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Can Treating Depression Reduce Mortality After an Acute Myocardial Infarction?

From the Department of Psychiatry (R.M.C., K.E.F.), Washington University School of Medicine, St. Louis, MO; Geriatric Research, Education, and Clinical Center (R.C.V.), Veterans Administration Puget Sound Health Care System, University of Washington, Seattle, WA; and Department of Medicine (A.S.J.), State University of New York, Syracuse, NY.

Address reprint requests to: Robert M. Carney, PhD, Department of Psychiatry, Washington University School of Medicine, 4625 Lindell Blvd., Suite 420, St. Louis, MO 63108.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SAFETY AND EFFICACY OF... LINK BETWEEN DEPRESSION AND... EFFECTS OF TREATMENT FOR... ALTERNATIVE STRATEGIES CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Major depression affects about one in five patients in the weeks after an acute myocardial infarction and is associated with an increased risk of cardiac morbidity and mortality. Consequently, there is considerable interest in the question of whether treating depression will improve medical prognosis in these patients. Safe, effective treatments for depression are available, but unless they also improve the underlying pathophysiological or behavioral mechanisms that contribute to cardiac morbidity and mortality, they may not have beneficial effects on prognosis. Altered cardiac autonomic tone is one of the leading candidate mechanisms. Unfortunately, a review of the available research reveals that cardiac autonomic tone often fails to normalize in patients treated for depression, and the research suggests that currently available treatments for depression will not necessarily improve cardiac event–free survival in patients who have had an acute myocardial infarction. Until there is convincing evidence that treatment can reduce the risk of cardiac morbidity and mortality, the principal reason to treat depression should continue to be to improve the quality of life of the patient who has had an acute myocardial infarction.

Key Words: depression • coronary heart disease • mortality

Abbreviations: CHD = coronary heart disease; ECT = electroconvulsivetherapy; ENRICHD = Enhancing Recovery in Coronary Heart Disease; HPA = hypothalamic-pituitary-adrenal; HRV = heart ratevariability; MAOI = monoamine oxidase inhibitor; MI =myocardial infarction; NO = nitric oxide; PVC = prematureventricular contraction; SDANN = standard deviation of 5-minuteaverages of R-R intervals; SDNN = standard deviation of N-Nintervals; SSRI = selective serotonin reuptake inhibitor; SADHART = Sertaline and Depression Heart Attack RandomizedTrial; TCA = tricyclic antidepressant.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SAFETY AND EFFICACY OF... LINK BETWEEN DEPRESSION AND... EFFECTS OF TREATMENT FOR... ALTERNATIVE STRATEGIES CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Comorbid depression is a significant problem in patients with CHD. Major depression doubles the risk that patients with newly diagnosed CHD will experience a cardiac event within 12 months (1), and these patients remain at elevated risk for death due to a cardiac event for at least 5 years (2). Depression has an even worse impact on prognosis after acute MI (3–7). For example, Frasure-Smith et al. (4) reported that depression was associated with a more than four-fold increased risk of mortality during the first 6 months after acute MI after adjusting for other risk factors. Furthermore, they found depression to be as strongly predictive of mortality as more widely accepted risk factors, such as left ventricular dysfunction and previous MI.

Approximately 45% of post-MI patients have some form of unipolar depression (8), and between 16% and 22% have major depression (4, 8, 9). Furthermore, many patients who are free of depression during the first few weeks after their acute MI have a depressive episode within 1 year. Lesperance et al. (10), for example, found that approximately one of three patients develop major depression at some time during the 12 months after an acute MI.

Approximately 1,500,000 MIs occur per annum in the United States (11). The annual mortality rate among survivors of an initial MI is about 10%. Approximately one in five (300,000) post-MI patients meet the criteria for major depression within a few weeks after the MI (4, 8, 9). On the basis of Frasure-Smith et al.’s (4) finding of a four-fold relative risk of mortality in depressed vs. nondepressed patients after an initial MI, it is estimated that about 75,000 deaths per year among patients discharged alive after a first MI are attributable to comorbid depression.

