Cardiovascular morbidity and mortality in bipolar disorder
Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, IA, USAJess G. Fiedorowicz, MD, MS
Department of Psychiatry, Carver College of Medicine, Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA
BACKGROUND: There has been considerable interest in the elevated risk of cardiovascular disease associated with serious mental illness. Although the contemporary literature has paid much attention to major depression and schizophrenia, focus on the risk of cardiovascular mortality for patients with bipolar disorder has been more limited, despite some interest in the historical literature.
METHODS: We reviewed the historical and contemporary literature related to cardiovascular morbidity and mortality in bipolar disorder.
RESULTS: In studies that specifically assess cardiovascular mortality, bipolar disorder has been associated with a near doubling of risk when compared with general population estimates. This may be explained by the elevated burden of cardiovascular risk factors found in this population. These findings predate modern treatments for bipolar disorder, which may further influence cardiovascular risk.
CONCLUSIONS: Given the substantial risk of cardiovascular disease, rigorous assessment of cardiovascular risk is warranted for patients with bipolar disorder. Modifiable risk factors should be treated when identified. Further research is warranted to study mechanisms by which this elevated risk for cardiovascular disease are mediated and to identify systems for effective delivery of integrated medical and psychiatric care for individuals with bipolar disorder.
KEYWORDS: bipolar disorder, cardiovascular disease, mortality, metabolic syndrome, obesity, hypertension
ANNALS OF CLINICAL PSYCHIATRY 2011;23(1):40–47
There has been considerable interest in the mortality that accompanies many psychiatric disorders. The psychiatric field has long focused on suicide, but in the past few decades, increasing attention has been given to cardiovascular mortality with psychiatric disorders. This article reviews the research related to cardiovascular morbidity and mortality in bipolar disorder. As illustrated in FIGURE 1, vascular disease is a leading cause of excess death in bipolar disorder.
FIGURE 1 Excess deaths in bipolar disorder
This graph uses aggregate data from one of the largest studies of mortality in mood disorders to illustrate the primary causes of excess death with bipolar disorder. In their sample, a total of 2129 excess deaths were identified in those with bipolar disorder, 700 of which were attributable to vascular disease (592 cardiovascular, 108 cerebrovascular). Thus, nearly one-third of the excess deaths were attributable to vascular disease alone. The top 4 causes of excess deaths are illustrated in this figure.
Toward the close of the nineteenth century and beginning of the twentieth, studies of morbidity and mortality in bipolar disorder were based almost entirely on case studies. The term bipolar disorder was not used, but the cases of mania and the construct of manic-depressive insanity were analogous to the contemporary construct of bipolar disorder.1 In an early report, Bell reported on 40 patients with mania seen at the McLean Asylum from 1836 to 1849, more than three-quarters of whom died. A patient with Bell’s mania was said to “get so little food, so little sleep, and be exercised with such constant restlessness and anxiety, that he will fall off from day to day…. At the expiration of two or three weeks, your patient will sink into death….”2 Bell also compared their illnesses to delirium tremens, inflammation of the brain and meninges, and “passive congestion” of the cerebral circulation, yet none of the patients demonstrated these conditions at autopsy. Bell concluded that patients experiencing similar manias were at great risk of sudden death, or perhaps had an illness distinct from any previously defined.2 Similar cases were later presented, with continued debate about whether these cases represented sudden death in mania or a distinct condition altogether.3
Nearly 100 years later, Derby studied mortality in patients with manic depression.4 Between 1912 and 1932, 980 of the patients admitted to Brooklyn (NY) State Hospital for manic depression died during their stay. The cause of death in 40% was determined to be “exhaustion from acute mental illness,” a condition perhaps similar to what Bell had described. The next most common cause of death was cardiac disease, which accounted for an estimated 31% of deaths. In his review, Derby hypothesized that “many of these ‘exhaustion’ cases appeared to have actually died of somatic disease” with “cardiovascular disturbance” poised as a potential etiology.4 Interestingly, like Bell, he described “the typical case of exhaustion” as being characterized by dehydration, fatigue, increased pulse rate, and “some degree of temperature elevation.”4 Contemporaneously, from reviewing a series of case studies, Adlund drew the belief that the illness he referred to as acute exhaustive psychosis “originates as a psychogenic problem and that the psychopathology… is expressed through dysfunctions of the cardiovascular, heat regulatory, and hematopoietic systems.”5
These early reports consisted almost entirely of case studies and lacked the methodologic rigor of systematic observational studies. They occurred during a period lacking methods that would enable physicians to rule out medical illnesses or draw more definitive conclusions on autopsy. Further, the symptoms that characterize “acute exhaustive psychoses” (described variously as Bell’s mania, fatal catatonia, manic-depressive exhaustive deaths, Scheid’s cyanotic syndrome, and brain death) now suggest agitated delirium, with symptoms including disorientation, confusion, visual hallucinations, and fever.3,4 Thus, these early studies do not solidly support the connection between bipolar disorder and cardiovascular illness, although they are significant in showing that a link between the 2 conditions was already a topic of interest more than a century ago.
