Pathogenesis Of Bipolar Disorder Research Articles

Metabolomic biomarkers related to non-suicidal self-injury in patients with bipolar disorder

BackgroundNon-suicidal self-injury (NSSI) is an important symptom of bipolar disorder (BD) and other mental disorders and has attracted the attention of researchers lately. It is of great significance to study the characteristic markers of NSSI. Metabolomics is a relatively new field that can provide complementary insights into data obtained from genomic, transcriptomic, and proteomic analyses of psychiatric disorders. The aim of this study was to identify the metabolic pathways associated with BD with NSSI and assess important diagnostic and predictive indices of NSSI in BD.MethodNuclear magnetic resonance spectrometry was performed to evaluate the serum metabolic profiles of patients with BD with NSSI (n = 31), patients with BD without NSSI (n = 46), and healthy controls (n = 10). Data were analyzed using an Orthogonal Partial Least Square Discriminant Analysis and a t-test. Differential metabolites were identified (VIP > 1 and p < 0.05), and further analyzed using Metabo Analyst 3.0 to identify associated metabolic pathways.ResultsEight metabolites in the serum and two important metabolic pathways, the urea and glutamate metabolism cycles, were found to distinguish patients with BD with NSSI from healthy controls. Eight metabolites in the serum, glycine and serine metabolism pathway, and the glucose-alanine cycle were found to distinguish patients with BD without NSSI from healthy controls. Five metabolites in the serum and the purine metabolism pathway were found to distinguish patients with BD with NSSI from those with BD without NSSI.ConclusionsAbnormalities in the urea cycle, glutamate metabolism, and purine metabolism played important roles in the pathogenesis of BD with NSSI.

The potential protein marker of bipolar disorder

IntroductionDifficulties in the diagnosis of bipolar disorder (BD) are associated with a lack of understanding of the mechanisms of its pathogenesis. Identification of proteins involved in the pathogenesis of BD will bring us closer to an understanding of its mechanisms and can help in diagnosis.ObjectivesThe search of proteomic biomarkers of bipolar disorder.MethodsWe performed a proteomic analysis of the serum of 16 healthy people and 33 patients with BD. Patients were hospitalized in an acute state of the depressive phase, and they did not receive therapy for more than 6 months. Blood was collected before the start of therapy. Serum was purified from major proteins by affinity chromatographyandseparatedby1D-electrophoresis. After trypsinolysis, the proteins were identified by HPLC/mass spectrometry. The ELISA kit was used to determine the amount of zNMDAR1.ResultsWe identified a protein that does not occur in healthy people: a subunit of the glutamate NMDA receptor zeta-1 (zNMDAR1). As a result, we found a statistically significant (p = 0.037) almost fivefold increase in the concentration of this protein in the serum of patients with bipolar disorder (0.64 [0.18; 0.78] ng/ml) compared with healthy individuals.ConclusionsThus, in bipolar disorder NMDAR is damaged, which can lead appearance of their subunits in the serum, and which indicated a violation of glutamatergic neurotransmission. Then this protein claims the role of markers of bipolar disorder. Mass spectrometric analysis was carried out of the “Human Proteome” Core Facility of the Institute of Biomedical Chemistry Moscow. RSW project, state registration number AAAA-A19-119020690013-2.DisclosureNo significant relationships.

Functional genomic analysis delineates regulatory mechanisms of GWAS-identified bipolar disorder risk variants

