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Objectives: Although alcohol dependence is highly prevalent in patients with bipolar disorder, the causal relationship is not yet well-established. This study estimated the incidence of alcohol dependence in a nationwide bipolar disorder cohort and examined risk factors for alcohol dependence., Methods: Patients aged 15-65 years with consistent bipolar disorder who had their first psychiatric admission between 1999 and 2012 ( n  = 21,791) were enrolled from the National Health Insurance Research Database in Taiwan. We calculated the adjusted incidence rate ratio of alcohol dependence in the bipolar cohort relative to the general population after stratification by age and sex. In the nested case-control study, we included patients with incident alcohol dependence as cases and four age- and sex-matched controls for each case to analyze health care utilization, comorbidities and concomitant medications between them., Results: We identified 1261 patients with bipolar disorder with incident alcohol dependence. Relative to the general population, the adjusted incidence rate ratio of alcohol dependence was 9.20 in the bipolar cohort. All adjusted incidence rate ratios were high across all age subgroups. Cases had higher psychiatric and nonpsychiatric health care utilization than did controls. Multivariate analysis revealed that cases tended to have cardiovascular disease, diabetes mellitus, chronic hepatic disease, pneumonia and delirium before alcohol dependence diagnosis. Cases had higher psychiatric comorbidities, namely drug-induced mental disorders, anxiety disorder, personality disorder, adjustment disorder and sleep disorder., Conclusion: The bipolar cohort had a higher incidence of alcohol dependence. We identified specific groups with a high risk of alcohol dependence. Additional strategies for early detection, treatment and intervention for alcohol dependence should be developed.

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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.

Background : Evidence of patterns of medical utilization and distribution of comorbidities among individuals using methamphetamine remains limited Objective : This study aims to investigate changes in medical utilization and comorbidities before and after a diagnosis of methamphetamine use disorder. Methods : A total of 3321 cases (79% were male) of methamphetamine use disorder between January 1, 1996, and December 31, 2012, were identified from Psychiatric Inpatient Medical Claims database in Taiwan. Information was collected on demographics, diagnoses, and medical utilizations. The date of newly diagnosed with methamphetamine use disorder was defined as the baseline. Mirror-image study design was used to compare changes in medical utilization and comorbidities between the pre-baseline period (within 1 year before diagnosis) and the post-baseline period (within 1 year after diagnosis). Conditional logistic regression was used to estimate changes in medical utilization and comorbidities. Results : Most cases (77%) were first identified in a psychiatric department. There is a significant increase ( P < .001) in psychiatric admission (odds ratio[OR] = 2.19), psychiatric emergency visits (OR = 1.31), and psychiatric outpatient visits (OR = 1.15) after diagnosis. Multivariable analysis revealed significantly increased risks ( P < .001) of non-methamphetamine drug induced mental disorders (adjusted OR[aOR] = 29.47), schizophrenia (aOR = 2.62), bipolar disorder (aOR = 2.14), organic mental disorder (aOR = 1.82), and upper respiratory tract infection (aOR = 2.03) after diagnosis. Conclusions : We found significant increases of medical utilization and psychiatric comorbidities after diagnosed with methamphetamine use disorder. These findings may reflect the problem of delayed diagnosis and treatment. Enhancement of early identification of methamphetamine use disorder in general practice is required for early intervention and decreased subsequent morbidities.

The search for susceptibility genes underlying the heterogeneous bipolar disorder has been inconclusive, often with irreproducible results. There is a hope that narrowing the phenotypes will increase the power of genetic analysis. Early-onset bipolar disorder is thought to be a genetically homogeneous subtype with greater symptom severity. We conducted a genome-wide association study (GWAS) for this subtype in bipolar I (BPI) disorder. Study participants included 1779 patients of Han Chinese descent with BPI disorder recruited by the Taiwan Bipolar Consortium. We conducted phenotype assessment using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry and prepared a life chart with graphic depiction of lifetime clinical course for each of the BPI patient recruited. The assessment of onset age was based on this life chart with early onset defined as ≤20 years of age. We performed GWAS in a discovery group of 516 early-onset and 790 non-early-onset BPI patients, followed by a replication study in an independent group of 153 early-onset and 320 non-early-onset BPI patients and a meta-analysis with these two groups. The SNP rs11127876, located in the intron of CADM2, showed association with early-onset BPI in the discovery cohort (P = 7.04 × 10 -8 ) and in the test of replication (P = 0.0354). After meta-analysis, this SNP was demonstrated to be a new genetic locus in CADM2 gene associated with early-onset BPI disorder (P = 5.19 × 10 -8 ).

