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Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder

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Abstract

The neurobiology of bipolar disorder is not completely understood. Cytokines have received increasing attention as potential mediators of the interaction with immune, neuroendocrine system and specific pathways involved in mood, energy, and activity control. Previous reports have suggested the association of mania and bipolar depression with a proinflammatory state. However, they did not compare cytokine levels in all phases of bipolar disorder. Sixty-one bipolar patients were recruited for assessment of serum cytokine levels. Of these, 14 were in euthymic state, 23 and 24 were in manic and depressive episodes, respectively. A healthy comparison group included 25 healthy volunteers. Cytokines involved in Th1/Th2 balance, such as TNF-alpha, IL-2, IL-4, IL-6, IL-10, IFN-gamma, were examined by flow cytometry. During mania, proinflammatory cytokines, IL-2, IL-4 and IL-6, were increased in comparison with healthy subjects. Patients in depressive episode showed only increased IL-6 levels. There were no significant differences in cytokine levels between patients in remission and healthy subjects, except for IL-4. Mood symptoms showed a positive correlation with IL-6 and IL-2. These findings suggest that mania, and to a less extent, depression are associated with a proinflammatory state. These changes seem to be related to mood state, as changes in cytokine profile were more pronounced during acute episodes than in euthymia. This study provides further support to investigate the immune system as a target for future treatment development.

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... Immune system dysfunction leads to the occurrence of neuroinflammation in BD and increasingly implicated in the pathophysiology of this mental disorder (Najjar et al., 2013;Rosenblat & McIntyre, 2016). Several studies have shown elevated proinflammatory cytokines including but not limited to IL-6, IL-1β, and TNF-α in patients with BD (Brunoni et al., 2020;Pan et al., 2020), particular in acute mania (Brietzke et al., 2009;Fiedorowicz et al., 2015;Isgren et al., 2017;Modabbernia et al., 2013) and depressive episodes (Brietzke et al., 2009;Fiedorowicz et al., 2015;Isgren et al., 2017;Modabbernia et al., 2013). Previous metaanalyses have reported that IL-1β, IL-6, and TNF-α are the most common abnormal cytokines in BD patients (Goldsmith et al., 2016;Modabbernia et al., 2013;Rowland et al., 2018). ...
... Immune system dysfunction leads to the occurrence of neuroinflammation in BD and increasingly implicated in the pathophysiology of this mental disorder (Najjar et al., 2013;Rosenblat & McIntyre, 2016). Several studies have shown elevated proinflammatory cytokines including but not limited to IL-6, IL-1β, and TNF-α in patients with BD (Brunoni et al., 2020;Pan et al., 2020), particular in acute mania (Brietzke et al., 2009;Fiedorowicz et al., 2015;Isgren et al., 2017;Modabbernia et al., 2013) and depressive episodes (Brietzke et al., 2009;Fiedorowicz et al., 2015;Isgren et al., 2017;Modabbernia et al., 2013). Previous metaanalyses have reported that IL-1β, IL-6, and TNF-α are the most common abnormal cytokines in BD patients (Goldsmith et al., 2016;Modabbernia et al., 2013;Rowland et al., 2018). ...
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The pathophysiological mechanisms of bipolar disorder (BD) are not completely known, and systemic inflammation and immune dysregulation are considered as risk factors. Previous neuroimaging studies have proved metabolic, structural and functional abnormalities of the amygdala in BD, suggesting the vital role of amygdala in BD patients. This study aimed to test the underlying neural mechanism of inflammation-induced functional connectivity (FC) in the amygdala subregions of BD patients. Resting-state functional MRI (rs-fMRI) was used to delineate the amygdala FC from two pairs of amygdala seed regions (the bilateral lateral and medial amygdala) in 51 unmedicated BD patients and 69 healthy controls (HCs). The levels of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α were measured in the serum. The correlation between abnormal levels of pro-inflammatory cytokines and FC values were calculated in BD patients. The BD group exhibited decreased FC between the right medial amygdala and bilateral medial frontal cortex (MFC), and decreased FC between the left medial amygdala and the left temporal pole (TP), right orbital inferior frontal gyrus compared with HCs. The BD patients had higher levels of TNF-α than HCs. Correlation analysis showed negative correlation between the TNF-α level and abnormal FC of the right medial amygdala-bilateral MFC; and negative correlation between TNF-α levels and abnormal FC of the left medial amygdala-left TP in BD group. These findings suggest that dysfunctional and immune dysregulation between the amygdala and the frontotemporal circuitry might play a critical role in the pathogenesis of BD.
... 53 Disturbance in immune regulation is also a welldocumented abnormality in subpopulations of persons with mood disorders. 6,7 For example, it has been reported that subsets of populations with mood disorders exhibit increases in central and peripheral levels of acute-phase proteins, such as C-reactive peptide, and proinflammatory cytokines, such as interleukin 6 and tumor necrosis factor α. 6,[54][55][56][57] The inflammatory signature of mood disorders overlaps with clinical reports 57,58 of increased cytokine activity in persons affected with severe COVID-19. It is hypothesized that the cytokine disturbance intrinsic to mood disorders may be exacerbated in situations of COVID-19 infection, increasing the risk of death and complications from COVID-19. ...
Article
Importance Preexisting noncommunicable diseases (eg, diabetes) increase the risk of COVID-19 infection, hospitalization, and death. Mood disorders are associated with impaired immune function and social determinants that increase the risk of COVID-19. Determining whether preexisting mood disorders represent a risk of COVID-19 would inform public health priorities. Objective To assess whether preexisting mood disorders are associated with a higher risk of COVID-19 susceptibility, hospitalization, severe complications, and death. Data Sources Systematic searches were conducted for studies reporting data on COVID-19 outcomes in populations with and without mood disorders on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, LitCovid, and select reference lists. The search timeline was from database inception to February 1, 2021. Study Selection Primary research articles that reported quantitative COVID-19 outcome data in persons with mood disorders vs persons without mood disorders of any age, sex, and nationality were selected. Of 1950 articles identified through this search strategy, 21 studies were included in the analysis. Data Extraction and Synthesis The modified Newcastle-Ottawa Scale was used to assess methodological quality and risk of bias of component studies. Reported adjusted odds ratios (ORs) were pooled with unadjusted ORs calculated from summary data to generate 4 random-effects summary ORs, each corresponding to a primary outcome. Main Outcomes and Measures The 4 a priori primary outcomes were COVID-19 susceptibility, COVID-19 hospitalization, COVID-19 severe events, and COVID-19 death. The hypothesis was formulated before study search. Outcome measures between individuals with and without mood disorders were compared. Results This review included 21 studies that involved more than 91 million individuals. Significantly higher odds of COVID-19 hospitalization (OR, 1.31; 95% CI, 1.12-1.53; P = .001; n = 26 554 397) and death (OR, 1.51; 95% CI, 1.34-1.69; P < .001; n = 25 808 660) were found in persons with preexisting mood disorders compared with those without mood disorders. There was no association between mood disorders and COVID-19 susceptibility (OR, 1.27; 95% CI, 0.73-2.19; n = 65 514 469) or severe events (OR, 0.94; 95% CI, 0.87-1.03; n = 83 240). Visual inspection of the composite funnel plot for asymmetry indicated the presence of publication bias; however, the Egger regression intercept test result was not statistically significant. Conclusions and Relevance The results of this systematic review and meta-analysis examining the association between preexisting mood disorders and COVID-19 outcomes suggest that individuals with preexisting mood disorders are at higher risk of COVID-19 hospitalization and death and should be categorized as an at-risk group on the basis of a preexisting condition.
... As for the relationship between cytokines, the results of this study were consistent with previous studies in depression that found a correlation between TNF-a and IL-6 (Quinn et al. 2020) (Goldsmith et al. 2016). In addition, both IL-2 and IL-6 were reported to be higher in manic states (Brietzke et al. 2009). However, there is still no consensus on the correlation between cytokines in mood disorders. ...
Article
Objectives: The response to antidepressants varies significantly among individuals and is difficult to predict before treatment. In this randomized control trial, we explored cytokines that correlate with the therapeutic effect of mirtazapine (MIR) and selective serotonin reuptake inhibitors (SSRIs) and whether they could be predictors of remission for each antidepressant. Methods: Plasma cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assayed in 95 participants before medication and assayed by the enzyme-linked immunosorbent assay. The Hamilton Rating Scale for Depression assessed depressive symptoms over 4 weeks. Results: In the SSRI group, the baseline GM-CSF level was significantly higher in the remission group than in the non-remission group (p = 0.022). In the MIR group, the baseline level of TNF-α was significantly higher (p = 0.039) and IL-2 was lower (p = 0.032) in the remission group than in the non-remission group. In patients prescribed with MIR, the cut-off values of TNF-α (10.035 pg/ml) and IL-2 (1.170 pg/ml) calculated from the receiver operating characteristic curve suggested that the remission rate, which corresponds to a positive predictive value, could be increased from 31.3% to 60.0% and 50.0%, respectively. For those prescribed with SSRIs, the remission rate was 37.0% and using the cut-off value of GM-CSF (0.205 pg/ml), the remission rate could be almost doubled to 70%. Conclusions: Our study shows that pretreatment plasma concentrations of TNF-α, IL-2, and GM-CSF may suggest the predictability of remission by SSRIs or MIR.
... acetylsalicylic, celecoxib and omega-3 fatty acids) for managing BD, in particular bipolar depression (Muneer 2016). High concentrations of pro-inflammatory cytokines and low concentrations of anti-inflammatory cytokines were reported (Brietzke et al. 2009b) respectively when BD patients in manic and depressive phases are compared to normal controls with a return to normality in the euthymic phase. These illness-related fluctuations suggest that inflammation is a state dependent trait of the acute episodes rather than a trait marker of BD (Cetin et al. 2012). ...
Article
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Background Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. Endophenotype could help in reducing heterogeneity by defining biological traits that are more direct expressions of gene effects. The aim of this review is to examine the recent literature on clinical, epidemiological, neurobiological, and genetic findings and to select and evaluate candidate endophenotypes for bipolar disorder. Evaluating putative endophenotype could be helpful in better understanding the neurobiology of bipolar disorder by improving the definition of bipolar-related phenotypes in genetic studies. In this manner, research on endophenotypes could be useful to improve psychopathological diagnostics in the long-run by dissecting psychiatric macro phenotypes into biologically valid components. Main body The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiarity, and clinical and biological plausibility. Numerous findings regarding brain function, brain structure, neuropsychology and altered neurochemical pathways in patients with bipolar disorder and their relatives deserve further investigation. Overall, major findings suggest a developmental origin of this disorder as all the candidate endophenotypes that we have been able to select are present both in the early stages of the disorder as well as in subjects at risk. Conclusions Among the stronger candidate endophenotypes, we suggest circadian rhythm instability, dysmodulation of emotion and reward, altered neuroimmune state, attention and executive dysfunctions, anterior cingulate cortex thickness and early white matter abnormalities. In particular, early white matter abnormalities could be the result of a vulnerable brain on which new stressors are added in young adulthood which favours the onset of the disorder. Possible pathways that lead to a vulnerable brain are discussed starting from the data about molecular and imaging endophenotypes of bipolar disorder.
... Indeed, increased activity of pro-inflammatory cytokines and an imbalance with antiinflammatory cytokines have been implicated in the development of BD and neuroprogression (51)(52)(53) and (see Figure 1C). Of particular interest, varying cytokine profiles have been identified in distinct mood states of BD, including in mania, depression, euthymia and in healthy controls (54,55). Specifically, manic episodes are associated with a prominent pro-inflammatory profile state (38). ...
Article
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Bipolar disorder (BD) often progresses to a more chronic and treatment resistant (neuroprogressive) course. Identifying which patients are at risk could allow for early intervention and prevention. Bipolar disorder is highly comorbid with metabolic disorders including type II diabetes mellitus (T2DM), hypertension, obesity, and dyslipidemia. Our studies have shown that insulin resistance (IR) is present in over 50% of patients with BD and that IR might underlie the progression of BD. While no confirmed predictors exist for identifying which patients with BD are likely to develop a more chronic course, emerging evidence including our own studies suggest that IR and related inflammatory pathways lead to impairments in blood-brain barrier (BBB) functioning. For the first time in living psychiatric patients, we have shown that the severity of BBB leakage is proportional to BD severity and is associated with IR. In this hypothesis paper we (i) highlight the evidence for a key role of IR in BD, (ii) show how IR in BD relates to shared inflammatory pathways, and (iii) hypothesize that these modulations result in BBB leakage and worse outcomes in BD. We further hypothesize that (iv) reversing IR through lifestyle changes or the actions of insulin sensitizing medications such as metformin, or optimizing BBB function using vascular protective drugs, such as losartan, could provide novel strategies for the prevention or treatment of neuroprogressive BD.
