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Depression and Cardiac Mortality
Results From a Community-Based Longitudinal Study
Brenda W. J. H. Penninx, PhD;
Aartjan T. F. Beekman, MD, PhD;
Adriaan Honig, MD, PhD;
Dorly J. H. Deeg, PhD;
Robert A. Schoevers, MD;
Jacques T. M. van Eijk, PhD;
Willem van Tilburg, MD, PhD
Arch Gen Psychiatry. 2001;58:221-227.
ABSTRACT
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Background Depression may be a potential risk factor for subsequent cardiac death.
The impact of depression on cardiac mortality has been suggested to depend
on cardiac disease status, and to be stronger among cardiac patients. This
study examined and compared the effect of depression on cardiac mortality
in community-dwelling persons with and without cardiac disease.
Methods A cohort of 2847 men and women aged 55 to 85 years was evaluated for
4 years. Major depression was defined according to psychiatric DSM-III criteria.
Minor depression was defined by Center for Epidemiologic
Studies-Depression Scale scores of 16 or higher. Effects of minor and major
depression on cardiac mortality were examined separately in 450 subjects with
a diagnosis of cardiac disease and in 2397 subjects without cardiac disease
after adjusting for demographics, smoking, alcohol use, blood pressure, body
mass index, and comorbidity.
Results Compared with nondepressed cardiac patients, the relative risk of subsequent
cardiac mortality was 1.6 (95% confidence interval [CI], 1.0-2.7) for cardiac
patients with minor depression and 3.0 (95% CI, 1.1-7.8) for cardiac patients
with major depression, after adjustment for confounding variables. Among subjects
without cardiac disease at baseline, similar increased cardiac mortality risks
were found for minor depression (1.5 [95% CI, 0.9-2.6]) and major depression
(3.9 [95% CI, 1.4-10.9]).
Conclusion Depression increases the risk for cardiac mortality in subjects with
and without cardiac disease at baseline. The excess cardiac mortality risk
was more than twice as high for major depression as for minor depression.
INTRODUCTION
DEPRESSION has a large range of adverse health consequences, including
impaired physical function, increased morbidity, and an increased risk of
death.1, 2, 3, 4, 5
Several findings suggest that cardiac disease plays a central role in the
development of these consequences.6, 7, 8
Among patients hospitalized with a myocardial infarction, a psychiatric diagnosis
of major depression has been shown to be associated with a 2- to 4-fold increased
risk for cardiac mortality.9, 10, 11, 12, 13
Whether this risk is specific for the period of hospitalization or whether
it also exists among cardiac patients living in the community has not yet
been examined. Among persons initially free of cardiac disease, some studies14, 15, 16, 17, 18
but not others19, 20 found that
significant depressive symptoms, often referred to as subthreshold or minor
depression, increase the risk for fatal cardiac events.21
In their review of the literature, Glassman and Shapiro6
suggested that the impact of depression on cardiac mortality depends on baseline
cardiac disease status; the risk for cardiac events that depression confers
seems to be smaller in subjects without cardiac disease than in cardiac patients.
However, because of large differences in study settings (outpatient vs inpatient)
and depression measurements (depressive symptoms vs major depression), an
indirect comparison of previous results for cardiac patients and for subjects
without cardiac disease is only of limited value. Whether depression indeed
has more adverse cardiac consequences for cardiac patients than for subjects
without cardiac disease is crucial for our further understanding of the (pathophysiological)
link between depression and cardiac disease. In addition, since depression
is a potentially preventable and treatable condition, the identification of
subjects for whom depression has the strongest cardiac consequences has important
clinical implications. This study examines and compares the effect of significant
depressive symptoms (minor depression) and major depression on cardiac mortality
in a community-dwelling sample of older subjects both without and with cardiac
disease.
