Etiology Of Bipolar Disorder Research Articles

Depression and Mania Induce Pro-inflammatory Activation of Macrophages Following Application of Serum from Individuals with Bipolar Disorder.

ObjectiveEvidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood. This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of cultured macrophages.MethodsEighteen subjects with BD and five healthy individuals were included in this study. The human monocyte cell line U-937 was activated with phorbol 12-myristate 13-acetate (PMA) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 hours. Gene expression of selected M1 and M2 markers was assessed by quantitative PCR.ResultsMacrophages exposed to serum of manic and depressive BD patients displayed an increase of interleukin-1β (6.40±3.47 and 9.04±5.84 vs. 0.23±0.11; p<0.05) and tumor necrosis factor-α (2.23±0.91 and 2.03±0.45 vs. 0.62±0.24; p=0.002 and p=0.004, respectively) compared to euthymic group (there was no difference between euthymic and controls). In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29±0.20 vs. 1.86±1.61; p=0.006) and CXCL10 expression (0.36±0.15 and 0.86±0.24 vs. 1.83±0.88; p<0.000 and p=0.04) compared to the euthymia group.ConclusionOur results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system is involved in the etiology of BD.

Systemic autoimmune diseases are associated with an increased risk of bipolar disorder: A nationwide population-based cohort study

BackgroundStudies suggested autoimmunity plays a role in the etiology of bipolar disorder (BD). This study aimed to investigate the association between systemic autoimmune diseases (SADs) and the subsequent development of BD, and examine the potential risk factors for developing BD. MethodsPatients with SADs were identified in the Taiwan National Health Insurance Program (NHIP). A comparison cohort was created by matching patients without SADs with age. The SADs cohort consisted of 65,498 while the comparison cohort consisted of 261,992 patients. The incidence of BD was evaluated in both cohorts. ResultsThe major finding was the discovery of a higher incidence of subsequent BD among patients with SADs (adjusted hazard ratio: 1.98). Specifically, the risk of BD was observed to be significant increase in systemic lupus erythematosus, rheumatoid arthritis, autoimmune vasculitis, Sicca syndrome and Crohn's disease. Furthermore, our study revealed some potential risk factors for developing BD including female, younger age and patients who lived in eastern Taiwan. Also, some comorbidities including dyslipidemia, chronic obstructive pulmonary disease, diabetes mellitus, asthma, cerebrovascular disease, alcohol used disorder, liver cirrhosis, and malignancies were potential risk factors for incident BD. LimitationsThe diagnosis of SADs was based on the catastrophic illness certificate defined by Taiwanese NHIP. Thus, not every form of SADs was explored for subsequent developing BD. ConclusionThis study confirms that SADs are associated with higher incidence of BD, suggesting that abnormal autoimmune process is associated with increased expression of psychiatric disturbances.

S.12.08 - Reward deficits triggered by glucocorticoids are driven by laterodorsal tegmentum ventral tegmental area dysfunction

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.

Serum osmolarity in male patients with bipolar disorder manic episode.

What is the central question of this study? The main goal of this study was, for the first time, to investigate the role of the serum osmolarity in bipolar disorder manic episode. What is the main finding and its importance? Our results demonstrate a diminished serum osmolarity in manic episode compared with healthy control subjects. This finding supports the hypothesis of a fluid and electrolyte imbalance during acute episodes. Decreased serum osmolarity might be a reflection of a relative haemodilution in mania. Imbalance of water and electrolyte homeostasis has been suggested to be associated with acute episodes of bipolar disorder. In this study, we aimed to investigate, for the first time, the serum osmolarity in bipolar disorder manic episode. A total of 68 bipolar inpatients in manic episode and 60 age- and sex-matched healthy control subjects were included in the study. Serum osmolarity was calculated from sodium (Na+ ), glucose and blood urea nitrogen (BUN) according to following formula: (2×Na+ )+(BUN/2.8)+(glucose/18). The significance level was accepted as P<0.05. The serum osmolarity of manic patients was 295.34±4.90mosmol/l and that of the control group was 298.46±5.33mosmol/l. The serum osmolarity of the manic group was significantly lower than that of control subjects (P <0.001). When we compared the components of serum osmolarity, a statistically significant difference was also observed between groups in terms of glucose (85.85±12.25mg/dl for manic, 92.95±20.77mg/dl for control subjects, P=0.019) and Na+ (140.73±2.06mmol/l for manic, 142.06±2.48mmol/l for control subjects, P=0.001). For BUN concentrations, there was no statistically significant difference between manic (25.50±9.85mg/dl) and control (26.61±6.64mg/dl) groups (P=0.461). Our results demonstrate a diminished serum osmolarity in manic episode compared with healthy control subjects. This finding supports the hypothesis of a fluid and electrolyte imbalance during acute episodes. Decreased serum osmolarity might be a reflection of a relative haemodilution in mania. However, exploration of the role of fluid and electrolyte homeostasis and mechanisms of related hormones may contribute to a better understanding of the aetiology of bipolar disorder.

