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Florida Heart CPR*
The Link Between Coronary Artery Disease and
Depression
2 hours
Goal
The goal of this course is to describe the relationship between depression and coronary
artery disease (CAD) and learn how to recognize and treat depression in patients with
CAD.
Learning Objectives
Upon completion of this self-study activity, participants will be able to:
1. Describe the epidemiologic and pathologic links between depression and
CAD.
2. Identify the criteria for diagnosing depression in patients with CAD.
3. Detail the benefits and drawbacks of the various therapies for the
treatment of depression in patients with CAD.
Introduction
According to the World Health Organization (WHO) and the World Bank, depression is
currently the fourth leading cause of disability worldwide, and its incidence is increasing
rapidly. In Western countries, up to one third of the population have had an episode of
depression at some point in their lives and 15% to 20% can be diagnosed with chronic
depression.
It is projected that depression will be the second leading cause of death and/or
morbidity by the year 2020. Cardiovascular disease, which is currently the leading
cause of death and morbidity in the industrialized world, is projected to become the
number 1 single cause of mortality by 2020. Thus, if only because both conditions are
so common, there will be many patients with both diseases. However, there appears to
be an interaction between the two diseases that augments their respective importance
when they are combined.
This review will focus on the interaction between cardiovascular disease and
depression, specifically as it relates to patients with ischemic heart disease, the fifth
leading cause of disability worldwide. A clear understanding of the interactions between
these disease states will have important implications for the health and well-being of
patients. The emphasis on ischemic cardiovascular disease events does not mean that
there are not equally important effects in patients with congestive heart failure and after
coronary bypass surgery, only that they are beyond the scope of this review.
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Recognizing and understanding the needs of the patient who is afflicted with both
ischemic cardiovascular disease and depression can be difficult. As it is usually the
cardiovascular complaint that brings the patient to the physician's office, the goal is to
recognize the cardiovascular patient with depression and then to treat both problems.
Epidemiologic Evidence Linking Depression to Coronary Artery Disease
There is a growing body of data to suggest that the presence of medically diagnosed
depression may actually lead to the development of coronary artery disease (CAD).
This viewpoint must be considered controversial, however, since patients with
depression often have more risk factors for CAD compared with those who are not
depressed and may be less attentive to modifying those risk factors. In other words, it
may be that depression does not cause CAD; depression causes the behaviors that
lead to CAD.
If one longitudinally follows cohorts at risk for CAD, an increased frequency of
cardiovascular events is clearly noted in patients who are depressed. However, these
data generally emerge from long-term studies of patients with depressive symptoms,
rather than from studies of patients with a rigorous diagnosis of depression.
Nevertheless, analysis from the U.S. National Health and Nutrition Examination Survey
(NHANES), using a more robust diagnosis of depression, found the same results patients diagnosed with depression have an increased probability of developing CAD.
The clearest evidence on the link between CAD and depression, however, is found in
the reverse situation -- when the presence of CAD has already been established. In a
study by Frasure-Smith and colleagues, it was demonstrated that depression serves as
a marker of -- and perhaps as a contributor to -- an adverse cardiovascular prognosis.
The concurrence of depression and CAD has been estimated variably, but coincidence
rates as high as 45% have been reported. Of these, roughly half have major depression
and the remainder minor depression. Initial studies failed to show a relationship
between the degree of depression and prognosis, but later studies suggest that there is
a dose relationship. Thus, it appears that the more severely depressed the patient, the
shorter the expected survival time compared with medium and lower levels of
depression. Although patients with more severe symptoms of depression are at the
greatest risk for mortality and/or infarction (Figure 1), since minor depression can lead
to major depression, identification of both groups is of importance.
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CAD and Depression
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Figure 1. Long-term survival impact of increasing levels of post-MI depression. Risk of
cardiac mortality in relation to initial severity and 5-year changes in depression
symptoms after myocardial infarction.