... Four of these did not provide data suitable for the analyses (Boufidou et al., 2004;Karabulut et al., 2019;Kauer-Sant'Anna et al., 2008;Sanjay et al., 2017); 49 were included in the meta-analysis. (Aas et al., 2017;Bai et al., 2015;Barbosa et al., 2017Barbosa et al., , 2013Barbosa et al., , 2012bBarbosa et al., , 2012aBarbosa et al., , 2011Brietzke et al., 2009;Chakrabarty et al., 2019;Chang et al., 2017;Civil Arslan et al., n.d.;Cunha et al., 2008;da Silva et al., 2017;De Berardis et al., 2008;Dickerson et al., 2007;Doganavsargil-Baysal et al., 2013;Glaus et al., 2018;Guloksuz et al., 2010;Hope et al., 2015Hope et al., , 2011Hope et al., , 2009Hornig et al., 1998;Huang and Lin, 2007;Hung et al., 2007;Jacoby et al., 2016;Kapczinski et al., 2011;Kim et al., 2007;King et Data on more than one inflammatory mediator were reported in most of the 49 studies, yielding 135 data points, specifically 37 for CRP, 4 for IL-1β, 45 for IL-6, and 49 for TNF-α. Details on the distribution of outcomes across included studies as well as further characteristics on outcomes are reported in Table 1. ...
Article
Importance. It is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls. Objective To run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity. Data Sources. Systematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020. Study Selection. Case-control studies reporting inflammatory mediators' levels in BD and controls. Data Extraction and Synthesis. Summary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge’s g). Main Outcomes and Measures. Co-primary outcomes were inflammatory mediators' levels (Hedge’s g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls. Results Out of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g=0.70, 95% CI 0.31-1.09, k=37, BD=2,215 vs HC=3,750), IL-6 (g=0.81, 95% CI 0.46-1.16, k=45, BD=1,956 vs HC=4,106), TNF-α (g=0.49, 95% CI 0.19-0.78, k=49, BD=2,231 vs HC=3,017) were elevated in subjects with BD vs HC, but not IL-1β (g=-0.28, 95% CI -0.68-0.12, k=4, BD=87 vs HC=66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels. Conclusions and Relevance Peripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.
... Depression has also related to immune mechanisms and the biological molecules involved in these processes termed cytokines ( Figure 3) [11]. Indeed, depressed subjects show high levels of pro-inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6, and tumor necrosis factor-alpha (TNF-α) [85,86]. The activation of the inflammatory immune system inhibits neurogenesis, resulting in a reduction in the prefrontal cortex and hippocampus in depressed subjects [87]. ...
Article
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Depressive-like behavior is a highly prevalent worldwide neuropsychiatric disorder that owns a complex pathophysiologic mechanism. The available pharmacotherapy is ineffective for most patients and shown several adverse effects. Therefore, it is important to find efficacy and safe antidepressive compounds. Some phytochemicals compounds regulate the same genes and pathways targeted by drugs; therefore, diets rich in fruits and vegetables could be considered novel treatment approaches. Currently, the functional properties of quercetin acquired great interest, due to its beneficial effects on health. Quercetin is a flavonoid ubiquitously present in vegetables and fruits, interestingly for its strong antioxidant properties. The purpose of this review is to summarize the preclinical studies present in the literature, in the last ten years, aimed at illustrating the effects of quercetin pre-treatment in depressive-like behaviors. Quercetin resulted in antidepressant-like actions due to its antioxidant, anti-inflammatory, and neuroprotective effects. This pointed out the usefulness of this flavonoid as a nutraceutical compound against the development of psychological stress-induced behavioral perturbation. Therefore, quercetin or a diet containing it may become a prospective supplementation or an efficient adjuvant therapy for preventing stress-mediated depressive-like behavior.
... BD has been linked to a number of genetic predispositions; however, emerging evidence suggests that its clinical phenotype is reliably associated with a dysregulation in glial-neuronal interactions and with abnormalities more apparent in glia than in neurons. Importantly, microglia appear to be overactive in the context of bipolarity and several studies indicate that inflammation is also increased in the periphery in both depressive and manic phases of the illness (Barbosa et al., 2014;Brietzke et al., 2009), with at least some return to normality in the euthymic state (Brietzke et al., 2009). It has been shown that decreased serum BDNF correlates with clinical severity of BD and that pharmacological treatment normalizes BDNF levels (Lin, 2009). ...
Article
As the professional phagocytes of the brain, microglia orchestrate the immunological response and play an increasingly important role in maintaining homeostatic brain functions. Microglia are activated by pathological events or slight alterations in brain homeostasis. This activation is dependent on the context and type of stressor or pathology. Through secretion of cytokines, chemokines and growth factors, microglia can strongly influence the response to a stressor and can, therefore, determine the pathological outcome. Psychopathologies have repeatedly been associated with long-lasting priming and sensitization of cerebral microglia. This review focuses on the diversity of microglial phenotype and function in health and psychiatric disease. We first discuss the diverse homeostatic functions performed by microglia and then elaborate on context-specific spatial and temporal microglial heterogeneity. Subsequently, we summarize microglia involvement in psychopathologies, namely major depressive disorder, schizophrenia and bipolar disorder, with a particular focus on post-mortem studies. Finally, we postulate microglia as a promising novel therapeutic target in psychiatry through antidepressant and antipsychotic treatment.
... It is known that inflammation has been implicated in the pathophysiology and maintenance of MDD. In studies related to MDD and inflammation, changes in the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α as well as CRP have been previously reported (Raison et al., 2006;Brietzke et al., 2009;Howren et al., 2009;Krishnadas and Cavanagh, 2012;Mota et al., 2013;Serafini et al., 2013;Cubała and Landowski, 2014;Money et al., 2016;Kappelmann et al., 2018;Leighto et al., S.P. 2018;Milenkovic et al., 2019;Slavich and Sacher, 2019). These inflammatory markers have also been examined in associated to the severity of depression or suicidality severity in MDD and other mood disorders (O'Donovan et al., 2013;Serafini et al., 2013;Black and Miller, 2015;Ducasse et al., 2015) Other inflammatory markers that have been determined in MDD are complete blood inflammatory ratios such as the NLR, PLR, and MLR (Demir et al., 2015;Demircan et al., 2016;Ekinci and Ekinci, 2017;Gündüz et al., 2017; Fig. 1. ...
Article
We determined whether an elevated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were associated with depression in major depressive disorder (MDD), or suicide risk in MDD patients. A total of 137 adolescents with MDD who were antidepressant-naïve and 56 healthy controls (HC) were included. Recent suicidal behaviors were assessed. The NLR, PLR, and MLR were calculated from parameters obtained from a routine complete blood cell count parameters and compared between the MDD subgroups and HC. Cohen's d was calculated as a measure of effect size. The linear relationship between biomarkers with depression severity or suicidality severity was also analysed. Changes in CBC parameters and inflammatory ratios appeared to be more closely related to the suicidality severity than depressive severity. As compared with HC, the WBC count, neutrophil percentage, platelet count, NLR, and PLR were higher in MDD, whereas the lymphocyte percentage was lower. As compared to non-suicidal ideation (non-SI) MDD and HC, the lymphocyte percentage was decreased in MDD with suicidal attempts (SA), whereas monocyte count and MLR were increased. Suicidal attempts in MDD patients were associated with the lower lymphocytes percentage, as well as the elevated monocyte count and MLR.
... 30 however, there are studies that found that inflammation occurs in the manic and depressive phases, but not in the euthymic phase. 36,37 and similar to these recent studies all patients in the current study were in the euthymic (remission) period and there was no difference in terms of NLr; and even the PLr rate was lower in patients than control group. the low rate in PLr may be due to mood stabilizers' side effects. ...
Article
BACKGROUND: Metabolic syndrome, visceral obesity, and increased inflammation are common in patient with bipolar disorder. However, the relationship between inflammation and obesity in patients with bipolar disorder is not clear. Obesity is associated with increased inflammation. Visceral adipose tissue - the fat tissue that secretes cytokines and adipokines - plays a more important role than the total fat content and Body Mass Index (BMI) in obesity. In this study, we aimed to determine: 1) the Visceral Adiposity Index (VAI) to assess the visceral adipose tissue in patients in remission with bipolar disorder, neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) to assess subclinical inflammation; 2) the incidence of visceral adipose dysfunction (VAD) in the patients based on VAI cut-off values; and 3) the relationship between inflammation (based on NLR and PLR) and VAI in patients with bipolar disorder. METHODS: Seventy-eight patients with euthymic bipolar disorder (patient group) and 78 healthy individuals (control group) were included in this study. Anthropometric measurements (waist circumference, height, weight, and BMI), triglyceride and high-density lipoprotein (HDL) levels of the participants were recorded. Moreover, VAI, NLR, and PLR were calculated. RESULTS: VAI was significantly higher in the patient group than in the control group. According to the age-adjusted VAI cut-off values for metabolic syndrome risk, 40 patients (51%) (VAI=4.58+2.17) had VAD. There was no significant difference in NLR between the patient and control group (P=0.578), while PLR was significantly lower in the patient group than in the control group (P<0.001). Moreover, there was no significant difference in NLR (P=0.15) and PLR (P=0.35) between patients with and without VAD. CONCLUSIONS: NLR and PLR may be indicative of the absence of subclinical inflammation during the euthymic period of bipolar disorder. The absence of a relationship between VAI and NLR/PLR may support the presence of VAD in patients in remission, irrespective of inflammation.
... Chronic inflammation may induce oxidative stress [67]. In addition to playing a role in the genesis of symptoms, these conditions may also be responsible for comorbid medical conditions [66,68]. Cardiac steroids appear to mediate elaboration of oxidative stress [34], and the dramatic increase of EC in amphetamine treated rats may increase inflammation and oxidative stress as reflected by the increase of superoxide dismutase (SOD) activity in these animals [69]. ...
Article
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Bipolar disorder (BD) is a severe psychiatric illness with a poor prognosis and problematic, suboptimal, treatments. Treatments, borne of an understanding of the pathoetiologic mechanisms, need to be developed in order to improve outcomes. Dysregulation of cationic homeostasis is the most reproducible aspect of BD pathophysiology. Correction of ionic balance is the universal mechanism of action of all mood stabilizing medications. Endogenous sodium pump modulators (collectively known as endogenous cardiac steroids, ECS) are steroids which are synthesized in and released from the adrenal gland and brain. These compounds, by activating or inhibiting Na+, K+-ATPase activity and activating intracellular signaling cascades, have numerous effects on cell survival, vascular tone homeostasis, inflammation, and neuronal activity. For the past twenty years we have addressed the hypothesis that the Na+, K+-ATPase-ECS system may be involved in the etiology of BD. This is a focused review that presents a comprehensive model pertaining to the role of ECS in the etiology of BD. We propose that alterations in ECS metabolism in the brain cause numerous biochemical changes that underlie brain dysfunction and mood symptoms. This is based on both animal models and translational human results. There are data that demonstrate that excess ECS induce abnormal mood and activity in animals, while a specific removal of ECS with antibodies normalizes mood. There are also data indicating that circulating levels of ECS are lower in manic individuals, and that patients with BD are unable to upregulate synthesis of ECS under conditions that increase their elaboration in non-psychiatric controls. There is strong evidence for the involvement of ion dysregulation and ECS function in bipolar illness. Additional research is required to fully characterize these abnormalities and define future clinical directions.
... The IL-6 concentration was correlated with the intensity of the manic state. By contrast, the concentration of the anti-inflammatory cytokine IL-10 was reported to be higher in the depressed phase during the remission period by Brietzke et al. (2009), who also reported that the IL-6 levels were elevated in the depressive phase. The particular importance of IL-6 in BD relates to its pleiotropic properties, which result in the stimulation of T and B lymphocytes, and hepatocytes, which release acutephase proteins such as C-reactive protein (CRP). ...
Article
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Many patients under treatment for mood disorders, in particular patients with bipolar mood disorders, experience episodes of mood switching from one state to another. Various hypotheses have been proposed to explain the mechanism of mood switching, spontaneously or induced by drug treatment. Animal models have also been used to test the role of psychotropic drugs in the switching of mood states. We examine the possible relationship between the pharmacology of psychotropic drugs and their reported incidents of induced mood switching, with reference to the various hypotheses of mechanisms of mood switching.
