Open Journal of Psychiatry, 2012, 2, 284-291 OJPsych
http://dx.doi.org/10.4236/ojpsych.2012.24040 Published Online October 2012 (http://www.SciRP.org/journal/ojpsych/)
Depression as a risk factor for coronary heart
disease—How strong is the evidence?
Hans G. Stampfer, Dana A. Hince, Simon B. Dimmitt
School of Psychiatry and Clinical Neuroscience and School of Medicine and Pharmacology, University of Western Australia, Perth,
Australia
Received 9 July 2012; revised 12 August 2012; accepted 23 August 2012
ABSTRACT
A critical appraisal is made of the evidence that de-
pression is a causal risk factor for coronary heart
disease. PubMed and Science Citation Index were
searched for relevant papers. Forty eight papers sa-
tisfying inclusion criteria and reporting an associa-
tion between a measure of depression and a coronary
disease outcome were compared in terms of baseline
assessment, exposure and endpoint definition, covari-
ates measured and whether changes in, or treatment
of, depression was assessed during follow-up. There
was considerable variation in the definition of de-
pression and coronary heart disease and contradic-
tory findings are reported. Conventional risk factors
for coronary heart disease were not assessed consis-
tently or adequately. Only three of the forty-eight pa-
pers gave consideration to the time course of depres-
sion during follow-up and prior to study entry. Po-
tentially confounding variables such as anxiety, per-
sonality traits and other psychiatric disorders were
not taken into consideratio n in the majority of papers.
Treatment of depression during the follow-up period
was not mentioned in any of the papers. In light of
identified methodological shortcomings and the incon-
sistent findings reported we suggest that there is as yet
no convincing evidence that depression is an inde-
pendent causal risk factor for coronary heart disease.
Keywords: R eview; Depression; C or o nary Heart
Disease (CHD)
1. INTRODUCTION
Systematic reviews and meta-analyses of “quality fil-
tered” prospective studies have repeatedly concluded that
depression is a risk factor for coronary heart disease
(CHD) [1-4] and although the validity of this conclusion
has been challenged [5-9] the majority of published re-
ports support it. In 2003, a “position statement” by a
panel of experts [10] asserted that depression is an inde-
pendent risk factor for CHD, equal in magnitude to es-
tablished risk factors such as hypertension and obesity.
Depression is a high prevalence disorder and the World
Health Organization has predicted that by 2020, depres-
sion and CHD will be the two leading causes of disability-
adjusted life years in developed countries. If this predic-
tion proves to be correct and depression is a proven risk
factor for CHD, it follows that depression will contribute
substantially to the incidence of CHD. The suggested
causal link between depression and CHD should not af-
fect expected diligence in the diagnosis and treatment of
depression—any reduction in CHD resulting from effec-
tive treatment of depression should simply be an added
benefit. However there is a risk that awareness and en-
dorsement of the suggested link might contribute to an
over-diagnosis/treatment of depression and worry about
CHD by individuals diagnosed with depression. These
consequences would be particularly unfortunate if there
was no justification for the endorsement and the aim here
is to show that the evidence in support of the suggested
link is far from conclusive.
2. SEARCH STRATEGY AND
SELECTION CRITERIA
2.1. Study Eligibility
Studies were included if they described a prospective
cohort design, considered the relationship between depres-
sion and CHD and reported an association statistic for
this relationship. Selected studies treated “depression” as
the primary exposure or covariate and included fatal and
non-fatal outcomes of CHD. Selected studies defined “de-
pression” by self-report, symptom scale score, question-
naire-based personality dimension or clinical diagnostic
criteria defined in “Diagnostic and Statistical Manual”
(DSM) and “International Classification of Diseases”
(ICD). Studies relying on antidepressant prescription as a
proxy for depressio n [11] were excluded, as were studies
that included combined cardiovascular endpoints (e.g.
CHD and stroke) or non-specific “heart disease” [12,13].

