Depression and Cardiovascular Disease: An Incendiary Duo
Depression and Cardiovascular Disease: An Incendiary Duo
Authors: Randy A. Sansone, MD, Professor, Departments of Psychiatry and Internal Medicine, Wright State University School of Medicine, Dayton, OH, Director of Psychiatry Education, Kettering Medical Center, Kettering, OH; and Lori A. Sansone, MD, Civilian Family Physician, Medical DirectorPrimary Care Clinic, Wright-Patterson Air Force Base, Dayton, OH.
Peer Reviewer: Glenn Currier, MD, MPH, Associate Professor of Psychiatry and Emergency Medicine, University of Rochester Medical Center, Rochester, NY.
Note: The views and opinions expressed in this article are those of the authors and do not reflect the official policy or position of the US Air Force, Department of Defense, or US Government.
Introduction
Primary care clinicians invariably encounter seriously ill patients who suffer from both depression and cardiac disease. While the relationship between these syndromes may be bi-directional (i.e., depression contributes to cardiac disease and cardiac disease contributes to depression), in this edition of Primary Care Reports, we will only examine the role of depression and its effect on cardiovascular disease (CVD). We will also explore the recommended pharmacological approach for the treatment of depression when these two syndromes are comorbid.
Depression as a Risk Factor for CVD
For a number of years, clinicians and researchers have speculated about a possible relationship or link between pre-existing depressive symptoms and/or bonafide mood disorders, and the subsequent development of CVD. In response, the research in this area has experienced marked growth over the past 15 years.1 Due to space considerations, we can only review a sampling of these relevant studies.
Studies in Non-Clinical Populations. A number of studies have been undertaken in non-clinical samples (i.e., community populations) and support the notion that pre-existing depressive symptoms and/or mood disorders statistically increase the risk for subsequent CVD. For example, in a 12-year prospective follow-up study of nearly 1200 elderly Finnish men and women, self-reported depression scores at the outset of the study correlated with higher subsequent risks of mortality from CVD or myocardial infarction.2 In a community sample of more than 12,000 Hungarian participants, Kopp and colleagues found that, among other variables (e.g., low social support, hostility, alcohol use, cigarette smoking), depression was a meaningful contributory factor to the subsequent development of premature cardiovascular mortality.3 Finally, in a prospective study of 643 family caregivers of dementia patients, Mausbach and colleagues found that higher levels of depressive symptomatology correlated with shorter time periods to a diagnosis of CVD.4
Studies in Clinical Populations. Studies examining the relationship between depression and CVD have also been undertaken in various types of clinical populations. For example, in a sample of African-American women with type 2 diabetes, Collins-McNeil and colleagues confirmed statistical associations between depression scores on an assessment measure and mean cardiovascular risk scores.5
In an Australian study of 755 women, investigators found that participants with self-reported angina symptoms were about four times more likely than controls to report a lifetime history of depression.6 In this latter study, there were no inter-relationships between weight, cholesterol levels, hypertension, inactivity, and diabetes, and lifetime history of depression.
In a study undertaken by Janszky and colleagues, compared with hospital-catchment-area matched controls, participants with a first myocardial infarction had a greater likelihood of being previously hospitalized for depression (i.e., a calculated odds ratio of 2.9).7 In this study, lifestyle, lipid profile, coagulation, inflammation, prior cardiovascular events, and other comorbidity only partly decreased this observed relationship.
Compared with non-depressed controls, Gromova and colleagues found that depressed Russian men between the ages of 25 and 64 years had a two-times-greater risk of subsequent myocardial infarction.8 In this study, depression was assessed using an interview-based methodology, which is considered to be more robust than self-report approaches.
In a sample of over 900 dialysis patients, Boulware and colleagues found a relationship between depression, as measured on a five-item index, and subsequent cardiovascular events and deaths.9 Interestingly, in this study, depressive symptoms were also associated with all-cause deaths.
