Psychiatric Annals

CME Article 

An Update on the Other Cause of Excess Death in Bipolar Disorder: Cardiovascular Disease

Jess G. Fiedorowicz, MD, PhD

Abstract

Although much attention has appropriately been paid to suicide risk in bipolar disorder, cardiovascular disease has not received commensurate attention. People with bipolar disorder bear approximately twice the expected risk of cardiovascular disease and mortality. Several potential explanations for this alarming finding are reviewed with a focus on potential targets for clinical intervention. Many medications used to treat bipolar disorder may adversely impact risk factors for cardiovascular disease. People with bipolar disorder are additionally more likely to smoke, less likely to exercise regularly, and less likely to have healthy eating habits. Sleep problems are also nearly ubiquitous in bipolar disorder. Unacceptably, patients with bipolar disorder receive inadequate screening for and management of risk factors for cardiovascular disease, even in countries with universal access to health care. As providers with the most contact with many of these patients, psychiatrists are challenged to come to the fore in addressing this public health disparity. [Psychiatr Ann. 2019;49(9):380–385.]

Abstract

Although much attention has appropriately been paid to suicide risk in bipolar disorder, cardiovascular disease has not received commensurate attention. People with bipolar disorder bear approximately twice the expected risk of cardiovascular disease and mortality. Several potential explanations for this alarming finding are reviewed with a focus on potential targets for clinical intervention. Many medications used to treat bipolar disorder may adversely impact risk factors for cardiovascular disease. People with bipolar disorder are additionally more likely to smoke, less likely to exercise regularly, and less likely to have healthy eating habits. Sleep problems are also nearly ubiquitous in bipolar disorder. Unacceptably, patients with bipolar disorder receive inadequate screening for and management of risk factors for cardiovascular disease, even in countries with universal access to health care. As providers with the most contact with many of these patients, psychiatrists are challenged to come to the fore in addressing this public health disparity. [Psychiatr Ann. 2019;49(9):380–385.]

Psychiatrists and other mental health providers are deeply aware of the dramatic risk of suicide in bipolar disorder and consequently remain vigilant in regularly assessing risk. Vigilance to the risk of suicide in bipolar disorder is for good reason. One-half of those affected by bipolar disorder will at some point attempt suicide1 and 5% to 10% of patients first hospitalized for bipolar disorder die from suicide in the following 2 decades.2 Recognizing this, psychiatrists regularly screen patients with bipolar disorder for suicidal ideation at each encounter and carefully document suicide risk assessments. Potentially modifiable risk factors, such as depressive and anxiety symptoms, are aggressively treated. Other risk factors, such as access to firearms, are addressed where indicated. Yet, another substantial cause of morbidity and mortality of our patients with bipolar disorder lurks in the shadows. Cardiovascular disease, although insidious, is just as deadly, with excess mortality in comparable proportions to suicide in people with bipolar disorder.3 Psychiatrists, however, may neglect to address treatable risk factors for cardiovascular disease or relegate doing so to other medical providers. Patients, in turn, may fail to receive necessary care.

Population-based studies, largely done in northern European countries, have shown that those with bipolar disorder are about twice as likely to die as their peers who are the same age and same sex.3 This ultimately results in a 11- to 20-year shorter life expectancy.4 Another way to measure mortality differences is by excess mortality. Excess mortality is the difference between the number of deaths observed in a group and the number of deaths expected based on the relevant age- and gender-based mortality rates from the general population. This can be calculated for overall mortality or for a specific cause of death. By far, the two leading specific causes of excess death contributing to this shorter life expectancy are cardiovascular disease and suicide with each accounting for approximately one-third of the excess deaths.5Figure 1 highlights the primary role of cardiovascular disease and suicide in accounting for this excess mortality in bipolar disorder, using long-term follow-up data from a large, population-based sample.5 As illustrated in Figure 1, cardiovascular disease was the leading cause of excess mortality (33%), followed by suicide and other external causes of death (27%). Although risk for suicide has been the subject of much attention (and deservedly so), cardiovascular disease risk is finally getting some well-justified attention. In 2015, the American Heart Association released a scientific statement recognizing bipolar disorder (and major depressive disorder) as moderate-risk conditions for early cardiovascular disease.6 Nonetheless, these psychiatric risk factors remain absent from cardiovascular risk assessment guidelines and models or they are relegated to separate and cumbersome disease-specific models. This review seeks to provide an update on the risk of cardiovascular disease in bipolar disorder and to summarize key determinants underlying this risk that can serve as targets for clinical intervention. The review concludes with recommendations for psychiatrists to assess, minimize, and mitigate risk factors for cardiovascular disease.

