Depression, the Autonomic Nervous System, and Coronary Heart Disease
ROBERT M. CARNEY, PHD, KENNETH E. FREEDLAND, PHD, AND RICHARD C. VEITH, MD
Depression is a risk factor for medical morbidity and mortality in patients with coronary heart disease (CHD). Dysregulation of the
autonomic nervous system (ANS) may explain why depressed patients are at increased risk. Studies of medically well, depressed
psychiatric patients have found elevated levels of plasma catecholamines and other markers of altered ANS function compared with
controls. Studies of depressed patients with CHD have also uncovered evidence of ANS dysfunction, including elevated heart rate,
low heart rate variability, exaggerated heart rate responses to physical stressors, high variability in ventricular repolarization, and
low baroreceptor sensitivity. All of these indicators of ANS dysfunction have been associated with increased risks of mortality and
cardiac morbidity in patients with CHD. Further research is needed to determine whether ANS dysfunction mediates the effects of
depression on the course and outcome of CHD, and to develop clinical interventions that improve cardiovascular autonomic
regulation while relieving depression in patients with CHD. Key words: autonomic nervous system, coronary disease, depression,
depressive disorder, mortality, myocardial infarction.
ANS ? autonomic nervous system; CHD ? coronary heart disease;
HRV ? heart rate variability; MI ? myocardial infarction; NE ?
norepinephrine; SNS ? sympathetic nervous system.
patients are twice as likely as nondepressed patients to have a
major cardiac event within 12 months of the diagnosis of
coronary artery disease (1), and they are significantly more
likely to die in the years following the diagnosis (2). Depres-
sion also increases the risk of dying after an acute myocardial
infarction (3–10), an episode of unstable angina (11), or
coronary artery bypass graft surgery (12–14). Although some
studies have failed to find a relationship between depression
and mortality in patients after myocardial infarction (MI;
15,16), most have found depression to be a significant risk
factor for mortality and/or cardiac morbidity (17).
Although the relationship between depression and cardiac
events is well established, the mechanisms underlying this
relationship remain unclear. Dysregulation of the autonomic
nervous system (ANS) is one of the most plausible candidates
(18–21). Reduced parasympathetic and increased sympathetic
nervous system (SNS) activity can lower the threshold for
myocardial ischemia, ventricular tachycardia, ventricular fi-
brillation, and sudden cardiac death in patients with CHD
(22–24). Furthermore, coronary artery disease is a chronic
inflammatory process that is triggered by injury to the vascu-
lar endothelium (25,26), and high levels of circulating cat-
echolamines may contribute to recurrent endothelial injury
(26). Elevated catecholamines may also promote procoagulant
processes by potentiating platelet activation through direct
agonist effects, by increasing hemodynamic stress on vascular
epression has significant adverse effects on the course
and outcome of coronary heart disease (CHD). Depressed
walls, or by inhibiting vascular eicosanoid synthesis (27,28).
Both inflammatory and platelet coagulant processes associ-
ated with depression are described in detail elsewhere in this
issue (29,30). This review focuses on studies that have found
evidence of altered ANS regulation in depressed CHD pa-
CATECHOLAMINE LEVELS IN DEPRESSED
Some of the earliest evidence of ANS dysregulation in
depression was found in studies of medically well patients
with major depressive disorder. These studies found elevated
levels of plasma and urinary catecholamines, primarily nor-
epinephrine (NE), in depressed patients compared with con-
Because the concentration of plasma NE generally parallels
the level of activity of the SNS, elevated NE in depressed
patients suggests that SNS activity is increased. However, the
interpretation of plasma NE concentration is complex. When
plasma NE is sampled from antecubital venous blood, it
reflects local sympathetic activity in the forearm, but it may or
may not reflect cardiac or total body sympathetic activity
levels (38). Moreover, high levels of circulating NE could
result from increased NE release because of sympathetic hy-
peractivity, diminished NE clearance, or both (39). These
complexities make it difficult to interpret elevations in plasma
or urinary NE in human studies. It is possible to obtain better
estimates of systemic sympathetic activity by employing ar-
terialized venous sampling and plasma NE kinetic techniques
that rely on dilution of radiolabeled NE and mathematical
modeling to provide estimates of postganglionic NE release
and NE clearance (40). Using this approach, Veith et al. (37)
demonstrated that the elevated levels of circulating plasma NE
in medically healthy patients with major depression are a
result of increased total body sympathetic activity.
