Depression as a Risk Factor for Coronary Artery Disease: Evidence,
Mechanisms, and Treatment
HEATHER S. LETT, MA, JAMES A. BLUMENTHAL, PHD, MICHAEL A. BABYAK, PHD, ANDREW SHERWOOD, PHD,
TIMOTHY STRAUMAN, PHD, CLIVE ROBINS, PHD, AND MARK F. NEWMAN, MD
Objective: The present paper reviews the evidence that depression is a risk factor for the development and progression of coronary
artery disease (CAD). Methods: MEDLINE searches and reviews of bibliographies were used to identify relevant articles. Articles
were clustered by theme: depression as a risk factor, biobehavioral mechanisms, and treatment outcome studies. Results:
Depression confers a relative risk between 1.5 and 2.0 for the onset of CAD in healthy individuals, whereas depression in patients
with existing CAD confers a relative risk between 1.5 and 2.5 for cardiac morbidity and mortality. A number of plausible
biobehavioral mechanisms linking depression and CAD have been identified, including treatment adherence, lifestyle factors,
traditional risk factors, alterations in autonomic nervous system (ANS) and hypothalamic pituitary adrenal (HPA) axis functioning,
platelet activation, and inflammation. Conclusion: There is substantial evidence for a relationship between depression and adverse
clinical outcomes. However, despite the availability of effective therapies for depression, there is a paucity of data to support the
efficacy of these interventions to improve clinical outcomes for depressed CAD patients. Randomized clinical trials are needed to
further evaluate the value of treating depression in CAD patients to improve survival and reduce morbidity. Key words: depression,
coronary artery disease, physiological mechanisms, behavioral mechanisms, randomized clinical trials.
AMI ? acute myocardial infarction; ANS ? autonomic nervous
system; BDI ? Beck Depression Inventory; CABG ? coronary
artery bypass graft; CAD ? coronary artery disease; CBT ? cogni-
tive behavior therapy; CES-D ? Center for Epidemiological Studies
Depression Questionnaire; CHD ? coronary heart disease; CHF ?
congestive heart failure; DIS ? Diagnostic Interview Schedule;
ENRICHD ? Enhancing Recovery in Coronary Heart Disease;
HBP ? high blood pressure; HPA ? hypothalamic pituitary adrenal;
HRV ? heart rate variability; IHD ? ischemic heart disease;
MDD ? major depressive disorder; SNS ? sympathetic nervous
system; SSRI ? selective serotonin reuptake inhibitor.
United States (1). Psychosocial factors have long been impli-
cated in the etiology and progression of CAD (2). Recent
research suggests that depression is a particularly robust psy-
chosocial predictor of CAD onset and progression (3–6). This
paper reviews evidence for depression as a risk factor and
summarizes treatment strategies to improve prognosis in de-
pressed CAD patients.
Articles for the primary review of depression as a risk
factor were identified with MEDLINE (1966 to 2003) and
PsychINFO (1872 to 2003) searches using the terms “prog-
nosis,” “risk factors,” “depression,” “depressive disorder,”
“major depression,” “coronary disease,” “myocardial infarc-
tion,” “coronary artery bypass,” and “congestive heart fail-
ure.” The searches were limited to studies using human sub-
jects and available in English-language. Reference sections of
relevant articles were used to identify additional studies that
had not been identified by the database searches. Studies that
ver the past century, coronary artery disease (CAD) has
been the primary killer of both men and women in the
measured depression at baseline including both measures of
depressive symptoms and clinical depression, had longitudinal
or case-control designs, and included “hard” endpoints like
death or cardiac events were included in the primary review.