This figure summarizes the excess mortality observed in a population-based sample in Sweden that included 17,101 people with bipolar disorder and also included 20 years of follow-up. Cardiovascular diseases contributed to approximately one-third of the excess deaths observed; the mortality rate ratio for cardiovascular disease was 2.03 (95% confidence interval 1.93–2.13). Nearly one-half of the cardiovascular mortality was due to coronary heart disease with the bulk of the remaining due to acute myocardial infarction and cerebrovascular disease. Adapted from Westman et al.5

Figure 1.

This figure summarizes the excess mortality observed in a population-based sample in Sweden that included 17,101 people with bipolar disorder and also included 20 years of follow-up. Cardiovascular diseases contributed to approximately one-third of the excess deaths observed; the mortality rate ratio for cardiovascular disease was 2.03 (95% confidence interval 1.93–2.13). Nearly one-half of the cardiovascular mortality was due to coronary heart disease with the bulk of the remaining due to acute myocardial infarction and cerebrovascular disease. Adapted from Westman et al.5

Review

For this narrative review, PubMed was searched using the terms “bipolar disorder” and “cardiovascular disease” up to April 2019 to identify the most relevant articles. To highlight the public health problem, mortality studies were specifically identified from a search of “bipolar disorder” and “cardiovascular mortality.” In accordance with the journal's reference limits, studies were prioritized for inclusion based on relevance for this clinically focused, nonsystematic review.

Results

Cardiovascular Mortality

Studies have consistently shown a dramatically elevated risk of cardiovascular mortality in bipolar disorder. Even though cardiovascular disease is already the leading cause of mortality worldwide, the presence of bipolar disorder nearly doubles this already large general population risk. In a register-based study of 39,375 people with bipolar disorder in Denmark, Finland, and Sweden, Laursen et al.4 found a 1.6- to 2-fold elevation in risk for cardiovascular mortality for those with bipolar disorder across these Nordic countries and across sexes. A 20-year follow-up of a population-based sample in Sweden similarly found a 2-fold elevation in risk for cardiovascular mortality with bipolar disorder.5 Although most studies have lumped bipolar disorder into a single diagnostic entity, a long-term follow-up study of a well-described prospective cohort of 403 patients with mood disorders found a 1.6-fold elevation in risk for cardiovascular mortality in bipolar II disorder, a 2-fold elevation for bipolar I disorder, and a 3.2-fold elevation for those with mania without major depression.7 These results are further supported by findings from an earlier study of another well-characterized prospective cohort that showed the persistence or burden of manic symptoms over follow-up was associated with cardiovascular mortality.8 Other studies have suggested that depressive symptom burden may also play a role.9 In aggregate, these results suggest that a more persistent course of illness in those with bipolar disorder (ie, a higher longitudinal burden of mood symptoms) may predispose to cardiovascular disease with a dose-response relationship.

The presence of bipolar disorder appears to be a risk factor for cardiovascular mortality even in those who already have cardiovascular disease. In a population-based Swedish cohort after first diagnosis of myocardial infarction, those with bipolar disorder had a 63% higher overall mortality, after adjusting for age, sex, smoking, diabetes mellitus, hypertension, congestive heart failure, stroke, peripheral vascular disease, type of myocardial infarction, measures of severity, and treatment.10 Taking these research findings in aggregate, bipolar disorder is an important and independent risk factor for cardiovascular mortality, even in the presence of existing cardiovascular disease.

Unfortunately, there is evidence that the mortality gap between those with bipolar disorder and the rest of the population is only increasing.11 One factor contributing to this widening gap is that people with bipolar disorder are less likely to be treated with medications for cardiovascular risk factors and those who are left untreated experience even greater mortality.12 Interestingly, other studies have found that risk factors for cardiovascular disease, although associated with bipolar disorder, were not as strongly associated with bipolar disorder as was cardiovascular mortality. This may suggest that some component of risk is not mediated through traditional risk factors such as hypertension or hyperlipidemia. Nonetheless, traditional risk factors for cardiovascular disease are a critical and high-yield target for intervention. An analysis of a Swedish national cohort of 6.5 million by Crump et al.13 showed that the risk associated with bipolar disorder dropped after stratifying by risk factors. The authors subsequently suggested that improved primary care could improve mortality outcomes.13

Potential Mediators

Bipolar disorder may influence cardiovascular risk through a diverse array of mechanisms. Although there is some support for an elevated risk of cardiovascular disease beyond that explainable by traditional risk factors, many relevant mechanisms may involve traditional risk factors. Case control studies suggest that those with bipolar disorder have a higher prevalence of diabetes mellitus, hypertension, hypertriglyceridemia, and obesity.14–17 Each of these comorbidities can be treated to mitigate associated cardiovascular risk.