... Also, Dunjic-Kostic et al. [17] indicated "decreased concentrations of TNFα during acute and remission phase. The study is also in variance with other studies which showed increased serum concentrations of TNF-α after four to six weeks of treatment" [18,19]. "Tumour Necrosis Factor-Alpha is a pro-inflammatory cytokine, which is increased in innate immune responses and also during Th1 and Th17 activation. ...
Article
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The aim of the current study was to evaluate neutrophil to lymphocyte ratio and the levels of IL-6, TNF-α in patients with schizophrenia after six weeks of antipsychotic treatment with Risperidone and Clozapine. Total study sample of 50 subjects of schizophrenia patients and 50 apparently healthy subjects aged 25-60 years were recruited in this study. The cytokines 6 were measured by Enzyme Linked Immunosorbent Assay. The results showed increase in WBC (P=0.001), absolute neutrophil (P=0.000), NLR (P=0.025), IL-6 (P=0.000) and no significant difference in TNF-α (P=0.059) and no significant difference in absolute lymphocyte of schizophrenia patients before treatment compared to after treatment In conclusion, there were significantly higher values in IL-6, WBC and Neutrophil levels of schizophrenic drug naïve subjects when compared with schizophrenic treated subjects. Tumour Necrosis Factor-alpha serum levels among schizophrenic drug naïve subjects and schizophrenic drug treated subjects showed similar mean values.
... Предполагаемые механизмы связи между аффективными расстройствами и воспалением включают в себя резистентность к глюкокортикоидам, изменение проницаемости гематоэнцефалического барьера, нарушение метаболизма нейротрансмиттеров, активацию астроцитов и микроглии, повреждение и дегенерацию нейронов, а также снижение нейротрофической поддержки [12,13]. Несколько метаанализов подтверждают, что периферические провоспалительные цитокины повышены как в маниакальных -интерлейкины (ИЛ)-2, 4 и 6, -так и в депрессивных фазах (ИЛ-4) заболевания, но не в интермиссиях [14,15]. Известно, что другие маркеры воспаления, такие, например, как С-реактивный белок, могут быть повышены при обострениях БР и являются дополнительными факторами риска ССЗ без оценки по шкале Фремингема [16]. ...
Article
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Background. Bipolar disorder (BD) is one of the most common mental disorders characterized by alternating episodes of mania/hypomania and depression, as well as the possibility of developing mixed conditions. Correct and timely diagnosis of BD is important due to the presence of a high suicidal risk and a high predisposition to the development of cardiovascular disease (CVD). The risk of CVD is higher in ВD than in other mental disorders. Materials and methods. A sample assessment was made of current studies focusing on the vascular-bipolar link. The search was carried out in the PubMed and eLIBRARY databases for the following keywords: bipolar disorder, psychopharmacology, cardiovascular disease, biological mediators. Results. There are several biological factors which explain the close association and common pathogenetic mechanisms of BD and CVD. The most interesting of them are inflammation, oxidative stress, and brain-derived neurotrophic factor. Neuroimaging methods have shown similar structural brain changes in people with BD and with CVD. There is some evidence of the efficacy of statins and angiotensin-converting enzyme inhibitors in reducing cardio-vascular risk factors in BD patients. Conclusion. The predisposition of patients of BD to CVD is beyond doubt. It is necessary to consider the peculiarities of the course of BD and conduct active monitoring and preventive measures to reduce the risk of developing life-threatening CVDs. Further research focused on the pathogenetic relationship between BD and CVD could provide more insight into this area.
... Chronic T. gondii infection is characterized by increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), and IL-1β (Dogruman-Al et al., Meira et al., 2014). It seems that there exist specific patterns of increased levels of cytokines in different phases of bipolar disorders: the pro-inflammatory cytokines including IL-2, IL-6, and IL-8 and interferon (IFN)-γ are increased during mania, whereas only IL-6 is increased during depressive episodes (Brietzke et al., 2009). These data suggest that mostly manic phase of bipolar disorder is J o u r n a l P r e -p r o o f associated with a persistent and chronic pro-inflammatory state (Kim Y. K. et al., 2007). ...
Article
Background The relationship between toxoplasma gondii (T. gondii) infection and bipolar disorder (BD) is poorly understood. This review explores this relationship by estimating the strength of the association between the two conditions using data from published studies. Methods Following PRISMA guidelines, we performed a review and meta-analysis of published articles obtained from a systematic search of PubMed, PsycINFO, EMBASE and the Cochrane library up to January 10th, 2021. We included observational studies that compared seroprevalence of IgG class antibodies against T. gondii in patients with a diagnosis of BD with healthy controls. We excluded studies that included <10 participants in each study arm and patients with a serious concomitant medical illness. Discrepancies between the two independent researchers were resolved by consulting a third experienced researcher. Summary data were extracted from published reports. Analysis was conducted using both fixed-effects and random-effects models. The study is registered with PROSPERO number CRD42021237809. Findings The search yielded 23 independent studies with a total of 12690 participants (4021 with BD and 8669 controls). Persons with BD had a greater odd of seropositivity with toxoplasmosis than controls, both in the fixed-effects model (OR=1.34 [95%CI: 1.19 to 1.51]) and the random-effects model (OR=1.69 [95%CI: 1.21 to 2.36]). No publication bias was detected but reported results showed a high heterogeneity (I2=84% [95%CI:77% to 89%]). Interpretation The findings support the relationship between toxoplasmosis infection and BD and suggests a need for studies designed to explore possible causal relationship. Such studies may also improve our understanding of the pathophysiology of BD and open other avenues for its treatment. Funding P.O.R. Sardegna F.S.E. 2014-2020
... The pathogenesis of Sch [15] and BD [16] includes infections and inflammation. According to the various case-control or meta-analyses researches, the Sch and BD patients show signs of a peripheral inflammation with low grade, upregulating many cytokines [15,17,18]. IFN-γ, a member of the type 2 class of interferons, is produced by CD4+ Th1, natural killer (NK), and CD8+ cytotoxic T cells and is a central mediator of the Type 1/Type 2 immune balance. ...
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Background: Schizophrenia (Sch) and bipolar disorder (BD) are debilitating chronic psychiatric disorders that are both etiologically and clinically heterogeneous. According to the gathered evidence, multiple mental disorders are accompanied by inflammation. Interferon-γ (IFN-γ), as a regulatory cytokine, is involved in the immune response as a proinflammatory mediator. Several critical physiological functions are regulated and governed by nitric oxide (NO) in the central nervous system. This study aimed to investigate the association between IFN-γ +874T/A and eNOS 894G/T variants and Sch or BD susceptibility. Methods: Blood samples were collected from patients and healthy subjects. IFN-γ +874T/A and eNOS 894G/T variants were genotyped with the PCR-RFLP. We evaluated the patients with some clinical parameters (the duration of the disorder, age of onset, number of hospitalizations, family history, tobacco smoking or drug, alcohol usage). Statistical analyses were performed using the SPSS version. Results: When the genotype distributions and allele frequencies of the IFN-γ +874T/A and eNOS 894G/T in the patients diagnosed with Sch or BD were compared with the control group, there were not found to be significant differences between the groups. When comparing IFN-γ +874T/A and eNOS 894G/T genotype distributions and allele frequencies of Sch or BD patients due to clinical parameters, the genotype distribution of IFN-γ +874T/A in BD patients was significantly different between the groups due to the presence of tobacco smoking (OR: 0.217, 95%Cl: 0.054–0.878; p = 0.032). Conclusions: To the best of our knowledge, this is the first study that examines the association between the IFN-γ and eNOS gene variants and Sch or BD in a Turkish population. Although IFN-γ +874T/A and eNOS 894G/T variants are not considered as candidate genes for Sch or BD, the results indicated that the BD patients carrying IFN-γ +874T/A AA genotype were less susceptible to tobacco smoking in a Turkish population.
... Unless participants are grouped by current mood state (e.g., Van der Gucht et al., 2009), it is likely that any study's findings are a function of the specific sample's proportion of participants currently experiencing manic vs depressive symptoms (Fisher, Guha, Heller, & Miller, 2020;Tohen et al., 2009). Other studies have taken steps to either group participants based on mood state (e.g., Brietzke et al., 2009) or separately track (hypo)manic and depressive symptoms among participants diagnosed with bipolar disorders (e.g., Johnson et al., 2011). However, these studies usually focus more on tracking the development of symptoms than on examining trait vulnerabilities that may be associated with each state. ...
Article
Bipolar spectrum disorders are characterized by alternating intervals of extreme positive and negative affect. We performed a meta-analysis to test the hypothesis that such disorders would be related to dysregulated reinforcement sensitivity. First, we reviewed 23 studies that reported the correlation between self-report measures of (hypo)manic personality and measures of reinforcement sensitivity. A large relationship was found between (hypo)manic personality and BAS sensitivity (g = .74), but not with BIS sensitivity (g = -.08). This stands in contrast to self-reported depression which has a small, negative relationship with BAS sensitivity and a large positive one with BIS sensitivity (Katz et al., 2020). Next, we reviewed 33 studies that compared reinforcement sensitivity between euthymic, bipolar participants and healthy controls. There, bipolar disorder had a small, positive relationship with BAS sensitivity (g = .20) and a medium, positive relationship with BIS sensitivity (g = .64). These findings support a dualsystem theory of bipolar disorders, wherein BAS sensitivity is more closely related to mania and BIS sensitivity more closely to bipolar depression. Bipolar disorders show diatheses for both states with euthymic participants being BAS- and BIS- hypersensitive. Implications for further theory and research practice are expounded upon in the discussion.
... First, immunological factors have been implicated in the aetiology of psychoses unrelated to childbirth [81] and specifically in bipolar disorder [82]. Inflammatory cytokines (responsible for cell signalling and promotion of systemic inflammatory response) are found to be significantly elevated during acute phases of bipolar-related mood episodes, most consistently during episodes of mania [83,84]. Second, immune disorders such as postpartum thyroiditis, rheumatoid arthritis and multiple sclerosis are typically exacerbated in the postpartum period, sharing similarities with the clinical course of postpartum psychosis [85]. ...
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Postpartum psychoses are a severe form of postnatal mood disorders, affecting 1–2 in every 1000 deliveries. These episodes typically present as acute mania or depression with psychosis within the first few weeks of childbirth, which, as life-threatening psychiatric emergencies, can have a significant adverse impact on the mother, baby and wider family. The nosological status of postpartum psychosis remains contentious; however, evidence indicates most episodes to be manifestations of bipolar disorder and a vulnerability to a puerperal trigger. While childbirth appears to be a potent trigger of severe mood disorders, the precise mechanisms by which postpartum psychosis occurs are poorly understood. This review examines the current evidence with respect to potential aetiology and childbirth-related triggers of postpartum psychosis. Findings to date have implicated neurobiological factors, such as hormones, immunological dysregulation, circadian rhythm disruption and genetics, to be important in the pathogenesis of this disorder. Prediction models, informed by prospective cohort studies of high-risk women, are required to identify those at greatest risk of postpartum psychosis.
... Moreover, they are consistent with previous studies in which manic patients had higher levels of pro-inflammatory cytokines, such as C-reactive protein (CRP), soluble interleukin (IL)-6 receptor, and soluble tumor necrosis alpha (TNF-↵) receptor, as compared to patients with major depressive episodes, suggesting more severe inflammatory dysregulation in mania [28]. Pro-inflammatory cytokines appear to be a state marker, as they are increased in manic episodes but not in a euthymic state [29][30][31]. Moreover, their levels seem to be responsive to lithium therapy [32,33]. ...
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Background: Several inflammatory hypotheses have been suggested to explain the etiopathogenesis of bipolar disorder (BD) and its different phases. Neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and monocyte-to-lymphocyte (MLR) ratios have been proposed as potential peripheral biomarkers of mood episodes. Methods: We recruited 294 patients affected by BD, of which 143 were experiencing a (hypo)manic episode and 151 were in a depressive phase. A blood sample was drawn to perform a complete blood count. NLR, PLR, and MLR were subsequently calculated. A t-test was performed to evaluate differences in blood cell counts between depressed and (hypo)manic patients and a regression model was then computed. Results: Mean values of neutrophils, platelets, mean platelet volume, NLR, PLR, and MLR were significantly higher in (hypo)manic than depressed individuals. Logistic regression showed that PLR may represent an independent predictor of (hypo)mania. Conclusions: Altered inflammatory indexes, particularly PLR, may explain the onset and recurrence of (hypo)manic episodes in patients with BD. As inflammatory ratios represent economical and accessible markers of inflammation, further studies should be implemented to better elucidate their role as peripheral biomarkers of BD mood episodes.