EMPIRICAL EVIDENCE FOR DEPRESSION AS A
RISK FACTOR FOR CAD
Preliminary evidence to support a relationship between
depression and CAD has been provided by numerous cross-
sectional studies of CAD patients. These studies have docu-
mented a disproportionately high prevalence of depression in
CAD patients relative to the general population. Point preva-
lence estimates for the population at large range from 4 to 7%
(7,8). By comparison, point prevalences range from 14% to as
high as 47% in CAD patients, with higher rates recorded most
often in patients with unstable angina or in patients awaiting
coronary artery bypass graft (CABG) surgery (9–21). When
DSM criteria are used to establish diagnosis, estimates of the
prevalence of depression in CAD patients tend to be lower at
15 to 20% (9,11,12,15,17). The high prevalence of depression
in CAD patients suggests that depression may contribute to
the development of CAD, but evidence from these cross-
sectional studies may be confounded by selection factors and
other potential sources of bias. Therefore, prospective studies
have been conducted to determine if depressed individuals are
more likely to develop CAD and its complications.
Prospective Studies With Population Samples and
As highlighted in Table 1, these studies reveal that the
presence of depression in individuals without CAD most
consistently confers an approximately 1.5-fold to 2.0-fold
adjusted relative risk for the subsequent development of CAD
(22–30). Pennix et al (29) followed 2397 patients who were
free of CAD at baseline for 4 years. Those with a diagnosis of
major depressive disorder (MDD) were 3.9 times more likely
to die of cardiac causes compared with those without depres-
sion at baseline, even after controlling for disease severity and
other risk factors.
From the Departments of Psychiatry and Behavioral Sciences (H.S.L.,
J.A.B., M.A.B., A.S., C.R.) and Anesthesiology (M.F.N.), Duke University
Medical Center, Durham, North Carolina; and the Department of Psychology:
Social and Health Sciences (T.S.), Duke University, Durham, North Carolina.
Address correspondence and reprint requests to: Heather Lett, MA, Box
3119, Duke University Medical Center, Durham, NC 27710. E-mail:
Received for publication August 4, 2003; revision received November 14,
This research was supported in part by Grants No. HL 59672, MH49679,
and HC-55142 from the National Institutes of Health, Bethesda, Maryland.
305Psychosomatic Medicine 66:305–315 (2004)
Copyright © 2004 by the American Psychosomatic Society
Although most studies have reported greater risk for de-
pressed patients, a few have reported mixed or negative find-
ings or small effect sizes. Ariyo et al (26) followed 4493
patients free of cardiovascular disease at baseline for 6 years.
Depression (as measured by the 10-item CES-D) was a sta-
tistically significant predictor of CHD diagnosis, but the effect
size was relatively small, with a hazard ratio of 1.15 for a
5-point increase in the 10-item scale.
Other studies have suggested that the relation between
depression and clinical outcomes may not be consistent across
certain subgroups (25,27). For example, Hippisley-Cox et al
(25) conducted a population-based case-control study of 327
subjects free of CAD matched with 897 controls without CAD
and found that depression did not put woman at risk for
subsequent diagnosis of CAD. In contrast, depression at base-
line put men at 2.75 times greater risk for subsequent diag-
nosis of IHD. The negative findings notwithstanding, a recent
meta-analytic review of the literature concluded that depres-
sion is an independent risk factor for CAD with an overall risk
ratio of 1.64 (after controlling for a likely publication bias)
Prospective Studies With CAD Samples
Depression also has been shown to be predictive of out-
comes in CAD patients. A large number of studies have
measured depression in CAD patients using clinical inter-
views and/or questionnaires and followed them over time to
assess the extent to which depression predicts clinical out-
comes. Table 2 summarizes the relation of depression and
“hard” clinical endpoints such as death or MI.
Stable CAD and Prognosis
Studies of patients with stable CAD have reported signif-
icant associations of depression and clinical outcomes. Carney
et al (9) followed 52 patients for 12 months after catheteriza-
tion and found that a diagnosis of MDD was associated with
an adjusted risk ratio of 2.2. Barefoot et al (32) assessed 1250
patients with documented CAD using the Zung Self-Report
Depression Scale at the time of diagnostic coronary angiog-
raphy and followed patients for up to 19.4 years. Results
showed that patients with moderate to severe depression were
at 69% greater risk for cardiac death and 78% greater risk for
all-cause death (32).
