Regular Article

Risk factors for early cardiovascular mortality in patients with bipolar disorder Shang-Ying Tsai, MD ,1,2* Chao-Hsien Lee, PhD,3 Pao-Huan Chen, MD,1,2

Kuo-Hsuan Chung, MD,1,2 Shou-Hung Huang, MD,1,2 Chian-Jue Kuo, MD, PhD1,4

and Wen-Cheng Wu, MD5 1Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, 2Department of Psychiatry and Psychiatric Research Center, Taipei Medical University Hospital, Taipei, 3Department of Health Business Administration, Meiho University, Pingtung, 4Taipei City Psychiatric Center, Taipei City Hospital, Songde Branch, 5Hospital and Social Welfare Organizations Administration Commission, Ministry of Health and Welfare, Taipei, Taiwan

Aim: We attempted to determine risk factors, partic- ularly pathophysiological changes, for early cardio- vascular mortality in bipolar disorder (BD).

Methods: A total of 5416 inpatients with bipolar I disorder were retrospectively followed through rec- ord linkage for cause of death. A total of 35 patients dying from cardiovascular disease (CVD; ICD 9: 401443) 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 mor- tality were the leukocyte count and heart rate on the first day of the index hospitalization, as the deceased BD patients were compared with the liv- ing 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 inflamma- tion and sympathetic overactivity during the acute phase of BD may be risk factors for early CVD mortality.

Key words: bipolar disorder, cardiovascular disease, inflammation, mortality, sympathetic overactivity.

P ATIENTS WITH BIPOLAR disorder (BD) havean elevated cardiovascular mortality risk and this mortality occurs 10 years earlier than it does in the general population.1 Cardiovascular diseases (CVD) account for over one-third of mortality in patients with BD.2,3 Cardiovascular risk in indivi- duals with BD is multifactorial. The widely studied factors that increase cardiovascular risk in patients with BD include obesity, health behaviors (e.g.,

smoking, inappropriate diet, and physical inacti vity),4 adverse effects of long-term medication,5 psy- chosocial functioning,6 access to quality health care, and underlying pathophysiology.7 Accordingly, met- abolic syndrome involves several traditional cardio- vascular risk factors that may partially explain the elevated CVD mortality risk in patients with BD.8,9

BD is also associated with the inflammatory response system, which influences a spectrum of medical conditions, including CVD and type 2 diabe- tes, although this association has not been well articulated.10,11

Many of the prior studies on CVD mortality in patients with BD have been limited by their sample

*Correspondence: Shang-Ying Tsai, MD, Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, 252 Wu-Hsing Street, Taipei 110, Taiwan. Email:[email protected] 9 November 2016; revised 9 May 2017; accepted 15 May 2017.

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

716

Psychiatry and Clinical Neurosciences 2017; 71: 716724 doi:10.1111/pcn.12538

size or by using a population-based dataset without patients clinical features through chart review.12

Existing data support the association between BD and cardiovascular morbidity. However, it remains unclear if the increased mortality is mediated through traditional risk factors for cardiovascular disease or is related to unidentified and inherent mental illness pathophysiology.4

Furthermore, systemic inflammation during the acute phase of BD is considered a risk factor for early natural death, mainly CVD mortality.3 Moreo- ver, cardiac dysfunction in patients with BD during a manic phase is characterized by low heart-rate var- iability, reflecting autonomic dysfunction, which is also a strong and independent predictor of mortality in patients with acute myocardial infarction.13 How- ever, it remains unclear whether inflammatory acti- vation and autonomic dysfunction contribute to the high cardiovascular mortality in patients with BD. Because psychopathology involves potent physio-

logical changes involving the autonomic nervous sys- tem, metabolic dysfunction, and inflammation,3,13 it is hypothesized that a possible biological connection between psychopathological conditions and the CVD mortality risk may exist. To determine the pathophysi- ological predictors of early CVD deaths in patients with BD, we aimed to examine the generalizability of well-known risk factors for CVD mortality and to identify specific clinical characteristics as risk factors.

