DEPRESSION AND ANXIETY 30:328–341 (2013)

Special Article
TREATMENT OF DEPRESSION IN CARDIOVASCULAR
DISEASE
Nicole Mavrides, M.D. and Charles Nemeroff, M.D, Ph.D∗

Background and Objectives: Depression in patients with Cardiovascular Dis-

ease (CVD) is extremely common, with a prevalence of 17–47%, and is associated
with increased risk of morbidity and mortality. Treatment of depression has been
hypothesized to reduce cardiac mortality. Pharmacologic and psychotherapeutic
interventions have been studied and appear to be safe and in some studies effective
in reducing depressive symptoms in patients with cardiac disease. The impact on
cardiac outcomes remains unclear. This review briefly focuses on the prevalence
of depression in patients with CVD, the physiological links between depression
and CVD, and largely is concerned with the clinical trials that seek to demon-
strate efficacy and safety of antidepressant medications and psychotherapy in this
patient population. Methods: PubMed and PsycINFO databases were searched
through July 2012. Publications were included if they were in English, a review
article, or a clinical trial in the CVD population with comorbid depression. The
search was completed with key words of antidepressants, CVD, coronary artery
syndrome, SSRIs, depression, treatment of depression, post-MI (where MI is my-
ocardial infarction), major depression, and cardiac disease. Trials were included
if the patients were above the age of 18, both male and female genders, and
had cardiac comorbidity. No trials were excluded. Results: A total of 61 articles
and/or book chapters were included. The majority were from North America and
Europe. There were 7 clinical trials of tricyclic antidepressants (TCAs), one of
TCAs and bupropion, and 10 trials of selective serotonin reuptake inhibitors (SS-
RIs). We also evaluated five trials involving psychotherapeutic techniques and/or
collaborative care. Conclusions: There is considerable evidence from random-
ized controlled clinical trials that antidepressants, especially SSRIs, are safe in
the treatment of major depression in patients with CVD. Although efficacy has
been demonstrated in some, but not all, trials for both antidepressants and cer-
tain psychotherapies, large, well-powered trials are urgently needed. There are
virtually no data available on predictors of antidepressant response in depressed
patients with CVD. Whether successful treatment of depression is associated with
a reduction in cardiac morbidity and mortality remains unknown. Depression
and Anxiety 30:328–341, 2013. C 2013 Wiley Periodicals, Inc.

Key words: antidepressants; cardiovascular disease; depression; treatment; clin-

ical trials

Department of Psychiatry and Behavioral Sciences, Center on

Aging, Miller School of Medicine, University of Miami, Miami,
Florida
Contract grant sponsor: National Institutes of Health (NIH); Con-
tract grant sponsor: Agency for Healthcare Research and Quality
(AHRQ).
∗ Correspondence to: Charles B. Nemeroff, Department of Psychi-
atry and Behavioral Sciences, Center on Aging, Miller School of
Medicine, University of Miami, 1120 NW 14 ST #1455, Miami, FL
33136. E-mail: cnemeroff@med.miami.edu
Received for publication 18 September 2012; Revised 6 December
2012; Accepted 8 December 2012
DOI 10.1002/da.22051
Published online 4 January 2013 in Wiley Online Library (wileyon-
linelibrary.com).


