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Gender Differences in the Link Between Depression and Cardiovascular Disease

From the Division of Cardiology (T.Z.N., N.B.M.), Department of Medicine and the Department of Psychiatry (S.S.A.N.), Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, California.

Address correspondence and reprint requests to Tasneem Z. Naqvi, MD, Rm. 5341, Division of Cardiology, 8700 Beverly Blvd., Los Angeles, CA 90048. E-mail: tasneem.naqvi{at}cshs.org

	ABSTRACT

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Objectives: Cardiovascular disease is the leading cause of mortality in women costing more than 500,000 lives each year in the United States alone. Major depression in healthy subjects increases cardiovascular mortality in both men and women. The presence of major depression in patients with recent acute myocardial infarction (AMI) or unstable angina more than doubles the risk of cardiac death in both men and women. In the presence of depression, lack of social integration has an additive effect on cardiac events. Depression is more prevalent in women with coronary heart disease (CHD) than in men. Psychologic counseling as well as cognitive behavioral treatment in women post-AMI seems to adversely affect prognosis, whereas it has neutral effects in men. Pharmacologic treatment of depression with serotonin reuptake inhibitors is safe in men and women post-AMI and is particularly effective in patients with recurrent depression. Whether effective treatment of depression lowers cardiac mortality remains to be proven.

Key Words: depression • coronary artery disease • gender differences • mortality

Abbreviations: CHD = coronary heart disease; AMI = acute myocardial infarction; SSRIs = serotonin reuptake inhibitors; CABG = coronary artery bypass surgery.

	INTRODUCTION

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Because traditional cardiac risk factors do not account for all of the variance of coronary heart disease (CHD), there has been a growing interest in nontraditional cardiac risk factors, including psychosocial variables. Because of the increased prevalence of depression in women (1), it is a particularly relevant psychosocial and health variable for women with CHD. Ironically, although more women than men have died annually from CHD since 1984 (1), little of the investigation of links between CHD and psychosocial variables have focused specifically on women.

Gender Differences in Depressive Disorder
The prevalence of major depression is two times higher in women than in men, beginning in early adolescence (2). Biologic factors consisting of a lifetime of fluctuating hormonal levels from menstrual cycle and reproduction, and psychosocial factors may contribute to these gender differences (3). Clinical features of depression in women include more atypical symptoms, anxiety and eating disorders, and longer and more recurrent depressive episodes. There may also be gender differences in the response to treatment for depression. For example, women may respond more slowly to antidepressant treatment than men.

Depression as a Primary Risk Factor for Coronary Heart Disease in Women
In general, depression appears to increase the risk of development of CHD in men and women alike (4), and increases CHD mortality in both (5,6), independent of other traditional CHD risk factors. Depression rates are doubled in the presence of diabetes and are considerably higher in diabetic women compared with diabetic men (7), and depressed diabetic women have more rapid development of CHD compared with nondepressed diabetic women (8). In one study, depression was a predictor of CHD in women with insulin-dependent diabetes, but not in men (9), but more study is needed to determine if depression and diabetes have a more adverse interaction in women compared with men.

Depression as a Prognostic Variable in Women With Established Coronary Heart Disease
Depression is more prevalent in patients with established CHD (10) than in the general population. Depression is also associated with a significant and similar increase in cardiovascular risk in both women and men with established CHD (11). However, depression is far more prevalent in women post-acute myocardial infarction (AMI) compared with men irrespective of age and comorbidity (12–15). These gender differences in depressive symptoms are greatest among younger female patients (10). In addition, women with AMI have more severe depression compared with men, and depressive symptoms persist longer (16,17). Women also have a greater prevalence of depression as well as have more severe depressive symptoms than men after coronary artery bypass surgery (CABG).