Early intervention for bipolar disorder in adolescents: A psychosocial perspective.

Early intervention in bipolar disorder (BD) has received increasing attention in recent years. The identification of risk factors has improved, but researchers continue to struggle to find an effective treatment once the illness has become established. The aetiology of BD and feasibility of early intervention present a challenge, making it difficult to decide who to target, as well as how. This essay seeks to address the lack of guidance for managing patients with a possible emerging bipolar illness, by presenting a rough roadmap to psychological care. The psychological techniques currently showing the most potential for this challenging group are reviewed. Markers of risk and supplementary clinical targets, such as anxiety and sleep disruption, are also discussed. While research in this group remains in its infancy, various avenues of enquiry show promise, such as family-based approaches, CBT that targets features beyond the core illness, psychoeducation, and interventions that consider physical health. However, clearer pathways for establishing the course and stage of the illness are required to inform the intensity and type of treatment. It is argued that treating early, indistinct symptoms of psychological distress, that may or may not signify prodromal BD, is valuable beyond its utility as an early intervention tool, as it has the capacity to improve help-seeking behaviour, quality of life and the likelihood of functional recovery in those who go on to develop the illness as adults.

More Than an Association: Latent Toxoplasmosis Might Provoke a Local Oxidative Stress That Triggers the Development of Bipolar Disorder.

Introduction:Toxoplasma gondii, a common parasitic infection, has a special affinity to the brain. It has a lifelong existence without an apparent clinical disease. While the etiology of bipolar disorder (BD) remains unclear, epidemiological studies suggest a role for infections. Central nervous system is particularly susceptible to oxidative stress (OS) because of its high metabolic rate and its low levels of antioxidant defenses. OS is a contributor to the initiation and progression of many neurological illnesses. OS injury is a constantly and compelling finding associated with BD and toxoplasmosis.Aim:This cross-sectional study has investigated a possible role of toxoplasma-induced OS in the development of BD.Methods:Healthy controls and BD patients were examined for anti-Toxoplasma immunoglobulin-G (IgG) and two protein (3-nitrotyrosine) and DNA (8-hydroxy-2’ deoxyguanosine [8-OHdG]) OS markers.Results:Toxoplasma positivity was higher (40%) among BD patients compared to controls (12%). Significantly higher levels of anti-Toxoplasma IgG were detected in BD patients compared to controls. Nitrotyrosine (796.7 ± 106.28) and especially 8-OHdG (20.31 ± 8.38) were significantly higher among toxo-positive BD compared to toxo-negative BD (675.97 ± 144.19 and 7.44 ± 2.86) and healthy controls (464.02 ± 134.6 and 4.17 ± 1.43).Conclusion:These findings might indicate a role for Toxoplasma infection in the development of BD, possibly through creating a highly oxidative brain environment.

Longitudinal changes in the antecedent and early manifest course of bipolar disorder-A narrative review of prospective studies.