C 2013 Wiley Periodicals, Inc.
 Special Article: Treatment of depression in cardiovascular disease
INTRODUCTION
C ardiovascular disease (CVD) and depression are two
of the leading health problems in developed and de-
veloping countries.[1] Coronary artery disease (CAD) is
usually defined as ischemic symptoms associated with
coronary angiographic evidence of 50% or more block-
age in at least one major coronary artery, previous hospi-
talization for a myocardial infarction (MI), or angina.[2]
Depression is common in patients with CVD/CAD
and contributes to poor functional and cardiovascu-
lar outcomes.[3] Maltzberg’s seminal study published in
1937 revealed that patients with severe depression had
a higher mortality rate when compared to the general
population and that the excess deaths were attributable
to CVD.[4, 5]
Over the past two decades, many studies have scru-
tinized the relationship between depression and CVD.
Depression has been found to be associated with an in-
creased risk of developing CAD as well as a predictor
of poor outcome (increased morbidity and mortality) in
patients with CVD.[6, 7] Depression has been identified
as an independent risk factor for coronary heart disease,
angina, heart failure, MI, and cardiac mortality.[8, 9] It has
also been linked with poorer quality of life in both short-
and long-term follow-up studies, and being three times
less likely to adhere to medical treatment than those pa-
tients who are not depressed.[8–10]
The prevalence of major depression has been re-
ported to be 17–27% in hospitalized patients with CAD,
and most studies have also demonstrated a negative
cardiac prognostic impact in patients with comorbid
depression.[11] Due to the high prevalence of depression
among patients with CAD/CVD, as well as the associ-
ated increase in both psychiatric and medical morbidity
and mortality, treatment of depression is imperative. Al-
though many antidepressant agents have been studied
in clinical trials demonstrating their safety and efficacy
in healthy populations and even in certain medically ill
populations, only a small number of trials have evalu-
ated the use of antidepressants in patients with cardiac
disease.[7, 12, 13] In this review we will largely describe the
prevalence of depression in patients with CVD, the pos-
itive pathophysiological substrates for the link between
depression and CVD, and focus on the treatment options
based on the relevant clinical studies.
EPIDEMIOLOGY
CVD and depression are both common disorders. The
National Comorbidity Study reported a lifetime preva-
lence of MDD of 16.6%, higher in woman than men.
Minor depression is also common in community and
primary care clinics.[14] In the United States, the life-
time risk of cardiovascular death by age 80 years is 4.7–
6.4% among people without cardiovascular risk factors
and 20.5–29.6% among those with two or more risk fac-
tors. Those risk factors include diabetes mellitus, smok-
ing, total cholesterol level ≥180 mg/dl, and untreated
hypertension.[5] Many depressed patients exhibit cogni-
329
tive dysfunction involving difficulties in problem solving
and coping with challenges, resulting in poor adherence
to medical therapy and exercise regimens.
The prevalence of syndromal major depressive dis-
order (MDD) in patients with CAD, including stable
and unstable angina or MI, is estimated to be between
15 and 20%, with another estimated 30–45% having
clinically significant depressive symptoms without meet-
ing DSM-IV TR (Diagnostic and Statistical Manual of
Mental Disorders fourth edition) criteria for MDD.[3, 9]
Depressive symptoms are particularly prevalent in pa-
tients recently hospitalized for acute cardiac events. A
recent meta-analysis of hospitalized patients with con-
gestive heart failure (CHF) found a prevalence rate of
20–36%.[15] In addition, depressive symptoms often per-
sist in patients with CVD, partly due to under diagnosis
and partly due to lack of treatment or inadequate treat-
ment. In the course of a post-MI depression, symptoms
generally remain fairly stable in terms of severity for up
to 12 months.[3, 16]
In the National Health Examination Follow-up Study,
2,832 adults aged 45–77 with no history of CAD/CVD
who demonstrated depressed mood and hopelessness at
baseline exhibited an increased risk of both fatal ischemic
heart disease (relative risk [RR] 1.5, 95% CI 1.0–2.3)
and nonfatal ischemic heart disease (RR 1.5, 95% CI
1.11–4.06), even after controlling for demographics and
other risk factors.[5] A meta-analysis by Wulsin and Sin-
gal revealed that even after controlling for traditional
risk factors of CAD (e.g., physical inactivity, tobacco
use, hypertension), the presence of depressive symptoms
is a significant independent risk for the onset of CAD
(RR 1.64, 95% CI 1.41–1.90). Many studies have also
demonstrated that the RRs for heart disease is increased
as severity of depression increases.[14, 17]
The negative impact of depression in patients with
CVD was clearly demonstrated in the seminal studies
by Frasure-Smith and colleagues in the early 1990s at
the Montreal Heart Institute. They discovered that fol-
lowing an MI, patients with MDD had a three- to four-
fold increased mortality rate within the 6–18 months
post-MI period, with the vast majority of the increased
mortality occurring in the first 6 months after the in-
dex MI. The findings were independent of left ventricu-
lar ejection fraction and previous MI.[14, 18] More recent
studies have demonstrated that depression is associated
with a 2- to 2.5-fold increased risk of poor cardiovas-
cular outcome and mortality among patients hospital-
ized post-MI. In many, but not all, studies these effects
persist even after correction for traditional cardiac risk
factors.[3, 5, 14]
Taken together, the data strongly support the hypoth-
esis that depression is an independent risk factor in the
development and progression of CVD. The American
Heart Association recently issued recommendations for
screening, referral, and treatment of depression in pa-
tients with CVD, indicating their view that early recog-
nition and treatment of depression in patients with CVD
is crucial.[14, 17]
Depression and Anxiety
330 Mavrides and Nemeroff
LIFESTYLE FACTORS
In the 1980s, the “type A” personality (ambitious, ag-
gressive, hostile, competitive, chronic sense of urgency)
was linked to the heart disease. Later studies differed in
their findings as to whether the entire constellations of
symptoms of “type A” personality are a collective risk
factor for heart disease, but hostility remains a validated
risk factor. “Type D” personality is another psychosocial
risk factor in which patients experience negative emo-
tions paired with social inhibition and this may be a
more important personality risk factor of cardiac dis-
ease. The INTERHEART study is a case-control study
of attributable risk for MI in 52 countries. Stress, low
generalized locus of control, and depression accounted
for 32.5% of the attributable risk for an MI, which is only
slightly less than that of lifetime smoking, but greater
than hypertension and obesity.[5, 14, 19]
PATHOPHYSIOLOGY
Several mechanisms, behavioral and physiologic, have
been implicated in the connection between depression
and cardiac disease and these are reviewed in detail
elsewhere.[15]
ALTERATIONS IN PLATELET ACTIVITY
Platelets are responsible for thrombus formation, the
ultimate cause of MI. Platelets may also be involved in
recruiting inflammatory cells that can contribute to the
development of atherosclerosis.[5] It was first suggested
that enhanced platelet responses to physiological stress
can trigger adverse coronary artery ischemic events.[14]
Depressed patients exhibit exaggerated platelet reac-
tivity as assessed by markers of platelet activation.
Plasma concentrations of platelet factor IV (PF4) and
β-thromboglobulin (βTG), markers of the intermedi-
ate steps in the platelet clotting cascade, are higher
in depressed patients with ischemic heart disease than
nondepressed patients with ischemic heart disease and
controls.[19] Activated platelets are extremely adhesive,
secondary to the expression of integrins and selectins,
and they provide a unique interface between the injured
arterial wall and circulating inflammatory cells.[3, 14]
In SADHART (Sertraline Antidepressant Heart Attack
Randomized Trial), depressed post-MI patients had sub-
stantial increases in platelet activity, which was reduced
by sertraline treatment.[19]
INFLAMMATION
Inflammatory cytokines are associated with
atherosclerosis formation, a major contributor to
the pathogenesis of CAD. C-reactive protein (CRP),
interleukin-6 (IL-6), and interleukin-1 (IL-1) have
been shown to be independent risk factors for CVD.[3]
Depressed patients have consistently been shown to
exhibit evidence of a sustained inflammatory state with
increased concentrations of CRP, IL-6, and tumor
necrosis factor alpha (TNFα).[5, 19] The Prospec-
Depression and Anxiety
tive Epidemiologic Study of Myocardial Infarction
(PRIME), a study of healthy middle-aged men from
France and Belfast, is of interest. They compared 335
future cases of CVD with 670 controls for 5 years and
found a statistically significant correlation between
depression severity and levels of IL-6 and CRP. Men
with depression also had a 50% increase in the odds
ratio of CVD.[5, 14] The Heart and Soul study suggested
that CVD patients had higher levels of inflammatory
markers as depression severity increased, but the asso-
ciation was mainly due to physical inactivity, smoking,
and obesity. These results indicate that the relationship
between depression and inflammation is complex and
requires further study.[5, 19, 20]
HEART RATE VARIABILITY