Because comorbid depression is a common and potent risk factor for mortality after acute MI, there is intense interest in determining whether prognosis can be improved in these patients. There are not yet any published results from randomized, controlled clinical trials relating the treatment of depression to the subsequent risk of medical morbidity or mortality in post-MI patients, but two trials are in progress. SADHART is investigating the efficacy of sertraline (Zoloft), an SSRI. The ENRICHD trial is studying the efficacy of cognitive behavior therapy for depression and social isolation. Some of the depressed patients in ENRICHD also receive sertraline. Unfortunately, the results of these trials are not expected to be available for several years.

A case-control study by Avery and Winokur (12) provides some of the only relevant data published to date. They found that over a 3-year follow-up period, nonsuicidal deaths (particularly deaths from cardiac causes) were more prevalent in depressed patients who had received inadequate treatment for depression than in those whose treatment was thought to be adequate. It is possible, however, that the patients who received inadequate treatment for their depression also received inadequate care for other medical conditions. Thus, one cannot be certain that the adequacy of depression treatment accounted for the observed differences in mortality. Furthermore, the study was based on a small number of end points. Thus, we do not yet know whether treating depression will reduce the risk of mortality in post-MI patients.

There is evidence that traditional treatments for depression are effective for many depressed patients with CHD (13). However, these treatments will not necessarily reduce the risk of mortality in post-MI patients even if they successfully relieve their depression. Unless a treatment also improves the underlying pathophysiological or behavioral mechanisms that contribute to cardiac mortality, it may not alter mortality rates. For example, if depression is associated with a propensity for ventricular arrhythmias in vulnerable individuals due to an underlying physiological abnormality, it is possible that one might successfully ameliorate the patient’s depressive symptoms yet not change the physiological abnormality. Post (14) has argued that depressive episodes have residual neurophysiological effects that accumulate over recurrences and that never normalize, not even in successfully treated cases. These irreversible neurophysiological changes might continue to contribute to the increased mortality risk in post-MI patients even after their depressive episodes remit.

Whether any treatment for depression will succeed in increasing cardiac event–free survival depends on whether it is safe and effective and whether it either results in beneficial changes in the mechanisms through which depression affects prognosis after acute MI or incidentally alters another risk factor. In addition, it must effect these changes quickly. Up to 75% of post-MI mortality occurs within the first few months after the acute event (15). A treatment that requires months to change depression or the underlying mechanism may not have an appreciable impact on survival. The remainder of this article considers these questions.

	SAFETY AND EFFICACY OF TREATMENTS FOR DEPRESSION IN POST-MI PATIENTS

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Most studies of treatments for depression in patients with CHD have been concerned with their safety rather than efficacy. There have been very few randomized, controlled antidepressant efficacy studies in cardiac patients, but nearly all of them have found that comorbid depression can be successfully treated (13). For example, in a double-blind clinical trial reported by Veith et al. (16), participants were randomly assigned to receive 4 weeks of imipramine, doxepin, or placebo. Patients treated with imipramine or doxepin improved significantly, but those given a placebo did not.

A more recent randomized, controlled clinical trial compared paroxetine, an SSRI, to nortriptyline, a TCA, in a group of 81 depressed patients with documented CHD (17). The drugs were equally effective in an intent-to-treat analysis (61% improved on paroxetine vs. 55% on nortriptyline). However, there were significant differences between the groups in adverse cardiovascular effects. Neither drug had significant effects on blood pressure or conduction intervals, but nortriptyline was associated with an 11% increase in heart rate. Only 1 (2%) of the 41 patients on paroxetine, compared with 7 (18%) of the 40 patients on nortriptyline, experienced an adverse cardiac event.

Although supporting evidence is still less than abundant, many of the available treatments for depression are probably effective in patients with CHD. More clinical trials are needed to establish this conclusively, especially for some of the newer antidepressants.

On the other hand, there is substantial evidence that many traditional treatments for depression have cardiotoxic side effects and may be unsafe in post-MI patients. TCAs, for example, have undesirable effects on cardiac conduction, rate, and rhythm in some patients, and they commonly induce orthostatic hypotension (18–20). These effects are particularly problematic for older patients and those with unstable angina, conduction disorders (especially bundle branch block), heart failure, or other complications of coronary disease.

The Cardiac Arrhythmia Suppression Trial (21) demonstrated a paradoxical increase in mortality among patients given antiarrhythmic agents (including Type 1A antiarrhythmics) as compared with those given a placebo. TCAs have Type 1A antiarrhythmic action and may not be safe for patients known to have frequent ventricular arrhythmias or at high risk for developing them.