HEART RATE AND HEART RATE VARIABILITY
Resting heart rate has been studied in depressed patients
along with measures of catecholamine levels or other markers
of autonomic function. Most of these studies have found
higher heart rates in depressed patients than in nondepressed
controls (33,35–37,41,42), consistent with altered cardiac
ANS function. Elevated resting heart rate is a risk factor for
sudden cardiac death, even in the general population (43–45).
From the Department of Psychiatry, Washington University School of
Medicine, St. Louis, MO (R.M.C., K.E.F.); and the Department of Psychiatry
and Behavioral Sciences, University of Washington, Seattle, WA (R.C.V.).
Address correspondence and reprint requests to Robert M. Carney, PhD,
Behavioral Medicine Center, 4625 Lindell Blvd., Suite 420, St. Louis, MO
63108. E-mail: email@example.com
Received for publication May 5, 2004; revision received August 9, 2004.
In accordance with CME accreditation guidelines, the authors of this article
disclosed no real or potential conflicts of interest.
This research was supported in part by grant no. 1UO-1HL58946 from the
National Heart, Lung, and Blood Institute, and by the Lewis and Jean Sachs
Charitable Lead Trust.
S29 Psychosomatic Medicine 67, Supplement 1:S29–S33 (2005)
Copyright © 2005 by the American Psychosomatic Society
It also increases the risk for progression of atherosclerosis
(47,48), ventricular arrhythmias (23), myocardial ischemia
(46), and plaque disruption in acute coronary syndromes (49)
in individuals with CHD. Mean 24-hour heart rate has been
found to be higher in depressed than nondepressed patients
with CHD, with differences ranging from 5 to 11 bpm (49–53).
Depression is associated with exaggerated heart rate re-
sponses to physical and psychological stressors in medically
well subjects (54–58), and it increases cardiovascular reactiv-
ity to physical stressors in patients with CHD (52). In one
study, heart rate was measured at rest and during orthostatic
challenge in 50 depressed and 39 medically comparable non-
depressed patients with CHD. NE did not differ between the
depressed patients and the controls, but this may have been a
result of a measurement artifact (52). Resting heart rate did
differ between the groups, with a mean of 69.9 bpm ? 10.4
bpm in the depressed and 63.6 bpm ? 10.2 bpm in the
nondepressed groups (p ? .005). The changes from supine
heart rate at 2, 5, and 10 minutes after standing were signif-
icantly greater in the depressed patients than the nondepressed
controls (p ? .02, .004, and .02, respectively), with depressed
patients having a mean maximum change in heart rate of 11.9
bpm ? 6.8 bpm, compared with 7.9 bpm ? 6.8 bpm among
the nondepressed controls. These differences remained signif-
icant even after adjusting for covariates. Thus, depressed
patients with CHD have higher 24-hour heart rates and higher
heart rate responses to physical stressors than nondepressed
patients. To our knowledge, heart rate responses to psycho-
logical stressors have not yet been studied in depressed pa-
tients with CHD.
Heart rate variability (HRV) is one of the most widely used
methods for measuring cardiac autonomic activity in humans
(59). Beat-to-beat variability in the heart’s rhythm is deter-
mined primarily by ANS modulation of the intrinsic cardiac
pacemakers. HRV, then, reflects the balance between the
sympathetic and parasympathetic regulatory control of the
heartbeat; low HRV suggests excessive cardiac sympathetic
modulation, inadequate cardiac parasympathetic modulation,
or both (59). Low HRV also predicts mortality in patients with
a recent MI (60–63) or with stable coronary disease (64).
Many studies have found HRV to be lower in depressed
psychiatric patients compared with controls (65–67), although
some have not (e.g., 68). There is more consistent evidence
that HRV is lower in depressed than nondepressed patients
with stable coronary disease (53,69,70) or with a recent his-
tory of acute MI (71).
In addition to statistical significance, it is important to
consider the clinical significance of differences between de-
pressed patients and controls for any putative mechanism.
