Pathogenesis Of Bipolar Disorder Research Articles

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.

Impaired blood-brain barrier in the microbiota-gut-brain axis: Potential role of bipolar susceptibility gene TRANK1.

Bipolar disorder (BD) is a common psychiatric illness with high prevalence and disease burden. Accumulating susceptibility genes for BD have been identified in recent years. However, the exact functions of these genes remain largely unknown. Despite its high heritability, gene and environment interaction is commonly accepted as the major contributing factor to BD pathogenesis. Intestine microbiota is increasingly recognized as a critical environmental factor for human health and diseases via the microbiota‐gut‐brain axis. BD individuals showed altered diversity and compositions in the commensal microbiota. In addition to pro‐inflammatory factors, such as interleukin‐6 and tumour necrosis factor‐α, type 1 interferon signalling pathway is also modulated by specific intestinal bacterial strains. Disruption of the microbiota‐gut‐brain axis contributes to peripheral and central nervous system inflammation, which accounts for the BD aetiology. Administration of type 1 interferon can induce the expression of TRANK1, which is associated with elevated circulating biomarkers of the impaired blood‐brain barrier in BD patients. In this review, we focus on the influence of intestine microbiota on the expression of bipolar gene TRANK1 and propose that intestine microbiota‐dependent type 1 interferon signalling is sufficient to induce the over‐expression of TRANK1, consequently causing the compromise of BBB integrity and facilitating the entrance of inflammatory mediators into the brain. Activated neuroinflammation eventually contributes to the occurrence and development of BD. This review provides a new perspective on how gut microbiota participate in the pathogenesis of BD. Future studies are needed to validate these assumptions and develop new treatment targets for BD.

Association between the Arylalkylamine N-Acetyltransferase (AANAT) Gene and Seasonality in Patients with Bipolar Disorder.

Objective Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD. Methods We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway. Results Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality. Conclusion This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.

Abnormal gene expression of BDNF, but not BDNF-AS, in iPSC, neural stem cells and postmortem brain samples from bipolar disorder

BackgroundBrain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF. MethodsWe measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age- and sex-matched controls. ResultsThe expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects. In contrast, there were no changes in the expression of BDNF-AS mRNA in both iPSC and NSC between two groups. The expression of BDNF mRNA in the BA46 from BD patients (n = 35) was significantly lower than that of controls (n = 34) although the expression of BDNF mRNA in the corpus callosum and BA8 was not different between two groups (n = 15). In contrast, there were no changes in expression of BDNF-AS mRNA in the three brain regions between two groups. Interestingly, there were significant positive correlations between BDNF mRNA expression and BDNF-AS mRNA expression in the postmortem brain samples. LimitationsSample sizes are relatively low. ConclusionsOur data suggest that abnormalities in the expression of BDNF, but not BDNF-AS, play a role in the pathogenesis of BD.

The functional polymorphisms linked with interleukin-1β gene expression are associated with bipolar disorder.

Bipolar disorder (BD) is a severe psychiatric illness attributable to multifactorial risk components (e.g. environmental stimuli, neuroinflammation, etc.), and genetic variations affecting these risk components are considered pivotal predisposing factors. The interleukin-1β (IL-1β) gene and its protein product have been repeatedly highlighted in the pathogenesis of BD. As functional polymorphisms and haplotypes linked with IL-1β mRNA expression have been reported, whether they are correlated with the risk of developing BD remains to be tested. To examine whether variations in the IL-1β gene locus confer genetic risk of BD, we recruited 930 BD patients and 912 healthy controls for the current study. All subjects were Han Chinese, and were age- and gender-matched. We tested seven functional single nucleotide polymorphisms (SNPs) spanning the IL-1β gene and one haplotype composed of three SNPs for their associations with risk of BD. We found that the functional SNPs in the promoter region of IL-1β gene were significantly associated with risk of BD. The haplotype analyses further supported the involvement of IL-1β promoter SNPs in BD. The BD risk SNPs in our study have been previously reported to predict higher IL-1β levels in the brain and peripheral blood, which is consistent with the clinical observation of elevated IL-1β levels in the lymphocytes or peripheral blood of patients with BD compared with healthy subjects. Our results support the contention that IL-1β is likely a risk gene for BD, and further investigations on this gene may promote our understanding and clinical management of this illness.