METHODS All subjects in this study had been treated at Taipei Medical University Hospital, Taipei City Psychiatric Center, or Bali Psychiatric Center, which provide a total of 560 beds for acute patients and 604 beds for chronic patients in northern Taiwan. The investiga- tion was carried out in accordance with the latest version of the Declaration of Helsinki. This study was approved by the institutional review board of each hospital. Since the methodology has already been described extensively elsewhere and success- fully used in research on completed suicide14

and natural death3 in BD, it will only be briefly summarized here. The national identity (ID) number is unique for

each Taiwan resident. Multiple identifiers were used in the matching process to search for the deceased patients, including national ID, sex, and date of birth. A record linkage, in which a 19872008 roster of inpatients with mood disorders excluding major

depression (ICD-9 codes 296.2x and 296.3x) was elec- tronically matched with data from the Department of Health, Death Certification System in Taiwan recorded from 1 January 1987 to 31 December 2008. Psychiat- ric diagnoses were based on the DSM-III, DSM-III-R, or DSM-IV, which were the diagnostic systems used in these hospitals during this period. The cause of death was determined on the basis of records in death certi- ficates. More than 70% of circulatory system deaths are attributable to coronary artery disease and cerebro- vascular disease with the same pathogenesis athero- thrombosis.15 Atherothrombosis is a common pathophysiological process of morbid or fatal clinical ischemic events affecting cerebral, coronary, or periph- eral arterial circulation. Therefore, we included specific CVD categories in this study, namely coronary heart disease, cerebrovascular disease, congestive heart fail- ure, CVD-associated hypertensive diseases, and CVD- associated hyperlipidemia. Patients who died of CVD (hypertensive and coronary heart diseases, ICD-9: 401429; cerebrovascular diseases, ICD-9: 430438; and vascular diseases, ICD-9: 440443) were enrolled in the study. Information on each potential experi- mental participant, particularly psychiatric symptoms and history, was carefully and independently reviewed by two board-certified psychiatrists of our research group, with strict DSM-IV diagnostic criteria being reapplied to each deceased patient to confirm diag- noses along with history of rapid cycling and, in par- ticular, to exclude the possibility of mood disorder due to general medical conditions.

All deceased patients who had experienced at least one manic or mixed episode before 31 December 2008 were included in the study. Patients were excluded if they had unclear chart documentation or premature discharge from the index hospitalization. The cut-off age for early death was 65 years because it is well accepted as the geriatric age and is econom- ically relevant as the usual retirement age in devel- oped countries. During the study period, 51 patients who later died of circulatory diseases were diag- nosed with bipolar I disorder; 35 of these patients were younger than 65 years when they died and were included in the study. Each deceased patient was matched with two living patients with bipolar I disorder (as controls) according to age (birth year 2), sex, and the date of index admission (3 years). Two mentally healthy adults who had visited Taipei Medical University Hospital for general health screening were matched according to sex, age (birth year 2), and the date of the health screening

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2017; 71: 716724 Circulatory mortality and BD 717

examination (3 years) to compare the results of laboratory and physical examination with those of the deceased patients. These healthy controls were screened for a history of DSM-IV axis I disorders by using a well-validated Chinese version of the Gen- eral Health Questionnaire16 and by reviewing medi- cal records. The healthy controls gave their informed consent before participating in the study.

Data collection

A case note form was used for patients visiting these hospitals for the first time, and another form was used for inpatients. Both forms contain over 95 items structured to obtain specific and compre- hensive information from patients regarding demo- graphic characteristics, past and present illness, mental state examination, physical condition, alco- hol/drug use problem, and family history. Data on patient hospitalization were obtained through per- sonal interviews, serial clinical assessments, and direct observation by residents, nursing staff, and social workers. If the deceased patient had under- gone several hospitalizations during the study period, the most recent event was considered the index hospitalization. The index hospitalization for the living controls was the hospitalization date near- est to the date of index hospitalization of the matched deceased patient. Initial findings were reviewed by a consensus panel of experienced inves- tigators who specialized in major psychiatric-disor- der-related research for verifying the accuracy and completeness of data for each subject. Following an overnight period of fasting, the lab-

oratory examination of blood and other metabolic measures of inpatients was routinely conducted once on the morning after admission. The following variables were examined: present psychiatric illness, family history, medication history, and results of physical and laboratory examinations at the index hospitalization. The 2008 sex-specific version of the Framingham Risk Score17 was calculated according to age, sex, smoking history, hypertension treatment, systolic blood pressure, serum total cholesterol levels, and high-density lipoprotein levels at the index hospitalization. The four main vital signs were routinely monitored by nursing staff every morning after admission. Based on the hospitals standard procedure, heart rate was routinely determined according to the radial pulse measured during a 1- min recording at rest, and then blood pressure was

checked every morning. Resting electrocardiography (ECG) was obtained using a simultaneously recorded 12-lead machine with automatic measure- ments of parameters. The QT interval corrected for the heart rate (QTc) was calculated using Bazetts formula (Bazetts correction). A prolonged QTc interval was 440 ms in men and 450 ms in women.18

Statistical analyses

Two-group comparisons were made by using the 2- test with Yates correction or Fishers exact test for categorical explanatory variables or using the two- tailed Students t-test for continuous variables. The variables significantly associated with the outcome (P < 0.05) were entered into the multivariate regres- sion model. Conditional logistic regression models were applied to examine any interaction between potential risk factors and mortality by using SPSS Sta- tistics 17.0 for Windows (SPSS, Chicago, IL, USA). Given the exploratory nature of this study, the uni- variate analyses are presented without Bonferroni corrections.

