Chronic Partial Sleep Deprivation Increased the Incidence of Atrial Fibrillation by Promoting Pulmonary Vein and Atrial Arrhythmogenesis in a Rodent Model.

Sleep deprivation (SD) is a recognized risk factor for atrial fibrillation (AF), yet the precise molecular and electrophysiological mechanisms behind SD-induced AF are unclear. This study explores the electrical and structural changes that contribute to AF in chronic partial SD. We induced chronic partial SD in Wistar rats using a modified multiple-platform method. Echocardiography demonstrated impaired systolic and diastolic function in the left ventricle (LV) of the SD rats. The SD rats exhibited an elevated heart rate and a higher low-frequency to high-frequency ratio in a heart-rate variability analysis. Rapid transesophageal atrial pacing led to a higher incidence of AF and longer mean AF durations in the SD rats. Conventional microelectrode recordings showed accelerated pulmonary vein (PV) spontaneous activity in SD rats, along with a heightened occurrence of delayed after-depolarizations in the PV and left atrium (LA) induced by tachypacing and isoproterenol. A Western blot analysis showed reduced expression of G protein-coupled receptor kinase 2 (GRK2) in the LA of the SD rats. Chronic partial SD impairs LV function, promotes AF genesis, and increases PV and LA arrhythmogenesis, potentially attributed to sympathetic overactivity and reduced GRK2 expression. Targeting GRK2 signaling may offer promising therapeutic avenues for managing chronic partial SD-induced AF. Future investigations are mandatory to investigate the dose-response relationship between SD and AF genesis.

Lipid-modifying agents and risk of all-cause, natural and suicide mortality in schizophrenia: nationwide cohort study.

BACKGROUND: Individuals with schizophrenia face high mortality risks. The effects of lipid-modifying agents on this risk remain understudied. AIM: This study was conducted to investigate the effects of lipid-modifying agents on mortality risk in people with schizophrenia. METHOD: This nationwide cohort study collected the data of people with schizophrenia from Taiwan's National Health Insurance Research Database for the period between 1 January 2001 and 31 December 2019. Multivariable Cox proportional hazards regression with a time-dependent model was used to estimate the hazard ratio for mortality associated with each lipid-modifying agent. RESULTS: This study included 110 300 people with schizophrenia. Of them, 22 528 died (19 754 from natural causes and 1606 from suicide) during the study period, as confirmed using data from Taiwan's national mortality database. The use of lipid-modifying agents was associated with reduced risks of all-cause (adjusted hazard ratio [aHR]:0.37; P < 0.001) and natural (aHR:0.37; P < 0.001) mortality during a 5-year period. Among the lipid-modifying agents, statins and fibrates were associated with reduced risks of all-cause mortality (aHRs:0.37 and 0.39, respectively; P < 0.001 for both) and natural mortality (aHRs: 0.37 and 0.42, respectively; P < 0.001 for both). Notably, although our univariate analysis indicated an association between the use of lipid-modifying agents and a reduced risk of suicide mortality, the multivariate analysis revealed no significant association. CONCLUSIONS: Lipid-modifying agents, particularly statins and fibrates, reduce the risk of mortality in people with schizophrenia. Appropriate use of lipid-modifying agents may bridge the mortality gap between these individuals and the general population.

Association of lipids and inflammatory markers with left ventricular wall thickness in patients with bipolar disorder.

BACKGROUND: Individuals with bipolar disorder (BD) face a high risk of heart failure and left ventricular (LV) dysfunction. Despite strong evidence that high LV relative wall thickness (RWT) is a risk marker for heart failure, few studies have evaluated LV RWT and aggravating factors in individuals with BD. METHODS: We recruited 104 participants (52 patients with BD and 52 age- and sex-matched mentally healthy controls) to undergo echocardiographic imaging and biochemistry, high-sensitivity C-reactive protein (hs-CRP), and blood cell count measurements. LV RWT was estimated using the following equation: (2 × LV posterior wall end-diastolic thickness)/LV end-diastolic diameter. Clinical data were obtained through interviews and chart reviews. RESULTS: The BD group exhibited a significantly greater LV RWT (Cohen's d = 0.53, p = 0.003) and a less favorable mitral valve E/A ratio (Cohen's d = 0.54, p = 0.023) and LV global longitudinal strain (Cohen's d = 0.57, p = 0.047) than did the control group. Multiple linear regression revealed that in the BD group, serum triglyceride levels (ß = 0.466, p = 0.001), platelet-to-lymphocyte ratios (ß = 0.324, p = 0.022), and hs-CRP levels (ß = 0.289, p = 0.043) were all significantly and positively associated with LV RWT. LIMITATIONS: This study applied a cross-sectional design, meaning that the direction of causation could not be inferred. CONCLUSIONS: Patients with BD are at a risk of heart failure, as indicated by their relatively high LV RWT. Lipid levels and systemic inflammation may explain this unfavorable association.

