The association between carotid atherosclerosis and treatment with lithium and antipsychotics in patients with bipolar disorder.

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.

State-dependent alterations of lipid profiles in patients with bipolar disorder.

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.

Risk factors for early cardiovascular mortality in patients with bipolar disorder.

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.

A Prognosis Tool Based on Fuzzy Anthropometric and Questionnaire Data for Obstructive Sleep Apnea Severity.

Obstructive sleep apnea (OSA) are linked to the augmented risk of morbidity and mortality. Although polysomnography is considered a well-established method for diagnosing OSA, it suffers the weakness of time consuming and labor intensive, and requires doctors and attending personnel to conduct an overnight evaluation in sleep laboratories with dedicated systems. This study aims at proposing an efficient diagnosis approach for OSA on the basis of anthropometric and questionnaire data. The proposed approach integrates fuzzy set theory and decision tree to predict OSA patterns. A total of 3343 subjects who were referred for clinical suspicion of OSA (eventually 2869 confirmed with OSA and 474 otherwise) were collected, and then classified by the degree of severity. According to an assessment of experiment results on g-means, our proposed method outperforms other methods such as linear regression, decision tree, back propagation neural network, support vector machine, and learning vector quantization. The proposed method is highly viable and capable of detecting the severity of OSA. It can assist doctors in pre-diagnosis of OSA before running the formal PSG test, thereby enabling the more effective use of medical resources.

Psychological Outcomes and Medical Morbidity of Patients With Bipolar Disorder and Co-Occurring Alcohol Use Disorder.

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.

Use of oximetry as a screening tool for obstructive sleep apnea: a case study in Taiwan.

Obstructive sleep apnea (OSA) is a relatively common disease in the general population. Patients with OSA have a high risk of various comorbid medical diseases. Polysomnography (PSG) is the current gold standard for diagnosing OSA but is time consuming and expensive. This study aims to identify a sensitive screening parameter that can be used by clinicians to determine the time of referral for PSG examination in Taiwan. Eighty-seven patients, including 67 males and 20 females, were included in this study. We divided the patients into two groups: training data (n = 58) and testing group (n = 29). Pearson χ(2) test was used to perform bivariate analysis, and a decision tree was used to build a model. The decision model selected the frequency of desaturation > 4% per hour (DI4) as the indicator of OSA influence. The testing data accuracy of the C4.5 decision tree was 82.80%. External data were also used to validate the model reliability. The accuracy of the external data was 95.96%. Approximately one-third of patients with DI4 between 11 and 33 suffered from OSA. This population requires further diagnosis. Oximetry is an important and widely available screening method in Taiwan. This study proposes the need for PSG referral if DI4 is between 11 and 33.

Neuroprogressive effects of lifetime illness duration in older adults with bipolar disorder.

OBJECTIVE: The aim of the present study was to examine the long-term effects of bipolar disorder (BD) on brain structure (gray matter volumes). METHODS: Fifty-four adults with BD [mean (standard deviation) age = 64.4 (5.4) years] underwent brain MR imaging along with comprehensive clinical assessment. Total gray matter, hippocampal, and amygdala volumes were extracted using methods developed through the Geriatric Neuroimaging Laboratory at the University of Pittsburgh (Pittsburgh, PA, USA). RESULTS: Lower total gray matter volumes were related to longer duration of BD, even when controlling for current age and cerebrovascular accident (CVA) risk/burden. Additionally, longer exposure to antipsychotic medication was related to lower gray matter volumes. Lower hippocampal volumes were related to total years of antipsychotic agent exposure and CVA risk/burden scores. Older age was related to lower total gray matter, hippocampal, and amgydala volumes. CONCLUSIONS: Our study of older adults with BD supports the understanding that BD is a neuroprogressive disorder with a longer duration of illness and more antipsychotic agent exposure related to lower gray matter volume.

Persistent inflammation and its relationship to leptin and insulin in phases of bipolar disorder from acute depression to full remission.

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.

The link between high-sensitivity C-reactive protein and orbitofrontal cortex in euthymic bipolar disorder.