Both excessive stimulation of the sympathetic nervous
system and diminished vagal activation are associated
with higher rates of morbidity and possibly death.[19]
Heart rate variability (HRV) is a measure of the ability
of the heart to respond to physiological demands, and re-
flects a sympathetic vagal imbalance.[5, 19, 20] Decreased
HRV is associated with an increased risk of CVD, ven-
tricular arrhythmias, and sudden cardiac death. HRV is
also reduced in patients with depression.[5] Carney et al.
first showed that patients with depression had signif-
icantly reduced HRV than controls.[49] Additionally,
post-MI, depressed patients had a significantly more re-
duced HRV than nondepressed patients, suggesting that
decreased HRV may, in part, mediate the adverse effect
of depression on survival after an MI. The Heart and
Soul study found that somatic depressive symptoms in
CVD patients was associated with reduced HRV, but
Gehi et al. in the same study found no significant rela-
tionship between HRV and depression severity.[21]
HYPOTHALAMIC-PITUITARY-
ADRENOCORTICAL AND
SYMPATHOMEDULLARY HYPERACTIVITY
Many studies have documented evidence of
hypothalamic-pituitary-adrenocortical system hy-
peractivity in patients with major depressive disorder,
as evidence by the blunting of the ACTH response
to CRF, nonsuppression of cortisol secretion after
dexamethasone administration, and hypercortisolemia.
High cortisol levels can accelerate the development of
hypertension and atherosclerosis and lead to endothelial
vascular injury. Sympathoadrenal activation can also
lead to higher levels of catecholamines, predisposing to
vasoconstriction, rapid heart rate, and platelet activa-
tion. Conditions that cause sympathoadrenal activation
include coronary artery ischemia, heart failure, and
mental stress. Sudden emotional stress can cause tran-
sient left ventricular dysfunction, even in those without
coronary disease, an effect that potentially is mediated
by increased plasma catecholamine levels.[14, 19]
 Special Article: Treatment of depression in cardiovascular disease
OVERVIEW OF
ANTIDEPRESSANT THERAPY
Effective treatments for depression include pharmaco-
logical (antidepressant medications), nonpharmacologi-
cal somatic (ECT [electroconvulsive therapy], transcra-
nial magnetic stimulation, vagus nerve stimulation, deep
brain stimulation), and evidence-based psychotherapeu-
tic modalities (e.g., cognitive behavioral therapy [CBT],
interpersonal therapy [IPT], etc.). Selective serotonin
reuptake inhibitors (SSRIs) are currently considered the
first line of treatment of depression in patients with and
without cardiac disease. Current treatment guidelines
suggest 6–12 weeks of acute treatment followed by a
continuation phase of 3–9 months to maintain thera-
peutic benefit. For acute treatment of MDD, 60% of
patients respond to antidepressants (defined as a 50%
decline in depressive symptom severity) with up to a
40% relapse rate after 1 year.[22, 23] Remission rates are
considerably lower. The older tricyclic antidepressants
(TCAs) are less frequently used in general and espe-
cially in patients with CVD because of their many ad-
verse cardiac effects.[5] Antidepressants are believed to
act primarily by increasing the availability and/or signal
transduction of one or more monoamine neurotransmit-
ters, that is, norepinephrine, dopamine, and serotonin.
Certain antidepressants do exert cardiovascular side ef-
fects (orthostatic hypotension, hypertension, conduction
abnormalities).[23, 24]
Norepinephrine binds peripherally to α- and β-
adrenergic receptors, which can cause increases in blood
pressure, heart rate, enhanced contractility, and aug-
mentation of conduction velocity. In patients with CVD,
this could lead to ischemia, chest pain, hypertension,
and arrhythmias.[12] Dopamine is converted to nore-
pinephrine resulting in effects that are similar to those
of norepinephrine.[23]
Serotonin binds to multiple 5-HT receptors and each
has a specific response to activation, resulting in differ-
ent cardiovascular effects. Serotonin can also cause coro-
nary artery vasoconstriction in patients with atheroscle-
rotic coronary arteries, and an increase in platelet
aggregation.[12]
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
SSRIs inhibit the reuptake of serotonin at presynaptic
terminals, resulting in increased serotonergic availabil-
ity in the synaptic cleft. Some of the potential cardio-
vascular side effects of SSRIs are due to the fact that
some members of this class have drug–drug interactions
secondary to inhibition of certain of the isoenzymes of
the cytochrome p-450 enzyme system. Inhibition may
result in increased levels of certain antiarrhythmics, β-
blockers, antihistamines, and calcium channel blockers.
There are case reports documenting cardiovascular side
effects such as bradycardia, tachycardia, heart block, and
heart failure. However, overall, SSRIs have been shown
331
to be effective antidepressants and in healthy patients
they have minimal cardiovascular side effects.[12, 25] SS-
RIs appear to be safe in cardiac populations, but are asso-
ciated with an increased risk of gastrointestinal bleeding,
which may be an important issue in those cardiac patients
receiving anticoagulants or with a past history of bleed-
ing. For this reason, they should not be combined with
nonsteroidal anti-inflammatory agents. SSRIs have been
suggested to improve cardiovascular prognosis following
MI but this has not been reliably replicated.[9]
TRICYCLIC ANTIDEPRESSANTS
TCAs primarily act by blocking the reuptake of nore-
pinephrine or both norepinephrine and serotonin.[26]
The effects of TCAs on cardiac tissue are similar to class
I antiarrhythmic medications, such as quinidine, pro-
cainamide, flecanide, and disopyramide. They can pro-
long interventricular conduction secondary to sodium
channel blockade, which can be lethal when taken in
overdose.[27] Prolongation of conduction decreases the
frequency of premature ventricular contractions (PVCs),
an antiarrhythmic action. TCAs also inhibit the fast in-
activating rapid component of potassium channels in the
myocytes, which prolongs the QT interval. The QT in-
terval is a measure of the time between the start of the
Q wave and the end of the T wave in the heart’s electri-
cal cycle. The QTc is the corrected measure. Excessive
prolongation of QT can cause torsades de pointes, which
can occur when TCAs are used concurrently with other
agents that prolong the QT interval. In addition, TCAs
can cause first and second degree atrioventricular (AV)
block, asystole, and sudden cardiac death.[12, 26]
The most common cardiovascular side effect of TCAs
is tachycardia, secondary to blockade of norepinephrine
reuptake, which increases sympathetic nervous system
activity and anticholinergic effects that block parasym-
pathetic nervous system activity. Postural hypotension
occurs in up to 20% of patients due to the combined
pharmacologic effects of TCAs including α-adrenergic
receptor blockade in the CNS.[12]
OTHER ANTIDEPRESSANTS
The “other” category consists of selective sero-
tonin/norepinephrine reuptake inhibitors (SSNRIs)—
venlafaxine and duloxetine, as well as bupropion (whose
pharmacological mechanism of action remains obscure),
mirtazapine, trazodone, nefazodone, vilazodone, and
monoamine oxidase inhibitors (MAOIs). These have
been much less studied than both SSRIs and TCAs
in terms of their cardiovascular effects. Venlafaxine
has been frequently associated with dose dependent
increases in blood pressure and decreases in HRV.[5]
Mirtazapine has been noted to cause weight gain and
increased body fat mass, which is not associated with im-
proved cardiac outcomes. Duloxetine has not been stud-
ied in clinical trials of cardiac patients and to the best of
our knowledge; this is also true of the “other” antide-
pressants listed above. Bupropion may increase systolic
Depression and Anxiety
332 Mavrides and Nemeroff
blood pressure, which is common in many patients with
CVD, though it has been studied in small randomized
controlled trials in cardiac patients.[9, 28, 29]
PSYCHOTHERAPIES
The two major psychological therapies that have been
extensively studied in cardiac patients are CBT and IPT.
CBT focuses on altering cognitions and behavioral acti-
vation whereas, IPT is more focused on resolving inter-
personal issues related to one’s depression.[30] Both are
clearly effective treatments for depression and in cardiac
patients, exert no significant cardiovascular side effects.
Social support interventions as well as cardiac rehabili-
tation programs have also been studied and these have
no negative cardiovascular effects.[9, 12]
STUDIES OF ANTIDEPRESSANT
THERAPY
Despite the high prevalence rate of MDD and minor
depressive symptoms in cardiac patients and their poor
prognosis for survival and quality of life, relatively few re-
ceive treatment for their affective disorder. Commonly,
this is attributed to poor recognition of depression sec-
ondary to the overlap with sequelae of hospitalization
(fatigue, sleep disturbances, loss of appetite, preoccupa-
tion with death, feelings of guilt) or an atypical presen-
tation of depression. Moreover, physicians, particularly
nonpsychiatrists, may be reluctant to treat depression
because of concern about the safety of antidepressant
medications, including the potential for medication in-
teractions or unwanted cardiac adverse effects.[31]
TCAs
TCAs have been studied extensively in patients with
cardiac disease, but the studies were generally small and
comprised of a limited number of patients. As stated pre-
viously, TCAs are pharmacologically similar to class I an-
tiarrhythmics and as such, have the potential for many
cardiac adverse events. Raskind et al. studied 12 men
