Depression and Cardiovascular Disease: The Need for Improved ...

Editörden / Editorial
Depression and Cardiovascular Disease: The Need for
Improved Case Definition
Jorge Perez-Parada BSc, MD, MSc, FRCPC
ÖZET:
Depresyon ve kardiyovasküler hastalık: Gelişmiş
olgu tanımına duyulan ihtiyaç
Depresyon ve kardiyovasküler hastalık tüm dünyada yetiyitimine
en çok yol açan nedenlerden ikisidir. Depresyon
koroner arter hastalığına yol açan bağımsız bir faktördür ve
akut koroner sendrom sonrasında varlığında olumsuz prognostik
bir göstergedir. Bu şekilde açık ilişkilerine rağmen
bu iki hastalığı bir birine bağlayan altta yatan mekanizmalar
halen bilinmemektedir. Patofizyolojik mekanizmaların
açığa çıkarılması ile ilgili güçlük depresyon kriterlerini
karşılayan hastaların heterojen olmasında yatıyor olabilir.
Depresif semptomların daha iyi ayrıştırılması ve ölçülmesi
gelecekteki araştırmalarda daha rafine olgu tanımlarına
öncülük edebilir.
Anahtar sözcükler: Depresyon, kardiyovasküler hastalık,
eştanı
Kli nik Psi ko far ma ko lo ji Bül te ni 2011;21:7-10
Individuals with psychiatric disorders are well known
to have an increased risk of morbidity and mortality as
compared with the general population. Numerous factors
likely contribute to this increased mortality, including
suicide, sedentary lifestyle, poor diet, substance abuse, and
poor access to adequate preventative health care (1).
Epidemiological studies, however, point to a higher
association between psychiatric disorders and
cardiovascular disease than in the general population. This
association remains poorly understood, and the strength of
the association varies depending on which psychiatric
population is being studied.
Depression and cardiovascular disease are two of the
leading causes of isability worldwide according to the
World Health Organization. In middle- to high-income
countries, unipolar depression and cardiovascular disease
represent the number one and number two causes,
respectively, of disability-adjusted years lost (DALYs).
ABS TRACT:
Depression and cardiovascular disease: the need
for improved case definition
Depression and cardiovascular disease are two of the
leading causes of disability worldwide. Depression is an
independent risk factor for the development of coronary
heart disease and has been shown to be a negative
prognostic indicator when it is present following-acute
coronary syndrome. Despite these clear associations the
underlying mechanism(s) linking these disorders remains
unknown. The challenge in elucidating pathophysiologic
mechanisms may lie in the heterogeneity of patients
that meet the criteria for depression. Improved and
measurement of depressive symptoms may lead to refined
case definition in future research.
Key words: Depression, cardiovascular disease,
comorbidity
Bulletin of Clinical Psychopharmacology 2011;21:7-10
Klinik Psikofarmakoloji Bülteni, Cilt: 21, Sayı: 1, 2011 / Bulletin of Clinical Psychopharmacology, Vol: 21, N.: 1, 2011 - www.psikofarmakoloji.org
DOI: 10.5350/KPB-BCP201121102
1Assistant Professor, Department of Psychiatry
University of Alberta, Edmonton, Alberta
Canada T6G 2B7
Ya zış ma Ad re si / Add ress rep rint re qu ests to:
Jorge Perez-Parada BSc, MD, MSc, FRCPC,
Department of Psychiatry University of
Alberta, Edmonton, Alberta, Canada T6G 2B7
Elekt ro nik pos ta ad re si / E-ma il add ress:
jperez@ualberta.ca
Bağıntı beyanı:
J.P.P.: Yazar bu makale ile ilgili olarak
herhangi bir çıkar çatışması bildirmemiştir.
Declaration of interest:
J.P.P.: The author reported no conflict of
interest related to this article.
Together they represent over 10% of the total burden of
DALYs, and their impact on healthcare systems and
society is significant. Understanding the interaction of
these two disorders, therefore, remains an important area
of research.
Depression has been identified both as an independent
risk factor for the development of cardiovascular disease,
and as a negative prognostic indicator in individuals with
known cardiovascular disease (2). Many studies cite a
two- to three-fold increase in risk for negative outcomes in
patients with acute coronary syndromes and depressive
symptoms (3). In 2008, the American Heart Association
issued a scientific advisory (4) outlining recommendations
for the screening, referral, and treatment of depression in
patients with cardiovascular disease. This advisory further
emphasized the clinical light the impact that comorbid
depressive symptoms can have on cardiovascular
outcomes. Despite the recognition of the role of depressive
7

Depression and cardiovascular diseases: the need for improved case definition
symptoms in poorer cardiovascular outcomes, there is
insufficient evidence in the literature that treatment of
depressive symptoms alters cardiovascular outcomes.
