Etiology Of Bipolar Disorder Research Articles

Immunophenotypes associated with bipolar disorder and lithium treatment

Immune dysfunction is implicated in the etiology of bipolar disorder. The single-nucleotide polymorphism rs17026688 in the gene encoding glutamate decarboxylase–like protein 1 (GADL1) has been found to be associated with lithium response in Han Chinese patients with bipolar I disorder (BDI). However, whether patients with GADL1 polymorphisms have different immunophenotypes is unknown. To address this issue, differences in the immune profiles based on analysis of peripheral blood mononuclear cells (PBMCs) were compared among BDI patients and healthy controls who lack or carry the T allele of rs17026688. BDI patients had significantly higher percentages of total T cells, CD4+ T cells, activated B cells, and monocytes than healthy controls, suggesting that immunologic imbalance might be involved in BDI development or progression. Treatment of BDI patients-derived PBMCs with lithium in vitro increased the percentage of CD14+ monocytes and dendritic cells, suggesting that lithium plays an immunomodulatory role in CD14+ monocytes and dendritic cells. Among BDI patients, non-T carriers had a significantly higher percentage of CD11b+/CD33lo/HLA-DR− myeloid-derived suppressor cells than T carriers. Moreover, only T carriers exhibited differential sensitivity to lithium therapeutic use with respect to the percentage of myeloid cells. These findings suggest that rs17026688 polymorphisms in GADL1 are associated with immune dysfunction in BDI patients.

Theoretical Background and Clinical Aspects of the Use of EMDR in Patients With Bipolar Disorder

Bipolar disorder (BD) is associated with a lifelong episodic course of severe mood and behavioral disturbance. In last decades treatment improved with numerous pharmacological and psychosocial treatments; however, subsequent mood episode rates are still high and possible risk factors for subsequent mood episodes are not sufficiently addressed. Of note, childhood trauma and stressful life events represent significant, under-recognized, and often neglected environmental risk factors in the etiology and course of BD. Here, we summarize the evidence of eye movement desensitization and reprocessing (EMDR) therapy in BD with posttraumatic stress disorder (PTSD) or life traumatic events. So far, one case report study and one pilot randomized controlled trial (RCT) have been published suggesting positive effect of EMDR therapy in BD. Currently, two larger further RCTs are ongoing to increase scientific evidence of the use of EMDR therapy in this indication, especially with a focus on its effect on relapse prevention. In addition, a functional neuroimaging case report of a bipolar subject versus 30 healthy controls showed first evidence that EMDR might modulate the default mode network. These preliminary results suggest that EMDR could be a promising and safe psychotherapeutic approach for the add-on treatment of bipolar subjects, but confirmative large RCT are needed, with two currently being conducted.

Resolvin D1 as a novel anti-inflammatory marker in manic, depressive and euthymic states of bipolar disorder

Background: Resolvin D1 (RvD1) is a soluble mediator, which is the metabolite of docosahexaenoic acid (DHA), an omega-3 fatty acid. It is thought that RvD1 may contribute to the etiology of bipolar disorder (BD) because of its anti-inflammatory and antidepressant effect. In this study, it was aimed to compare the serum RvD1 levels of patients with BD diagnosed manic-depressive-euthymic episodes with those of healthy subjects. The secondary objective of this study is to investigate the relationship between RvD1 measures and inflammatory markers.Methods: We included 121 male patients with BD type I, 44 in a mania, 35 in depression and 42 in euthymic state, and 41 healthy controls. Serum RvD1 levels and inflammation indicators (CRP, neutrophil, leukocyte, and albumin) were measured.Results: When the RvD1 values of patients were compared, the median (interquartile range) RvD1 value was 11.2 (5.2) for manic patients, 11.2 (6.6) for depressive patients, 9.6 (5.6) for euthymic patients and 8.4 (7.7) for the control group. There were statistically significant differences between the groups in terms of RvD1 values (p < .001). After adjustment for age and current state with ANCOVA, there were statistically significant differences between manic vs. control groups and depression vs. control groups (p < .001, p=.047). Also mean CRP measures (p=.029) and neutrophil counts (p=.009) were significantly correlated with log transformed RvD1 levels.Conclusions: Our results of increased anti-inflammatory RvD1 during manic and depressive states suggest RvD1 may serve as a delayed resolvent possibly improving inflammatory imbalance. Further research is needed to confirm our findings.

