When Bipolar Disorder Presents, Consider Cardiovascular Comorbidities

Heart, rhythm, echocardiogram
Heart, rhythm, echocardiogram
Screening for cardiovascular disease risk is recommended for clinicians who manage patients with bipolar disorder.

Although bipolar disorder (BD) and cardiovascular disease (CVD) are frequently comorbid, clinicians may not seize the opportunity to prevent CV events in patients with the comorbidities. Yet in people with BD, CVD is the leading cause of death.1

Several mechanisms underlie the BD-CVD connection: inflammation, oxidative stress, and brain-derived neurotrophic factor (BDNF).1 The proinflammatory markers C-reactive protein, interleukin 6, and tumor necrosis factor-alpha are increased in the presence of BD symptoms and are also implicated in atherosclerosis. Oxidative stress, also present during BD symptoms, causes dysfunction in the endothelium.1 During the symptomatic phase of BD, BDNF levels decrease, thereby damaging the endothelial cells, which increases the risk for CV events.1 

Why It Is Important to Recognize the Connection

Adolescents with BD tend to develop CVD earlier than people in the general population.1 BD onset occurs before CVD, so clinicians have an opportunity to slow CVD progression.1 Because adults with BD have 5 times the risk of CVD, clinicians should recognize that young patients with BD show signs of CVD 17 years earlier than those who do not have BD.1

When patients with BD are treated for a CV event, they tend to be readmitted to the hospital more often than those without BD (adjusted hazard ratio 1.66; 95% CI, 1.36-2.03; P<.001).1 Likewise, patients with metabolic syndrome have more unemployment, functional impairment, suicide attempts, rapid cycling, manic and depressive episodes, healthcare costs, and hospitalizations.1

“The literature is so compelling, not just in North America but worldwide, that the strength of the CVD-BD link is not really questioned,” said Benjamin I. Goldstein, MD, PhD, FRCPC, director of research in the department of psychiatry at the Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. “The bigger challenge is communicating the message that while all the ‘usual suspects’ — smoking, sedentary lifestyle, obesity, medications — are important, there is more to the story. The notion that BD is in part a systemic vascular disease is not at this point widely held. If research continues to support this notion of BD as a systemic vascular disease, it would have important implications for assessment, treatment, and stigma reduction.”

Testing the Mental Illness-CV Association

Tong and colleagues tested the hypothesis of the BD-CVD association by assessing endothelial function (reactive hyperemia index) and arterial stiffness (augmentation index) in participants with BD (n = 56; mean age, 40.3 years) and healthy controls (n = 26; mean age, 41.2 years).2 The researchers theorized that participants with BD would register a lower reactive hyperemia index and a higher augmentation index, but there were no differences seen between the 2 groups.2

“While we did not find an association between endothelial function and BD in this sample, there is robust literature suggesting that individuals with BD are at a substantially increased risk for CV disease relative to the general population,” said Jess G. Fiedorowicz, MD, PhD, editor-in-chief of the Journal of Psychosomatic Research and associate professor and director of the Mood Disorders Center at the University of Iowa in Iowa City. “I hope that providers approach their patients with BD early with regard to assessing for CV risk factors and address these appropriately where indicated.”

In a retrospective chart study of patients who were admitted to the hospital (N = 5416), Tsai and colleagues found that patients with BD were likelier to die younger than those who did not have BD.3 Of the 51 patients who died during the study, 35 were aged <65 years. Patients with BD were also likelier to have higher BMI and faster heart rates. Of the patients who died, 74.3% had hypertension and coronary heart disease, 22.9% had cerebrovascular diseases, and 2.9% died of other vascular diseases.3

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To reverse the trend of premature morbidity and mortality of patients with comorbid BD and CVD, Shang-ying Tsai, MD, chair of the psychiatry department at Taipei Medical University in Taipei, Taiwan, advises clinicians to “regularly check blood pressure in the outpatient setting. While patients exhibit recurrent manic/depressive episodes, they should monitor those [patients] with elevated systolic blood and higher leukocyte counts and advise them to receive cardiac assessment in a subsequent remission phase.”

Genetics and Environment Play a Role in BD and CVD

In determining patients’ risk for BD and CVD, clinicians should consider epigenetic factors when taking a patient’s history.4 Genetics and the environment have demonstrated effects on whether someone will eventually develop the comorbidities.4 The monozygotic concordance between the metabolic syndrome and BD is 70%.4 BD is also linked genetically to coronary artery disease, hypertension, and diabetes. It is therefore not surprising that as many as half of those with BD also have metabolic syndrome.4 Environmental factors such as childhood trauma, seasonal changes, and sleep also play a role in predicting the occurrence of the metabolic syndrome.4

“Regarding the pathophysiological association of metabolic syndrome and BD, I believe that the importance of sleep, diet, physical exercise, and photoperiodicity in preventive treatment should not be neglected,” said Sermin Kesebir, MD, professor of psychiatry at Üsküdar University in Istanbul, Turkey.

Interventions to Slow CVD Progression

While the BD-CVD association appears incontrovertible, changes in diet, exercise, and weight could alter modifiable risk factors.5 Indeed, the earlier that clinicians recognize the comorbidities, the earlier they can slow the progression to CV events, even in adolescents recently diagnosed with BD.6

“The approach to such conditions involves more assertive monitoring, more stringent benchmarks for CV risk factors, and lower thresholds for intervening when necessary to address these risks,” advised Dr Goldstein. “I hope that clinicians will be aware that CV risk in BD occurs prematurely, the importance of evaluating and, if needed, treating CV risk factors even in young patients.”


  1. Goldstein BI. Bipolar disorder and the vascular system: mechanisms and new prevention opportunities. Can J Cardiol. 2017;33(12):1565-1576.
  2. Tong B, Abosi O, Schmitz S, Myers J, Pierce GL, Fiedorowicz JG. Bipolar disorder and related mood states are not associated with endothelial function of small arteries in adults without heart disease. Gen Hosp Psychiatry. 2018;51:36-40.
  3. Tsai SY, Lee CH, Chen PH, et al. Risk factors for early cardiovascular mortality in patients with bipolar disorder. Psychiatry Clin Neurosci. 2017;71(10):716-724.
  4. Kesebir S. Epigenetics of metabolic syndrome as a mood disorder. J Clin Med Res. 2018;10(6):453-460.
  5. Sodhi SK, Linder J, Chenard CA, Miller del D, Haynes WG, Fiedorowicz JG. Evidence for accelerated vascular aging in bipolar disorder. J Psychosom Res. 2012;73(3):175-179.
  6. Goldstein BI, Carnethon MR, Matthews KA, et al. Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2015;132(10):965-986.