OBJECTIVE: C-reactive protein (CRP), a marker of underlying low-grade inflammation, has been associated with the pathophysiology of bipolar disorder. Additionally, bipolar disorder may be accompanied by functional or structural cerebral alterations. We attempted to discover whether serum high-sensitivity CRP (hs-CRP) levels are linked to the structural volume change of a specific brain region along with cognitive performance. METHODS: We recruited 17 physically healthy patients with bipolar I disorder (DSM-IV), aged 18-45 years and euthymic, to undergo the Wisconsin Card Sorting Test (WCST) and volumetric magnetic resonance imaging at 1.5 T. The analytic method was based on the hidden Markov random field model with an expectation-maximization algorithm, and the volume of each brain region was presented as a percentage of the total intracranial volume. RESULTS: Among the various regions, only the orbitofrontal cortex had a significantly negative correlation with serum hs-CRP levels after adjustment for age and gender (left and right orbitofrontal cortex: r = -0.62, p < 0.01, and r = -0.67, p < 0.005, respectively). Regarding cognitive function, poor WCST performance was also associated with certain subregions of the orbitofrontal cortex. CONCLUSION: Elevation of serum hs-CRP levels, an indicator of inflammation, may be associated with reduced volume of the orbitofrontal cortex. Persistent inflammation in the euthymic phase of bipolar disorder may involve the pathogenesis or pathophysiology of alteration of the frontal pathway.

The risk factors for elderly patients with bipolar disorder having cerebral infarction.

OBJECTIVE: Patients with bipolar disorder are at high risk of developing strokes in the older life. Silent cerebral infarctions (SCIs) could be common in the elderly patients with bipolar disorder, but only small sample size reports are available. The purpose of this study was to assess the proportion of SCIs and determine the risk factors for cerebral infarction in elderly patients with bipolar disorder. METHODS: We recruited 43 patients with bipolar disorder over the age of 60 to undergo whole-brain magnetic resonance imaging (MRI). We divided them into 2 groups depending on whether infarction was present, and compared the potential variables of these 2 groups. RESULTS: There were 28 elderly patients with bipolar disorder (65.1%) having MRI-proven cerebral infarction. The SCIs were detected in 59.5% (N = 22) of 37 patients without a history of stroke, including 61.3% of 13 patients with late-onset age (>50 years) and 46.7% of 30 patients with typical-onset age (<50 years). Logistic regression revealed that comorbidity with metabolic diseases (95% confidence interval [CI] for odds ratio [OR] = 1.24-40.59) was most strongly associated with cerebral infarction. The leukocyte counts (95% CI for OR = 1.10-3.93) and fasting blood sugar (95% CI for OR = 1.00-1.07) during the most recent acute psychiatric admission may be substituted as the risk factors. CONCLUSIONS: Cerebral infarctions tend to be neglected in more than half of the elderly patients with bipolar disorder, regardless of their age at onset. Metabolic abnormality and systemic inflammation may be the risk factors.

Volumetric reduction in various cortical regions of elderly patients with early-onset and late-onset mania.

BACKGROUND: Few studies have examined alterations of the brain in elderly bipolar patients. As late-onset mania is associated with increased cerebrovascular morbidity and neurological damage compared with typical/early-onset mania, we investigated differences in the volume of various cortical regions between elderly patients with early-onset versus late-onset mania. METHODS: We recruited 44 bipolar patients aged over 60 years, who underwent volumetric magnetic resonance imaging at 1.5 T. The analytic method is based on the hidden Markov random field model with an expectation-maximization algorithm. We determined the volume of each cortical region as a percentage of the total intracranial volume. The cutoff age for defining early versus late onset was 45 years. RESULTS: The study participants consisted of 25 patients with early-onset mania and 19 patients with late-onset mania; their mean ages were 65.7 years and 62.8 years, respectively. The demographic variables of the two groups were comparable. The volumes of the left caudate nucleus (p = 0.022) and left middle frontal gyrus (p = 0.013) were significantly greater and that of the right posterior cingulate gyrus (p = 0.019) was significantly smaller in the late-onset group. More patients with late-onset mania had comorbid cerebrovascular disease (p = 0.072). CONCLUSIONS: The right posterior cingulate gyrus is smaller and the left caudate nucleus and left middle frontal gyrus are larger in patients with late-onset mania compared with those with early-onset mania. Volumetric change in brain regions may vary in elderly bipolar patients with early and late-onset mania.