Disrupted brain structural connectivity in Pediatric Bipolar Disorder with psychosis

Bipolar disorder (BD) has been linked to disrupted structural and functional connectivity between prefrontal networks and limbic brain regions. Studies of patients with pediatric bipolar disorder (PBD) can help elucidate the developmental origins of altered structural connectivity underlying BD and provide novel insights into the aetiology of BD. Here we compare the network properties of whole-brain structural connectomes of euthymic PBD patients with psychosis, a variant of PBD, and matched healthy controls. Our results show widespread changes in the structural connectivity of PBD patients with psychosis in both cortical and subcortical networks, notably affecting the orbitofrontal cortex, frontal gyrus, amygdala, hippocampus and basal ganglia. Graph theoretical analysis revealed that PBD connectomes have fewer hubs, weaker rich club organization, different modular fingerprint and inter-modular communication, compared to healthy participants. The relationship between network features and neurocognitive and psychotic scores was also assessed, revealing trends of association between patients’ IQ and affective psychotic symptoms with the local efficiency of the orbitofrontal cortex. Our findings reveal that PBD with psychosis is associated with significant widespread changes in structural network topology, thus strengthening the hypothesis of a reduced capacity for integrative processing of information across brain regions. Localised network changes involve core regions for emotional processing and regulation, as well as memory and executive function, some of which show trends of association with neurocognitive faculties and symptoms. Together, our findings provide the first comprehensive characterisation of the alterations in local and global structural brain connectivity and network topology, which may contribute to the deficits in cognition and emotion processing and regulation found in PBD.

Aberrant cognition in newly diagnosed patients with bipolar disorder and their unaffected relatives.

Patients with bipolar disorder (BD) experience persistent impairments in both affective and non-affective cognitive function, which is associated with a worse course of illness and poor functional outcomes. Nevertheless, the temporal progression of cognitive dysfunction in BD remains unclear and the identification of objective endophenotypes can inform the aetiology of BD. The present study is a cross-sectional investigation of cognitive baseline data from the longitudinal Bipolar Illness Onset-study. One hundred seventy-two remitted patients newly diagnosed with BD, 52 of their unaffected relatives (UR), and 110 healthy controls (HC) were compared on a large battery of behavioural cognitive tasks tapping into non-affective (i.e. neurocognitive) and affective (i.e. emotion processing and regulation) cognition. Relative to HCs, patients with BD exhibited global neurocognitive deficits (ps < 0.001), as well as aberrant emotion processing and regulation (ps ⩽ 0.011); including decreased emotional reactivity to positive social scenarios, impaired ability to down-regulate positive emotion, as well as a specific deficit in the ability to recognise surprised facial expressions. Their URs also showed a trend towards difficulties identifying surprised faces (p = 0.075). No other differences in cognitive function were found for URs compared to HCs. Neurocognitive deficits and impairments within emotion processing and regulation may be illness-related deficits of BD that present after illness-onset, whereas processing of emotional faces may represent an early risk marker of BD. However, longitudinal studies are needed to examine the association between cognitive impairments and illness progression in BD.

The Relationship Between Neuroimmunity and Bipolar Disorder: Mechanism and Translational Application.

Neuroimmune system may be involved in the pathological process of bipolar disorder (BD), but the essential association is not fully understood. Accumulating evidence has shown that BD involves the activation of immune cells and the release of inflammatory substances in the central nerve system (CNS). Meanwhile, neuroimmune responses also interact with other hypothesis of the etiology of BD that are widely recognized, such as neurotransmitter systems, neuroendocrine systems, neurotrophic factors, and oxidative stress. Simultaneously, related genes and immune changes in peripheral blood vary with it. Overall, neuroimmunity may play an important role in the pathogenesis of BD, and the inflammatory cytokines, especially interleukin-6 and tumor necrosis factor-alpha, have potential value for the clinical diagnosis and prognosis of BD, as well as predicting the therapeutic effects of drugs. Large-scale studies are needed to extend the evidence on neuroimmunity in BD, and to examine its clinical value for applications such as early prediction and treatment.