In the SADHART study, Glassman et al. (5) evaluated
the safety and efficacy of the use of sertraline on patients
admitted to hospital for recent myocardial infarction or
unstable angina with major depression. Although they
were able to demonstrate that the use of sertraline was safe
in this population, there were not statistically significant
decreases in Hamilton Depression (HAM-D) scores in
sertraline-treated patients as compared to placebo. Subgroup
analysis did demonstrate that patients with a
previous history of depression showed a statistically
significant response to sertraline. When they compared the
incidence of severe cardiovascular events in the sertralinetreated
group (14.5%) versus the placebo group (22.4%)
they were unable to find statistical significance. So
although sertraline was effective in treating depressive
symptoms in a recurrent depression sub-group post
myocardial infarct, they were unable to show an impact
between groups in cardiovascular outcomes.
The ENRICHD study (6) compared a cognitive
behavioural therapy (CBT) intervention in patients
admitted with acute myocardial infarction who fulfilled
criteria for major or minor depression or low perceived
social support as compared to a usual care group. A total
of 2,481 subjects were randomized to either the CBT
intervention or usual care group. Within the intervention
group, if patients had scores on the Hamilton Rating Scale
for Depression (HAM-D) greater than 24 or failed to have
a 50% reduction in Beck Depression Inventory (BDI)
scores after five weeks of intervention, they were referred
for consideration of antidepressant add-on treatment
(sertraline>other SSRIs>nortriptyline). Antidepressant
use reached 20.6% and 28% in the usual care and
intervention groups respectively. Although the intervention
in this study decreased depressive symptoms and improved
social support as compared to the usual care group, it did
not affect the primary end points of death and non-fatal
myocardial infarction. The trend was again to see a
reduction in reinfarction and mortality in patients on
antidepressant therapy. The authors, however, concluded
that given their design study this finding may have been
related to a pharmacodynamic effect of SSRIs, such as
platelet inhibition, rather than to an improvement in
depressive symptoms.
Honig et al. (7) opted to study the effects of a dual
acting antidepressant, mirtazapine, to evaluate its safety
and efficacy in depressed patients post-myocardial
infarction. Ninety-one patients who met criteria for major
or minor depressive disorder were randomized to either
placebo or mirtazapine treatment and were followed for 24
weeks. Using a last observation carried forward model, the
authors did not find a statistically significant difference in
mirtazapine versus placebo in either the acute phase (8
weeks) or the entire treatment phase (24 weeks) using the
primary measure of reduction in HAM-D score. Statistical
significance was, however, found when the authors
compared the efficacy of mirtazepine on the secondary
outcome measures of scores on the BDI, the depression
subscale of the Symptom Checklist 90(dSCL-90) and the
Clinical Global Impression (CGI). Mirtazapine was also
shown to be safe in this post-myocardial infarction
population, although, as in the SADHART study,
medications were not prescribed until 3 months after the
incident event. The authors speculate that including major
and minor depression may have influenced the statistical
significance of their findings on their primary outcome
measure. This reflects one of the major limitations in most
of the depression and cardiovascular literature, which is
that the operational and inclusion criteria for defining and
measuring depression and depressive symptoms are
inconsistent. It is plausible that the rating scales used as
outcome measures are distinct in how they identify and
track depressive symptoms post acute coronary syndrome.
There is some debate as to why depressive symptoms
post-myocardial infarction do not respond to antidepressant
therapy or psychological intervention as expected when
compared to a “healthy” depression population. There
seems to be some distinction in response between patients
with a previous history of major depressive disorder and
patients who develop incident depressive symptoms post
myocardial infarction (8). Similarly, the failure to show,
that treating depressive symptoms improves cardiovascular
outcomes promotes reflection on the etiology and biologic
underpinnings of these depressive symptoms. One of the
challenges in studying underlying pathophysiologic
mechanisms lies in the inherent heterogeneity of subjects
who meet the DSM-IV criteria for major depressive
disorder. Patients meeting the criteria for depression often
have a wide variance in symptom severity and symptom
expression that likely represents important sub-types.
8 Klinik Psikofarmakoloji Bülteni, Cilt: 21, Sayı: 1, 2011 / Bulletin of Clinical Psychopharmacology, Vol: 21, N.: 1, 2011 - www.psikofarmakoloji.org

Furthermore, the presence of co-morbid syndromes such
as anxiety may play a significant role. The literature
linking anxiety spectrum disorders and phobic anxiety to
adverse cardiovascular outcomes is almost as extensive as
that of depression (9). Does this mean that each separate
psychiatric diagnosis that has been linked to the
development or progression of cardiovascular disease is
operating via a mutually exclusive mechanism?