BackgroundGenome-wide association studies (GWASs) have identified multiple risk loci for bipolar disorder (BD). However, pinpointing functional (or causal) variants in the reported risk loci and elucidating their regulatory mechanisms remain challenging.MethodsWe first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) data from human brain tissues (or neuronal cell lines) and position weight matrix (PWM) data to identify functional single-nucleotide polymorphisms (SNPs). Then, we verified the regulatory effects of these transcription factor (TF) binding–disrupting SNPs (hereafter referred to as “functional SNPs”) through a series of experiments, including reporter gene assays, allele-specific expression (ASE) analysis, TF knockdown, CRISPR/Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. Finally, we overexpressed PACS1 (whose expression was most significantly associated with the identified functional SNPs rs10896081 and rs3862386) in mouse primary cortical neurons to investigate if PACS1 affects dendritic spine density.ResultsWe identified 16 functional SNPs (in 9 risk loci); these functional SNPs disrupted the binding of 7 TFs, for example, CTCF and REST binding was frequently disrupted. We then identified the potential target genes whose expression in the human brain was regulated by these functional SNPs through eQTL analysis. Of note, we showed dysregulation of some target genes of the identified TF binding–disrupting SNPs in BD patients compared with controls, and overexpression of PACS1 reduced the density of dendritic spines, revealing the possible biological mechanisms of these functional SNPs in BD.ConclusionsOur study identifies functional SNPs in some reported risk loci and sheds light on the regulatory mechanisms of BD risk variants. Further functional characterization and mechanistic studies of these functional SNPs and candidate genes will help to elucidate BD pathogenesis and develop new therapeutic approaches and drugs.

Downregulation of long non-coding RNAs in patients with bipolar disorder.

The abnormal function of signaling cascades is currently a candidate in the pathophysiology of bipolar disorder (BD). One of the factors involved in activating these signals is oxidative stress. Some long non-coding RNAs (lncRNA) are involved in the oxidative stress. In this study, we compared expression levels of lincRNA-p21, lincRNA-ROR, and lincRNA-PINT in the peripheral blood mononuclear cells (PBMC) from BD patients (n = 50) and healthy individuals (n = 50). Expression levels of lincRNA-p21, lincRNA-ROR, and lincRNA-PINT were significantly reduced in patients with BD compared to controls. In sex-based analyses, down-regulation of these lncRNAs was revealed only in male BD patients compared to male healthy subjects. Also, in BD patients, all three lncRNAs showed a significant pairwise positive correlation in expression level. The area under curve values for lincRNA-p21, lincRNA-ROR, and lincRNA-PINT was 0.66, 0.75, and 0.66, respectively. Thus, the ROC curve analysis showed that lncRNA-ROR might serve as a diagnostic biomarker for distinguishing between BD patients and controls. Altogether, the current study proposes a role for lincRNA-p21, lincRNA-ROR, and lincRNA-PINT in the pathogenesis of bipolar disorder. Moreover, the peripheral expression of these lncRNAs might be useful as potential biomarkers for BD.

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder

BackgroundWe aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). MethodsBased on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. ResultsIn genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. ConclusionsBD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Significant reduction of long non-coding RNAs expression in bipolar disorder

Long non-coding RNAs (lncRNAs) have been recently emerged as critical modulators of oxidative stress pathway. Likewise, rising evidence currently highlights dysfunction of oxidative stress pathways in bipolar disorder (BD) patients.In the current study, we evaluated the expression levels of H19, SCAL1 (LUCAT1), RMST, MEG3 and MT1DP lncRNAs in the PBMC from 50 patients with BD and 50 control subjects (male/female ratio in each group: 70%/30%). Expression levels of SCAL1, RMST and MEG3 but not H19 and MT1DP were considerably decreased in BD patients compared with healthy individuals. Such significant decrease in the expression of MEG3, RMST and SCAL1 was only reported in male BD patients compared with male controls. Substantial pairwise correlations were observed between expression levels of these lncRNAs in BD subjects. The area under curve values for RMST, MEG3 and SCAL1 were 0.70, 0.63 and 0.61 respectively. On the basis of this finding, RMST had the best efficiency in the discrimination of disease status between BD patients and controls. Taken together, the current results suggest a role for MEG3, RMST and SCAL1 lncRNAs in the pathogenesis of BD. In addition, peripheral expression levels of these lncRNAs might serve as potential peripheral markers for BD.

Transmembrane protein 108 inhibits the proliferation and myelination of oligodendrocyte lineage cells in the corpus callosum

BackgroundAbnormal white matter is a common neurobiological change in bipolar disorder, and dysregulation of myelination in oligodendrocytes (OLs) is the cause. Transmembrane protein 108 (Tmem108), as a susceptible gene of bipolar disorder, is expressed higher in OL lineage cells than any other lineage cells in the central nervous system. Moreover, Tmem108 mutant mice exhibit mania-like behaviors, belonging to one of the signs of bipolar disorder. However, it is unknown whether Tmem108 regulates the myelination of the OLs.ResultsTmem108 expression in the corpus callosum decreased with the development, and OL progenitor cell proliferation and OL myelination were enhanced in the mutant mice. Moreover, the mutant mice exhibited mania-like behavior after acute restraint stress and were susceptible to drug-induced epilepsy.ConclusionsTmem108 inhibited OL progenitor cell proliferation and mitigated OL maturation in the corpus callosum, which may also provide a new role of Tmem108 involving bipolar disorder pathogenesis.