with ischemic heart disease, post-MI and CABG, who
met criteria for secondary major depression, defined as
depression that follows a major illness. The goals were to
evaluate changes in cardiac conduction, frequency of or-
thostatic hypotension, and the efficacy of the antidepres-
sant imipramine.[32] The starting dose was 50 mg/day
and the maximum dose was 175 mg/day, which was
maintained for 4 weeks. Depression scores were eval-
uated at baseline and weekly with the Hamilton Psy-
chiatric Rating Scale for Depression (HAM-D), the
Clinical Global Impression (CGI) Scale, and the Zung
Self-Rating Scale. Two (17%) of the 12 patients devel-
oped first-degree AV block. There were no significant
changes in ventricular depolarization, but the QTc in-
terval was significantly greater at day 21 than at baseline
(441 vs. 420 msec, P < 0.05). The postural systolic blood
pressure reduction was significantly different from base-
line when measured at week 4 (4.3 ± 8.5 mmHg vs. 12.6
Depression and Anxiety
± 10.7 mmHg, P < 0.05). One patient dropped out of
the study because of symptomatic orthostatic hypoten-
sion. There was no significant change in HAM-D scores
compared to baseline at the end of 4 weeks. The authors
concluded that imipramine was safe in a patient with sta-
ble ischemic heart disease and minimal conduction de-
fects; however, if a person had pretreatment orthostatic
hypotension, the frequency of orthostatic hypotension
with imipramine should be considered and prescribed
cautiously.[12, 32]
Imipramine and doxepin were evaluated by Veith et al.
in a randomized, double-blind, placebo-controlled trial
of 24 patients,[12, 27] of whom 23 had experienced an MI,
8 had coronary artery bypass graft (CABG) surgery, one
had a pacemaker, and one had a prosthetic heart valve.
The purpose of the study was to evaluate the effects of
imipramine and doxepin on cardiac conduction and de-
termine the antidepressant efficacy in depressed patients
with cardiac disease. Patients were randomized to re-
ceive imipramine (50 mg/day), doxepin (50 mg/day), or
placebo. Doses were increased weekly over the 4-week
period of the trial. The final daily doses were imipramine,
129 ± 57 mg and doxepin, 153 ± 72 mg. The number
of PVCs (preventricular contractions) was decreased in
the imipramine group at 4 weeks compared to baseline
(28 ± 44 vs. 8 ± 13, P < 0.05). There was no signifi-
cant change in PVCs in the doxepin or placebo group.
Both treatment groups displayed a significant increase
in heart rate from baseline at 4 weeks (imipramine 81 ±
8 beats/min vs. 85 ± 13 beats/min, P < 0.001; doxepin
77 ± 13 beats/min vs. 79 ± 11 beats/min, P < 0.005).
There were no significant changes in EKG (electrocar-
diogram) measures. Symptomatic orthostatic hypoten-
sion occurred in one (12.5%) of eight patients treated
with imipramine and three (33%) of nine patients treated
with doxepin. Both groups of patients in the active treat-
ment arms showed significant improvement in depres-
sion rating scores after 4 weeks of treatment. Veith et al.
concluded that post-MI patients could safely be treated
with either imipramine or doxepin, though if they are at
risk for developing orthostatic hypotension, they should
receive alternative treatments.[12, 31]
Glassman et al. evaluated the use of imipramine in
depressed patients with left ventricular impairment in a
prospective trial with 15 depressed patients undergoing
radionuclide angiography. Patients received imipramine
and the dose gradually increased to 3.5 mg/kg/day
over the course of 3 weeks; the radionuclide angiog-
raphy was then repeated. Only 11 of the 15 patients
completed the entire 3-week treatment period because
of adverse effects. Of those who completed the treat-
ment period, imipramine was reported to be effective
in treating the depressive symptoms, though no infor-
mation was provided regarding how this was assessed
and measured. No significant changes in left ventricu-
lar ejection fraction were found (38 ± 14% vs. 39 ±
15%). Seven (47%) of the 15 patients developed severe
enough orthostatic hypotension to warrant imipramine
discontinuation. Glassman et al. concluded that although
 Special Article: Treatment of depression in cardiovascular disease
imipramine does not affect ventricular function, ortho-
static hypotension was clinically significant and clearly
needs to be monitored.[33, 34]
In a similarly designed study, Roose et al. evaluated
the effects of nortriptyline in 21 depressed patients with
decreased left ventricular ejection fraction. The dose was
titrated over the course of a week to 1.4 mg/kg/day,
with an average daily dose of 76 ± 29 mg. Radionu-
clide angiography was repeated after the patients had
been treated with nortriptyline for 18–21 days. Left
ventricular function was not significantly different from
baseline. Only one (5%) of the 21 patients developed
intolerable orthostatic hypotension. The nortriptyline
was efficacious in treating the patient’s depressive symp-
toms over the 3-week treatment period. The authors
suggested that nortriptyline might be a safe medication
for the treatment of depression in patients with heart
failure.[12, 35]
Roose et al. conducted another trial comparing
imipramine (3.5 mg/kg/day) and nortriptyline (1.4
mg/kg/day) in 196 depressed patients with cardiac con-
duction disease. The patients were enrolled for over
10 years. During the first 5 years, plasma levels of the
TCAs were not routinely monitored. Of the 196 pa-
tients, 41 had abnormal EKGs at baseline. The primary
goal of the study was to compare the rates of cardiovascu-
lar complications and orthostatic hypotension between
imipramine and nortriptyline. The final daily doses of
the study drugs were imipramine 288 ± 109 mg and nor-
triptyline 89 ± 33 mg. Both medications were associated
with significant increases in serious conduction abnor-
malities, especially in patients with preexisting bundle
branch block. Three (12.5%) of 24 patients with bun-
dle branch block had serious conduction abnormalities.
In contrast, only 1 (0.7%) of 150 patients with nor-
mal EKGs developed similar abnormalities (P < 0.05).
Among patients with normal EKGs, 9 (7%) of 122 pa-
tients receiving imipramine developed significant ortho-
static hypotension; none of the nortriptyline-treated pa-
tients developed this side effect. Both nortriptyline and
imipramine were found to be effective antidepressants,
with nortriptyline causing less cardiac side effects. The
authors concluded that in patients with cardiac conduc-
tion deficits, with or without heart failure, nortriptyline
is preferable to imipramine.[35–37]
Dietch et al. studied 10 elderly, depressed pa-
tients with cardiac conduction disease treated with
nortriptyline[12, 38] with the primary goal to evaluate
EKG changes associated with the medication. Each pa-
tient had abnormal EKGs at baseline, with first-degree
AV block, hemiblocks, bundle branch blocks, and brady-
cardia. Each patient was initially treated with nortripty-
line, 10 mg/day, and slowly titrated to a target dose of
40 mg/day. The mean daily dose was 58 mg/day after
10 days of therapy. There were no significant changes in
the EKG, or in heart rate. Nortriptyline was effective in
treating depressive symptoms of elderly patients and was
associated with minimal risk in patients with conduction
disease.[12, 38]
333
Cohen et al. evaluated trimipramine in an open study
of 22 patients with mild heart disease and mild to moder-
ate depression in a 28-day trial.[39, 40] Depression severity
was assessed using the CGI Scale and Hamilton Depres-
sion Scale (HAM-D). The goal of the trial was to evaluate
the efficacy of trimipramine and monitor cardiac changes
and adverse effects. The initial dose was 50 mg/day
and the maximal dose was 200 mg/day. The mean fi-
nal daily dose was 92.7 mg/day. The HAM-D scores did
demonstrate significant improvement. On day 5 of treat-
ment, trimipramine produced significant prolongation
of the QRS duration compared to baseline (0.095 sec vs.
0.087 sec, P = 0.013). Remarkably, no patients experi-
enced orthostatic hypotension. Trimipramine seemed to
be safe and effective for depression in patients with mild
heart disease.[39, 40]
The major side effect of concern with TCAs, based on
these seven clinical trials reviewed here, is orthostatic hy-
potension. Although they do not appear to cause left ven-
tricular depression or severe conduction abnormalities
in the short term, long-term studies have not been com-
pleted. Few direct trials compared individual TCAs but
nortriptyline appears to have a more favorable side effect
profile than the others studied. In patients without left
ventricular dysfunction or significant CAD, imipramine
or doxepin can be used safely. In patients with signifi-
cant heart disease, neither imipramine nor nortriptyline
alters left ventricular function, but orthostatic hypoten-
sion occurs frequently with imipramine. If TCAs must
be utilized, nortriptyline would appear to be the pre-
ferred medication. The TCAs as a group are certainly
effective in the treatment of depression in the noncar-
diac population. Their efficacy in patients with cardiac
disease has not been established in well-powered stud-
ies. They are not the drugs of choice for depression in
patients with cardiac disease because of their overdose
death liability and the availability of newer medications
with fewer cardiac side effects.[12, 35, 36, 38, 40]
TCA/BUPROPION
Roose et al. compared the effects of imipramine
and bupropion in depressed patients with heart fail-
ure. This double-blind crossover study was comprised
of 10 patients.[29] All of the patients were randomized to
treatment with imipramine or bupropion and titrated to