Renewed concern about an association between bipolar disorder and cardiovascular disease followed the publication of several cohort studies. Two German publications suggested that arteriosclerotic disease occurred more often, and earlier, in those with manic depression than in the general population.6,7 Several comprehensive studies of state hospital populations were conducted in the 1940s and early 1950s. Alstrom compared the death rates of psychiatric patients in the New York Civil State Hospitals to the death rates of the general population in New York. He found that the annual death rate of patients with manic depression was more than twice that of patients with schizophrenia, at 7.7% vs 3.2%, respectively. Alstrom also estimated that the risk of cardiovascular disease was twice of the general population in patients with manic depression.8 Ødegard reported on mortality from Norwegian mental hospitals over a period of approximately 15 years. There were 3,370 deaths in a sample of 21,522 first admissions, a mortality rate 5 to 6 times that of the general population. He also reported that those with manic depression had higher mortality rates than those with schizophrenia. Men and women with schizophrenia had death rates 3.2 and 4.8 times higher than the general population, respectively, whereas men and women with manic depression had mortality rates 3.8 and 6.4 times higher, respectively.
For circulatory diseases, these rates in men and women with schizophrenia were 1.0 and 2.3 times higher, respectively, and 3.9 and 3.5 times higher for those with other diagnoses, including manic depression. Ødegard concluded that excess mortality from circulatory diseases was lower in those with schizophrenia compared with the rest of the mentally ill population. He hypothesized that these individuals “may be protected against circulatory disturbance by their less intensive emotional reactions and their physical inactivity.”9 Malzberg reviewed the rates of mortality and discharge among first admissions to the New York Civil State Hospitals. Although Malzberg did not focus his attention on the cause of death or on diagnoses, he concluded that mortality rates were lower for individuals with “dementia praecox” (schizophrenia).10-12 These studies show that patients admitted to public mental health hospitals had a mortality risk 4 to 10 times that of the general population, and they further identified individuals with bipolar disorder as being particularly at risk for cardiovascular disease.
The excess mortality identified by Malzberg, Ødegard, and Alstrom was largely attributed to the conditions of public mental health facilities. More than 20 years later, Babigian and Odoroff examined mortality in all cases of psychiatric illness reported to the Monroe County (NY) Psychiatric Case Register between 1960 and 1966, about 6% of that county’s population.13 This study found that “the relative risk for the registered group, when adjusted for age, sex, marital status, and socioeconomic status, is three times the general population.”13 The study also found that 4 causes of death were elevated in patients with mental illness: circulatory illness, respiratory illness, accidents, and suicide.13
Although a representative sample was used in the Babigian and Odoroff study, the potential for selection bias persists in the registry. A patient’s mental disease may have been identified only because medical treatment was sought for a separate physical illness, making it possible that the sampled cases included a disproportionate medical burden. This potential selection bias has been called Berkson’s bias.14 Because cases in such studies are drawn from clinical samples, Berkson’s bias unavoidably affects research on mortality associated with mental illness.15
Bipolar disorder has consistently been associated with an elevated risk for cardiovascular mortality, relative to the general population. Less consistent elevations in risk are seen when bipolar disorder is compared with unipolar depression. Elevations in mortality are often described with the standardized mortality ratio (SMR). The SMR represents the ratio of observed to expected deaths.
In a seminal “Iowa 500” study that included 100 patients with mania, Tsuang et al found an increased risk of cardiovascular mortality in women (SMR=1.63) but not men.16 A larger study in Denmark reported a similar estimate for cardiovascular mortality in patients with bipolar disorder when compared with the general population (SMR=1.60).17 In a subsample that included patients with bipolar and unipolar disorders, those with bipolar disorder were found to have a significantly increased incidence of cardiovascular mortality compared with patients with unipolar disorder.18
A British study also showed a dramatic difference between expected and observed deaths from cardiovascular disease in patients with bipolar disorder. During the period of study, 57 of 472 patients identified using the Edinburgh Psychiatric Case Register died; 42.1% of deaths were from cardiovascular illness, whereas a mortality of 14% was expected.19
A Swiss study followed 406 patients with bipolar (N=220) and unipolar (N=186) disorder who were hospitalized between 1959 and 1963 and followed for up to 38 years, at which point 76% of the patients had died. The patients with bipolar disorder were more likely to have died from cardiovascular disease than were those with unipolar depression (an SMR of 1.84 for those with bipolar depression vs 1.36 for patients with unipolar depression). Additionally, patients with bipolar I disorder had higher rates of death from cardiovascular disease than did those with bipolar II disorder.20 No subsequent study has compared cardiovascular mortality by bipolar subtype.