MAOIs do not affect cardiac conduction but, like the TCAs, can cause orthostatic hypotension. MAOIs also require special dietary restrictions, and noncompliance can trigger hypertensive crises (20). Given the critical relationship of blood pressure to coronary perfusion, both increases and decreases in blood pressure could be detrimental.

There has been little research on the safety for CHD patients of other non-TCA antidepressants, such as bupropion, venlafaxine, and nefazodone. These agents are thought to have little effect on cardiac conduction, but some have been associated with blood pressure elevation (22, 23).

SSRIs are thought to be much less cardiotoxic than the other antidepressants discussed above. Consequently, they may be safer for patients with CHD. However, there may be a significant risk of adverse drug-drug interactions with SSRIs, because they inhibit the activity of the cytochrome P450 liver enzymes involved in the metabolic breakdown of certain other drugs. Unfortunately, these include medications commonly prescribed for cardiac patients, such as ß-blockers, warfarin, and Type 1C antiarrhythmics (24).

There are differences among the SSRIs as to the specific P450 enzymes they inhibit and the strength of the inhibition. Thus, the risk of adverse effects can be minimized by carefully selecting an SSRI that does not interact with other drugs in the patient’s regimen. Because the therapeutic options may be limited in some cases, however, drug-drug interactions may be difficult to avoid at times. Whenever an SSRI is administered along with any other agent that is metabolized by the same P450 enzymes, it is necessary to start with a conservative dosing schedule, titrate it cautiously, and monitor the patient carefully. Nevertheless, even when the potential for adverse drug-drug interactions is taken into account, SSRIs are still the antidepressants of choice for patients with CHD because of their relative safety (17, 25, 26).

ECT has also been found to be relatively safe when administered with proper precautions to depressed patients with cardiac disease (27, 28). However, it has not been established whether ECT can be safely administered in patients recovering from a recent acute MI.

Psychotherapy has no known cardiotoxic side effects (or any known medical side effects for that matter). However, during the first few weeks of recovery from an acute MI or post-MI coronary artery bypass graft surgery, some patients may be unable to tolerate the level of activity required to engage in psychotherapy. Furthermore, although there have been numerous studies of psychotherapy for various problems in patients with heart disease, there have not been any studies specifically evaluating the efficacy of psychotherapy for depression. Clinical trials of established psychotherapeutic interventions for depression in CHD patients are needed.

In summary, the potential for cardiotoxic side effects and drug-drug interactions must be considered when choosing a treatment. However, when administered with appropriate precautions, it is likely that depression can be safely treated in depressed CHD patients (17, 25). More studies of the safety and efficacy of the newer antidepressants are needed. Finally, the efficacy of psychotherapy for depression in post-MI patients should be established.

	LINK BETWEEN DEPRESSION AND CARDIAC EVENTS

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The mechanism or mechanisms linking depression to cardiac events have not yet been firmly established. This is a critical issue because the mechanism may not change regardless of the treatment’s effect on depression, or at least it may not change at the same rate as depression. Several candidate mechanisms have been suggested (29). First, depressed CHD patients may have more severe heart disease than their nondepressed counterparts and consequently have a higher risk of mortality. Although this is an intuitively appealing explanation, there is little evidence to support it. The cardiac effects of depression have been found in most studies to be independent of the severity of coronary artery disease, the size of the MI (in post-MI patients), the degree of left ventricular dysfunction, and most other recognized indices of cardiac disease severity (3–5). Nevertheless, it is possible that with improved understanding of the pathophysiology of CHD and with further advances in diagnostic technology, we may eventually discover that depression is a marker of more severe heart disease.

Another possibility is that depression indirectly increases the risk of mortality because it is associated with other recognized risk factors. Smoking (30, 31) and hypertension (32, 33), but not elevated serum cholesterol (34), seem to be more common in depressed patients. However, many of the studies that have linked depression with cardiac events have controlled for these risk factors or have not found them to be related to either depression or cardiac events in their samples (eg, see Refs. 1 and 35).