Finally, there is the phenomenon of acute emotional stress precipitating cardiac symptoms (i.e., broken heart syndrome). This condition has also been called stress cardiomyopathy and can mimic a heart attack, but is thought to be caused by prolonged adrenalin and other stress hormone secretions that temporarily 'stun' the heart. Typically, affected patients are middle-aged or elderly women who have been previously healthy with few risk factors for heart disease. These patients often present with the signs and symptoms of a typical heart attack such as chest pain, shortness of breath, and heart failure, and with associated elevated cardiac enzymes and MRI evidence of seemingly irreversible muscle damage. Unlike genuine heart attack victims, these patients seemed to recover faster. Related to this discussion, the patients characteristically have a history of sudden emotional stress, such as the news of a death, shock from a surprise party, fear of public speaking, armed robbery, a court appearance, or a car accident. Significantly elevated levels of stress hormones and metabolites such as catecholamines, neuropeptide Y, brain natriuretic peptide, and serotonin are presentsubstances that can be temporarily toxic to the heart. These substances effectively stun the heart muscle or induce coronary spasm, which produces symptoms. A unifying factor in these patients is a unique abnormal contraction pattern found on echocardiogram.10
Conclusions. Several conclusions may be drawn from this sampling of studies. First, regardless of the nature of the population under investigation (i.e., clinical or non-clinical), depressive symptoms (not necessarily formal DSM diagnoses such as major depression or dysthymia), in addition to other types of lifestyle and medical variables, appear to contribute meaningfully to the development of CVD in terms of both forthcoming cardiac events and mortality. Second, the fact that these data come from a number of different epidemiological samples suggests that this relationship (i.e., the propensity for depressive symptoms to contribute to the development of cardiac disease), to whatever degree, is likely to be a universal phenomenon.
The Effects of Current Depression on Existing CVD
According to the preceding findings, in conjunction with other contributory variables (e.g., lifestyle, obesity), depression appears to modestly predict for higher rates of CVD and mortality. What about the effects of current depression on existing CVD? Several investigators have explored this relationship.
Sample Studies. In a study of 468 patients with myocardial infarctions, de Jonge and colleagues examined participants for depressive symptoms in the year following the index cardiac event. These investigators found that, compared to those without depression, participants with new-onset depression (as opposed to ongoing or recurrent depressions, or no depression at all) were at an increased risk of post-infarction cardiovascular events.11
Rutledge and colleagues assessed more than 500 women with cardiac ischemia for depression and followed them for a mean of 4.9 years. They found an association between depressive symptoms at study onset and a subsequent increased incidence of cardiac events and death.12
In a similar vein, Jaffe and colleagues followed nearly 2500 post-myocardial-infarction patients for a mean of 2.5 years. Among the multivariate predictors (e.g., age, heart failure, pulmonary disease, Killip class, ejection fraction, elevated creatinine, prior myocardial infarction, diabetes), those with depression at baseline had an increased risk of non-fatal re-infarctions or death.13
Sherwood and colleagues examined outpatients with ventricular ejection fractions of 40% or less (i.e., those with heart failure). Using scores on the Beck Depression Inventory, they determined that participants' current level of depression increased the subsequent risk for cardiovascular hospitalization as well as death.14
Conclusions. This sampling of studies suggests that current depression in those with existing CVD has a negative impact on various aspects of medical outcome. Specifically, higher levels of depression are associated with greater risks of subsequent cardiovascular events as well as mortality.
Explanations for the Association Between Depression and CVD
What might explain the relationship between depressive symptoms/mood disorders and the development and outcome of CVD? A number of authors have offered hypotheses, both pathophysiological and psychosocial.
Pathophysiological Hypotheses. Garcia-Gomez and colleagues suggest that the relationship between depression and CVD might be explained by some type of dysfunction in the central autonomic network. They propose that this dysfunction occurs in the areas of the hippocampus, prefrontal cortex, and brain stem nuclei, and as a result, causes lowered levels of serotonin, sympathetic excess, and a loss of cardiac vagal tone.15 Bounhoure and colleagues propose that this relationship is mediated by sympathetic stimulation, endothelial dysfunction, low heart rate variability, and abnormal platelet function.16
Fenton and Stover note that dysregulation in the hypothalamic-pituitary-adrenal axis, which often is encountered in depression, may contribute to CVD.17
Finally, Parissis and colleagues emphasize that the "pathophysiological mechanisms underlying the link between depression and adverse cardiac events in coronary artery disease patients ... remain poorly understood." As possible explanations, they propose immune activation, inflammation, hypercoagulation, cardiac rhythm disturbances, and metabolic disorders.18 (See Table 1.)