H. G. Stampfer et al. / Open Journal of Psychiatry 2 (2012) 284-291 285
2.2. Search Strategy
We used a modified version of the search strategy adopted
by Kuper et al. [1]. This strategy combines a conven-
tional subject-heading search in PubMed with citation
tracking through the Science Citation Index (SCI). The
citation tracking includes a forward search (finding pa-
pers citing those identified in an index review) and a
backward search (finding papers citing studies listed in
the reference lists of papers identified in the index re-
view). This strategy has been shown to identify more
relevant papers than a PubMed search alone, particularly
papers reporting a null result [1]. We limited the SCI
search to the forward citation-tracking component. Nicho-
lson et al. [5] was taken as the index review. Papers ref-
erenced in this review that met the selection criteria de-
fined above were entered into the SCI to identify papers
that cited these studies. Both the SCI and PubMed sear-
ches were limited to English publications.
2.3. Data Extraction
Information about the following variables was extracted
from selected studies: Cohort details; positive/null trial
(“positive” if association statistic p < 0.05 was found in
at least one of the relevant analyses); association statistic;
duration of follow-up; exposure details; wheth er existing
CHD or cardiovascular disease (CVD) was excluded at
baseline; endpoint details; whether depression was as-
sessed during follow-up and covariates measured. A meta-
analysis was not attempted, as we were not interested in
the combined effect size across studies, but in the details
of the individual studies that are often obscured in meta-
analyses but are of vital importance to understanding the
significance of a reported association.
3. RESULTS
The number of studies identified by each search strategy
and the number meeting inclusion criteria are shown be-
low in Table 1.
The study variables considered in this review are
summar ized below in Tabl e 2. Forty-eight published arti-
cles based on 36 cohorts were included. Depression was
considered a covariate in 5 studies [14-18] and the prim ary
or one of the primary exposures in the remaining 43
studies. Sample size varied from 76 [19] to 73,098 [20].
The populations studied varied considerably in age and
included “healthy” men and women, war veterans, hy-
pertensive and diabetic patients. Thirty seven percent
(37%) of papers included in this review reported a posi-
tive result for all relevant endpoints/group analyses, 29%
reported mixed results and 33% found no relationship
between depr ession and CHD. No association was found
between positive findings and whether CHD/CVD was
excluded at baseline (

2
1

= 0.39, p = 0.53) or whether
depression was treated as a primary exposure variable or
covariate (

2
1

= 0.05, p = 0.82). However there was an
association between positive findings (as defined above)
and the definition of “depression”, with 100% positive
findings in the 17% of studies that used DSM or ICD
diagnostic criteria, rather than symptom scale/self report
scores. (

2
1

= 5.27, p = 0.02). Positive findings were
also related to sample size. Seventy five percent (75%)
of studies with n < 3000 but only 47% with n > 3000
showed a positive relation ship (

2
1

= 3.74, p = 0.051).
3.1. Exposure and Endpoint Definitions
The definition of depression and CHD varied considerab-
ly across studies. Only 17% of studies used DSM or ICD
diagnostic criteria and/or clinical interview to determine
depression. The remaining 83% of studies used various
symptom rating scales. The most common were the Cen-
tre for Epidemiological Studies Depression Scale (CES-
D), (29%) and various subscales of the Minnesota Mul-
tiphasic Personality Inventory (MMPI) (15%).
CHD was measured by fatal (e.g. myocardial infarc-
tion, MI), non-fatal (e.g. angina, angioplasty, coronary
artery bypass grafting) and combined endpoints that were
based on medical records, death certificates, self-report
and/or hospital records. Multiple endpoints were often
considered in a single study, resulting at times in con-
flicting results [27,45].
3.2. Removal of CHD at Baseline
Twenty percent (20%) of studies did not report the ex-
clusion of participants with evidence for CHD/CVD at
baseline, although three of these studies [18,51,54] at-
tempted to control for this by using baseline eviden ce of
Table 1. Number of papers identified and meeting eligibility criteria for the review from the 3 sources accessed.
Source No. papers identified No. papers included
Index papers - 23
PubMed 1691 20
SCI 1084 35
Total number of papersa - 48
a13 papers were included through SCI a n d PubMed searches; 17 pape rs were included t hrough both the index review and SCI searches.