Dysregulated Prefrontal Cortical RhoA Signal Transduction in Bipolar Disorder with Psychosis: New Implications for Disease Pathophysiology.

While research has identified alterations in dorsolateral prefrontal cortical function as a key factor to the etiology of bipolar disorder, few studies have uncovered robust changes in protein signal transduction pathways in this disorder. Given the direct relevance of protein-based expressional alterations to cellular functions and because many of the key regulatory mechanisms for the disease pathogenesis likely include alterations in protein activity rather than changes in expression alone, the identification of alterations in discrete signal transduction pathways in bipolar disorder would have broad implications for understanding the disease pathophysiology. As prior microarray data point to a previously unrecognized involvement of the RhoA network in bipolar disorder, here we investigate the protein expression and activity of key components of a RhoA signal transduction pathway in dorsolateral prefrontal cortical homogenates from subjects with bipolar disorder. The results of this investigation implicate overactivation of prefrontal cortical RhoA signaling in specific subtypes of bipolar disorder. The specificity of these findings is demonstrated by a lack of comparable changes in schizophrenia; however, our findings do identify convergence between both disorders at the level of activity-mediated actin cytoskeletal regulation. These findings have implications for understanding the altered cortical synaptic connectivity of bipolar disorder.

Genetic variants in the bipolar disorder risk locus SYNE1 that affect CPG2 expression and protein function.

Bipolar Disorder (BD) is a common mood disorder characterized by recurrent episodes of mania and depression. Both genetic and environmental factors have been implicated in BD etiology, but the biological underpinnings remain elusive. Recently, genome-wide association studies (GWAS) of neuropsychiatric disorders have identified a risk locus for BD containing the SYNE1 gene, a large gene encoding multiple proteins. The BD association signal spans, almost exclusively, the part of SYNE1 encoding CPG2, a brain-specific protein localized to excitatory postsynaptic sites, where it regulates glutamate receptor internalization. Here we show that CPG2 protein levels are significantly decreased in postmortem brain tissue from BD patients, as compared to control subjects, as well as schizophrenia and depression patients. We identify genetic variants within the postmortem brains that map to the CPG2 promoter region, and show that they negatively affect gene expression. We also identify missense single nucleotide polymorphisms (SNPs) in CPG2 coding regions that affect CPG2 expression, localization, and synaptic function. Our findings link genetic variation in the CPG2 region of SYNE1 with a mechanism for glutamatergic synapse dysfunction that could underlie susceptibility to BD in some individuals. Few GWAS hits in human genetics for neuropsychiatric disorders to date have afforded such mechanistic clues. Further, the potential for genetic distinction of susceptibility to BD from other neuropsychiatric disorders with overlapping clinical traits holds promise for improved diagnostics and treatment of this devastating illness.

Gene expression pattern of CCL2, CCL3, and CXCL8 in patients with bipolar disorder.

Background:Bipolar disorder (BD) is one of the most important psychiatric disorders in the world. There is evidence suggesting the role of inflammatory mediators such as chemokines in the etiology of BD. The objective of the current study was to evaluate the gene expression of CCL2, CCL3, and CXCL8 in patients with BD and compare them to healthy controls.Materials and Methods:A total of 48 patients with confirmed BD and 48 healthy controls enrolled in this study. All patients were recruited from April to August 2016 at Ibn-Sina Psychiatric Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. RNA was extracted from the whole blood samples and then cDNA was synthesized. Gene expression of CCL2, CCL3, and CXCL8 was measured using SYBR® Green real-time polymerase chain reaction. The difference of delta-CT values between patients and healthy controls was compared with the independent samples t-tests.Results:CCL2 and CXCL8 genes expressed at higher levels in patients with BD as compared to healthy controls, but not significant. On the contrary, we found lower expression levels for CCL3 gene in our patients compared to healthy controls, but the difference was not statistically significant.Conclusion:Our findings do not show an association between the gene expression of CCL2, CCL3 and CXCL8 and BD. Increasing the sample size and evaluation on the gene expression of other chemokines in depression and mania phases of BD might be helpful to get a better conclusion.