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It is worth noting that several investigators have identified mechanisms that do not seem to mediate the relationship between depression and CVD. These etiological dead-ends include cardiovascular reactivity19,20 and inflammatory markers. (Note that this is in opposition to the preceding theory of Parissis and colleagues.)21
Psychosocial Hypotheses. In addition to pathophysiological explanations for the link between depression and CVD, several psychosocial factors have also been suggested. (See Table 2.) For example, Kamphuis and colleagues found that depression in men was associated with physical inactivity, which is not an unexpected finding.22 However, during a 10-year follow-up period, these investigators confirmed that physical inactivity was subsequently associated with greater cardiovascular mortality.
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Spernak and colleagues found an association between depression and less adherence to a post-operative cardiac rehabilitation program.23 This finding has been noted by others and may reflect the motivational as well as hopelessness components of depression.
Fenton and Stover suggest that poor diet may have a negative impact on the outcome of CVD in depressed individuals.17 They also discuss the role of reduced exercise in relationship to depression and CVD.
Finally, among the depressed, Parissis and colleagues implicate poor self-care, continued smoking, low motivation, noncompliance with treatment, and low participation in cardiac rehabilitation programs.18
Summary. While researchers have not completely clarified the relationship between depression and cardiovascular phenomena, it seems likely that there are multiple factors, both pathophysiological and psychosocial, that mediate this complex association.
Assessment of Depression in the Clinical Setting
Given the association between depression and CVD, depression assessment of all cardiac patients seems warranted. There are a number of available depression screening assessments that are self-report in design, brief, reasonably valid and reliable, and of no cost to the clinician. Examples include the Beck Depression Inventory,24 the Zung Self-Rating Depression Scale,25 and the Patient Health Questionnaire-9.26 These measures may be used for both the initial screening and assessment of depressive symptoms as well as the monitoring of symptom response to pharmacological treatment. However, like all self-report measures, these preceding assessment tools have clinical limitations. For example, a respondent may over- or under-endorse items because of the context of the testing environment and/or the perceived expectations of others. In addition, some items that are typically associated with depression may be related to medical illness, such as fatigue, sleep disturbance, and appetite changes. Therefore, these measures are viewed as screening tools and should be corroborated with further clinical exploration.
Beck Depression Inventory. The Beck Depression Inventory24 is an historic self-report measure for the assessment of depression. Now in its third version (i.e., the Beck Depression Inventory-II27), each item has a range of graded possible responses, and individual items for the latest version include sleep changes, appetite change, loss of sexual interest, feelings of being punished, and thoughts of suicide. Scores of 14 or higher are indicative of clinical depression, with higher scores indicating more severe depression.
In addition to the previous general versions, there is a short self-report version that was specifically designed for use in primary carethe Beck Depression Inventory for Primary Care (BDI-PC).28 The 7 items in this inventory are considered to be independent of the physical symptoms that are encountered in those with medical illness.
Zung Self-Rating Depression Scale. The Zung Self-Rating Depression Scale25 is a 20-item self-report assessment for depression that explores affective, psychological, and somatic symptoms. Response options are in Likert-style format (i.e., 1 = a little, 2 = some, 3 = a good part of the time, 4 = most of the time). Scores above 50 are considered indicative of depression, with higher scores indicating more severe depression. Like the Beck Depression Inventory, the Zung Self-Rating Depression Scale25 has been an historically popular measure in both clinical and empirical settings.
Patient Health Questionnaire-9. One of the newer measures in the field is the Patient Health Questionnaire-9.26 This measure is a 9-item self-report assessment for depression that is based on the diagnostic criteria for major depression that are noted in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The measure queries respondents about symptoms "over the past 2 weeks" and response options are graduated by the degree of symptom presence (i.e., "not at all," "several days," "more than half the days," "nearly every day"). Scores of 0-4 indicate no depression, 5-9 mild depression, 10-14 moderate depression, 15-19 moderately severe depression, and 20-27 severe depression. (See Figure 1.)
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The Role of Antidepressants
If depression contributes to CVD, both prospectively and concurrently, does depression treatment exert an impact on medical outcome? There is very little available research in this area.