RESULTS At the time of death, the mean age of the 35 deceased patients was 47.2 11.7 years. Twenty- eight deaths (80.0%) occurred within 10 years after the last admission. Twenty-six (74.3%) patients died of hypertensive and coronary heart diseases, eight (22.9%) died of cerebrovascular diseases, and one (2.9%) died of other vascular disease. No significant difference was observed in sociodemographic char- acteristics, rates of cigarette smoking habit or lowest socioeconomic class, personal and family histories pertaining to the index hospitalization, medical morbidities, abnormal ECG findings, or prolonged QTc values between the deceased and the living con- trol BD groups (Table 1). The mean values of the leukocyte count, body

mass index (BMI), systolic pressure, and heart rate on day 1 of the index hospitalization were signifi- cantly higher in the deceased patients than in the living controls (Tables 2,3). The mean heart rate value obtained from ECG of the deceased patients during the index hospitalization was higher than that of the living controls with a marginal statistical significance (Table 2). The deceased patients and

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

718 S.-Y. Tsai et al. Psychiatry and Clinical Neurosciences 2017; 71: 716724

living controls did not show a significant difference in the Framingham Risk Score. The healthy control group had significantly lower

mean BMI values (24.5 3.2 kg/m2, t = 2.55, P = 0.04) and ECG heart rate measurements (66.2 10.0 b.p.m., t = 6.42, P < 0.001) than the deceased BD group (data not shown). According to the associations identified in all univariate analyses of the deceased patients and the healthy controls (Table 3), three variables remained significantly pre- dictive of increased risk for CVD mortality in BD patients: hemoglobin level (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.370.83, P = 0.014), leukocyte count (OR, 1.56; 95%CI, 1.172.08, P = 0.003), and heart rate (OR, 1.08; 95% CI, 1.031.13, P = 0.001). To assess the simultaneous impact of several

potential risk factors for early CVD mortality, a con- ditional logistic regression analysis was conducted on the basis of preliminary univariate associations identified in the preceding analyses (Tables 13). Results of a multivariate logistic regression are dis- played in Table 4. The mean values of BMI on day 1 and the discharge day were relatively similar;

therefore, only the BMI on day 1 of the index hospi- talization was included in the model. In the regres- sion model, only one risk factor (leukocyte counts) was significant at the 0.05 level.

Further statistical analysis was carried out and yielded two explanatory models for predicting early CVD mortality that was highly significant overall. The greatest predictive validity of CVD mortality was provided by leukocyte counts (OR, 1.25; 95% CI, 1.031.53; P = 0.025) and heart rate on day 1 of the index hospitalization (OR, 1.04; 95%CI, 1.001.08; P = 0.038). Furthermore, the predictive validity of early CVD mortality was also provided by leukocyte counts (OR, 1.23; 95%CI, 1.011.49; P = 0.04) and systolic pressure on day 1 of the index hospitalization (OR, 1.03; 95%CI, 1.001.06; P = 0.038).

DISCUSSION The strength of this study is that two types of con- trol subjects were recruited and relatively valid labo- ratory data along with physiological variables, such as the leukocyte count, ECG, and vital signs, were

Table 1. Demographic characteristics of patients with bipolar I disorder dying from cardiovascular causes and living controls with bipolar I disorder by comparisons of categorical variables

Characteristics

Deceased patients Living controls

2 P n = 35 n = 70 n (%) n (%)

Male 16 (45.7) 32 (45.7) 0.00 1.00 Education 12 years 29 (82.9) 52 (74.3) 0.96 0.79 Married or widowed 14 (40.0) 33 (47.1) 1.19 0.61 Social class V 29 (82.9) 47 (67.1) 1.32 0.50 Living with family members 27 (77.1) 62 (88.6) 1.12 0.63 History of rapid cycling 11 (31.4) 14 (20.0) 1.68 0.20 Abnormal ECG finding at the index admission 20 (60.6) 35 (50.0) 0.75 0.39 Prolonged QTc on ECG 7 (20.0) 8 (11.6) 1.39 0.49 Comorbid alcohol use disorders during lifetime 9 (25.7) 24 (34.3) 0.80 0.37 Cigarette smoking habit 17 (48.6) 34 (48.6) 0.00 1.00 History of first-degree relative with mood disorders 9 (25.7) 12 (17.1) 1.51 0.47 Significant concurrent medical morbidity

Cardiovascular diseases 7 (20.0) 15 (21.4) 0.24 0.62 Brain and cerebrovascular diseases 5 (14.3) 2 (2.9) 0.07 Endocrine 11 (31.4) 20 (28.6) 0.09 0.91 Gastrointestinal system 5 (14.3) 13 (18.6) 0.58

Rate-corrected QT interval. Fishers exact test. ECG, electrocardiogram.

