesis that the mRNA expression of membrane-bound receptors for proinflammatory cytokines will be altered in the lymphocytes of patients with BP. We determined protein and mRNA expression of proinflammatory cytokines, and mRNA expression of their receptors in the lymphocytes from 29 drug-free, hospitalized patients with BP and 30 drug-free normal control subjects. The subjects were diagnosed according to DSM-IV criteria. Plasma protein levels of cytokines were determined by enzyme-linked immunosorbent assay (ELISA); mRNA levels in lymphocytes were determined by the quantitative polymerase chain reaction (qPCR) method. We found that mean mRNA levels of the proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and their receptors TNFR1, IL-1R1, and the antagonist I...