Some of the behavioral patterns associated with depression might also increase the risk of cardiac events. For example, depression is associated with poor adherence to cardiac rehabilitation (36), and older depressed patients with documented coronary artery disease are less adherent than comparable nondepressed patients to a prophylactic aspirin regimen (37). Although the relationship between depression and disease severity, other risk factors, and adherence to cardiac treatment regimens all deserve attention, there is a consensus among researchers in the area that altered cardiac autonomic tone is arguably the most promising candidate mechanism (29, 38, 39). Dysregulation of the autonomic nervous system and of the HPA axis has been found in medically well patients with major depressive disorder. The evidence for this includes elevated plasma and urinary catecholamines and their metabolites (40–45), elevated plasma and urinary cortisol (42), elevated resting heart rate (41, 45–47), and decreased HRV (48–50). Numerous studies have demonstrated that increased sympathetic and/or decreased parasympathetic nervous system activity predisposes CHD patients to ventricular tachycardia, ventricular fibrillation, and sudden cardiac death (51–55).

If depression increases the risk of mortality in post-MI patients by disturbing the regulation of cardiac autonomic tone, it should confer an especially high risk on patients who are already vulnerable to lethal arrhythmias and sudden cardiac death. Specifically, a disproportionately high cardiac mortality rate would be expected among post-MI patients who are not only depressed but who also have significant ventricular arrhythmias and/or poor ventricular function.

Consistent with this prediction, depressed patients with CHD have been found to have more frequent and longer runs of ventricular tachycardia compared with nondepressed CHD patients (56). Kennedy et al. (57) found that depressed patients at high risk for mortality who were being evaluated for the treatment of ventricular arrhythmias had a five-fold greater risk of dying compared with the nondepressed patients in their sample. In the Cardiac Arrhythmia Pilot Study, a controlled trial of antiarrhythmic therapy in post-MI patients at high risk for sudden cardiac death, depression was found to be a significant risk factor for resuscitated cardiac arrest or death after adjusting for clinical predictors of disease severity (3). Finally, Frasure-Smith et al. (5) found that depressed post-MI patients who had 10 or more PVCs per hour were at considerably higher risk for mortality than either depressed patients without PVCs or nondepressed patients with 10 or more PVCs per hour. Thus, although we do not yet know whether altered autonomic tone is the primary underlying mechanism linking depression to increased risk of cardiac mortality, it is certainly a strong candidate.

Will treating depression normalize autonomic tone and HPA axis activity? Unfortunately, there is evidence that it may not, at least not in patients with chronic or recurrent episodes of depression (58–60). Sheline et al. (61), for example, have shown that patients with a history of major depression have significantly smaller hippocampal volumes bilaterally compared with matched control subjects. The decrement in hippocampal volume correlates with the cumulative lifetime duration of major depression, possibly as a result of a progressive process mediated by glucocorticoid neurotoxicity. This process may be responsible for an increase in corticotropin-releasing factor secretory drive and may thereby contribute to the elevated HPA axis activity observed in depression. Corticotropin-releasing factor is also a potent stimulus for sympathetic nervous system activation, which may account for the sympathetic hyperactivity observed in major depression. Thus, the Sheline et al. study shows that one of the most likely mechanisms linking depression to increased mortality may persist even after depression is successfully treated. This suggests that we may not be able to reduce mortality in CHD patients by treating them for depression.

Because the relationship between altered cardiac autonomic tone and sudden cardiac death is so well documented, there has been intense interest in the development of inexpensive, noninvasive, and readily quantifiable measures of cardiac autonomic activity. HRV analysis is one of the most promising technologies for obtaining such measures (62). Beat-to-beat variability in the rhythm of the heart is determined primarily by the autonomic nervous system’s modulation of the intrinsic cardiac pacemakers. HRV is generally thought to reflect the interaction between the sympathetic and parasympathetic regulatory control of the heartbeat, such that low HRV reflects inadequate cardiac parasympathetic and/or excessive cardiac sympathetic tone. Furthermore, HRV is highly specific to cardiac autonomic tone, in contrast to plasma and urinary catecholamines and other measures of systemic autonomic activity.

Low HRV is a strong, independent predictor of mortality in CHD patients. This effect has been documented in patients with a recent acute MI (63), in patients with stable coronary disease (64), and in patients with congestive heart failure (65).