Weighted Gene Coexpression Network Analysis Reveals Essential Genes and Pathways in Bipolar Disorder.

Bipolar disorder (BD) is a major and highly heritable mental illness with severe psychosocial impairment, but its etiology and pathogenesis remains unclear. This study aimed to identify the essential pathways and genes involved in BD using weighted gene coexpression network analysis (WGCNA), a bioinformatic method studying the relationships between genes and phenotypes. Using two available BD gene expression datasets (GSE5388, GSE5389), we constructed a gene coexpression network and identified modules related to BD. The analyses of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways were performed to explore functional enrichment of the candidate modules. A protein-protein interaction (PPI) network was further constructed to identify the potential hub genes. Ten coexpression modules were identified from the top 5,000 genes in 77 samples and three modules were significantly associated with BD, which were involved in several biological processes (e.g., the actin filament-based process) and pathways (e.g., MAPK signaling). Four genes (NOTCH1, POMC, NGF, and DRD2) were identified as candidate hub genes by PPI analysis and CytoHubba. Finally, we carried out validation analyses in a separate dataset, GSE12649, and verified NOTCH1 as a hub gene and the involvement of several biological processes such as actin filament-based process and axon development. Taken together, our findings revealed several candidate pathways and genes (NOTCH1) in the pathogenesis of BD and call for further investigation for their potential research values in BD diagnosis and treatment.

Diacylglycerol Kinase η Activity in Cells Using Protein Myristoylation and Cellular Phosphatidic Acid Sensor.

Diacylglycerol kinase (DGK) phosphorylates diacylglycerol to produce phosphatidic acid (PtdOH) and regulates the balance between two lipid second messengers: diacylglycerol and PtdOH. Several lines of evidence suggest that the η isozyme of DGK is involved in the pathogenesis of bipolar disorder. However, the detailed molecular mechanisms regulating the pathophysiological functions remain unclear. One reason is that it is difficult to detect the cellular activity of DGKη. To overcome this difficulty, we utilized protein myristoylation and a cellular PtdOH sensor, the N-terminal region of α-synuclein (α-Syn-N). Although DGKη expressed in COS-7 cells was broadly distributed in the cytoplasm, myristoylated (Myr)-AcGFP-DGKη and Myr-AcGFP-DGKη-KD (inactive (kinase-dead) mutant) were substantially localized in the plasma membrane. Moreover, DsRed monomer-α-Syn-N significantly colocalized with Myr-AcGFP-DGKη but not Myr-AcGFP-DGKη-KD at the plasma membrane. When COS-7 cells were osmotically shocked, all DGKη constructs were exclusively translocated to osmotic shock-responsive granules (OSRG). DsRed monomer-α-Syn-N markedly colocalized with only Myr-AcGFP-DGKη at OSRG and exhibited a higher signal/background ratio (3.4) than Myr-AcGFP-DGKη at the plasma membrane in unstimulated COS-7 cells (2.5), indicating that α-Syn-N more effectively detects Myr-AcGFP-DGKη activity in OSRG. Therefore, these results demonstrated that the combination of myristoylation and the PtdOH sensor effectively detects DGKη activity in cells and that this method is convenient to examine the molecular functions of DGKη. Moreover, this method will be useful for the development of drugs targeting DGKη. Furthermore, the combination of myristoylation (intensive accumulation in membranes) and α-Syn-N can be applicable to assays for various cytosolic PtdOH-generating enzymes.