SUBJECTS, MATERIALS, AND METHODS
SAMPLE
Data are from the Longitudinal Aging Study Amsterdam (LASA), a study
among men and women aged 55 to 85 years. Data collection procedures and response
have been described in detail previously.2
In short, a random sample of community-dwelling older persons, stratified
by age and sex, was drawn from the population registries of 11 municipalities
in the Netherlands. The cohort was originally recruited for the study, Living
Arrangements and Social Networks of Older Adults (LSN) (N = 3805 [response
rate, 62.3%]). After 10 months, between September 1992 and September 1993,
participants were approached to participate in the baseline LASA interview.
A total of 3107 (81.7%) gave informed consent and took part; 126 (3.3%) had
died; 44 (1.2%) could not be contacted; 134 (3.5%) were too ill or impaired
to be interviewed; and 394 (10.4%) refused to participate.
Because of missing baseline depression data, 51 (1.6%) of the 3107 subjects
were lost to subsequent analyses. For 209 (6.8%) of the remaining 3056 respondents,
a cardiac disease diagnosis could not be confirmed or ruled out with complete
certainty, because of contradictory (n = 110) or incomplete (n = 99) data
on cardiac disease status. These 209 subjects were somewhat older, more often
male, and more often had minor depression than subjects without cardiac disease,
but were somewhat younger, less often male, and less often had minor depression
than those with ascertained cardiac disease. Also, they had more cardiac deaths
during follow-up (11.5%) than subjects without cardiac disease (3.8%) (P<.001), but less than those with ascertained cardiac
disease (20.7%) (P = .004). The 209 subjects with
an uncertain cardiac disease diagnosis were left out in further analyses,
leaving 2847 participants for the analyses.
MEASUREMENTS
Depression
As in previous publications,2, 5
a measurement of both minor and major depression is used. At baseline, the
Center for Epidemiologic-Depression Scale (CES-D22)
was used to assess depressive symptoms experienced during the previous week.
This 20-item self-report scale, ranging from 0 to 60, has been shown to be
a valid and reliable instrument in older populations.23
In our study, the internal consistency was high (Cronbach  = .87).
Four weeks after baseline, all subjects scoring above the commonly used CES-D
cutoff score of 16 were approached for a diagnostic interview (response, 86.0%
relative to baseline). Nonresponse of this interview was higher among subjects
with higher age and more chronic diseases (P<.001),
but not related to sex. Using the Diagnostic Interview Schedule (DIS24), a psychiatric diagnosis of major depression (6-month
recency) was defined according to DSM-III criteria.25 The criterion validity of the CES-D for major depression
seemed to be excellent (sensitivity, 100%; specificity, 88%).23
Minor depression was considered present if subjects scored above the CES-D
cutoff, but did not fulfill the diagnostic severity threshold for major depression.
This definition of minor depression identifies subjects with a clinically
relevant level of depressive symptoms, often referred to as a subthreshold
depressive syndrome.21 As expected, subjects
with major depression had a higher mean CES-D score (25.9) than those with
minor depression (22.3) (P<.01), which confirms
more severe depressive symptoms in major depression. The minor depression
category included 69 subjects who scored above the CES-D cutoff but did not
participate in the follow-up diagnostic DIS interview. Consequently, these
subjects could have had major depression instead of minor depression. To check
the effect of this potential misclassification, analyses were repeated after
excluding those with missing DIS interview data.
Cardiac Disease
Cardiac disease was present when a diagnosis of either coronary heart
disease (CHD) (angina pectoris or a history of myocardial infarction) or congestive
heart failure was confirmed. These diagnoses were ascertained by combining
3 data resources: self-reported (symptoms of) cardiac disease, medication
use during the past 2 weeks registered by medical interviewers, and reports
of cardiac disease by subject's general practitioners. Angina pectoris was
considered present when at least 2 of the following criteria were met: (1)
self-reported cardiac disease with symptoms of pain or a heavy, uncomfortable
feeling in the chest during exertion that disappeared within 10 minutes after
stopping or taking sublingual nitroglycerine; (2) the current use of nitroglycerine;
and (3) a confirmed cardiac disease diagnosis given by the general practitioner.