Is it really depression, per se? It has been argued that rather than "depression," it is
really factors such as job stress, anger/hostility, type A behavior, anxiety, and lack of
social support that are the real prognostic factors for death from CAD in the depressed
patient. However, when the occurrence of death from CAD is correlated with these
various other factors and then correlated with depression, it is the association of CAD
with depression that is the most consistent. The majority of studies demonstrate that
depression is associated with at least a doubling of risk for cardiovascular events,
independent of age and various other cardiac risk factors. Similar data exist for survival
and myocardial infarction (MI) after an acute presentation in patients with unstable
angina (Figure 2).
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CAD and Depression
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Figure 2. Depression and 1-year cardiac prognosis in unstable angina. [Lespérance F,
Frasure-Smith N, Juneau M, Théroux P. Depression and 1-year prognosis following
unstable angina. Arch Intern Med. 2000;160:1354-1360.]
Pathologic Connection Between Depression and Coronary Heart
Disease
Several plausible mechanisms have been proposed to explain the relationship between
depression and CAD (Figure 3).
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CAD and Depression
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Figure 3. Biologically plausible mechanisms linking depression with CHD.
Patients With Depression Are Sicker
The possibility that CAD patients with depression are in worse cardiovascular shape
than those without depression has to be considered as a possibility. In other words, it is
possible that these patients are depressed simply because they have more severe
cardiovascular disease. Unfortunately, this is a difficult issue to examine since the
psychological symptoms are subjective and often are more correlated with "mood" than
with objective evidence of disease. In addition, the matching of cardiac anatomy and
function can never be done completely. Nevertheless, many studies, including some in
patients with acute myocardial infarction and unstable angina, have been unable to
discern clear differences between patients with and without depression.
Cardiotoxic Antidepressants
There are data to suggest that the frequency of cardiac events is enhanced when
depressed patients are treated with tricyclic antidepressants (TCAs). Specifically, it is
possible that TCAs are associated with the occurrence of cardiac arrhythmias, perhaps
severe enough to result in sudden arrhythmic cardiac death in arrhythmia-prone
patients. Given the adrenergic stimulation that TCAs provide, it could be that either their
effects on the release of catecholamines or the membrane effects that these agents
cause (similar to the effects of class 1C anti-arrhythmic agents) are responsible for the
genesis of arrhythmias or a propensity to sustained arrhythmias. Newer antidepressive
agents that inhibit serotonin - known as the selective serotonin reuptake inhibitors
(SSRIs) - do not manifest these same effects and are not associated with increased
events when used in patients with CAD. These are important considerations that are
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under continuing study. However, since the association of increased cardiovascular
mortality was described prior to the widespread use of the TCAs as antidepressive
medication, drug toxicity is clearly not the sole cause of the increased mortality seen in
depressed CAD patients.
Increased Risk Factors
It is well known among practicing physicians that patients who are depressed do not
take their medications as reliably as patients who are not depressed. For example,
Carney and associates have shown that depressed patients are less likely to take
aspirin on time compared with their nondepressed colleagues. In addition, depressed
patients are less prone to exercise and are far less likely to enroll in cardiac
rehabilitation. Moreover, depressed patients are more apt to smoke and have
substantially more trouble adhering to smoking cessation programs. Depressed CAD
patients are also less compliant with dietary restrictions and physician appointments.
Finally, although unproven, it may be that depressed patients recognize and respond to
symptoms less rapidly, thus reducing the impact of aggressive therapies on their
cardiovascular disease. This lack of involvement in behaviors of healthy living may play
a role in explaining why depressed patients have increased morbidity and mortality after
acute cardiovascular events.
In addition to these diagnostic and behavioral parameters, there are also several
biologic factors that stand out when cardiovascular disease occurs concomitantly with
depression.
Catecholamines
Circulating catecholamine levels (adrenaline, epinephrine, or norepinephrine) are
increased in heart disease patients. These endogenous neuroactive transmitters can be
a trigger for malignant cardiac arrhythmias, especially in patients with diminished left
ventricular function. Likewise, high levels of norepinephrine spillover have been
documented in depressed patients. It is conceivable that the combination is synergistic
and leads to an increased frequency of sudden cardiac death. In a small study, Carney
and colleagues found that depressed patients with CAD at cardiac catheterization had a
significantly higher prevalence of ventricular tachycardia and a longer duration of each
episode compared with a group of nondepressed controls with CAD. These patients
were far less ill medically than those at risk for sudden death, but the principle
established may still be relevant.