Tricyclic Antidepressants: The Limitations. While tricyclic antidepressants have been explored in patient populations with cardiac disease, these drugs are associated with a number of adverse cardiac effects. These problematic effects include orthostatic hypotension, tachycardia, slowing of the cardiac conduction system, and an undesirable cardiac arrhythmic effect. In addition, tricyclic antidepressants have anticholinergic effects (e.g., constipation, memory impairment) and most cause weight gain, a very undesirable effect for patients with cardiac disease. With regard to tricyclic antidepressant treatment in patients with CVD, Paraskevaidis and colleagues29 have broached the uncomfortable clinical bindthey state that tricyclic antidepressants should be avoided during the first 2 to 3 months following a myocardial infarction, but indicate that this may be the time when depressive symptoms are most pronounced in those with CVD. Given the advent of effective non-tricyclic antidepressants, tricyclic antidepressants are no longer pragmatic treatment options for depression in this population.
Other Antidepressants: The Evidence. Sertraline is the most-studied non-tricyclic antidepressant in patients with CVD. There are also studies with citalopram and mirtazapine. Each of these newer antidepressants appears to be well tolerated and safe in patients with cardiac disease, although mirtazapine is associated with weight gain and therefore may be a less attractive option. Both sertraline and citalopram have clearly demonstrated efficacy in treating depression in this population30 and appear to improve overall quality of life.31 However, at this juncture, the predictive effect of antidepressant treatment with regard to cardiovascular outcome remains unclear.31
Given the preceding caveat, several studies suggest that antidepressants may modestly improve CVD outcome. In this regard, Glassman and colleagues examined the efficacy of sertraline in preventing subsequent cardiac events in a group of depressed hospitalized patients with myocardial infarctions.32 In this controlled study, the subgroup of patients on sertraline experienced fewer subsequent cardiac events (14.5%) compared with non-treated individuals (22.4%). However, there was not a statistically significant between-group difference.
de Jonge and colleagues compared antidepressant-responders with untreated controls. Antidepressant-responders to citalopram and mirtazapine were the least likely subgroup to develop new cardiac events following myocardial infarction.33
Finally, in a small study by Mohapatra and colleagues of depressed post-myocardial-infarction patients, cardiac events were around three times more frequent in the no-antidepressant-treatment subgroup compared to participants on antidepressant treatment with sertraline.34
In summary, preliminary findings modestly lean in the direction of a positive effect regarding several newer antidepressants and their impact on cardiovascular outcome. However, we must emphasize that this effect appears to be modest.
Antidepressant Efficacy in Cardiac Disease: Possible Explanations. If the newer antidepressants, particularly the selective serotonin reuptake inhibitors (SSRIs), are ultimately confirmed to be efficacious in CVD outcome, their effects may not be limited to the alleviation of depression. Parissis and colleagues have suggested that there may be relevant effects of these drugs on platelets (e.g., an inhibition of platelet activity).18 In addition, Paraskevaidis and colleagues indicate that SSRIs may deter immune activation (i.e., prevent an inflammatory response) as well as normalize neurohormonal dysfunction (e.g., autonomic dysregulation) in CVD patients.31
SSRI Selection in Patients with CVD. Whether or not antidepressant treatment will effectively ward off CVD or reduce morbidity remains unclear, but the few available studies do suggest modest effects. Given their very low risk, it seems pragmatic to use SSRIs in patients with cardiac disease and depression.
General Side Effects. The most common initial side effects of SSRIs are headaches, nausea, mild fatigue, and sexual dysfunction (i.e., decreased libido, delayed ejaculation). Most of these side effects are well tolerated and/or subside with time, with the exception of sexual dysfunction, which may persist with ongoing treatment.
Psychomotor Effects. In considering the pharmacological treatment of cardiac patients with SSRIs, the individual properties of these drugs become essential. (See Table 3.) Note in Table 3 that the SSRIs are ordered from top to bottom according to their tendency to cause psychomotor activation. Fluoxetine is the only predictably activating SSRI. For some individuals, this activation effect may manifest as anxiety, nervousness, jitteriness, and insomnia. The remainder of the SSRIs are either psychomotor neutral or have mild-to-moderate sedation.
