Abstract Bipolar disorder is one of two major psychotic disorders together with schizophrenia and causes severe psychosocial disturbance. Lack of adequate animal models hampers development of new ...mood stabilizers. We proposed a mitochondrial dysfunction hypothesis and have been studying the neurobiology of bipolar disorder based on this hypothesis. We showed that deletions of mitochondrial DNA (ΔmtDNA) play a pathophysiological role at least in some patients with bipolar disorder possibly by affecting intracellular calcium regulation. Mutant polymerase γ transgenic mice that accumulate ΔmtDNA in the brain showed recurrent spontaneous depression-like episodes which were prevented by a serotonin-selective reuptake inhibitor and worsened by lithium withdrawal. The animal model would be useful to develop new mood stabilizers.
Biological studies of bipolar disorder initially focused on the mechanism of action for antidepressants and antipsychotic drugs, and the roles of monoamines (e.g., serotonin, dopamine) have been ...extensively studied. Thereafter, based on the mechanism of action of lithium, intracellular signal transduction systems, including inositol metabolism and intracellular calcium signaling, have drawn attention. Involvement of intracellular calcium signaling has been supported by genetics and cellular studies. Elucidation of the neural circuits affected by calcium signaling abnormalities is critical, and our previous study suggested a role of the paraventricular thalamic nucleus. The genetic vulnerability of mitochondria causes calcium dysregulation and results in the hyperexcitability of serotonergic neurons, which are suggested to be susceptible to oxidative stress. Efficacy of anticonvulsants, animal studies of candidate genes, and studies using induced pluripotent stem cell‐derived neurons have suggested a relation between bipolar disorder and the hyperexcitability of neurons. Recent genetic findings suggest the roles of polyunsaturated acids. At the systems level, social rhythm therapy targets circadian rhythm abnormalities, and cognitive behavioral therapy may target emotion/cognition (E/C) imbalance. In the future, pharmacological and psychosocial treatments may be combined and optimized based on the biological basis of each patient, which will realize individualized treatment.
Recent developments in DNA sequencing technologies have allowed for genetic studies using whole genome or exome analysis, and these have been applied in the study of mood and psychotic disorders, ...including bipolar disorder, depression, schizophrenia, and schizoaffective disorder. In this review, the current situation, recent findings, methodological problems, and future directions of whole genome/exome analysis studies of these disorders are summarized. Whole genome/exome studies of bipolar disorder have included pedigree analysis and case–control studies, demonstrating the role of previously implicated pathways, such as calcium signaling, cyclic adenosine monophosphate response element binding protein (CREB) signaling, and potassium channels. Extensive analysis of trio families and case–control studies showed that de novo mutations play a role in the genetic architecture of schizophrenia and indicated that mutations in several molecular pathways, including chromatin regulation, activity‐regulated cytoskeleton, post‐synaptic density, N‐methyl‐D‐aspartate receptor, and targets of fragile X mental retardation protein, are associated with this disorder. Depression is a heterogeneous group of diseases and studies using exome analysis have been conducted to identify rare mutations causing Mendelian diseases that accompany depression. In the near future, clarification of the genetic architecture of bipolar disorder and schizophrenia is expected. Identification of causative mutations using these new technologies will facilitate neurobiological studies of these disorders.
In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several ...candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22‐24), MLC1 (22q13), GABRA5 (15q11‐q13), BCR (22q11), CUX2, FLJ32356 (12q23‐q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow‐up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene–environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field.
Variants in mitochondrial DNA (mtDNA) and nuclear genes encoding mitochondrial proteins in bipolar disorder, depression, or other psychiatric disorders have been studied for decades, since ...mitochondrial dysfunction was first suggested in the brains of patients with these diseases. Candidate gene association studies initially resulted in findings compatible with the mitochondrial dysfunction hypothesis. Many of those studies, however, were conducted with modest sample sizes (N < 1000), which could cause false positive findings. Furthermore, the DNA samples examined in these studies, including genome-wide association studies, were generally derived from peripheral tissues. One key unanswered question is whether there is an association between mood disorders and somatic mtDNA mutations (deletions and point mutations) in brain regions that accumulate a high amount of mtDNA mutations and/or are involved in the regulation of mood. Two lines of robust evidence supporting the importance of mtDNA mutations in brain tissues for mood disorders have come from clinical observation of mitochondrial disease patients who carry primary mtDNA mutations or accumulate secondary mtDNA mutations due to nuclear mutations and an animal model study. More than half of mitochondrial disease patients have comorbid mood disorders, and mice with neuron-specific accumulation of mtDNA mutations show spontaneous depression-like episodes. In this review, we first summarize the current knowledge of mtDNA and its genetics and discuss what mtDNA analysis tells us about neuropsychiatric disorders based on an example of Parkinson’s disease. We also discuss challenges and future directions beyond mtDNA analysis toward an understanding of the pathophysiology of “idiopathic” mood disorders.