The role of microRNA (miRNA) in the etiology of bipolar disorder

The role of microRNA (miRNA) in the etiology of bipolar disorder

Bipolar Disorder: Its Etiology and How to Model in Rodents.

Characterized by the switch of manic and depressive phases, bipolar disorder was described as early as the fifth century BC. Nevertheless up to date, the underlying neurobiology is still largely unclear, assuming a multifactor genesis with both biological-genetic and psychosocial factors. Significant process has been achieved in recent years in researching the causes of bipolar disorder with modern molecular biological (e.g., genetic and epigenetic studies) and imaging techniques (e.g., positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)). In this chapter we will first summarize our recent knowledge on the etiology of bipolar disorder. We then discuss how several factors observed to contribute to bipolar disorder in human patients can be manipulated to generate rodent models for bipolar disorder. Finally, we will give an overview on behavioral test that can be used to assess bipolar-disorder-like behavior in rodents.

SA26 - SPARSE CANONICAL CORRELATION IN APPLICATION TO BIPOLAR PSYCHOTIC PHENOTYPES AND SCHIZOPHRENIA GENOME-WIDE SIGNIFICANT GENETIC LOCI

Background The aetiology of Bipolar Disorder (BD) and Schizophrenia (SZ) involves a complex gene-environment interplay and this involves common risk alleles that are shared across the disorders. Bipolar disorder is heterogeneous in presentation and we and others have postulated that the particular clinical presentation is in part determined by the particular risk alleles carried. To investigate this, we have employed sparse Canonical Correlation Analysis (sCCA), to seek patterns of correlation between psychotic symptoms and schizophrenia risk alleles in a large (N=3903) deeply phenotyped sample of subjects with BD. Methods Canonical Correlation Analysis (CCA) seeks linear relationships between two sets of multi-dimensional variables. In the psychiatric genetics field, this approach can be adapted to enable the analysis of both phenotype and genetic variables in one framework. This has the advantage of minimizing the number of statistical tests required. A recent extension of CCA to sparse canonical correlation analysis (sCCA) allows application of the general approach to high dimensional genomic data (Witten et al., 2009). sCCA has advantages compared to CCA in terms of precision of parameter estimates and statistical power. We employed sCCA to analyse 30 psychotic symptoms assessed with the OPerational CRITeria checklist (OPCRIT) and 82 independent genome-wide significant SNPs that were identified by the SZ PGC2 study (The Psychiatric Genomics Consortium, 2014) for which we had data in our BD sample. We applied the sCCA as a purely data driven approach to individual OPCRIT psychotic symptoms and also to groups of OPCRIT psychotic symptoms (“positive”, “negative”, “disorganised”) defined by a previously published factor analysis study of schizophrenia. Results sCCA analysis of the individual OPCRIT items with the set of significantly associated with SZ 82 sCCA analysis based on individual psychotic symptoms revealed a significant association (p=0.045) with the largest weights attributed to delusions of influence, bizarre behaviour and grandiose delusions and an indel SNP on chromosome 3 (3:180594593, build 37). sCCA analysis on the same set of SNPs and OPCRIT symptom groups confirmed association with the same SNP and the “disorganised” group of OPCRIT symptoms (p=0.01). The results also show significant association when we use less stringent p-value thresholds in SZ. In this case the most heavily weighted SNP remains 3:180594593, but other SNPs also contribute to the analysis. Discussion Our results suggest the CCA canonical correlation approach might be a useful tool to explore phenotype-genotype relationships. It can be applied to generate data-driven hypotheses with the potential to provide further insights into the complex architecture of psychiatric disorders. To the best of our knowledge, this is the first study to apply this approach in analysing phenotypes and genotypes together. sCCA offers the potential to be extended to include a larger number of fine grained systematic descriptors of BD, and for testing for correlation with genetic profiles from other co-morbid disorders.

