Bipolar Disorder and Risk of Cardiometabolic Disease, Heart Failure, and Mortality

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CASE VIGNETTE

“Mr Kennedy” is a 34-year-old Caucasian male with a history of bipolar I disorder. In his most recent episode, he was depressed with psychotic features. The onset of his mood disorder was at age 21 years. He is currently taking clozapine 125 mg BID and valproic acid 1500 mg at bedtime. He is morbidly obese (BMI = 50) and has comorbid hypertension and hyperlipidemia. He has impaired fast glucose, but does not meet criteria for diabetes.

At an outpatient visit, Mr Kennedy and his psychiatrist decided to stop valproic acid due to elevation of liver function tests. Mr Kennedy was tapered off of valproic acid over 4 months. A year later, he had lost 26 pounds (~8% of his total body weight) and his BMI had decreased to 45, without any change in psychiatric symptoms. Four years after stopping valproic acid, he lost an additional 22 pounds and his BMI was 42. Three weeks after his most recent outpatient visit, his mother called to inform his psychiatrist that Mr Kennedy died of an apparent myocardial infarction.

Bipolar disorder is associated with increased cardiovascular disease comorbidity and mortality and a shorter life expectancy.^1-5 Most previous studies were conducted in Europe and North America, with more limited evidence in Asian populations. In patients with bipolar disorder, heart failure may be a major cause of excessive sudden cardiac death in patients aged >50 years.⁶ Another small study found evidence of unfavorable cardiac structural measures in patients with bipolar disorder.⁷

The Current Study

Lee and colleagues⁸ hypothesized that Asian patients with bipolar disorder would have significantly increased cardiometabolic disease, including hospitalization for heart failure (hHF) and early all-cause mortality. They compared risks of ischemic stroke, ischemic heart disease (IHD), composite cardiometabolic disease, and all-cause mortality in individuals with bipolar disorder and non-psychiatric age- and sex-matched controls through a nationwide, population-based cohort study in South Korea.

The investigators analyzed data from the Korean National Health Insurance Service (KNHIS), an anonymized public database that covers all Korean residents, from 2002 to 2018. From all individuals who had first been diagnosed with bipolar disorder between 2003 and 2107, a representative sample cohort comprising 20% of the total sample was selected with stratified random sampling with proportional allocation within strata for age, sex, residential area, and household income.

Inclusion criteria were a primary diagnosis of F30-31 and ≥1 claims for psychiatric medications. Individuals with a recording of a psychotic disorder code (F20-29) were excluded. For comparison, a representative 20% sample cohort of healthy controls who had never been diagnosed with major psychiatric disorders (depression, bipolar disorder, or psychotic disorder) were selected with the same sampling method as used for patients with bipolar disorder.

Exclusion criteria for both groups were individuals who died within 90 days after baseline, had claims for cardiometabolic disease or coronary procedures, or had been hospitalized for a transient ischemic attack before or within 3 months of baseline, and/or < age 18 years.

The study cohort consisted of 11,329 participants with bipolar disorder and 1:1 matched controls. Outcomes were incident ischemic stroke, IHD, hHF, a cardiometabolic disease composite, and all-cause mortality during follow-up. The cohort was followed from baseline until death, outcome development, or December 31, 2018 (whichever came first). Using Kaplan-Meier curves, the cumulative incidence of outcomes was compared between individuals with bipolar disorder and healthy controls using a log-rank test. Multivariable Cox regression analyses were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the outcomes in individuals with bipolar disorder and controls.

The mean duration of follow-up for the cohort was approximately 11 years. The cumulative incidence of all outcomes was significantly higher in individuals with bipolar disorder than controls. The incidence per 1000 person years in individuals with bipolar disorder was 0.94 for ischemic stroke, 9.5 for IHD, 0.95 for hHF, 85.1 for composite cardiometabolic disease, and 5.5 for all-cause mortality. The hazard of all outcomes was significantly higher in individuals with bipolar disorder: ischemic stroke HR=2.0, 95% CI 1.4-2.7, IHD HR=1.6, 95% CI 1.4-1.7, hHF HR=2.5, 95% CI 1.8-3.6, cardiometabolic composite HR=1.94, 95% CI 1.86-2.02, and all-cause mortality HR=2.2, 95% CI 1.9-2.5.

In subgroup analyses by age, the association between bipolar disorder and all outcomes, except ischemic stroke, were more prominent in younger individuals. In subgroup analyses by sex, the association between bipolar disorder and all outcomes, except hHF, were more prominent in females. In sensitivity analyses, the pattern of findings was unchanged regardless of history of treatment with mood stabilizers and whether the initial diagnosis was depression or bipolar disorder.

Study Conclusions

In this population-based nationwide cohort of low-risk individuals without baseline hypertension, dyslipidemia, diabetes, or any other cardiometabolic or vascular disease, bipolar disorder was associated with an increased risk of ischemic stroke, IHD, hHF, composite cardiometabolic disease, and all-cause mortality during follow-up. In subgroup analyses, these associations were more prominent in younger individuals and women.

Study strengths include the use of a large, representative, nationwide dataset with rigorous matching. Study limitations include the focus on Korean adults with low baseline cardiovascular risk, which delimits generalization to other populations; the observational nature of the study design; and the lack of specific information on cause of death.

The Bottom Line

Bipolar disorder was associated with increased risk of cardiometabolic disease and premature all-cause mortality, particularly in younger individuals and women. Findings suggest that regular screening and preventive measures for cardiovascular disease are warranted for individuals with bipolar disorder of all ages. Potentially relevant interventions include patient education, lifestyle modification, and cardioprotective pharmacological treatments.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Vieta E, Berk M, Schulze TG, et al. Bipolar disorders. Nat Rev Dis Primers. 2018;4:18008.

2. Hayes JF, Miles J, Walters K, et al. A systematic review and meta-analysis of premature mortality in bipolar affective disorder. Acta Psychiatr Scand. 2015;131(6):417-425.

3. Westman J, Hällgren J, Wahlbeck K, et al. Cardiovascular mortality in bipolar disorder: a population-based cohort study in Sweden. BMJ Open. 2013;3(4):e002373.

4. Callaghan RC, Khizar A. The incidence of cardiovascular morbidity among patients with bipolar disorder: a population-based longitudinal study in Ontario, Canada. J Affect Disord. 2010;122(1-2):118-123.

5. Foroughi M, Medina Inojosa JR, Lopez-Jimenez F, et al. Association of bipolar disorder with major adverse cardiovascular events: a population-based historical cohort study. Psychosom Med. 2022;84(1):97-103.

6. Chen PH, Tsai SY, Pan CH, et al. Incidence and risk factors of sudden cardiac death in bipolar disorder across the lifespan. J Affect Disord. 2020;274:210-217.

7. Chen PH, Chiang SJ, Hsiao CY, et al. Echocardiographic study of cardiac structure and function in people with bipolar disorder after midlife. J Affect Disord. 2022;296:428-433.

8. Lee YB, Kim H, Lee J, et al. Bipolar disorder and the risk of cardiometabolic diseases, heart failure, and all-cause mortality: a population-based matched cohort study in South Korea. Sci Rep. 2024;14(1):1932.