Detailed analyses of transcriptome have revealed complexity in regulation of alternative splicing (AS). These AS events often undergo modulation by genetic variants. Here we analyse RNA-sequencing ...data of prefrontal cortex from 206 individuals in combination with their genotypes and identify cis-acting splicing quantitative trait loci (sQTLs) throughout the genome. These sQTLs are enriched among exonic and H3K4me3-marked regions. Moreover, we observe significant enrichment of sQTLs among disease-associated loci identified by GWAS, especially in schizophrenia risk loci. Closer examination of each schizophrenia-associated loci revealed four regions (each encompasses NEK4, FXR1, SNAP91 or APOPT1), where the index SNP in GWAS is in strong linkage disequilibrium with sQTL SNP(s), suggesting dysregulation of AS as the underlying mechanism of the association signal. Our study provides an informative resource of sQTL SNPs in the human brain, which can facilitate understanding of the genetic architecture of complex brain disorders such as schizophrenia.
Bipolar disorder is a mental disorder that involves a manic or hypomanic state and a depressive state, and was once called manic-depressive disorder and was considered one of the two major mental ...disorders along with schizophrenia. Major depressive disorder, on the other hand, is a disorder in which only depressive states occur, and the two are sometimes referred to together as “mood disorders. This review will introduce the pathophysiology, diagnosis, epidemiology, and treatment of bipolar disorder, focusing on the current situation in Japan.
Although the role of a genetic factor is established in bipolar disorder, causative genes or robust genetic risk factors have not been identified. Increased incidence of subcortical hyperintensity, ...altered calcium levels in cells derived from patients and neuroprotective effects of mood stabilizers suggest vulnerability or impaired resilience of neurons in bipolar disorder. Mitochondrial dysfunction or impaired endoplasmic reticulum stress response is suggested to play a role in the neurons’ vulnerability. Progressive loss or dysfunction of ‘mood-stabilizing neurons’ might account for the characteristic course of the illness. The important next step in the neurobiological study of bipolar disorder is identification of the neural systems that are responsible for this disorder.
Psychiatric disorders such as schizophrenia and bipolar disorder are caused by complex gene-environment interactions. While recent advances in genomic technologies have enabled the identification of ...several risk variants for psychiatric conditions, including single-nucleotide variants and copy-number variations, these factors can explain only a portion of the liability to these disorders. Although non-inherited factors had previously been attributed to environmental causes, recent genomic analyses have demonstrated that de novo mutations are among the main non-inherited risk factors for several psychiatric conditions. Somatic mutations in the brain may also explain how stochastic developmental events and environmental insults confer risk for a psychiatric disorder following fertilization. Here, we review evidence regarding somatic mutations in the brains of individuals with and without neuropsychiatric diseases. We further discuss the potential biological mechanisms underlying somatic mutations in the brain as well as the technical issues associated with the detection of somatic mutations in psychiatric research.
•The lifetime prevalence of BD and MDD in Japan was estimated to be 0.60% and 5.16%.•BD patients had poorer health-related quality of life compared to controls.•BD patients had higher work ...productivity loss than MDD patients and controls.•BD patients with more severe depressive symptoms had poorer outcomes.•The national morbidity cost of BD in Japan was estimated to be JPY 1,236 billion.
Previous studies have shown that bipolar disorder (BD) patients frequently present with difficulties in interpersonal relationships, education or employment and suffer poorer quality of life. This study aimed to estimate the impact of BD on health-related quality of life (HRQOL), work productivity loss and indirect costs.
Data was from the online, self-administered 2019 National Health and Wellness Survey. Outcomes were compared for those who self-reported a physician diagnosis of BD (N=179), major depressive disorder (MDD, N=1,549) and controls who have never experienced BD, MDD and schizophrenia (N=27,485).
The lifetime prevalence was estimated to be 0.60% for BD and 5.16% for MDD. Significantly lower Mental Component Summary (MCS), Role Component Summary (RCS) scores and EuroQol 5-dimension scale (EQ-5D-5L) summary index and significantly higher presenteeism, total work productivity impairment and activity impairment assessed by Work Productivity and Activity Impairment questionnaire and indirect costs for BD versus controls and BD PHQ-9≥10 versus PHQ-9<10 were observed. Compared to MDD patients, BD patients had significantly lower RCS score and greater work productivity loss and activity impairment. The national morbidity cost of BD in Japan was estimated to be Japanese yen 1,236 billion using a human-capital approach.
The data used were self-reported and is cross-sectional in nature, thus causal relationship cannot be assumed.
BD patients and those with severe depressive symptoms experience significantly poorer HRQOL and greater work productivity loss and indirect costs. These findings highlight the importance of proper screening, diagnosis and treatment of BD and bipolar depression.
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