Phenotypes, mechanisms and therapeutics: insights from bipolar disorder GWAS findings

Genome-wide association studies (GWAS) have reported substantial genomic loci significantly associated with clinical risk of bipolar disorder (BD), and studies combining techniques of genetics, neuroscience, neuroimaging, and pharmacology are believed to help tackle clinical problems (e.g., identifying novel therapeutic targets). However, translating findings of psychiatric genetics into biological mechanisms underlying BD pathogenesis remains less successful. Biological impacts of majority of BD GWAS risk loci are obscure, and the involvement of many GWAS risk genes in this illness is yet to be investigated. It is thus necessary to review the progress of applying BD GWAS risk genes in the research and intervention of the disorder. A comprehensive literature search found that a number of such risk genes had been investigated in cellular or animal models, even before they were highlighted in BD GWAS. Intriguingly, manipulation of many BD risk genes (e.g., ANK3, CACNA1C, CACNA1B, HOMER1, KCNB1, MCHR1, NCAN, SHANK2 etc.) resulted in altered murine behaviors largely restoring BD clinical manifestations, including mania-like symptoms such as hyperactivity, anxiolytic-like behavior, as well as antidepressant-like behavior, and these abnormalities could be attenuated by mood stabilizers. In addition to recapitulating phenotypic characteristics of BD, some GWAS risk genes further provided clues for the neurobiology of this illness, such as aberrant activation and functional connectivity of brain areas in the limbic system, and modulated dendritic spine morphogenesis as well as synaptic plasticity and transmission. Therefore, BD GWAS risk genes are undoubtedly pivotal resources for modeling this illness, and might be translational therapeutic targets in the future clinical management of BD. We discuss both promising prospects and cautions in utilizing the bulk of useful resources generated by GWAS studies. Systematic integrations of findings from genetic and neuroscience studies are called for to promote our understanding and intervention of BD.

Gut Microbiota - A Potential Contributor in the Pathogenesis of Bipolar Disorder.

Bipolar disorder (BD) is one of the major psychiatric disorders that is characterized by recurrent episodes of depression and mania (or hypomania), leading to seriously adverse outcomes with unclear pathogenesis. There is an underlying relationship between bacterial communities residing in the gut and brain function, which together form the gut-brain axis (GBA). Recent studies have shown that changes in the gut microbiota have been observed in a large number of BD patients, so the axis may play a role in the pathogenesis of BD. This review summarizes briefly the relationship between the GBA and brain function, the composition and changes of gut microbiota in patients with BD, and further explores the potential role of GBA-related pathway in the pathogenesis of BD as well as the limitations in this field at present in order to provide new ideas for the future etiology research and drug development.

Dysfunction of the Purinergic System in Bipolar Disorder

Objective: To verify the purinergic hypothesis of bipolar disorder (BD), we assessed the concentration of various components of the purinergic system in manic and depressed bipolar patients. Methods: Sixty-two patients (19 male and 43 female), aged 22–69 (49 ± 14) years, with BD were studied. Twenty-three patients (9 male and 14 female) were assessed during a manic episode and subsequent remission, and 39 patients (10 male and 29 female) were investigated in a depressive episode and the following remission. Twenty-two healthy subjects (8 male and 14 female), aged 19–70 (41 ± 14) years, served as the control group (CG). The severity of symptoms was evaluated using the Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS). The concentrations of uric acid (UA) were estimated by the uricase-based method, whereas xanthine dehydrogenase (XDH), adenosine (Ado), and adenosine deaminase (ADA) by ELISA. Results: The mean score in the acute episode was 32 ± 8 points in the YMRS for mania and 31 ± 8 in the HDRS for depression. UA levels were significantly higher in female bipolar patients compared to the females in the CG. The concentrations of XDH, Ado, and ADA were significantly lower in bipolar patients both during an acute episode and remission compared to CG. Conclusions: A significant dysfunction of the purinergic system in patients with BD was observed. In most instances, the disturbances were not different in the acute episode than in remission what qualifies them as trait dependent. The results may confirm the role of the purinergic system in the pathogenesis of BD.