Autonomic Dysfunction
Autonomic dysfunction - as measured by heart rate variability - occurs in patients with
depression and in patients who have suffered an acute myocardial infarction (MI).
Patients with both acute MI and depression have substantially worse heart rate
variability, even when other factors are taken into account, and abnormal heart rate
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CAD and Depression
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variability is known to presage an adverse prognosis in post-MI patients. Furthermore,
the treatment of depression in patients with CAD leads to improvements in indexes of
parasympathetic tone in a direction thought to be cardioprotective.
Platelets
Platelets play a key role in the pathogenesis of acute coronary syndromes, and
antiplatelet agents are now a mainstay of therapy. Musselman and colleagues used flow
cytometry to identify specific epitopes on the prothrombinase complex to demonstrate
that patients with depression had increased activation of their glycoprotein IIb/IIIa
receptors. Furthermore, preliminary data suggest that treatment with SSRIs reduces the
level of platelet activation to that of normal controls.
Stress
It is well known that the response to stress can induce ischemia and/or malignant
arrhythmias and the stress response may be modified in patients with depression.
There is a substantial increase in sudden cardiac death and MI in the hours following
extremely stressful activities, such as those related to natural disasters or severe
emotional trauma. In fact, using modern imaging techniques, it has been shown that
stressful activities are actually capable of inducing ischemia.
The "stress response" usually evokes alpha-adrenergic stimulation, which results in
vasoconstriction, thus raising blood pressure. Under normal circumstances, the
coronary arteries then dilate in response to the increase in blood pressure. In CAD
patients, however, coronary vasoconstriction is induced, even small amounts of which
can have a marked effect on vessel cross-sectional area. Invasive studies do not show
that this occurs with coronary vasospasm and suggest instead that the abnormalities
may be in the small vessels. In a series from Duke University (Durham, North Carolina),
positive mental stress test results were more predictive than exercise tests for provoking
cardiac distress, and it may well be that patients with depression have an exaggerated
response to stressful situations.
Inflammation
Depression is associated with increases in markers of subacute inflammation such as
white blood cells, C-reactive protein, interleukin 6, and tumor necrosis factor alpha
(TNF-alpha), as well as in shifts in the relative distribution of B and T cells. It is believed
that depression or chronic stress may contribute to an enhanced inflammatory
response, which might contribute to the development of CAD. On the other hand, a
state of subchronic inflammation is thought to be a core feature of CAD, and this may
induce a "sickness behavior," a syndrome that mimics depression, in some individuals.
Thus, depression may turn out to be either a cause or an effect of inflammatory
processes that are also involved in CAD.
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Diagnosing Depression in Patients With CAD
Diagnosing major depression in patients with CAD can be difficult, since many of the
symptoms of depression, such as loss of interest in usual activities, fatigue, and sleep
difficulties, are often attributed to the aftermath of surgery, MI, or other CAD-related
events. Thus, knowing how to distinguish between true depression and "normal"
cardiac-related symptoms may be particularly challenging. In the absence of a clear
cause for a specific symptom of depression, such as midnight insomnia in patients with
sleep apnea syndrome or fatigue in patients with thyroid dysfunction, it is wise to be
inclusive and attribute the symptoms to the depression rather than to the cardiac
disease.
To diagnose a major depressive episode, the symptoms must be present for most of the
day, every day, for at least 2 weeks, preferably 1 month, and they must result in
impairment of daily activities (Table 1). Key elements that should alert the clinician,
beyond the usual chronic sadness and loss of interest, include statements from the
patient that life is "out of control," descriptions of anxiety (feeling strained by daily minor
stresses, hypervigilance, multiple somatic complaints), signs of irritability (sudden bursts
of anger and hostility, frequent negative and unpleasant comments to others,
hypersensitivity to noise), and reports of chronic tiredness. In addition, if clinicians
discuss the frequency of depression in CAD with their patients, it may help reduce the
reluctance to discuss their symptoms and to seek treatment.