maximum dosages of 3.5 mg/kg/day or 450 mg/day,
respectively, for 12 days. The washout period was 5
days between each agent. The average daily dose of
imipramine was 197 ± 78 mg and for bupropion was
445 ± 16 mg. Radionuclide angiography was completed
at baseline, 3 weeks after treatment with the first agent,
and 3 weeks after treatment with the second agent. No
significant changes were seen in ejection fraction with
either medication compared to baseline. Fifty percent of
the patients receiving imipramine (5/10) developed sig-
nificant orthostatic hypotension and stopped treatment.
Bupropion and imipramine were equally efficacious in
the treatment of depression. The authors concluded that
Depression and Anxiety
334 Mavrides and Nemeroff
bupropion was safer than imipramine for use in depres-
sion accompanied by heart failure secondary to the low
frequency of orthostatic hypotension and negligible ef-
fects on left ventricular function.[12, 29]
SSRIs
A small double-blind, randomized, controlled 6-week
trial comparing paroxetine to nortriptyline in 81 pa-
tients with both depression and ischemic heart disease
assessed the efficacy and cardiovascular safety of the two
medications.[37, 41] Forty-one patients received paroxe-
tine (20–30 mg/day) and 40 patients received nortripty-
line, the latter titrated to a therapeutic plasma level of
50–150 mg/ml. The average final daily dosages were
22 ± 5 mg of paroxetine and 74 ± 30 mg nortripty-
line. No significant difference was seen in the antide-
pressant effect at the end of the 6-week trial, but 10
of the 40 patients receiving nortriptyline (25%) dis-
continued treatment due to significant cardiovascular
side effects including sinus tachycardia, angina with ST
changes on EKG, and pro-arrhythmias. Only one pa-
tient in the paroxetine group stopped the treatment
due to unstable angina. Nortriptyline produced a sta-
tistically significant increase in heart rate compared to
baseline (83 beats/min vs. 75 beats/min, P < 0.001). Al-
though paroxetine and nortriptyline were both effective
antidepressants, nortriptyline was associated with signif-
icantly more frequent and serious cardiac events than
paroxetine.[12, 37, 42]
Roose and colleagues used a historical control group
to compare the potential cardiovascular effects of fluoxe-
tine and nortriptyline, 27 patients received the SSRI and
60 patients received the TCA. The patients had a variety
of cardiac diseases, including heart failure (n = 45), con-
duction disease (n = 62), ventricular arrhythmia (n = 49),
and MI (n = 47).[43] Fluoxetine was initiated at a dose of
20 mg/day and increased to a maximum of 60 mg/day by
week 4. Nortriptyline was initiated at 1 mg/kg/day and
increased to a therapeutic plasma level (50–150 mg/ml).
Mean final dosages were not reported for either medica-
tion. Both fluoxetine and nortriptyline improved depres-
sive symptoms with no differences in efficacy noted. No
significant differences between the two groups were ob-
served in the cardiovascular measures, but numerically
more adverse effects were seen in the nortriptyline group
compared to the fluoxetine group. At week 2, a statisti-
cally significant decrease in heart rate was see in the flu-
oxetine group (78 ± 14 beats/min vs. 73 ± 12 beats/min,
P = 0.0002) and an increase in supine systolic blood pres-
sure (128 ± 3 mmHg vs. 131 ± 14 mmHg, P = 0.02).
Fluoxetine treatment was also associated with an increase
in ejection fraction in the patients with an ejection frac-
tion of 50% or below at baseline (35 ± 11.1% vs. 37.4
± 11.8%, P = 0.05). Patients in the nortriptyline group
had statistically significant increases in both heart rate
and diastolic supine blood pressure at week 2 ([75 ± 9
beats/min vs. 82 ± 9 beats/min, P < 0.0001] and [74 ± 8
vs. 77 ± 8 mmHg, P = 0.0002]). In addition, in patients
Depression and Anxiety
with an ejection fraction of less than 50% at baseline
in the nortriptyline group, there was a significant de-
crease in ejection fraction at week 2 (33.1 ± 9.4% vs.
30.9 ± 10.7%, P = 0.04). Although this was a historical
control nonprospective trial, fluoxetine did not exhibit
the cardiovascular side effects that were observed with
nortriptyline.[5, 12, 35]
Additional evidence from a clinical trial that SSRIs
might be beneficial and safe in cardiac patients came in
1999, when Shapiro et al. performed an open-label study
evaluating the safety, tolerability, and efficacy of sertra-
line in post-MI patients in the Sertraline Antidepressant
Heart Attack Trial (SADHAT).[44] Using the Diagnos-
tic Interview Schedule (DIS), modified DSM-IV criteria,
and Beck Depression Inventory (BDI), 26 patients post-
MI with MDD were treated with sertraline. The initial
sertraline dose was 50 mg/day and was slowly titrated to
a maximum dosage of 200 mg/day; however only two
patients received final daily doses above 100 mg. Ef-
ficacy was evaluated by using the HAM-D, BDI, and
CGI scales. Sertraline led to improvement in depressive
symptoms without any increased risk of adverse cardiac
events.[3, 12, 44]
In the follow-up study to SADHAT, the SADHART,
369 patients with MDD and either acute MI (n =
294) or unstable angina (n = 75) were enrolled in a
randomized, double-blind, placebo-controlled 24-week
trial.[44, 45] The patients were randomly assigned either
sertraline or placebo. There was a 2-week placebo run-in
period for all patients. Sertraline was initiated at a dose
of 50 mg/day. By the end of week 12, the patients could
receive a maximum dosage of 200 mg/day. For the total
sample, depression severity was in the mild to moderate
range, with 24% (sertraline, n = 50; placebo, n = 40)
of the sample in the more severe subgroup, defined by
higher depression severity measured by HAM-D ≥ 18
and multiple prior episodes of depression. There was also
a subgroup of patients with no prior history of MDD re-
gardless of severity (sertraline, n = 96; placebo, n = 90).
No significant difference was found in ejection fraction
or in any of the cardiovascular measures between placebo
and sertraline groups. The rate of cardiovascular adverse
events was lower but not statistically significant different
in the sertraline group compared to the placebo group
(14.5% vs. 22.4%). Sertraline was safe in patients fol-
lowing an acute MI or in unstable angina. In terms of
efficacy, in the overall analysis, sertraline was not statis-
tically superior to placebo based on HAM-D measure-
ments over 16 weeks. However, sertraline was signifi-
cantly superior to placebo on the CGI scale, which was
measured over 24 weeks. In the two subgroups with re-
current depressive episodes, sertraline was significantly
superior to placebo on both the CGI and HAM-D mea-
sures. Responder rates for placebo treated patients de-
creased as severity of depression increased.[5, 44, 45]
Further evidence of the potential efficacy of SSRIs
in CVD patients came from a double-blind, placebo-
controlled trial of fluoxetine.[46] In this 25-week study,
54 patients with depression and recent MI were enrolled.
 Special Article: Treatment of depression in cardiovascular disease
They were diagnosed with depression using the DSM-
III criteria and the HAM-D measured symptom sever-
ity. Patients receiving fluoxetine were initially treated
with 20 mg/day and could be increased to a maximum
of 60 mg/day by week 6. Increased response rates and
reduction in depressive symptoms in the fluoxetine
treated compared to the placebo treated patients were
observed at 25 weeks, but not earlier (48% vs. 26%, P ≤
0.05).[3, 46] No significant changes were seen between the
placebo and fluoxetine groups in ejection fraction, heart
rate, or other cardiac measures. There were no signifi-
cant differences between the two groups in adverse car-
diac effects; the authors concluded that fluoxetine is a safe
and effective antidepressant in patients post-MI.[12, 46]
Further evidence for the efficacy of SSRIs in depressed
patients with cardiac disease is derived from the Cana-
dian Cardiac Randomized Evaluation of Antidepressant
and Psychotherapy Efficacy (CREATE) study. This
2 × 2 factorial designed trial evaluated the efficacy of
IPT and citalopram in 284 patients with CAD over
a 12-week period.[11, 47] Patients were diagnosed with
depression using the Structured Clinical Interview for
Depression (SCID). DSM-IV and the HAM-D and
BDI measured symptom severity. Participants under-
went two separate randomizations: once to receive
IPT versus clinical management only, and once to
receive citalopram versus placebo; resulting in four
groups; IPT plus clinical management and citalopram,
IPT plus clinical management and placebo, clinical
management with citalopram, and clinical management
with placebo. IPT was studied because similar to CBT,
it has been shown to be effective in the treatment of
depression. Indeed, it has been reported to be more
effective than CBT in treating depression in patients
with HIV, a group also dealing with comorbid medical
and emotional problems.[11] Citalopram was superior to
placebo in reducing depressive symptoms, by week 6 of
the trial, as evidenced by changes in the HAM-D (effect
size 0.33) and BDI (0.33). There was no difference
between citalopram and placebo on measures of cardiac
safety, suggesting that citalopram is safe and effective in
patients with CAD.[3, 11] There was also no significant
difference between IPT and clinical management on
depression symptom severity, as assessed by both clinical
rating or self-reports. Surprisingly, some of the sub-
group analyses suggested that clinical management may
be more effective than IPT in patients with low baseline
social support or poor day-to-day functioning.[11, 47]
Two large multicenter trials, ENRICHD and MIND-
IT assessed the treatment of depression in patients with