Objective: The authors investigated the distributions and trajectories of physical illnesses preceding the diagnosis of bipolar disorder with comparison to schizophrenia and general populations., Methods: Using data from the Taiwan National Health Insurance Research Database entered from 1996 to end of 2012, we identified 13,079 patients newly diagnosed as having bipolar disorder between the age of 13 and 40 years (ie, cases). For each case with bipolar disorder, two age- and sex- and diagnosis year- schizophrenia comparisons (n=26,158)(n=26,158) and four age- and sex-matched comparisons representing the general population (n=52,316)(n=52,316) were randomly selected from the cohort. Multivariate conditional logistic regression analyses were conducted to estimate the risk of physical illness before the diagnosis (index date). Variables exhibiting a powerful association (p<0·001) were retained in the final model., Results: During the year before diagnosis, patients with newly diagnosed bipolar disorder had a higher risk of numerous physical illnesses across the cardiovascular, respiratory, gastrointestinal, endocrine/metabolic, and musculoskeletal/integument systems compared with those with schizophrenia and the general population. Trends in the risk of specific physical illnesses, mainly hypertension, heart disease, asthma, ulcer disease, hyperlipidemia, and connective tissue disease, were increased across the 3-year prodromal phase of bipolar disorder relative to schizophrenia., Conclusions: Intriguingly, physical illnesses before the diagnosis of bipolar disorder are pervasive with higher risk. Moreover, the trajectories of physical illnesses markedly differ from those of schizophrenia before full manifestation., (Copyright © 2020. Published by Elsevier B.V.)

Aim: Home care case management (CM) is the main intervention for patients with severe mental disorders (SMDs) requiring outreach care. This study investigated the long-term mortality outcome and associated risk factors in patients who received home care CM., Methods: This nationwide study enrolled patients who received home care CM ( n  = 10,255) between 1 January 1999 and 31 December 2010. Each patient was followed up from the baseline (when patients underwent home case CM for the first time during the study period) to the censor (i.e. mortality or the end of the study). We calculated the standardized mortality ratio (SMR) and presented by age and diagnosis. Multivariate regression was performed to assess independent risk factors for mortality., Results: Among 10,255 patients who received home care CM, 1409 died during the study period; the overall SMR was 3.13. Specifically, patients with organic mental disorder had the highest SMR (4.98), followed by those with schizophrenia (3.89), major depression (2.98), and bipolar disorder (1.97). In the multivariate analysis, patients with organic mental disorder or dementia had the highest risk, whereas the mortality risk in patients with schizophrenia was comparable to that in patients with bipolar disorder or major depression. Deceased patients had a significantly higher proportion of acute or chronic physical illnesses, including cancer, chronic hepatic disease, pneumonia, diabetes mellitus, cardiovascular disease, and asthma., Conclusion: This study presented the gap of mortality in patients with SMDs receiving home care CM in Taiwan. We highlight the need for effective strategies to improve medical care for this specified population.

Objectives: Patients with bipolar disorder are at high risk of cardiovascular diseases. Among cardiovascular diseases, coronary heart disease and stroke are the leading causes of premature death and both share the pathogenesis of arterial atherosclerosis. Increased carotid intima-media thickness is sensitive for detecting early atherosclerosis and a practical index for predicting cardiovascular diseases. However, few studies investigated carotid intima-media thickness in adults with bipolar disorder. We attempted to determine the factors associated with carotid intima-media thickness in adults with bipolar disorder., Methods: The euthymic out-patients with bipolar I disorder aged over 20 years were recruited to measure the carotid intima-media thickness value through B-mode carotid ultrasound. Those with any psychiatric disorder, acute or life-threatening medical condition were excluded. All clinical information was obtained by reviewing medical records and directly interviewing patients with reliable others., Results: Of the 106 participants with a mean age of 44.5 years, 40.6% ( N  = 43) had concurrent cardiovascular/endocrine/metabolic diseases. A multivariate regression indicated that higher assumed daily lithium dosage was significantly associated with a decreased carotid intima-media thickness in the whole sample. In the young subgroup (⩽45 years old, N  = 63), higher current daily lithium dosage and lower body mass index were associated with lower carotid intima-media thickness. In those without concurrent cardiovascular/endocrine/metabolic diseases, higher ratio of first-generation antipsychotics exposure in relation to illness chronicity was associated with higher carotid intima-media thickness, after controlling for body mass index or age., Conclusion: Lithium treatment may be associated with less progression in carotid intima-media thickness and the reduced risk for atherosclerosis in adults with bipolar disorder, including those with high cardiovascular disease risk. In addition to age and body mass index, antipsychotics may increase carotid intima-media thickness even in the low cardiovascular disease-risk patients.