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2017; 71: 716724 Circulatory mortality and BD 719

Table 2. Clinical characteristics and measurement of patients with bipolar I disorder dying from cardiovascular causes and living controls with bipolar I disorder by comparisons of continuous variables

Deceased patients Living controls n = 35 n = 70

Characteristics Mean (SD) Mean (SD) t P

Illness variables Age at onset (years) 25.6 (9.7) 24.4 (7.7) 0.68 0.50 Age at first psychiatric visit to TCPC, TMUH, or BPC 28.3 (9.2) 27,2 (8.1) 0.51 0.62 Age at first psychiatric admission (years) 30.4 (12.6) 29.0 (11.2) 0.60 0.55 Age at index admission (years) 41.5 (12.6) 40.7 (11.7) 0.34 0.73 Age at last psychiatric visit (years) 43.8 (12.2) 46.2 (12.3) 0.87 0.38 Total affective episodes 10.6 (6.6) 10.4 (6.6) 0.12 0.90 Total hospitalizations 5.5 (4.6) 5.9 (4.1) 0.37 0.71

Duration of medication before last visit (years) Lithium 5.2 (6.2) 6.5 (5.7) 1.08 0.29 Valproate 0.7 (2.3) 1.2 (2.6) 0.92 0.36 All antipsychotics 8.7 (7.7) 7.3 (7.4) 0.88 0.38 Typical antipsychotics 8.3 (7.2) 6.9 (6.9) 0.91 0.37 Atypical antipsychotics 0.7 (1.6) 0.4 (1.1) 0.93 0.36

Body mass index of the index hospitalization (kg/m2) Day 1 26.6 (5.8) 24.1 (3.5) 2.26 0.03 Discharge day 26.9 (5.9) 24.7 (3.7) 2.25 0.03

Systolic pressure of index hospitalization (mmHg) Day 1 129.7 (18.9) 121.8 (13.9) 2.19 0.03 Day 2 124.0 (20.2) 118.6 (14.0) 1.40 0.17 Day 3 124.1 (17.8) 120.1 (16.0) 1.15 0.25 Discharge day 120.8 (12.6) 115.0 (16.3) 1.80 0.08

Diastolic pressure of index hospitalization (mmHg) Day 1 83.5 (14.9) 79.5 (10.4) 1.43 0.16 Day 2 79.7 (10.3) 76.3 (9.8) 1.67 0.09 Day 3 80.0 (11.5) 78.9 (10.6) 0.46 0.65 Discharge day 77.4 (8.4) 74.2 (11.4) 1.41 0.16

Pulse pressure of index hospitalization (mmHg) Day 1 46.2 (15.3) 42.5 (10.6) 1.27 0.21 Day 2 44.2 (13.1) 42.1 (11.0) 0.86 0.35 Day 3 44.2 (12.5) 41.2 (10.9) 0.33 0.79 Discharge day 43.5 (9.6) 39.9 (9.4) 1.73 0.08

Heart rate (b.p.m.) Day 1 92.7 (14.5) 87.1 (11.3) 2.15 0.03 Day 2 93.8 (12.6) 88.6 (13.9) 1.86 0.07 Day 3 92.2 (12.5) 87.6 (14.8) 1.58 0.12 Discharge day 85.2 (11.1) 84.7 (12.3) 0.20 0.84

ECG measurements Heart rate (b.p.m.) 83.8 (18.7) 77.0 (15.1) 1.71 0.09 QRS duration (ms) 94.5 (20.5) 101.5 (154.0) 0.24 0.85 QT interval (ms) 352.1 (43.2) 367.0 (44.9) 1.34 0.16 QTc (Bazetts) (ms) 414.7 (33.6) 411.9 (30.8) 0.41 0.69 Framingham risk score 3.9 (4.1) 4.3 (4.6) 0.45 0.68

ALT, alanine aminotransferase, formerly SGPT; AST, aspartate aminotransferase, formerly SGOT; BPC, Bali Psychiatric Center; ECG, electrocardiogram; TCPC, Taipei City Psychiatric Center; TMUH, Taipei Medical University Hospital.