Analysis of Biological Pathways Involved in the Pathogenesis of Bipolar Disorder

Analysis of Biological Pathways Involved in the Pathogenesis of Bipolar Disorder

Brain-derived Neurotrophic Factor: a Key Gene Risk Factor and Potential Therapy Target in Bipolar Disorder

Bipolar Disorder (BD) is a worldwide, multifactorial mental disorder characterized by manic and depressive symptoms of varying degrees. Among all the genetic risk factors correlated with BD, brain-derived neurotrophic factor (BDNF) has emerged as a crucial neutropin that influences BD susceptibility with strong conservative across species and multiple downstream signaling pathways. However, the mechanisms of how BDNF polymorphism can contribute to BD are not yet lucid and systematically reviewed. BDNF Val66Met variant is capable of inducing neurodegenisis and Long-term Depression (LTD), both of which account for pathogenesis in BD. The Val66Met variant is associated with rapid cycling episodes in BD. Another variant, Arg125Met is a potential BD risk variant which elicits neuronal apoptosis by affecting the maturation of BDNF. In this paper, we briefly summarized BD epidemiology, symptoms, BDNF structure, and its action of function. We reviewed various mechanisms of BDNF Val66Met and Arg125Met variant for BD pathogenesis in detail and provided insights into possible BD clinical treatment targets. BDNF has been proven to be a noteworthy gene factor in BD and gene therapy targeted on BDNF is a promising therapeutic strategy that requires further research.

Metabolic Profiling in Bipolar Disorder Patients During Depressive Episodes.

Bipolar disorder (BD) is a common and debilitating mental disorder. Bipolar depression is the main episode of BD. Furthermore, there are no objective biomarkers available for diagnosing the disorder. In this research, a Nuclear Magnetic Resonance (NMR) spectroscopy based on a metabonomics technique was used to analyze serum samples from 37 patients with bipolar depression and 48 healthy control participants to determine potential biomarkers for bipolar depression. In total, seven different metabolites were identified that could effectively distinguish patients from healthy controls. The metabolites indicated that disturbances of amino acid and energy metabolisms might be involved in the pathogenesis of BD. Finally, a panel consisting of four potential biomarkers (lactate, trimethylamine oxide, N-acetyl glycoprotein, and α-glucose) was identified, which showed a higher combined diagnostic ability with an area under the curve of 0.893. Our findings may contribute to the development of an objective method for diagnosing bipolar depression.

Gut microbial clues to bipolar disorder: State-of-the-art review of current findings and future directions.

Trillions of microorganisms inhabiting in the human gut play an essential role in maintaining physical and mental health. The connections between gut microbiome and neuropsychiatric diseases have been recently identified. The pathogenesis of bipolar disorder, a spectrum of diseases manifesting with mood and energy fluctuations, also seems to be involved in the bidirectional modulation of the microbiome‐gut‐brain (MGB) axis. In this review, we briefly introduce the concept of MGB axis, and then focus on the previous findings in human studies associated with bipolar disorder. These studies provided preliminary evidences on the gut microbial alterations in bipolar disorder. Limitations in these studies and future directions in this research field, such as fecal microbiome transplantation and microbiome‐targeted therapy, were discussed. A research framework linking gut microbiome to determinants and health‐related outcomes in BD was also proposed. Better characterizing and understanding of gut microbial biosignatures in bipolar patients contribute to clarify the etiology of this intractable disease and pave the new way for treatment innovation.