Lithium downregulates phosphorylated acetyl­CoA carboxylase 2 and attenuates mitochondrial fatty acid utilization and oxidative stress in cardiomyocytes.

Acetyl-CoA carboxylase 2 plays a crucial role in regulating mitochondrial fatty acid oxidation in cardiomyocytes. Lithium, a monovalent cation known for its cardioprotective potential, has been investigated for its influence on mitochondrial bioenergetics. The present study explored whether lithium modulated acetyl-CoA carboxylase 2 and mitochondrial fatty acid metabolism in cardiomyocytes and the potential therapeutic applications of lithium in alleviating metabolic stress. Mitochondrial bioenergetic function, fatty acid oxidation, reactive oxygen species production, membrane potential and the expression of proteins involved in fatty acid metabolism in H9c2 cardiomyocytes treated with LiCl for 48 h was measured by using a Seahorse extracellular flux analyzer, fluorescence microscopy and western blotting. Small interfering RNA against glucose transporter type 4 was transfected into H9c2 cardiomyocytes for 48 h to induce metabolic stress mimicking insulin resistance. The results revealed that LiCl at a concentration of 0.3 mM (but not at a concentration of 0.1 or 1.0 mM) upregulated the expression of phosphorylated (p-)glycogen synthase kinase-3 beta and downregulated the expression of p-acetyl-CoA carboxylase 2 but did not affect the expression of adenosine monophosphate-activated protein kinase or calcineurin. Cotreatment with TWS119 (8 µM) and LiCl (0.3 mM) downregulated p-acetyl-CoA carboxylase 2 expression to a similar extent as did treatment with TWS119 (8 µM) alone. Moreover, LiCl (0.3 mM) inhibited mitochondrial fatty acid oxidation, improved coupling efficiency and the cellular respiratory control ratio, hindered reactive oxygen species production and proton leakage and restored mitochondrial membrane potential in glucose transporter type 4 knockdown-H9c2 cardiomyocytes. These findings suggested that low therapeutic levels of lithium can downregulate p-acetyl-CoA carboxylase 2, thus reducing mitochondrial fatty acid oxidation and oxidative stress in cardiomyocytes.

Prevalence and 3-year incidence of physical illnesses after schizophrenia diagnosis: Comparison with general population.

AIM: People with schizophrenia are at a greater risk of poor physical health than the general population. This study investigated the annual incidence of physical illnesses after a new schizophrenia diagnosis, which has rarely been investigated in the literature. METHODS: The authors collected data from Taiwan's National Health Insurance Research Database from January 1, 1996, to December 31, 2013, and enrolled 1910 patients with newly diagnosed schizophrenia cases aged 10-40 years and 7640 age- and sex-matched controls from the general population. They estimated the 1-year prevalence and annual incidence rate ratio (IRR) of specified physical diseases across 3 years in the schizophrenia group compared with the controls. RESULTS: Several physical illnesses were prevalent within 1 year of schizophrenia diagnosis. Regarding incident physical illnesses, patients had a moderate to strong risk of numerous physical illnesses (IRR > 3.0: ischemic heart disease, cerebrovascular disease, diabetes mellitus, and cancer; IRR 1.8-3.0: other forms of heart disease, vein and lymphatic diseases, pneumonia, chronic hepatic disease, and ulcer disease) within the first year after schizophrenia diagnosis. The IRRs of most physical illnesses declined over 3 years, except for that of cerebrovascular disease, which significantly increased (IRR > 3.0) over the 3 years after schizophrenia diagnosis. Cerebrovascular disease had a significant incidence risk (IRR > 3) persistently across the 3 years. CONCLUSION: Various comorbid physical illnesses can occur in the early stages of schizophrenia. Clinicians should consider these vulnerabilities to physical illnesses during the evaluation of patients with newly diagnosed schizophrenia by attempting to prevent, screen for, and manage them.