Table 1. Criteria for Diagnosing Depression



Five or more features, including at least 1 from Group 1 and the remainder from
Group 2, must be present nearly every day for at least 2 weeks.
Group 1:
o Depressed mood for most of the day
o Loss of interest or pleasure in almost all activities most of the day
Group 2:
o Significant weight loss or gain or an increase or decrease in appetite
o Insomnia or hypersomnia
o Psychomotor agitation or retardation
o Fatigue or loss of energy
o Feelings of worthlessness or excessive or inappropriate guilt
o Diminished ability to think or concentrate, or indecisiveness
o Recurrent thoughts of death, recurrent suicidal ideation without a specific
plan, a suicide attempt, or a specific plan for committing suicide
Adapted from the American Psychiatric Association. Diagnostic & Statistic Manual of
Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
Establishing the Differential Diagnosis
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When determining whether a patient with CAD is depressed, it is important to consider
alternative diagnoses whose symptoms mimic those of depression. Vascular or
atherosclerotic depression, a term used to describe late-onset depression associated
with cerebrovascular disease, must be considered. Notably, elderly patients with newonset depression are less likely to have a family history of depression and are more
likely to have comorbidities compared with those who experienced depressive episodes
earlier in life. However, for most patients, depression is a multicausal disease, and for
those with CAD, some brain-related cerebrovascular damage should be suspected.
Tight control of the risk factors for cerebrovascular disease, specifically hypertension
and diabetes, may in fact be a long-term prophylactic antidepressant strategy.
Other disorders, such as alcoholism, personality disorders, sleep apnea, and
hypothyroidism, can also result in depressive-like symptoms. Thyroid function, in
particular, should be routinely evaluated in all patients showing symptoms of
depression.
The possible role of beta-blocker therapy as a cause of depression remains
controversial. Although beta-blockade causes central nervous system side effects that
can be confused with symptoms due to depression, including sedation, nightmares, and
fatigue, no difference between the treatment and placebo groups with regard to the
frequency of depressive symptoms was noted in the first 30 months of the Beta-Blocker
Heart Attack Trial (BHAT). Given the lack of data demonstrating otherwise, the benefits
of beta-blockade therapy far outweigh any potential risk of depression in patients with
CAD and should therefore be prescribed when indicated.
Not all patients require psychological or psychiatric referral, but if there is confusion
about the diagnosis, consultation is appropriate.
Management of Depression
The decision of when and how to treat depression in an individual patient relies on
weighting several factors: the severity and duration of the current episode, the severity
and the number of past episodes of depression, the level of impairment, the foreseeable
level of stresses, comorbid psychiatric disorders, and the level of social support.
In cases of severe major depression of long duration (several months), antidepressant
therapy should be initiated. Although the presence of depressive symptoms for 2 weeks
may be sufficient to justify a diagnosis of depression, it is probably not sufficient to
warrant treatment. The existence of comorbid psychiatric disorders and any major
stressors can affect the decision-making process. For example, a significant proportion
of post-MI patients who exhibit their first set of depressive symptoms show spontaneous
remission within a few weeks. These patients may only need reassurance and followup. In addition, patients with mild-to-moderate level of depressive symptoms but with
good level of social support may improve on their own and may simply need some
psychological support.
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CAD and Depression
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Thus, unless the depressive symptoms are particularly severe, allowing for more than
the standard diagnostic window of 2-4 weeks in some patients with CAD is appropriate.
In addition, patients with a previous history of a major depressive episode require closer
monitoring and aggressive treatment. If the level of impairment is severe, such that the
patient's personal grooming, interpersonal relationships, and work environment are
affected, more rapid intervention is warranted.
Finally, any patient with suicidal ideation should be referred for psychiatric evaluation.
Pharmacologic Intervention
Treatment of depression in patients who are not medically ill is usually divided into 2
phases. The first phase, which typically lasts for 6-12 weeks, is designed to rapidly
ameliorate the depressive symptoms and improve the patient's level of daily functioning.