AMI and Prognosis
A number of studies have assessed the relationship of
depression and CAD outcomes in patients hospitalized for
acute myocardial infarction (AMI; Table 2). These studies
suggest that the presence of depression during or shortly after
hospitalization confers 2 to 3 times the risk for mortality or
nonfatal cardiac events (11,33–39). Frasure-Smith et al (34)
followed 896 patients with a recent AMI for 1 year. The
presence of elevated depressive symptoms on the Beck De-
pression Inventory (BDI) was a significant predictor of car-
diac mortality after controlling for other multivariate predic-
tors of mortality (OR ? 3.29 for women; 3.05 for men).
Although there have been some null findings in this area
(40–44), most have been from small studies with limited
follow-up or inadequate assessment of depression (5). For
example, Jenkinson et al (40) followed 1376 patients hospi-
talized for MI for 3 years and reported no association between
depression at the time of hospitalization and all-cause mortal-
ity. Although the large sample size was a strength of the study,
one possible explanation for the null finding was that depres-
sion was assessed using a nonvalidated scale consisting of
only 3 items related to depression. Lane et al (42–44) fol-
lowed 288 patients hospitalized for AMI for up to 1 year and
also found that depression (assessed by the BDI) was not
related to cardiac or all-cause mortality at 4 months or 1 year,
nor was it related to cardiac events at 1 year. However, a
notable limitation of this series of studies is the small sample
size and event rate, which can yield highly unstable estimates
TABLE 1. Studies Assessing Depression and the Initial Onset of CAD in Initially Healthy Individuals
AuthorNFollow-up TimeEndpoint(s)Adjusted Relative Risk
Anda et al (22)2832 Mean ? 12.4 yr Fatal IHD
CHD events; MI
RR ? 1.5
RR ? 1.71
RR ? 1.7
Barefoot et al (23)
Ford et al (24)
Mendes de Leon et al (30)2812 10 yr CHD deaths
Diagnosis of CHD
Diagnosis of IHDHippisley-Cox et al (25) 327 with IHD matched to
897 controls without IHD
Not specified NS for women
OR ? 2.75 for men
HR ? 1.15
Women: CHD RR ? 1.73,
CHD mortality NS;
Men: CHD RR ? 1.71,
CHD mortality 2.34
RR ? 3.9
Women: RR ? 2.59;
Men: RR ? 3.45
(controlling for age only)
Ariyo et al (26)
Ferketich et al (27)
Diagnosis of CHD
Pennix et al (29)
Aromaa et al (28)
2397 ages 55–85 yr
H. S. LETT et al.
306Psychosomatic Medicine 66:305–315 (2004)
Studies Assessing the Effect of Depression on Outcomes in CAD Samples
Adjusted Relative Risk
Carney et al (9)
RR ? 2.2
Barefoot et al (32)
Cardiac and all-cause mortality
Cardiac mortality RR ? 1.7; all-cause
mortality RR ? 1.8
Jiang et al (17)
OR ? 2.23
Murberg et al (58)
119/22 cardiac deaths
HR ? 1.9
Frasure-Smith et al (11)
DIS:HR ? 4.29
Frasure-Smith et al (33)
DIS NS; BDI OR ? 6.64
Frasure-Smith et al (34)
Men OR ? 3.05; Women OR ? 3.29
Frasure-Smith et al (35)
HR ? 3.13–3.17
Lane et al (42)
Cardiac or all-cause mortality
Lane et al (43)
Cardiac or all-cause mortality
Lane et al (44)
Ahern et al (36)
Mortality; Cardiac arrest
RR ? 1.38
Jenkinson et al (40)
Ladwig et al (41)
560/12 deaths; 17
Cardiac death; Arrhythmic event
Welin et al (37)
RR ? 3.16
Bush et al (38)
RR ? 3.5
Horsten et al (39)
Acute CHD event
(MI or Angina)
Death or cardiac event
RR ? 1.9
Lesperance et al (14)
430/16 deaths; 28
Cardiac death or MI
OR ? 6.73
Connerney et al (15)
309/8 deaths; 42
Cardiac event; mortality
Cardiac events, RR ? 2.3; mortality NS;
Baker et al (20)
Median ? 24 months
OR ? 6.24
Saur et al (47)
Blumenthal et al (50)
Mean ? 5.2 yr
Moderate-severe depression HR ? 2.84;
persistent depression HR ? 2.33
Burg et al (49)
OR ? 23.16
N/A ? not available.