Inflammation associated with left ventricular hypertrophy in bipolar disorder: A cross-sectional study.

OBJECTIVE: Inflammation has received increasing attention as a contributor to the pathophysiology of bipolar disorder (BD) and cardiac hypertrophy into heart failure (HF). Accordingly, we chose BD-related inflammatory markers to investigate their relationships with cardiac left ventricular function and structure in BD. METHODS: Sixty physically healthy and euthymic patients with bipolar I disorder were recruited to compare with 50 healthy normal controls. The echocardiography was performed to estimate left ventricular mass index (LVMI) as a parameter of LV hypertrophy (LVH) and left ventricle ejection fraction (LVEF) as a parameter of systolic function. An LVEF above the normal range (>70%) was defined as a hyperdynamic heart. Participants' levels of inflammatory and atherosclerosis-related parameters were measured. RESULTS: Compared with normal controls, BD group had significantly higher rates of LVH (63% vs. 42%) and hyperdynamic heart (32% vs. 2%) and higher mean values of LVMI and LVEF. After adjustment for the effects of BMI and age, multiple regression analyses of BD group showed that the peripheral level of interleukin-8 was positively associated with LVMI and the level of soluble tumor necrosis factor receptor 1 (sTNF-R1) was positively associated with LVEF. CONCLUSIONS: Patients with BD from young adulthood are likely to have LVH with normal LV function and hyperdynamic heart associated with diastolic dysfunction. Low-grade inflammation may underlie the mechanisms of LV hypertrophy and cardiac dysfunction in BD patients.

Clozapine and its protective effect on all-cause, natural, and suicide mortality in patients with schizophrenia: A nationwide cohort study in Taiwan.

AIM: Clozapine is indicated as the last-line agent for the treatment of refractory schizophrenia due to its side effects. This study included an Asian schizophrenia population and investigated the effect of clozapine on the risks of all-cause, natural, and suicide mortality. METHODS: This study included a large-scale schizophrenia inpatient cohort derived from the National Health Insurance Research Database from January 1, 2001, to December 31, 2019 (n = 43,025). Of them, we selected those who received clozapine (clozapine cohort, n = 5800). From those who never used clozapine, we selected two individuals for each patient in the clozapine cohort by matching by age, sex, and the year of the index date (ratio: 1:2, control cohort, n = 11,583). The clozapine and nonclozapine control cohorts together were defined as the study cohort (n = 17,383). Multivariate Cox proportional-hazards regression with a time-dependent model was performed to investigate the effect of individual antipsychotic agents on mortality. RESULTS: All individual first-generation antipsychotics were not associated with mortality risk. However, most individual second-generation antipsychotics exerted protective effects against all-cause and natural mortality. Furthermore, only clozapine and risperidone were significantly associated with a low risk of suicide mortality. Only clozapine exhibited a dose-dependent relationship with all-cause, natural, and suicide mortality. CONCLUSIONS: This study provides robust evidence supporting the strong protective effect of clozapine on all-cause, suicide, and natural mortality risks in an Asian population. Under close monitoring, clozapine use can be advantageous in patients with schizophrenia who are at a high risk of suicide.

Prediction of the Duration to Next Admission for an Acute Affective Episode in Patients with Bipolar I Disorder.

Objective: Predicting disease relapse and early intervention could reduce symptom severity. We attempted to identify potential indicators that predict the duration to next admission for an acute affective episode in patients with bipolar I disorder. Methods: We mathematically defined the duration to next psychiatric admission and performed single-variate regressions using historical data of 101 patients with bipolar I disorder to screen for potential variables for further multivariate regressions. Results: Age of onset, total psychiatric admissions, length of lithium use, and carbamazepine use during the psychiatric hospitalization contributed to the next psychiatric admission duration positively. The all-in-one found that hyperlipidemia during the psychiatric hospitalization demonstrated a negative contribution to the duration to next psychiatric admission; the last duration to psychiatric admission, lithium and carbamazepine uses during the psychiatric hospitalization, and heart rate on the discharge day positively contributed to the duration to next admission. Conclusion: We identified essential variables that may predict the duration of bipolar I patients' next psychiatric admission. The correlation of a faster heartbeat and a normal lipid profile in delaying the next onset highlights the importance of managing these parameters when treating bipolar I disorder.