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

720 S.-Y. Tsai et al. Psychiatry and Clinical Neurosciences 2017; 71: 716724

examined for all subjects. Age and sex are important risk factors for CVD morbidity and mortality;17

therefore, age and sex were controlled in the present study to explore other CVD risk factors linked with BD. The present study has two major findings. First,

the elevated leukocyte counts in patients with BD in acute affective episodes are more associated with CVD mortality than traditional cardiovascular risk factors, such as smoking, BMI, and hyperlipidemia. Our early work showing that elevated leukocyte counts potentially predict premature natural

mortality in patients with BD3 supports the present finding. The total leukocyte count is a marker of sys- temic inflammation and has been shown to be a predictor of coronary heart disease progression and in patients with pre-existing vascular diseases.19 Fur- thermore, the leukocyte count is vital for stratifying risks in patients with myocardial infarction and can be used as a universal marker for predicting 1-year mortality after any treatment.20 Immune dysfunc- tion appears to be a mediator of the association between BD and CVD.11 Furthermore, chronic inflammation is observed in patients with bipolar

Table 4. Conditional logistic regression of factors for cardiovascular mortality of bipolar I disorder

Adjusted OR 95%CI for OR P

Leukocyte count 1.23 1.0011.51 0.049 Heart rate on day 1 of index hospitalization 1.04 1.001.08 0.052 Systolic pressure on Day 1 of index hospitalization

1.01 0.981.04 0.55

Body mass index on Day 1 of index hospitalization

0.998 0.991.01 0.79

Goodness of fit, 2 = 8.79, d.f. = 1, P = 0.003. CI, confidence interval; OR, odds ratio.

Table 3. Results of laboratory examination of patients with bipolar I disorder dying from cardiovascular causes, living controls with bipolar I disorder at the index hospitalization, and healthy controls

Deceased patients(A) Living controls(B) A vs B

Healthy controls(C) A vs Cn = 35 n = 70 n = 70

Mean (SD) Mean (SD) t Mean (SD) t

Fasting blood sugar (mg/dL) 103.2 (20.1) 98.4 (24.1) 1.01 91.1 (20.8) 2.57** Blood urea nitrogen (mg/dL) 12.4 (4.9) 11.3 (3.9) 1.20 13.8 (3.6) 0.81 Creatinine (mg/dL) 1.0 (0.3) 1.1 (1.0) 0.67 0.8 (0.2) 3.42*** Uric acid (mg/dL) 7.2 (2.6) 6.5 (2.4) 1.27 5.9 (1.7) 2.71** AST (U/L) 27.6 (14.0) 25.4 (15.2) 0.71 25.7 (14.7) 1.05 ALT (U/L) 27.5 (16.9) 30.5 (41.3) 0.41 32.8 (41.3) 0.65 Cholesterol (mg/dL) 178.7 (33.3) 171.5 (38.3) 0.93 194.8 (37.0) 2.20* Triglyceride (mg/dL) 125.9 (51.5) 133.1 (68.3) 0.41 124.0 (70.2) 0.10 Sodium (mg/dL) 143.9 (3.9) 140.2 (17.1) 1.23 142.0 (2.9) 0.84 Thyroxine (T4) (mg/dL) 8.2 (2.5) 7.4 (2.8) 1.49 7.3 (3.0) 0.44 Leukocytes, 103/L 8.1 (2.6) 7.1 (2.0) 2.22* 6.0 (1.7) 4.78**** Erythrocytes, 106/L 4.6 (0.6) 4.7 (1.4) 0.25 4.9 (0.5) 2.25* Hemoglobin (g/dL) 13.5 (1.6) 14.2 (3.8) 0.91 14.5 (1.3) 3.78**** Platelets, 103/L 253.0 (76.8) 234.8 (71.4) 0.99 237.4 (63.1) 0.89

*P < 0.05. **P < 0.01. ***P < 0.025. ****P < 0.005. ALT, alanine aminotransferase, formerly SGPT; AST, aspartate aminotransferase, formerly SGOT.