A history of myocardial infarction was considered present when (1) a subject
reported having had a myocardial infarction in the past and (2) a confirmed
cardiac disease diagnosis was given by the general practitioner. Congestive
heart failure was considered present when at least 2 of the following criteria
were met: (1) self-reported cardiac disease with symptoms of edema of the
lower extremities when waking up in the morning and/or having to sleep with
more than 1 pillow because of shortness of breath; (2) the current use of
diuretic medication and either a digitalis or vasodilator preparation; and
(3) a confirmed cardiac disease diagnosis by the general practitioner.
Cardiac Mortality
Death certificates were traced through the registries of the municipalities
in which respondents were registered. Vital status ascertainment was 100%
complete. All deaths that occurred between the baseline interview and October
1, 1997, were recorded. The follow-up period lasted on average 50 months (4.2
years), ranging from 1 to 60 months. Information about causes of death was
obtained through the Dutch Central Bureau of Statistics and coded according
to the International Classification of Diseases, Ninth Revision
(ICD-9 codes).26 International Classification of Diseases, Ninth Revision codes 410
through 429 identify all cardiac deaths, and ICD-9
codes 410 through 414 identify deaths by CHD.
COVARIATES
Potentially confounding factors, assessed at study baseline, included
age, sex, level of education, smoking status (nonsmoker or former or current
smoker), excessive alcohol intake (an average of  3 drinks per day), and
body mass index, computed as weight in kilograms divided by the square of
height in meters. The average of 2 readings of the blood pressure, measured
using an oscillometric digital finger blood pressure monitor (Omron model
HEM-812F; Omron Healthcare Inc, Vernon Hills, Ill), was classified as normotensive
(systolic pressure, <140 mm Hg, and diastolic pressure, <90 mm Hg);
systolic hypertension (diastolic pressure, <90 mm Hg; and systolic pressure, 140
mm Hg); and diastolic hypertension (diastolic pressure, >90 mm Hg). The presence
of comorbid conditions was indicated by self-reported stroke, diabetes mellitus,
lung disease, or cancer.
STATISTICAL ANALYSES
Characteristics of subjects with and without cardiac disease were compared
using  2 statistics for categorical variables and t statistics for continuous variables. Subjects with no cardiac death
were censored on October 1, 1997, or at the time of death, whichever occurred
first. For subjects with and without cardiac disease, cardiac and CHD mortality
rates per 1000 person-years were calculated according to depression status.
Cox proportional hazards regression models were used to examine the effects
of minor and major depression on time to cardiac mortality. Relative risks
(RRs) and 95% confidence intervals (CIs) were used as the measure of association
and adjusted for confounding variables. The assumption of proportionality
of hazard was checked with log minus log plots and by tests of the interaction
of time with exposure (minor and major depression).
RESULTS
The mean (SD) age of the 2847 participants was 70.5 years (8.7 years)
and 52.0% were female. Of the respondents, 278 (9.8%) had angina pectoris,
278 (9.8%) had a history of myocardial infarction, and 178 (6.3%) had congestive
heart failure. Four hundred fifty subjects (15.8%) had a confirmed diagnosis
of cardiac disease. Cardiac patients were significantly older, more often
male, less educated, more often past smokers, and more often had diabetes,
stroke, or lung disease than subjects without cardiac disease (Table 1). Minor depression was significantly (21 = 11.0, P<.001) more often present among
subjects with cardiac disease (17.8%) than among those without cardiac disease
(12.0%). The prevalence of major depression was not significantly (21 = 0.9, P = .35) associated with
cardiac disease status: 1.8% and 2.4% of the subjects without and with cardiac
disease, respectively, had major depression.