Article
Background Inflammation might play a role in bipolar disorder (BD), but it remains unclear the relationship between inflammation and brain structural and functional abnormalities in patients with BD. In this study, we focused on the alterations of functional connectivity (FC), peripheral pro-inflammatory cytokines and their correlations to investigate the role of inflammation in FC in BD depression. Methods In this study, 42 unmedicated patients with BD II depression and 62 healthy controls (HCs) were enrolled. Resting-state-functional magnetic resonance imaging was performed in all participants and independent component analysis was used. Serum levels of Interleukin-6 (IL-6) and Interleukin-8 (IL-8) were measured in all participants. Correlation between FC values and IL-6 and IL-8 levels in BD was calculated. Results Compared with the HCs, BD II patients showed decreased FC in the left orbitofrontal cortex (OFC) implicating the limbic network and the right precentral gyrus implicating the somatomotor network. BD II showed increased IL-6 ( p = 0.039), IL-8 ( p = 0.002) levels. Moreover, abnormal FC in the right precentral gyrus were inversely correlated with the IL-8 ( r = −0.458, p = 0.004) levels in BD II. No significant correlation was found between FC in the left OFC and cytokines levels. Conclusions Our findings that serum IL-8 levels are associated with impaired FC in the right precentral gyrus in BD II patients suggest that inflammation might play a crucial role in brain functional abnormalities in BD.
Article
Objectives: This study examined cognition-immune interactions, specifically executive function, working memory, peripheral levels of tumour necrosis factor-alpha (TNF-α), and soluble tumour necrosis factor receptors-1 and -2 (sTNFR1 and 2) levels in patients in comparison with controls. Methods: Thirty-one BD participants and twenty-seven controls participated in the study. The neurocognitive assessment was performed through three of CogState Research BatteryTM tasks for executive function and working memory. Plasma levels of TNF-α, sTNFR1, and sTNFR2 were measured after overnight fasting. Sociodemographic data and symptom severity of depression and mania were assessed. Results: BD presented a significantly worse performance in the working memory task (p = 0.005) and higher levels of TNF-α (p = 0.043) in comparison to controls. A trend level of significance was found for sTNFR1 between groups (p = 0.082). Among BD participants, there were significant correlations between sTNFR2 and neurocognitive tasks (Groton Maze Learning Task: ρ = 0.54, p = 0.002; Set-Shifting Task: ρ = 0.37, p = 0.042; and the Two-Back Task: ρ=-0.49, p = 0.005), and between sTNFR1 and mania, depression and anxiety symptoms (respectively ρ = 0.37, p = 0.038; ρ=-0.38, p = 0.037; and ρ = 0.42, p = 0.002). Conclusion: TNF-α and its receptors might be an important variable in cognitive impairment in BD. Future studies might focus on the development of anti-inflammatory therapeutic targets for cognitive dysfunction in BD.
Chapter
Bipolar disorder (BD) is a severe mental illness associated with significant illness burden. The exact etiology of BD remains elusive, but inflammation is suggested to be one of the numerous causes leading to BD. Accumulating evidence also supports an association between BD and inflammation. In this chapter, we first discuss the role of inflammatory conditions such as infections and autoimmune disorders in BD pathophysiology. We then discuss how the gut microbiome can be one of the perpetrators of the inflammatory response seen in BD patients. We highlighted the inflammatory mechanisms involving inflammatory cytokines, oxidative stress production, mitochondrial dysfunction, and microglial activation. Moreover, we explain how they contribute to the development of BD. We also included scientific evidence of immune markers evaluated in blood, cerebrospinal fluid, and postmortem brain samples, which demonstrates the involvement of inflammation and immune-regulated pathways in the neurobiology of BD. Understanding the biological basis of BD pathophysiology will open up new targets for novel therapies.
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Regulation of emotions is generally associated exclusively with the brain. However, there is evidence that peripheral systems are also involved in mood, stress vulnerability vs resilience and emotion‐related memory encoding. Prevalence of stress and mood disorders such as major depression, bipolar disorder and posttraumatic stress disorder is increasing in our modern societies. Unfortunately, 30‐50% of individuals respond poorly to currently available treatments highlighting the need to further investigate emotion‐related biology to gain mechanistic insights that could lead to innovative therapies. Here we provide an overview of inflammation‐related mechanisms involved in mood regulation and stress responses discovered using animal models. If clinical studies are available, we discuss translational value of these findings including limitations. Neuroimmune mechanisms of depression and maladaptive stress responses have been receiving increasing attention and thus the first part is centered on inflammation and dysregulation of brain and circulating cytokines in stress and mood disorders. Next, recent studies supporting a role for inflammation‐driven leakiness of the blood‐brain and gut barriers in emotion regulation and mood are highlighted. Stress‐induced exacerbated inflammation fragilizes these barriers which become hyperpermeable through loss of integrity and altered biology. At the gut level, this could be associated with dysbiosis, an imbalance in microbial communities, and alteration of the gut‐brain axis which is central to production of mood‐related neurotransmitter serotonin. Novel therapeutic approaches such as anti‐inflammatory drugs, the fast‐acting antidepressant ketamine and probiotics could directly act on the mechanisms described here improving mood disorder‐associated symptomatology. Discovery of biomarkers has been a challenging quest in psychiatry, and we end by listing promising targets worth further investigation.
Chapter
The relationship between bipolar disorder (BD) and biological rhythms has been extensively investigated. Alterations in biological rhythms, including sleep, have been identified in patients, and polymorphisms in genes that make up the genesis of circadian rhythms have been associated with the disorder and linked to its phenotypic particularities. Moreover, different studies have also reported the presence of abnormalities in infradian rhythms. Finally, antidepressants and mood stabilizers affect the circadian clock, and chronobiological treatments have shown to have an important effect on mood. Nowadays, there is an ample debate whether the effects of the disruption of biological rhythms are merely symptoms of this psychiatric disorder, or rather contributing causes. Nonetheless the circadian clock influences multiple systems and pathways, not least immune system and metabolism, which are thought to underlie mood disorders and in most cases there are reciprocal interactions which in turn regulate circadian rhythms.
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Background Prefrontal dopamine D1 receptor (D1R) mediates behavior related to anxiety, reward and memory, and is involved in inflammatory processes, all of which are affected in bipolar disorder. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is increased in patients with bipolar disorder in plasma samples, imaging studies and postmortem tissue and is an indicator for an inflammatory state. We could previously show that lentiviral overexpression of D1R in the medial prefrontal cortex (mPFC) of male adult rats and its termination induces bipolar disorder-like behavior. The purpose of this study was to investigate anxiety and the role of the immune system, specifically IL-6 positive neurons in this animal model. Due to its high density of inflammatory mediator receptors and therewith sensibility to immune activation, the hippocampus was investigated. Methods Expression of the gene for D1R in glutamatergic neurons within the mPFC of male, adult rats was manipulated through an inducible lentiviral vector. Animals over-expressing the gene (mania-like state), after termination of the expression (depressive-like) and their respective control groups were investigated. Anxiety behavior was studied in the elevated plus maze and marble burying test. Furthermore, IL-6-positive cells were counted within several subregions of the hippocampus. Results D1R manipulation in the mPFC had only mild effects on anxiety behavior in the elevated plus maze. However, subjects after termination buried more marbles compared to D1R over-expressing animals and their respective control animals indicating elevated anxiety behavior. In addition, animals in the depressive-like state showed higher numbers of IL-6 positive cells reflecting an elevated pro-inflammatory state in the hippocampus, in the CA3 and dentate gyrus. Consistently, inflammatory state in the whole hippocampus and anxiety behavior correlated positively, indicating a connection between anxiety and inflammatory state of the hippocampus. Conclusions Behavioral and neurobiological findings support the association of manipulation of the D1R in the mPFC on anxiety and inflammation in the hippocampus. In addition, by confirming changes in the inflammatory state, the proposed animal model for bipolar disorder has been further validated.
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Sodium valproate (VPA) is a histone deacetylase (HDAC) inhibitor, widely prescribed in the treatment of bipolar disorder, and yet the precise modes of therapeutic action for this drug are not fully understood. After exposure of the rat serotonergic cell line RN46A to VPA, RNA-sequencing (RNA-Seq) analysis showed widespread changes in gene expression. Analysis by four bioinformatic pipelines revealed as many as 230 genes were significantly upregulated and 72 genes were significantly downregulated. A subset of 23 differentially expressed genes was selected for validation using the nCounter® platform, and of these we obtained robust validation for ADAM23, LSP1, MAOB, MMP13, PAK3, SERPINB2, SNAP91, WNT6, and ZCCHC12. We investigated the effect of lithium on this subset and found four genes, CDKN1C, LSP1, SERPINB2, and WNT6 co-regulated by lithium and VPA. We also explored the effects of other HDAC inhibitors and the VPA analogue valpromide on the subset of 23 selected genes. Expression of eight of these genes, CDKN1C, MAOB, MMP13, NGFR, SHANK3, VGF, WNT6 and ZCCHC12, was modified by HDAC inhibition, whereas others did not appear to respond to several HDAC inhibitors tested. These results suggest VPA may regulate genes through both HDAC-dependent and independent mechanisms. Understanding the broader gene regulatory effects of VPA in this serotonergic cell model should provide insights into how this drug works and whether other HDAC inhibitor compounds may have similar gene regulatory effects, as well as highlighting molecular processes that may underlie regulation of mood.
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Lowered high-density lipoprotein (HDL) cholesterol has been reported in major depressive disorder, bipolar disorder, first episode of psychosis, and schizophrenia. HDL, its major apolipoprotein component, ApoA1, and the antioxidant enzyme paraoxonase (PON)1 (which is normally bound to ApoA1) all have anti-atherogenic, antioxidant, anti-inflammatory, and immunomodulatory roles, which are discussed in this paper. The paper details the pathways mediating the anti-inflammatory effects of HDL, ApoA1 and PON1 and describes the mechanisms leading to compromised HDL and PON1 levels and function in an environment of chronic inflammation. The molecular mechanisms by which changes in HDL, ApoA1 and PON1 might contribute to the pathophysiology of the neuroprogressive disorders are explained. Moreover, the anti-inflammatory actions of ApoM-mediated sphingosine 1-phosphate (S1P) signalling are reviewed as well as the deleterious effects of chronic inflammation and oxidative stress on ApoM/S1P signalling. Finally, therapeutic interventions specifically aimed at improving the levels and function of HDL and PON1 while reducing levels of inflammation and oxidative stress are considered. These include the so-called Mediterranean diet, extra virgin olive oil, polyphenols, flavonoids, isoflavones, pomegranate juice, melatonin and the Mediterranean diet combined with the ketogenic diet.
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Bipolar disorder (BD) is a chronic psychiatric disease, characterized by frequent behavioral episodes of depression and mania, and neurologically by dysregulated neurotransmission, neuroplasticity, growth factor signaling, and metabolism, as well as oxidative stress, and neuronal apoptosis, contributing to chronic neuroinflammation. These abnormalities result from complex interactions between multiple susceptibility genes and environmental factors such as stress. The neurocellular abnormalities of BD can result in gross morphological changes, such as reduced prefrontal and hippocampal volume, and circuit reorganization resulting in cognitive and emotional deficits. The term “neuroprogression” is used to denote the progressive changes from early to late stages, as BD severity and loss of treatment response correlate with the number of past episodes. In addition to circuit and cellular abnormalities, BD is associated with dysfunctional mitochondria, leading to severe metabolic disruption in high energy-demanding neurons and glia. Indeed, mitochondrial dysfunction involving electron transport chain (ETC) disruption is considered the primary cause of chronic oxidative stress in BD. The ensuing damage to membrane lipids, proteins, and DNA further perpetuates oxidative stress and neuroinflammation, creating a perpetuating pathogenic cycle. A deeper understanding of BD pathophysiology and identification of associated biomarkers of neuroinflammation are needed to facilitate early diagnosis and treatment of this debilitating disorder.