Prospective study designs ideally allow patients to be followed from the first manifestations of the illness or even from an at-risk stage. It can thus provide data on the predictive value of changes in clinical symptomatology, cognition or further biological markers to broaden our understanding of the etiopathology and symptomatic trajectory of bipolar disorders. The scope of this narrative review is to summarize evidence from prospectively collected data on psychopathological and other clinical and biological changes in the early developmental course of bipolar disorders. The narrative review was based on a literature search conducted in February 2016 within the PubMed library for prospective study data of persons in antecedent and early manifest stages of manifest bipolar disorder published within the last 15 years. A total of 19 prospective studies were included. Regarding psychopathological features; personality, temperament and character traits as well as changes in sleep and circadian rhythm, the evidence suggests that risk factors for the development of bipolar disorder can already be described and should be studied further to understand their interaction, mediation with other factors and timing in the developmental process of bipolar disorder. Apart from the positive family history, childhood anxiety, sleep problems, subthreshold (hypo)manic symptoms and certain character traits/emotionality should be identified and monitored already in clinical practice as their presence likely increases risk of bipolar disorder. Up to date no substantiated evidence was found from prospective studies addressing cognitive features, life events, immunological parameters and morphological central nervous system changes as potential risk factors for bipolar disorder. For an improved understanding of episodic disorders, longitudinal data collection is essential. Since the etiology of bipolar disorders is complex, a number of potential risk factors have been proposed. Prospective studies addressing this spectrum and resilience factors are critical and will be best conducted within multi-site research networks or initiatives.

The concentration of the factors involved in trafficking of stem cells in long-term treated bipolar disorder patients

IntroductionAfter analysis of biological and pharmacological data, we formulated the hypothesis that the factors involved in trafficking of stem cells could be engaged in aetiology of bipolar disorder (BP).AimsIn this study, we considered the role of complement cascade proteins, stromal derived factor-1 (SDF-1), and sphingosine-1-phosphate (S1P) in long-term treated BP.MethodsA group of 30 patients with BP, without the history of lithium treatment, was examined in remission and compared with a group of 30 healthy volunteers. In peripheral blood, we have analysed the concentration of stromal derived factor-1 (SDF-1), sphingosine-1-phosphate (S1P), and some proteins of the complement cascade (C3a, C5a, C5b-9).ResultsPeripheral blood concentration of C3a, C5a, C5b-9 and SDF-1 was significantly higher in BP group compared to control group. The concentration of S1P does not distinguish BP patients from controls.ConclusionOur results suggest the possible role of the regeneration system in aetiology of BP.This work was supported by grant POIG.01.01.02-00-109/09.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Assessment of serum IL-4, 15d-PGJ2, PPAR gamma levels in patients with bipolar disorder

IntroductionMany hypotheses have been proposed about development of bipolar disorder including inflammatory processes due to the external and endogenous factors. There are strong evidences that immunological dysfunction is present in bipolar disorder. In the pathophysiology of bipolar disorder, there are many data that support the inflammatory hypothesis.ObjectivesIn this study, to clarify the etiology of bipolar disorder, based on the inflammatory process hypothesis, it is aimed to measure and evaluate serum 15d-PGJ2 and PPARγ, anti-inflammatory cytokine IL-4 levels in patients with bipolar disorder.MethodsThis study was performed at Ankara Numune Training and Research Hospital. Ninety-five patients are included in the study that were in their mania or remission periods and meet the DSM-V criteria for bipolar disorder. Forty-four healthy volunteers are included in the study as well. Serum IL-4, 15d-PGJ2, PPARγ levels are measured in both groups. Young Mania Scale, Hamilton Depression Scale, demographic data form were given to patient group.ResultsIn our study, 15d-PGJ2, PPARγ levels were found statistically significantly lower in patients with bipolar disorder compared to healthy controls.ConclusionThere are differences in anti-inflammatory prostaglandin levels in patients with bipolar disorder who are in their mania period when compared to healthy controls and patients in their remission period. This does not show any significance according to smoking and gender. This implies that inflammation markers could be a good candidate to determine trait markers, which will provide an insight for preventing patient from mania period or prognosis after the diagnosis of bipolar disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

MiR-149 and miR-29c as candidates for bipolar disorder biomarkers.

