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Dysregulation of the NF-κB pathway as a potential inducer of bipolar disorder
... The NF-κB signaling pathway, as part of the immune system, leads to the activation of proinflammatory cytokines and ultimately to inflammation. [21] Also, it is activated by acute stress and sleep disorders and may be involved in cellular responses to stressful life events. [22] So, it may be related to BD. [7,21,23] Although few studies have been conducted. ...
... [21] Also, it is activated by acute stress and sleep disorders and may be involved in cellular responses to stressful life events. [22] So, it may be related to BD. [7,21,23] Although few studies have been conducted. ...
... This lncRNA reduces the inflammatory pathway by increasing the stability of the IKB/NF-κB complex in the cytoplasm and prevents NF-κB enter the nucleus. [21,26] In this study, by reducing the expression of NKILA, the IKB/NF-κB complex may be less stable than normal and will cause more inflammation when NF-κB enters the nucleus. Unlike David J Miklowitz's study in which the expression of the NF-κB gene was increased in BD compared to healthy individuals, [7] our results indicated that the difference in expression of this gene between patients and healthy individuals was not significant, which could further highlight the role of the sample size and the involvement of factors other than the inflammatory pathway. ...
Bipolar disorder (BD) is a severe condition characterized by periods of mania and depression. Despite advances in the neurobiology of bipolar disorder, the exact etiology of the disease remains unclear. There is evidence that Inflammation is associated with bipolar disorder. COX-2 and NF-κB are two critical mediators in the inflammatory pathways. Long non-coding RNAs (lncRNAs) are a new class of non-coding RNAs that play a wide range of roles, especially in developing and maintaining normal brain functions. Two lncRNAs called PACER and NKILA control the expression of COX-2 and NF-κB genes, respectively. In this study, Expression levels of PACER and NKILA lncRNAs, as well as, COX-2 and NF-κB genes were measured in fifty patients with bipolar disorder and 50 healthy individuals by real-time PCR. Expression levels of NKILA and COX2 were considerably reduced in BD patients compared with healthy controls. Such significant downregulation in the expression of NKILA and PACER was only observed in male patients with BD compared with male healthy subjects. Also, according to the results of the ROC curve, the area under curve values for NKILA and COX2 were 0.68 and 0.52 respectively. Consequently, the NKILA gene could be considered a biomarker. By examining the degree of pairwise correlation between genes, all genes had a significant positive correlation with each other. Taken together, these results revealed a function for NKILA and PACER lncRNAs in the pathogenesis of BD.
... TNF-α has been shown to increase serotonin transporter activity in mice [87]. Patients with BD presented increased blood levels of inflammatory components, during acute affective episodes in particular [4][5][6][88][89][90], and levels of inflammatory constituents were found to be elevated in the postmortem brain [16,17] and CSF [13][14][15]91] of BD patients as compared to matched control subjects. A systematic review amalgamating 22 studies found a strong positive association between elevated IL-6 levels in blood, CSF and the postmortem brain and suicidal ideation and/or attempts or death [92]. ...
... Therefore, we tested the effects of low-dose Li and low-dose aspirin on plasma and brain IL-6 and TNF-α levels of LPS-treated rats to explore their anti-inflammatory properties when administered each by themselves or in combination. We scrutinized these two cytokines because a large body of data links them to the pathophysiology and treatment of BD, as well as to other psychiatric conditions [4,5,[13][14][15]17,88,89,[91][92][93][94]. As summarized in Table 1, LPS administration resulted in a significant increase in plasma and brain IL-6 and TNF-α levels. ...
... Similarly, several studies have demonstrated that aspirin attenuates NF-κB elicitation [99,112]. These findings corroborate the accumulating data attesting to altered NF-κB activity/levels in bipolar patients [18,89,113,114]. In preliminary rat experiments in our lab [Uzzan, Shvartsur and Azab-personal communication] exploring whether chronic low-dose Li or low-dose aspirin, as compared with their combination, influence NF-κB activity, FC, HT and HC nuclear p65 levels were measured. ...
... TNF-α has been shown to increase serotonin transporter activity in mice [87]. Patients with BD presented increased blood levels of inflammatory components, during acute affective episodes in particular [4][5][6][88][89][90], and levels of inflammatory constituents were found to be elevated in the postmortem brain [16,17] and CSF [13][14][15]91] of BD patients as compared to matched control subjects. A systematic review amalgamating 22 studies found a strong positive association between elevated IL-6 levels in blood, CSF and the postmortem brain and suicidal ideation and/or attempts or death [92]. ...
... Therefore, we tested the effects of low-dose Li and low-dose aspirin on plasma and brain IL-6 and TNF-α levels of LPS-treated rats to explore their anti-inflammatory properties when administered each by themselves or in combination. We scrutinized these two cytokines because a large body of data links them to the pathophysiology and treatment of BD, as well as to other psychiatric conditions [4,5,[13][14][15]17,88,89,[91][92][93][94]. As summarized in Table 1, LPS administration resulted in a significant increase in plasma and brain IL-6 and TNF-α levels. ...
... Similarly, several studies have demonstrated that aspirin attenuates NF-κB elicitation [99,112]. These findings corroborate the accumulating data attesting to altered NF-κB activity/levels in bipolar patients [18,89,113,114]. In preliminary rat experiments in our lab [Uzzan, Shvartsur and Azab-personal communication] exploring whether chronic low-dose Li or low-dose aspirin, as compared with their combination, influence NF-κB activity, FC, HT and HC nuclear p65 levels were measured. ...
Mounting evidence suggests that immune-system dysfunction and inflammation play a role in the pathophysiology and treatment of mood-disorders in general and of bipolar disorder in particular. The current study examined the effects of chronic low-dose aspirin and low-dose lithium (Li) treatment on plasma and brain interleukin-6 and tumor necrosis factor-α production in lipopolysaccharide (LPS)-treated rats. Rats were fed regular or Li-containing food (0.1%) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. On days 21 and 42 rats were injected with 1 mg/kg LPS or saline. Two h later body temperature was measured and rats were sacrificed. Blood samples, the frontal-cortex, hippocampus, and the hypothalamus were extracted. To assess the therapeutic potential of the combined treatment, rats were administered the same Li + aspirin protocol without LPS. We found that the chronic combined treatment attenuated LPS-induced hypothermia and significantly reduced plasma and brain cytokine level elevation, implicating the potential neuroinflammatory diminution purportedly present among the mentally ill. The combined treatment also significantly decreased immobility time and increased struggling time in the forced swim test, suggestive of an antidepressant-like effect. This preclinical evidence provides a potential approach for treating inflammation-related mental illness.
... Anxiety is a common feature among patients with depressive disorders, including post-stroke (depressed) patients. A large body of data has linked NF-κB to the pathophysiology and treatment of mood disorders [50][51][52][53]. For instance, it was found that NF-κB levels are elevated in patients with mood disorders [50,53] and that psychotropic drugs alter the function of the NF-κB machinery [51]. ...
... A large body of data has linked NF-κB to the pathophysiology and treatment of mood disorders [50][51][52][53]. For instance, it was found that NF-κB levels are elevated in patients with mood disorders [50,53] and that psychotropic drugs alter the function of the NF-κB machinery [51]. Therefore, in the present study, we examined the effects of MEDS-23 treatment on the behavioral phenotype of post-MCAO rats in two models used for the assessment of depressive-like and anxiety-like behaviors: the sucrose consumption test and the elevated plus-maze test, respectively. ...
Aim:
Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats.
Main methods:
Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments.
Key findings:
MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α.
Significance:
These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.
... When considering the potential role of TNFR2 in mood disorders, it is also notable that several pathways activated during transmembrane TNFR2 forward signaling have been implicated in mood disorder pathology, including mitogen-activated protein kinase, 79,80 PI3K/Akt 81 and NF-jB signaling. 82,83 For instance, mitogen-activated protein kinase blockade induces depressive symptoms in rats and inhibits the antidepressant effects of ketamine. 80 Elevated NF-jB activity has been implicated in bipolar disorder, 83 with adolescent bipolar disorder patients showing increased NF-jB activation in peripheral blood and immune cells, compared with healthy control individuals. ...
... 82,83 For instance, mitogen-activated protein kinase blockade induces depressive symptoms in rats and inhibits the antidepressant effects of ketamine. 80 Elevated NF-jB activity has been implicated in bipolar disorder, 83 with adolescent bipolar disorder patients showing increased NF-jB activation in peripheral blood and immune cells, compared with healthy control individuals. 82 Furthermore, recombinant human TNF administration induces greater increases in NF-jB levels in adolescent mood disorder patients, compared with controls, with NF-jB elevations associated with exacerbation of depressive symptoms. ...
A large body of work implicates cytokines and their related pathways in the pathophysiologies of mood disorders. Much of the data on the role of cytokines in major depression and bipolar disorder suggest that pathways regulated by tumor necrosis factor (TNF)‐α make a significant contribution to their pathophysiologies. In the present review, we contrast the well‐established role of TNF‐related pathways acting to mediate classic pro‐inflammatory cytokine activity with growing evidence that such pathways have more diverse functions in the human central nervous system. Here, it will be argued that changes in levels of the TNF receptor type 2 in mood disorders would be consistent with a neuroprotective role for the receptor against the pathophysiologies of mood disorders. This hypothesis is of significance when considering how interventions that act to modulate TNF‐regulated pathways can be used to treat the symptoms of mood disorders. A large body of work implicates cytokines and their related pathways in the pathophysiologies of mood disorders. Much of the data on the role of cytokines in major depression and bipolar disorder suggest pathways regulated by tumor necrosis factor‐α make a significant contribution to their pathophysiologies. Here, we propose that the tumor necrosis factor receptor 2 is a potential target for antidepressant drug design.
... The growth of the blastocyst into the uterus is similar to a bacterial infection and has to be considered as a stressful event for the mother [58]. During pregnancy a reduction of the steroidal hormone androstenediol takes place in the first trimester, which is a key steroidal hormone to facilitate innate immunity protection [59] and can be related to the gene expression of p53 gene, a hallmark gene for cell differentiation and apoptosis in mammals [60]. In mice, androstenediol plays a key role in parturition, as it modifies immunity [60]. ...