Article
Chronic systemic inflammation is associated with an increased risk of cardiovascular disease in an environment of low low-density lipoprotein (LDL) and low total cholesterol and with the pathophysiology of neuroprogressive disorders. The causes and consequences of this lipid paradox are explored. Circulating activated neutrophils can release inflammatory molecules such as myeloperoxidase and the pro-inflammatory cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha. Since activated neutrophils are associated with atherosclerosis and cardiovascular disease and with major depressive disorder, bipolar disorder and schizophrenia, it seems reasonable to hypothesise that the inflammatory molecules released by them may act as mediators of the link between systemic inflammation and the development of atherosclerosis in neuroprogressive disorders. This hypothesis is tested by considering the association at a molecular level of systemic inflammation with increased LDL oxidation; increased small dense LDL levels; increased lipoprotein (a) concentration; secretory phospholipase A2 activation; cytosolic phospholipase A2 activation; increased platelet activation; decreased apolipoprotein A1 levels and function; decreased paroxonase-1 activity; hyperhomocysteinaemia; and metabolic endotoxaemia. These molecular mechanisms suggest potential therapeutic targets.
Article
Introduction : Peripheral inflammatory markers, such as C-reactive protein (CRP), are elevated among adolescents and adults with bipolar disorder (BD), particularly during symptomatic episodes. Neurocognition, predominantly in the domain of executive function, is also impaired among adults and youth with BD. In adults with BD, CRP is negatively associated with neurocognitive functioning. We aim to investigate this relationship in BD adolescents. Methods : Serum levels of CRP and five other inflammatory markers (interleukin (IL)-1β, IL-6, IL-10, IL-4 and tumor necrosis factor α (TNF)) were examined in 60 adolescents with BD (34 symptomatic, 26 asymptomatic) age- and sex-matched to 51 healthy controls (HC). Diagnoses were confirmed using semi-structured interviews. Pro- to anti-inflammatory marker ratios were also examined. Neurocognitive flexibility was assessed via the intra/extradimensional shift (IED) task from the CANTAB battery. Multivariate linear regression controlled for age, sex and race. Results : Within symptomatic BD adolescents, but not asymptomatic BD or HC adolescents, lower IL-6/IL-10 and lower CRP/IL-10 ratios were significantly associated with worse performance on the neurocognitive flexibility task (p=0.03 and p=0.04, respectively). Both models accounted for 13.3% of variance in neurocognitive flexibility. No significant CRP by diagnosis interaction effects were observed on neurocognitive flexibility. Limitations : Limited sample-size restricted ability to separate the symptomatic BD adolescents into varying mood states. Conclusion : More balanced pro- to anti-inflammatory ratios were associated with better neurocognitive flexibility in symptomatic BD adolescents. Prospective studies are warranted to assess the direction of these findings.
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Background Pro-inflammatory/anti-inflammatory cytokine imbalance in cerebrospinal fluid or plasma of schizophrenia (SCZ) and bipolar disorder (BD) patients has been documented over the last decade. We aim to examine the interleukin-1 receptor antagonist (IL-1RA) and IL-4 variable number of tandem repeat (VNTR) polymorphisms in SCZ and BD patients by comparing them with healthy controls. Methods Two hundred and thirty-four unrelated patients (127 patients with SCZ, 107 patients with BD) and 204 healthy controls were included. The Structured Clinical Interview for DSM-IV Axis I Disorders was used to confirm the diagnosis. In addition, the polymerase chain reaction technique was used to investigate IL-1RA and IL-4 VNTR polymorphisms. Results Our results showed that the distributions of IL-1RA and IL-4 genotype and the allele frequencies of SCZ or BD patients were not significantly different from the healthy control group. IL-1RA allele 2 homozygous genotype and IL-1RA allele 2 frequencies were non-significantly higher among SCZ patients than in controls. Conclusions Our study indicates that the IL-1RA and IL-4 VNTR polymorphisms are not considered risk factors for developing SCZ and BD among Turkish patients.
Article
Background Altered peripheral immune/inflammatory system and brain volumetric changes have been implicated in the pathophysiology of bipolar disorder (BD). This study aimed to evaluate how peripheral levels of cytokines are related to volumetric brain changes in euthymic patients with BD. Methods Euthymic patients with BD (n = 21) and healthy controls (n = 22) were enrolled in this exploratory study. Blood samples were collected on the same day of clinical assessment and neuroimaging. Cytokines were measured through cytometric bead array method. Neuroimaging data were acquired using a sagittal three-dimensional magnetic resonance imaging T1-weighted fast field echo sequence and was processed using FreeSurfer. Results Compared to controls, BD patients had significantly lower volumes in the cingulate, medial-orbitofrontal (MOF) and parahippocampal regions. We found a negative correlation between right MOF volume and interferon-gamma levels ( β = −0.431, P = .049) and a positive correlation between interleukin-10 levels and left posterior cingulate volume ( β = 0.457, P = .048). Conclusion Our results support the involvement of inflammatory pathways in structural brain changes in BD.
Article
Introduction Women with bipolar disorder (BD) present a high prevalence of polycystic ovary syndrome (PCOS) and other reproductive disorders even before diagnosis or treatment of the disease. Postulations on the potential molecular mechanisms of comorbid PCOS in women with BD remain limited to influence of medications and need further extension. Objectives This review focuses on evidence suggesting that common metabolic and immune disorders may play an important role in the development of BD and PCOS. Results The literature covered in this review suggests that metabolic and immune disorders, including the dysfunction of the hypothalamic–pituitary–adrenal axis, chronic inflammatory state, gut microbial alterations, adipokine alterations and circadian rhythm disturbance, are observed in patients with BD and PCOS. Such disorders may be responsible for the increased prevalence of PCOS in the BD population and indicate a susceptibility gene overlap between the two diseases. Current evidence supports postulations of common metabolic and immune disorders as endophenotype in BD as well as in PCOS. Conclusions Metabolic and immune disorders may be responsible for the comorbid PCOS in the BD population. The identification of hallmark metabolic and immune features common to these two diseases will contribute to the clarification of the effect of BD on the reproductive endocrine function and development of symptomatic treatments targeting the biomarkers of the two diseases.
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Objective: A large amount of evidence shows that the abnormal expression of miRNA plays an important role in the development of depression. Therefore, we investigated the effect of miR-124-3p on neuronal damage in the hippocampus of depression rats. Methods: The target genes of miR-124-3p were predicted by the database; the depression model was prepared by subcutaneous injection of corticosterone (CORT), and LV-miR-124-3p asponge lentiviral suspension was given to determine the weight of rats and open-field test, sugar preference experiment, Serum CORT, 5-HT, DA, and NE were measured, observe and record the behavior of rats, including behavior, diet, and hair. The expression of miR-124-3p, STAT3, Bcl-2, and Bax in rat hippocampus was measured. The rat hippocampal neuron cells were extracted and transfected with miR-124-3p inhibitor; the cells were cultured with CORT, and the cell survival rate was evaluated by MTT experiment, and the expressions of miR-124-3p, STAT3, Bcl-2, and Bax in the cells were detected. Luciferase reporter gene verifies the targeted regulation of miR-124-3p on STAT3. Results: Compared with depression rats, silencing miR-124-3p increased the weight of the rats, increased the number of open-field activities, and significantly improved the general state and pathological state of the rats. The sugar water preference rate was significantly increased, the CORT content in the serum of rats decreased significantly, and the levels of 5-HT, DA, and NE increased significantly. After the treatment of silencing miR-124-3p, the expression level of miR-124-3p was decreased, while the STAT3 mRNA and protein expression levels were increased. And the protein and mRNA expression levels of Bcl-2 were increased, and the Bax protein and mRNA expression were decreased. Cell experiments verified that silencing miR-124-3p increased cell survival, the expression level of miR-124-3p decreased remarkably, while the expression levels of STAT3 mRNA and protein increased significantly. Silencing miR-124-3p reversed the effects of CORT treatment on miR-124-3p and STAT3 in neuronal cells. The luciferase reporter gene experiment confirmed that miR-124-3p targets and regulates STAT3 expression. Conclusion: Silencing miR-124-3p may protect hippocampal neurons from damage in depression rats by upregulating STAT3 gene.
Article
Aim: Palmitoylethanolamide (PEA) is an endogenous fatty acid amide with neuroprotective and anti-inflammatory actions. This is a randomized, double-blind, placebo-controlled clinical trial to investigate the efficacy and safety of PEA combination therapy in acute mania. Methods: Patients in acute phase of mania were assigned into two parallel groups given either lithium (blood level of 0.8- 1.1mEq/L) and risperidone 3 mg plus PEA 600 mg or placebo twice per day for 6 weeks. All participants were assessed with the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), and Extrapyramidal Symptom Rating Scale (ESRS) at baseline and weeks 1, 2, 4, and 6. Results: A total of 63 patients (32 in PEA and 31 in placebo groups) completed the trial. We found a significant effect for time × treatment interaction on the YMRS score (F = 5.22, df = 2.34, P-value = 0.004) from baseline to study endpoint. The independent t-test showed a significantly greater decrease in YMRS scores in the PEA group, compared with the placebo group, from baseline to weeks 4 and 6 (p-value = 0.018 and 0.002, respectively). There was no significant difference between PEA and placebo groups based on ESRS scores or ESRS changes in scores (p-value > 0.05). Conclusions: Our findings provide preliminary evidence that PEA is an effective adjunctive medication that improves manic symptoms and overall clinical status in acute episodes of mania. However, larger sample sizes and more extended follow-up therapy are needed in future studies to confirm our findings. This article is protected by copyright. All rights reserved.
Article
Background and objectives Over the past few decades, research has revealed complex interactions between type 2 diabetes mellitus (T2DM) and a wide range of comorbid conditions. The present paper sought to examine the relationship between bipolar disorder and T2DM and clarify the clinical impact of therapeutic interventions, highlighting the interpretation and implications of recent literature reports. Methods The PubMed electronic database was searched for keywords “bipolar disorder” AND “diabetes” OR “glucose”. Based on this literature search, 15 meta-analyses/systematic reviews and numerous research studies were identified that examined interrelationships between bipolar disorders and T2DM. Results Patients with bipolar disorder have higher rates of T2DM compared to the general population. Further, type 2 diabetic patients with comorbid bipolar disorder often experience deteriorated long-term glucose control and increased cardiovascular morbidity and mortality. Recent literature suggests shared risk factors and underlying disease mechanisms. In addition, genetic factors, sedentary life-style, lack of exercise, increased simple carbohydrate intake, adverse effects of bipolar pharmacotherapy, and bipolar depressive symptoms phenomenology may affect glucose metabolism. Conclusions The observed bidirectional interaction merits screening for psychiatric disorders in T2DM and vice versa to allow for early detection and treatment of this at risk population. Selection of drugs with neutral metabolic effects and dose individualization hold significant promise for optimizing therapy with antipsychotic and antidiabetic agents.
Article
Bipolar disorder (BD) is one of the most disabling diseases characterized by severe humor fluctuation. It is accompanied by cognitive and functional impairment in addiction to high suicide rates. BD is often underdiagnosed and treated incorrectly because many of the reported symptoms are not exclusive to the disorder. Once the diagnosis is exclusively clinical, it is not possible to state precisely. From that, proteomic approaches were used to identify, in a large scale, all proteins involved in cellular or tissue processes. This review aggregate data from blood proteomes, by using protein association network, of subjects with BD and healthy controls to suggest dysfunctional molecular pathways involved in disease. Original articles containing proteomic analysis were searched in PubMed. Seven studies were selected and data were extracted for posterior analysis. A protein-protein interaction network was created by STRING database. A final set of proteins in this network were employed as input in ClueGO and, the main biological process was visualized using R package pathview. The analysis revealed proteins associated with many biological processes, including growth and endocrine regulation, iron transportation, protease inhibition, protection against pathogens and cholesterol transport. Moreover, pathway analysis indicated the association of uncovered proteins with two main metabolic pathways: complement system and coagulation cascade. Thus, a better understanding on the pathophysiology of psychiatric disorders and the identification of potential biomarker candidates are essential to improve diagnostic, prognostic and design pharmacological strategies.