Biological Targets Underlying the Antisuicidal Effects of Lithium

This article highlights the potential relationship of lithium’s cellular and molecular targets to its antisuicidal effects in bipolar disorder (BD). Lithium is the mood stabilizer that shows the most robust therapeutic evidence in relapse prevention and mood episodes in BD. Compelling evidence also elucidates lithium’s unique effects in reversing and preventing suicidal behavior (SB), mostly in individuals with BD. The following review is an up-to-date summary of studies related to the anti-suicidal effects of lithium in patients with BD. We focused on studies investigating the similarities in pathogenesis of BD and SB and the related treatment targets for lithium’s anti-suicidal actions. Lithium seems to have beneficial effects in reversing pathophysiological changes in SB and BD associated with its ability to reduce suicidal risk. Several neurobiological targets have been associated with the antisuicidal effects of lithium such as brain atrophy and demyelination, alterations in glutamatergic neurotransmission, and increased central and peripheral inflammation as well as HPA axis hyperactivation, cell signaling pathways, and neurotrophic system dysfunctions. Further studies are required to elucidate the presence of a specific neurobiological signature of SB as an independent clinical dimension and not solely in the context of mood episodes.

Higher cortisol levels may proceed a manic episode and are related to disease severity in patients with bipolar disorder

BackgroundRegulation of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the pathogenesis of bipolar disorder (BD). However, the relationship between HPA-activity and disease severity is not fully elucidated. In this pilot study we aimed to explore the temporal relationship between HPA-activity and the risk of a manic episode in BD patients type I, by assessing long-term hair cortisol concentrations (HCC). Second, we explored the relation between HCC and the number of previous episodes. MethodsHair samples were collected from 45 BD I patients in euthymic or manic state and compared to 17 controls. From each participant, two hair samples of 3 cm length were used to measure long-term cortisol, reflecting retrospect time frames of 1–3 months and 4–6 months respectively prior to sampling. ResultsHCC in the BD group was slightly higher than in the control group in both hair segments (p = 0.049 and 0.03; after adjustment for age, sex, BMI and hair washing frequency p = 0.222 and 0.139). A significant peak in hair cortisol was observed prior to a manic episode (p = 0.036). Furthermore, we found a positive correlation between the number of mood episodes HCC (p = 0.03). ConclusionsOur results indicate that long-term cortisol levels are slightly higher in BD, and in particular elevated in the months prior to a manic relapse. In addition HCC are positively associated with the number of previous mood episodes in the course of BD type I.

Case report: manic episode with psychotic symptoms induced by hyponatremia

SummaryIn the literature, several cases of an association between hyponatremia and psychotic symptoms have been reported. We present the case of a young Caucasian male presenting with rapid, incoherent speech, religious and megalomanic delusions, and emotional lability. The patient was described by his relatives as being healthy until a few days before admission. He had no significant medical or psychiatric history, except a short drug-induced psychotic episode a few years earlier. Somatic workup showed moderate hyponatremia, but no other abnormalities. Tests for narcotics, in particular, were also negative. Antipsychotic treatment with risperidone was initiated. After normalization of sodium levels using intravenous saline, the patient remitted within a few days and risperidone was discontinued on day 3. He was discharged by day 13 without further pharmacological treatment.Dysfunction of voltage-gated ion channels, particularly sodium and calcium channels, has been implicated in the pathogenesis of bipolar disorder. We therefore assume a causal relationship between hyponatremia and manic-psychotic symptoms in our patient. Hyponatremia was most likely induced by excessive water intake during a period of fasting in the context of a wellness practice.

Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice

The pathogenesis of bipolar disorder (BD) has remained enigmatic, largely because genetic animal models based on identified susceptible genes have often failed to show core symptoms of spontaneous mood cycling. However, pedigree and induced pluripotent stem cell (iPSC)-based analyses have implicated that dysfunction in some key signaling cascades might be crucial for the disease pathogenesis in a subpopulation of BD patients. We hypothesized that the behavioral abnormalities of patients and the comorbid metabolic abnormalities might share some identical molecular mechanism. Hence, we investigated the expression of insulin/synapse dually functioning genes in neurons derived from the iPSCs of BD patients and the behavioral phenotype of mice with these genes silenced in the hippocampus. By these means, we identified synaptotagmin-7 (Syt7) as a candidate risk factor for behavioral abnormalities. We then investigated Syt7 knockout (KO) mice and observed nocturnal manic-like and diurnal depressive-like behavioral fluctuations in a majority of these animals, analogous to the mood cycling symptoms of BD. We treated the Syt7 KO mice with clinical BD drugs including olanzapine and lithium, and found that the drug treatments could efficiently regulate the behavioral abnormalities of the Syt7 KO mice. To further verify whether Syt7 deficits existed in BD patients, we investigated the plasma samples of 20 BD patients and found that the Syt7 mRNA level was significantly attenuated in the patient plasma compared to the healthy controls. We therefore concluded that Syt7 is likely a key factor for the bipolar-like behavioral abnormalities.