... During pregnancy a reduction of the steroidal hormone androstenediol takes place in the first trimester, which is a key steroidal hormone to facilitate innate immunity protection [59] and can be related to the gene expression of p53 gene, a hallmark gene for cell differentiation and apoptosis in mammals [60]. In mice, androstenediol plays a key role in parturition, as it modifies immunity [60]. Androstenediol stimulates innate immune cell function in nerve system cells and in healthy cells reduces DNA damage and induces genes that modulate genes related to the innate immunity in nerve cells [61]. ...
There are two forms of immune defense, the specific or adaptive immune defense and the unspecific innate immune defense. Vaccination is utilized against specific bacteria via the adaptive immune system. The innate immunity DNA stress defense is a non-toxic mechanism developed in yeasts and conserved in mammals and in plants. Although the steroidal hormone cascade has overtaken the stress response and allows superfast response via non-genomic receptors, the old innate immunity response is still mediated via the steroidal hormones cascade. The classical drug/receptor model has provided for many solutions, however, in antibiotics, cancer, and in severe mental diseases this model reaches to certain limits. The NIH/Department of Mental Health has developed a new model that shows severe mental diseases may be immune diseases that can be treated by replacing old diseased nerve cells by new healthy nerve cells, where the old innate immunity may be exploited. This means that severe mental diseases are physical diseases. A newly developed model, where modifications of the steroidal hormone cascade help to understand bipolarity, schizophrenia, and PTSD in men and women can be transferred to gynecological hormone modifications in women, where innate immunity is mediated via the same steroidal hormone cascade. Treatment via immune response via the DNA cascade should be developed in cancer, infections and severe mental disease, because foreign cells or diseased cells may be removed by the unspecific innate immunity.
... NF-κB has also been deregulated in schizophrenia, bipolar disorder, and Major Depression (Miklowitz et al. 2016;Safa et al. 2020c). Based on a recent study, the expression levels of several NF-κB family members enhanced in the prefrontal cortex of bipolar disorder (Roman et al. 2021;Elhaik and Zandi 2015). Three famous NF-κB-related lncRNAs are namely CHAST, DILC, and DICER1-AS1 in PBMC of patients with BD. ...
Long non-coding RNAs (lncRNAs) are major genetic factors whose disruption lead to many diseases, including nervous system diseases. Bipolar disorder (BD) is a neuro-psychiatric disease with no definitive diagnosis and incomplete treatment. Regarding the role of NF-κB-associated lncRNAs in the neuro-psychiatric disorders, we examined the expression of three lncRNAs, DICER1-AS1, DILC, and CHAST, in BD patients. To assess lncRNA expression in peripheral blood mononuclear cells (PBMCs) of 50 BD patients and 50 healthy individuals, Real-time PCR was used. Additionally, some clinical characteristics of BD patients were investigated via an analysis of ROC curves and correlations. Based on our results, the expression level of CHAST increased significantly in BD patients in comparison with healthy people, in BD men compared with healthy men, as well as in BD women in comparison with control females (p < 0.05). A similar increase in expression was observed for DILC and DICER1-AS1 lncRNAs in female patients compared with healthy women. Whereas compared to healthy men, DILC was decreased in diseased men. Based on the results of the ROC curve, the area under the curve (AUC) for CHAST lncRNA was 0.83 with a P value of 0.0001. So, the expression level of CHAST lncRNA could play a role in the pathobiology of the BD and be considered a good putative biomarker for individuals with bipolar disorder.
... Another important intracellular signaling route related to the immune response is the nuclear factor kappa B (NF-κB) pathway. Alterations in the NF-κB pathway are associated with BD [82]. As a pleiotropic transcription factor, NF-κB is reported to mediate the effects of HPA axis dysregulation on stress-induced pleasure anhedonia and impaired neurogenesis [83], and NF-κB also regulates the balance between neuroprotective and pro-apoptotic mechanisms in the CNS via Nod-like receptor proteins 1/3 inflammasome regulation [84]. ...
Bipolar disorder (BD) is a distinctly heterogeneous and multifactorial disorder with a high individual and social burden. Immune pathway dysregulation is an important pathophysiological feature of BD. Recent studies have suggested a potential role for T lymphocytes in the pathogenesis of BD. Therefore, greater insight into T lymphocytes’ functioning in patients with BD is essential. In this narrative review, we describe the presence of an imbalance in the ratio and altered function of T lymphocyte subsets in BD patients, mainly in T helper (Th) 1, Th2, Th17 cells and regulatory T cells, and alterations in hormones, intracellular signaling, and microbiomes may be potential causes. Abnormal T cell presence explains the elevated rates of comorbid inflammatory illnesses in the BD population. We also update the findings on T cell-targeting drugs as potentially immunomodulatory therapeutic agents for BD disease in addition to classical mood stabilizers (lithium, valproic acid). In conclusion, an imbalance in T lymphocyte subpopulation ratios and altered function may be involved in the development of BD, and maintaining T cell immune homeostasis may provide an overall therapeutic benefit.
... NF-κB pathway has an indispensable part in the development of innate and adaptive immunity 25 , which are dysregulated in BD 26 . The impact of NF-κB signals in inflammation, neuroprotection, and apoptosis are particularly obvious in the nervous system 27 . ...
Bipolar disorder (BD) is a mental disorder that leads to abnormal swings in mood, energy, activity level, attention, and the capability to accomplish daily tasks. Several long non-coding RNAs (lncRNAs) are dysregulated in BD patients. We have compared expression levels of five NF-κB-associated lncRNAs, namely ANRIL, CEBPA-DT, H19, NKILA and HNF1A-AS1 in blood samples of BD patients compared with controls. While ANRIL, CEBPA-DT and HNF1-AS1 were significantly under-expressed in BD patients compared with controls, NKILA levels were higher in patients versus controls. Among differentially expressed genes, HFN1A-AS1 exhibited the best diagnostic parameters in the separation of patients from controls (AUC ± SD = 0.86 ± 0.03, sensitivity = 0.82, specificity = 0.82, P value < 0.0001). AUC values for NKILA, ANRIL and CEBPA-DT were 0.71, 0.68 and 0.65, respectively. In accordance with the previously reported participation of NF-ƙB in the pathophysiology of BD, the current study provides evidence for dysregulation of NF-κB-associated lncRNAs in BD.
... Studies have indicated that manic episodes are associated with a pro-inflammatory state [79]. Furthermore, regulating the expression of inflammatory cytokines is considered as one of the GSK-3β/β-catenin downstream signaling molecules that is responsible for maintaining the balance between the pro-inflammatory and the anti-inflammatory cytokines [80]. ...
Adenosinergic system dysfunction is implicated in the pathophysiology of multiple neuropsychiatric disorders including mania and bipolar diseases. The established synergistic interaction between A 2A and D 2 receptors in the prefrontal cortex could highlight the idea of A 2A receptor antagonism as a possible anti-manic strategy. Hence, the present study was performed to examine the effect of a selective adenosine A 2A receptor blocker (SCH58261) on methylphenidate-induced mania-like behavior while investigating the underlying mechanisms. Rats were injected with methylphenidate (5 mg/kg/day, i.p.) for 3 weeks with or without administration of either SCH58261 (0.01 mg/kg/day, i.p.) or lithium (150 mg/kg/day, i.p.) starting from day 9. In the diseased rats, adenosine A 2A R antagonism reduced locomotor hyperactivity and risk-taking behavior along with decreased dopamine and glutamate levels. Meanwhile, SCH58261 restored NMDA receptor function, suppressed PKC-α expression, down-regulated β-Arrestin-2, up-regulated p S473-Akt and p S9-GSK-3β. Further, SCH58261 promoted synaptic plasticity markers through increasing BDNF levels along with down-regulating GAP-43 and SNAP-25. The A 2A antagonist also reduced NF-κBp65 and TNF-α together with elevating IL-27 level giving an anti-inflammatory effect. In conclusion, suppression of PKC-α and modulation of Akt/GSK-3β/β-catenin axis through A 2A R inhibition, could introduce adenosine A 2A R as a possible therapeutic target for treatment of mania-like behavior. This notion is supported by the ability of the A 2A R antagonist (SCH58261) to produce comparable results to those observed with the standard anti-manic drug (Lithium).
... Similarly, decreased PPARγ levels and/or activity have been reported in MDD [284], BD [285] and first-episode SZ [286]. NF-κB activity is also increased in MDD, BPD and SZ, once again speaking to the potential utility of CBD in treating these illnesses [287][288][289]. Finally, and perhaps predictably, TRPV1 and other members of the TRP family of receptors also appear to be involved in the pathophysiology of neuropsychiatric disease, and excessive TRP activity mediated by oxidative stress may be a source of calcium dyshomeostasis in these illnesses [290,291]. ...
The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB1 and CB2) and the enzymes involved in their synthesis and metabolism (N-acyltransferase and fatty acid amide hydrolase (FAAH) in the case of AEA and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) in the case of 2-AG). The origins of ECS dysfunction in major neuropsychiatric disorders remain to be determined, and this paper explores the possibility that they may be associated with chronically increased nitro-oxidative stress and activated immune-inflammatory pathways, and it examines the mechanisms which might be involved. Inflammation and nitro-oxidative stress are associated with both increased CB1 expression, via increased activity of the NADPH oxidases NOX4 and NOX1, and increased CNR1 expression and DNA methylation; and CB2 upregulation via increased pro-inflammatory cytokine levels, binding of the transcription factor Nrf2 to an antioxidant response element in the CNR2 promoter region and the action of miR-139. CB1 and CB2 have antagonistic effects on redox signalling, which may result from a miRNA-enabled negative feedback loop. The effects of inflammation and oxidative stress are detailed in respect of AEA and 2-AG levels, via effects on calcium homeostasis and phospholipase A2 activity; on FAAH activity, via nitrosylation/nitration of functional cysteine and/or tyrosine residues; and on 2-AG activity via effects on MGLL expression and MAGL. Finally, based on these detailed molecular neurobiological mechanisms, it is suggested that cannabidiol and dimethyl fumarate may have therapeutic potential for major depressive disorder, bipolar disorder and schizophrenia.
... 45,46 Also, NF-κB upregulation was detected in bipolar patients, potentially contributing to the pro-in ammatory balance of the disorder. 47,48 One potential limitation of the present study is that Na + /K + -ATPase activity was not measured to con rm that OUA effects are related to an inhibition of this enzyme. However, this parameter was not altered by the glycoside in the Valvassori and coworkers' paper, 16 which provided the experimental platform for the present study, although OUA is a well-known inhibitor. ...