Association between resting-state functional connectivity of amygdala subregions and peripheral pro-inflammation cytokines levels in bipolar disorder.

The pathophysiological mechanisms of bipolar disorder (BD) are not completely known, and systemic inflammation and immune dysregulation are considered as risk factors. Previous neuroimaging studies have proved metabolic, structural and functional abnormalities of the amygdala in BD, suggesting the vital role of amygdala in BD patients. This study aimed to test the underlying neural mechanism of inflammation-induced functional connectivity (FC) in the amygdala subregions of BD patients. Resting-state functional MRI (rs-fMRI) was used to delineate the amygdala FC from two pairs of amygdala seed regions (the bilateral lateral and medial amygdala) in 51 unmedicated BD patients and 69 healthy controls (HCs). The levels of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α were measured in the serum. The correlation between abnormal levels of pro-inflammatory cytokines and FC values were calculated in BD patients. The BD group exhibited decreased FC between the right medial amygdala and bilateral medial frontal cortex (MFC), and decreased FC between the left medial amygdala and the left temporal pole (TP), right orbital inferior frontal gyrus compared with HCs. The BD patients had higher levels of TNF-α than HCs. Correlation analysis showed negative correlation between the TNF-α level and abnormal FC of the right medial amygdala-bilateral MFC; and negative correlation between TNF-α levels and abnormal FC of the left medial amygdala-left TP in BD group. These findings suggest that dysfunctional and immune dysregulation between the amygdala and the frontotemporal circuitry might play a critical role in the pathogenesis of BD.

Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress-Induced Damage in Patients with Bipolar Disorder.

Bipolar disorder (BD) is characterized by mood changes, including recurrent manic, hypomanic, and depressive episodes, which may involve mixed symptoms. Despite the progress in neurobiological research, the pathophysiology of BD has not been extensively described to date. Progress in the understanding of the neurobiology driving BD could help facilitate the discovery of therapeutic targets and biomarkers for its early detection. Oxidative stress (OS), which damages biomolecules and causes mitochondrial and dopamine system dysfunctions, is a persistent finding in patients with BD. Inflammation and immune dysfunction might also play a role in BD pathophysiology. Specific nutrient supplements (nutraceuticals) may target neurobiological pathways suggested to be perturbed in BD, such as inflammation, mitochondrial dysfunction, and OS. Consequently, nutraceuticals may be used in the adjunctive treatment of BD. This paper summarizes the possible roles of OS, mitochondrial dysfunction, and immune system dysregulation in the onset of BD. It then discusses OS-mitigating strategies that may serve as therapeutic interventions for BD. It also analyzes the relationship between diet and BD as well as the use of nutritional interventions in the treatment of BD. In addition, it addresses the use of lithium therapy; novel antipsychotic agents, including clozapine, olanzapine, risperidone, cariprazine, and quetiapine; and anti-inflammatory agents to treat BD. Furthermore, it reviews the efficacy of the most used therapies for BD, such as cognitive–behavioral therapy, bright light therapy, imagery-focused cognitive therapy, and electroconvulsive therapy. A better understanding of the roles of OS, mitochondrial dysfunction, and inflammation in the pathogenesis of bipolar disorder, along with a stronger elucidation of the therapeutic functions of antioxidants, antipsychotics, anti-inflammatory agents, lithium therapy, and light therapies, may lead to improved strategies for the treatment and prevention of bipolar disorder.

New Evidence of Gut Microbiota Involvement in the Neuropathogenesis of Bipolar Depression by TRANK1 Modulation: Joint Clinical and Animal Data.