A cohort study of over 5.5 million Danes followed from either their 15th birthday or the beginning of 1973 through the beginning of 2001 found that of the 11,648 who were admitted for the first time due to bipolar disorder, 3669 had died by the end of the study period. The SMR for cardiovascular disease was 1.59 for men and 1.47 for women.21 This study strongly supported prior evidence of an elevated risk of cardiovascular morbidity for those with bipolar disorder. A similar study in Sweden found a cardiovascular SMR for those with bipolar disorder of 1.9 for men and 2.6 for women, compared with a cardiovascular SMR for individuals with unipolar depression of 1.5 for men and 1.7 for women.22
In 1966, Perris and d’Elia investigated mortality in a Swedish sample of 797 patients with “depressive psychoses” admitted between 1950 and 1963, 120 of whom had bipolar disorder. They reported that individuals with bipolar disorder had higher mortality than those with unipolar depression, independent of suicide.23 Sims and Prior estimated mortality in 1482 inpatients treated for severe neurosis in Birmingham (United Kingdom) hospitals between 1959 and 1968 and found excess mortality in diseases of the nervous, respiratory, and circulatory systems (SMR 1.6), although the sample was not restricted to individuals with bipolar disorder.24
The studies detailed above reporting cardiovascular SMRs for samples of patients with bipolar disorder are summarized in TABLE 1. Included are studies published in the past quarter century in which estimates of cardiovascular mortality for samples of individuals exclusively with bipolar disorder could be extracted. Several studies were not included because they presented composite data from mixed diagnostic samples,25-28 did not specifically assess cardiovascular mortality,25,28-30 or did not express mortality relative to the general population.30
Of studies from diagnostically mixed samples or those focusing on natural deaths (inclusive of cardiovascular mortality), some have failed to demonstrate elevated mortality. In an Iowa study of mortality in patients hospitalized between 1972 and 1981, Black et al found no excess of natural death in patients with mood disorders (SMR=0.9).31 Similarly, in 1987, Meloni et al did not find excess natural deaths in 179 inpatients with affective psychosis from an Italian sample, although the entire sample of 845 psychiatric inpatients had a significantly elevated SMR for circulatory disease of 2.5.32 Rorsman also found no excess in natural deaths for those with affective disorders treated at an outpatient clinic in Sweden in 1962.33Individuals with bipolar disorder were not examined separately from other patients with affective disorders in these studies. A study by Martin et al separated diagnostic groups for analysis but did not find any increase in natural deaths among 19 outpatients with bipolar disorder.34Although the assessment of natural mortality in bipolar disorder by Martin et al was limited by its small sample size, the presence of these negative studies, notably the outpatient sample of Rorsman, supports some suspicion of Berkson’s bias.
Several issues influence the results of mortality studies in psychiatry. Choice of study population may be particularly relevant, given the concern for Berkson’s bias. To facilitate case selection, studies to date have mainly involved clinical samples. The potential impact of selection bias on these samples must consider illness acuity (eg, inpatient or outpatient), the nature of the cohort design (retrospective or prospective), and secular trends. Additional considerations include determination of death, psychiatric assessment, and statistical inference.35 Limitations in statistical power may be particularly evident when estimating a cause-specific mortality for a specific psychiatric diagnosis, as highlighted in this review of cardiovascular mortality in bipolar disorder. When considering the aggregate data, mindful of these limitations, an association between bipolar disorder and cardiovascular mortality is likely, particularly after weighting the larger, contemporary studies of Laursen et al21 and Osby et al.22
Despite data supporting an association between bipolar disorder and cardiovascular morbidity, many questions remain. Whether bipolar disorder leads to an increased risk of cardiovascular disease or whether cardiovascular disease elevates the likelihood that a person will suffer from bipolar disorder remain unanswered. Whether there is a temporal association between affective disorder and cardiovascular comorbidity is also unknown, as is the nature of that association. Most relevant studies included patients who had been admitted to hospitals because of their mental illness, leading to ascertainment bias and potential overestimation of the risk of cardiovascular mortality. Lastly, the question remains as to whether excess mortality is related to an unidentified, inherent feature of mental illness or is mediated through traditional risk factors for cardiovascular disease.