Objective: The present study aims to investigate the effects of Lithium (Li) on manic- and depressive-like behaviors and inflammatory parameters in rats submitted to the bipolar disorder (BD) model induced by ouabain (OUA).
Material and methods: Adult male rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (aCSF). On the fourth day after the ICV injection, the rats received intraperitoneal injections of saline (NaCl 0.9%) or Li (47.5 mg/kg), two times a day, for 14 days. On the seventh day after OUA injection, the locomotor activity was assessed (open field test), and on the fourteenth day, locomotion was evaluated again, which was followed by the forced swimming test to evaluate depressive-like behavior. After euthanasia, inflammatory parameters were evaluated in the frontal cortex and hippocampus.
Results: After seven days of OUA administration, the animals showed a hyperactive behavior that was reversed by treatment with Li. After 14 days of ICV injections, rats exhibited a depressive behavior. Regarding the inflammatory parameters, measured after 14 days of the ICV infusions, OAU induced an increase in the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor α, and cytokine-induced neutrophil chemoattractant-1. In contrast, Li treatment decreased these parameters.
Conclusion: The animal model of BD induced by an OUA is able to induce neuroinflammation, which supports its construct validity for the BD research.
... First, among its beneficial characteristics Li has been shown to exert anti-neuroinflammatory/anti-inflammatory effects [70,73]. Given that low-dose aspirin has also been reported to exert anti-inflammatory effects [119,120] along with the well-established involvement of inflammation in the pathophysiology of BD [45][46][47][48][49], we hypothesized that co-administration of low-dose aspirin and Li could enable reduction in the required Li dose to gain mood stabilization. Second, prior to the above, given the devastating renal side effects of Li treatment in BD-NDI, and even CKD following long-term use, we first probed the safety of chronic administration of aspirin plus Li. ...
Despite established efficacy in bipolar disorder patients, lithium (Li) therapy has serious side effects, particularly chronic kidney disease. We examined the safety and behavioral effects of combined chronic low-dose aspirin plus low-dose Li in rats to explore the toxicity and therapeutic potential of this treatment. Rats were fed regular or Li-containing food (0.1% [low-dose, LLD-Li] or 0.2% [standard-dose, STD-Li]) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. Renal function and gastric mucosal integrity were assessed. The effects of the combination treatment were evaluated in depression-like and anxiety-like behavioral models. Co-treatment with aspirin did not alter plasma Li levels. Chronic STD-Li treatment resulted in significant polyuria and polydipsia, elevated blood levels of creatinine and cystatin C, and increased levels of kidney nephrin and podocin—all suggestive of impaired renal function. Aspirin co-treatment significantly damped STD-Li-induced impairments in kidney parameters. There were no gastric ulcers or blood loss in any treatment group. Combined aspirin and LLD-Li resulted in a significant increase in sucrose consumption, and in the time spent in the open arms of an elevated plus-maze compared with the LLD-Li only group, suggestive of antidepressant-like and anxiolytic-like effects, respectively. Thus, we demonstrate that low-dose aspirin mitigated the typical renal side effects of STD-Li dose and enhanced the beneficial behavioral effects of LLD-Li therapy without aggravating its toxicity.
... Nuclear factor (NF-κB proteins are a family of a substantial transcription factor required for the expression of many inflammatory genes in response to inflammatory stimuli [44]. Peripheral LPS administration activates NF-κB signaling to produce pro-inflammatory cytokines associated with the development of neuroinflammation and major depressive disorders [44][45][46]. In order to investigate the anti-inflammatory mechanisms of Xn, we then determine the level of pNF-κB (p-p65), by western blot. ...
Depression is the most common psychiatric disorder associated with brain and immune system abnormalities. In recent years, xanthohumol (Xn) a bioactive prenylated flavonoid has received ample attention for its polypharmacological effects, therefore, here we aimed to explore the protective effects of Xn against the LPS-induced depressive-like symptoms mediated by inflammation and oxidative stress. We tested the effect of Xn against LPS-induced behavioural changes in mice by means of forced swimming test (FST), tail suspention test (TST), sucrose preference test (SPT) and open field test (OPT). Examined the neuroinflammation and oxido-nitrosative stress (O&NS) markers and analyze Nrf2 and NF-κB signalling pathways in the hippocampus. Our results indicated that peripheral repeated administration of lipopolysaccharides (LPS) (1 mg/kg, intra peritoneally) induced depressive-like behavior, neuroinflammation and O&NS in mice. Pretreatment with Xn (10 and 20 mg/kg, intra gastrically) reverse the behavioural impairments prophylactically as obvious in the FST and TST without effecting locomotion, however only 20 mg dose improve anhedonic behavior as observed in SPT. Similarly, Xn pretreatment in dose-dependent manner prevented the LPS induced neuro-inflammation and O&NS. Immunofluorescence analysis showed that Xn reduced activated gliosis via attenuation of Iba-1 and GFAP in hippocampus. In addition, Xn considerably reduced the expression of phospho-NF-κB and cleaved caspase-3 while enhanced Nrf2 and HO-1 expression in the hippocampus. To the best of our knowledge, this is the first study to examine the underlying beneficial prophylactic effects of the Xn in neuroinflammation and O&NS mediating depressive-like behaviors.
... Additionally, agents such as GLP-I agonists, garlic, lcysteine and N-acetyl-cysteine that enhance hydrogen sulphide which inhibits NF-kappa B (Oh et al., 2006;Dai et al., 2013) in tissues may prevent drug reinstatement (Selley et al., 2014;Baker et al., 2003;Peana et al., 2010) especially when combined with metformin which also inhibits NF-kappa β (Isoda et al., 2006) that regulate structural and behavioural plasticity to drugs of abuse such as cocaine (Russo et al., 2009). Additionally, a dysregulated NF-kappa β signalling may be a core characteristic of bipolar disorder (Elhaik and Zandi, 2015), diabetes mellitus (Kiechi et al., 2013); temporal lobe epilepsy (Teocchi et al., 2013) and Alzheimer's disease (Granic et al., 2009). ...
... Bipolar disorder (BD) is a chronic psychiatric illness, involving mood swings that range from extreme high (mania) to extreme low (depression) that occur with distinctive beginnings and ends, but may arise together (Elhaik & Zandi 2015). Based on a large cross sectional study over 11 countries in the Americas, Europe and Asia, the overall lifetime prevalence of bipolar spectrum disorders was documented as 2.4% (Merikangas et al. 2011). ...
... The allostatic load hypothesis, initially proposed to explain how stress influences the pathogenesis of diseases [94] and later applied to specific disorders e.g. [95], proposes that prolonged and repetitive stressful, painful, and traumatic experiences during the peri-and pre-natal developmental periods lead to the accumulation of allostatic load that may be lethal [5]. Thereby, both hypotheses consider genetic vulnerabilities and external stressors but disagree on the definition of at-risk infants and the sequence of events that lead to SIDS. ...
Background
Sudden infant death syndrome (SIDS) is the most common cause of postneonatal unexplained infant death. The allostatic load hypothesis posits that SIDS is the result of cumulative perinatal painful, stressful, or traumatic exposures that tax neonatal regulatory systems.
Aims
To test the predictions of the allostatic load hypothesis we explored the relationships between SIDS and two common phenotypes, male neonatal circumcision (MNC) and prematurity.
Methods
We collated latitudinal data from 15 countries and 40 US states sampled during 2009 and 2013. We used linear regression analyses and likelihood ratio tests to calculate the association between SIDS and the phenotypes.
Results
SIDS mortality rate was significantly and positively correlated with MNC. Globally (weighted): Increase of 0.06 (95% CI: 0.01-0.1, t = 2.86, p = 0.01) per 1000 SIDS mortality per 10% increase in circumcision rate. US (weighted): Increase of 0.1 (95% CI: 0.03-0.16, t = 2.81, p = 0.01) per 1000 unexplained mortality per 10% increase in circumcision rate. US states in which Medicaid covers MNC had significantly higher MNC rates (χ̄ = 0.72 vs 0.49, p = 0.007) and male/female ratio of SIDS deaths (χ̄ = 1.48 vs 1.125, p = 0.015) than other US states. Prematurity was also significantly and positively correlated with MNC. Globally: Increase of 0.5 (weighted: 95% CI: 0.02-0.086, t = 3.37, p = 0.004) per 1000 SIDS mortality per 10% increase in the prematurity rates. US: Increase of 1.9 (weighted: 95% CI: 0.06-0.32, t = 3.13, p = 0.004) per 1000 unexplained mortalities per 10% increase in the prematurity rates. Combined, the phenotypes increased the likelihood of SIDS.
Conclusions
Epidemiological analyses are useful to generate hypotheses but cannot provide strong evidence of causality. Biological plausibility is provided by a growing body of experimental and clinical evidence linking aversive preterm and early-life SIDS events. Together with historical and anthropological evidence, our findings emphasize the necessity of cohort studies that consider these phenotypes with the aim of improving the identification of at-risk infants and reducing infant mortality.
Relevance for patients
Preterm birth and neonatal circumcision are associated with a greater risk of SIDS, and efforts should be focused on reducing their rates.
... There is accumulating evidence for a role of the immune system in psychiatric diseases including schizophrenia and bipolar disorder, 20 and there is correlative evidence for NF-kB activation in bipolar disorder. 21 As observed in keratinocytes in the skin, the inability to activate NF-kB in IKBKGdeficient neurons likely increases their susceptibility to apoptosis. However, a direct causal relationship between IKBKG deficiency on NF-kB signaling and the neuronal abnormalities in bipolar disorder is yet to be elucidated. ...
... Additionally, agents such as GLP-I agonists, garlic, lcysteine and N-acetyl-cysteine that enhance hydrogen sulphide which inhibits NF-kappa B (Oh et al., 2006;Dai et al., 2013) in tissues may prevent drug reinstatement (Selley et al., 2014;Baker et al., 2003;Peana et al., 2010) especially when combined with metformin which also inhibits NF-kappa β (Isoda et al., 2006) that regulate structural and behavioural plasticity to drugs of abuse such as cocaine (Russo et al., 2009). Additionally, a dysregulated NF-kappa β signalling may be a core characteristic of bipolar disorder (Elhaik and Zandi, 2015), diabetes mellitus (Kiechi et al., 2013); temporal lobe epilepsy (Teocchi et al., 2013) and Alzheimer's disease (Granic et al., 2009). ...