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Table 1. Population Characteristics According to Baseline Cardiac Disease
Status
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Five hundred one subjects (17.8% of baseline sample) died during the
follow-up period of, on average, 50 months. Of these deaths, 184 (36.7%) were
cardiac deaths and 108 (21.6%) were CHD deaths. The cardiac mortality rate
for the total sample was 15.3 per 1000 person-years. As expected, this rate
was much higher among subjects with cardiac disease (53.1 per 1000 person-years)
than among those without cardiac disease (8.3 per 1000 person-years). In univariate
regression analyses, other significant predictors (P<.05)
of cardiac mortality were higher age, male sex, lower education, current smoker,
low body mass index, stroke, diabetes, and lung disease.
In subjects without cardiac disease at baseline, the crude cardiac mortality
rate per 1000 person-years was 7.7 in the nondepressed, but much higher in
those with minor (16.2) and major (22.3) depression (Figure 1). In these subjects, the same trend was found for CHD mortality,
with rates of 3.9, 6.3, and 16.7 in subjects with no, minor, and major depression,
respectively. The age- and sex-adjusted Cox proportional hazards model among
subjects without cardiac disease (Table
2) showed that minor depression was associated with a 1.7-fold increased
risk for cardiac mortality (95% CI, 1.0-2.8). This mortality risk reduced
somewhat after further adjustment for education, smoking, drinking, hypertension,
body mass index, stroke, diabetes, lung disease, and cancer (RR, 1.5 [95%
CI, 0.9-2.6]). Subjects with major depression were 4.9 times and, after full
adjustment 3.9 times, more likely to have a cardiac death than nondepressed
subjects. When the outcome was restricted to CHD mortality only, major depression,
but not minor depression, significantly increased the risk for dying (adjusted
RR, 5.2; 95% CI, 1.5-17.7).
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Figure 1. Cardiac death and cardiac heart
disease (CHD) death rates per 1000 person-years by depression status in subjects
without cardiac disease (n = 2397) (A) and in subjects with cardiac disease
(n = 450) (B). Note that the scales for the upper and lower graphs are different.
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Table 2. Relative Risks (RRs) for Cardiac and Ischemic Heart Disease
(IHD) Mortality According to Depression Status in Subjects Without and With
Cardiac Disease*
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Similar analyses were conducted among the 450 cardiac patients. Again,
the crude cardiac mortality rate per 1000 person-years was much lower in the
nondepressed (47.1) than in those with minor depression (72.4) and major depression
(126.8) (Figure 1). A similar pattern
was observed for CHD mortality, with rates of 30.1, 55.1, and 101.4, respectively.
Among cardiac patients, the fully adjusted RR for cardiac mortality was 1.6-fold
increased when minor depression was present (95% CI, 1.0-2.7) and 3.0-fold
increased when major depression was present (95% CI, 1.1-7.8) (Table 2). When only CHD mortality was considered, fully adjusted
RRs were even higher (minor depression: RR, 2.1; 95% CI, 1.1-3.8; major depression:
RR, 3.9; 95% CI, 1.3-11.8). Overall, Table
2 shows increased risks for cardiac mortality associated with minor
depression and, most pronounced, with major depression. These risks seem to
be similar for subjects with and without cardiac disease. An analysis among
all subjects confirms that the risks in both groups were not dissimilar, since
the interaction term between cardiac disease and depression status was not
significant (P = .53).
The minor depression category included 69 persons who scored above the
CES-D cutoff but did not participate in the second interview. Consequently,
these persons could have had major depression instead of minor depression.
Analyses were repeated after excluding those with missing DIS interview data.
These analyses yielded similar cardiac mortality risk estimates for minor
depression in subjects without cardiac disease (fully adjusted RR, 1.5; 95%
CI, 0.8-2.7) and in cardiac patients (RR, 1.9; 95% CI, 1.1-3.3), which confirms
that potential misclassification of those with missing DIS data did not influence
our results (Figure 2).