Objective: Data on the incidence and risk factors of sudden cardiac death in patients with bipolar disorder are lacking in the literature., Methods: By using data from the Taiwan National Health Insurance Research Database and Department of Health Death Certification System between 2000 and 2016, we conducted a prospective national cohort study to determine the incidence and risk factors of sudden cardiac death in bipolar disorder patients. The study cohort included 46,490 patients with bipolar disorder, 467 of whom experienced sudden cardiac death., Results: Stratified analyses showed that the standardized mortality ratios (SMRs) of sudden cardiac death were all above 1.00 across each age interval, with the highest SMR in patients aged <30 years (31.96, 95% CI: 20.47-47.55). Notably, hypertension raised the risk of sudden cardiac death in both patients aged <50 years (1.85, 95% CI: 1.23-2.79) and aged ≥50 years (1.44, 95% CI: 1.14-1.83). In addition, venous and lymphatic disorders (1.97, 95% CI: 1.23-3.16), and alcohol use-related disorder (2.34, 95% CI: 1.62-3.38) elevated the risk of sudden cardiac death in patients aged <50 years. Congestive heart failure (1.59, 95% CI: 1.13-2.23) and dementia (1.75, 95% CI: 1.30-2.35) increased the risk of sudden cardiac death in patients aged ≥50 years., Conclusions: The risk of sudden cardiac death is remarkably high in bipolar disorder patients across the lifespan. Prevention strategies specific to individuals with bipolar disorder are urgently required., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: Older community-dwelling patients with severe mental illness (SMI), particularly those with illness onset at young age, constitute a group of survivors with unique long-term care needs. Using an Asian sample in Taiwan, we attempted to find out the differences in outcomes related to physical health, cognition, and social functioning between older community-dwelling adults with bipolar disorder and schizophrenia with early age onset., Methods: Community-dwelling patients aged >50 years with bipolar I disorder or schizophrenia whose illness developed before the age of 40 years were recruited. Clinical data were obtained by reviewing all available medical records and by interviewing the patients and their reliable family members. Medical morbidities, Mini-Mental State Examination (MMSE), Cumulative Illness Rating Scale for Geriatrics (CIRS-G), and Global Assessment of Functioning (GAF) scores were compared between the two groups., Results: In total, 113 bipolar patients and 104 schizophrenic ones (mean ages = 59.8 and 59.2 years, respectively) became the final subjects. The rates of cognitive impairment (MMSE score <24) were comparable in bipolar disorder (26.5%) and schizophrenia (24.0%) and the mean MMSE scores did not significantly differ from each other. The concurrence (54.9%) of cardiovascular disease (CVD) in the bipolar group was also similar to 51.0% in the schizophrenic one. In a multiple logistic regression analysis, the bipolar group exhibited significantly higher CIRS-G total scores (95% confidence interval (CI) for odds ratio (OR) = 1.01-1.27), body mass index (95% CI for OR = 1.02-1.21), and GAF scores (95% CI for OR = 1.04-1.14)., Conclusion: Given better social functioning and the same cognitive function in older community-dwelling patients with bipolar disorder, they may remain at higher risk for obesity and medical morbidity than schizophrenic patients. Treatments targeting cognitive impairment and CVDs across their life span are both necessary to promote the health of community-dwellers with SMI., (© 2020 Japanese Psychogeriatric Society.)

Background: Research on the risk of stroke following the use of mood stabilisers specific to patients with bipolar disorder is limited.AimsIn this study, we investigated the risk of stroke following the exposure to mood stabilisers in patients with bipolar disorder., Method: Data for this nationwide population-based study were derived from the Taiwan National Health Insurance Research Database. Among a retrospective cohort of patients with bipolar disorder (n = 19 433), 609 new-onset cases of stroke were identified from 1999 to 2012. A case-crossover study design utilising 14-day windows was applied to assess the acute exposure effect of individual mood stabilisers on the risk of ischaemic, haemorrhagic and other types of stroke in patients with bipolar disorder., Results: Mood stabilisers as a group were significantly associated with the increased risk of stroke in patients with bipolar disorder (adjusted risk ratio, 1.26; P = 0.041). Among individual mood stabilisers, acute exposure to carbamazepine had the highest risk of stroke (adjusted risk ratio, 1.68; P = 0.018), particularly the ischaemic type (adjusted risk ratio, 1.81; P = 0.037). In addition, acute exposure to valproic acid elevated the risk of haemorrhagic stroke (adjusted risk ratio, 1.76; P = 0.022). In contrast, acute exposure to lithium and lamotrigine did not significantly increase the risk of any type of stroke., Conclusions: Use of carbamazepine and valproic acid, but not lithium and lamotrigine, is associated with increased risk of stroke in patients with bipolar disorder.Declaration of interestNone.