Article
Background Bipolar disorder may undertake a progressive course in a subset of patients, and research efforts have been made to understand the biological basis underlying this process. This systematic review examined the literature available on biological markers associated with illness progression in bipolar disorder. Methods Peer-reviewed articles were assessed using Embase, PsycINFO and PubMed, as well as from external sources. After initial screening, a total of 871 citations from databases and other sources were identified. Participants with a diagnosis of bipolar disorder were included in our systematic review; however, studies with participants younger than 15 or older than 65 were excluded. All studies were assessed using the Newcastle-Ottawa Scale assessment tool, and data pertaining to the results were extracted into tabular form using Google Sheets and Google Documents. The systematic review was registered on PROSPERO international prospective register of systematic reviews (ID Number: CRD42020154305). Results A total of 35 studies were included in the systematic review. Increased ventricular size and reduction of grey matter volume were the most common brain changes associated with illness progression in bipolar disorder. Among the several biomarkers evaluated in this systematic review, findings also indicate a role of peripheral inflammatory markers in this process. Discussion The studies evaluating the biological basis of the illness progression in bipolar disorder are still scarce and heterogeneous. However, current evidence supports the notion of neuroprogression, the pathophysiological process related to progressive brain changes associated with clinical progression in patients with bipolar disorder. The increase in peripheral inflammatory biomarkers and the neuroanatomical changes in bipolar disorder suggest progressive systemic and structural brain alterations, respectively.
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Purpose: To determine if enhanced flow cytometry (CellPrint™) can identify intracellular proteins of lithium responsiveness in monocytes and CD4+ lymphocytes from patients with bipolar disorder. Methods: Eligible bipolar I or II patients were openly treated with lithium for 16-weeks. Baseline levels of Bcl2, BDNF, calmodulin, Fyn, phospho-Fyn/phospho-Yes, GSK3β, phospho-GSK3αβ, HMGB1, iNOS, IRS2, mTor, NLPR3, PGM1, PKA C-α, PPAR-γ, phospho-RelA, and TPH1 in monocytes and CD4+ lymphocytes of lithium responders and non-responders were measured with CellPrint™. Their utility of discriminating responders from non-responders was explored. Protein-protein network and pathway enrichment analyses were conducted. Results: Of the 24 intent-to-treat patients, 12 patients completed the 16-week study. Eleven of 13 responders and 8 of 11 non-responders were available for this analysis. The levels of the majority of analytes in lithium responders were lower than non-responders in both cell types, but only the level of GSK3β in monocytes was significantly different (p = 0.034). The combination of GSK3β and phospho-GSK3αβ levels in monocytes correctly classified 11/11 responders and 5/8 non-responders. Combination of GSK3β, phospho-RelA, TPH1 and PGM1 correctly classified 10/11 responders and 6/7 non-responders, both with a likelihood of ≥ 85%. Prolactin, leptin, BDNF, neurotrophin, and epidermal growth factor/epidermal growth factor receptor signaling pathways are involved in the lithium treatment response. GSK3β and RelA genes are involved in 4 of 5 these pathways. Conclusion: CellPrint™ flow cytometry was able to detect differences in multiple proteins in monocytes and CD4+ lymphocytes between lithium responders and non-responders. A large study is warranted to confirm or refute these findings.
Article
Background Numerous studies have found elevated pro-inflammatory markers and reduced brain-derived neurotrophic factor (BDNF) during symptomatic episodes of bipolar disorder (BD) in adults. There is a paucity of research examining these markers in youth with BD, or longitudinally in any BD age group. Methods 79 adolescents, ages 13-19 years, were enrolled, including 43 symptomatic adolescents with BD and 36 age-matched healthy controls (HC). Blood samples were collected from all participants at intake, and repeatedly from BD participants at pre-specified intervals over the course of two years. Serum was assayed for levels of pro-inflammatory markers (c-reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor alpha [TNF-α]), BDNF and the anti-inflammatory marker, IL-10. Week-by-week severity of mood symptoms was assessed using semi-structured interviews. Results Adolescents with BD provided an average of 4.6 blood samples, on average every 5.0 months. During the most severe symptomatic interval (i.e., highest sum of mood symptom scores) among BD adolescents, levels of CRP (p=0.01) and pro- to anti-inflammatory ratios (CRP/IL-10 and IL-6/IL-10; p<0.05) were significantly greater, and IL-10 levels (p=0.004) were significantly lower, vs. HC. There were no differences between BD and HC in IL-6, TNF-α or BDNF. Within BD participants, higher BDNF (p=0.01) and IL-10 levels (p=0.001) significantly predicted greater burden of mood symptoms over the subsequent epoch. Moreover, higher CRP levels (p=0.009) at intake predicted greater time to recovery from the index symptomatic episode. Conclusions In the first repeated-measures study on this topic in adolescents with BD, we found evidence that CRP, an inexpensive and ubiquitous blood test, may be useful in predicting the prospective course of BD symptoms. Future larger studies are warranted.
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Bipolar disorder (BD) poses a significant public health concern, with roughly one‐quarter of sufferers attempting suicide. BD is characterized by manic and depressive mood cycles, the recurrence of which can be effectively curtailed through lithium therapy. Unfortunately, the most frequently employed lithium salt, lithium carbonate (Li2CO3), is associated with a host of adverse health outcomes following chronic use: these unwanted effects range from relatively minor inconveniences (e.g., polydipsia and polyuria) to potentially major complications (e.g., hypothyroidism and/or renal impairment). As these undesirable effects can limit patient compliance, an alternative lithium compound with a lesser toxicity profile would dramatically improve treatment efficacy and outcomes. Lithium orotate (LiC5H3N2O4; henceforth referred to as LiOr), a compound largely abandoned since the late 1970s, may represent such an alternative. LiOr is proposed to cross the blood–brain barrier and enter cells more readily than Li2CO3, which will theoretically allow for reduced dosage requirements and ameliorated toxicity concerns. This review addresses the controversial history of LiOr, complete with discussions of experimental and clinical efficacy, putative mechanisms of action, adverse effects, and its potential future in therapy.
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Objective Suicidal behavior and different mood states of bipolar I disorder (BD) have been shown to be associated with dysregulated proinflammatory cytokines. Only a few studies have examined the association between inflammation and SB in BD, and the association between proinflammatory cytokines, SB, and cognitive deficits in patients with BD remains unclear. Methods 77 patients with BD and 61 age-/sex-matched healthy controls were recruited. Patients were divided into two groups: with suicidal ideation (SI; n = 21) and no SI (n = 56). SI was defined by a score of ≥1 in item 10 of Montgomery Åsberg Depression Rating Scale. Levels of proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), and C-reactive protein (CRP), were measured, and cognitive function was assessed using 2-back task and Go/No-Go task. Results Patients with SI had higher levels of sTNF-αR1 than those without SI and the controls (p = .004). BD patients with or without a history of suicide attempt had higher levels of CRP than the controls. SI was associated with serum levels of sTNF-αR1 and IL-6sR, even after additionally controlling for working memory and inhibitory control (p < .05). Conclusion This study indicates that serum levels of sTNF-αR1 have distinct differences between BD patients with or without SI, and our findings strengthen the hypothesis of a link between suicidal behavior and neuro-inflammation pathophysiology in BD.
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Introduction: : The innate immune complex, an inflammasome complex has a role in the etiology of psychiatric disorders. Preclinical studies have demonstrated that the inflammasome activation leads to psychiatric disorders and clinical studies have proved that specific psychiatric illnesses are associated with aberrant levels of inflammatory cytokines and inflammasome. The inflammasome complex could be a major factor in the progression and pathology of psychiatric disorders. Area covered: : We discuss the pathogenesis of psychiatric disorders with respect to the activation of the inflammasome complex. Inflammasome-associated inflammatory cytokines are observed in patients and animal models of psychiatric disorders. The article also reflects on inflammasome regulatory options for the prevention and treatment of psychiatric disorders. Relevant literature available on PubMed from 1992 to 2021 has been included in this review. Expert opinion: : Modulating the inflammasome complex is a potential therapeutic strategy to treat symptom severity for patients with psychiatric disorders, particularly those with inflammasome-associated disorders. However, the nature of the psychiatric disorders should be considered when targeting inflammasome.
Article
Background Patients with bipolar disorder (BD) have increased plasma IL-6 levels, which are higher in depressed BD (dBD) than remitted BD (rBD). However, the mechanism that differentiates the cytokine levels between dBD and rBD is not understood. First, we determined whether brain-derived mtDNA can be detected in plasma using neuron-specific mutant Polg1 transgenic (Tg) mice. Second, we investigated whether the brain-derived plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) differentiate the cytokine levels between dBD and rBD. Methods Mouse plasma ccf-mtDNA levels were measured using real-time PCR targeting two regions of the mtDNA (CO1 and D-loop) in Tg mice and non-Tg littermates. Human plasma ccf-mtDNA levels were measured using real-time PCR targeting two regions of the mtDNA (ND1 and ND4) and IL-6 levels were evaluated in 10 patients in different states (depressed and remitted) of BD in a longitudinal manner and 10 healthy controls. Results The mouse plasma CO1/D-loop ratio was significantly lower in Tg than non-Tg mice (P = 0.0029). Human plasma ccf-mtDNA copy number, ND4/ND1 ratio, and IL-6 levels were not significantly different between dBD and rBD. Human plasma ccf-mtDNA levels showed a nominal significant correlation with delusional symptoms (P = 0.033, ρ = 0.68). Limitations A larger sample size is required to generalize the results and to determine whether plasma ccf-mtDNA is associated with systemic inflammation. Conclusions Tg mice revealed that brain-derived mtDNA could be present in peripheral blood. The present findings did not coincide with our hypothesis that plasma ccf-mtDNA differentiates the cytokine levels between dBD and rBD.
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A growing number of studies support a bidirectional relationship between inflammation and bipolar disorders. Tumor Necrosis Factor-α (TNF-α) inhibitors have recently attracted interest as potential therapeutic compounds for treating depressive symptoms, but the risk for triggering mood switches in patients with or without bipolar disorders remains controversial. Thus, we conducted a systematic review to study the anti-TNF-α medication-induced manic or hypomanic episodes. PubMed, Scopus, Medline, and Embase databases were screened for a comprehensive literature search from inception until November 2020, using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Out of the initial 75 references, the screening resulted in the inclusion of 4 case reports (each describing one patient) and a cohort study (in which 40 patients out of 7600 – 0.53% – experienced elated mood episodes after infliximab administration). Of these 44 patients, 97.7% experienced a manic episode and 2.3% hypomania. 93.2% of patients had no history of psychiatric disorder or psychotropic treatment. Only 6.8% had a history of psychiatric disorders with the affective spectrum (4.6% dysthymia and 2.3% bipolar disorder). The time of onset of manic or hypomanic symptoms varied across TNF-α inhibitors with an early onset for Infliximab and a later onset for Adalimumab and Etanercept. These findings suggest that medications targeting the TNF-α pathway may trigger a manic episode in patients with or without affective disorders. However, prospective studies are needed to evaluate the relative risk of such side effects and identify the population susceptible to secondary mania. This article is protected by copyright. All rights reserved.
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The will to live and the ability to maintain one’s well-being are crucial for survival. Yet, almost a million people die by suicide globally each year (Aleman and Denys, 2014), making premature deaths due to suicide a significant public health problem (Saxena et al., 2013). The expression of suicidal behaviors is a complex phenotype with documented biological, psychological, clinical, and sociocultural risk factors (Turecki et al., 2019). From a brain disease perspective, suicide is associated with neuroanatomical, neurophysiological, and neurochemical dysregulations of brain networks involved in integrating and contextualizing cognitive and emotional regulatory behaviors. From a symptom perspective, diagnostic measures of dysregulated mood states like major depressive symptoms are associated with over sixty percent of suicide deaths worldwide (Saxena et al., 2013). This paper reviews the neurobiological and clinical phenotypic correlates for mood dysregulations and suicidal phenotypes. We further propose machine learning approaches to integrate neurobiological measures with dysregulated mood symptoms to elucidate the role of inflammatory processes as neurobiological risk factors for suicide.
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Background According to the diathesis-stress model, some individuals may have a certain underlying vulnerability (diathesis) that can be environmental or biological, such as a childhood trauma or a genetic predisposition. Hence, it is important to understand the epigenetic factors and the presence of biomarkers related to mental illness and suicide risk. Objective The present study aimed to evaluate if the presence of rs1800871 (IL- 10), rs2020933 (5-HTT) and rs1800629 (TNF – α) polymorphisms express different outcomes in terms of physical, psychological health and quality of life, considering the relations among them and the social environment, through observation of the psychological, physical, environment domains and the quality of social relations. Method A multivariate analysis (MANOVA) of the data was conducted, in which 481 participants were assessed through the instruments Quality of Life Brief Questionnaire (QOL – brief), Beck's Scale of Suicide Ideation (BSI) and the Mini International Neuropsychiatric Interview (MINI 5.5.0). The participants´ DNA was collected through a saliva sample of the oral mucosa. From the studied sample, 306 participants had mental disorder (MD) with no history of suicide attempt (HSA), 145 showed MD with HSA and 175 participants. Results A statistically significant difference (0.001 and 0.004) was found in the interaction of two factors, namely the social relationships domain and the presence of the IL- 10 polymorphism, leading to increased suicide risk and lower levels of quality of life in the physical domain. The interaction between the rs1800871 (IL-10) polymorphism and lower levels of quality of life in the environment and social environment domains appears to be related to a worse perception of physical health and a higher risk of suicide, which highlights the epigenetic influence for both physical and mental illness.