The objective of the second phase of treatment, which lasts for up to 12 months in
patients experiencing their first depressive episode, is to prevent a recurrence of the
depression. Since relapse is common if treatment is terminated prematurely,
maintenance of therapy over the long term is important. Patients who experience
multiple episodes of depression or who express suicidal ideation should be referred to a
psychiatrist. Many patients can be treated without psychiatric consultation, but if the
patient is severely depressed or on a complex medical regimen, consultation to guide
the therapeutic approach is appropriate.
Efficacy. Until further research on the efficacy of treatment of depression in patients
with CAD becomes available, clinicians have to rely on data collected from patients
without comorbid medical conditions. At this time, antidepressant medications are
indicated for patients with severe major depression, and are probably useful for patients
with mild-to-moderate major depression and chronic mild depression. Nevertheless, it is
important for both the patient and the physician to have reasonable expectations of
success. Antidepressants have demonstrated significant improvement, usually defined
as at least 50% reduction in depressive symptoms, in 55% of patients.
One trial compared the SSRI paroxetine with the TCA nortriptyline in patients with
stable CAD, and suggested equivalent efficacy for the 2 agents and superior tolerability
for SSRIs compared with TCAs. Preliminary data presented at the American Heart
Association (AHA) Scientific Sessions from a randomized trial of nearly 400 hundred
patients treated with sertraline or placebo following acute MI or unstable angina suggest
that this medication is safe. With regard to efficacy, sertraline improved depression
among patients with at least 2 prior episodes of major depression in the past but not in
the overall group. These data also suggest high placebo response rates among patients
experiencing their first episode of depression. Larger studies are needed to document
whether antidepressants can improve prognosis among high-risk depressed patients.
Side effects and safety. Side effects of antidepressant medications, such as
nervousness, fatigue, sedation, and gastrointestinal distress, have resulted in a 15% to
25% dropout rate. In order to minimize adverse effects, treatment should be started at a
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low dose, followed by gradual upward titration. Frequent medical visits can help monitor
the drug's efficacy and side effects, as can changes in diet and the timing of
medications.
Drug safety is an important issue in all depressed patients, but particularly in those with
cardiac disease. The following considerations must be taken into account when treating
depressed patients with cardiac disease:



TCAs influence adrenergic tone. Thus, although these agents have antiarrhythmic properties, they can also be pro-arrhythmic. They have also been
known to cause postural hypotension. TCAs should be avoided in patients with
CAD and should be used only in patients who have failed on other
antidepressants.
The SSRIs have no direct significant effects on heart rate, blood pressure, or
cardiac conduction and have not been reported to increase CAD events.
However, patients who are also taking warfarin need more frequent monitoring of
their international normalized ratio (INR).
Newer agents that exert combined adrenergic and serotoninergic effects have
not been evaluated in this patient group.
Drug-drug interactions are also of particular concern in patients with CAD (Figure 5).
For example, antidepressant agents that inhibit the cytochrome P450 liver isoenzyme
system (eg, paroxetine, fluoxetine, and probably sertraline) should not be prescribed for
patients taking class IC antiarrhythmic agents (eg, encainide, flecainide, mexiletine, and
propafenone). In addition, these antidepressants should be used cautiously in patients
taking beta-blockers, since they may augment beta-blockade. Other inhibitors of the
cytochrome P450 system, such as nefazodone and fluvoxamine, can interfere with the
metabolism of calcium-channel blockers, some statins, some antiarrhythmics, and
cyclosporine.
Psychotherapeutic Intervention
Psychological evaluation and treatment is an important part of the management strategy
for depressed patients. The effectiveness of 2 types of psychotherapy, cognitivebehavioral therapy and interpersonal therapy, has been demonstrated in patients with
depression without a comorbid medical condition.
In cognitive-based therapy (CBT), the therapist helps to clarify the thought processes
and perceptions that contribute to the patient's ability to function on a regular basis. The
goal is to help the patient modify these thought processes so that he can better cope
with the stressors of daily life. By contrast, interpersonal therapy evaluates the patient's
interaction with others in family, work, and social structures. The goal here is to help the
patient readjust his interpersonal relationships so that, instead of contributing to the
depression, they help to resolve his emotional and behavioral needs.