Risk factors for early circulatory mortality in patients with schizophrenia.

Patients with schizophrenia have higher mortality and shortened life expectancy than the general population, and cardiovascular disease (CVD) accounts for up to 50% cases of early mortality in schizophrenia. We determined risk factors, particularly pathophysiological changes, for early circulatory mortality in schizophrenia. In this multi-institutional, nested, case-control study, we enrolled consecutive inpatients with schizophrenia admitted to three psychiatric hospitals in the northern Taiwan. Seventy-nine patients who died of CVD before 65 years of age were identified as cases through record linkage, and 158 controls were randomly selected in a 2:1 ratio through risk-set density sampling, after matching for age (±2 years), sex, and index admission (±3 years). Data were obtained through medical record reviews. At the time of death, the mean age of the patients was 47.5 years (standard deviation = 10.3). Conditional logistic regression revealed that the duration of antipsychotic treatment was significantly associated with a lower risk of early circulatory mortality, and leukocyte counts at index hospitalization were significantly associated with a higher risk. Systemic inflammation may be a risk factor for early circulatory mortality in schizophrenia, but antipsychotic treatment, in particular typical antipsychotic treatment, could be a protective factor.

Diabetes mellitus and first episode mania associated with cardiovascular diseases in patients with older-age bipolar disorder.

Patients with bipolar disorder (BD) are at high risk for developing cardiovascular diseases (CVDs) during aging process. However, investigations are lacking regarding the risk factors for CVDs specific to BD patients. The aim of this study was to examine the relationship between CVDs and traditional risk factors in association with the characteristics of BD in older age. Totally, we recruited 124 patients with BD-I (DSM-IV) who had at least one psychiatric admission and cardiologist-confirmed CVD diagnosis (ICD-9 code 401-414) at mean age of 61.7+4.9 years. Each case subject was matched with one BD-I patient without CVDs based on age, sex, and date of the most recent psychiatric admission (+2 years). Clinical data were obtained by retrospectively reviewing the medical record. A multiple logistic regression model showed that not only traditional risk factor (e.g., diabetes mellitus) but also non-traditional one associated with BD (e.g., first episode mania) significantly increased the risk of CVDs. Given the limitation of this cross-sectional study, longitudinal investigations are needed to elucidate the contributions of both traditional risk factors and the BD characteristics for CVD risk in patients with BD.

Physiological characteristics of patients with schizophrenia prematurely dying from circulatory diseases.

INTRODUCTION: Patients with schizophrenia before reaching geriatric age are at high risk of circulatory mortality. However, investigations are lacking on the characteristics of physiological measurement among these at-risk patients. METHODS: In this study, we followed acutely inpatients with schizophrenia disorder for cause of death through record linkage to the Death Certification System in Taiwan. Cases of patients who died because of circulatory morbidity (ICD-9 401-443) before turning 65 years old were used. Each schizophrenia case was then matched with two mentally healthy controls for the age and sex, and date of laboratory examination. Clinical data of all subjects were obtained by reviewing medical records. RESULTS: Totally, 81 patients with schizophrenia who died from circulatory diseases at mean ages of 48.0 ± 10.7 years were investigated. The mean age at the final acute psychiatric hospitalization was 43.0 ± 10.9 years. Multivariate analysis showed that elevated fasting serum glucose levels (95% confidence interval [CI] for odds ratio (OR) = 1.00-1.03), blood leukocyte counts (95% CI for odds ratio (OR) = 1.07-1.55), and heart rates on electrocardiogram (95% CI for OR = 1.04-1.10) in the final psychiatric hospitalization collectively provided the predictive validity for premature circulatory death. CONCLUSION: Systemic inflammatory activation and autonomic nervous system dysfunction along with dysregulation of glucose metabolism rather than lipids could be the physiological characteristics of schizophrenia patients at risk of premature circulatory mortality.

Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder.

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.