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Background Neurobiological research frequently implicates inflammatory and neurogenic components with core aspects of bipolar disorder. Even in periods of symptom remission (euthymia), individuals with bipolar disorder experience cognitive impairments, which are increasingly being proposed as an outcome for interventions; identifying biomarkers associated with cognitive impairment in people with bipolar disorder could advance progress in this therapeutic field through identifying biological treatment targets. Aims We aimed to identify proteomic biomarker correlates of cognitive impairment in individuals with euthymic bipolar disorder. Method Forty-four adults with a bipolar disorder diagnosis in euthymia underwent a battery of cognitive assessments and provided blood for biomarkers. We examined a comprehensive panel of inflammatory and trophic proteins as putative cross-sectional predictors of cognition, conceptualised according to recommended definitions of clinically significant cognitive impairment (binary construct) and global cognitive performance (continuous measure). Results A total of 48% of the sample met the criteria for cognitive impairment. Adjusting for potentially important covariates, regression analyses identified lower levels of three proteins as significantly and independently associated with cognitive deficits, according to both binary and continuous definitions (interleukin-7, vascular endothelial growth factor C and placental growth factor), and one positively correlated with (continuous) global cognitive performance (basic fibroblast growth factor). Conclusions This study identifies four candidate markers of cognitive impairment in bipolar disorder, none of which have been previously compared with cognitive function in participants with bipolar disorder. Pending replication in larger samples and support from longitudinal studies, these markers could have implications for treating cognitive dysfunction in this patient population.
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Background: Euthymic patients with bipolar disorder reportedly demonstrated increased levels of proinflammatory cytokines and cognitive function deficits. Because uncertain differences exist in cognitive function and proinflammatory cytokines between remitted bipolar I (BD1) and bipolar II (BD2) disorders, we performed this study to further investigate these differences. Method: We enrolled 58 patients with remitted BD1 and 27 with remitted BD2, and matched them for age and sex with 51 controls. Proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), C-reactive protein, and soluble tumor necrosis factor receptor 1 (sTNFR1) were measured, and performance in the Word List Memory Task (WLMT) and Wisconsin Card Sorting Task (WCST) was assessed. Results: Significantly elevated levels of sTNFR1 were observed among patients with BD1 (p < .001) and BD2 (p = .038) compared with the controls; however, they did not differ between patients with BD1 and BD2 (p =.130). Working memory deficit measured by the WLMT was significantly greater in patients with BD1 (p < .001) and BD2 (p < .05) compared with controls, but did not differ between patients with BD1 and BD2 (p > 0.1). Furthermore, sTNFR1 levels were negatively correlated with cognitive function measured using the WLMT and WCST (all p < .05). Discussion: Our results showed that euthymic patients with BD1 and BD2 showed similar levels of sTNFR1 and cognitive function (especially working memory) impairments. Further investigation is required to explore whether a common pathophysiology may contribute to the shared inflammatory and cognitive alterations between BD1 and BD2.
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Increasing evidence exists that heavy metals modulate T helper cell (Th) responses and thereby elicit various pathological manifestation. Interleukin (IL)-12, a crucial innate cytokine, was found to be regulated by such xenobiotic agents. This study aimed at testing whether IL-12 profiles may be indicative of heavy metals-induced immunomodulation. Human immunocompetent cells, activated either by monoclonal antibodies or heat-killed Salmonella enterica, were cultured in the absence or presence of cadmium (Cd) acetate or mercuric (Hg) chloride. In vivo experiments were set up where BALB/c mice were exposed to sub-lethal doses of Cd or Hg salts for 3 or 5 weeks. Cytotoxicity was assessed by MTT-reduction assay. Modulation of cytokine profiles was evaluated by enzyme-linked immunosorbent assay (ELISA), cytometric bead-based array (CBA) and real-time polymerase chain reaction (RT-PCR); the relevance of these methods of cytokine quantification was explored. Modulation of IL-12 profiles in Cd- or Hg-exposed human PBMC was dose-dependent and significantly related to IFN-gamma levels as well as to the Th1- or Th2-polarized responses. Similarly, skewing the Th1/Th2 ratios in vivo correlated significantly with up- or down-regulation of IL-12 levels in both cases of investigated metals. It can be inferred that: (i) IL-12 profiles alone may represent a relevant indicator of heavy metal-induced immune modulation; (ii) evaluating cytokine profiles by CBA is relevant and can adequately replace other methods such as ELISA and RT-PCR in basic research as well as in immune diagnostics; and (iii) targeting IL-12 in therapeutic approaches may be promising to modify Th1/Th2-associated immune disorders.
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Our knowledge concerning immune functioning in bipolar affective disorder (BAD) is limited, while lithium's immunomodulatory effects seem multiple and conflicting. Our aim was to evaluate cytokine production and lithium's effect on it in BAD patients, using ELISPOT technique as a sensitive tool. Cytokine (IL-2, IL-6, IL-10 and IFN-gamma) production from isolated peripheral blood lymphocytes (PBLs) was evaluated (ELISPOT technique) in 40 euthymic BAD patients under chronic lithium treatment, in 20 healthy volunteers, and in 10 never medicated BAD patients before and after the introduction of lithium therapy. In all cases, cytokine plasma levels were also measured using ELISA. BAD patients under chronic lithium treatment had significantly lower numbers of IL-2, IL-6, IL-10 and IFN-gamma secreting cells compared to healthy volunteers. The number of cytokine secreting cells decreased in never medicated patients after 3 months of lithium treatment. In vitro stimulation of PBLs with lithium did not affect the number of cytokine secreting cells either in the patients or in the healthy volunteers. The significantly lower number of PBLs producing cytokines (IL-2, IL-6, IL-10 and IFN-gamma) in euthymic BAD patients under chronic lithium treatment result from the long-term (over 3 months) lithium administration. In vitro stimulation of PBLs with lithium did not change the number of cytokine producing cells. Our findings may be useful in elucidating possible downregulatory effects of lithium in humans.
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Since the inception of Brain, Behavior and Immunity twenty years ago, many exciting developments have occurred regarding the relationship between depression and the immune system. These developments have increasingly put the field of psychoneuroimmunology into a clinical context with important translational implications. Initial studies focused on the impact of depression on relatively narrowly defined immunologic endpoints, which ultimately found their relevance in studies examining the effect of depression on immunologically-based diseases including infectious illnesses, autoimmune disorders, and cancer as well as more recently cardiovascular disease. Mechanistic studies have also greatly contributed to an understanding of those facets of depression, which might mediate these effects. More recently, the reciprocal influences of the immune system on the brain and behavior including depression have taken center stage. Increasing data now indicate that activated inflammatory processes can influence multiple aspects of CNS function including neurotransmitter metabolism, neuroendocrine function, and information processing leading to behavioral changes in humans that bespeak depression. These latter developments have intrigued scientists investigating the pathophysiology of depression and warrant consideration as some of the most exciting new developments in psychiatry in the past 20 years. What the future holds is a world of promise as multiple translational targets derived from the cytokine model of depression work their way into the clinical arena as drug targets for further development. Moreover, the work has served to instantiate brain-immune interactions as an essential component in psychiatric and medical co-morbidities and their impact on health and illness.
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Bipolar disorder (BPD) is characterized by recurrent episodes of disturbed affect including mania and depression as well as changes in psychovegetative function, cognitive performance, and general health. A growing body of data suggests that BPD arises from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits. Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In addition, commonly used mood-stabilizing drugs that are effective in treating BPD have been shown to target intracellular signaling pathways that control synaptic plasticity and cellular resilience. In this article we draw on clinical, preclinical, neuroimaging, and post-mortem data to discuss the neurobiology of BPD within a conceptual framework while highlighting the role of neuroplasticity in the pathophysiology and treatment of this disorder.
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Initial descriptions of bipolar disorder (BD) emphasized that patients returned to a baseline condition after acute episodes. Such definitions were operational in teasing bipolar disorder apart from schizophrenia, where patients were described to be permanently impaired after the initial episodes. However, this view of BD as a disorder where cognition and overall functioning was spared has been changing after the scrutiny of new research. Currently, the cognitive impairment and neuroanatomical changes related to cumulative mood episodes, particularly manic episodes, are well described. In terms of neuropathological findings, recent data suggest that changes in neuronal plasticity, particularly in cell resilience and connectivity, are the main findings in BD. Data from differential lines of research converge to BDNF as an important contributor to the pathophysiology of BD. Serum BDNF levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. Moreover, factors that negatively influence the course of BD, such as life stress and trauma, have been shown to be associated with a decrease in serum BDNF levels among bipolar patients. These findings suggest that BDNF plays a central role in the transduction of psychosocial stress and recurrent episodes into the neurobiology of bipolar disorder. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD.
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Sodium valproate (VPA) is frequently used to treat epilepsy and convulsive disorders. Several reports have indicated that anti-epileptic drugs (AED) affect the immune system, but the mechanism has not been clear. We examined whether the commonly used AEDs, diazepam (DZP), carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and VPA, can inhibit activation of the nuclear transcription factor kappa B (NF-κB), in human monocytic leukemia cells (THP-1) and in human glioma cells (A-172). NF-κB is essential to the expression of the kappa light chain of immunoglobulin and proinflammatory cytokines. Electrophoretic mobility shift assays (EMSA) of nuclear extracts demonstrated that VPA inhibits NF-κB activation induced by lipopolysaccharide (LPS), but the other AEDs do not. Western blot analysis revealed that this inhibition is not linked to preservation of expression of IκBα protein. Chloramphenicol acetyltransferase (CAT) assay indicated that NF-κB-dependent reporter gene expression is suppressed in glioma cells pretreated with VPA. VPA significantly inhibited LPS-induced production of TNF-α and IL-6 by THP-1 cells, whereas other AEDs did not. The findings are consistent with the idea that VPA suppresses TNF-α and IL-6 production via inhibition of NF-κB activation. Our results suggest that VPA can modulate immune responses in vitro. These findings raise the possibility that such modulation might occur with clinical use of VPA.
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Now that peptides are no longer considered too large to cross the blood–brain barrier, attention has turned to the possibility that larger substances like polypeptides might also enter the central nervous system (CNS). This review summarizes evidence showing that many cytokines and neurotrophins not only enter the brain but also enter the spinal cord, sometimes faster than into the brain.
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Sodium valproate (VPA) is frequently used to treat epilepsy and convulsive disorders. Several reports have indicated that anti-epileptic drugs (AED) affect the immune system, but the mechanism has not been clear. We examined whether the commonly used AEDs, diazepam (DZP), carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and VPA, can inhibit activation of the nuclear transcription factor kappa B (NF-kappaB), in human monocytic leukemia cells (THP-1) and in human glioma cells (A-172). NF-kappaB is essential to the expression of the kappa light chain of immunoglobulin and proinflammatory cytokines. Electrophoretic mobility shift assays (EMSA) of nuclear extracts demonstrated that VPA inhibits NF-kappaB activation induced by lipopolysaccharide (LPS), but the other AEDs do not. Western blot analysis revealed that this inhibition is not linked to preservation of expression of IkappaBalpha protein. Chloramphenicol acetyltransferase (CAT) assay indicated that NF-kappaB-dependent reporter gene expression is suppressed in glioma cells pretreated with VPA. VPA significantly inhibited LPS-induced production of TNF-alpha and IL-6 by THP-1 cells, whereas other AEDs did not. The findings are consistent with the idea that VPA suppresses TNF-alpha and IL-6 production via inhibition of NF-kappaB activation. Our results suggest that VPA can modulate immune responses in vitro. These findings raise the possibility that such modulation might occur with clinical use of VPA.