... For example, polymorphisms of Toll-like receptor (TLR) genes [41] and altered expression of TLRs in the brain [42] have been found in individuals with BPD. Similarly, NF-κB has been found to be dysregulated in BPD and postulated to exert its effect by the transcriptional activation of TLRs [43]. In addition, variants in the genes encoding serotonin transporters have been associated with an increased risk of BPD and of mania in response to the administration of antidepressant medications [44]. ...
Mania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individuals without a psychiatric disorder. We found that a history of eating nitrated dry cured meat but not other meat or fish products was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24-5.45, p < 8.97 × 10-8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human bipolar disorder, and changes in intestinal microbiota. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions.
... The allostatic load hypothesis, initially proposed to explain how stress influences the pathogenesis of diseases [94] and later applied to specific disorders (e.g. [95]), proposes that prolonged and repetitive stressful, painful, and traumatic experiences during the peri-and pre-natal developmental periods lead to the accumulation of allostatic load that may be lethal [5]. Thereby, both hypotheses consider genetic vulnerabilities and external stressors but disagree on the definition of at-risk infants and the sequence of events that leads to SIDS. ...
Sudden Infant Death Syndrome (SIDS) is the most common cause of postneonatal infant death. The allostatic load hypothesis posits that SIDS is the result of perinatal cumulative painful, stressful, or traumatic exposures that tax neonatal regulatory systems. To test it, we explored the relationships between SIDS and two common stressors, male neonatal circumcision (MNC) and prematurity, using latitudinal data from 15 countries and over 40 US states during the years 1999-2016. We used linear regression analyses and likelihood ratio tests to calculate the association between SIDS and the stressors. SIDS prevalence was significantly and positively correlated with MNC and prematurity rates. MNC explained 14.2% of the variability of SIDS's male bias in the US, reminiscent of the Jewish myth of Lilith, the killer of infant males. Combined, the stressors increased the likelihood of SIDS. Ecological analyses are useful to generate hypotheses but cannot provide strong evidence of causality. Biological plausibility is provided by a growing body of experimental and clinical evidence linking adversary preterm and early-life events with SIDS. Together with historical evidence, our findings emphasize the necessity of cohort studies that consider these environmental stressors with the aim of improving the identification of at-risk infants and reducing infant mortality.
... Oxidative stress exists in all phases of the illness and again appears to be higher in patients suf-fering from mania. The mechanisms driving this trait dependent cellular environment of chronically elevated oxidative stress are not fully understood but there is accumulating evidence that a dysfunctional NF-B system is at least partly responsible (Elhaik and Zandi, 2015). It is particularly noteworthy that NF-B levels and activity is higher in bipolar depression than in unaffected controls (Spiliotaki et al., 2006). ...
... We speculate that SIDS is caused by prolonged and repetitive iatrogenic stressful, painful, or traumatic experiences during critical development stages that constitute allostatic overload (156). Over the past years, allostatic load models were proposed to explain several leading medical conditions, including mental health disorders (157,158), preterm birth (159), and chronic stress (160). ...
Sudden infant death syndrome (SIDS) is the leading cause of death among USA infants under 1 year of age accounting for ~2,700 deaths per year. Although formally SIDS dates back at least 2,000 years and was even mentioned in the Hebrew Bible (Kings 3:19), its etiology remains unexplained prompting the CDC to initiate a sudden unexpected infant death case registry in 2010. Due to their total dependence, the ability of the infant to allostatically regulate stressors and stress responses shaped by genetic and environmental factors is severely constrained. We propose that SIDS is the result of cumulative painful, stressful, or traumatic exposures that begin in utero and tax neonatal regulatory systems incompatible with allostasis. We also identify several putative biochemical mechanisms involved in SIDS. We argue that the important characteristics of SIDS, namely male predominance (60:40), the significantly different SIDS rate among USA Hispanics (80% lower) compared to whites, 50% of cases occurring between 7.6 and 17.6 weeks after birth with only 10% after 24.7 weeks, and seasonal variation with most cases occurring during winter, are all associated with common environmental stressors, such as neonatal circumcision and seasonal illnesses. We predict that neonatal circumcision is associated with hypersensitivity to pain and decreased heart rate variability, which increase the risk for SIDS. We also predict that neonatal male circumcision will account for the SIDS gender bias and that groups that practice high male circumcision rates, such as USA whites, will have higher SIDS rates compared to groups with lower circumcision rates. SIDS rates will also be higher in USA states where Medicaid covers circumcision and lower among people that do not practice neonatal circumcision and/or cannot afford to pay for circumcision. We last predict that winter-born premature infants who are circumcised will be at higher risk of SIDS compared to infants who experienced fewer nociceptive exposures. All these predictions are testable experimentally using animal models or cohort studies in humans. Our hypothesis provides new insights into novel risk factors for SIDS that can reduce its risk by modifying current infant care practices to reduce nociceptive exposures.
... A second possibility is that the higher rate of presumed bacterial infections in individuals with mania is reflective of decreased levels of ability of the immune system to prevent infections in this population. This hypothesized mechanism is consistent with studies documenting decreased levels of innate immunity in individuals with mood disorders through inherited or acquired alterations in the activity of toll-like receptors, transcription factors, as expression of pentraxin proteins and other mechanisms (21)(22)(23)(24)(25). ...
Objectives:
We have preciously documented that many individuals with acute mania have immune activation. However, the sources of immune activation have not been identified. We investigated whether individuals hospitalized with acute mania have evidence of bacterial infections as determined by the prescription of systemic antimicrobial agents.
Methods:
We assessed the recent prescription of systemic antimicrobial medications and the site of presumed bacterial infection in 234 individuals hospitalized for acute mania in either an inpatient unit or a day hospital. We also assessed individuals hospitalized for other psychiatric disorders (n=368) and controls (n=555). We employed logistic regression models to compare the rates of antibiotic prescription in individuals with the different diagnoses, employing demographic variables as covariates.
Results:
We found that individuals hospitalized with acute mania had a substantially increased rate of recent antimicrobial prescription, defined as exposure within three days of ascertainment (adjusted odds ratio=5.5, 95% confidence interval: 2.2-14.1, P<.0002). Overall, a total of 18 of the 234 (7.7%) individuals hospitalized for acute mania were prescribed antibiotics as opposed to seven of 555 (1.3%) controls. The prescription of antibiotics was associated with being on an inpatient unit as opposed to being in the day hospital, and having increased mania symptom severity but not with other clinical ratings, demographic variables, or psychiatric medications. Hospitalization for other psychiatric disorders was not associated with the recent prescription of antimicrobial medications. The urinary tract was the most common site of infection in women, while the respiratory tract and mucosal surfaces were the most common sites in men.
Conclusions:
Individuals hospitalized with acute mania have a markedly increased rate of bacterial infections, as evidenced by the recent prescription of antimicrobial agents. The prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania.
... Accumulating evidence has shown that there is a strong correlation between mood disorders and elevated levels of CSF cytokines, such as TNF-α and IL-1β, as well as increased PGE2 levels (103). Thus, it has been suggested that NKA activity and its modulation may also have a pertinent role in the etiology of mental disorders, especially bipolar disorder, which is associated with NKA activity abnormalities in erythrocytes (104) and high peripheral levels of pro-inflammatory cytokines (105). ...
Cardiotonic steroids (CTS) are a class of specific ligands of the Na+,K+- ATPase (NKA). NKA is a P-type ATPase that is ubiquitously expressed and although well known to be responsible for the maintenance of the cell electrochemical gradient through active transport, NKA can also act as a signal transducer in the presence of CTS. Inflammation, in addition to importantly driving organism defense and survival mechanisms, can also modulate NKA activity and memory formation, as well as being relevant to many chronic illnesses, neurodegenerative diseases and mood disorders. The aim of the current review is to highlight the recent advances as to the role of CTS and NKA in inflammatory process, with a particular focus in the central nervous system.
... In the earlier stages of the disorder, interleukins and TNF-α are up-regulated while in later stages IL-6 and TNF-α levels expression are maintained (Rege and Hodgkinson, 2013). An up-regulation of all these pro-inflammatory cytokines could be related to overexpression of NF-κB; as the expression subunit of NF-κB, NF-κB2, has been found to be overexpressed in frontal cortex of BD patients (Elhaik and Zandi, 2015). The alteration in NF-κB might account for brain atrophy and apoptosis observed in BD. ...
Bipolar Disorder is a severe psychiatric disorder that affects up to 15% of the worldwide population. Characterized by switches in mood between mania and depression, its etiology is still unknown and efforts have been made to elucidate the mechanisms involved in first episode, development, and progression of the disorder. Microglia activation, abnormal activity of GSK-3β and reduction in neurotrophic factor expression related to neuroinflammatory processes have been indicated to be part of the disorder's pathophysiology. Lithium, the main mood stabilizer used for the treatment and prevention of relapses, acts as an anti-inflammatory agent. Based on that, here we suggest a neuroinflammatory pathway for BD progression, in which microglia activation states are modulated via constitutive induction of kinin-B1 receptor and reduction of kinin-B2 receptor expression and activity.
Background:
Cognitive impairment is one of the major symptoms of individuals with bipolar disorder (BD). Purine system disorders may play an important role in cognitive dysfunction. So far, the relationship between cognitive deficits and purinergic metabolism in BD has been seldom discussed in previous studies. This study aims to explore its relevance and potential biological mechanisms.
Methods:
In this cross-sectional study, 205 first time diagnosed drug-naive individuals with BD and 97 healthy volunteers were recruited. The uric acid(UA) level was measured using automatic biochemical analyzer, and cognitive function was assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Stroop color-word test. In addition, general information and clinical symptoms were collected and evaluated.
Results:
In this study, the UA level of BD group (U = 8475.000, p = 0.038) was found to be significantly higher than that of the healthy controls, but the scores of RBANS (t = -11.302, p < 0.001) and Stroop color-word test (t = -6.962, p < 0.001) were significantly lower than that of the healthy controls. In gender subgroup analysis, females had lower UA level and higher RBANS scores. In correlation analysis, the cognitive function of individuals with BD was found to present a significant negative correlation with UA level in attention (r = -0.23, p = 0.001) and delayed memory(r = -0.16, p = 0.022).
Limitations:
This is a cross-sectional design.
Conclusion:
Elevated UA levels may be a potential mechanism of cognitive impairment in BD. This provides a new possible strategy for the prevention and treatment of cognitive impairment in BD.