Unless the difference is large enough to affect clinical out-
comes, it is unlikely to be responsible for the depressed
patients’ increased risk for mortality. The Cardiac Arrhythmia
Pilot Study assessed HRV 1 year after an acute MI (62). All
of the measured indices of HRV were strong predictors of
mortality. Patients with a log(n) of very low frequency power
?6.4 had a 4.4 relative risk of mortality over the next 2 years.
In a recent study of a similar group of medically stable (i.e.,
event-free for at least 6 months) CHD patients, 47% of those
who were moderately to severely depressed, 29% of those
who were mildly depressed, and 13% of those who were not
depressed had very low frequency power below this cut-point
(53). In the Multicenter Post Infarction Project study (61),
log(n) of very low frequency power ?5.2 was associated with
a relative risk of 4.7 for cardiac mortality over the 2.5 years
after the acute MI. In our study of post-MI patients, 7% of the
nondepressed patients and 16% of the depressed patients had
very low frequency power below this value, a difference that
was significant even after adjusting for covariates (p ? .006;
10). Thus, mean 24-hour HRV is low enough in depressed
patients with medically stable CHD and after an acute MI to
have prognostic significance.
Low HRV has consistently been found in studies of de-
pressed CHD patients, but in only approximately half of the
studies of medically well depressed patients. Furthermore,
although several HRV indices are highly predictive of cardiac
mortality, the relative contributions of the sympathetic and
parasympathetic nervous systems and other physiological pro-
cesses remain unclear. HRV clearly has the potential to ex-
plain much of the effect of depression on cardiac mortality,
but more work is needed to delineate the underlying physio-
Ventricular tachycardia can be precipitated by cardiac au-
tonomic imbalance (23,24), as reflected by lower HRV, and
this is the arrhythmia that usually precedes ventricular fibril-
lation and sudden cardiac death (72,73). One study found that
depressed patients with stable coronary artery disease and
preserved ventricular function had more frequent and longer
runs of ventricular tachycardia than medically comparable
nondepressed patients (74). Twenty-three percent of the de-
pressed patients in this study and 3.5% of the nondepressed
patients with stable CHD had episodes of ventricular tachy-
cardia (p ? .008). Depression remained a significant predictor
of ventricular tachycardia even after controlling for potential
confounds (p ? .01). The relative risk for ventricular tachy-
cardia among the depressed patients was 8.2 (95% confidence
limits, 2.1–31.7). Research is needed to determine whether the
increased prevalence of ventricular tachycardia in depressed
patients, especially those with poor left ventricular function,
explains the increased risk for sudden cardiac death in these
OTHER EVIDENCE FOR CARDIAC AUTONOMIC
DYSFUNCTION IN DEPRESSION
Less is known about the effects of depression on two other
parameters reflecting cardiac ANS modulation: baroreflex
function and ventricular repolarization. The arterial baroreflex
is modulated by the ANS and by other mechanisms involved
in cardiovascular regulation. Like low HRV, impaired barore-
flex sensitivity predicts cardiac events, including ventricular
arrhythmias (75) and sudden cardiac death (76). Watkins and
Grossman (77) found that depression was associated with a
R. M. CARNEY et al.
S30Psychosomatic Medicine 67, Supplement 1:S29–S33 (2005)
reduction in baroreflex control of heart rate in patients with
CHD. A more recent study from this group failed to find
evidence for lower baroreflex control in post-MI patients with
depression, but they did find an association with anxiety (78).
Pitzalis et al. (79), on the other hand, found reduced baroreflex
function in a group of unmedicated post-MI patients with
depression, but not in anxious patients or in depressed patients
receiving ?-blockers. Approximately 80% of the depressed
patients in the second Watkins et al. study were taking
?-blockers at the time of study (78), which may explain why
this group did not find an lower baroreflex control of heart rate
in their depressed patients. Thus, it is possible that the SNS
may contribute to reduced baroreflex sensitivity in depressed
CHD patients, and this may increase their risk for cardiac
events. Clearly, more research is needed to determine the
relationship of depression to baroreflex dysfunction and car-
The QT interval is the electrocardiographic representation
of ventricular repolarization time. Variability in the QT inter-
val reflects beat-to-beat fluctuations in myocardial recovery
time, and increased variability is a significant predictor of
arrhythmic events and sudden cardiac death (80–83). Postural
challenge and isoproterenol infusion have been shown to
increase QT interval variability (84), which suggests that
ventricular repolarization is modulated, at least in part, by the
In the only study to date of depressed cardiac patients, QT
variability was found to be significantly higher in the de-
pressed patients than in a group of age-matched and gender-
matched nondepressed CHD patients during two of eight
sampling periods over 24 hours of ambulatory monitoring
(85). Sudden cardiac death has been shown to have a circadian
pattern, with the peak incidence occurring in the early morn-
ing hours (86). The difference in QT variability between
depressed and nondepressed patients was greatest during the
early morning, just after 6:00 AM. This may reflect a greater
increased risk for arrhythmias and sudden death for depressed
patients during this normally high-risk time. Thus, depression
may increase the risk of mortality after an acute MI by
contributing to dysregulation of ventricular repolarization.