Serum zonulin and claudin-5 levels in patients with bipolar disorder

The etiology in bipolar disorder has not been fully understanding. There are limited data regarding the relationship between the permeability of intestinal and blood-brain barrier (BBB), and bipolar disorder etiology. Zonulin is regarded as a non-invasive biomarker for intestinal permeability. Claudin-5 is an important part of BBB permeability. In this study, we assumed that there may be a deterioration in serum zonulin and claudin-5 levels in patients with bipolar disorder and this may affect the severity of the disease. Forty-one bipolar disorder patients (21 patients in remission and 20 patients with manic episodes) and 41 healthy controls were included in this study. The patients were administered Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) to determine the severity of manic and depressive symptoms, respectively. Venous blood samples were collected, and serum zonulin and claudin-5 levels were measured. The mean serum zonulin and claudin-5 levels in patients were significantly higher than healthy controls. There is no difference zonulin and claudın-5 levels between patients with manic episodes and patients in remission. This study's small sample size limits the generalization of these outcomes to a larger population. Also, a major limitation of our study is lack of evaluations of gut microbiota in patients with bipolar disorder and controls. In conclusion, the current research indicates that zonulin and claudin-5 are increased in patients with bipolar disorder and this finding may contribute to the role of intestinal permeability or BBB in the pathogenesis of bipolar disorder.

Hypothesis: bipolar disorder is an Epstein-Barr virus-driven chronic autoimmune disease - implications for immunotherapy.

Bipolar disorder (BD) is a chronic disease characterised by episodes of major depression and episodes of mania or hypomania, with a worldwide prevalence of 2.4%. The cause of BD is unknown. Here, I propose the hypothesis that BD is a chronic autoimmune disease caused by Epstein–Barr virus (EBV) infection of autoreactive B cells. It is postulated that EBV‐infected autoreactive B cells accumulate in the brain where they provide costimulatory survival signals to autoreactive T cells and differentiate into plasma cells producing pathogenic autoantibodies targeting brain components such as the N‐methyl‐D‐aspartate receptor. It is also proposed that the accumulation of EBV‐infected autoreactive B cells in the brain is a consequence of a genetically determined defect in the ability of CD8+ T cells to control EBV infection. The theory is supported by studies indicating that autoimmunity, EBV infection and CD8+ T‐cell deficiency all have roles in the pathogenesis of BD. According to the hypothesis, BD should be able to be treated by EBV‐specific T‐cell therapy and to be prevented by vaccination against EBV in early childhood. Exposure to sunlight or appropriate artificial light should also be beneficial in BD by augmenting CD8+ T‐cell control of EBV infection.

Circadian Misalignment and Bipolar Disorder

The circadian rhythm is a periodic and continuous change caused by the light/dark cycle as the Earth rotates around its own axis in a 24- hour cycle. The circadian clock system regulates the 24-hour daily rhythms of human physiology and behavior such as the sleep/wake cycle, body temperature, hormone secretion, and mood. The influence of circadian rhythm on the body and mind is obvious, but considerable research has not dealt with its effects on human disease, especially on mental illnesses. However, several recent studies have shown that circadian misalignment may play an important role in the pathogenesis of bipolar disorder. Evidence for circadian rhythm misalignment in bipolar disorder suggests that circadian rhythm phase shift is a key pathophysiologic mechanism. Keywords: Circadian rhythm; Bipolar disorder; Pathogenesis