Objective Serum lipid levels may be associated with the affective severity of bipolar disorder, but data on lipid profiles in Asian patients with bipolar disorder and the lipid alterations in different states of opposite polarities are scant. We investigated the lipid profiles of patients in the acute affective, partial, and full remission state in bipolar mania and depression. Methods The physically healthy patients aged between 18 and 45 years with bipolar I disorder, as well as age-matched healthy normal controls were enrolled. We compared the fasting blood levels of glucose, cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein of manic or depressed patients in the acute phase and subsequent partial and full remission with those of their normal controls. Results A total of 32 bipolar manic patients (12 women and 20 men), 32 bipolar depressed participants (18 women and 14 men), and 64 healthy control participants took part in this study. The mean cholesterol level in acute mania was significantly lower than that in acute depression (p < 0.025). The lowest rate of dyslipidemia (hypertriglyceridemia or low high-density lipoprotein cholesterol) was observed in acute bipolar mania. Conclusion Circulating lipid profiles may be easily affected by affective states. The acute manic state may be accompanied by state-dependent lower cholesterol and triglyceride levels relative to that in other mood states.

Aim: Patients with bipolar disorder (BD) tend to have poorer outcomes after pneumonia and could have a higher risk for recurrence of pneumonia. We aimed to investigate the incidence and risk factors of recurrent pneumonia in patients with BD., Methods: In a nationwide cohort of BD patients (derived from the National Health Insurance Research Database in Taiwan) who were hospitalized for pneumonia between 1996 and 2012, we identified 188 patients who developed recurrent pneumonia after a baseline pneumonia episode. Applying risk-set sampling at a 1:2 ratio, 353 matched controls were selected from the study cohort. We used multivariate conditional logistic regression analysis to explore the association between recurrent pneumonia and physical illness, concomitant medications, and psychotropic drugs., Results: The findings showed that the incidence of recurrent pneumonia in BD was 6.60 cases per 100 person-years, which was higher than that in the general population. About 10% (9.24%) of cases with recurrent pneumonia died within 30 days of hospitalization. Patients had increased risk of recurrent pneumonia if they had hypertension, diabetes mellitus, cancer, or asthma. Conversely, psychotropic drugs, both first- and second-generation antipsychotics, which are known to increase susceptibility to baseline pneumonia, were not associated with risk of pneumonia recurrence., Conclusion: We found an excess incidence of recurring pneumonia in patients with BD, and this risk was associated with pre-existing medical conditions but not psychotropic agents. Physicians should carefully consider the comorbid medical conditions of patients with BD that could lead to recurrent pneumonia., (© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.)

Aim: The change in psychiatric diagnoses in clinical practice is not an unusual phenomenon. The interchange between the diagnoses of schizophrenic disorders and bipolar disorders is a major clinical issue because of the differences in treatment regimens and long-term prognoses. In this study, we used a nationwide population-based sample to compare the diagnostic consistency and interchange rate between schizophrenic disorders and bipolar disorders., Methods: In total, 25 711 and 11 261 patients newly diagnosed as having schizophrenic disorder and bipolar disorder, respectively, were retrospectively enrolled from the Psychiatric Inpatient Medical Claims database between 2001 and 2005. We followed these two cohorts for 7 years to determine whether their diagnoses were consistent throughout subsequent hospitalizations. The interchange between the two diagnoses was analyzed., Results: In the schizophrenic disorder cohort, the overall diagnostic consistency rate was 87.3% and the rate of change to bipolar disorder was 3.0% during the 7-year follow-up. Additional analyses of subtypes revealed that the change rate from schizoaffective disorder to bipolar disorder was 12.0%. In the bipolar disorder cohort, the overall diagnostic consistency rate was 71.9% and the rate of change to schizophrenic disorder was 8.3%., Conclusion: Changes in the diagnosis of a major psychosis are not uncommon. The interchange between the diagnoses of schizophrenic disorders and bipolar disorders might be attributed to the evolution of clinical symptoms and the observation of preserved social functions that contradict the original diagnosis. While making a psychotic diagnosis, clinicians should be aware of the possibility of the change in diagnosis in the future., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

Aim: We attempted to determine risk factors, particularly pathophysiological changes, for early cardiovascular mortality in bipolar disorder (BD)., Methods: A total of 5416 inpatients with bipolar I disorder were retrospectively followed through record linkage for cause of death. A total of 35 patients dying from cardiovascular disease (CVD; ICD 9: 401-443) before the age of 65 years were identified. Two living BD patients and two mentally healthy adults were matched with each deceased patient as control subjects according to age (±2 years), sex, and date (±3 years) of the final/index admission or the date of general health screening. Data were obtained through medical record reviews., Results: Eighty percent of CVD deaths occurred within 10 years following the index admission. Conditional logistic regression revealed that the variables most strongly associated with CVD mortality were the leukocyte count and heart rate on the first day of the index hospitalization, as the deceased BD patients were compared with the living BD controls. Systolic pressure on the first day of the index hospitalization can be substituted for heart rate as another risk factor for CVD mortality., Conclusion: It is suggested that systemic inflammation and sympathetic overactivity during the acute phase of BD may be risk factors for early CVD mortality., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

