This study supports previous reports of association between BPD and CVD and extends the potential relationship to focus on the longitudinal association between mania, hypomania and incident CVD among community dwelling persons. A history of manic or hypomanic episodes was associated with odds of incident CVD 2.5–3 times higher than the odds among individuals with no history of manic, hypomanic, or depressive episodes, and odds of incident CVD 1.5–2.18 times that of individuals with a history of only major depressive episodes. In addition, the association between manic symptom count at baseline and incident CVD at 11.5 year follow-up suggests a possible dose-dependent relationship and further supports the longitudinal relationship between manic symptoms and incident CVD.
The explanation as to why MHEs are more at risk for CVD is likely to be multifactorial. Increased severity of illness, worse treatment outcome, and less time spent in recovered state are associated with negative health behaviors in BPD (Berk, et al, 2008
; Dalton, et al, 2003
; Goldberg, et al, 1999
; Levin and Hennessy, 2004
; Vanable, et al, 2003
; Weiss, et al, 2005
). Elevated levels of smoking have been associated with bipolar disorder and have been reported to increase with severity of mental illness (Vanable, et al, 2003
). Smoking has also been correlated with worse treatment outcome in acutely manic patients (Berk, et al, 2008
). As in previous studies, smoking in this study was highest in MHEs. Also, in our study, participants with history of mania or hypomania were more likely to have comorbid history of alcohol abuse or dependence. This is consistent with two other large, population based studies where individuals with mania were six (Helzer, 1988
; Helzer and Pryzbeck, 1988
) and eight (Kessler, et al, 1996
; Kessler, et al, 1997
) times more likely to have substance use disorders than the general population. The impact of smoking and substance abuse or dependence on manic and hypomanic individuals may contribute to higher risk of CVD in this population (Schoppet and Maisch, 2001
; Stefanatou, 2008
). However, adjusting for smoking or alcohol abuse/dependence the odds of CVD in MHEs remained the same. This could indicate that these behaviors, in addition to their known direct cardiopathic effect, indirectly increase the risk by contributing to more prevalent, severe and prolonged manic episodes.
Cardiovacular risk factors could be mediators or effect-modifiers in the longitudinal relationship between mania or hypomania and incident CVD. Higher prevalence of diabetes (Beyer, et al, 2005
; McIntyre, et al, 2005
; Regenold, et al, 2002
) and hypertension (Beyer, et al, 2005
; Johannessen, et al, 2006
; McIntyre, et al, 2006
) have been observed in patients with both BPD and depression. Weight gain, over weight and obesity (Keck and McElroy, 2003
; Morriss and Mohammed, 2005
), and metabolic disorder (Beyer, et al, 2005
; Fagiolini, et al, 2005
) are other common comorbid medical conditions in BPD. While higher prevalence of neither diabetes nor hypertension was observed in our sample, other metabolic risk factors (e.g hypercholesteromia) not measured in our study could contribute to the increased odds of CVD in MHEs.
A third possible explanation for higher odds of CVD in MHEs is the use of psychotropic medications. We found an association between CVD and typical antipsychotics, antidepressants, and lithium. Because this association existed in all three types of psychotropic medications as opposed to a specific class of medication, it is more likely that the relationship reflects treatment of an underlying condition, such as mania, rather than a direct cardiotoxic effect (Pratt, et al, 1996
; Thorogood, et al, 1992
). Furthermore, the potential side effects of psychotropic medications (i.e. obesity and diabetes) which are risk factors for cardiovascular disease were not observed in this sample, suggesting that it is the effects of mania, not the effects of medications, that is increasing the risk of incident CVD.
A final explanation for increased odds of CVD in the manic and hypomanic population is that MHEs may be more biologically vulnerable. Manic and depressed patients are more vulnerable to mental stress. Physiologic changes including elevated cortisol in response to stress has been found in manic subjects as well as in depressed subjects (Cassidy, et al, 1998
; Schmider, et al, 1995
). Chronic over activation of pathophysiologically mediated stress response may contribute to atherosclerosis inducing states and mechanisms, including hypercorisolemia, pituitary adrenal gland enlargement, and increased hypothalamic corticotropic-releasing factor (Musselman, et al, 1998
). These abnormal physiologic responses to psychological stress may put manic patients at heightened risk of developing CVD.
Biological vulnerability is a potential explanation for the finding from this study was the MHEs were five years younger than MDEs and nine years younger than NMEs. This was unexpected as older age is among the most significant predictors of CVD (American Heart Association, 2008
). However, it has been hypothesized inability to mediate stress response leads to chronic overactivity (i.e. “allostatic load”) of organs and tissues involved in the physiologic response (McEwen, 2002
). These systems, of which the cardiovascular system is included, experience excessive use which expedites the aging process (McEwen, 2002
). Hypothetically, these physiological abnormalities could lead to exacerbation or development of cardiovascular disease. When examining only subjects in this study who had experienced a cardiovascular event, the age discrepancy was even more pronounced. MHEs were eleven years younger than MDEs and twenty years younger than NMEs. This is consistent with findings from a VA study where bipolar subjects with CVD were significantly younger compared to the general VA population (Kilbourne, et al, 2004
). The physiological impact of labile mood and heightened affective states expedites the aging process, making manic, hypomanic, and bipolar individuals more prone to develop CVD and more vulnerable at a younger age (McEwen, 2002
There are several limitations to this study. Due to the low prevalence of mania and hypomania, our study sample size was small and subsequently the number of incident CVD was also small. Also, 37.3% of MHEs had comorbid MDE. While we adjusted for history of MDE in our study, it is still possible that comorbid mild depression may have contributed to the increased risk of CVD among MHEs. Nevertheless, it is notable that MHE is associated with higher risk of incident CVD than depressive episode alone. Most epidemiological studies assess depressive symptoms only. Our study results suggest the need for assessment for manic symptoms in future epidemiological studies.
Studies have shown elevated CVD related mortality in bipolar individuals compared to the general population and to those with major depression (Angst, et al, 2002
; Osby, et al, 2001
). Examining only non fatal incidence is a conservative ascertainment of CVD, failing to account for more severe incidents. Future prospective studies should extend to look at fatal as well as non fatal CVD.
Finally, the sample of participants with a history of manic episodes and major depressive episodes was based upon DIS symptom criterion at wave I and II. Often, bipolar disorder initially presents itself in depressive episodes (Akiskal, et al, 1995
; Bhugra and Flick, 2005
), leading to misdiagnosis of major depression. Later presentation of mania or hypomanic (e.g. “switching over” to bipolar disorder (Akiskal, et al, 1995
), could not be detected. New onset of manic or hypomanic episodes or major depressive disorder also could not be detected. Presence of manic symptoms was not assessed in Wave III; therefore, it was not possible to account for onset of manic episodes in other groups.
The summation of the limitations in this study suggests an under-ascertainment of participants with history of affective disorders, which is an important consideration when evaluating the results of this study. Future studies should extend to look at fatal as well as non fatal CVD in a manic and hypomanic population excluding comorbid major depressive disorder.