DEPRESSION AND CAD
307Psychosomatic Medicine 66:305–315 (2004)
(45). Women are at higher risk for mortality after MI (46) and
have higher rates of depression than men. Frasure-Smith et al
(35) investigated the possibility that the increased risk for
women is due higher rates of depression or gender differences
in the impact of depression on clinical events. They failed to
find any evidence in support of these possibilities. However
with only 290 patients (133 women) and 42 deaths, the study
may have had inadequate power to detect any gender effects.
CABG Surgery and Prognosis
CABG surgery is a common surgical intervention for CAD
patients, and depression rates are known to be particularly
high in CABG patients both before and immediately after
surgery (15,18–21,47,48). However, there are very few pro-
spective studies of patients undergoing CABG surgery
(15,20,47,49,50). Connerney et al (15) followed 309 CABG
patients for 1 year after surgery. Compared with nondepressed
patients, depressed patients (as assessed by the DIS) were
more than twice as likely to have a cardiac event within 12
months after surgery but were not at higher risk for mortality
within the first year. In a larger sample of 817 CABG patients
followed for up to 12 years (mean ? 5.2 years), Blumenthal et
al (50) assessed the effect of depression on mortality after
CABG surgery. Depression was assessed both at baseline and
6 months after surgery. Results indicated that moderate to
severe depression (CES-D scores ? 27) on the day before
surgery as well as depression that persisted from baseline to 6
months after surgery (CES-D scores ? 16) were indepen-
dently associated with 2-fold to 3-fold increased risk of mor-
Although women are at increased risk compared with men
for poor outcomes after surgery (15,51,52) and may be more
likely to be depressed before and after cardiac surgery (18,53–
55), there is no evidence that depression places women at
greater risk compared with men. It is more likely that in-
creased medical comorbidities might place women at greater
risk for depression and adverse clinical outcomes. Women are
more likely to have other features putting them at risk for
poorer outcome, such as decreased functionality, older age at
the time of surgery (55), increased angina, more severe hy-
pertension and diabetes (56,57), and smaller coronary artery
CHF and Prognosis
Although only a subset of patients with congestive heart
failure (CHF) have underlying CAD, both Jiang et al (17) and
Murberg et al (59) have reported that depression in patients
with CHF is associated with reduced life expectancy. Murberg
et al followed 119 patients with CHF for 24 months. De-
pressed mood, as assessed by the Zung Self-Rating Depres-
sion Scale, was associated with a significant hazard ratio of
1.9 for predicting cardiac mortality.
As depicted in Figure 1, a number of plausible biobehav-
ioral mechanisms have been hypothesized to underlie the
relationship between depression and CAD: treatment adher-
ence; lifestyle factors such as smoking, heavy alcohol use, and
physical inactivity; traditional risk factors including hyperten-
sion, diabetes, and insulin resistance; changes in platelet re-
activity; dysregulation of the autonomic nervous system and
hypothalamic pituitary adrenal (HPA) axis; and alterations in
the immune response/inflammation. However, much of the
existing evidence for the mechanisms that underlie the rela-
tionship between depression and CAD is derived from cross-
sectional studies. Few prospective studies have been con-
ducted to date.