Recent genetic studies have identified variants associated with bipolar disorder (BD), but it remains unclear how brain gene expression is altered in BD and how genetic risk for BD may contribute to these alterations. Here, we obtained transcriptomes from subgenual anterior cingulate cortex and amygdala samples from post-mortem brains of individuals with BD and neurotypical controls, including 511 total samples from 295 unique donors. We examined differential gene expression between cases and controls and the transcriptional effects of BD-associated genetic variants. We found two coexpressed modules that were associated with transcriptional changes in BD: one enriched for immune and inflammatory genes and the other with genes related to the postsynaptic membrane. Over 50% of BD genome-wide significant loci contained significant expression quantitative trait loci (QTL) (eQTL), and these data converged on several individual genes, including SCN2A and GRIN2A. Thus, these data implicate specific genes and pathways that may contribute to the pathology of BP. The authors obtained transcriptomes from anterior cingulate cortex and amygdala samples from post-mortem brains of individuals with bipolar disorder and neurotypical controls. They observed decreased expression of neuroimmune and synaptic pathways.
Millions of people around the world suffer from psychiatric illnesses, causing unbearable burden and immense distress to patients and their families. Accumulating evidence suggests that inflammation may contribute to the pathophysiology of psychiatric disorders such as major depression and bipolar disorder. Copious studies have consistently shown that patients with mood disorders have increased levels of plasma tumor necrosis factor (TNF)-α. Given these findings, selective anti-TNF-α compounds were tested as a potential therapeutic strategy for mood disorders. This mini-review summarizes the results of studies that examined the mood-modulating effects of anti-TNF-α drugs.
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.
Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.
A growing body of evidence has moved the scientific community to view inflammation as one of the key processes that might improve understanding of the pathoetiology of major psychiatric disorders. A recent transdiagnostic meta-analysis by Goldsmith et al.¹ showed that levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), soluble IL-2 receptor (sIL-2R) and IL-1 receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD).
Shudderer
(Shu) is an X-linked dominant mutation inDrosophila melanogasteridentified more than 40 years ago. A previous study showed thatShucaused spontaneous tremors and defects in reactive climbing behavior, and that these phenotypes were significantly suppressed when mutants were fed food containing lithium, a mood stabilizer used in the treatment of bipolar disorder (Williamson, 1982). This unique observation suggested that theShumutation affects genes involved in lithium-responsive neurobiological processes. In the present study, we identifiedShuas a novel mutant allele of the voltage-gated sodium (Nav) channel geneparalytic(para). Given that hypomorphicparaalleles and RNA interference-mediatedparaknockdown reduced the severity ofShuphenotypes,Shuwas classified as aparahypermorphic allele. We also demonstrated that lithium could improve the behavioral abnormalities displayed by other Navmutants, including a fly model of the human generalized epilepsy with febrile seizures plus. Our electrophysiological analysis ofShushowed that lithium treatment did not acutely suppress Navchannel activity, indicating that the rescue effect of lithium resulted from chronic physiological adjustments to this drug. Microarray analysis revealed that lithium significantly alters the expression of various genes inShu, including those involved in innate immune responses, amino acid metabolism, and oxidation-reduction processes, raising the interesting possibility that lithium-induced modulation of these biological pathways may contribute to such adjustments. Overall, our findings demonstrate that Navchannel mutants inDrosophilaare valuable genetic tools for elucidating the effects of lithium on the nervous system in the context of neurophysiology and behavior.
Bakcground:
Few studies have investigated the relationship between chronic obstructive pulmonary disease (COPD) and bipolar outcomes in the world. We sought to investigate the association between COPD and risk of bipolar disorder in a large national sample.
Methods:
The insured aged 15 years or more with a new primary diagnosis of COPD (ICD-9: 491, 492, 494 and 496) between 2000 and 2007 were identified from Taiwan's National Health Insurance Research Database. We included individuals with an inpatient diagnosis of COPD and/or at least 1 year of two diagnoses of COPD in outpatient services. These 35,558 cases were compared to 35,558 sex-, age-, residence- and insurance premium-matched controls. We followed both groups until the end of 2008 for incidence of bipolar disorder, defined as ICD-9 codes 296.0-296.16, 296.4-296.81 and 296.89. Competing risk-adjusted Cox regression analyses were applied with adjusting for sex, age, residence, insurance premium, prednisone use, Charlson comorbidity index, diabetes, hypertension, hyperlipidemia, cardiovascular diseases, hospital admission days, outpatients' visits and mortality.
Results:
Of the total 71,116 subjects, 202 were newly diagnosed with bipolar disorder during the study period. The mean follow-up time was 6.0 (SD=2.2) years. COPD, younger age, lower economic status, lower dose of prednisone use, higher hospital admission days and higher outpatient visits were independent predictors of bipolar disorder.
Conclusions:
COPD was associated with increased risk of bipolar disorder independent of a number of potential confounding factors in this study.
OBJETIVO: Pesquisas sugerem as citocinas como potenciais mediadores da interação entre os sistemas imune e neuroendócrino, e que existe um estado pró-inflamatório associado com transtorno bipolar e esquizofrenia. O objetivo deste estudo é comparar os níveis de citocinas entre os dois distúrbios. MÉTODO: Vinte pacientes com transtorno bipolar eutímicos, 53 pacientes com esquizofrenia cronicamente estabilizados e 80 controles saudáveis foram recrutados. Todos os indivíduos são não-fumantes e não-obesos. As citocinas TNF-α, IL-6 e IL-10 foram examinadas por ELISA sanduíche. RESULTADOS: A IL-6 estava aumentada nos pacientes com esquizofrenia quando comparados aos controles (p < 0,0001) e aos pacientes bipolares eutímicos (p < 0,0001). Os níveis de IL-6 não foram diferentes nos controles em comparação com pacientes com transtorno bipolar eutímicos (p = 0,357). Os níveis de IL-10 foram menores nos controles quando comparados aos esquizofrenia (p = 0,001) ou aos bipolares (p = 0,004). Não houve diferença significativa nos níveis séricos de TNF-α entre os grupos (p = 0,284). A separação por sexo não mostrou diferenças significativas e não houve correlação entre a dose de antipsicóticos e os níveis de citocinas em pacientes com esquizofrenia. DISCUSSÃO: Estes resultados evidenciam uma ativação imune crônica na esquizofrenia. O transtorno bipolar parece apresentar um aumento da atividade inflamatória relacionado ao episódio de humor. Níveis maiores de IL-10 no transtorno bipolar e esquizofrenia sugerem diferentes padrões de equilíbrio inflamatório entre esses dois transtornos. Resultados fornecem apoio adicional para a investigação de citocinas como possíveis biomarcadores para a atividade da doença ou resposta ao tratamento.
Here we review evidence of roles for NF-jB in the regulation of developmental and synaptic plasticity, and cell survival in physiological and pathological settings. Signaling pathways modulating NF-jB activity include those engaged by neuro-trophic factors, neurotransmitters, electrical activity, cytokines, and oxidative stress. Emerging findings support a pivotal role for NF-jB as a mediator of transcription-dependent enduring changes in the structure and function of neuronal circuits. Distinct subunits of NF-jB may uniquely affect cognition and behavior by regulating specific target genes. NF-jB activation can prevent the death of neurons by inducing the production of antiapoptotic proteins such as Bcl-2, IAPs and manganese superoxide dismutase (Mn-SOD). Recent findings indicate that NF-jB plays important roles in disorders such as epilepsy, stroke, Alzheimer's and Parkinson's diseases, as well as oncogenesis. Molecular pathways upstream and downstream of NF-jB in neurons are being elucidated and may provide novel targets for therapeutic intervention in various neurological disorders.
Objective
Immune activation in bipolar disorder (BD) has been frequently reported. Damage-associated molecular patterns (DAMPs) are key players in the immune activation reaction. The aim of this study was to assess DAMP levels in drug-free patients with BD during acute episodes.Method
Serum levels of a predetermined set of DAMPs were assessed in drug-free patients with BD (n = 20) during an acute mood episode. We also included two control groups: healthy subjects, used as a negative control (n = 20); and patients with sepsis, used as a positive control for severe immune activation (n = 20).ResultsMultivariate analysis using generalized linear mixed model indicated that all DAMPs differed as a function of group membership after controlling for age and addressing multiplicity (P < 0.0006 for all comparisons). Follow-up analyses showed higher levels in BD subjects of circulating cell-free (ccf) nuclear (n)DNA (P = 0.02), HSP70 (P = 0.03) and HSP90α (P = 0.02) as compared to healthy subjects. Also, patients with BD showed lower levels of ccf nDNA (P = 0.04), HSP60 (P = 0.03), HSP70 (P = 0.01), and HSP90α (P = 0.002) as compared to patients with sepsis and higher levels of ccf mitochondrial DNA (P < 0.0001).Conclusion
The present findings may be linked to the inflammatory activity previously described among patients with BD and may help in the development of more targeted and personalized treatments for patients under acute episodes of BD.
Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive "founder" mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients.
To provide a systematic review of the literature regarding the efficacy of anti-inflammatory drugs in three major mental disorders [major depressive disorder (MDD), schizophrenia and bipolar disorders].
Four databases were explored, without any year or language restrictions. The baseline search paradigm was limited to open-labelled clinical and randomized controlled trials (RCTs).
Four major classes of anti-inflammatory drugs were identified, namely polyunsaturated fatty acids (PUFAs), cyclooxygenase (COX) inhibitors, anti-TNFalpha and minocycline. Effectiveness and benefit/risk ratio of each class in MDD, bipolar disorders and schizophrenia was detailed when data were available. Several meta-analyses indicated effectiveness of PUFAs in MDD with a good tolerance profile. One meta-analysis indicated that COX-2 specific inhibitors showed effectiveness in schizophrenia. Anti-TNFalpha showed important effectiveness in resistant MDD with blood inflammatory abnormalities. Minocycline showed effectiveness in schizophrenia.
Polyunsaturated fatty acids seem to have the best benefit/risk ratio profile but proved their effectiveness only in MDD. A number of anti-inflammatory drugs are available as adjunct treatment for treatment-resistant patients with MDD, schizophrenia and bipolar disorder. If used with caution regarding their possible side-effects, they may be reasonable therapeutic alternatives for resistant symptomatology.
