Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

Rosenblat, Joshua D.; McIntyre, Roger S.

doi:10.3390/brainsci7110144

Cited by 208 publications

(147 citation statements)

References 144 publications

(187 reference statements)

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“…Whether these immunity-related mechanisms play a role in the mood stabilizing effects of lithium remains to be determined. Immune components of psychiatric illness including BD 57 have long been recognized, but it remains unclear if they represent a causal pathway, a property of the disease state, or a consequence of environmental factors like body mass index or smoking. These results contribute to the understanding of the genomics of lithium action, which may be essential for the future of personalized psychiatric medicine for patients with BD.…”

Section: Discussionmentioning

confidence: 99%

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

Krebs

Ori

Vreeker

et al. 2018

Preprint

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23Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and 24 poorly understood etiology. We performed a whole blood transcriptome analysis in a BD case-25 control sample (Nsubjects = 480) by RNA sequencing. While we observed widespread differential 26 gene expression patterns between affected and unaffected individuals, these effects were largely 27 linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD 28 diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell 29 signaling and immune response functional annotations, among others, and were associated with 30 neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered 31 expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression 32 genetic risk based on information from genome-wide association studies, nor was gene 33 expression associated with polygenic risk scores for BD. Our findings suggest that BD is 34 associated with minimal changes in whole blood gene expression independent of medication use 35 but underline the importance of accounting for medication use and cell type heterogeneity in 36 psychiatric transcriptomic studies. The results of our study add to mounting evidence of lithium's 37 cell signaling and immune-related mechanisms. 38 39 strategy for uncovering disease mechanisms. Many such studies have been carried out for BD, 48and in Table 1 we present a summary that reveals a lack of consistency between findings likely 49 owing to clinical heterogeneity, differing study designs, and the low numbers of samples 50 investigated (N ≤ 62 BD subjects) . Moreover, there are many potential confounds that impact 51 gene expression, including medication. 52 Therefore, to explore gene expression changes associated with BD, we generated RNA 53 sequencing data from peripheral whole blood collected in a large, well-characterized case-control 54 cohort from The Netherlands. We examined gene expression differences between groups both at 55 the individual gene level and at the level of gene co-expression. Upon correction for technical and 56 biological variables including the use of lithium, the most widely used prescription drug in our 57 cohort, gene expression differences between subjects with BD and controls were minor. 58Differences in subjects being treated with lithium compared to those who are not, however, were 59 widespread. These differences were partially but not entirely explained by differences in cell-type 60 composition, driven by elevated neutrophil proportions in lithium users. The lithium-associated 61 changes in gene expression were independent of psychiatric genetic risk, though. Our results 62 suggest nominal BD-related gene expression effects in blood but numerous effects related to 63 lithium treatment. This work highlights the importance of accounting for medication use in 64 psychiatric transcriptomic studies and provides insight into lithium's mole...

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Section: Discussionmentioning

confidence: 99%

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

Krebs

Ori

Vreeker

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…During infection, TNF levels increase, and sustained TNF elevation and dysregulation have been implicated in the development of autoimmune diseases, including rheumatoid arthritis and Crohn's disease . Interestingly, autoimmune diseases share significant comorbidity with mood disorders, to an extent that cannot be explained by chance . Furthermore, both severe infection and autoimmune disease have been cited as risk factors for the development of depressive symptoms; in particular, repeated infections have been shown to be associated with an increase in the likelihood of the onset of depressive symptoms …”

Section: Tnf Abnormalities In Mood Disordersmentioning

confidence: 99%

“…31 Interestingly, autoimmune diseases share significant comorbidity with mood disorders, to an extent that cannot be explained by chance. [32][33][34] Furthermore, both severe infection and autoimmune disease have been cited as risk factors for the development of depressive symptoms; 34,35 in particular, repeated infections have been shown to be associated with an increase in the likelihood of the onset of depressive symptoms. 35 Currently, studies in the periphery provide the strongest link implicating TNF in the pathophysiologies of mood disorders, with these data arguing a relationship between immune-related dysfunction and mood disorder pathology.…”

Section: Tnf Abnormalities In Mood Disordersmentioning

confidence: 99%

Tumor necrosis factor receptor 2: A potential target for antidepressant drug development

Seymour

Gibbons

Dean

2019

Clinical & Exp Neuroim

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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.

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“…The dysregulation of inflammatory responses has recently been implicated in the neuroimmunopathogenesis of mental disorders, specifically as an etiological factor in disorders such as BPAD, unipolar depression, and schizophrenia [9-17]. A recent study found that patients with bipolar disorder (BD) who are in manic or depressed states have higher levels of circulating, activated T cells and serum interleukin (IL)-2 receptors when compared to healthy controls [18, 19].…”

Section: What Is the Role Of Psychoneuroimmunology In Bpad?mentioning

confidence: 99%

In the Realm of Psychoneuroimmunology: The Role of Celecoxib as an Add-On Treatment for Bipolar Mania

2018

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Bipolar affective disorder (BPAD) is a chronic debilitating psychiatric illness seriously affecting the quality of patients’ life. The available treatment is effective in about half of those suffering from the illness. The neurobiological basis of the disorder is not fully unraveled. With such lacunae, attempts have been made to decipher the underlying neuroimmunological process of the illness as is the case with other mental disorders. As a result, some inflammatory processes have been implicated in the etiology of BPAD, as described in this communication. Subsequently, the role of anti-inflammatory agents such as celecoxib was investigated by treating different phases of BPAD. Given the promising outcomes of several trials and reviews, celecoxib has gained momentum and has been recommended as an adjunctive treatment by some guidelines for treating resistant BPAD cases. This brief communication highlights some of the caveats in the randomized trials using celecoxib as an add-on treatment in bipolar mania specifically, which need to be addressed in future work.

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Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

Cited by 208 publications

References 144 publications

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

Tumor necrosis factor receptor 2: A potential target for antidepressant drug development

In the Realm of Psychoneuroimmunology: The Role of Celecoxib as an Add-On Treatment for Bipolar Mania

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