Objective: Patients with bipolar disorder are at a high risk for comorbid alcohol use disorder, and both disorders are associated with poor outcomes and multiple morbidities. This study aimed to explore not only the psychosocial functioning and psychopathological outcomes but also the medical morbidity of patients with bipolar disorder with and without alcohol use disorder., Methods: Outpatients with bipolar I disorder (DSM-IV) were recruited from a psychiatric teaching hospital in Taiwan (N = 393). Data on psychiatric symptoms, psychosocial functioning, and physical health were obtained through interviews with patients and collaterals, patient self-report, and medical record reviews., Results: Participants had a mean age of 41.1 years (SD = 11.9) and were mostly female (n = 255, 64.9%). Fewer than 10% (n = 34, 8.7%) met criteria for alcohol use disorder, and these participants were more likely to be male, to smoke, and to have a history of rapid cycling, higher mean body mass index, and higher incidences of gastrointestinal and hepatobiliary morbidities. A multiple logistic regression analysis revealed that patients with, versus those without, alcohol use disorder were more prone to gastrointestinal diseases (adjusted OR = 4.25, 95% CI [1.44-12.53], p <.01), hepatobiliary diseases (adjusted OR = 3.14, 95% CI [1.20-8.25], p <.025), and history of rapid cycling (adjusted OR = 2.53, 95% CI [0.91-7.01], p <.075)., Conclusions: Comorbid alcohol use disorders may have a stronger impact on physical health than on psychosocial or psychopathological outcomes of patients with bipolar disorder.

Objective: Coronary heart disease (CHD) remains the principal cause of excessive natural deaths in bipolar patients; however, electrocardiogram analyses and clinical features predicting CHDs in elderly bipolar patients remain limited. We sought to examine the relationship between CHDs, as determined by electrocardiogram, and clinical characteristics., Methods: We recruited bipolar I outpatients Diagnostic Statistical Manual of Mental Health (DSM-IV) who were more than 60 years old and had at least one psychiatric admission. Subjects were divided into two groups based on the presence or absence of CHD diagnosed by electrocardiogram analysis at entry of study. Clinical data were obtained by a combination of interviewing patients and family members and retrospectively reviewing medical records of the most recent acute psychiatric hospitalization., Results: Eighty patients with bipolar disorder were enrolled. A total of 20 (25%) in the study had CHDs. The mean age at the time of entry into study was 67.6 ± 5.5 years old in group with CHD and 66.8 ± 6.8 years old in that without CHD. Among the clinical characteristics examined, higher mean levels of serum sodium and thyroxine during the acute affective phase as well as more first-degree family history with bipolar disorder were related to having CHD, particularly the serum sodium level., Conclusions: About one fourth of old bipolar patients have CHDs in both Asian and Western populations. Aging patients with bipolar disorder may have unique clinical factors (e.g., hypernatremia or elevated thyroxine) related CHDs that could warrant special attention in their psychiatric and medical care to minimize cardiovascular disease and mortality., (© The Author(s) 2015.)