Objective:
Several lines of evidence indicate that white matter integrity is compromised in bipolar disorder, but the nature, extent, and biological causes remain elusive. To determine the extent to which white matter deficits in bipolar disorder are familial, the authors investigated white matter integrity in a large sample of bipolar patients, unaffected siblings, and healthy comparison subjects.
Method:
The authors collected diffusion imaging data for 64 adult bipolar patients, 60 unaffected siblings (including 54 discordant sibling pairs), and 46 demographically matched comparison subjects. Fractional anisotropy was compared between the groups using voxel-wise tract-based spatial statistics and by extracting mean fractional anisotropy from 10 regions of interest. Additionally, intraclass correlation coefficients were calculated between the sibling pairs as an index of familiality.
Results:
Widespread fractional anisotropy reductions in bipolar patients (>40,000 voxels) and more subtle reductions in their siblings, mainly restricted to the corpus callosum, posterior thalamic radiations, and left superior longitudinal fasciculus (>2,000 voxels) were observed. Similarly, region-of-interest analysis revealed significant reductions in most white matter regions in patients. In siblings, fractional anisotropy in the posterior thalamic radiation and the forceps was nominally reduced. Significant between-sibling correlations were found for mean fractional anisotropy across the tract-based spatial statistic skeleton, within significant clusters, and within nearly all regions of interest.
Conclusions:
These findings emphasize the relevance of white matter to neuropathology and familiality of bipolar disorder and encourage further use of white matter integrity markers as endophenotypes in genetic studies.
Markers of immune activation have been associated with mania but have not been examined in combination. We studied the association between mania and an inflammation score based on four immune markers.
A total of 57 individuals with mania were assessed at up to three time points: the day of hospital admission, evaluation several days later, and six-month follow-up. Also assessed were 207 non-psychiatric controls and 330 individuals with recent onset psychosis, multi-episode schizophrenia, or bipolar disorder depression. A combined inflammation score was calculated by factor analysis of the levels of class-specific antibodies to the NR peptide of the NMDA receptor; gliadin; Mason-Pfizer monkey virus protein 24; and Toxoplasma gondii. Inflammation scores among groups were compared by multivariate analyses. The inflammation score of the mania group at evaluation was studied as a predictor of re-hospitalization in the follow-up period.
The combined inflammation score of the mania group at hospital admission and at evaluation differed significantly from that of the non-psychiatric controls (t = 3.95, 4.10, p<.001). The inflammation score was significantly decreased at six month follow-up (F = 5.85, p = 0.004). There were not any significant differences in the inflammation scores of any of the other psychiatric groups and that of the controls. Within the mania group, an elevated inflammation score at evaluation predicted re-hospitalization (Hazard ratio = 7.12, p = .005).
Hospitalization for mania is associated with immune activation. The level of this activation is predictive of subsequent re-hospitalization. Interventions for the modulation of inflammation should be evaluated for the therapy of individuals with mania.
Do hospice services as shaped by a western perspective adequately fulfil the needs of persons from non-Western cultures? Based on a Western view of palliative care, the vision outlined in the New Zealand Palliative Care Strategy (2001) is to deliver palliative care services, including hospice services, to all patients and their families requiring them in the context of an increasingly pluralistic and multicultural society. It is predicted that over the next two decades the proportion of people identifying as Māori, Pacific and Asian will dramatically increase within New Zealand. Ministry of Health information provided through a GAP analysis identified hospices as facing access-to-care pressures for Māori, Pacific and Asian patients. It is therefore critical to identify the challenges to hospice service access for Māori, Asian and Pacific patients. This project involved qualitative interviews with 37 cancer patients (Māori, Pacific and Asian self-identified ethnicities), whānau/family and bereaved whanua/family, as well as 15 health professionals (e.g. referring GPs, oncologists, allied health professionals) within one District Health Board. Patients and their families included both those who utilised hospice services, as well as those non-users of hospice services identified by a health professional as having palliative care needs. Challenges to hospice service utilisation reported in the findings include a lack of awareness in the communities of available services, as well as continuing misconceptions concerning the nature of hospice services. Language barriers were particularly reported for Asian patients and their families. Issues concerning the ethnic representativeness of the hospice services staff were raised. The findings highlight the importance of patient and family knowledge of hospice care for utilisation of services. This information can be used for future planning to enable hospices to both provide high quality evidence based palliative care services for patients and families and provide consultative services to primary healthcare providers in the community.
The use of clinical staging models is emerging as a novel and useful paradigm for diagnosing severe mental disorders. The term "neuroprogression" has been used to define the pathological reorganization of the central nervous system along the course of severe mental disorders. In bipolar disorder (BD), neural substrate reactivity is changed by repeated mood episodes, promoting a brain rewiring that leads to an increased vulnerability to life stress.
A search in the PubMed database was performed with the following terms: "staging", "neuroprogression", "serum", "plasma", "blood", "neuroimaging", "PET scan", "fMRI", "neurotrophins", "inflammatory markers" and "oxidative stress markers", which were individually crossed with "cognition", "functionality", "response to treatments" and "bipolar disorder". The inclusion criteria comprised original papers in the English language. Abstracts from scientific meetings were not included.
We divided the results according to the available evidence of serum biomarkers as potential mediators of neuroprogression, with brain imaging, cognition, functioning and response to treatments considered as consequences.
The challenge in BD treatment is translating the knowledge of neuronal plasticity and neurobiology into clinical practice. Neuroprogression and staging can have important clinical implications, given that early and late stages of the disorder appear to present different biological features and therefore may require different treatment strategies.
The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-κB. For the past 25 years, NF-κB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the κ light chain gene in B cells, research on NF-κB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-κB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-κB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-κB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-κB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.
Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a). During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes. The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis. In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases.
Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory
cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis
and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic
neuroinflammation,which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated
hypothalamus–pituitary–adrenal (HPA) axis have close interactionswith pro-inflammatory cytokines and
neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most
widely investigated factors in the pathophysiology of depression. These two major components create a vicious
cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro-inflammatory
cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an
imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression.
Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they
are essential components of a whole system of inflammatory and endocrine interactions, rather than playing
independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the
pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship
between depression and neuroinflammation.
Objective
Immunologic abnormalities have been found in bipolar disorder and acute mania. However, there have been fewer studies of patients with acute bipolar depression.Method
Blood samples were obtained from individuals with acute bipolar depression, acute mania, and controls. These samples were evaluated for antibodies to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3 using immunoassay methods. Linear regression models were used to compare the levels of the markers controlling for demographic and clinical variables. A subset of the bipolar depressed group was evaluated at a 6-month follow-up.ResultsThe sample consisted of 82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls. The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group. Levels of pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32 individuals 6 months after hospitalization for bipolar depression showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers.Conclusion
Individuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania.
No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders.
There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions.
Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.
NF-κB protects malignant cells from death and therefore it was considered as a cancer treatment target. However, systemic NF-κB inhibition resulted in inflammation and other undesired outcomes. In this issue of Cancer Cell, Tornatore and colleagues solve this problem by targeting the GADD45:MKK7 module mediating NF-κB-induced survival of multiple myelomas. NF-κB protects malignant cells from death and therefore it was considered as a cancer treatment target. However, systemic NF-κB inhibition resulted in inflammation and other undesired outcomes. In this issue of Cancer Cell, Tornatore and colleagues solve this problem by targeting the GADD45:MKK7 module mediating NF-κB-induced survival of multiple myelomas.
Social connections moderate the effects of high negative affect on health. Affective states (anger, fear, and anxiety) predict interleukin-6 (IL-6) reactivity to acute stress; in turn, this reactivity predicts risk of cardiovascular disease progression.
Here, we examined whether perceived social support mitigates the relationship between negative affect and IL-6 stress reactivity.
Forty-eight postmenopausal women completed a standardized mental lab stressor with four blood draws at baseline and 30, 50, and 90 min after the onset of the stressor and anger, anxiety, and fear were assessed 10 min after task completion. Participants self-rated levels of social support within a week prior to the stressor.
Only anger was related to IL-6 stress reactivity-those experiencing high anger after the stressor had significant increases in IL-6. IL-6 reactivity was marginally associated with perceived support, but more strikingly, perceived support mitigated anger associations with IL-6 stress reactivity.
Supportive ties can dampen the relationship of anger to pro-inflammatory reactivity to acute stress. Implications to cardiovascular disease are discussed.
Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions. The reviewed data of affective and nonaffective psychosis show that if immune biomarkers exist for such immune abnormality, they may be found in raised macrophage/monocyte inflammatory activation patterns (monocytosis, high-inflammatory gene expression, raised glucocorticoid receptor β/glucocorticoid receptor α ratio, and high levels of proinflammatory and anti-inflammatory monocyte/macrophage derived cytokines in serum/plasma), reduced T cell numbers/proliferation, and TH1 skewing. This activation of the inflammatory response system may be suggestive for microglia activation, as these cells are the macrophages of the brain. Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model. Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.
Cognitive impairments are a feature of bipolar disorder (BD) and could be worsened by inflammatory cytokines. We determined whether (i) serum interleukin-1 receptor antagonist (IL-1RA) was increased in elderly BD subjects; (ii) whether IL-1RA was associated with worse neurocognitive function; and (iii) whether IL-1RA was associated with white matter integrity.
Twenty-one euthymic BD patients (65 +/- 9 years) with serum available for IL-1RA measures by enzyme-linked immunoassays were compared with 26 similarly aged control participants. Four factor analysis-derived z-scores and a global z-score were obtained from a battery of 21 neurocognitive tests. Diffusion tensor images were used to obtain fractional anisotropy (FA), and an automated labeling pathway algorithm was used to obtain white matter hyperintensity burden.
Interleukin-1 receptor antagonist was elevated in BD subjects compared with controls (439+/-326 pg/mL vs. 269+/-109 pg/mL; p = 0.004). Moreover, IL-1RA was inversely correlated with three cognitive function factors and global cognition (r = -0.37; p = 0.01). IL-1RA continued to correlate with global cognitive function even when covarying for either IL-6 or brain-derived neurotrophic factor. Although FA was lower in BD subjects (0.368 +/- 0.02 vs. 0.381 +/- 0.01; p = 0.02), IL-1RA was not associated with FA or white matter hyperintensity burden.
Elevated serum levels of IL-1RA in BD subjects, even during euthymic states, were associated with worse cognitive function. This association was not explained by co-occurring increases in IL-6, by decreased brain-derived neurotrophic factor, nor by measures of white matter integrity. These cross-sectional findings support the possibility that the IL-1 family may contribute to cognitive impairments in BD. Copyright © 2013 John Wiley & Sons, Ltd.