Tetratricopeptide repeat and ankyrin repeat containing 1 (TRANK1) is a robust risk gene of bipolar disorder (BD). However, little is known on the role of TRANK1 in the pathogenesis of BD and whether the gut microbiota is capable of regulating TRANK1 expression. In this study, we first investigated the serum mRNA level of TRANK1 in medication-free patients with a depressive episode of BD, then a mice model was constructed by fecal microbiota transplantation (FMT) to explore the effects of gut microbiota on brain TRANK1 expression and neuroinflammation, which was further verified by in vitro Lipopolysaccharide (LPS) treatment in BV-2 microglial cells and neurons. 22 patients with a depressive episode and 28 healthy individuals were recruited. Serum level of TRANK1 mRNA was higher in depressed patients than that of healthy controls. Mice harboring ‘BD microbiota’ following FMT presented depression-like phenotype. mRNA levels of inflammatory cytokines and TRANK1 were elevated in mice hippocampus and prefrontal cortex. In vitro, LPS treatment activated the secretion of pro-inflammatory factors in BV-2 cells, which was capable of upregulating the neuronal expression of TRANK1 mRNA. Moreover, primary cortical neurons transfected with plasmid Cytomegalovirus DNA (pcDNA3.1(+)) vector encoding human TRANK1 showed decreased dendritic spine density. Together, these findings add new evidence to the microbiota-gut-brain regulation in BD, indicating that microbiota is possibly involved in the neuropathogenesis of BD by modulating the expression of TRANK1.

Immunological Indicators of Infl ammation in Late-Life Bipolar Disorder

The aim of the study was to determine the immune markers of infl ammation in the blood plasma of the elderly patients with bipolar affective disorders (BD) in relation to the clinical specifi cities of the disease. Patients and methods: 134 blood samples from the elderly patients aged from 52 to 88 years old (mean age 66.7 ± 7.7 years) with diagnose of bipolar disorder were examined. Infl ammatory markers in the blood plasma were determined as follows: the enzymatic activity of leukocyte elastase (LE) and the functional activity of the D1-proteinase inhibitor (D1-PI), as well as the level of autoantibodies (aAB) to S100b and myelin basic protein (MBP), and the protease inhibitor index (PII), which was the ratio of LE and D1-PI activity and characterized the activity of the proteolytic system as the most important component of infl ammation. Cluster analysis was used to reveal immunotypes. Results and discussion: а signifi cant increase in D1-PI and the level of aAB to S100b was revealed in elderly patients diagnosed with bipolar disorders, as well as low proteolytic activity of infl ammation (according to PII). Immune markers of infl ammation in different types of affective episodes (depressions, manias, mixed affective states) and in therapeutic remission did not differ from each other. Immunological parameters in elderly patients with bipolar disorders depended on the severity degree of the affective disorder. A relationship was found between the severity of depression and the level of aAB to S100b; the difference between mania and hypomania in terms of LE and PII activity was shown; in mixed affective states immunological parameters differed from the control only in moderate disorders. Remission with residual symptoms differed from asymptomatic therapeutic remission in terms of LE and PII activity. The two identifi ed clusters (immunotypes) differed in the activity of LE and PII. Conclusion: the results indicated the participation of infl ammation in the pathogenesis of bipolar disorder, and the isolated immunotypes confi rmed the clinical diversity of the disease. The study of the pathogenetic signifi cance of infl ammation and the identifi cation of various immunotypes was aimed at search for new therapy targets, taking into account the contribution of infl ammation.

Bioinformatics Analysis of circRNA Expression and Construction of "circRNA-miRNA-mRNA" Competing Endogenous RNAs Networks in Bipolar Disorder Patients.

Bipolar disorder (BD) is a severe mood disorder disease in China, and its underlying pathogenesis remains unknown. Circular RNAs (circRNAs) have been reported to play a key role in mental disorders and can be used as competitive endogenous RNAs (ceRNAs). However, little is known about the correlation of circRNAs with BD. In this study, Deep RNA sequencing was used to identify differentially expressed circRNAs (DE-circRNAs) and differentially expressed mRNAs (DE-mRNAs) between BD patients and a control group. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to validate the differentially expressed RNAs (DE-RNAs). In all 9,593 circRNAs and 20,030 mRNAs were found in the two groups of specimens, among which 50 DE-circRNAs and 244 DE-mRNAs were significantly upregulated, and 44 DE-circRNAs and 294 DE-mRNAs were significantly downregulated. Based on the regulatory mechanism of ceRNAs, circRNAs can directly bind microRNAs (miRNAs) to affect mRNA expression, and the expression trends of circRNAs and mRNAs are consistent. According to this mechanism, we constructed two ceRNA networks by using the RNA sequencing data. The function of these DE-circRNAs was further elucidated by enrichment analysis. In summary, the present study showed that the circRNA expression profile of BD patients is altered, and a ceRNA regulatory network was constructed, which provided a hypothesis about the pathogenesis of BD.