Sex-specific risk profiles for suicide mortality in bipolar disorder: incidence, healthcare utilization and comorbidity.

BACKGROUND: Evidence on sex-specific incidence and comorbidity risk factors of suicide among patients with bipolar disorder is scarce. This study investigated the sex-specific risk profiles for suicide among the bipolar disorder population in terms of incidence, healthcare utilization and comorbidity. METHODS: Using data from the Taiwan National Health Insurance Research Database between 1 January 2000 and 31 December 2016, this nationwide cohort study included patients with bipolar disorder (N = 46 490) and individuals representative of the general population (N = 185 960) matched by age and sex at a 1:4 ratio. Mortality rate ratios (MRRs) of suicide were calculated between suicide rates of bipolar disorder cohort and general population. In addition, a nested case-control study (1428 cases died by suicide and 5710 living controls) was conducted in the bipolar disorder cohort to examine the sex-specific risk of healthcare utilization and comorbidities. RESULTS: Suicide risk was considerably higher in the cohort (MRR = 21.9) than in the general population, especially among women (MRR = 35.6). Sex-stratified analyses revealed distinct healthcare utilization patterns and physical comorbidity risk profiles between the sexes. Although female patients who died by suicide had higher risks of nonhypertensive cardiovascular disease, pneumonia, chronic kidney disease, peptic ulcer, irritable bowel syndrome, and sepsis compared to their living counterparts, male patients who died by suicide had higher risks of chronic kidney disease and sepsis compared to the living controls. CONCLUSIONS: Patients with bipolar disorder who died by suicide had sex-specific risk profiles in incidence and physical comorbidities. Identifying these modifiable risk factors may guide interventions for suicide risk reduction.

Electroencephalographic Microstates are Correlated with Global Functioning in Schizophrenia But Not in Bipolar Disorder.

Objectives. Microstate studies of electroencephalograms (EEGs) on schizophrenia (SCZ) and bipolar disorder (BD) demonstrated categorical differences. The relationship between microstate indices and clinical symptoms in each group, however, remained unclear. Our objective was to examine associations between EEG microstates and the core features of SCZ and BD. Methods. This study examined the resting EEG data of 40 patients with SCZ, 19 patients with BD (12 BD type I and 7 BD type II), and 16 healthy controls. EEG topographic maps were divided into four canonical microstate classes: A, B, C, and D. The Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale, Hamilton Depression Rating Scale (HAMD), and Global Assessment of Functioning (GAF) were used to measure clinical symptoms and global functioning. Results. There was a significant inverse correlation between the proportion of time spent in microstate class A and GAF in patients with SCZ but not BD. Furthermore, the occurrence of microstate class A was positively correlated with the Positive Scale scores of the PANSS. Nevertheless, there were no group differences between the microstate classes. Conclusions. The results of this study indicate a negative correlation between microstate class A and global functioning in SCZ but not in BD. The association may be mediated by positive symptoms of SZ. Neural mechanisms underlying this relationship require further investigation.

Cardioprotective potential of lithium and role of fractalkine in euthymic patients with bipolar disorder.

OBJECTIVE: Over a half century, lithium has been used as the first-line medication to treat bipolar disorder. Emerging clinical and laboratory studies suggest that lithium may exhibit cardioprotective effects in addition to neuroprotective actions. Fractalkine (CX3CL1) is a unique chemokine associated with the pathogenesis of mood disorders and cardiovascular diseases. Herein we aimed to ascertain whether lithium treatment is associated with favorable cardiac structure and function in relation to the reduced CX3CL1 among patients with bipolar disorder. METHODS: We recruited 100 euthymic patients with bipolar I disorder aged over 20 years to undergo echocardiographic study and measurement of plasma CX3CL1. Associations between lithium treatment, cardiac structure and function and peripheral CX3CL1 were analyzed according to the cardiovascular risk. The high cardiovascular risk was defined as (1) age ⩾ 45 years in men or ⩾ 55 years in women or (2) presence of concurrent cardiometabolic diseases. RESULTS: In the high cardiovascular risk group (n = 61), patients who received lithium as the maintenance treatment had significantly lower mean values of left ventricular internal diameters at end-diastole (Cohen's d = 0.65, p = 0.001) and end-systole (Cohen's d = 0.60, p = 0.004), higher mean values of mitral valve E/A ratio (Cohen's d = 0.51, p = 0.019) and superior performance of global longitudinal strain (Cohen's d = 0.51, p = 0.037) than those without lithium treatment. In addition, mean plasma levels of CX3CL1 in the high cardiovascular risk group were significantly lower among patients with lithium therapy compared with those without lithium treatment (p = 0.029). Multiple regression models showed that the association between lithium treatment and mitral value E/A ratio was contributed by CX3CL1. CONCLUSION: Data from this largest sample size study of the association between lithium treatment and echocardiographic measures suggest that lithium may protect cardiac structure and function in patients with bipolar disorder. Reduction of CX3CL1 may mediate the cardioprotective effects of lithium.