Despite finding higher resting heart rates and exaggerated heart rate responses to orthostatic challenge, we did not observe differences between depressed and nondepressed medically stable CHD patients in either resting norepinephrine level or norepinephrine response to orthostatic challenge (66). However, we have found lower HRV in depressed than in medically comparable nondepressed patients with stable coronary disease (67–68, 97). The clinical significance of these HRV differences can be appreciated by comparing HRV in depressed CHD patients with that of patients found to be at significant risk for mortality in studies of the prognostic significance of reduced HRV. In a study of patients with congestive heart failure (65), for example, an SDANN of 55 ms or less was a significant independent risk factor for mortality. In the Carney et al. (68) study, 26% of the depressed patients and none of the nondepressed patients were below 55 ms on this measure of HRV.

Rechlin (69) studied a group of psychiatric patients with major depression or dysthymia who were being treated with amitriptyline. Patients with major depression had reduced high-frequency HRV, suggestive of a decrease in parasympathetic activity, compared with dysthymic patients. This suggests the possibility that HRV may be inversely associated with the severity of depression. This finding is similar to that reported by Stein et al. (manuscript submitted), who found that CHD patients with moderate to severe major depression had lower HRV than patients with milder depression or nondepressed control subjects.

This relationship between HRV and the severity of depression is also consistent with the reported linear relationship between the severity of depression and the risk of mortality. For example, Barefoot et al. (2) found that patients with documented coronary disease who had moderate to severe depressive symptoms had a 57% greater risk of mortality than did mildly depressed patients and an 84% greater risk than nondepressed control subjects.

	EFFECTS OF TREATMENT FOR DEPRESSION ON HRV

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Assuming that altered autonomic tone is the principal underlying mechanism linking depression and cardiac mortality and that HRV analysis can be used to assess changes in cardiac autonomic activity, treatments for depression that increase HRV may be able to reduce the risk of cardiac mortality associated with depression.

Schultz et al. (70) tested the hypothesis that treatment of depression with bilateral ECT results in an increase in cardiac vagal activity as measured by HRV. An unselected series of nine hospitalized, depressed psychiatric patients participated in the study. Patients taking TCAs were excluded from participation, and all patients who were taking other antidepressants were maintained on the same drugs throughout the study. Electrocardiographic and respiratory measures were obtained over a 30-minute period according to standard protocol, both before the initial ECT treatment and on the day after the final session. Power spectral analysis was used to determine changes in HRV, and changes in respiratory sinus arrhythmia were used as an index of vagal activity.

All patients responded to treatment, with Hamilton Depression Scale scores decreasing from an average of 34.4 to 11.2. Before each ECT session, patients were administered 0.2 mg of glycopyrrolate, an anticholinergic agent used to control secretions and optimize airway management during ECT. Although vagal blockade peaks within 30 to 45 minutes after the administration of glycopyrrolate, the second HRV assessment was delayed until the day after their final ECT session to eliminate the possibility of confounding. Contrary to the authors’ hypothesis, both total HRV and the amplitude of respiratory sinus arrhythmia (which represents vagal activity) decreased significantly over the course of treatment.

Although ECT produces transient autonomic effects, and although anesthetics are used during ECT, these factors are unlikely to affect HRV as long as 24 hours after the treatment session and are therefore unlikely to account for the results of the study. The magnitude of improvement in depressive symptoms, as measured by the Hamilton Depression Scale, was highly negatively correlated with change in HRV indices of vagal activity. Consequently, the authors concluded that the observed changes in HRV might not have been due to the ECT per se but rather to improvement in depression.

Several studies have found that TCAs are associated with reduced HRV, presumably because of their anticholinergic side effects (71–73). Rechlin et al. (74), for example, compared depressed psychiatric patients treated with amitriptyline or paroxetine before and after treatment. HRV was determined at rest and during deep respiration, the Valsalva maneuver, and a postural test. After 2 weeks of treatment, the amitriptyline-treated patients showed decreased HRV, whereas patients treated with paroxetine showed no changes in HRV. However, the investigators did not correlate change in depression to change in HRV.

The effect of the SSRIs on HRV is less clear. As discussed earlier, Roose et al. (17) treated a group of depressed CHD patients with either paroxetine or nortriptyline for 6 weeks. Both groups fared equally well in terms of resolution of their depression. However, the nortriptyline-treated patients showed a decrease in 24-hour HRV at weeks 2 and 6. Patients treated with paroxetine, on the other hand, exhibited an increase in 24-hour HRV at week 2, but HRV returned to pretreatment levels by week 6. Roose et al. also did not correlate changes in HRV to changes in depression. In any event, although the treatment was successful in 61% of cases, it did not have a detectable effect on HRV.