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Figure 2. Adjusted relative risk for cardiac
death according to level of depressive symptoms in subjects without cardiac
disease (n = 2397) (A) and in subjects with cardiac disease (n = 450) (B).
All depression groups are compared to the lowest level of depressive symptoms
(Center for Epidemiologic Studies-Depression Scale [CES-D] score of 0-2).
Bars indicate relative risks; lines indicate 95% confidence intervals. P = .06, for trend, in subjects without cardiac disease. P = .04, for trend, in subjects with cardiac disease.
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Table 3 presents adjusted
RRs for cardiac mortality and CHD mortality in 6 groups according to depression
and cardiac disease status. When compared with nondepressed subjects without
cardiac disease (reference group), minor and major depression in subjects
without cardiac disease significantly increased the risk for cardiac mortality
(RRs, 1.6 and 3.8, respectively). Nondepressed cardiac patients had a significant
3.4-fold increased risk for cardiac mortality when compared with the reference
group. In cardiac patients with minor and major depression, RRs were 5.1 and
10.5, respectively. The RRs for CHD mortality were even more pronounced; compared
with nondepressed subjects without cardiac disease, RRs were 1.4 and 5.1 for
subjects without cardiac disease with minor and major depression, respectively,
4.5 for nondepressed cardiac patients, 8.5 for cardiac patients with minor
depression, and 17.7 for cardiac patients with major depression. Finally,
we checked whether there was a sex difference in the effect of depression
on cardiac mortality by entering an interaction term sexxdepression
in the Cox proportional hazards analysis. However, no significant interaction
could be demonstrated (P = .68), and stratified analyses
confirmed that the RR estimates for depression were comparable for men and
women.
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Table 3. Adjusted Relative Risks (RRs) for Cardiac and Ischemic Heart
Disease (IHD) Mortality According to Cardiac Disease Status and Depression
Status*
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COMMENT
This study shows that depressed older persons were significantly more
likely to die because of cardiac disease during 50 months of follow-up than
nondepressed older persons. The increased cardiac mortality risk associated
with depression was present—and very similar—in both subjects
with and without cardiac disease. The risk for cardiac mortality was about
1.6 times increased in persons with minor depression and more than 3 times
increased in persons with major depression. When causes of death were restricted
to CHD deaths, the risks associated with minor and major depression were even
somewhat more increased.
In their review of the literature, Glassman and Shapiro6
suggested that depression has 2 times stronger prognostic consequences for
cardiac patients than for persons free of cardiac disease. Our study is the
first to examine and directly compare the effect of depression on cardiac
mortality in community-dwelling older subjects with and without cardiac disease.
We did not find evidence of a stronger adverse cardiac effect of depression
in cardiac patients than in subjects without cardiac disease: in both subgroups
the excess risk for cardiac mortality associated with depression was present
and very similar. However, cardiac mortality risks did differ according to
level of depression: risks were about twice as high for major depression as
for minor depression. These results suggest that the severity of depression
shows a gradient of risk for subsequent cardiac mortality. Consequently, measurement
differences for depression (symptoms vs psychiatric diagnosis) in earlier
studies may explain a large part of the earlier reported differences in the
prognostic strength of depression for cardiac mortality.
Several plausible mechanisms for the link between depression and cardiac
mortality exist, of which pathophysiological and behavioral ones are the most
important. Direct pathophysiological alterations caused by depression have
been described, including impairment of platelet functions6, 7, 27, 28
and a decreased heart rate variability as a consequence of an imbalance in
the autonomic tone.29 Also, immune activation
and hypercortisolemia as stress responses to depression30, 31, 32, 33
may result in decreased insulin resistance and increased steroid production
and blood pressure, thereby increasing the risk of cardiac disease.34 Unhealthy lifestyles have been found to be more common
among depressed than among nondepressed persons.5, 8
Although we adjusted the analyses for smoking and drinking, it is likely that
depressed people are less compliant with treatment recommendations and less
willing to exercise and eat healthy, which may explain part of our results.