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2017; 71: 716724 Circulatory mortality and BD 721

depression or mania from the acute phase to full remission.21,22 Therefore, our findings may provide additional evidence that systematic inflammation is a possible risk factor for early CVD mortality in patients with BD. Second, increased heart rate or systolic pressure

on the first day of the index hospitalization may be another risk factor for early circulatory mortality in BD. An elevated heart rate increasing the mechanical stress on the heart and the arterial wall, particularly in middle-aged adults, has been associated with car- diovascular mortality.23 The heart rate acts as an indicator of sympathetic nervous system activity and depends on the balance between vagal and adrener- gic tones.24 Therefore, a high heart rate in the acute phase of BD may be due to autonomic imbalance. Systolic pressure is mainly determined by the arterial compliance and total peripheral resistance, and it is a more effective predictor of coronary heart disease and congestive heart failure than the diastolic pres- sure, particularly in patients aged at least 50 years.25

The heart rate and systolic pressure of patients with BD in the acute phase may increase with sympa- thetic activity and severity of manic phase. However, some of the present bipolar subjects might suffer from depressive episode with higher sympathetic activity but not increasing heart rate and systolic pressure.26 Therefore, symptomatic severity cannot account for increased heart rate and systolic pres- sure. Under the assumption that the illness severity during the acute phase in the deceased patients and living controls was comparable, sympathetic overac- tivity superior to greater symptom severity may be another explanation for the significant elevation in the heart rate and systolic pressure observed in the deceased patients. Disappearance of the significant elevation of heart rate and systolic pressure from the second day of acute hospitalization may partially contribute to the effects of medication on both the psychopathology and cardiovascular system. Taking our findings together, patients with BD

who exhibit more inflammatory load and sympa- thetic overactivity may be susceptible to circulatory morbidity and mortality. The inflammatory reflex ensures that the autonomic nervous system regulates the inflammatory response in real time as it controls the heart rate and other vital functions.27 Therefore, a dysfunctional inflammatory reflex may be a poten- tial cause of elevated leukocyte counts and sympa- thetic activity in the acute phase of these deceased BD patients. A known association between a high

inflammation level and heart rate28 supports this finding. The Framingham Risk Score has been used to pre-

dict the 10-year risk of fatal cardiac events in the general population,29 but it fails to predict the mor- tality risk of the BD patients in this study. Although 80% of the deceased patients died within 10 years following the index admission, their mean Framing- ham Risk Score at the time of index admission was comparable to those of the living controls. The mean values of the 10-year Framingham Risk Score and BMI for the present deceased patients are close to those of a large population-based sample in Tai- wan (4.7 scores and 24.1 kg/m2, respectively) with the mean age of 47.8 years. The deceased patients did not exhibit any remarkable ECG-related abnormalities, including QTc interval prolongation. This result supports that there is no consistent asso- ciation between prolonged QTc interval and cardio- vascular mortality or morbidity in the general population.30 Therefore, performing ECG is unable to detect the risk of cardiac mortality reliably. The pathophysiology of cardiovascular disease associated with BD may differ from that in the general popula- tion.31 Our findings support that BD with an exces- sive risk of new-onset CVD is not fully explained by traditional CVD risk factors32 and provide addi- tional evidences that physiological changes of BD may increase the risk of early CVD mortality. Com- parisons with mentally healthy controls found that lower hemoglobin level could be an additional risk factor for circulatory mortality in BD. Strong evi- dence suggests that patients with anemia have increased mortality with cerebrovascular disease.33

The prevalence of anemia among chronic psychiatry patients is higher than the general population.34

Regular measures of hemoglobin of bipolar patients may be necessary to reliably detect associations between anemia and CVD mortality. This study has some methodological limitations.

First, one-fifth of the deaths occurred more than 10 years after the last admission. The leukocyte count was measured only once at the beginning of the index hospitalization; therefore, determining whether systemic inflammation is a state or trait phenomenon remains difficult. Second, before referral for psychiatric admission, concurrent physi- cal diseases may be neglected by psychiatrists in outpatient clinics. Certain CVD risk factors or somatic diseases may have been present but are not identified in the chart review. Third, death