Many of the medications used to treat bipolar disorder may also worsen these cardiovascular risk factors. For instance, antipsychotics and valproic acid derivatives may promote insulin resistance and increase risk of diabetes mellitus. Stimulant medications, which may be used to treat co-occurring attention-deficit disorder, serotonin-norepinephrine reuptake inhibitors, valproic acid derivatives, and some antipsychotics may increase blood pressure. Antipsychotics, especially clozapine and olanzapine, and valproic acid derivatives may promote hypertriglyceridemia. Medications may also promote weight gain and subsequently indirectly worsen these other cardiovascular risk factors. Many antipsychotics, such as clozapine, olanzapine, quetiapine, and risperidone, can cause substantial weight gain, as can valproic acid derivatives. Lithium and nearly all antidepressants except for bupropion can also cause weight gain, especially with long-term use. Mirtazapine appears to have the highest risk for weight gain with antidepressants.18 Cardiometabolic comorbidities may also influence mood treatment outcomes. Those with comorbid cardiovascular risk factors may have a greater burden of mood symptoms and reduced response to treatment.19

There are a variety of behaviors that have been associated with bipolar disorder that may adversely impact risk for cardiovascular disease. The symptoms of mood episodes (eg, anhedonia, fatigue) or a desire to regulate mood may promote these behaviors, which are potential targets for intervention. Globally, the odds that someone with bipolar disorder is a current smoker are 3.5 times that of the general population and over 2 times that of those with major depression. Bipolar disorder uniquely carries some sort of vulnerability for co-occurring nicotine addiction. Those with bipolar disorder are furthermore less likely to quit smoking.20 They are additionally less likely to consume a healthy diet or engage in adequate exercise.21 As part of the diagnostic criteria for both major depressive and manic episodes, sleep disturbances are characteristic of bipolar disorder and can persist even outside of mood episodes. Sleep deprivation conveys a greater likelihood for persistent mood symptoms despite treatment.22

Beyond treatments and associated health behaviors, mood episodes in bipolar disorder may perturb stress response systems in a manner that contributes to risk of chronic diseases, such as cardiovascular disease. Dysregulation of the autonomic nervous system and the hypothalamic-pituitary axis have been observed. Abnormalities in inflammation and oxidative stress have also been described with bipolar disorder. There is some evidence that the levels of proinflammatory cytokines may be higher during mood episodes compared to periods of normal mood (euthymia) in those with bipolar disorder.9 These and other physiological sequelae of bipolar disorder may account for at least some portion of the aforementioned elevated risk for cardiovascular disease that cannot be explained by traditional risk factors for cardiovascular disease or other covariates.

Disparities

Further exacerbating the problem, there are notable disparities in the care received between those with and without bipolar disorder for cardiovascular risk factors. Patients with bipolar disorder are less likely to be screened for hypertension. When hypertension is identified, they are less likely to receive appropriate treatment. Even when appropriate treatment is prescribed, they may be more likely to struggle with adherence.16 Similar issues exist related to care of diabetes mellitus, where patients with bipolar disorder receive lower quality of care relative to those without bipolar disorder. Patients with bipolar disorder and diabetes mellitus are less likely to have their hemoglobin A1c and lipids checked, less likely to receive routine screening ophthalmologic examinations, and less likely to have glucose monitoring. Not surprisingly, this results in poorer glycemic control and more frequent end-stage organ damage with devastating complications such as end-stage renal disease, heart failure, and stroke.23

These disparities are not limited to the assessment and management of risk factors for cardiovascular disease. They further cannot be explained by limited access to health care alone as they are observed in countries or settings with universal access to care. An analysis of the National Health Insurance Research Database of Taiwan found that after acute myocardial infarction, those with a diagnosis of bipolar disorder were less likely to receive interventional procedures.24 These disparities appear to be global and span the full spectrum from primary prevention to the treatment of acute cardiovascular disease.