With respect to other concurrent psychosocial risk factors, women report lower levels of social support after AMI compared with men (18,19). In women who present with AMI or unstable angina, lack of social support and social integration, as well as presence of depression, are strong predictors of adverse CHD outcome and both independently enhance the risk of cardiac death, recurrent AMI, or revascularization by 2- to 2.5-fold (20). In addition, marital stress enhances the risk of recurrent coronary events and death (21), whereas work stress does not appear to enhance CHD risk in women. These findings are in contrast to those in men in whom work stress is associated with increased CHD incidence and cardiac death (22).

Other research indicates that men and women with CAD differ in various behavioral and coping responses after acute cardiac events. For example, the rate of return to work after AMI or CABG is significantly lower in women than in men (23). Social support networks that may affect recovery post-AMI differ significantly by gender (23). A metaanalysis of studies that examined coping strategies after AMI found that women minimized the impact of the disease, tended to delay seeking treatment, and did not want to bother others with their health problems (24). Household activities, on the other hand, were important to women and aided their recovery. The metaanalysis also revealed that women received less information about their disease and rehabilitation and experienced a lack of belief in their heart problems from caregivers. Furthermore, they received less assistance with household duties from informal caregivers. Men were more likely to involve their spouses in their recovery, and resuming work and keeping physically fit were important to them. Men tended to report more support from their spouses than did women. Data on sexual activity of women after AMI or CABG are scarce, and there seems to be a complete lack of physician counseling on this topic (25). Combined, these data suggest that women differ from men in a variety of psychosocial dimensions that may impair recovery post-AMI. These data further imply that specific preventive measures should be considered that could be tailored to the needs of women with CHD.

Women, in general, have a more adverse post-MI prognosis than men (26–28), and they are also more likely than men to have a history of hypertension, congestive heart failure, and diabetes. However, when adjusted for these baseline differences, the gender gap in post-MI mortality for women persists in some studies (26), suggesting that this gap may not be entirely the result of these age-related comorbid conditions. Evidence also suggests that younger women with AMI may experience an increased risk for adverse outcomes even after adjustment for other prognostic variables (29). It has been suggested that the higher prevalence of depression in women may contribute to this gender difference in post-AMI prognosis (28), but prospective study is needed to clarify this point. Although depression enhances CHD mortality in women (18), this adverse cardiovascular effect of depression appears to be similar in men and women. In summary, when depression is present after MI, it may be a potent risk factor in men and women, but the higher prevalence of depression in women post-MI may help account for their increased risk.

	BEHAVIORAL INTERVENTION STUDIES IN WOMEN

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Several studies have found that more women refuse to participate in assessment of depression than men (30). Elderly women in particular are difficult to enroll in randomized, controlled trials (31). With respect to the actual conduct of studies, very sparse data are available. Women comprised approximately one third of the study sample of the 369 patients in the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) (30). Treatment with serotonin reuptake inhibitors (sertraline [Zoloft]) appeared effective for depression in those with recurrent depression in this trial, but the small numbers of women did not allow separate examination of this issue based on gender. However, the Montreal Heart Attack Readjustment Trial (M-HART) (32) did permit a specific comparison of effect of psychologic counseling based on gender. In this study, although women had significantly more home nursing visits for counseling, telephone calls, and duration of nursing contact than men, the program had no impact on psychologic symptoms for women. Furthermore, although the M-HART program did not have a significant impact on 1-year cardiac mortality in men, cardiac mortality (9.4 versus 5.0%, p = .064) and all-cause mortality (10.3 versus 5.4, p = .05) was higher in women in the treatment group than in the control group. Patients with short-term successful changes in psychologic distress had better long-term prognosis than patients with unsuccessful short-term changes (33). However, women were significantly less likely to experience a short-term reduction in psychologic distress. Adverse consequences of cognitive behavioral therapy in women post-AMI have also been observed in the ENRICHD study (31). Specifically, women who received cognitive behavioral therapy had worse outcomes than their usual care group counterparts. A similar finding was not noted in men. However, post hoc adjustment for age and comorbidity attenuated this gender–treatment effect.