ANK3 Gene Polymorphism Rs10994336 Influences Executive Functions by Modulating Methylation in Patients With Bipolar Disorder.

Background: A large body of evidence suggests that epigenetic modification including DNA methylation plays a critical role in BD's pathogenesis while the identification of methylation quantitative trait loci (meQTLs) shed light on the interpretation of the function of genetic variants in non-coding regions. The intronic single nucleotide polymorphism (SNP) rs10994336 within the ANK3 has emerged as one of the most replicated risk variants for bipolar disorder (BD) in genome-wide association studies. Whether rs10994336 functions as a meQTL to mediate the association between genotype and phenotype remains unclear.Method: A total of 154 patients with BD and 181 healthy controls (HC) were recruited. The genotypes of rs10994336 and methylation levels of CpG sites within ANK3 were tested. Executive functions were assessed using a computerized version of the Wisconsin Card Sorting Test (WCST).Results: Bipolar disorder patients with the risk-T allele of rs10994336 scored lower on tests of executive function compared to homozygous CC carriers, after controlling for age, gender, and education level. No significant difference was found in HC individuals. The risk-T allele is associated with a lower methylation level of CpG site cg02172182 in HC after multiple corrections and replicated in the BD group in the same direction. Further mediation analysis revealed that the cg02172182 methylation significantly mediated the association between the polymorphism rs10994336 and PE index of WCST in patients with BD.Conclusion: Our study suggests that BD-related genetic variant rs10994336 in ANK3 impacts executive functions by modulating ANK3 methylation, supporting the theory that methylation acts as a mediator between genotype and phenotype.

Identification of lncRNA NR_028138.1 as a biomarker and construction of a ceRNA network for bipolar disorder

The pathogenesis of bipolar disorder (BD), a chronic mood disorder, is largely unknown. Noncoding RNAs play important roles in the pathogenesis of BD. However, little is known about the correlations of long noncoding RNAs (lncRNAs) with BD. Illumina high-throughput sequencing in BD patients and normal controls was used to identify differentially expressed (DE) genes. Two-step real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate DE-RNAs in the first cohort (50 BD and 50 control subjects). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and lncRNA-mRNA coexpression and lncRNA-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) network analyses were used to predict the functions of DE-RNAs. Receiver operating characteristic (ROC) curve analysis and logistic regression were applied to evaluate diagnostic performance in an additional testing group (80 BD and 66 control subjects). A total of 576 significantly DE-lncRNAs and 262 DE-mRNAs were identified in BD patients, and 95 lncRNA-miRNA-mRNA interactions were used to construct a ceRNA regulatory network. Analysis of the first cohort showed that six RNAs (NR_028138.1, TCONS_00018621, TCONS_00002186, TNF, PID1, and SDK1) were differentially expressed in the BD group (P < 0.01). NR_028138.1 was used to establish a BD diagnostic model (area under the ROC curve 0.923, P < 0.004, 95% CI: 0.830–0.999). Verification in the second cohort revealed uniformly significant differences in NR_028138.1 (P < 0.0001). This study constructed a ceRNA regulatory network and provided a hypothesis for the pathogenesis of BD. NR_028138.1 was identified as a central element involved in the transcriptional regulation in BD and a potential biomarker.

Involvement of Kynurenine Metabolism in Bipolar Disorder: An Updated Review.