Bipolar disorder and 1513A>C P2RX7 polymorphism frequency

Although the etiology of Bipolar Disorder (BD) remains unknown, a strong genetic component to the pathogenesis and risk for this disorder has been widely hypothesized. Several risk genes for BD have been identified; of these, the purinergic P2 × 7 receptor (P2 × 7R) constitutes a pro-inflammatory receptor and a potential risk gene candidate. The purpose of the present study was to assess the frequency of the 1513 A > C P2RX7 polymorphism (rs3751143; Glu496Ala), which leads to receptor loss-of-function, in 154 BD patients versus 184 control subjects. The existence of a differential modulation of P2 × 7R was also analyzed in 22 euthymic BD patients, in comparison to 18 healthy controls. Our data show a decrease in 1513C allele frequency (p = 0.045) and a potential increase in 1513 A A/AC (p = 0.055) genotype frequency in BD patients, compared to controls, indicating an enhanced function of the pro-inflammatory P2 × 7 receptor in BD subjects. Interestingly, no differences in P2RX7 gene and protein expression were found between euthymic BD patients and matched healthy controls. In conclusion, our results suggest that P2 × 7R might play a role in the pathophysiology of BD and add new information regarding this receptor as a potential biomarker for the prediction and diagnosis of the disorder.

Neutrophil-lymphocyte and platelet-lymphocyte ratios among adolescents with bipolar disorder: A preliminary study

We aimed to evaluate the neutrophil lymphocyte and platelet lymphocyte ratios among euthymic adolescents with bipolar disorder (BD) type I. Thirty-six adolescents with BD and 30 healthy controls were included in the study. The diagnosis was made by experienced physicians using the Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version and the affective module of Washington University in St. Louis Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia-Present State and Lifetime. Blood samples were taken during euthymia, which was defined as Young Mania Rating Scale and Hamilton Depression Rating Scale scores below 7. There was no significant difference in neutrophil lymphocyte ratio and platelet lymphocyte ratio between the patient and control group. Considering the literature, we may speculate that in the early stages, euthymia is associated with a lower inflammatory response, and prolongation of BD causes increased inflammatory processes predominant even in euthymia. In pediatric BD, further studies that assess neutrophil lymphocyte ratio and platelet lymphocyte ratio during different mood episodes and that identify neutrophil lymphocyte ratio and platelet lymphocyte ratio changes during the course of the disease will clarify the role of inflammation in the etiology of pediatric BD.

Na⁺, K⁺-ATPase Signaling and Bipolar Disorder.

Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Although in past decades the “monoamine hypothesis” has dominated our understanding of both the pathophysiology of depressive disorders and the action of pharmacological treatments, recent studies focus on the involvement of additional neurotransmitters/neuromodulators systems and cellular processes in BD. Here, evidence for the participation of Na+, K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), in the etiology of BD is reviewed. Proof for the involvement of brain Na+, K+-ATPase and ECS in behavior is summarized and it is hypothesized that ECS-Na+, K+-ATPase-induced activation of intracellular signaling participates in the mechanisms underlying BD. We propose that the activation of ERK, AKT, and NFκB, resulting from ECS-Na+, K+-ATPase interaction, modifies neuronal activity and neurotransmission which, in turn, participate in the regulation of behavior and BD. These observations suggest Na+, K+-ATPase-mediated signaling is a potential target for drug development for the treatment of BD.

Implication of the DGKH genotype in openness to experience, a premorbid personality trait of bipolar disorder

AimsThe diacylglycerol kinase η gene (DGKH) is one of the few replicated risk genes for bipolar disorder. Meanwhile, specific personality traits, especially openness to experience, have been suggested as premorbid personality traits of the disorder. The aim of the present study was to examine the relation of the DGKH genotype with broad dimensions of personality, to obtain further evidence for its implication in the etiology of bipolar disorder. MethodsThe subjects were 319 Japanese healthy volunteers. Personality was assessed by the NEO Personality Inventory-Revised, which has the neuroticism, extraversion, openness to experience, agreeableness and conscientiousness dimensions. The A/G polymorphism of DGKH (rs9525580) was detected by a PCR-RFLP method. The subjects were divided into two groups with respect to the presence or absence of the A allele, which is a putative risk allele for bipolar disorder. ResultsThe group with the A allele had significantly (p < 0.05) higher scores of openness to experience compared to that without this allele. Scores of other dimensions were not different between the two groups. LimitationsThe subjects had a homogeneous but rather specific background, and we did not employ a longitudinal design. ConclusionsThe present study shows that a bipolar-risk allele of DGKH is associated with higher openness to experience, providing further evidence for the implication of this gene in the etiology of bipolar disorder.