Mood stabilizers and risk of all-cause, natural, and suicide mortality in bipolar disorder: A nationwide cohort study.

OBJECTIVES: People with bipolar disorder have an elevated risk of mortality. This study evaluated associations between the use of mood stabilizers and the risks of all-cause mortality, suicide, and natural mortality in a national cohort of people with bipolar disorder. METHODS: In this nationwide cohort study, we used data from January 1, 2000, to December 31, 2016, collected from Taiwan's National Health Insurance Research Database and included 25,787 patients with bipolar disorder. Of these patients, 4000 died during the study period (including 760 and 2947 from suicide and natural causes, respectively). Each standardized mortality ratio (SMR) was calculated as the ratio of observed mortality in the bipolar cohort to the number of expected deaths in the general population. Multivariable Cox proportional hazards regression with a time-dependent model was performed to estimate the hazard ratio (HR) of each mood stabilizer with each mortality outcome. RESULTS: The SMRs of all-cause mortality, suicide, and natural mortality in the bipolar disorder cohort were 5.26, 26.02, and 4.68, respectively. The use of mood stabilizers was significantly associated with decreased risks of all-cause mortality (adjusted HR [aHR] = 0.58, p< 0.001), suicide (aHR = 0.60, p < 0.001), and natural mortality (aHR = 0.55, p < 0.001) within a 5-year follow-up period after index admission. Among the individual mood stabilizers, lithium was associated with the lowest risks of all-cause mortality (aHR = 0.38, p < 0.001), suicide (aHR = 0.39, p < 0.001), and natural mortality (aHR = 0.37, p < 0.001). CONCLUSION: In addition to having protective effects against suicide and all-cause mortality, mood stabilizers also exert a substantial protective effect against natural mortality, with lithium associated with the lowest risk of mortality.

Lithium Treatment Improves Cardiac Dysfunction in Rats Deprived of Rapid Eye Movement Sleep.

Rapid eye movement (REM) sleep deprivation triggers mania and induces cardiac fibrosis. Beyond neuroprotection, lithium has cardioprotective potential and antifibrotic activity. This study investigated whether lithium improved REM sleep deprivation-induced cardiac dysfunction and evaluated the potential mechanisms. Transthoracic echocardiography, histopathological analysis, and Western blot analysis were performed in control and REM sleep-deprived rats with or without lithium treatment (LiCl of 1 mmol/kg/day administered by oral gavage for 4 weeks) in vivo and in isolated ventricular preparations. The results revealed that REM sleep-deprived rats exhibited impaired contractility and greater fibrosis than control and lithium-treated REM sleep-deprived rats. Western blot analysis showed that REM sleep-deprived hearts had higher expression levels of transforming growth factor beta (TGF-ß), phosphorylated Smad 2/3, and alpha-smooth muscle actin than lithium-treated REM sleep-deprived and control hearts. Moreover, lithium-treated REM sleep-deprived hearts had lower expression of angiotensin II type 1 receptor, phosphorylated nuclear factor kappa B p65, calcium release-activated calcium channel protein 1, transient receptor potential canonical (TRPC) 1, and TRPC3 than REM sleep-deprived hearts. The findings suggest that lithium attenuates REM sleep deprivation-induced cardiac fibrogenesis and dysfunction possibly through the downregulation of TGF-ß, angiotensin II, and Ca2+ signaling.

Lithium exposure and chronic inflammation with activated macrophages and monocytes associated with atherosclerosis in bipolar disorder.