Clinical Interventions

For the most part, there are established treatments for cardiovascular risk factors and diseases that excessively burden those afflicted with bipolar disorder. Dispatching existing, albeit underutilized, resources for the cardiovascular health of those with bipolar disorder requires a concerted effort to mitigate these considerable health disparities. There may also be opportunities to address risk with interventions specifically tailored for those with bipolar disorder, although studies of these approaches have been somewhat limited. For instance, the highly successful cognitive-behavioral therapy for insomnia has been adapted for bipolar disorder to more carefully utilize sleep restriction, given the potential for reduced sleep to precipitate mood episodes. Behavioral therapy-based interventions targeting nutrition, exercise and wellness have also been studied in small samples with bipolar disorder.25 Collaborative care interventions have been found to successfully address both mood symptoms and control of cardiovascular risk factors in those with bipolar disorder and at least one risk factor for cardiovascular disease.26 Unfortunately, dissemination of these innovative treatments lags behind evidence of efficacy.

Discussion

People with bipolar disorder are nearly twice as likely to suffer or die from cardiovascular disease as the general population,3 which is especially staggering when considering that cardiovascular disease is already the leading cause of death worldwide. Yet, in daily clinical interactions, suicide tends to dominate the attention of psychiatric care providers. This review seeks to inspire psychiatrists to pay similar attention to the long-term risk of cardiovascular disease.

Although not all psychiatrists may feel comfortable with the assessment and management of risk factors for cardiovascular disease, psychiatrists, often the physicians with the most contact with those with a bipolar disorder diagnosis, can play a pivotal role in ensuring appropriate care is received. At a minimum, psychiatrists should be mindful of the cardiometabolic burden of medications prescribed and monitor treatments accordingly. Sadly, psychiatrists have previously been shown to be less likely than primary care physicians to consider metabolic risk in the selection of psychotropic medications.27 With the field slowly rising to meet this important unmet patient need, psychiatrists have the potential to become leaders in the mental and other medical care of their patients. With regard to medication selection, it is important to note the considerable individual variability in the propensity for adverse cardiometabolic effects of psychotropic medications.18 For a given patient, weight gain can be considerable, even for the agents not considered highest risk in the class. For instance, 8% to 11% of patients may gain more than 7% of body weight after just 4 weeks of treatment with aripiprazole.28 This happens to correspond to a critical time frame as weight gain of more than 5% in the first month was found to be the best predictor of substantial long-term weight gain with those psychotropic medications associated with weight gain.29 This provides an opportunity to intervene before even greater weight gain accrues. Once gained, weight can be especially difficult to lose as the set point in the arcuate nucleus of the hypothalamus will defend the acquired fat mass. Thus, providers are called upon to intervene early to address cardiometabolic side-effects and to heed changes observed with agents that may not be on their radar. Although the association between cardiovascular disease and bipolar disorder predates the widespread use of contemporary psychotropic medications, vigilance to iatrogenic cardiometabolic side effects of prescribed medications is an important strategy to mitigate risk and should begin soon after prescribing.

Many risk factors for cardiovascular disease can and should be addressed in the context of routine psychiatric care. Psychiatrists and other mental health providers are uniquely positioned to address behavioral risk factors, such as diet, exercise, and adherence to medications. Motivational interviewing and behavioral techniques used to treat mental and substance use disorders may also be effective in modifying these health behaviors. Psychiatrists also routinely assess and manage sleep disturbances in their patients, which can have a positive impact on cardiovascular health. Smoking, another important risk factor, is highly prevalent and more severe in people with bipolar disorder.30 Aggressive interventions for smoking cessation have the potential to reduce risk for both cardiovascular disease and cancer. Underutilized in those with bipolar disorder, varenicline has been shown to be more effective than nicotine replacement or bupropion in the large EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study) trial, in which most of the large sample had mood disorders. Although psychiatric adverse events were common, they were not significantly more common with active treatment than placebo.31 There is no compelling reason to withhold aggressive interventions for smoking cessation in this group with risk factors.

Conclusion

Bipolar disorder confers a large and unfortunately growing risk for cardiovascular disease. Psychiatrists are invited to see this as a call to action. Psychiatrists have a broad and arguably well-tailored skill set to address patients' physical and mental health challenges. As physicians, psychiatrists are also well-positioned to provide appropriate referrals and assist patients in navigating health care systems to meet their needs. Awareness, action, and collaboration are needed to overcome these disparities in treatments and combat this often overlooked public health crisis.

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Authors

Jess G. Fiedorowicz, MD, PhD, is an Associate Professor, Departments of Psychiatry, Epidemiology, and Internal Medicine, University of Iowa.

Disclosure: The author has no relevant financial relationships to disclose.

Address correspondence to Jess G. Fiedorowicz, MD, PhD, The University of Iowa, 200 Hawkins Drive, W278 GH, Iowa City, IA, 52242; email: jess-fiedorowicz@uiowa.edu.

10.3928/00485713-20190806-01

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