MDD and CAD. In the ENRICHD trial (Enhanc-
ing Recovery in Coronary Heart Disease), 2,481 pa-
tients with acute MI and major depressive disorder, mi-
nor depressive disorder, or dysthymia were randomized
to CBT or treatment as usual. If patients scored >24
on the HAM-D, they also received an SSRI. The ad-
ministration of the SSRI was not blinded or random-
ized and the patient could be in either treatment group
and receive an SSRI. Depression was diagnosed using
335
the SCID and depression severity measured with the
HAM-D and BDI. The study period was 12 months.
At 6 months, patients who were being treated with an
SSRI had significantly lower rates of death and recur-
rent MI when compared to those not being treated with
any antidepressants.[3, 5, 48, 49] The group receiving CBT
showed a small but statistically significant decrease in
their depressive symptoms, but exhibited no change in
the incidence of cardiac events during the initial 6-month
treatment period.[48, 49]
In MIND-IT (Myocardial Infarction Depression
Intervention Trial), 91 post-MI depressed patients
were randomized to receive either mirtazapine or
citalopram.[50] Patients were diagnosed with depres-
sion with the SCID and monitored with the BDI and
HAM-D. The first choice for the double-blind, placebo-
controlled treatment was mirtazapine. If patients refused
or did not respond to the mirtazapine, they were of-
fered citalopram in an open treatment design. Patients
were followed for an average of 27 months. The antide-
pressant efficacy of mirtazapine and citalopram was not
superior to placebo. Interestingly, patients who did not
respond to antidepressant treatment exhibited a higher
rate of cardiac events when compared to those who re-
sponded to the antidepressant [5, 50] .
In the SADHART-CHF trial, O’Connor et al.
studied the antidepressant efficacy and cardiovascular
safety of sertraline versus placebo in depressed pa-
tients with CHF. This was a 12-week randomized,
double-blind, placebo-controlled trial.[51, 62] Depression
symptom severity was rated using the HAM-D. Pa-
tients were treated with sertraline (50–200 mg/day)
or placebo in addition to nurse-facilitated support.
Of the 469 patients enrolled, 234 patients received
sertraline and 235 patients received placebo. Sertra-
line was not superior to placebo (P = 0.89, 95%
CI −1.7 to 0.9), though both groups exhibited a
statistically significant reduction in HAM-D scores
(P < 0.001). A significantly larger number of subjects
in the sertraline group withdrew from the study due to
medication side effects (27/234; 11.5%) compared to the
placebo group (14/235; 6%; P = 0.03). There was no
statistically significant difference in all-cause mortality
between the groups. The authors concluded that sertra-
line neither improved depression nor cardiac outcomes
compared to placebo.[3, 51] One of the possible limita-
tions of the study was the relatively moderate severity
of depression of the patients that comprised the study
(HAM-D scores were 19.9 in the sertraline group and
18.4 in placebo).
In a more recent study, 240 patients were randomly
assigned following an acute coronary syndrome event,
to receive either escitalopram or placebo.[52] The goal of
this DECARD study (Depression in Patients with Coro-
nary Artery Disease) was to determine if SSRI treatment
with escitalopram would protect patients from develop-
ing depression. Of the 120 patients treated with escitalo-
pram, two developed depression compared to 10 of 120
patients receiving placebo (P = 0.022). No differences
Depression and Anxiety
336 Mavrides and Nemeroff
were found in adverse events between the two groups.
The authors suggested that SSRIs could prevent depres-
sion following an acute coronary syndrome event.[5, 52]
In a nursing home population of elderly patients (age
> 80 years) with depression, Santangelo et al. studied
110 patients to determine if SSRIs would reduce the
cardiovascular risk in this age group. Depression was di-
agnosed by DSM-IV criteria. The patients were treated
with sertraline or citalopram and they were then divided
into responders or nonresponders. The SSRI respon-
ders exhibited a 60% reduction in cardiovascular events
in a 12-month period. This early treatment of depres-
sion in elderly subjects may be a component of CVD
prevention.[5, 53] Another small double-blind, random-
ized, placebo-controlled study evaluated the efficacy of
paroxetine CR on depression and quality of life in 28
patients with chronic heart failure. Half were random-
ized to receive paroxetine CR and half to placebo over
a 12-week treatment period. The patients’ entry crite-
ria were ≥10 on the BDI. Paroxetine was significantly
more effective than placebo in reducing BDI scores (re-
sponse rate in the paroxetine group 69% vs. 23% in the
placebo group, P = 0.018). The paroxetine-treated pa-
tients exhibited higher general health levels compared
to placebo treated patients as assessed by the Medical
Outcomes Study 36-item Short Form survey (38 ± 10
vs. 30 ± 6, P = 0.016). Improvements in depression were
correlated with improvements in psychological aspects
of quality of life. The authors concluded that paroxetine
CR was effective in treating depression in patients with
chronic heart failure. This study did not carefully assess
the safety profile or the potential adverse cardiac effects
of this medication [54] . Interestingly, a reduction in lev-
els of lipoprotein (a), a potential risk factor for cardiac
mortality, was reported by Paslakis et al., in patients with
depression after treatment with paroxetine (n = 21), but
not amitriptyline (n = 14).[55]
A recent case-time-control study in Denmark, exam-
ined 19,110 patients who experienced an out-of-hospital
cardiac arrest (OHCA); 2,913 (15.2%) were receiving
antidepressant treatment at the time of the OHCA.
Citalopram was the most commonly used antidepres-
sant (50.8%). Both TCAs (OR = 1.69, CI 1.14–2.50) and
SSRIs (OR = 1.21, CI 1.00–1.47) were associated with
comparable increases in the risk of OHCA, whereas no
association was found for SNRIs/noradrenergic and spe-
cific serotonergic antidepressants. The increased risk
were primarily driven by citalopram (OR = 1.29, CI
1.02–1.63) and nortriptyline (OR = 5.14, CI 2.17–
12.2).[56] Whether these effects are due to untoward ef-
fects of these antidepressants or to the pathophysiologi-
cal effects of the depression per se is unclear.
PSYCHOTHERAPEUTIC INTERVENTIONS
The Coronary Psychosocial Evaluation Studies Ran-
domized Controlled Trial (COPES) was a 6-month ran-
domized intervention study of 157 patients who had per-
sistent depressive symptoms following an acute coronary
Depression and Anxiety
syndrome.[57, 58] The patients were randomized to either
the intervention group (problem solving therapy ± phar-
macotherapy, n = 80) or to the usual care group (n = 77).
Also included were 80 nondepressed patients who also
underwent usual care as defined by their primary physi-
cians. The intervention group had higher satisfaction
(54%) with their depression care than the group receiv-
ing care as usual (19%; 95% CI 2.2–12.9, P < 0.001). BDI
scores also were more significantly reduced in the inter-
vention group (95% CI −7.6 to −3.8; P = 0.005) com-
pared to the care as usual group (95% CI −3.8 to −0.1).
Of note, 3 (4%) patients in the intervention group and
10 (13%) patients in the usual care group experienced
major cardiac adverse events, which was a statistically
significant difference (P = 0.047).[5, 57, 58]
Freedland et al. recently reported on the efficacy of
CBT in the treatment of depressed patients with CAD,
more specifically those post-CABG. Depression was di-
agnosed using DSM-IV criteria and a BDI ≥ 10, or as
determined by the Depression Interview and Structured
Hamilton (DISH). Patients with depression who had un-
dergone CABG within the year (n = 123) were random-
ized to either receive CBT, supportive stress manage-
ment, or usual care for 12 weeks. Patients in the CBT
and supportive stress management group had statistically
significantly higher rates of remission from depression
at 3 months compared to the usual care group (71%
vs. 57% vs. 33%, respectively, P = 0.002). Only the pa-
tients in the CBT group exhibited higher remission rates
at 9 months. The CBT intervention group also expe-
rienced greater improvements in anxiety, hopelessness,
perceived stress, and mental health related quality of life
when compared with usual care. These findings suggest
that CBT is an effective treatment for depression in post-
CABG patients.[59]
The Bypassing the Blues study was intended to ex-
amine the impact of telephone delivered collaborative
care for treating depression after CABG surgery over
an 8-month period. The study was comprised of 302
patients, 150 randomized to receive the telephone deliv-
ered intervention and 152 patients who received care as
usual. Depression was assessed using the Physical Health
Questionnaire (PHQ9) and the HAM-D. Both mental
and physical health related quality of life was evaluated.
The intervention group showed greater improvements
in both mental and physical health related quality of life
and also exhibited a greater depression remission rate
(based on the HAM-D) compared to the care as usual
group (95% CI, P = 0.009). The authors suggested
that this interaction, a phone based collaborative care
method, can be utilized to reduce patients’ depressive
symptoms and enhance their quality of life.[60]
DISCUSSION
Major depressive disorder and depressive symptoms
in general are highly prevalent in both the gen-
eral population and even more prevalent in patients
with CVD. Depression is associated not only with
 TABLE 1. Clinical Trials of Antidepressants and Psychotherapies