H. G. Stampfer et al. / Open Journal of Psychiatry 2 (2012) 284-291 286
Table 2. Definition of depression and covariates included in studies.
Number of studies reporting: % (n) References
At least one significant associationa 65% (31) [14,15,18,19,21-47]
Depression defined by:
DSM/ICD criteria 17% (8) [19,21,23,32,3 7-39,42]
Single question self-report 6% (3) [17,18,46]
Symptom scale 77% (37) [14-16,20,22,24-31,33-36,40,41,43-45,47-61]
Controlled for CHD/CVD at baselineb 81% (39) [14-17,20-27,29-37,39-43,45-49,52,53,55-59,61]
Covariates measuredc:
Anxiety (symptom/personality scale) 12% (6) [15,16,30,49,52,56]
Other psychiatric comorbidity 2% (1) [39]
Other psychological constructs 19% (9) [15-17,27,30,48,49,52,56]
Lipids/Cholesterol 58% (28) [15,16,19,20,22-24,26,30,32-35,38,40,41,43,46-53,56,57,61]
Blood pressure 81% (39) [15-17,19,20, 22-26,30,32-43,45-58,60,61]
Diabetes/BGL 60% (29) [15,17-20,22-26,32-40,42,45,46,49,50,54,55,57,59,61]
Other medical comorbidity 40% (19) [17,18,22-26,29,34,39,40,42,46,51,54,55,57,59, 6 0 ]
BMI 65% (31) [17-20,22,23,25,30,32-38,41-43,45-47,49,50,52-54,56-58,60,61]
Waist-hip or waist circumference 10% (5) [23,24,26,37,58]
Physical activity 37% (18) [17,20,22-2 4,26,32,33,35 ,40,41,45,47 ,50,53,56,57,60]
Smoking 83% (40) [15,17-20,22-26,30,32-43,45-61]
Alcohol and/or substance u s e 52% (25) [17,22,25,30,32-35,37-40,42,43,45-47,51,53,54,56-58,60,61]
Antidepressant use at baseline 10% (5) [32,37- 3 9,45]
Family Hx CHD 12% (6) [22,30,35,38,43,57]
Age 83% (40) [14-20,22,24-26,29-37,39-44,46-49,51,52,54-61]
Sexd 96% (46) [14-43,45-49,51-61]
Ethnicity 21% (10) [14,20,33,40,45-47,51,55,59]
Marital status 31% (15) [16,18,23,31,33,34,36,37, 39 ,40,45-47,55,60]
Education 40% (19) [16,20,30,34-37,39,40,42,46,47,51,53,55,57-60]
SES 17% (8) [20,23,32,36,45,52,55,56]
Change in depression across follow-u p period 6% (3) [38,40,59]
Change in other risk factors across follow-up period 2% (1) [38]
Treatment for depression during follow-up period 0% (0) N/A
aStudies often report separate analyses for different groups or have multiple relevant endpoints. Only one association (based on the multivariate adjusted asso-
ciation if reported) needed to be statistically significant (p < 0.05) in order to be considered a positive study; bSome attempt was made in at least one analysis to
exclude p articipants with evidence of C HD at baseline; cAll covariates measu red are reported in the table, i rrespective of whet her it was in cluded in the fi nal
model reported; dSex w as cons id ered a co var iat e ( n = 2 3) OR on ly on e s ex was included in the study (n = 18) OR men and women were analysed separately
(n = 6).
CHD as a covariate. The definition of “evidence of CHD/
CVD at baseline” was highly variable across studies as
were criteria for exclusion. For example, in some stud-
ies participants were excluded if there was a history or
evidence of angina, previous MI, ischemia on ECG,
coronary artery bypass graft or percutaneous translu-
minal coronary angioplasty [36]. In other studies, indi-
viduals with self-report of previously diagnosed heart
disease were included [47]. The criteria used to deter-
mine whether CHD was present at baseline were not
always stated.
3.3. Control for Recognized Risk Factors
Figure 1 shows the percentage of studies that controlled
for indicated risk factors. It can be seen that hypertension,
smoking and family history of CHD were controlled for
in around 80% of studies but that significantly less con-
sideration was given to other recognized risk factors and
potentially relevant variables. Some studies measured a
covariate but did not take it into consideration in the re-
ported model or in any analysis relevant here. Hence
Figure 1 probably overestimates the degree of control
for possible confounding factors. In addition, interactions