Objective: A proinflammatory phase with various immunomodulatory mechanisms has been noted in bipolar mania and major depression. Weight gain and increased production of leptin may be associated with immunomodulation and insulin resistance in bipolar disorder. However, immunomodulation and its linkage with leptin and insulin in the depressive episode of bipolar disorder remain unclear. We investigated alterations in inflammatory markers and their relationship with leptin and insulin levels in patients with phases of bipolar disorder from acute depression to full remission., Methods: Thirty-two physically healthy bipolar I depressed patients aged <45 years and age- and sex-matched healthy controls participated in this study. We measured their circulating levels of leptin, insulin, high-sensitivity C-reactive protein (hs-CRP), soluble interleukin-2 receptor (sIL-2R), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor 1 (sTNF-R1), and interleukin-1 receptor antagonist (IL-1Ra) in three phases, i.e., acute depression, subsequent partial remission, and full remission., Results: In acute depression, subsequent partial remission, and full remission, patients with bipolar disorder had significantly higher mean levels of hs-CRP, IL-1Ra, sTNF-R1, and sIL-2R compared with control subjects. The IL-1Ra and sTNF-R1 levels in various affective phases were significantly correlated to body mass index, leptin level, circulating lipids, and medication status. The sIL-2R levels in the three affective phases were all independent of other inflammatory markers and clinical and laboratory variables. Patients showed no alteration of sIL-6R levels through the depressive episode., Conclusions: Patients with bipolar disorder in depressive episodes may exhibit persistent inflammation with elevated levels of hs-CRP, IL-1Ra, sTNF-R1, and sIL-2R but not sIL-6R from the acute phases to full remission. Only sIL-2R production seems to be tightly linked with the pathophysiology of bipolar depression and is independent of insulin and leptin levels., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Like mood stabilizers, most second-generation antipsychotics are widely used to treat patients with bipolar disorder, yet their safety is still a concern. This study explored the association between antipsychotics and mood stabilizers and the risk of pneumonia, and it provides evidence-based information for clinical practice., Method: In a nationwide cohort of bipolar patients (ICD-9 codes 296.0 to 296.16, 296.4 to 296.81, and 296.89) derived from the National Health Insurance Research Database in Taiwan, who were admitted between July 1, 1998, and December 31, 2006 (N = 9,999), we identified 571 patients who developed pneumonia (ICD-9 codes 480 to 486 and 507) requiring hospitalization defined as cases. On the basis of risk-set sampling in a 1:4 ratio, 2,277 matched controls were selected from the same cohort. We used conditional logistic regression to assess the association between drug exposure and pneumonia and sensitivity analyses to validate the association., Results: Current use of several antipsychotics separately, including olanzapine (adjusted risk ratio [RR] = 2.97, P < .001), clozapine (RR = 2.59, P < .01), and haloperidol (RR = 3.68, P < .001), is associated with a dose-dependent increase in the risk of pneumonia. Interestingly, lithium has a dose-dependent protective effect from pneumonia. Among certain drug combinations, olanzapine plus carbamazepine had the highest risk (RR = 11.88, P < .01), followed by clozapine plus valproic acid (RR = 4.80, P < .001)., Conclusions: Several antipsychotics, but not mood stabilizers, were associated with the risk of pneumonia, which deserves our concern regarding patient safety. Some of the combinations of therapy resulted in synergy of risk., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Background: Weight gain and increased production of leptin may be associated with immuno-modulation and insulin resistance in bipolar disorder. The links among inflammatory markers, leptin, and insulin of bipolar patients from acute mania to full remission remain unclear., Methods: Thirty-three healthy, bipolar I patients under 45 years of age were enrolled. We measured the circulating levels of high-sensitivity C-reactive protein (hs-CRP), anti-inflammatory mediators (interleukin-1 receptor antagonist [IL-1Ra] and soluble tumor necrosis factor receptor 1 [sTNF-R1]), leptin, and insulin during acute mania and subsequent partial and full remission. The results were compared with 33 age- and gender-matched healthy subjects., Results: The levels of IL-1Ra and hs-CRP of bipolar patients in both acute mania and partial remission were significantly higher than their levels of control subjects. The hs-CRP level of bipolar patients was also elevated in full remission. The elevation of IL-1Ra and hs-CRP levels in acute mania was independent of each other. They were also independent of the body mass index (BMI) and levels of leptin and insulin measurements. The levels of leptin were all positively associated with insulin levels in the normal subjects and bipolar patients in three phases. However, a significant relationship between leptin and immunoparameter was only seen in full remission with sTNF-R1 (r=0.51). Furthermore, IL-1Ra was inversely correlated with sTNF-R1 (r=-0.37, p<0.05) during partly remission, and while levels of IL-1Ra tended to normalize when patients remitted, levels of hs-CRP and sTNF-R1 showed the opposite trend., Conclusions: Activated inflammation was found in acute mania, as evidenced by high levels of IL-1Ra, hs-CRP, and sTNF-R1. The production of leptin may be more tightly linked to insulin than the immunomodulators. Chronic inflammation may exist in bipolar patients and is reflected by elevations of IL-1Ra and hs-CRP levels in acute mania and persistent higher hs-CRP in full remission., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: The authors investigated the differences in cognitive function, medical burden, and sociodemographic characteristics between elderly community-dwelling bipolar patients and age-matched and education-matched normal individuals., Design: Case-control study., Setting: Taipei Medical University Hospital, with 75 psychiatric beds, and Taipei City Psychiatric Center-a 612-bed psychiatric teaching hospital providing comprehensive psychiatric services., Participants: Eighty-two euthymic outpatients with bipolar I disorder aged older than 60 years received assessment for research purpose, 59 of whom were matched with one normal control for age and years of education., Measurements: All subjects had measurements of cognitive function (Clock-drawing test and Mini-Mental State Examination [MMSE]). Medical morbidity and health condition were according to the medical records, results of free annual elderly health examination, and physical examination on research interviewing., Results: Elderly bipolar patients were found to be more likely than the comparison group to have diabetes mellitus (27.1%), atopic diseases (20.3%), abnormal education-adjusted MMSE scores (32.2%), smoking habit (23.7%), and unfavorable social functioning (22%). Despite having noticeably higher heart rates, the bipolar patients' mean systolic blood pressure and prevalence of hypertension (44.1%) were significantly lower than those of the comparison group., Conclusions: Although community-dwelling elderly patients with bipolar disorder seem to be characterized by a greater likelihood of developing cognitive dysfunction and concurrent diabetes mellitus, there is no apparent increase in the morbidity of circulatory diseases, particularly less hypertension among those without previous dementia.