Despite the wealth of neuroimaging and neuropathologic evidence for abnormalities of brain structure and function in schizophrenia that has evolved over the past two decades, considerably less is known of their origins or of how they might relate mechanistically to the clinical features and the course of the disorder. 41 In the 1980s, there emerged renewed interest in an old and neglected question, the apparent answer to which continues to exert a powerful influence over contemporary research and theory: Do these abnormalities reflect a brain that was once normal but that became subject to some later pathological process (at or somewhat before the onset of psychosis), or do they reflect a brain whose early development was disrupted so as to preclude the development of normal cerebral structure and function? 126,186 Epidemiologic (see article by Jones elsewhere in this issue) and neuropathologic (see article by Kleinman elsewhere in this issue) evidence synergise in contemporary emphasis on schizophrenia as a neurodevelopmental disorder, 174,175,185 and the ascendancy of this perspective has implications that extend beyond causal theorizing to other equally material aspects thereof; for example, in relation to course of illness, it has been argued that schizophrenia is, therefore, a static (i.e., nonprogressive) condition, in a manner antithetical to active (i.e., progressive) disease as encapsulated in classic Kraepelinian deterioration. 69,185 This debate as to origin(s) and course(s) of illness 48,133,179 is surely fundamental to any meaningful concept of schizophrenia. The present article has a threefold purpose: First, the recent proposals for network pathophysiologies that seek to unite otherwise diverse abnormalities of brain structure and function and the extent to which they might contain clues to their origin are considered. Second, indices of early developmental disturbance and the extent to which such putative network dysfunction can be related thereto are examined. Third, from such a developmental anchor, a cascade process for schizophrenia that encompasses a later, progressive element to the disorder is articulated.
BACKGROUND: Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder. METHODS: We measured the levels of high sensitivity CRP in serum samples from 107 individuals with bipolar disorder. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Trail Making Test Part A and WAIS Information and Letter Number Sequencing. We estimated the odds of RBANS scores <=70 for participants whose CRP levels were above the 75th and the 90th percentile of the level of non-psychiatric controls. We also examined the association between cognitive scores and CRP levels. Covariates included demographic factors, mood symptom severity, cigarette smoking status, and body mass index. RESULTS: There was a significantly increased odds of low RBANS total score for individuals who had a CRP level higher than the 90th percentile (OR=4.32, p=.018) and the 75th percentile (OR=3.07, p=.04)) of the control group. There was an inverse relationship between CRP levels and performance on RBANS total (t=-2.48, p=.015); RBANS immediate memory (t=-2.16, p=.033); RBANS attention (t=-2.18, p=.032); RBANS language (t=-2.13, p=.036); Trail Making A (t=-2.39, p=.019). LIMITATIONS: Factors which we did not measure such as diet, allergen exposure, and underlying autoimmune disorders may contribute to CRP levels. CONCLUSIONS: Inflammation may play a major role in the cognitive deficits associated with bipolar disorder.
Curcumin is a polyphenolic nonflavonoid compound extracted from the rhizome of turmeric (Curcuma longa), a plant commonly used in Indian and Chinese traditional medicine to treat rheumatism, cough, inflammation and wounds. Curcumin putative targets, known based on studies of diverse central nervous system disorders other than bipolar disorders (BD) include several proteins currently implicated in the pathophysiology of BD. These targets include, but are not limited to, transcription factors activated by environmental stressors and pro-inflammatory cytokines, protein kinases (PKA, PKC), enzymes, growth factors, inflammatory mediators, and anti-apoptotic proteins (Bcl-XL). Herein, we review previous studies on the anti-inflammatory and anti-oxidant properties of curcumin and discuss its therapeutic potential in BD.
Background:
We conducted a meta-analysis of studies comparing cytokine concentrations between patients with bipolar disorder (BD) and healthy control subjects (HCs).
Methods:
We searched ISI Web of Science, MEDLINE, BIOSIS Previews, Scopus, Current Contents Connect, and Biological Abstracts for relevant studies. Based on heterogeneity status, we used fixed-effect or restricted maximal likelihood model to perform meta-analysis.
Results:
Thirty studies with a total of 2599 participants (1351 BD and 1248 HCs) were eligible for the analysis. Concentrations of interleukin (IL)-4 (p = .008), IL-6 (p = .073), IL-10 (p = .013), soluble IL-2 receptor (sIL-2R; p < .001), sIL-6R (p = .021), tumor necrosis factor (TNF)-α (p = .010), soluble TNF receptor-1 (sTNFR1; p < .001), and IL-1 receptor antagonist (p value in mania < .001 and euthymia = .021) were significantly elevated in patients compared with HCs. Moreover, IL-1β (p = .059), and IL-6 (p = .073) tended to show higher values in patients. Levels of IL-2 (p = .156), interferon (INF)-γ (p = .741), C-C motif ligand 2 (p = .624), and IL-8 (p = .952) did not significantly differ between patients and HCs. Subgroup analysis based on mitogen stimulation status partially or completely resolved heterogeneity for most of the cytokines. Concentrations of IL-2, IL-4, sIL-6R, and INF-γ were unrelated to medication status. Phasic difference was present for TNF-α, sTNFR1, sIL-2R, IL-6, and IL-1RA, whereas it was absent for IL-4 and IL-10.
Conclusions:
This meta-analysis provides evidence for significant elevation of proinflammatory, anti-inflammatory, and regulatory cytokines in BD.
Literature published over the past few years indicates that bipolar disorder has an inflammatory component but does not explicitly define bipolar disorder as an inflammatory or a noninflammatory condition.
Recent studies have shown that bipolar disorder involves microglial activation and alterations in peripheral cytokines and have pointed to the efficacy of adjunctive anti-inflammatory therapies in bipolar depression.
The presence of active microglia and increased proinflammatory cytokines in bipolar disorder suggests an important role of inflammatory components in the pathophysiology of the disease, as well as a possible link between neuroinflammation and peripheral toxicity.
The apparently progressive nature of a considerable proportion of cases of bipolar disorder (BD) has been acknowledged in recently proposed clinical staging models. This has been part of an attempt to facilitate and refine diagnosis, treatment selection, and establish a prognosis. The study of the progressive nature of some cases of BD has given raise to the hypothesis of neuroprogression, which postulates that different stages of BD are associated with distinct neurobiological underpinnings. Given that BD may be intimately associated with chronic stress response and coping mechanisms over the course of illness, we propose that cellular resilience mechanisms may play a key role in the neuroprogression in BD. In the present study, we review neuroanatomical evidence of the progression that occurs in many cases of BD, as well as cellular resilience mechanisms and peripheral biomarkers associated with distinct stages of this disorder. In summary, cellular resilience mechanisms seem to be less efficient at later stages of BD, especially mitochondrial and endoplasmic reticulum-related responses to stress. These insights may help in developing staging models of BD, with a special emphasis on the search for biomarkers associated with illness progression.
There is now strong evidence of progressive neuropathological processes in bipolar disorder (BD). On this basis, the current understanding of the neurobiology of BD has shifted from an initial focus on monoamines, subsequently including evidence of changes in intracellular second messenger systems and more recently to, incorporating changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis into a more comprehensive model capable of explaining some of the clinical features of BD. These features include progressive shortening of the inter-episode interval with each recurrence, occurring in consort with reduced probability of treatment response as the illness progresses. To this end, emerging data shows that these biomarkers may differ between early and late stages of BD in parallel with stage-related structural and neurocognitive alterations. This understanding facilitates identification of rational therapeutic targets, and the development of novel treatment classes. Additionally, these pathways provide a cogent explanation for the efficacy of seemingly diverse therapies used in BD, that appear to share common effects on oxidative, inflammatory and neurotrophic pathways.Research highlights▶ Bipolar disorder is associated with an active process of neuroprogression. ▶ Oxidative, inflammatory and neurotrophic factors play a role in the process. ▶ Both available treatments and novel options impact these pathways.
There is by now substantial clinical evidence for an association between specific mood disorders and altered immune function. More recently, a number of hypotheses have been forwarded to explain how components of the innate immune system can regulate brain function at the cellular and systems levels and how these may underlie the pathology of disorders such as depression, PTSD and bipolar disorder. In this review we draw reference to biochemical, cellular and animal disease models, as well as clinical observations to elucidate the role of the innate immune system in psychiatric disorders. Proinflammatory cytokines, such as IL-1β IL-6 and TNFα, which feature prominently in the immune response to pathogen in the periphery, have unique and specific actions on neurons and circuits within the central nervous system. Effects of these signaling molecules on neurotransmission, memory, and glucocorticoid function, as well as animal behaviors such as social withdrawal and fear conditioning relevant to psychiatric disorders are elucidated. Finally, we highlight future directions for studies, including the use of peripheral biomarkers, relevant for developing new therapeutic approaches for treating psychiatric illnesses.
Individual differences in the aging process can be conceptualized as an accumulation of wear and tear of daily experiences and major life stressors that interact with the genetic constitution and predisposing early life experiences. The neuroendocrine system, autonomic nervous system, and immune system are mediators of adaptation to challenges of daily life, referred to as allostasis, meaning "maintaining stability through change." Physiological mediators such as adrenalin from the adrenal medulla, glucocorticoids from the adrenal cortex, and cytokines from cells of the immune system act upon receptors in various tissues and organs to produce effects that are adaptive in the short run but can be damaging if the mediators are not shut off when no longer needed. When release of the mediators is not efficiently terminated, their effects on target cells are prolonged, leading to other consequences that may include receptor desensitization and tissue damage. This process has been named "allostatic load," and it refers to the price the tissue or organ pays for an overactive or inefficiently managed allostatic response. Therefore, allostatic load refers to the "cost" of adaptation. This article discusses the mediators of allostasis and their contributions to allostatic load as well as their role in resilience of the aging organism to stressful experiences.