Study No. of patients Length of trial Treatment Findings

Raskind et al.[32] N = 12 4 weeks Imipramine No significant change in HAM-D

Safe in patients with stable ischemic heart
disease, minimum conduction defects
Veith et al.[27] (randomized double-blind N = 24 4 weeks Imipramine vs. doxepin vs. placebo Active treatment groups had improved
placebo-controlled trial) depression scores
Significant orthostatic hypotension safe
post-MI
Glassman et al.[33, 34,45] N = 15 3 weeks Imipramine Effective in treatment depression;
7 of 15 severe orthostatic hypotension
Roose et al.[29,35–37,43] N = 21 3 weeks Nortriptyline Effective in treating depression
No orthostatic hypotension
Roose et al.[29,35–37,43] (randomized N = 196 10 years Imipramine vs. nortriptyline Both effective antidepressants,
controlled trial) Nortriptyline causing less cardiac side
effects
Dietchand Fine[38] N = 10 (elderly) unclear Nortriptyline Effective for depression
Minimum risk conduction disease
Cohen et al.[39, 40] (open study) N = 22 28 days Trimipramine Effective for depression
No orthostatic hypotension
Roose et al.[29,35–37,43] (double-blind N = 10 6 weeks (3 weeks each Imipramine vs. bupropion Equally effective for depression
crossover study) medication)
Bupropion safer than imipramine
Roose et al.[29,35–37,43] (double-blind N = 81 6 weeks Paroxetine vs. nortriptyline No significant difference in depression
randomized controlled trial) Significant cardiac side effects with
nortriptyline
Roose et al.[29,35–37,43] (historical control N = 27 (SSRI), N = 60 Fluoxetine vs. nortriptyline Nortriptyline had significant cardiac side
study) (TCA) effects compared to fluoxetine
Strik et al.[46] (randomized double-blind N = 54 (27 each group) 25 weeks Fluoxetine vs. placebo Greater response to fluoxetine compared
placebo-controlled) to placebo
No significant difference in side effects;
Sertraline Antidepressant Heart Attack N = 26 16 weeks Sertraline Significant improvement in depression
Trial (SADHAT; open label) No significant changes in cardiac outcome
Special Article: Treatment of depression in cardiovascular disease

variables
Sertraline Antidepressant Heart N = 369 (186 sertraline, 24 weeks Sertraline vs. placebo Sertraline > placebo on CGI scores and
Randomized Trial (SADHART; 183 placebo) HRS-D. Caused more improvement in
randomized double-blind, depression than placebo
placebo-controlled) No differences between cardiac variables
between groups
Canadian Cardiac Randomized Evaluation N = 284 (142 12 weeks Interpersonal therapy vs. citalopram vs. Citalopram > placebo on all measures of
of Antidepressant and Psychotherapy citalopram, 142 placebo depression
Efficacy (CREATE; 2 × 2 factorial placebo) No significant differences in cardiac
design) variables between groups