Bipolar disorder (BD) is a common, recurring psychiatric illness with unknown pathogenesis. Recent studies suggest that microRNA (miRNA) levels in brains of BD patients are significantly altered, and these changes may offer insight into BD pathology or etiology. Previously, we observed significant alterations of miR-29c levels in extracellular vesicles (EVs) extracted from prefrontal cortex (Brodmann area 9, BA9) of BD patients. In this study, we show that EVs extracted from the anterior cingulate cortex (BA24), a crucial area for modulating emotional expression and affect, have increased levels of miR-149 in BD patients compared to controls. Because miR-149 has been shown to inhibit glial proliferation, increased miR-149 expression in BA24-derived EVs is consistent with the previously reported reduced glial cell numbers in BA24 of patients diagnosed with either familial BD or familial major depressive disorder. qPCR analysis of laser-microdissected neuronal and glial cells from BA24 cortical samples of BD patients verified that the glial, but not neuronal, population exhibits significantly increased miR-149 expression. Finally, we report altered expression of both miR-149 and miR-29c in EVs extracted from brains of Flinders Sensitive Line rats, a well-validated animal model exhibiting depressive-like behaviors and glial (astrocytic) dysfunction. These findings warrant future investigations into the potential of using EV miRNA signatures as biomarkers to further enhance the biological definition of BD. © 2017 Wiley Periodicals, Inc.

The Efficacy of Group-Cognitive Behavior Therapy for Patients with Bipolar Disorder Based on Psychological Behaviorism

The study’s aim was to conduct group Cognitive Behavior Therapy (CBT) for patients with bipolar I disorder (n=11) and test its efficacy. All subjects didn’t have manic or depressive episode fully met DSM-5 criteria and they are all under proper medication as a maintenance treatment. The intervention was administered to ameliorate eight psychosocial factors, as measured by the Bipolar Disorder Etiology Scale, which was administered with the Korean versions of the Young Mania Rating Scale and Beck Depression Inventory before and after the intervention. The same measuring procedures were followed with a waiting-list control group (n=14). Subjects were not assigned with fully randomized method, however there is no significant differences in baseline measurement. Manic emotional response, lack of social skills, pursuit of short-term pleasure, and lack of problem solving-skills decreased significantly, but lack of support, sleep problems, antidepressant side effects, and positive arousal to threats did not change significantly in the intervention group. Significant reductions in residual depressive and manic symptoms were found during their maintenance medication periods. Even in the absence of florid manic symptoms, interventions to ameliorate the manic emotional response should be used.

Simple markers for subclinical inflammation in the different phases of bipolar affective disorder

Recently, a growing number of publications have suggested that the immune-inflammatory system may be involved in the etiology of bipolar disorder (BD). Objective: The aim of this study was to investigate neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and red cell distribution width (RDW) in the three different phases of BD patients compared to each other and controls. Methods: One hundred eighty-seven bipolar patients (78 euthymic, 53 manic/hypomanic and 56 depressed), and 62 age and sex matched controls were enrolled. Sociodemographic variables and complete blood count parameters of the patients and the control group were recorded. Results: The groups did not differ from each other on the hematological parameters, except for NLR and RDW. Post-hoc analyses revealed that NLR values were significantly higher in the euthymic and manic/hypomanic bipolar groups compared to control group. In addition, post-hoc analyses revealed that RDW values were significantly higher in the manic/hypomanic bipolar group relative to the control group. Discussion: Longitudinal studies evaluating the levels of inflammatory markers in the early phases of the disorder, and their relationship with the development of different episodes and medical comorbidities may be useful to understand the role of inflammation in BD

Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1.

Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P meta = 5.72 × 10-4), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10-16). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a "proxy phenotype" of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is ∼1.2Mb 3' downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis.

Diacylglycerol Kinases as Emerging Potential Drug Targets for a Variety of Diseases: An Update.

Ten mammalian diacylglycerol kinase (DGK) isozymes (α–κ) have been identified to date. Our previous review noted that several DGK isozymes can serve as potential drug targets for cancer, epilepsy, autoimmunity, cardiac hypertrophy, hypertension and type II diabetes (Sakane et al., 2008). Since then, recent genome-wide association studies have implied several new possible relationships between DGK isozymes and diseases. For example, DGKθ and DGKκ have been suggested to be associated with susceptibility to Parkinson's disease and hypospadias, respectively. In addition, the DGKη gene has been repeatedly identified as a bipolar disorder (BPD) susceptibility gene. Intriguingly, we found that DGKη-knockout mice showed lithium (BPD remedy)-sensitive mania-like behaviors, suggesting that DGKη is one of key enzymes of the etiology of BPD. Because DGKs are potential drug targets for a wide variety of diseases, the development of DGK isozyme-specific inhibitors/activators has been eagerly awaited. Recently, we have identified DGKα-selective inhibitors. Because DGKα has both pro-tumoral and anti-immunogenic properties, the DGKα-selective inhibitors would simultaneously have anti-tumoral and pro-immunogenic (anti-tumor immunogenic) effects. Although the ten DGK isozymes are highly similar to each other, our current results have encouraged us to identify and develop specific inhibitors/activators against every DGK isozyme that can be effective regulators and drugs against a wide variety of physiological events and diseases.