Also, the link between depression and cardiac mortality may be caused by pharmacotherapeutic
treatment. Antidepressants, in particular tricyclic antidepressants, may have
a cardiotoxic effect.35 However, in our community-based
sample, antidepressants were used only sparingly and dosages were generally
low.2 Adjustment for antidepressants in the
analyses did not change the RRs for minor and major depression, and therefore
cannot explain our results. Finally, it is possible that depression may be
an indirect indication of disease severity or it may represent a reaction
to (sub)clinical cardiovascular symptoms (eg, dyspnea) that places subjects
at greater risk for cardiac mortality.16, 19
The community-based setting of our study made it impossible to collect detailed
clinical information about the severity of cardiac disease among cardiac patients.
However, the strength of the elevated cardiac mortality risks, the community-based
setting of our sample, and the fact that similar elevated risks were found
among persons without cardiac disease suggest that depression is not only
a surrogate marker of cardiac disease severity but that it has effects in
itself. Our large sample size, the detailed measurement of depression and
the inclusion of subjects both with and without cardiac disease, provided
the unique opportunity to gain more insight into the prognostic importance
of depression for subsequent cardiac mortality in a community-based sample.
The described potential mechanisms explaining the excess cardiac mortality
risk among depressed subjects can operate in both subjects with and without
cardiac disease. Our findings suggest that these mechanisms are active irrespective
of baseline cardiac disease status. We could not demonstrate an interaction
(ie, multiplicative effects) between depression and baseline cardiac disease
status in predicting cardiac mortality. Consequently, it is not very likely
that some mechanisms are triggered only when cardiac disease is present. Baseline
cardiac disease and depression rather seem to have independent, additive effects
on cardiac mortality.
Depression is common in older community-dwelling populations. The prevalence
of a psychiatric diagnosis of major depression in our study was 2%, and a
further 13% suffered from minor depression. These prevalences are in line
with other community-based studies.36 Despite
its high prevalence, depression often goes unrecognized.37
Untreated, minor and major depression are not self-limiting disorders. The
vast majority (62%) of those with a minor depression in our study were still
depressed after 5 months,38 illustrating the
chronic nature of depression. Our results show that minor depression and,
most strongly, major depression place both community-dwelling cardiac patients
and persons free of cardiac disease at an increased risk for cardiac mortality.
Since the "basis" risk for fatal cardiac events is substantially elevated
when cardiac disease is already present, especially cardiac patients with
(major) depression should be recognized as a high-risk population. Prevention
and treatment of depression may be one of the most effective targets for interventions
aimed at reducing the risk for fatal cardiac events. Future clinical trials
should point out whether more appropriate care for depressed persons may prevent
fatal cardiac events.
AUTHOR INFORMATION
Accepted for publication July 20, 2000.
The Longitudinal Aging Study Amsterdam is largely funded by the Ministry
of Welfare, Health, and Sports, the Hague, the Netherlands.
From the Institute for Research in Extramural Medicine, (Drs Penninx,
Beekman, Deeg, and van Tilburg) and the Department of Psychiatry (Drs Beekman,
Deeg, Schoevers, and van Tilburg), Vrije University, Amsterdam, the Netherlands;
Department of Psychiatry, Academic Hospital Maastricht, Maastricht, the Netherlands
(Dr Honig); and the Department of Medical Sociology, University of Maastricht,
Maastricht, the Netherlands (Dr van Eijk). Dr Penninx is now with the Sticht
Center on Aging, Wake Forest University School of Medicine, Winston-Salem,
NC.
Corresponding author: Brenda W. J. H. Penninx, PhD, Sticht Center
on Aging, Wake Forest University School of Medicine, Medical Center Boulevard,
Winston-Salem, NC 27157 (e-mail: bpenninx{at}wfubmc.edu).
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