Many studies have shown that depression predicts poor
adherence to prescribed regimens. In a recent meta-analysis,
Di Matteo et al (60) concluded that depression puts patients
with a variety of medical problems at twice the risk for
nonadherence with prescribed therapies, including patients
with CAD (61–64). Nonadherence to recommended lifestyle
changes and medication regimes itself is associated with de-
creased survival for CAD patients (65–67), suggesting that
adherence may be a mechanism linking depression and CAD
Lifestyle Factors: Smoking, Alcohol Consumption,
and Physical Activity
Smoking and physical inactivity are important risk factors
for CAD and are often targets for the prevention and treatment
(68). Although many studies have shown that low to moderate
levels of alcohol consumption actually confer a protective
effect for CAD, the highest levels of alcohol consumption put
CAD clinical events.
Biobehavioral model for the relationship between depression and
H. S. LETT et al.
308Psychosomatic Medicine 66:305–315 (2004)
patients, especially women, at risk for increased mortality
(69,70). Depression is associated with increased rates of
smoking in CAD patients (71) and may lower the success of
smoking cessation programs (72). Depression also is associ-
ated with increased alcohol use and physical inactivity (73).
Cross-sectional and longitudinal studies have shown that ac-
tive persons are less depressed compared with their sedentary
counterparts and that inactive persons who become active are
less likely to become depressed (73–80). Furthermore, there is
evidence that depression may potentiate other risk factors. For
example, in a case control study Panagiotakos et al (75)
demonstrated that depression, especially when accompanied
by alcohol use, physical inactivity and/or smoking, was asso-
ciated with increased risk for the development of CAD.
Traditional Risk Factors and the Metabolic Syndrome
The American Heart Association has recently classified
obesity as a major modifiable risk factor for CAD and has
called for more research and interventions in this area (81).
Furthermore, obesity tends to cluster with several other risk
factors for CAD including diabetes, hypertension, and hyper-
lipidemia. Together, these risk factors have been described as
the “metabolic syndrome,” which has been shown to contrib-
ute to both the onset and progression of CAD (82–84). Dia-
betes and obesity in particular have been linked to depression
Platelet activity is an important factor in the development
of atherosclerosis, acute coronary syndromes, and thrombosis,
and anti-platelet medications have been used as secondary
prevention for CAD (87,88). In addition, increased platelet
reactivity has been associated in cross-sectional studies with
higher levels of depression in healthy (89,90) and CAD pop-
ulations (91). The role of serotonin in both platelet function
(92) and depression (93) also provides suggestive evidence
linking platelet activity and depression.
Hypothalamic Pituitary Adrenal (HPA) Axis
Alteration of the functioning of the HPA axis is another
possible mechanism of action (6,94). A number of studies
have demonstrated that depression is associated with imbal-
ances in HPA axis functioning. Depressed patients tend to
exhibit higher basal cortisol levels (95,96) and nonsuppression
of endogenous cortisol secretion after dexamethasone admin-
istration, providing an overall picture of impaired feedback
and consequent HPA axis hyperactivity in depression (97,98).
However, current research highlights the variability in HPA
axis functioning within depressed samples and suggests that
HPA axis functioning in depression is best described as dys-
regulated (95,99,100). HPA axis dysregulation is related to
many cardiovascular disease risk factors such as truncal obe-
sity, hypercholesterolemia, hypertriglyceridemia, increased
blood pressure, and elevated heart rate (101,102).
Autonomic Nervous System
ANS dysregulation has been implicated in CAD. Hyperac-
tivity of the SNS has been linked to HBP (103) and other risk
factors for CAD mortality such as decreased HRV, decreased
vagal tone, and reduced heart rate recovery (104–106). SNS
activation may elicit coronary vessel constriction in CAD
patients, resulting in myocardial ischemia (107,108). Abnor-
mal ANS functioning has also been shown in depressed pa-
tients. Conflicting evidence suggests that depression is not
associated simply with global increases or decreases in ANS
activity, but it may be better conceptualized by ANS dysregu-
lation (109–112). The link between depression and impaired
ANS function has been demonstrated in CAD populations. For
example, several cross-sectional studies have shown de-
pressed patients with CAD to have decreased HRV (113–116).