EFFECTS OF TREATING DEPRESSION ON CARDIAC
A number of studies have examined the effects of various
treatments for depression on heart rate and HRV. Tricyclic
antidepressants tend to increase heart rate and decrease HRV,
presumably because of their anticholinergic side effects (87–
89), and they are generally not recommended for treatment of
depression in patients with heart disease. The selective sero-
tonin reuptake inhibitors appear to have no significant cardio-
toxic side effects and are recommended for treating depression
in these patients. In a preliminary study among healthy vol-
unteers, short-term sertraline administration suppressed circu-
lating plasma NE appearance, which is compatible with a
reduction in total body SNE activity (90). However, whereas
some studies have shown that treatment of depression with
selective serotonin reuptake inhibitors improves HRV (91–
93), others have found only temporary or no improvement
To our knowledge, there is only one study that assessed
whether heart rate or HRV improves following a psychother-
apeutic intervention for depression. Fifty patients with stable
CHD and comorbid major depression were given as many as
16 sessions of cognitive behavior therapy, a recognized psy-
chotherapeutic treatment for depression (51). After complet-
ing treatment, 90% of the depressed patients were in full or
partial remission. The mean 24-hour heart rate dropped 5 bpm
in the depressed patients over the course of treatment, com-
pared with less than 1 bpm in a group of nondepressed
controls. There was also a significant increase in an index of
HRV (rMSSD) that reflects primarily parasympathetic mod-
ulation, and a trend (p ? .07) toward an increase in an index
of HRV (SDNNIDX) that reflects a mixture of sympathetic
and parasympathetic influences.
The clinical significance of these changes is difficult to
estimate. However, heart rate reduction is one of the best
predictors of improved survival in patients receiving ?-block-
ers, in both short-term and long-term intervention trials. Re-
duction in heart rate and the percent reduction in mortality and
nonfatal reinfarction correlated at approximately 0.60 across
the major ?-blocker post-MI intervention trials (97). On av-
erage, heart rate decreased by approximately 11 bpm among
patients randomized to ?-blockers in the major trials (97). The
mean heart rate of the severely depressed patients receiving
the psychotherapeutic intervention decreased by approxi-
mately 5 bpm between the pretreatment and posttreatment
assessments, or nearly half of the reduction that is typically
achieved by giving patients ?-blockers. These results, al-
though intriguing, await replication. However, the implica-
tions for treating depression and possibly improving cardiac
prognosis are clear. More studies are needed to evaluate the
effects of depression treatment on cardiac autonomic function,
cardiac morbidity, and mortality.
SUMMARY AND CONCLUSIONS
It is not yet certain that altered ANS activity is responsible
for the increased risk of mortality and medical morbidity
associated with depression in patients with CHD. Neverthe-
less, there is considerable evidence of autonomic cardiovas-
cular dysregulation in depressed patients. Furthermore, many
indicators of cardiovascular autonomic dysregulation, includ-
ing elevated resting and 24-hour heart rates, increased heart
rate responses to physical stressors, reduced HRV and barore-
ceptor sensitivity, and high variability in ventricular repolar-
ization, have been associated with increased mortality and
cardiac morbidity, especially in vulnerable populations such
as post-MI patients. More studies are needed to determine
whether these factors mediate the increased risk of mortality
in depressed patients with CHD, and to identify clinical inter-
ventions that can improve them.
DEPRESSION, ANS, AND CHD
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DEPRESSION, ANS, AND CHD
S33Psychosomatic Medicine 67, Supplement 1:S29–S33 (2005)