Balogh et al. (75), on the other hand, followed 11 patients treated with fluoxetine, 1 treated with bupropion, and 1 who was participating in a clinical trial and was treated with either placebo or fluvoxamine. They found significant relationships between pre- and posttreatment changes in two indices of HRV and in Hamilton Depression Scale scores (r = 0.61 and 0.51). These relationships were stronger in the eight patients who were classified as responders (score < 10; r = 0.86 and 0.75). Unfortunately, the study did not include a control group. Of greater concern, the sample was quite small, and the correlations would have been much smaller were it not for a single outlier.

In a more recent study, Khaykin et al. (76) assessed HRV in 36 depressed patients who received either doxepin, a TCA, or fluoxetine, an SSRI, for 6 weeks. As the authors note, doxepin has relatively minimal anticholinergic effects compared with the rest of the TCAs. Unfortunately, for reasons left unexplained, HRV data were available for only 14 patients. Seven of nine patients who received doxepin, and three of five who received fluoxetine, were subsequently classified as responders. Regardless of which drug was administered, response to treatment was associated with a significant increase in SDNN, and nonresponse was associated with a significant decrease in SDNN and SDANN. The authors did not report HRV data for each subject, so it is not known whether a small number of patients accounted for the effects as in the Balogh et al. study. In any case, the small sample sizes makes interpretation of these results difficult.

There are no published studies of the effects on HRV of treating depression in CHD patients with other agents or with psychotherapy. However, we have nearly completed a controlled study of the HRV effects of cognitive behavior therapy for depression in patients with stable CHD, and the results should be available soon.

In summary, little is known about the effects on HRV of many of the available treatments for depression. However, ECT and most TCAs seem to worsen HRV. SSRIs may improve HRV, but the effect is quite modest and falls short of normalization. There are at least two possible explanations for this. First, HRV may eventually normalize, but perhaps the patients in these studies were not followed long enough to detect this effect. Future studies should include follow-up HRV assessments several weeks or months after termination of treatment. However, unless HRV can be normalized within the first few weeks after an acute MI, it may be too late to prevent depressed patients from dying prematurely, because the post-MI mortality rate peaks during this period (15). Second, it is possible that HRV may never return to normal once there has been an episode of major depression. If treating depression does not affect the underlying mechanism within the first few weeks of treatment, can we still reduce associated mortality risk in these patients?

	ALTERNATIVE STRATEGIES

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One way that treatments for depression could improve cardiac outcomes without directly affecting the mediating mechanism is by coincidentally modifying another risk factor, thereby compensating for the risk associated with the mediating mechanism. For example, an antidepressant might relieve depression without improving the underlying mechanism, yet it might also decrease blood pressure and thereby reduce the risk of cardiac-related mortality. Although this is an intriguing possibility, none of the available antidepressant treatments are known to have any beneficial cardiovascular side effects that could possibly produce a substantial reduction in mortality risk. However, the possibility that such effects might occur must be considered.

Another alternative is to treat the underlying mechanism directly. Although there is no evidence that increasing HRV will improve survival in depressed post-MI patients, several interventions have been shown to improve both HRV and survival. For example, ß-blockers have been found to reduce sympathetic outflow and increase HRV (77, 78) and to reduce mortality in post-MI patients (79).

Similarly, smoking cessation improves HRV (80) and reduces mortality after an MI (81). The confounding effects of smoking have been controlled for in many studies of depressed post-MI patients, so it is unlikely that smoking explains the effect of depression on mortality. Furthermore, smoking does not account for the differences in HRV that have been observed between depressed and nondepressed CHD patients (29, 39). Nevertheless, depressed patients are more likely to smoke than nondepressed patients; thus, smoking cessation may be an effective means of improving HRV in depressed patients. Exercise training is another potential intervention. It has been shown to improve HRV in studies of healthy older adults (82), although the results have been inconsistent in post-MI patients (83, 84).

However, there are problems with each of these interventions in depressed post-MI patients. Although there is good evidence that ß-blockers do not cause depression, they are known to be associated with numerous central nervous system side effects, which can be difficult for depressed patients to tolerate. Also, older depressed patients are less adherent to medication regimens, even to medications without appreciable side effects, than nondepressed patients (37). Additionally, smoking cessation has been shown to be more difficult for depressed than for nondepressed smokers (85, 86), and depression predicts poor adherence to exercise programs and cardiac rehabilitation (87). Thus, even if treating depression does not ameliorate the factors responsible for increased risk of cardiac mortality, it may nevertheless be necessary to treat the depression before beginning interventions that directly affect HRV and autonomic tone.