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In a recent large clinical trial reported at the AHA in November 2001, 2481 patients with
either depression or social isolation were randomized to either CBT or usual care. CBT
improved depression scores significantly over time. The response to therapy was similar
to that seen in patients without MI, but patients in the usual care group also had a
significant reduction in their scores as well. Thus, by 6 months, although there was a
statistically significant difference between the groups, it was modest and of questionable
biological significance. There was no difference in the hard end points of death and/or
recurrent MI. These data, along with similar findings seen in a trial with sertraline,
suggest that if a clinician doubts that the indication is unequivocal, close follow-up and
support may suffice for many patients during this period.
Key Points in the Treatment of Depression in CAD Patients
1. Depression is a chronic disease and thus will probably need to be treated and
monitored for several years.
2. Some minimal psychological support and education should always accompany
prescriptions for antidepressants.
3. Dosages of antidepressant medication should start low and increase gradually.
4. Sick leave is important, since depression requires rest for recovery.
5. Social interaction and family participation should be encouraged in the depressed
patient's care.
6. Cardiac rehabilitation may be useful, but is not a specific treatment for
depression.
7. Smoking cessation is especially challenging in the depressed patient.
8. Expectations should be reasonable, as a significant percentage of patients will
not experience complete remission. This finding is especially true in patients with
comorbid medical conditions.
Conclusions
The diagnosis and management of depression in patients with cardiac disease can be
challenging. Patients and physicians may be unwilling to attribute symptoms to
depression, and may instead assume that they result from cardiac-related morbidities.
However, given the high rate of depression and its association with increased mortality
in this population, physicians and patients cannot afford to ignore depressive symptoms.
A combination of pharmacologic and psychotherapeutic treatments can effect positive
changes in the patients' emotional and psychological framework. Clearly, the most
effective approach is to forge collaboration among cardiologists, psychiatrists,
psychologists, and internists, all of whom can work together in lifting depression in
patients with cardiac disease.
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CAD and Depression
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Florida Heart CPR*
CAD and Depression Assessment
1. According to the World Health Organization (WHO) and the World Bank,
depression is currently the ___ leading cause of disability worldwide.
a. Second
b. Third
c. Fourth
d. Fifth
2. It is projected that depression will be ____leading cause of death and/or
morbidity by the year 2020.
a. The
b. The second
c. The third
d. The fifth
3. Cardiovascular disease, which is currently the leading cause of death and
morbidity in the industrialized world, is projected to become the _____ leading
cause of mortality by 2020.
a. Single
b. Second
c. Third
d. Fourth
4. As it is usually the cardiovascular complaint that brings the patient to the
physician's office, the goal is to recognize the cardiovascular patient with
depression and then to treat:
a. The cardiovascular disease, which, in turn, will resolve the depression.
b. The cardiovascular disease only.
c. The depression only. The cardiovascular disease will resolve on its own.
d. Both problems.
5. In a study by Frasure-Smith and colleagues, it was demonstrated that depression
serves as a marker of -- and perhaps as a contributor to :
a. An uncomplicated cardiovascular prognosis
b. An adverse cardiovascular prognosis
c. An unknown cardiovascular prognosis
d. None on the above.
6. The concurrence of depression and CAD has been estimated variably, but
coincidence rates as high as ___ % have been reported.
a. 35
b. 45
c. 55
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d. 65
7. It appears that the _______ depressed the cardiovascular patient, the ______
the expected survival time compared with medium and lower levels of
depression.
a. Less; shorter
b. More; shorter
c. More; longer
d. The question errs. No relationship between depression and CVD exists.
8. It is well known among practicing physicians that patients who are depressed
a. do not take their medications as reliably as patients who are not depressed.
b. Rarely take medications on their own
c. Are of lower socioeconomic status that other types of patients
d. None of the above
9. It is well known that the response to stress can induce ischemia and/or malignant
arrhythmias and the stress response may be modified in patients with ______.
a. Mental disorders
b. Depression
c. Cancer
d. None of the above
10. To diagnose a major depressive episode, the symptoms must be present for
most of the day, every day, for at least 2 weeks, preferably 1 month, and they
must result in
a. Cardiovascular disease
b. Feeling sad
c. Impairment of daily activities
d. A psychotic break
Florida Heart CPR*
CAD and Depression