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Half-life. With regard to half-life, all SSRIs have a sufficient duration to be dosed once-per-day. However, it is important to note that the active metabolite of fluoxetine has a half-life of 16 days. Given that it takes approximately 4-1/2 to 5 half-lives to eliminate a drug from the body, fluoxetine may remain present up to 2 or more months following its discontinuation. This is particularly problematic if fluoxetine was discontinued due to intolerable side effects.
Discontinuation Syndromes. After treatment for several months, all SSRIs can cause withdrawal symptoms upon their prompt discontinuation. These withdrawal symptoms are not medically dangerous and are collectively referred to as a "discontinuation syndrome." Symptoms typically include headaches, nausea, light-headedness, irritability, mood lability, sleep disturbance, and insomnia. On occasion, particularly with paroxetine, patients may experience cerebral paresthesias (i.e., "electrical shocks in my head") or gait difficulties. Because all SSRIs are structurally different and each affects a different complement of serotonin sub-receptors, discontinuation symptoms can only be suppressed with the re-institution of the offending SSRI. In comparison with the other SSRIs, paroxetine is the most serotonergic and appears to have the most robust discontinuation syndrome.
P-450 Effects. With regard to drug interactions via the P-450 isoenzyme system, SSRIs potentially may slow down metabolic enzymes and each has a different profile. For example, fluvoxamine potentially affects the most P-450 isoenzymes and is the SSRI that is most likely to affect other co-prescribed drugs by elevating their serum levels. Given that cardiac patients will be prescribed adjunctive medications, this particular SSRI is more difficult to use because of the risk of drug interactions. In contrast, sertraline, citalopram, and escitalopram have low propensities to cause drug interactions and are excellent selections in cardiac patients who are prescribed other medications.
Weight Effects. SSRIs run the risk of causing weight gain. While these risks seem modest at the end of 12-months of treatment with fluoxetine, sertraline, and citalopram, extended use may still result in an increase in body weight. In contrast, paroxetine has a predictable tendency to cause weight gain, although this effect may be delayed for several months, up to a year or more. Because of the substantially greater risk of weight gain with paroxetine, it is less attractive for the treatment of cardiac patients with depression.
Conclusions. In reviewing the overall profiles of the individual SSRIs, three appear to be the most practical to use in cardiac patientssertraline, citalopram, and escitalopram. Not surprisingly, the current studies of antidepressants in cardiac patients have utilized two of these threesertraline and citalopram. Both of these SSRIs are available in generic form.
Other Antidepressant Alternatives. Whether or not other antidepressants can be effectively used in the treatment of depression in cardiac patients remains to be determined. One candidate might be extended-release venlafaxine. However, extended-release venlafaxine is known to elevate diastolic blood pressure in some individuals, particularly those in middle age. So, this antidepressant may be very limited by its side effect profile. Likewise, other options such as duloxetine will have to be individually explored in terms of their cardiac safety profile.
Conclusions
According to available data, there is convincing evidence that depression is one of several contributory variables to the evolution of CVD. In addition, acute depression appears to influence the outcome of those with existing CVD. While the reasons remain unclear, antidepressant therapy with non-tricyclic antidepressants (particularly SSRIs) appears to modestly reduce the risk of subsequent cardiac events in individuals with depression and CVD. Given the low risk of side effects and the potential modest benefits, it seems prudent to utilize SSRIs in cardiac patients with even minimal depressive symptoms. The most studied SSRIs in cardiac patients are sertraline and citalopram. In addition to escitalopram, these three SSRIs appear to have the profiles that are most likely to complement the needs of cardiac patients.
Like many other areas in medicine, the relationship between depression and CVD is an incendiary one, with each syndrome reinforcing the other. This area will clearly benefit from additional researchparticularly the degree to which antidepressant therapy, particularly treatment with SSRIs, will consistently prevent CVD in the depressed as well as stave off cardiac complications in those with comorbid depression and CVD. For the time being, SSRIs appear to be the pharmacological treatment of choice for those patients with depression and CVD. An unanswered question is whether these drugs should be used in patients with cardiac disease without depression.
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In this edition of Primary Care Reports, we will only examine the role of depression and its effect on cardiovascular disease (CVD). We will also explore the recommended pharmacological approach for the treatment of depression when these two syndromes are comorbid.Subscribe Now for Access
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