As discussed previously, it is not certain that altered autonomic tone is the principal mechanism that increases the risk of mortality in depressed post-MI patients. Even if it is, its most important effects may not be on cardiac autonomic tone, as measured by HRV, but on other physiologic factors, such as coronary vasomotion or platelet activation. It has been shown that depressed patients exhibit enhanced platelet activation and responsiveness compared with nondepressed patients (88, 89). Increased platelet activation has been associated with an increased risk of MI and even sudden cardiac death (90). Whether treatment of depression reduces platelet activation is not yet known, although there have been case reports of altered platelet aggregation (91) and hemostasis (92) in patients receiving SSRIs.

The relationship between platelet activation and HRV is also unknown at this time. However, it has recently been proposed that depression may be associated with altered NO metabolism (93). NO has been shown to have extensive cardiovascular and hemodynamic effects and is important for the normal response to coronary vasoconstrictive stimuli. In addition, NO decreases systemic vascular resistance and platelet aggregation (94–96). Inhibition of any of these mechanisms could contribute to the potential for cardiac events through paradoxical coronary vasoconstriction, peripheral vasoconstriction, and/or enhanced platelet aggregation. Furthermore, because NO is an effector molecule in signal transduction pathways in the autonomic nervous system, a defect in NO could be the mechanism by which HRV is altered (93). In any event, it seems clear that low HRV, a known risk factor for mortality in post-MI patients, is found in depressed patients and may remain unimproved, or even made worse, by some of the available depression treatments. Furthermore, even those depression treatments that do result in improved HRV may not improve it sufficiently to reduce the mortality risk to a level comparable to that of nondepressed patients.

	CONCLUSION

TOP ABSTRACT INTRODUCTION SAFETY AND EFFICACY OF... LINK BETWEEN DEPRESSION AND... EFFECTS OF TREATMENT FOR... ALTERNATIVE STRATEGIES CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Will treating depression in CHD patients reduce their risk of mortality? The answer is still unknown, but some treatments for depression are very unlikely to improve the odds of survival. Altered cardiac autonomic tone, as measured by HRV, may be a marker of increased risk of mortality associated with depression. Because of their cardiotoxicity and HRV-attenuating effects, tricyclic antidepressants are contraindicated in many cardiac patients, particularly ones recovering from an acute MI. ECT may also reduce HRV and is not recommended for acute post-MI patients. SSRIs are less cardiotoxic and may actually improve HRV in depressed cardiac patients, but better-controlled studies with larger numbers of patients and longer follow-up periods are clearly needed. More studies of psychotherapeutic treatments of depression and their effects on HRV are also needed. We must await the results of the ENRICHD and SADHART trials to determine whether cognitive behavior therapy and/or SSRIs can reduce the rates of reinfarction and mortality in post-MI patients. Some of the studies discussed in this review suggest the possibility that these interventions, by themselves, may not be sufficient to reduce the rates of these end points.

Regardless of whether treatment of depression can improve the prognosis of post-MI patients, comorbid depression can have devastating effects on functioning and quality of life; thus, it is a psychiatric disorder worthy of treatment in its own right. Until there is convincing evidence that treatment can reduce the risk of cardiac morbidity and mortality, the principal reason to treat depression should continue to be to improve the post-MI patient’s quality of life. Nevertheless, improving prognosis remains one of the most important goals in this area. Further research on the mechanisms underlying the relationship between depression and mortality in CHD, and on treatments that can directly affect these mechanisms, is needed to achieve this goal.

	ACKNOWLEDGMENTS

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Preparation of this manuscript was supported in part by Grant 1UO-1HL58946 from the National Heart, Lung, and Blood Institute, US Public Health Service, Bethesda, Maryland, Robert M. Carney, PhD, principal investigator, and Grant R21MH52629 from the National Institute of Mental Health, US Public Health Service, Kenneth E. Freedland, PhD, principal investigator.

Received for publication June 19, 1998.

Revision received October 16, 1998.

	REFERENCES

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