Reduced baroreflex cardiac control (another measure of ANS
activity) also has been shown to correlate with depressive
symptom severity in CAD patients (117).
Emerging evidence suggests that alterations in immune
functioning and inflammation may contribute to the develop-
ment and clinical manifestations of CAD. The body’s inflam-
matory response to chronic hypercholesterolemia and hyper-
tension may contribute to atherosclerosis as damage to the
arterial lining occurs over time (118). For example, Ridker et
al (119) showed that patients who were initially disease free
but who developed peripheral arterial disease over 5 years
differed from controls in having higher levels of C-reactive
protein after controlling for other risk factors. There is also
evidence from both population and CAD samples that in-
(90,120,121) and with other CAD risk factors such as the
metabolic syndrome (122,123). Thus, some preliminary evi-
dence exists to show that inflammation may mediate the
relation between depression and CAD.
There are currently several empirically validated treatments
for depression. However, to our knowledge, there have been
only two completed clinical trials treating depression in car-
diac patients (124,125), and no clinical trials with nonCAD
populations have examined CAD outcomes.
Psychosocial interventions (including individual or group
psychotherapy, support, stress reduction) have been used as
treatments for depression in CAD patients. The aim of these
interventions is to reduce psychological distress, which in
theory would ultimately improve clinical outcomes. Method-
ological limitations of many of the existing studies in this area
include lack of a control group (126), “soft” endpoints (127–
129), and small sample sizes (130,133). There have been
several studies of psychosocial interventions for a general
(nondepressed) cardiac population (130–139). For example,
in the M-HART trial (139) 1376 patients with a recent MI
DEPRESSION AND CAD
309 Psychosomatic Medicine 66:305–315 (2004)
were randomly assigned to 12 months of a psychosocial
nursing intervention or usual care. The intervention consisted
of monthly phone monitoring by an untrained person. Patients
who reported high levels of distress were visited in their
homes by a nurse. Twelve-month follow-up data indicated that
the intervention did not protect against re-infarction or cardiac
or all-cause mortality. Furthermore, there were no significant
reductions in symptoms of depression or anxiety as a result of
the intervention. Similarly, Jones and West (133) randomized
2328 patients with a recent AMI to usual care or seven 2-hour
sessions of a psychosocial intervention that included group
and individual psychotherapy, relaxation training, and stress
management. Twelve-month follow-up data revealed that the
intervention did not decrease the risk for mortality or re-
infarction. However, the intervention was not successful in
decreasing symptoms of depression, which may account for
the lack of effect.
Despite these negative studies, other studies have shown
(135,137,140,141). For example, in the Ischemic Heart Dis-
ease Life Stress Monitoring Program (135), 461 men with a
recent AMI were randomly assigned to usual care or a psy-
chosocial intervention identical to the intervention used later
in the M-HART trial. At 1-year follow-up, patients in the
intervention group had greater reductions in distress and de-
creased mortality. In the Myocardial Ischemia Intervention
Trial (141), 136 patients with documented CAD and recent
exercise-induced ischemia were assigned to usual care, exer-
cise training, or a psychosocial stress management interven-
tion. The psychosocial intervention resulted in reductions in
general distress and hostility relative to control. Furthermore,
patients who took part in the psychosocial intervention
showed reduced ischemia and were less likely to suffer a
cardiac event over a mean follow-up time of 38 months.