Objective: Many of the prior mortality studies on bipolar disorder have emerged primarily from the larger health service groups, with a tendency to focus on suicide alone. This study examines personal and clinical characteristics of bipolar patients in Taiwan in order to identify the factors associated with early natural death., Method: Bipolar patients admitted to a psychiatric hospital in Taiwan between 1987 and 2002 were retrospectively followed through record linkage for cause of death. One living bipolar individual was matched to each deceased patient as a control subject for age, gender, and date of index admission. Clinical data and the results of laboratory examinations during the last period of hospitalization were obtained through a review of medical records., Results: In a total of 60 natural deaths, the principal cause was circulatory disease (33.3%). Conditional logistic regressions revealed that the variables most strongly associated with natural deaths were years of antipsychotic treatment prior to the last visit (95% CI for odds ratio [OR] = 0.77 to 0.98), serum alanine aminotransferase levels (95% CI for OR = 1.02 to 1.25), and leukocyte counts (95% CI for OR = 1.01 to 2.50). Years of lithium treatment (95% CI for OR = 0.74 to 0.97) may be substituted for antipsychotic treatment as a protective factor., Conclusions: Systemic inflammation and nonhepatic tissue damage during the acute phase of bipolar disorder may be risk factors for early natural death. Psychiatric treatment, including medication with antipsychotics or lithium, could be a factor in protecting against early natural death.

Background: Because Chinese bipolar patients in Taiwan, unlike Western patients, exhibit low comorbidity of substance abuse disorders, this retrospective and controlled study of completed suicide in bipolar patients explored the risk period and other risk factors for such an outcome., Method: All acute inpatients with bipolar I disorder (DSM-IV) were followed from date of admission after January 1, 1985, until December 31, 1996, in regard to their death. The patients were followed by record linkage to the Death Certification System in Taiwan, which was issued throughout 1996. Nineteen female and 24 male patients died as a result of suicide within this period. Forty-one of 43 of the total number of patients were matched with 1 living bipolar individual (as a control subject) for age, sex, and date of admission. Demographic data, family history, and clinical characteristics were collected from the patients' medical records and were formally confirmed at every admission., Results: The lifetime prevalence of alcohol/drug use disorders was 14.6% in suicide completers. Thirty suicide completers (69.8%) revealed duration of illness of at least 7 years at the time of death. The latency period from the presumed time of onset to completing suicide averaged 12.2 years. The mean age at the first suicide attempt was 31.1 years among 43 completers and 10 living controls who had ever attempted suicide. Conditional logistic regression revealed a strong association of suicide (p < .001) with the following factors: onset with mood-congruent psychotic feature (adjusted odds ratio [OR] = 0.18, 95% confidence interval [CI] = 0.04 to 0.74), positive first-degree family history of completed suicide (adjusted OR = 15.08, 95% CI = 1.39 to 163.50), and making a suicide attempt at least once in 7 years of illness (adjusted OR = 4.96, 95% CI = 1.03 to 23.83). There appeared to be no significant difference in fasting levels of serum cholesterol or blood sugar between the suicide completers and the living controls., Conclusion: The first 7 to 12 years subsequent to onset of affective illness and age less than 35 years may be the high-risk periods for suicide in bipolar disorder. Those bipolar disorder patients who have a first-degree family history of suicide and who have more suicide attempts (at least once in 7 years of illness) are likely to commit suicide. Symptomatology (e.g., mood congruence of psychotic features) at the time of presumed disease onset may potentially differentiate subgroups of bipolar patients with various levels of suicide risk.

Background: Few studies have analyzed healthcare utilization before suicide among individuals with attention-deficit/hyperactivity disorder (ADHD). This study examined the pattern of healthcare utilization and comorbidities shortly before death among patients with ADHD who died by suicide and compared these data with those of living controls. This study used Taiwan's National Health Insurance Research Database to identify patients with ADHD (N = 379,440) between January 1, 2001, and December 31, 2016. Subsequently, the researchers identified 159 suicide decedents by linking each patient with the National Mortality Database. By conducting a nested case–control study with risk-set sampling from the ADHD cohort, the researchers selected 20 age- and sex-matched controls (n = 3180) for each patient who died by suicide (cases). The researchers then applied conditional logistic regression to investigate differences in healthcare utilization as well as psychiatric and physical comorbidities between case patients and controls. Case patients had higher healthcare utilization within 3 months before suicide, particularly in the psychiatry, emergency, internal medicine, neurosurgery, and plastic surgery departments. These patients also had higher risks of psychiatric comorbidities, including schizophrenia, bipolar disorder, depressive disorder, and sleep disorder, as well as physical comorbidities such as hypertension and other forms of heart disease. Among patients with ADHD, suicide decedents had increased healthcare utilization and higher risks of specific psychiatric and physical comorbidities than living controls. Thus, for suicide prevention among individuals with ADHD, suicide risk must be detected early and comorbidities should be adequately managed. [ABSTRACT FROM AUTHOR]