Ant1 mutant mice bridge the mitochondrial and serotonergic dysfunctions in bipolar disorder

Although mitochondrial and serotonergic dysfunctions have been implicated in the etiology of bipolar disorder (BD), the relationship between these unrelated pathways has not been elucidated. A family of BD and chronic progressive external ophthalmoplegia (CPEO) caused by a mutation of the mitochondrial adenine nucleotide translocator 1 (ANT1, SLC25A4) implicated that ANT1 mutations confer a risk of BD. Here, we sequenced ANT1 in 324 probands of NIMH bipolar disorder pedigrees and identified two BD patients carrying heterozygous loss-of-function mutations. Behavioral analysis of brain specific Ant1 heterozygous conditional knockout (cKO) mice using lntelliCage showed a selective diminution in delay discounting. Delay discounting is the choice of smaller but immediate reward than larger but delayed reward and an index of impulsivity. Diminution of delay discounting suggests an increase in serotonergic activity. This finding was replicated by a 5-choice serial reaction time test. An anatomical screen showed accumulation of COX (cytochrome c oxidase) negative cells in dorsal raphe. Dorsal raphe neurons in the heterozygous cKO showed hyperexcitability, along with enhanced serotonin turnover in the nucleus accumbens and upregulation of Maob in dorsal raphe. These findings altogether suggest that mitochondrial dysfunction as the genetic risk of BD may cause vulnerability to BD by altering serotonergic neurotransmission.

Multi-factorial Etiology of Bipolar Disorder and Schizophrenia in Iran: No Evidence of Borna Disease Virus Genome

Multi-factorial Etiology of Bipolar Disorder and Schizophrenia in Iran: No Evidence of Borna Disease Virus Genome

T123. Decreased Fractional Anisotropy as a Marker of Aberrant White Matter Integrity in Unaffected Offspring of Patients With Bipolar Disorder

Bipolar disorder (BD) is a psychiatric disorder affecting 1-2% of the population. The etiology and pathogenesis of BD are complex and not well understood. There is compelling evidence for genetic contribution to the risk of this familial disease. BD is associated with structural and functional brain abnormalities, some of which have been found in unaffected relatives. These have included white matter (WM) changes identified in voxel-based studies.

The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder

Considerable evidence suggests that autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorder (BD) and obsessive-compulsive disorder (OCD) share a common molecular aetiology, despite their unique clinical diagnostic criteria. The aim of this study was therefore to determine and characterise the common and unique molecular architecture of ASD, SCZ, BD and OCD. Gene lists were obtained from previously published studies for ASD, BD, SCZ and for OCD. Genes identified to be common to all disorders, or unique to one specific disorder, were included for enrichment analyses using the web-server tool Enrichr. Ten genes were identified to be commonly associated with the aetiology of ASD, SCZ, BD and OCD. Enrichment analyses determined that these genes are predominantly involved in the dopaminergic and serotonergic pathways, the voltage-gated calcium ion channel gene network, folate metabolism, regulation of the hippo signaling pathway, and the regulation of gene silencing and expression. In addition to well-characterised and previously described pathways, regulation of the hippo signaling pathway was commonly associated with ASD, SCZ, BD and OCD, implicating neural development and neuronal maintenance as key in neuropsychiatric disorders. In contrast, a large number of previously associated genes were shown to be disorder-specific. And unique disorder-specific pathways and biological processes were presented for ASD, BD, SCZ and OCD aetiology. Considering the current global incidence and prevalence rates of mental health disorders, focus should be placed on cross-disorder commonalities in order to realise actionable and translatable results to combat mental health disorders.