Indeed, the benefits appeared to persist for up to 5 years
among patients receiving stress management training, and the
clinical benefits were also associated with significant changes
in medical expenses (142). Considering these studies together,
a recent meta-analytic review concluded that psychosocial
interventions increase quality of life and improve clinical
There are several empirically validated therapies for MDD,
including behavior therapy, interpersonal therapy, and cogni-
tive therapy (144). Until recently, none have been applied to a
clinically depressed CAD population. The recently completed
ENRICHD study (125,145) is the first clinical trail to include
patients with clinical depression. On the basis of evidence that
both low social support and depression confer a risk for poorer
clinical outcomes, patients with an MI within 1 month who
also had a diagnosis of MDD, minor depression with a history
of MDD, dysthymia, or low social support were randomly
assigned to usual care or a psychosocial intervention. The
psychosocial intervention consisted of 6 sessions to 6 months
of individual CBT, group therapy (when feasible), and con-
comitant treatment with antidepressant medication for severe
or persistent depression.
Initial results of the ENRICHD trial indicate that the inter-
vention was associated with statistically significant improve-
ments in depression and low social support compared with
usual care. However, the CBT intervention was not effective
in reducing rates of mortality or recurrent cardiac events in the
overall sample or in a sub-sample including only patients with
depression. At 3-year follow-up, 24.4% of the patients in the
treatment group had either died or had another heart attack,
compared with 24.2% in the usual care group. Furthermore,
there was a trend approaching statistical significance showing
that the intervention may actually have had a detrimental
effect on female patients (125). The relatively modest be-
tween-group differences (ie, the treatment group showed a
57% reduction in HAM-D scores, the usual care group showed
a 47% reduction) might have been a factor that contributed to
the negative findings, although the magnitude of change in
depression was comparable to that seen with trials of antide-
There are several classes of antidepressant medications that
have been shown to be effective in treating depression (146).
The SSRI class of antidepressants is currently considered the
safest to use with CAD patients, in contrast with the tricyclics,
which may alter heart rate and rhythm (143,144). The recently
completed SADHART trial compared the effects of sertraline
and placebo for 24 weeks in MDD patients with unstable
angina or recent MI (124). Initial follow-up data extending to
the time the treatment ended suggested that SSRI treatment
did not adversely affect cardiac function and was considered
to be safe for most patients. However, as was the case in the
ENRICHD trial, improvements in depression were rather
modest. In subsequent analyses, it was found that patients with
at least 1 prior episode of depression or more severe depres-
sion showed consistent improvement in depression relative to
control, suggesting that treatment with SSRIs is a good option
for this subset of depressed CAD patients. Although
SADHART was not powered to detect a treatment effect on
mortality and a composite measure of “hard” and “soft” out-
comes was used, there was a tendency for the patients treated
with sertraline to have fewer serious adverse events (death or
rehospitalization for MI, CHF, stroke, or angina) than those
receiving placebo. The ENRICHD trial also found that treat-
ment with antidepressant medication improved prognosis for
MI patients. Patients who were treated with antidepressants
(regardless of randomization assignment to the intervention or
usual care) were at decreased risk for death and reinfarction
compared with those who did not take antidepressants (125).
In addition to reducing symptoms of depression, SSRIs have
anticoagulation attributes, which may be effective in reducing
risk for cardiac events in susceptible patients with CAD (147–
Exercise is a particularly promising treatment for depres-
sion in CAD patients. In a recent meta-analysis, Jolliffe et al
H. S. LETT et al.
310 Psychosomatic Medicine 66:305–315 (2004)
(150) reported an overall mortality odds ratio of 0.69 for
exercise interventions representing a 31% decrease in the odds
of cardiac mortality. In addition, there is preliminary evidence,
mostly from noncontrolled trials, that exercise is an effective
treatment for depression (74,151). In one of the better-con-
trolled studies in this area (152), depressed adult patients with
MDD were randomized to treatment with exercise, antidepres-
sant medication, or both. Exercise was shown to be about as
effective as antidepressant medication in treating depression
by the end of the 16-week treatment. Moreover, patients who
continued to exercise were less likely to relapse after 10
months (153). Studies of CAD patients (again primarily non-
controlled trials) suggest that exercise may be a viable treat-
ment for depression in this population as well (50,132,154–
160). In one of the few controlled studies in this area, Stern et
al (132) randomized 106 male patients with a recent AMI and
elevated depression, anxiety, or low fitness to 12 weeks of
exercise training, group therapy, or a usual care control group.