BACKGROUND: Atherosclerosis accounts for cardiovascular diseases (CVDs). This study aimed to explore the association between carotid intima-media thickness (CIMT), psycho-pharmacotherapy, and inflammatory markers along with other molecules related to atherosclerosis in bipolar disorder (BD). METHODS: The euthymic patients with bipolar I disorder (BD-I) aged over 20 years were recruited to measure CIMT through ultrasound and the blood levels of lipid profiles, soluble tumor necrosis factor receptor-1 (sTNF-R1), soluble interleukin-6 receptor (sIL-6R), monocyte chemoattractant protein-1, chitinase 3-like 1, endothelial adhesive proteins, and thrombin-antithrombin complex. RESULTS: Participants were 103 BD-I patients with mean 44.3 years old. The ratio of lithium exposure in relation to illness chronicity and the current daily dosage of lithium therapy exhibited an inverse relationship with CIMT in the entire sample. After controlling for age and BMI, multivariate regression indicated that a higher lithium level was significantly associated with decreased CIMT in the entire sample, high-risk (those with CVDs or endocrine diseases, N = 48), middle-risk (those without CVDs and endocrine diseases, N = 55), and low-risk (those aged <45 years in the middle-risk subgroup, N = 43) subgroups. Furthermore, higher levels of sTNF-R1 in the entire sample and high-risk subgroup and sIL-6R in the middle- and low-risk subgroups were statistically associated with greater CIMT. LIMITATION: The age range was too wide to control for the effect of age on CIMT and medication. CONCLUSIONS: Lithium exposure may be a protective factor for atherosclerosis progression in BD-I. The chronic inflammation in BD-I with activated macrophages and monocytes may link with the atherosclerosis development over time.

Premature death and causes of death among patients with panic disorder and comorbid psychiatric disorders: A nationwide cohort study.

OBJECTIVES: Panic disorder (PD) is associated with high psychiatric and physical comorbidity, but the cause of mortality has not been well studied. This study investigated mortality rates and causes of death in an Asian cohort with PD. METHODS: We enrolled a nationwide retrospective cohort of 298,466 persons diagnosed with PD from January 1, 2001, to December 31, 2016. Each cohort member was matched with a comparison one randomly selected from the general population with the same sex, age at entry, and birth year. The data of both the PD cohort and the comparison group were linked with the national mortality database to obtain each individual's mortality status. We used mortality rate ratios (MRRs) to compare mortality risks between the patients with PD and the general population. Stratified analysis of mortality risks was performed based on sex and psychiatric comorbidities. RESULTS: PD was associated with a slightly increased mortality risk (MRR, 1.14 [99% CI, 1.11-1.17]). The risk of unnatural death (MRR, 2.83 [99% CI, 2.59-3.10]) was significantly higher among the individuals with PD than among the general population, whereas the risk of overall natural death across all categories was not (MRR, 1.01 [99% CI, 0.98-1.04]). The mortality risk was the highest for suicide (MRR, 4.94 [99% CI, 4.32-5.72]) and was higher in women (MRR, 6.37 [99% CI, 5.25-7.96]) than in men (MRR, 3.77 [99% CI, 3.14-4.64]). Comorbid substance use disorders increased the risk of mortality from natural (MRR, 3.23 [99% CI, 2.59-4.14]) and unnatural (MRR, 9.45 [99% CI, 6.29-17.85]) causes. CONCLUSION: PD was associated with increased all-cause mortality, especially suicide. Substance use further increased mortality risk in persons with PD. Targeted treatment for substance use and suicide prevention are essential among persons with PD.

Echocardiographic study of cardiac structure and function in people with bipolar disorder after midlife.

BACKGROUND: Heart failure is the leading cause of mortality in older people with bipolar disorder (BD). Studies examining cardiac structure and function in middle-aged patients with BD by using echocardiography and cardiac strain imaging are scant. METHODS: We recruited 48 patients with bipolar I disorder (BD-I) older than 45 years to undergo conventional and tissue speckle tracking echocardiography. Data of 31 mentally healthy adults older than 45 years were randomly retrieved from the echocardiographic dataset and compared with the data of BD patients. RESULTS: Patients with BD-I had significantly higher mean values of interventricular septal thickness (Cohen's d = 0.83, p = 0.001) and left ventricular internal diameter (Cohen's d = 0.90, p = 0.001) at end-diastole relative to controls. Additionally, BD-I patients exhibited significantly lower mean values of mitral valve E/A ratio (Cohen's d = 0.67, p = 0.007) and a more reduced global longitudinal strain (Cohen's d = 0.72, p = 0.029) than controls. Multiple linear regression revealed that body mass index was negatively correlated with the mitral valve E/A ratio (adjustment R2 = 0.363, p = 0.043) in patients with BD-I. LIMITATIONS: A relatively small sample size may limit generalization. CONCLUSIONS: After midlife, BD patients exhibit cardiac diastolic (low mitral valve E/A ratio) and systolic (reduced global longitudinal strain) dysfunction. High body mass index may play a role in the unfavorable cardiac function in aging patients with BD.