Background:
Previous cross-sectional studies report that cognitive impairment is associated with poor psychosocial functioning in euthymic bipolar patients. There is a lack of long-term studies to determine the course of cognitive impairment and its impact on functional outcome. Method A total of 54 subjects were assessed at baseline and 6 years later; 28 had DSM-IV TR bipolar I or II disorder (recruited, at baseline, from a Lithium Clinic Program) and 26 were healthy matched controls. They were all assessed with a cognitive battery tapping into the main cognitive domains (executive function, attention, processing speed, verbal memory and visual memory) twice over a 6-year follow-up period. All patients were euthymic (Hamilton Rating Scale for Depression score lower than 8 and Young mania rating scale score lower than 6) for at least 3 months before both evaluations. At the end of follow-up, psychosocial functioning was also evaluated by means of the Functioning Assessment Short Test.
Results:
Repeated-measures multivariate analysis of covariance showed that there were main effects of group in the executive domain, in the inhibition domain, in the processing speed domain, and in the verbal memory domain (p<0.04). Among the clinical factors, only longer illness duration was significantly related to slow processing (p=0.01), whereas strong relationships were observed between impoverished cognition along time and poorer psychosocial functioning (p<0.05).
Conclusions:
Executive functioning, inhibition, processing speed and verbal memory were impaired in euthymic bipolar out-patients. Although cognitive deficits remained stable on average throughout the follow-up, they had enduring negative effects on psychosocial adaptation of patients.
To evaluate the longitudinal course and outcome of cognitive deficits and their clinical correlates in bipolar disorder.
One hundred thirteen participants (68 patients and 45 healthy controls) were assessed by the means of a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions at baseline: 68 euthymic outpatients with a DSM-IV diagnosis of bipolar disorder (53 bipolar I and 15 bipolar II) were enrolled at the Bipolar Disorder Unit of the Hospital Clinic of Barcelona. Forty-five patients completed the follow-up. The assessments started in February 1999 and finished in July 2010. The primary outcome of the study was the change in the neuropsychological performance in the patient group.
Repeated-measures analyses showed significant effects of time in 2 cognitive domains: attention and executive functions. Attention slightly improved (P = .043) but executive function worsened (P = .001). Regression analyses showed that the duration of illness and baseline subdepressive symptoms were associated with poor performance in executive function. Subdepressive symptoms at endpoint were associated with poor functioning. The best predictor of low functioning was verbal memory dysfunction at baseline.
The cognitive impairment remained stable across the follow-up period in many measures assessed except for a worsening of executive measures, which have been found to be associated with the duration of illness and subdepressive symptoms.
Tricyclic antidepressants and selective serotonin reuptake inhibitors are here shown to induce cell death in a neural cell line. The exposure to these drugs led to increased generation of reactive oxygen species and a concomitant reduction of intracellular glutathione levels. Furthermore, these antidepressants induced DNA fragmentation and increased the transcriptional and DNA-binding activity of NF-κB. In contrast, treatment with type A and B monoamine oxidase inhibitors did not induce changes in NF-κB activity and did not exert a detrimental influence on cell viability. These results indicate that some antidepressant drugs may cause both oxidative stress and changes in cellular antioxidative capacity, resulting in altered NF-κB activity and, ultimately, cell death.
Background:
Current research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according to affective state.
Methods:
We conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement.
Results:
Thirteen studies were included, comprising 556 bipolar disorder patients and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-α (TNF-α), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared with healthy control subjects (p<0.01 for each). Levels of sTNF-R1 and TNF-α were elevated in manic patients compared to euthymic patients (p=0.01 and p=0.04, respectively). sTNF-R1 levels were elevated in euthymic patients compared with healthy control subjects (p<0.01). There were no significant findings for other comparisons, including intra-individual alterations of cytokine levels.
Limitations:
Stratification according to mood state resulted in small study numbers for some cytokines. Findings were limited by heterogeneity, small sample sizes and a lack of control for confounding factors in individual studies.
Conclusions:
This meta-analysis found some support for immune dysregulation in bipolar disorder. Future research is warranted to elucidate the role of endogenous cytokine alterations in bipolar disorder. Clinical studies examining longitudinal changes within individuals are recommended.
Recent theories regarding the neuropathology of bipolar disorder suggest that both neurodevelopmental and neurodegenerative processes may play a role. While magnetic resonance imaging has provided significant insight into the structural, functional, and connectivity abnormalities associated with bipolar disorder, research assessing longitudinal changes has been more limited. However, such research is essential to elucidate the pathophysiology of the disorder. The aim of our review is to examine the extant literature for developmental and progressive structural and functional changes in individuals with and at risk for bipolar disorder.
We conducted a literature review using MEDLINE and the following search terms: bipolar disorder, risk, child, adolescent, bipolar offspring, MRI, fMRI, DTI, PET, SPECT, cross-sectional, longitudinal, progressive, and developmental. Further relevant articles were identified by cross-referencing with identified manuscripts.
There is some evidence for developmental and progressive neurophysiological alterations in bipolar disorder, but the interpretation of correlations between neuroimaging findings and measures of illness exposure or age in cross-sectional studies must be performed with care. Prospective longitudinal studies placed in the context of normative developmental and atrophic changes in neural structures and pathways thought to be involved in bipolar disorder are needed to improve our understanding of the neurodevelopmental underpinnings and progressive changes associated with bipolar disorder.
Current knowledge of the role of autoimmunity in the pathogenesis of the main psychiatric disorders is briefly outlined. The significance of immunological effects on synaptic transmission and associated neuropsychiatric syndromes is emphasised. Clinical psychiatrists are encouraged to keep abreast of developments in this increasingly important area.
Background:
Allostatic load (AL) relates to the neural and bodily "wear and tear" that emerge in the context of chronic stress. This paper aims to provide clinicians with a comprehensive overview of the role of AL in patophysiology of bipolar disorder (BD) and its practical implications.
Methods:
PubMed searches were conducted on English-language articles published from 1970 to June 2011 using the search terms allostatic load, oxidative stress, staging, and bipolar disorder cross-referenced with cognitive impairment, comorbidity, mediators, prevention.
Results:
Progressive neural and physical dysfunction consequent to mood episodes in BD can be construed as a cumulative state of AL. The concept of AL can help to reconcile cognitive impairment and increased rates of clinical comorbidities that occur over the course of cumulative BD episodes.
Conclusions:
Data on transduction of psychosocial stress into the neurobiology of mood episodes converges to the concept of AL. Mood episodes prevention would not only alleviate emotional suffering, but also arrest the cycle of AL, cognitive decline, physical morbidities and, eventually, related mortality. These objectives can be achieved by focusing on effective prophylaxis from the first stages of the disorder, providing mood-stabilizing agents and standardized psychoeducation and, potentially, addressing cognitive deficits by the means of specific medication and neuropsychological interventions.
Patients with bipolar disorder are known to be at high risk of premature death. Comorbid cardio-vascular diseases are a leading cause of excess mortality, well above the risk associated with suicide. In this review, we explore comorbid medical disorders, highlighting evidence that bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease.
We conducted a systematic PubMed search of all English-language articles recently published with bipolar disorder cross-referenced with the following terms: mortality and morbidity, cardio-vascular, diabetes, obesity, metabolic syndrome, inflammation, auto-antibody, retro-virus, stress, sleep and circadian rhythm.
Evidence gathered so far suggests that the multi-system involvement is present from the early stages, and therefore requires proactive screening and diagnostic procedures, as well as comprehensive treatment to reduce progression and premature mortality. Exploring the biological pathways that could account for the observed link show that dysregulated inflammatory background could be a common factor underlying cardio-vascular and bipolar disorders. Viewing bipolar disorder as a multi-system disorder should help us to re-conceptualize disorders of the mind as "disorders of the brain and the body".
The current literature substantially lacks longitudinal and mechanistic studies, as well as comparison studies to explore the magnitude of the medical burden in bipolar disorder compared to major mood disorders as well as psychotic disorders. It is also necessary to look for subgroups of bipolar disorder based on their rates of comorbid disorders.
Comorbid medical illnesses in bipolar disorder might be viewed not only as the consequence of health behaviors and of psychotropic medications, but rather as an early manifestation of a multi-systemic disorder. Medical monitoring is thus a critical component of case assessment. Exploring common biological pathways of inflammation should help biomarkers discovery, ultimately leading to innovative diagnostic tools, new methods of prevention and personalized treatments.
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.
The vast majority of research on nuclear factor κB (NF-κB) signaling in the past 25 years has focused on its roles in normal and disease-related processes in vertebrates, especially mice and humans. Recent genome and transcriptome sequencing efforts have shown that homologs of NF-κB transcription factors, inhibitor of NF-κB (IκB) proteins, and IκB kinases are present in a variety of invertebrates, including several in phyla simpler than Arthropoda, the phylum containing insects such Drosophila. Moreover, many invertebrates also contain genes encoding homologs of upstream signaling proteins in the Toll-like receptor signaling pathway, which is well-known for its downstream activation of NF-κB for innate immunity. This review describes what we now know or can infer and speculate about the evolution of the core elements of NF-κB signaling as well as the biological processes controlled by NF-κB in invertebrates. Further research on NF-κB in invertebrates is likely to uncover information about the evolutionary origins of this key human signaling pathway and may have relevance to our management of the responses of ecologically and economically important organisms to environmental and adaptive pressures.
An association between allergic disease and depression has been consistently reported, but whether the key mediating ingredients are predominantly biological, psychological, or mere artifacts remains unknown. In the current study, we examined a hypothesized relationship between allergen-specific immunoglobulin E (IgE) status and changes in allergy symptoms with worsening in depression scores.
In patients with recurrent mood disorders, we individually coupled sensitization to specific seasonal aeroallergens (as assessed by allergen-specific IgE) with temporal windows of exposure to aeroallergens (low versus high tree or ragweed pollen counts, measured according to the National Allergy Bureau guidelines). We compared Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) depression score changes in 41 patients with mood disorders [25 with major depression and 16 with bipolar I disorder, diagnosed by Structured Clinical Interview for DSM (SCID)] seropositive for tree or ragweed pollen-specific IgE antibody versus 53 patients with mood disorders (30 with major depression and 23 with bipolar I disorder) seronegative for aeroallergen-specific IgE.
Worsening in total depressive scores from low to high pollen exposure was greater in allergen-specific IgE-positive patients as compared to allergen-specific IgE antibody-negative patients (p = 0.01). When stratified by polarity, the association was significant only in patients with bipolar I disorder (p = 0.004). This relationship was resilient to adjustment for changes in allergy symptom scores.
To our knowledge, this is the first report of coupling a molecular marker of vulnerability (allergen-specific IgE) with a specific environmental trigger (airborne allergens) leading to exacerbation of depression in patients with bipolar I disorder.