White blood cell count correlates with mood symptom severity and specific mood symptoms in bipolar disorder.

Immune alterations may play a role in bipolar disorder etiology; however, the relationship between overall immune system functioning and mood symptom severity is unknown. The two comparative effectiveness trials, the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study (Bipolar CHOICE) and the Lithium Treatment Moderate-Dose Use Study (LiTMUS), were similar trials among patients with bipolar disorder. At study entry, white blood cell count and bipolar mood symptom severity (via Montgomery-Aasberg Depression Rating Scale and Bipolar Inventory of Symptoms Scale) were assessed. We performed analysis of variance and linear regression analyses to investigate relationships between deviations from median white blood cell and multinomial regression analysis between higher and lower white blood cell levels. All analyses were adjusted for age, gender, body mass index, smoking, diabetes, hypertension and hyperlipidemia. Among 482 Bipolar CHOICE participants, for each 1.0 × 109/L white blood cell deviation, the overall Bipolar Inventory of Symptoms Scale severity increased significantly among men (coefficient = 2.13; 95% confidence interval = [0.46, -3.79]; p = 0.013), but not among women (coefficient = 0.87; 95% confidence interval = [-0.87, -2.61]; p = 0.33). Interaction analyses showed a trend toward greater Bipolar Inventory of Symptoms Scale symptom severity among men (coefficient = 1.51; 95% confidence interval = [-0.81, -3.82]; p = 0.2). Among 283 LiTMUS participants, higher deviation from the median white blood cell showed a trend toward higher Montgomery-Aasberg Depression Rating Scale scores among men (coefficient = 1.33; 95% confidence interval = [-0.22, -2.89]; p = 0.09), but not among women (coefficient = 0.34; 95% confidence interval = [-0.64, -1.32]; p = 0.50). When combining LiTMUS and Bipolar CHOICE, Montgomery-Aasberg Depression Rating Scale scores increased significantly among men (coefficient = 1.09; 95% confidence interval = [0.31, -1.87]; p = 0.006) for each 1.0 × 109/L white blood cell deviation, whereas we found a weak association among women (coefficient = 0.55; 95% confidence interval = [-0.20, -1.29]; p = 0.14). Lower and higher white blood cell levels correlated with greater symptom severity and specific symptoms, varying according to gender. Deviations in an overall immune system marker, even within the normal white blood cell range, correlated with mood symptom severity in bipolar disorder, mostly among males. Studies are warranted investigating whether white blood cell count may predict response to mood-stabilizing treatment.

Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder.

Bipolar disorder (BD) is a highly heritable and heterogeneous mental illness whose manifestations often include impulsive and risk-taking behavior. This particular phenotype suggests that abnormal striatal function could be involved in BD etiology, yet most transcriptomic studies of this disorder have concentrated on cortical brain regions. We believe we report the first transcriptome sequencing of the postmortem human dorsal striatum comparing bipolar (18) and control (17) subjects. Fourteen genes were detected as differentially expressed at a 5% false discovery rate, including a few immune response genes such as NLRC5, S100A12, LILRA4 and FCGBP, as well as an assortment of non-protein coding genes. Functional pathway analysis found an enrichment of upregulated genes across many immune/inflammation pathways and an enrichment of downregulated genes among oxidative phosphorylation pathways. Co-expression network analysis revealed 20 modules of highly interconnected genes; two of the modules were significantly enriched for BD susceptibility single-nucleotide polymorphisms deriving from a large genome-wide association study data set. Remarkably, the module with the highest genetic association signal for BD, which contained many genes from signaling pathways, was also enriched in markers characteristic of gene expression in dorsal striatum medium spiny neurons-unlike most other modules, which showed no such regional and neuronal specificity. These findings draw a link between BD etiology at the gene level and a specific brain region, and highlight striatal signaling pathways as potential targets for the development of novel treatments to manage BD.