There are several possible explanations for the excess cardiovascular mortality observed with bipolar disorder. Although the associations between bipolar disorder and cardiovascular mortality predate modern pharmacologic treatments, medication could conceivably contribute to cardiovascular risk. Lithium can cause weight gain36,37 and adversely influence glucose metabolism.38 Valproic acid has been even more strongly associated with both weight gain and insulin resistance.39,40 Second-generation antipsychotics are associated with hyperlipidemia,41-45 insulin resistance or increased risk of diabetes mellitus,42,46-51 and weight gain.42,52-54 Beyond iatrogenic effects, individuals with bipolar disorder may have poor diets and obtain inadequate exercise.55 Smoking is more common among those with bipolar disorder, even when compared with other serious mental illnesses.56
Several cardiovascular risk factors are more common in individuals with bipolar disorder than in the general population, which may help to explain the elevated risk of cardiovascular mortality. These risk factors include obesity, hypertension, diabetes, and hyperlipidemia. Each could contribute to excess cardiovascular mortality.
Obesity has been associated with bipolar disorder. A study of 644 patients with bipolar disorder from private, academic, and community mental health clinics found that 79% were overweight or obese, in contrast to 60% of the general population.57 Another study found that 45% of patients with bipolar disorder were obese, while another 29% were overweight.58 In a case-control study, participants with bipolar disorder weighed more, had a greater body mass index, and had a higher percentage of fat than controls; interestingly, the premorbid weights of the participants with bipolar disorder were not significantly different than those of controls, leading the authors to conclude that weight gain is caused by the illness or its treatment.59 A Norwegian study of 110 patients with bipolar disorder also found more obesity among the patients than in the general population (24.9% vs 14.1%, respectively). The differences were more pronounced when central obesity was measured (defined as a waist circumference of >102 cm in men or >88 cm in women). In the general population, only 16% met criteria for central obesity, compared with 39.9% of individuals with schizophrenia and 54.2% with bipolar disorder.60 In a recent study at the University of Iowa, evaluation of available weight and height information of 161 patients with bipolar disorder found that >75% of patients were overweight, and nearly half of these patients met criteria for obesity.61
Hypertension has been less consistently linked with bipolar disorder. Although 2 studies indicate that hypertension was not more common among those with bipolar disorder,58,62 some studies suggest otherwise. An Iowa study showed an increased prevalence of hypertension among those with bipolar disorder but not among those with unipolar mood disorders.63 Although the prevalence of hypertension in the control population was 5.6%, the prevalence of hypertension was 14% in patients with bipolar disorder and 5% in patients with unipolar depression.63 In the Yates and Wallace study, hypertension was identified by a diagnosis of hypertension, treatment with an antihypertensive, or systolic or diastolic blood pressure >160/95 mm Hg. A Norwegian study estimated a prevalence of hypertension of 61% in those with bipolar disorder as compared with a prevalence of 41% in the general population.60 This study used a much lower threshold, with a systolic or diastolic pressure ≥130/85 mm Hg. The largest study (involving 25,339 people with bipolar disorder and a control population of 113,698) showed an increased rate of new-onset hypertension among those with bipolar disorder, compared with both the control population and individuals with schizophrenia. The incident rate ratio in this study was 1.3, indicating that those with bipolar disorder were significantly more likely to be newly diagnosed with hypertension than were individuals in the general population.64 The assessment of incidence rather than prevalence may lessen some of the bias inherent in the study of medical comorbidity in psychiatric populations. With its size and rigorous assessment of incident cases, the study by Johannessen et al strongly supports a link between bipolar disorder and hypertension.64
The association between bipolar disorder and diabetes was first suggested nearly a century ago.65,66 Clinical studies have supported a greater prevalence of diabetes among patients with bipolar disorder. Another study found that 9.9% of inpatients with bipolar disorder had diabetes—3 times that expected in the general population (3.3%).67 A study of 4210 veterans with an average age of 53 also showed a statistically significant greater prevalence of diabetes among patients with bipolar disorder (17.2% vs 15.6%).62 Finally, in Norway, 5.5% of 113 patients with bipolar disorder were found to have diabetes, as compared with 2.2% of the general population.60 Overall, the data support a link between bipolar disorder and diabetes.
A possible association between bipolar disorder and hyperlipidemia has also been suggested.68 In one study, almost half of the patients with bipolar disorder met metabolic syndrome criteria for hypertriglyceridemia, in contrast to only 32% of the general population.58 At the University of Iowa Hospitals and Clinics, of 77 patients with bipolar disorder and a recorded lipid profile, almost one-third were diagnosed with hypertriglyceridemia, though some potential for surveillance bias existed.61 Available evidence indicates that individuals with bipolar disorder may be at increased risk for hyperlipidemia, specifically hypertriglyceridemia.