At 1-year follow-up, both the counseling and the exercise
group showed improvements in depression relative to control.
However, only the exercise group showed improved health
outcomes. The evidence that exercise affects both depression
and CAD outcomes suggests that exercise is a promising
intervention for depression in this population, perhaps because
is it able to directly target both depression and CAD risk
factors. Indeed, many of the proposed physiological mecha-
nisms linking depression and CAD outcomes, such as alter-
ations in ANS (161–163) and HPA axis functioning
(6,94,98,99,164–167), insulin resistance (168), and inflamma-
tion (169), are likely to be directly targeted by exercise.
Recent evidence suggests that depression is a significant
and independent risk factor for CAD in both healthy and CAD
populations, with a relative risk of about 2.0. It is possible that
depression is merely a marker of a broader phenomenon, such
as negative affect, or is tapping a related psychosocial risk
factor, such as vital exhaustion (170), decreased social support
(37), personality factors (171,172), anger expression (173),
hostility (174), negative emotions (175,176), and anxiety
(177). However, studies that have been able to compare the
unique predictive value of these related constructs have sug-
gested that depression and negative affect are the factors that
emerge as most predictive of increased risk (175,176) and thus
warrant closer clinical attention and further study.
Research on potential mechanisms suggests that there are
several plausible biobehavioral mechanisms for which prelim-
inary support exists, including treatment adherence, lifestyle
factors, traditional risk factors including the metabolic syn-
drome, platelet reactivity, ANS and HPA axis dysregulation,
and inflammation. Future work may work toward identifying
genetic factors that increase risk for both depression and CAD.
For example, recent evidence points to the role of a polymor-
phism in the promoter region of the serotonin transporter gene
in predisposing patients to depression after stressful life events
(178). Other work has investigated the possibility that this
polymorphism is common to both altered serotonergic func-
tion and cardiovascular reactivity to stress (179). A study of
monozygotic and dizygotic twins has provided further evi-
dence for a genetic risk factor common to both depression and
heart disease (180).
In a recent editorial, Frasure-Smith and Lesperance (181)
suggested that depression is a risk factor in search of a
treatment. Indeed, it is clear that depression is an important
risk factor for CAD patients, yet the question remains how to
best to treat it. The results of the ENRICHD trial indicate that
CBT is not effective in reducing rates of mortality or cardiac
events in MI patients. However, it is possible that other
psychosocial interventions may prove to be effective. On the
other hand, the SADHART trial and ENRICHD trial both
have provided suggestive evidence that treatment with SSRIs
improves prognosis for depressed CAD patients. Larger ran-
domized clinical trials of SSRIs are needed to further evaluate
the potential of this treatment. In addition, exercise training is
emerging as a promising intervention, as there is mounting
evidence that it is an effective treatment for depression and
affects a wide array of risk factors linking depression and
CAD. Future trials are warranted to address the potential of
exercise as an intervention.
Further research on patient-treatment match and the timing
of treatment also may improve treatment efficacy. For exam-
ple, the ENRICHD trial was designed to intervene with de-
pression detected shortly after an AMI. In retrospect, this may
not be the optimal time to assess and intervene with depres-
sion as the chance of detecting an adjustment disorder or
transient depressed mood is high (181). Existing evidence
suggests that more severe or chronic depression detected at
this time puts patients at higher risk and is most likely to
respond to treatment (32,49,124). However, some patients
may be unwilling to address psychological issues at the time
of surgery or AMI and may be more amenable to medication
or exercise at that time. The SADHART and ENRICHD trials
both reported statistically significant changes in depression,
but the effect sizes may not have been clinically meaningful,
suggesting the need to increase the efficacy of depression
interventions for CAD patients. Although it is not possible at
this point to recommend treatment for depression to reduce
cardiac risk, depression is common in this population and
certainly warrants treatment due to quality of life concerns
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