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There is a convincing body of evidence linking depression, cardiovascular disease, and mortality. There is also growing evidence that depression is a risk factor for congestive heart failure (CHF) and that CHF patients with major depression have higher rates of mortality and repeat hospitalizations. Currently there are no proposed neurobiological or neuroimmune mechanisms for the comorbidity of heart failure and depression. This review focuses on the recent literature about the role of cytokines in CHF and depression as separate conditions. This review also attempts to identify the overlapping immunological mechanisms that have a potential for future research in the pathophysiology of comorbid depression and CHF. Results of current studies suggest that cytokines exert deleterious effects on the heart and that soluble tumor necrosis factor (TNF) receptor 2 leads to reversal of the cardiotoxic effects of TNF, although the clinical significance of this is unclear. Major depression has been associated with alteration of various aspects of the innate immune system, including cellular components (such as microphages, neutrophils, and natural killer cells) and soluble mediators (such as acute-phase reaction proteins and cytokines). It is inconclusive whether antidepressants have immunoregulatory effects. The literature has not yet addressed the role of cytokines in comorbid depression and CHF. But cytokines may provide a new avenue in understanding brain-body interaction in depression and heart failure.
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The brain controls both the physiologic and the behavioral coping responses to daily events as well as major stressors, and the nervous system is itself a target of the mediators of those responses through circulating hormones. The amygdala and hippocampus interpret what is stressful and regulate appropriate responses. The amygdala becomes hyperactive in posttraumatic stress disorder (PTSD) and depressive illness, and hypertrophy of amygdala nerve cells is reported after repeated stress in an animal model. The hippocampus expresses adrenal steroid receptors. It undergoes atrophy in several psychiatric disorders and responds to repeated stressors with decreased dendritic branching and reduction in number of neurons in the dentate gyrus. Stress promotes adaptation ("allostasis"), but a perturbed diurnal rhythm or failed shutoff of mediators after stress ("allostatic state") leads, over time, to wear and tear on the body ("allostatic load"). Neural changes mirror the pattern seen in the cardiovascular, metabolic, and immune systems, that is, short-term adaptation versus long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in brain. Allostatic load is seen in major depressive illness and may also be expressed in other chronic anxiety disorders such as PTSD and should be documented.
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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 pro-inflammatory and anti-inflammatory cytokines in both phases of bipolar affective disorder (BPAD). Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in patients with BPAD who were depressed, or manic and in healthy controls. Bipolar depression had significantly higher production of the pro-inflammatory cytokines, IL-8 (p < 0.001) and TNF-alpha (p < 0.05) compared to healthy subjects. The manic group also had increased production of IL-8 (p < 0.05) and TNF-alpha (p < 0.001) as compared to healthy subjects. Anti-inflammatory cytokine levels did not differ across the 3 groups. A small sample size was studied. All patients remained on medication for this study. BPAD is associated with increased production of pro-inflammatory cytokines both in the manic and in the depressed phase as compared to healthy subjects. This is the first study, which examined both mania and bipolar depression.
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A number of lines of converging evidence suggest that brain-derived neurotrophic factor (BDNF) may play a role in the onset and treatment of bipolar disorder. We review pertinent data on BDNF from several different areas of preclinical and clinical investigation that suggest novel theoretical and treatment implications for the recurrent affective disorders. Data from several recent studies have also converged showing that the val66met allele of BDNF, a common single nucleotide polymorphism (SNP), is associated with selective minor deficits in cognitive functioning in subjects with schizophrenia, bipolar illness, and normal controls. Yet, paradoxically, the better functioning val66val allele of BDNF appears to be associated with an increased risk for bipolar disorder and perhaps early onset or rapid cycling. All the primary antidepressant modalities, as well as the mood stabilizers lithium and valproate, increase BDNF. Stressors decrease BDNF and this effect can be blocked by antidepressants. Serum BDNF is low in proportion to the severity of mania and depression and increases with clinical improvement. Assessment of the val66val BDNF allele and a range of other SNPs as potential vulnerability factors for bipolar illness and its early onset could facilitate studies of early intervention, help reduce long delays between the onset of first symptoms and the first treatment, and help in the prediction of individual patient's likelihood of responding to a given treatment.
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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. 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. 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. The effect of various types of mood stabilizers on cytokine production should be considered. These findings suggest that the increased activity of pro-inflammatory cytokines and an imbalance between pro-inflammatory and anti-inflammatory cytokines may play a role in the pathophysiology of bipolar disorder.
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Recent technological advances offer an opportunity to further elucidate the complex cytokine network in Major Depressive Disorder (MDD). Twenty cytokines were simultaneously assessed in 49 individuals with MDD and 49 age and gender matched controls. Multiple pro-inflammatory and two anti-inflammatory cytokines were significantly elevated in the MDD sample, including an antidepressant naïve subset. These data support a generalized chronic inflammatory state in MDD, and implicate additional cytokines and chemokines previously linked to cardiovascular disease.
Article
To characterize the immunological variations of patients with a bipolar disorder (BD) diagnosis in manic (BDm) and depressive (BDd) phases, by the quantification of the serum levels of interleukin (IL)-1beta, -2, -4, -6 and tumor necrosis factor alpha (TNF-alpha). Twenty physically healthy patients with a BD type I diagnosis and 33 matched controls were studied, after giving informed consent. The inclusion criteria included at least three weeks without any kind of psychopharmacological treatment, Young Mania Rating Scale score > or =20 for BDm (n = 10) and Hamilton Depression Rating Scale score > or =21 for BDd patients (n = 10). Exclusion criteria included any infectious diseases, allergies or any other kind of medical illness that required treatment with immunosuppressors, as well as any other diagnosis in Axis I. Physical and laboratory examinations were performed to rule out any clinical illness. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the serum cytokines concentration. BD patients, when compared to controls, showed significant differences (p < or = 0.05) in the serum levels of the measured cytokines. The sub-group of BDd patients showed an increase in IL-6 and TNF-alpha, as well as a decrease in IL-2 concentration. The BDm sub-group, on the other hand, showed an increase in TNF-alpha and IL-4 values, with a low concentration of IL-1 and IL-2. The comparison between both sub-groups suggests that there is a distinctive cytokine pattern for the specific phases of the disorder: for mania, we found a high IL-4 and low IL-1beta and IL-6 concentration, while in the depressive phase, the inverse pattern was found. Our results show the existence of phasic differences in the serum levels of cytokines in BD.
Article
Radiation pneumonitis (RP) is a restricting complication of non-small-cell lung cancer irradiation. Three-dimensional conformal radiotherapy (3D-CRT) represents an advance because exposure of normal tissues is minimised. This study tries to identify prognostic factors associated with severe RP. Eighty patients with stage IIIA (20%) and IIIB (80%) NSCLC treated with cisplatin- based induction chemotherapy followed by concurrent chemotherapy and hyperfractionated 3D-CRT (median dose: 72.4 Gy, range: 54.1-85.9) were retrospectively evaluated. Acute and late RP were scored using RTOG glossary. Potential predictive factors evaluated included clinical, therapeutic and dosimetric factors. The lungs were defined as a whole organ. Univariate and multivariate analyses were performed. Early and late RP grade>or=3 were observed in two patients (2%) and 10 patients (12%), respectively. Five patients (6%) died of pulmonary toxicity, 3 of whom had pre-existing chronic obstructive pulmonary disease (COPD). Median time to occurrence of late RP was 4.5 months (range: 3-8). Multivariate analysis showed that COPD (OR=10.1, p=0.01) and NTCPkwa>30% (OR=10.5, p=0.007) were independently associated with late grade>or=3 RP. Incidence of RP>or=3 grade for patients with COPD and/or NTCPkwa>30% was 25% vs. 4% for patients without COPD and NTCPkwa<30% (p=0.01). Risk of severe RP was higher for patients with COPD and/or NTCPkwa>30% (OR=7.3; CI 95%=1.4-37.3, p=0.016). COPD and NTCP are predictive of severe RP. Careful medical evaluation and meticulous treatment planning are of paramount importance to decrease the incidence of severe RP.
Article
To study the ex vivo interleukin (IL)-1beta and IL-6 production of monocytes in bipolar disorder (BD) patients in the absence/presence of lithium. Monocytes of outpatients with DSM-IV BD (n=80, of whom 64 were lithium-treated) and of healthy control subjects (n=59) were cultured in vitro and exposed (24 h) or not exposed to lipopolysaccharide (LPS) and/or graded concentrations of lithium chloride (LiCl). IL-1beta and IL-6 production was assessed by enzyme-linked immunosorbent assay (ELISA) (supernatants). Monocytes stimulated by LPS from non-lithium-treated bipolar patients were characterized by an abnormal IL-1beta/IL-6 production ratio, i.e., low IL-1beta and high IL-6 production. Lithium treatment increased IL-1beta and decreased IL-6 production and thus restored the aberrant ratio. In vitro exposure of monocytes to LiCl did not have the same effects as lithium treatment: the procedure decreased IL-1beta production and had minimal effects on IL-6 production. Blood monocytes have an altered proinflammatory status in BD. Lithium treatment restores this altered status. Short-term in vitro exposure of monocytes to lithium has other effects than lithium treatment.
Article
To investigate whether the cox-2 inhibitor celecoxib has antidepressant effects in bipolar disorder (BD) patients during depressive or mixed phases. We studied 28 DSM-IV BD patients who were experiencing a depressive or mixed episode and were on a stable dose of a mood stabilizer or atypical antipsychotic medication. Subjects were randomized to receive 6 weeks of double-blind placebo or celecoxib (400 mg/day) treatment. Current mood stabilizer or antipsychotic medication remained at the same doses during the trial. Intention-to-treat analysis showed that the patients receiving celecoxib had lower Hamilton Depression Rating Scale (HamD) scores after 1 week of treatment compared to the patients receiving placebo, but this difference was not statistically significant (p = 0.09). The improvement in the first week of treatment was statistically significant when the analysis included only the subjects who completed the full 6-week trial (p = 0.03). The two groups did not differ significantly on depressive or manic symptoms from the second week until the end of the trial. Celecoxib was well tolerated with the exception of two subjects who dropped out of the study due to rash. Our findings suggest that adjunctive treatment with celecoxib may produce a rapid-onset antidepressant effect in BD patients experiencing depressive or mixed episodes.
Article
Current literature on the effects of chronic stress in general health converges to the concept of allostatic load (AL). AL is the bodily 'wear and tear' that emerges with sustained allostatic states. In the field of bipolar disorder (BD), AL offers an important clue as to why patients who undergo recurrent mood episodes are clinically perceived as less resilient. In addition, AL helps explaining the cumulative disruptive health effects of intermittent episodes and stressors. Stress- and episode-induced changes in brain regions involved in the emotional circuitry may lead to dysfunctional processing of information, which would render BD patients more vulnerable to subsequent environmental stressors, episodes, and drugs of abuse. Mood stabilizing agents exert opposite effects than chronic stress in neurons, increasing neuroprotective factors what may help to quench the cycle of affective episode recurrence and neural and bodily deterioration. Therefore, AL provides an explanatory link to apparently unrelated findings such as cognitive impairment and higher rates of physical comorbidity and mortality that are observed in the course of BD and further highlight the importance of effective long-term prophylaxis.
Article
The pathophysiology of bipolar disorder (BD) is poorly understood. An emerging body of evidence points to impairments in neuroplasticity, cell resilience and neuronal survival as the main neuropathological correlates of BD. It has been suggested that inflammatory cytokines, particularly TNF-alpha may play a critical role in this process. In the present review we examine the evidence suggesting that TNF-alpha regulates apoptotic cascades which may be related to neuronal and glial loss in BD. Current evidence suggests that an increase in serum levels of TNF-alpha takes place during manic and depressive episodes. The present article reviews the therapeutic implications of TNF-alpha signaling pathways involvement in the pathophysiology of BD.
Cytokine profiles in bipolar disorder: focus on acutely ill patients
  • O 'brien
  • S M Scully
  • P Scott
  • L V Dinan
O'Brien, S.M., Scully, P., Scott, L.V., Dinan, T.G., 2006. Cytokine profiles in bipolar disorder: focus on acutely ill patients. J. Affect. Disord. 90, 263-267.
Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder
  • R Schloesser
  • J Huang
  • P Klein
  • H Manji
Schloesser, R., Huang, J., Klein, P., Manji, H., 2008. Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 33, 110-133.
Depressive disorders and immunity: 20 years of progress and discovery
  • Irwin
Irwin, M., Miller, A., 2007. Depressive disorders and immunity: 20 years of progress and discovery. Brain. Behav. Immun. 21, 374-383.
Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder
  • Schloesser