Bipolar disorder (BD) is a severe affective disorder, mainly characterized by alternative depressive and manic or hypomanic episodes, yet the pathogenesis of BD has not been fully elucidated. Recent researches have implicated the altered kynurenine (KYN) metabolism involved in the neurobiology of BD. Excessive activation of the immune system also occurs in patients with BD, which further accelerates the KYN pathway for tryptophan metabolism. Changes of the KYN metabolites have effects on neuronal receptors and are involved in neuroendocrine transmissions. Interactions between KYN metabolism and the immune system may contribute to the neuropathogenesis of BD. Various studies have shown that alterations of the KYN metabolites were associated with mood, psychotic symptoms, and cognitive functions in patients with BD. In this review, we briefly introduce the KYN pathway and describe the immune dysregulation in BD as well as their interactions. We then focus on the research advances on the KYN metabolism in BD, which hold promise for identifying novel treatment targets in patients stricken with this disorder.

Variations immunologiques après traitement d’un épisode maniaque

Bipolar disorder is a chronic and disabling mental illness affecting approximately 1–2% of the general population, characterized by the occurrence of manic episodes alone or alternating with depressive episodes. Bipolar disorder is associated with significant morbidity, mortality and personal suffering. The mechanisms underlying the onset and progression of bipolar disease are still poorly understood. Recently, immunological dysfunctions have been suggested in the pathogenesis of bipolar disorder, and many studies have focused on the interaction between bipolar disorder and immunity. Immunological changes have been widely studied during depressive episodes but less explored during manic episodes. The objective of our study was to explore changes in serum proteins and autoantibodies after treatment for a manic episode of bipolar I disorder. This study was carried out over a 30-month period from January 2017 to June 2019, in collaboration between the psychiatry department B of the Hédi Chaker CHU and the immunology department of the Habib Bourguiba CHU, in Sfax, Tunisia. It focused on a sample of 45 bipolar patients with manic relapse, naïve to psychotropic treatment, or discontinuing treatment for a period of at least three months and without a history of autoimmune disease. The study was conducted in two stages : on admission and after treatment. The mean plasma levels of IgG and complement C3 fraction were significantly higher in bipolar patients with relapsing mania. Studies of variation in immunoglobulins and complement fractions during relapses of bipolar disorder have all objected to variations in these serum proteins, but their results were inconsistent regarding the direction of variation and the fractions affected. After treatment, there was a statistically significant increase in the mean plasma levels of IgG and IgA and a decrease in the mean plasma level of the C4 fraction of complement. No significant variation in autoantibodies was noted after treatment. The mean plasma IgM level was significantly lower with sodium valproate. On atypical antipsychotic medication, the mean plasma level of fraction C3 was statistically lower, whereas on conventional antipsychotic medication it was statistically higher. This is in line with the data in the literature which support the immunomodulatory role of thymoregulators and antipsychotics. Serum proteins have been more sensitive than autoantibodies to the effect of psychotropic therapy during manic relapse.

Combined cortisol and melatonin measurements with detailed parameter analysis can assess the circadian rhythms in bipolar disorder patients.

ObjectivesBipolar disorder (BD) is a common chronic mental illness. The circadian clock disorder shows a significant correlation with the pathogenesis, phenotype and recurrence of BD. We aim to evaluate non‐invasive methods that can comprehensively assess the circadian rhythmicity in BD patients.MethodsWe non‐invasively collected salivary samples and oral epithelial cells from recruited subjects. Then the levels of cortisol and melatonin in saliva were measured and the circadian clock gene expressions (PER2 and BMAL1) of epithelial cells were analyzed. Due to the disease characteristics of the manic patients who were difficult to cooperate with the protocol, only one patient at manic episode was recruited. Besides, 11 patients at the depressive episode, 15 healthy controls and four patients at recovery stage were recruited.ResultsOur results exhibited that the peak phase of cortisol level mainly manifested around 8:00 a.m., and the maximal melatonin level reached around 5:00 a.m. The phase of cortisol in patients with depression did not change significantly, but the level of cortisol decreased significantly, while the phase of melatonin level moved forward about 2.5 hr. Furthermore, the levels and phases of cortisol and melatonin in recovery patients tended to be similar to those of healthy controls.ConclusionsWith detailed parameter analysis, the combined detection of melatonin and cortisol can better judge the biological clock disorder of bipolar patients. The circadian rhythms of patients at the recovery stage tend to be normal. The clock gene expression examination needs strict quality control and more investigations before being applied to assess human circadian rhythms.