More generally, treatment of depression in the ENRICHD trial and in some other studies did not result in improved cardiac outcome in either men or women. This lack of apparent benefit has been attributed to multiple factors. For example, aggressive pharmacologic, antiplatelet, and revascularization treatment has reduced CHD mortality, making further reductions in CHD events in controlled trials increasingly difficult to observe. Lipid-lowering therapy may also mediate antidepressive effects through an antiinflammatory mechanism. Depressed CHD patients, at least in those who are treatment-resistant, may also be different from patients without CHD. Depression in CHD patients may be a manifestation of atherosclerosis, such that treatment of the "vascular depression" itself is not effective for CHD event reduction. Finally, postmenopausal women with CHD may have a biologically different pathophysiology of depression, such that future studies should aim to have a better understanding of sex and gender-specific pathophysiology, and specifically plan sex-specific interventions. Overall, the adverse findings for women reported for the M-HART trial as well as in the ENRICHD study support the view that there may indeed be something important about the observed gender–treatment effect.

	SEX AND GENDER SPECIFIC DEPRESSION PATHOPHYSIOLOGY

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An often overlooked issue with gender is that of oppression. Men on average continue to dominate women in physical, emotional, and financial societal terms. Although one in three women has experienced sexual abuse (child molestation, rape, domestic violence) in her lifetime, the figure for men remains less than 10% (34). Domestic violence and rape are deemed the sixth cause for loss of life years as a result of death or physical incapacitation among women aged 15 to 44 years—more than all types of cancer, traffic accidents, and wars (35). Adverse experiences in childhood and adolescence increase the risk of anxiety and depression in adulthood (36). In women, the onset of depression and anxiety is often provoked by a severely threatening event, and early adverse experiences also increase the risk of both depression and anxiety later in life (37).

Few studies have examined the specific issue of how depression contributes to the development of CHD in women. Pathophysiological insights come from observations made on experimental animals. In one experimental model of stress, the social stress of subordination caused hypothalamic–pituitary–adrenal and hypothalamic–pituitary–ovarian dysfunction in adult female cynomolgus monkeys (38). These submissive female cynomolgus monkeys developed more atherosclerosis than nonstressed females. Interestingly, these subordinate females also developed signs of depression and poor ovarian function, which along with hypercortisolemia, increases cardiovascular reactivity and metabolic syndrome (both also seen with depression). These pathophysiological pathways may help account for the enhanced atherosclerosis seen in women, especially after menopause.

The response to physical or social stressors, however, is considerably blunted by the availability of coping responses such as social outlets for frustration or social support (39). Thus, the extent to which social stress has physiological or pathophysiological consequences is not merely a function of the frequency or severity with which an individual is exposed to stressors. Availability and efficacy of coping responses to offset the physiological impact of social stressors are important adaptive responses (40). Therefore, extrapolation from experimental animal to human studies must not only consider the presence and magnitude of stressors, but also measure the adequacy of coping responses relative to their impact on the frequency of subsequent depression and adverse event rates among stressed women.

	SUMMARY

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Although there is limited evidence to support a clinical benefit of CHD event reduction with psychologic treatment of depression in women, depression delays recovery post-AMI and after CABG in women. Treatment guidelines in women with CHD emphasize evaluation and referral for depression in women with CHD (class II a indication) (41). Pharmacologic treatment with SSRI appears safe and effective in treating depression in women with CHD. However, the development of safe but effective cognitive-based interventions in depressed women still requires prospective study.

	NOTES

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In accordance with CME accreditation guidelines, author Syed S. A. Naqvi disclosed that he has received research support from, served as a consultant for, and/or served on the speakers' bureau for Jansen, Eli Lilly, and AstraZeneca. The other authors of this article disclosed no real or potential conflicts of interest.

DOI:10.1097/01.psy.0000164013.55453.05

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