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

722 S.-Y. Tsai et al. Psychiatry and Clinical Neurosciences 2017; 71: 716724

certificates may be incorrectly attributed to certain categories of causes of death (e.g., heart failure), masking other types of underlying causes (e.g., diabetes mellitus, obstructive pulmonary dis- eases, and cancer). Moreover, neither validation nor adjudication of the circulatory mortality was performed and a limited number of events was observed. Fourth, using formerly hospitalized patients as a sample may have led to Berksons bias, which is a selection bias toward severely ill patients with current physical diseases or comorbid psychiatric disorders. Furthermore, there is likely considerable variability in our methodology in clin- ical care. However, less than 3 years is estimated between mean age at illness onset and mean age at first psychiatric visit at any hospital of this study. Both BD groups manifested typical age at onset, which is during the 20s, according to the literature. Furthermore, additional information from family members may make our data more reliable. The average of 5.55.9 hospitalizations in the present BD groups and information available from family members make the identification of recurrent epi- sodes between two admissions reliable in both BD groups. Fifth, medication used by the people included in the study could not be controlled for. Although the medication statuses throughout the lifetime of a patient were comparable between the patient groups, cardiovascular and metabolic effects of long-term medication involving antipsychotics or lithium may confound the results of ECG (e.g., QTc) and routine laboratory examinations upon admission. Finally, there were limited data available for prediction and lack of systematic col- lection of such data in the exploratory study. In conclusion, systemic inflammation and sympathetic overactivity during the acute phase of BD are con- sidered as additional risk factors for CVD mortality. We suggest that bipolar-illness-related pathophysio- logical factors partially contribute to CVD mortal- ity. Further investigation should focus on the inflammatory reflex of patients with BD. This would help to prevent early circulatory morbidity and mortality.

ACKNOWLEDGMENTS This study was supported by grants from the National Science Council, Taiwan (NSC98-2314-B- 038-020-MY3). The authors thank Miss Ying-Fang Wang for her assistance in data collection.

DISCLOSURE STATEMENT None of the authors have conflicts of interest, finan- cial or nonfinancial, regarding the content described in this paper.

AUTHOR CONTRIBUTIONS S.Y.T. was the principal investigator, designed the study, and wrote the first draft of the manuscript. C.H.L. and C.J.K. undertook statistical analyses and helped with numerous revisions of the manuscript. S.Y.T., P.H.C., K.H.C., and S.H.H. collected the clini- cal information and reviewed references. All authors participated in interpreting data and contributed to revision of the manuscript and have approved the final version.

REFERENCES 1. Westman J, Hllgren J, Wahlbeck K, Erlinge D,

Alfredsson L, Osby U. Cardiovascular mortality in bipolar disorder: A population-based cohort study in Sweden. BMJ Open 2013; 3: e002373.

2. sby U, Brandt L, Correia N, Ekbom A, Sparn P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch. Gen. Psychiatry 2001; 58: 844850.

3. Tsai SY, Lee CH, Kuo CJ, Chen CC. A retrospective analy- sis of risk and protective factors for natural death in bipo- lar disorder. J. Clin. Psychiatry 2005; 66: 15861591.

4. Weiner M, Warren L, Fiedorowicz JG. Cardiovascular morbidity and mortality in bipolar disorder. Ann. Clin. Psychiatry 2011; 23: 4047.

5. Murray-Thomas T, Jones ME, Patel D et al. Risk of mortal- ity (including sudden cardiac death) and major cardiovas- cular events in atypical and typical antipsychotic users: A study with the general practice research database. Cardio- vasc. Psychiatry Neurol. 2013; 2013: 247486.

6. Laursen TM, Wahlbeck K, Hllgren J et al. Life expectancy and death by diseases of the circulatory system in patients with bipolar disorder or schizophrenia in the Nordic countries. PLoS ONE 2013; 24: e67133.

7. Murray DP, Weiner M, Prabhakar M, Fiedorowicz JG. Mania and mortality: Why the excess cardiovascular risk in bipolar disorder? Curr. Psychiatry Rep. 2009; 11: 475480.

8. Baune BT, Adrian I, Arolt V, Berger K. Associations between major depression, bipolar disorders, dysthymia and cardiovascular diseases in the general adult popula- tion. Psychother. Psychosom. 2006; 75: 319326.

9. Chung KS, Tsai SY, Lee HC. Mood symptoms and serum lipids in acute phase of bipolar disorder in Taiwan. Psy- chiatry Clin. Neurosci. 2007; 61: 428433.

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2017; 71: 716724 Circulatory mortality and BD 723

10. Slomka JM, Piette JD, Post EP et al. Mood disorder symp- toms and elevated cardiovascular disease risk in patients with bipolar disorder. J. Affect. Disord. 2012; 138: 405408.

11. Rosenblat JD, McIntyre RS. Are medical comorbid condi- tions of bipolar disorder due to immune dysfunction? Acta Psychiatr. Scand. 2015; 132: 180191.

12. Walker ER, Mcgee RE, Druss BG. Mortality in mental dis- orders and global disease burden implications: A system- atic review and meta-analysis. JAMA Psychiatry 2015; 72: 334341.

13. Henry BL, Minassian A, Paulus MP, Geyer MA, Perry W. Heart rate variability in bipolar mania and schizophrenia. J. Psychiatr. Res. 2010; 44: 168176.

14. Tsai SY, Kuo CJ, Chen CC, Lee HC. Risk factors for com- pleted suicide in bipolar disorder. J. Clin. Psychiatry 2002; 63: 469476.