The metabolic syndrome can be conceptualized as a composite measure of many of these cardiovascular risk factors: visceral obesity, hypertriglyceridemia, low high-density lipoprotein, hypertension, and insulin resistance. US studies indicate that patients with bipolar disorder may have an elevated risk of metabolic syndrome. Estimates suggest that metabolic syndrome has a prevalence of 30% to 53% among those with bipolar disorder, as compared with a national prevalence of 27%.58,61,69 Several studies outside the United States have also found evidence of an elevated risk for metabolic syndrome in bipolar disorder. In Spain, 22.4% of those with bipolar disorder had metabolic syndrome, as opposed to the national prevalence of 14.2%,70 and more than double the prevalence was seen in a Belgian study.71,72Similar trends were found in studies from Brazil and Turkey (38.3% vs 23.7% and 32% vs 17.9%, respectively).73,74TABLE 2 summarizes estimates of the prevalence of metabolic syndrome, as defined by the National Cholesterol Education Program, in bipolar disorder.
Standardized mortality ratios (SMR) for cardiovascular deaths in bipolar disorder
|Weeke et al, 198717
||Inpatients, Denmark, male, index admission 1950 to 1956 (N=1133) or 1969 to 1976 (N=2662)
|Sharma and Markar, 199419
||Inpatients, Scotland, index admission 1970 to 1975 (N=472)
|Osby et al, 200122
||Inpatients, Sweden, index admission 1973 to 1995 (N=15,386)
|Angst et al, 200220
||Inpatients, Switzerland, index admission 1959 to 1963 (N=220)
|Laursen et al, 200721
||Inpatients, Denmark, living or born after 1973 (N=11,648)
Estimates of NCEP-defined metabolic syndrome prevalence with bipolar disorder
|Cardenas et al, 200869
||Outpatients from a West Los Angeles Veterans Affairs clinic
|Fagiolini et al, 200558
||Consecutive recruits from 2003 to 2004 for bipolar disorder center in Pennsylvania
|Fiedorowicz et al, 200861
||Outpatients from a tertiary care center with primary diagnosis of bipolar disorder
||60 to 125 (46/79)
||36% to 55% (52% to 64%/27% to 46%)
|Garcia-Portilla et al, 200870
||Naturalistic, multicenter, cross-sectional study in Spain
|Teixeira and Rocha, 200773
||Consecutive sample of psychiatric inpatients
|van Winkel et al, 200871
||Prescreening for patients with bipolar disorder started on antipsychotics
|Yumru et al, 200774
||Young sample of outpatients with bipolar disorder in Turkey
Individuals with bipolar disorder have a significantly greater burden of cardiovascular morbidity and mortality than expected, based on general population estimates. Further, there is evidence that this risk may exceed that seen with other mental disorders. The strength and robustness of this association as indicated by the evidence suggests this association cannot be dismissed. Although there may be features inherent in bipolar disorder that contribute to cardiovascular risk, the preponderance of cardiovascular risk factors in this population warrants public health focus on traditional risk factors. Cardiovascular risk factors are readily identifiable with established screening approaches, and risk factors can be modified. Unfortunately, patients with serious mental illness may be less likely to be monitored for75 and appropriately treated for cardiovascular risk factors.76 Treatment for bipolar disorder may further increase cardiovascular risk and require more rigorous monitoring. Additional research is needed to enable us to better understand the many potential mediators of cardiovascular risk in this at-risk population.
DISCLOSURES: Dr. Fiedorowicz is supported by the National Institute of Mental Health (1K23MH083695-01A210), the Nellie Ball Trust Research Fund, and a NARSAD Young Investigator Award, and the Institute for Clinical and Translational Science at the University of Iowa (3 UL1 RR024979-03S4). Dr. Fiedorowicz currently serves on colleagues’ studies with Neurosearch, Vitalin/Enzymatic Therapy, and the National Center for Complementary and Alternative Medicine/Food and Drug Administration Orphan Products division. He also has received research support for participating in a colleague’s investigator-initiated study with Eli Lilly and Company. Ms. Weiner and Ms. Warren report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
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CORRESPONDENCE: Jess G. Fiedorowicz, MD, MS, Department of Psychiatry, Carver College of Medicine, Department of Epidemiology, College of Public Health, The University of Iowa, 200 Hawkins Drive, W278GH, Iowa City, IA 52242, USA E-mail: firstname.lastname@example.org
Annals of Clinical Psychiatry ©2011 Quadrant HealthCom Inc.