A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.

l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of ‘brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

Deficiency of diacylglycerol kinase η induces lithium-sensitive mania-like behavior.

The η isozyme of diacylglycerol kinase (DGK) is highly expressed in the hippocampus and Purkinje cells in the central nervous system. Recently, several genome-wide association studies have implicated DGKη in the etiology of bipolar disorder (BPD). However, it is still unknown whether DGKη is indeed related to BPD. In this study, we generated DGKη-knockout (KO) mice and performed behavioral tests such as the open field test, the elevated plus maze test and tail suspension test using the KO mice to investigate the effects of DGKη deficits on psychomotor behavior. Intriguingly, DGKη-KO mice displayed an overall behavioral profile that is similar to human mania, including hyperactivity, less anxiety and less depression-like behavior. In addition, these phenotypes were significantly attenuated by the administration of a BPD (mania) remedy, namely, lithium. Moreover, DGKη-KO mice showed impairment in glycogen synthase kinase (GSK) 3β signaling, which is closely related to BPD. These findings clearly support the linkage between BPD and DGKη that is implicated by genome-wide association studies. Moreover, this study provides DGKη-KO mice as a previously unrecognized model that reflects several features of human BPD with manic episodes and revealed an important role for DGKη in regulating behavior and mood through, at least in part, GSK3β signaling. Several genome-wide association studies have implicated diacylglycerol kinase (DGK) η gene in the etiology of bipolar disorder (BPD). In this study, we revealed that DGKη-knockout (KO) mice displayed an overall behavioral profile that is similar to mania of BPD and is lithium (BPD (mania) remedy)-sensitive. DGKη may regulate behavior and mood through, at least in part, glycogen synthase kinase (GSK) 3β signaling.

Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations.

Although numerous genetic studies have been conducted for bipolar disorder (BD), its genetic architecture remains elusive. Here we perform, to the best of our knowledge, the first trio-based exome sequencing study for BD to investigate potential roles of de novo mutations in the disease etiology. We identified 71 de novo point mutations and one de novo copy-number mutation in 79 BD probands. Among the genes hit by de novo loss-of-function (LOF; nonsense, splice site or frameshift) or protein-altering (LOF, missense and inframe indel) mutations, we found significant enrichment of genes highly intolerant (first percentile of intolerant genes assessed by Residual Variation Intolerance Score) to protein-altering variants in general population, an observation that is also reported in autism and schizophrenia. When we performed a joint analysis using the data of schizoaffective disorder in published studies, we found global enrichment of de novo LOF and protein-altering mutations in the combined group of bipolar I and schizoaffective disorders. Considering relationship between de novo mutations and clinical phenotypes, we observed significantly earlier disease onset among the BD probands with de novo protein-altering mutations when compared with non-carriers. Gene ontology enrichment analysis of genes hit by de novo protein-altering mutations in bipolar I and schizoaffective disorders did not identify any significant enrichment. These results of exploratory analyses collectively point to the roles of de novo LOF and protein-altering mutations in the etiology of bipolar disorder and warrant further large-scale studies.

Age at menarche is related to number of previous depressive episodes in patients with bipolar disorder

IntroductionOestrogen fluctuations may be an important factor in the etiology of bipolar disorder and age at menarche is associated with the clinical course of BD. Moreover, it is associated with traits related to mood.AimsThe aim of our study was to explore the differences in age at menarche between euthymic BD patients and healthy controls, as well as to explore the relationship between age at menarche and lifetime psychopathology within BD.MethodsThe study group consisted of 83 patients diagnosed with BD, compared to the healthy control group (n = 73) and matched according to age, gender, and body mass index (BMI). Lifetime psychopathology has been assessed according to predominant polarity as well as previous history of suicide attempts and psychotic episodes.ResultsAge at menarche in BD patients was similar to that in controls. After covarying for confounders, we observed that age at menarche is negatively related to number of previous depressive episodes in euthymic BD patients, but not other indicators of lifetime psychopathology.ConclusionsBD patients with earlier age at menarche are more likely to present with more depressive episodes in the course of illness. Systemic, longitudinal monitoring of the course of illness, and potential hormonal fluctuations within particular groups of patients are warranted.Disclosure of interestThe authors have not supplied their declaration of competing interest.