Depression and Anxiety

337

TABLE 1. Continued
Study
Depression and Anxiety
Enhancing Recovery in Coronary Heart
Disease (ENRICHD; randomized,
placebo-controlled)
Myocardial Infarction Depression
Intervention Trial (MIND-IT;
randomized double-blind
placebo-controlled)
Sertraline Antidepressant Heart
Randomized Trial of CHF patients
(SADHART-CHF; randomized
double-blind, placebo-controlled)
Depression in Patients with Coronary
Artery Disease (DECARD; randomized
double-blind placebo-controlled)
Santangelo et al.[53] (randomized
double-blind placebo-controlled)
Gottlieb et al.[54] (double-blind
placebo-controlled)
Weeke et al.[56] (case-time-control)
Coronary Psychosocial Evaluation Studies
Randomized Controlled Trial (COPES)
Freedland et al.[59] (randomized
controlled trial)
Bypassing the Blues (randomized
controlled trial)
338
No. of patients Length of trial Treatment Findings
N = 2,481 (1,238 CBT, 6-month active, CBT plus antidepressant (if indicated) CBT modestly but significantly improved
1,243 usual care) 18-month follow-up depressive symptoms
No effect on cardiac outcomes
Antidepressant use associated with
decreased risk of death or nonfatal MI
N = 91 27 months Mirtazapine vs. citalopram Efficacy of mirtazapine/citalopram was not
superior to placebo
Those who did not respond to
antidepressant treatment had higher
rates cardiac events
N = 469 (234 sertraline, 12 weeks Sertraline vs. placebo Sertraline was not superior to placebo,
235 placebo) both had statistically significant
reduction in depression scores
No difference in all-cause mortality
N = 240 (120 Unclear time length Escitalopram vs. placebo 2 of 120 escitalopram developed
escitalopram, 120 depression, 10 of 120 placebo patients
placebo) developed depression
SSRIs could prevent depression following
ACS
N = 110 12 months Sertraline vs. citalopram SSRI responders had 60% reduction in
cardiovascular disease prevention
N = 28 12 weeks Paroxetine vs. placebo Paroxetine > placebo reducing BDI scores
Mavrides and Nemeroff
N = 19,110 Antidepressant treatment TCAs and SSRIs associated with
comparable increases in risk of
out-of-hospital cardiac arrest
N = 157 6 months Intervention (problem solving ± meds) vs. Intervention group had higher satisfaction
usual care with depression care, significantly
reduced BDI scores
N = 123 12 weeks CBT vs. supportive stress management vs. CBT/supportive stress management
usual care significantly higher rates of remission 3
months
Only CBT had higher remission at
9-month follow-up
N = 302 (150 phone, 8 months Phone intervention vs. usual care Intervention group had greater
152 usual care) improvements in mental/physical
quality of life and greater depression
remission rate
 Special Article: Treatment of depression in cardiovascular disease
psychiatric morbidity but poor functional and cardiac
outcomes, including more than a twofold increase in
mortality following MI.[3] Depression alone is a large
public health concern with severe morbidity and mor-
tality that remains insufficiently addressed. When car-
diovascular comorbidity is added, the concern is even
greater in terms of both the morbidity and mortality.[8]
It is imperative that patients with the cardiac risk factors
of recent history of MI, CAD, heart failure, conduction
abnormalities, and preexisting postural hypotension, be
evaluated and treated for depression.[12] This literature
review has focused mainly on the clinical treatment trials
that have evaluated the safety and efficacy of antidepres-
sants and psychotherapy in the treatment of the depres-
sion in the cardiac population (see Table 1).
There is strong evidence for a bidirectional associ-
ation between depression and CVD. Patients post-MI
are at considerable risk for depression and suicide,[3, 14]
and depressed patients are at considerably increased risk
for development of CAD and for poor outcome post-
MI. There have been studies suggesting that the treat-
ment of depression improve cardiovascular outcome, but
these are relatively small and the findings are equivocal.
Depression is associated with decreased adherence with
medications/medical appointments, dietary and exercise
regimens, in short, an unhealthy lifestyle.
Short-term treatment of depression with TCAs is
relatively safe in patients with ischemic heart disease,
heart failure, or previous MI. However, long-term treat-
ment has not been well studied and is clearly not de-
void of adverse effects. Orthostatic hypotension is a se-
rious complication observed with TCAs, more frequent
with imipramine than with nortriptyline. The conclu-
sion from the seven studies that were reviewed suggest
that TCAs should be used cautiously in patients with
cardiac disease, especially those with baseline postural
systolic blood pressure reductions.
Bupropion has only been studied in small trials and
only in one study was it compared to a TCA. It was
found to be safe in patients with cardiac conduction dis-
ease and left ventricular systolic dysfunction. Further tri-
als are warranted especially in view of its favorable sex-
ual dysfunction profile, a problem with the SSRIs and
SNRIs.
Based on the multiple clinical trials, both controlled
and uncontrolled, SSRIs are considered to be the safest
of the antidepressants for patients with cardiac disease.
They are associated neither with orthostatic hypoten-
sion nor conduction abnormalities. In general, the SS-
RIs are safe and probably effective in treating depres-
sion in patients with ischemic heart disease. However,
well-powered, large-scale studies, similar to those that
demonstrated the efficacy of statins in treating hyper-
cholesterolemia, are sorely needed. Sertraline has been
the most commonly studied and is often considered to
be the first line drug of choice in this patient popu-
lation, though the primary outcome measure for de-
pression in the SADHART trial did not achieve sta-
tistical significance. Fluoxetine, paroxetine, citalopram,
339
and escitalopram have also been studied in smaller tri-
als and in some are effective, though their drug–drug
interactions and side effect profiles need to be consid-
ered prior to prescribing them. Again large scale trials
are warranted. Mirtazapine was evaluated in one clini-
cal trial, MIND-IT, and was found to be no more ef-
fective than placebo in treating depression in patients
following MI.
The results of the clinical trials of psychotherapy in
depressed patients with cardiac disease are mixed with
one demonstrating that CBT has a positive impact on
survival and is effective in treating depression. Psy-
chotherapeutic interventions, specifically those that are
supportive and work to improve adherence may also be
helpful. The CREATE trial demonstrated that there was
no additional benefit in receiving IPT as compared to
usual care. This was a surprising result, because IPT had
shown significant benefit in another medically ill popu-
lation with depression, specifically HIV, when compared
to CBT. Future studies that compare IPT to CBT
as well as other forms of psychotherapy are urgently
needed. The latter should include brief psychodynamic
psychotherapy and group therapy. Coordinated care
models also appear to be effective at improving depres-
sive symptoms and increasing adherence to both treat-
ment and medications based on the Bypassing the Blues
Study.
FURTHER RESEARCH
IMPLICATIONS
In addition to the obvious need for well-powered,
large-scale safety and efficacy trials of depression in the
cardiac population is the need to evaluate predictors of
treatment response in individual patients, that is, person-
alized medicine. More intricate knowledge of the mech-
anisms that mediate the link between depression and
cardiac disease is needed to attain this goal and to help
develop treatments that target the underlying patho-
physiology that leads to cardiac events in depressed
patients. Study of some of the newer antidepressants
(duloxetine, vilazodone, venlafaxine, bupropion) would
be helpful to ensure both their safety and efficacy in
this population. There are relatively few studies that
have looked at differences between antidepressants, psy-
chotherapy, and cardiac rehabilitation on depression
symptom severity in patients with CVD.[61] A striking
un-researched area for further research is the relation-
ship of CVD and anxiety disorders. Very little research
has been conducted in patients with heart disease and
syndromal anxiety disorders, although SSRIs and SNRIs
are used to treat certain anxiety disorders as well as de-
pression. Anxiety is frequently comorbid in patients with
ischemic heart disease, following an acute MI or acute
coronary syndrome, or in heart failure. Further research
is needed to determine the significance of anxiety on car-
diac morbidity and mortality and the potential clinical
implications of its treatment.
Depression and Anxiety
340 Mavrides and Nemeroff
Acknowledgments. This work was funded by Na-
tional Institutes of Health (NIH) and Agency for Health-
care Research and Quality (AHRQ).
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