Prevalence and 5-year trend of incidence for medical illnesses after the diagnosis of bipolar disorder: A nationwide cohort study.

OBJECTIVE: Medical comorbidities are prevalent in patients with bipolar disorder. Evaluating longitudinal trends of the incidence of medical illnesses enables implementation of early prevention strategies to reduce the high mortality rate in this at-risk population. However, the incidence risks of medical illnesses in the early stages of bipolar disorder remain unclear. This study investigated the incidence and 5-year trend of medical illnesses following bipolar disorder diagnosis. METHODS: We identified 11,884 patients aged 13-40 years who were newly diagnosed as having bipolar disorder during 1996-2012 and 47,536 age- and sex-matched controls (1:4 ratio) who represented the general population from Taiwan's National Health Insurance Research Database. We estimated the prevalence and incidence of individual medical illnesses yearly across the first 5 years after the index date. The adjusted incidence rate ratio was calculated to compare the occurrence of specific medical illnesses each year between the bipolar disorder group and control group using the Poisson regression model. RESULTS: Apart from the prevalence, the adjusted incidence rate ratios of most medical illnesses were >1.00 across the first 5-year period after bipolar disorder diagnosis. Cerebrovascular diseases, ischaemic heart disease, congestive heart failure, other forms of heart disease, renal disease and human immunodeficiency virus infection exhibited the highest adjusted incidence rate ratios during the first year. Except for that of renal disease, the 5-year trends of the adjusted incidence rate ratios decreased for cerebrovascular diseases, cardiovascular diseases (e.g. ischaemic heart disease, other forms of heart disease, and vein and lymphatic disease), gastrointestinal diseases (e.g. chronic hepatic disease and ulcer disease) and communicable diseases (e.g. human immunodeficiency virus infection, upper respiratory tract infection and pneumonia). CONCLUSION: Incidence risks of medical illnesses are increased in the first year after bipolar disorder diagnosis. Clinicians must carefully evaluate medical illnesses during this period because the mortality rates from medical illnesses are particularly high in people with bipolar disorder.

Peripheral inflammatory markers associated with brain volume reduction in patients with bipolar I disorder.

BACKGROUND: Neuroinflammation and brain structural abnormalities are found in bipolar disorder (BD). Elevated levels of cytokines and chemokines have been detected in the serum and cerebrospinal fluid of patients with BD. This study investigated the association between peripheral inflammatory markers and brain subregion volumes in BD patients. METHODS: Euthymic patients with bipolar I disorder (BD-I) aged 20-45 years underwent whole-brain magnetic resonance imaging. Plasma levels of monocyte chemoattractant protein-1 (MCP-1), chitinase-3-like protein 1 (also known as YKL-40), fractalkine (FKN), soluble tumour necrosis factor receptor-1 (sTNF-R1), interleukin-1ß, and transforming growth factor-ß1 were measured on the day of neuroimaging. Clinical data were obtained from medical records and interviewing patients and reliable others. RESULTS: We recruited 31 patients with a mean age of 29.5 years. In multivariate regression analysis, plasma level YKL-40, a chemokine, was the most common inflammatory marker among these measurements displaying significantly negative association with the volume of various brain subareas across the frontal, temporal, and parietal lobes. Higher YKL-40 and sTNF-R1 levels were both significantly associated with lower volumes of the left anterior cingulum, left frontal lobe, right superior temporal gyrus, and supramarginal gyrus. A greater number of total lifetime mood episodes were also associated with smaller volumes of the right caudate nucleus and bilateral frontal lobes. CONCLUSIONS: The volume of brain regions known to be relevant to BD-I may be diminished in relation to higher plasma level of YKL-40, sTNF-R1, and more lifetime mood episodes. Macrophage and macrophage-like cells may be involved in brain volume reduction among BD-I patients.