H. G. Stampfer et al. / Open Journal of Psychiatry 2 (2012) 284-291 287
%
Figure 1. Percentage of studies that controlled for indicated
risk factors for CHD.
between covariates were rarely considered [56]. This is
probably due to insufficient sample size for assessing
potential interactions but the resulting lack of informa-
tion regarding the relationship between confounding
variables limits understanding of the primary association
of interest.
3.4. Control for Psychosocial Variables Apart
from Depression
Figure 2 shows the percentage of studies that controlled
for the broadly termed “psychosocial” variables indicated.
Psychological variables including anger, hostility, g eneral
distress, vital exhaustion, social support and several
measures of anxiety were considered as potential covari-
ates in only 21% of studies. The failure to control for
anxiety in 85% studies is surprising considering the fre-
quent co-morbidity of anxiety and depression [62]. Pratt
[39] found that the addition of panic disorder, phobia and
alcohol and drug dependence did not significantly affect
the depression/CHD association. Davidson [15] found
depressive symptoms (CES-D) to significantly predict
CHD events when anxiety (among other covariates) was
included in the model. On the other hand Shen et al. [16]
reported that the significant association between anxiety
(MMPI scale) and CHD remained when depression and
other personality/emotional variables were included as a
covariate in the analyses and that depression was not sig-
nificant in the model. Kubzansky [30] report ed de press ion
(MMPI-derived scale) did not predict CHD when entered
into the model alone, or in the prese nce of anxiet y, ang er
or general distress measures (also MMPI-derived).
Boyle et al. [49] found that in men CHD was signifi-
cantly associated with depression, anxiety, anger and
hostility in individual models. However a single model
including these four potential predictors did not find any
of them significant. A composite score accounting for
66% of the shared variance between the four variables
did significantly predict CHD and was a better predictor
than depression. Two studies [52,56] did not include
anxiety as a covariate because the association between
%
Figure 2. Percentage of studies that controlled for indicated
psychosocial variables.
depression and CHD was not significant in initial analy-
ses.
3.5. Variations in Depression Prior to and during
Follow-Up
Only 8% of studies measured changes in depression
across the follow up period, only 4% gave consideration
to depression prior to baseline and no studies gave con-
sideration to the treatment of depression during follow-
up. The poverty of information about depression apart
from a baseline rating with considerable variation in rat-
ing methods precludes any firm conclusion about a dose-
effect relationship that would support a causal role of
depression in CHD.
4. DISCUSSION
A critical examination of the inconsistencies and meth-
odological shortcomings in primary studies along with
the contradictory findings reported leaves serious doubt
about the extent to which depression can be regarded as
an independent risk factor for CHD. As noted by other
authors [5,6] and recognized in this review, inadequate
control for conventional risk factors fails to rule out a
mediating factor or factors for the suggested relationship
and inadequate removal of CHD cases at baseline fails to
rule out reverse causality, two pre-requisites for reaching
any firm conclusion about a causal role for depression.
Furthermore no systematic attention has been given to
co-morbid psychological variables or psychiatric disor-
ders that may have contributed to, or better accounted for,
the association between depression and CHD. Reported
findings are contradictory and difficult to integrate given
the variation in statistical approaches and exposure defi-
nition, which is a likely consequence of most studies not
being designed specifically to question the role of de-
pression in CHD. This review gave emphasis to anxiety,
as it is highly comorbid with depression, but other psy-
chological and psychiatric variables might also have con-
tributed a confounding effect.
Inconsistencies are evident in the definition and mea-

H. G. Stampfer et al. / Open Journal of Psychiatry 2 (2012) 284-291 288
sure of exposure and endpoints. In particular, there is he-
terogeneity in exposure measures (different scales, cli-
nically or symptom defined, differing cut-offs, dichoto-
mous v continuous), endpoint definitions (e.g. fatal CHD,
angina, non-fatal MI, or combination outcomes) and in
subgroup analyses (usually based on gender). This situ-
ation is further complicated by the fact that these be-
tween study differences are sometimes observed within
studies, where separate analyses for different outcomes,
different exposure categorizations, or different subgroups
are reported and on occasion yield conflicting results
[43,45]. It is also worth noting that there is substantial
variability between studies in how covariates are mea-
sured (e.g. blood pressure: clinical cut-offs, categorical
or continuous measure and SES: Income or composite
poverty index) and the impact of this on any observed
relationship is unknown. Meta-analyses [4,5] have re-
ported that depression satisfying DSM- or ICD-diagnos-
tic criteria has a stronger association with CHD than
symptom based measures. We also found evidence of
such a stronger association but suggest that this does not
automatically imply a causal relationship. Given reports
that a shared variance between negative emotions shows
a stronger association with CHD than depression alone
[49] there is reason to doubt the causal role attributed
solely to depression since most studies have failed to
control for possible confounding psychological and psy-
chiatric variables.
Only 6% of studies gave consideration to changes in
depression during follow up (variation in severity and
duration) and only 2% gave consideration to changes in
other risk factors. Apart from the mention of antidepres-
sant use at baseline in 10% of studies, there is no men-
tion of treatment at baseline or during follow up in 93%
of the studies. Seemingly there was insufficient concern
about the severity of baseline depression in these studies
to refer anyone for treatment—if there was, one would
expect mention of it. This wou ld suggest relativ ely min o r
depression in by far the majority of subjects and without
further information of worsening depression during fol-
low-up it might be difficult to explain a causal relation-
ship between “depression not requiring treatment” and
CHD on physiological grounds. The lack of information
about changes in depression during follow up would also
question the validity of any conclusions about “dose-
effect” in the suggested relationship.
This review cannot exclude th e possibility that depres-
sion does play a causal role in the development of CHD.
It does, however, highlight the fact that there are good
reasons for questioning the validity of the supporting evi-
dence. Many of these reasons (inadequate covariate con-
trol, reverse causality) may not be adequately addressed
with prospective cohort designs because the studies re-
quired (very large sample sizes, very long duration of
follow-up, intense contact during follow up, extensive
baseline testing etc.) may seem daunting. However, the
question is important and deserves more systematic in-
vestigation. More aggressive treatment of depression/
depressive symptoms may be warranted if a causal role is
established. The conclusion in this review of the evi-
dence is that it remains to be shown that depression is a
causal risk factor for CHD.
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