Affective switch is an important clinical issue when treating bipolar disorder. Though commonly seen in clinical practice, the benefits of prescribing antidepressants for bipolar depression are still controversial. To date, there have been few genetic studies and no genome-wide association study (GWAS), focusing on manic switch following bipolar depression. This study aims to investigate the effects of individual genomics and antidepressant medication on the risk of manic switch in bipolar I disorder (BPI). A total of 1004 patients with BPI who had at least one depressive episode with complete data on antidepressant treatment and outcome were included. Clinical assessment of mania and depression was performed by trained psychiatric nurses and psychiatrists using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN), and the diagnosis of BPI was made according to DSM-IV criteria. Manic switch was defined as a manic episode occurring within eight weeks of remission from an acute depressive episode. The age at first depressive episode of the study patients was 30.7 years (SD 12.5) and 56% of all patients were female. GWAS was carried out in a discovery group of 746 patients, followed by replication in an independent group of 255 patients. The top SNP rs10262219 on chromosome 7 showed the strongest allelic association with manic switch (p = 2.21 × 10−7) in GWAS, which was however not significantly replicated. Antidepressant treatment significantly (odds ratio 1.7; 95% CI 1.3–2.2; p < 0.001) increased the risk of manic switch. In logistic regression analysis, the CC genotype of rs10262219 (odds ratio 3.0; 95% CI 1.7–5.2) and antidepressant treatment (odds ratio 2.3; 95% CI 1.4–3.7) significantly increased the risk of manic switch with a joint effect (odds ratio 5.9; 95% CI 3.7–9.4). In conclusion, antidepressant medication and rs10262219 variants jointly increased the risk of manic switch after bipolar depression. [ABSTRACT FROM AUTHOR]

We characterized the heterogeneity and risk factors of cognitive decline in euthymic bipolar disorder (BD), and their magnitude of associations with subjective daily functions. In this retrospective cohort, BD type I patients (N = 128) were followed for an average of 6.5 years. Intelligence quotient (IQ) at index date was recorded, and premorbid IQ was estimated. We used Brief Assessment of Cognition in Affective Disorders (BAC-A) to assess cognition at follow-up. We evaluated current functions with World Health Organization Disability Assessment Schedule 2.0. Clinical and sociodemographic factors were examined for their independent effects on longitudinal cognitive decline. In addition, we employed multivariate adaptive regression spline to detect inflection points for the nature of slope changes in cognitive decline among BD patients. During follow-up years, 21 BD patients (16.4%) showed longitudinal cognitive decline. In cognitive decline group, all cognitive domains of BAC-A were significantly worsened. We found that density of episodes with psychotic features was an independent risk factor for cognitive decline after adjusted for age, gender and dose of mood stabilizer. After the age of 42 years, a steeper cognitive change was observed in the cognitive decline group. The correlation pattern between cognitive domains and functional outcomes differed between patients with and without cognitive decline. The present study characterized cognitive heterogeneity longitudinally in BD patients. As density of episodes play roles for cognitive decline, our results emphasize the importance of relapse prevention. Our findings provide hints for future personalized interventions and facilitating genetic and biological studies for dissecting the heterogeneity of bipolar illness. [ABSTRACT FROM AUTHOR]

Background: Many studies have used Taiwan's National Health Insurance Research database (NHIRD) to conduct psychiatric research. However, the accuracy of the diagnostic codes for psychiatric disorders in NHIRD is not validated, and the symptom profiles are not available either. This study aimed to evaluate the accuracy of diagnostic codes and use text mining to extract symptom profile and functional impairment from electronic health records (EHRs) to overcome the above research limitations.Methods: A total of 500 discharge notes were randomly selected from a medical center's database. Three annotators reviewed the notes to establish gold standards. The accuracy of diagnostic codes for major psychiatric illness was evaluated. Text mining approaches were applied to extract depressive symptoms and function profiles and to identify patients with major depressive disorder.Results: The accuracy of the diagnostic code for major depressive disorder, schizophrenia, and dementia was acceptable but that of bipolar disorder and minor depression was less satisfactory. The performance of text mining approach to recognize depressive symptoms is satisfactory; however, the recall for functional impairment is lower resulting in lower F-scores of 0.774-0.753. Using the text mining approach to identify major depressive disorder, the recall was 0.85 but precision was only 0.69.Conclusions: The accuracy of the diagnostic code for major depressive disorder in discharge notes was generally acceptable. This finding supports the utilization of psychiatric diagnoses in claims databases. The application of text mining to EHRs might help in overcoming current limitations in research using claims databases. [ABSTRACT FROM AUTHOR]