15. Aronow WS, Ahn C. Prevalence of coexistence of coro- nary artery disease peripheral arterial disease and athero- thrombotic brain infarction in men and women > or = 62 years of age. Am. J. Cardiol. 1994; 74: 6465.

16. Cheng TA, Williams P. The design and development of a screening questionnaire (CHQ) for use in community studies of mental disorders in Taiwan. Psychol. Med. 1986; 16: 415422.

17. DAgostino RB SR, Vasan RS, Pencina MJ et al. General cardiovascular risk profile for use in primary care the Fra- mingham Heart Study. Circulation 2008; 117: 743753.

18. Sharp DS, Masaki K, Burchfiel CM, Yano K, Schatz IJ. Pro- longed QTc interval impaired pulmonary function and a very lean body mass jointly predict all-cause mortality in elderly men. Ann. Epidemiol. 1998; 8: 99106.

19. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen C-reactive protein albumin or leukocyte count with coronary heart disease. JAMA 1998; 279: 14771482.

20. Kojima S, Sakamoto T, Ishihara M et al. The white blood cell count is an independent predictor of no-reflow and mortality following acute myocardial infarction in the coronary interventional era. Ann. Med. 2004; 36: 153160.

21. Tsai SY, Chung KH, Wu JY, Kuo CJ, Lee HC, Huang SH. Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J. Affect. Disord. 2012; 136: 110116.

22. Tsai SY, Chung KH, Huang SH, Chen PH, Lee HC, Kuo CJ. Persistent inflammation and its relationship to leptin and insulin in phases of bipolar disorder from

acute depression to full remission. Bipolar Disord. 2014; 16: 800808.

23. Jouven X, Empana JP, Escolano S et al. Relation of heart rate at rest and long-term (>20 years) death rate in ini- tially healthy middle-aged men. Am. J. Cardiol. 2009; 103: 279283.

24. Grassi G, Vailati S, Bertinierei G, Tverdal A, Hjellvik V, Selmer R. Heart rate as a marker of sympathetic activity. J. Hypertens. 1998; 16: 16351639.

25. Franklin SS, Larson MG, Khan SA et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 2001; 103: 12451249.

26. Hildrum B, Mykletun A, Holmen J, Dahl AA. Effect of anxi- ety and depression on blood pressure: 11-year longitudinal population study. Br. J. Psychiatry 2008; 193: 108113.

27. Tracey KJ. The inflammatory reflex. Nature 2002; 420: 853859.

28. Whelton SP, Narla V, Blaha MJ et al. Association between resting heart rate and inflammatory biomarkers (high- sensitivity C-reactive protein, interleukin-6, and fibrino- gen) (from the Multi-Ethnic Study of Atherosclerosis). Am. J. Cardiol. 2014; 113: 644649.

29. Balady GJ, Larson MG, Vasan RS, Leip EP, ODonnell CJ, Levy D. Usefulness of exercise testing in the prediction of coronary disease risk among asymptomatic persons as a function of the Framingham risk score. Circulation 2004; 110: 212321.

30. Montanez A, Ruskin JN, Hebert PR, Lamas GA, Hennekens CH. Prolonged QTc interval and risks of total and cardiovascular mortality and sudden death in the general population: A review and qualitative overview of the prospective cohort studies. Arch. Intern. Med. 2004; 164: 943948.

31. Swartz HA, Fagiolini A. Cardiovascular disease and bipo- lar disorder: Risk and clinical implications. J. Clin. Psychi- atry 2012; 73: 15631565.

32. Goldstein BI, Schaffer A, Wang S, Blanco C. Excessive and premature new-onset cardiovascular disease among adults with bipolar disorder in the US NESARC Cohort. J. Clin. Psychiatry 2015; 76: 163169.

33. Barlas RS, Honney K, Loke YK et al. Impact of hemoglo- bin levels and anemia on mortality in acute stroke: Anal- ysis of UK regional registry data, systematic review, and meta-analysis. J. Am. Heart Assoc. 2016; 17: e003019.

34. Korkmaz S, Yldz S, Korucu T et al. Frequency of anemia in chronic psychiatry patients. Neuropsychiatr. Dis. Treat. 2015; 11: 27372741.

2017 The Authors Psychiatry and Clinical Neurosciences 2017 Japanese Society of Psychiatry and Neurology

724 S.-Y. Tsai et al. Psychiatry and Clinical Neurosciences 2017; 71: 716724

Copyright of Psychiatry & Clinical Neurosciences is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder’s express written permission. However, users may print, download, or email articles for individual use.