More recent studies have begun to try to identify the
key component(s) of depressive symptoms that confre(s)
the cardiotoxic effect(s) (10). The worldwide genome
project has lead to much excitement in trying to identify
candidate genes for a number of psychiatric disorders. In a
review article, Hasler et al. (11) describe a number of
potential phenotypes of depression and potential
biomarkers that may lead to the discovery of
endophenotypes that may aid researchers in refining
criteria for the complex syndrome that is presently termed
depression.
In this vein, two recent studies have begun to identify
important elements or symptoms of depression that are
more clearly identified with negative cardiovascular
outcomes. Hoen et al. (12) looked at the relationship
between cognitive and somatic depressive symptoms and
cardiovascular outcomes in outpatients with stable
coronary heart disease. The 9-item Patient Health
Questionnaire was administered to 1,019 patients with
stable heart disease to determine the presence and severity
of depressive symptoms as outlined in the DSM-IV.
Depressive symptoms categorized as primarily cognitive
were depressed mood, lack of interest, worthlessness,
concentration difficulties and suicidal ideation. Depressive
symptoms categorized as somatic were challenges with
appetite, sleeping difficulties, psychomotor changes and
fatigue. Patients were followed with annual phone calls to
determine if there were any deaths or hospitalizations for
“heart trouble”. Chart reviews were conducted for any
patient with an adverse cardiovascular event. The outcome
measures were cardiovascular events including heart
failure, myocardial infarction, stroke, transient ischemic
attack or death. In age-adjusted analyses both somatic and
cognitive symptoms were associated with an increased
risk for cardiovascular events (21% and 12% respectively).
Once this data was adjusted for confounding variables the
cognitive sum score did not significantly predict
cardiovascular events. The somatic symptoms of sleeping
Klinik Psikofarmakoloji Bülteni, Cilt: 21, Sayı: 1, 2011 / Bulletin of Clinical Psychopharmacology, Vol: 21, N.: 1, 2011 - www.psikofarmakoloji.org
J. Perez-Parada
difficulties, fatigue and appetite problems were, however,
independently predictive of cardiovascular events after
adjustment for age, sex, diabetes, history of myocardial
infarction, history of heart failure, left ventricular ejection
fraction, body mass index, smoking and use of
cardioprotective agents. It may be argued that in patients
with coronary heart disease somatic symptoms such as
fatigue, sleeping difficulties and psychomotor slowing
merely reflect an increased severity of heart disease at
baseline. The authors attempted to correct for this by using
a stable outpatient population and correcting for
confounding factors. They argue that a focus on treatment
of the somatic symptoms identified may lead to improved
cardiovascular outcomes. The authors, however,
acknowledge that a further understanding of how the
mechanisms of sleep disturbance, changes in appetite and
psychomotor abnormalities lead to worsening
cardiovascular prognosis is crucial for the design of future
trials.
Davidson et al. (10) used an observational cohort study
design to determine if one of two core diagnostic criteria
of depression, i.e. depressed mood or anhedonia, predicts
one-year medical outcomes for patients with acute
coronary syndromes. They looked at 453 consecutive
patients with an acute coronary syndrome admitted to one
of three hospitals. Patients underwent a semi-structured
interview to determine criteria for a major depressive
episode, and the BDI was used to assess depressed mood
and anhedonia. Using these measures, 48 patients met the
criteria for major depressive disorder, 108 were rated as
having depressed mood and 77 were rated as having
anhedonia. The primary end point of the study was either
the first occurrence of a major adverse cardiac event or allcause
mortality at twelve months. Both depressed mood
and anhedonia predicted major adverse cardiac events and
all-cause mortality in an age-adjusted model, however,
only anhedonia remained as a significant predictor for
adverse cardiovascular outcome after adjusting for age,
sex and medical covariates. Anhedonia remained a
significant predictor after adjusting for major depressive
disorder and severity of depressive symptoms.
It is postulated that depressed mood and anhedonia (13)
may represent distinct biologic pathophysiologies, and
therefore may help distinguish whether one entity is more
predictive in cardiovascular disease. Anhedonia in
particular has some overlap with somatic symptoms
9

Depression and cardiovascular diseases: the need for improved case definition
including sleep, appetite, weight gain, satisfaction and
libido. Hasler et al. (11) describe anhedonia as more closely
associated with catecholaminergic dysfunction as opposed
to serotonergic dysfunction, which is linked more closely
to depressed mood. The identification of correlations
between anhedonia and the somatic symptoms of depression
may also allow for further study into their mechanisms.
Linking the identification of sub-types of depression with
potential biological markers such as platelet reactivity
(14,15), heart rate variability (16), REM sleep patterns (11)
and endothelial function (17) may lead to a further
understanding of the complex relationship between
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10 Klinik Psikofarmakoloji Bülteni, Cilt: 21, Sayı: 1, 2011 / Bulletin of Clinical Psychopharmacology, Vol: 21, N.: 1, 2011 - www.psikofarmakoloji.org