Immuno- inflammatory markers of bipolar disorder: a review of evidence (original) (raw)
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Background: Recently, a growing number of publications have suggested that the immune-inflammatory system may be involved in the etiology of bipolar disorder (BD). Objective: The aim of this study was to investigate neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and red cell distribution width (RDW) in the three different phases of BD patients compared to each other and controls. Methods: One hundred eighty-seven bipolar patients (78 euthymic, 53 manic/hypomanic and 56 depressed), and 62 age and sex matched controls were enrolled. Sociodemographic variables and complete blood count parameters of the patients and the control group were recorded. Results: The groups did not differ from each other on the hematological parameters, except for NLR and RDW. Post-hoc analyses revealed that NLR values were significantly higher in the euthymic and manic/hypomanic bipolar groups compared to control group. In addition, post-hoc analyses revealed that RDW values were significantly higher in the manic/hypomanic bipolar group relative to the control group. Discussion: Longitudinal studies evaluating the levels of inflammatory markers in the early phases of the disorder, and their relationship with the development of different episodes and medical comorbidities may be useful to understand the role of inflam mation in BD.
Simple markers for subclinical inflammation in the different phases of bipolar affective disorder
Background: Recently, a growing number of publications have suggested that the immune-inflammatory system may be involved in the etiology of bipolar disorder (BD). Objective: The aim of this study was to investigate neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and red cell distribution width (RDW) in the three different phases of BD patients compared to each other and controls. Methods: One hundred eighty-seven bipolar patients (78 euthymic, 53 manic/hypomanic and 56 depressed), and 62 age and sex matched controls were enrolled. Sociodemographic variables and complete blood count parameters of the patients and the control group were recorded. Results: The groups did not differ from each other on the hematological parameters, except for NLR and RDW. Post-hoc analyses revealed that NLR values were significantly higher in the euthymic and manic/hypomanic bipolar groups compared to control group. In addition, post-hoc analyses revealed that RDW values were significantly higher in the manic/hypomanic bipolar group relative to the control group. Discussion: Longitudinal studies evaluating the levels of inflammatory markers in the early phases of the disorder, and their relationship with the development of different episodes and medical comorbidities may be useful to understand the role of inflam mation in BD.
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.
Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder
Journal of Affective Disorders, 2007
Background: The role of cytokines in bipolar disorder is still controversial. Although a few studies have found alterations of cytokines in bipolar disorder, their findings were inconsistent. The aim of this study was to determine whether the cytokines are involved in the pathophysiology of bipolar disorder. Methods: A total of 37 manic patients with bipolar disorder and 74 control subjects were recruited. The mitogen-induced production of tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6), IL-4, interferon (IFN)-gamma, and IL-2 was measured using quantitative sandwich ELISA at the time of admission and 6 weeks after mood stabilizer treatment. Results: IL-6 and TNF-alpha production of bipolar manic patients was significantly higher than those of normal controls, while IL-4 values of the patients were significantly lower than normal controls. IL-6/IL-4, TNF-alpha/IL-4, IL-2/IL-4, and IFN-gamma/IL-4 ratios were significantly higher in bipolar manic patients than in normal controls. After 6 weeks of treatment, the levels of IL-6 significantly decreased compared with baseline. Limitations: The effect of various types of mood stabilizers on cytokine production should be considered. Conclusions: These findings suggest that the increased activity of pro-inflammatory cytokines and an imbalance between proinflammatory and anti-inflammatory cytokines may play a role in the pathophysiology of bipolar disorder.
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.
Neuroinflammation in Bipolar Depression
Frontiers in Psychiatry, 2020
Bipolar disorder (BD) is a leading cause of worldwide disability among mood disorders. Pathological mechanisms are still vastly unclear, and current treatments with conventional medications are often unsatisfactory in maintaining symptoms control and an adequate quality of life. Consequently, current research is focusing on shedding new light on disease pathogenesis, to improve therapeutic effectiveness. Recent evidence has suggested a prominent role of inflammation in mood disorders. Elevated levels of peripheral proinflammatory mediators have been reported in BD, as well as in other mood disorders, and people with systemic autoimmune diseases have an increased risk of developing BD. These immunological alterations are stable, and current medications are unable to alter peripheral concentrations even when clinical improvement is evident. These findings have also been replicated in the central nervous system (CNS) milieu, whereas genetic studies have shown that these immune alterations are not due to the disorder itself, being detectable before the illness onset. Moreover, these inflammatory modifications seem to be affected by and linked to other biomarkers of the disorder, such as alterations of white matter (WM) microstructure, metabolism, kynurenine pathway, and circadian rhythmicity. Finally, these immune variations seem to be useful as predictors of therapeutic responsiveness to medications, and in discriminating between clinically different outcomes. The objective of this review is to summarize available evidence on the connection between inflammation and BD, focusing on peripheral inflammatory markers and recent findings on their connection with other typical features of BD, to outline a general overview of the disorder. Moreover, it is meant to analyze the issues with data gathering and interpretation, given the partially contradictory and inconsistent nature of results.
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.
Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder
2011
Background: In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. Methods: We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar dis order type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system. Results: The mean interleukin (IL)-1β level (4.2 pg/mL, standard error of the mean [SEM] 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respect ively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1β (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). Limitations: All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. Conclusion: Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1β in bipolar disorder.