Depression and Cardiovascular

Disease

Dr. dr. Starry H. Rampengan, SpJP(K), FIHA, MSi, CHt,

FICA, FACC, FAHA, FESC
Department Cardiology and Vascular Medicine/
Internal Medicine
Faculty of Medicine, Sam Ratulangi University
Manado
2013

 A figurative interdependence between the

heart and sadness has long existed in
language and in literature.
In 1628, English physician William Harvey
noted every affection of the mind that is
attended either with pain or pleasure,
hope or fear, is the cause of an agitation
whose influence extends to the heart

 1970s - epidemiologists start to

associate/correlate heart disease and
depression.

Global Burden of
Disease
CAD & MDD
will be the 1
&2
contributors
to the burden
of disease by
the year 2020.
Murray, CL Alterantive projections of mortality and disability by cause 1990-2020:Global Burden
Disease Study Lancet May 1997 vol. 349, pp 1498-1504

Global Burden of
Disease

WHO 2002

MEN

WOMEN

Objectives:
Review some of the literature regarding:
-the course of depression following cardiac events
-depression as a risk factor for cardiac events
-the links between depression and heart disease

Review evidence for treatment of

depression in pts with CHD
Review the ACC AHA guidelines
Discuss the professional recommendations
with ramifications relevant to local health
care system and evironment

Major depressive disorder (MDD)

DSM-IV requires that five of the following are
present:
Depressed mood most of the day
Anhedonia
Significant change in weight
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness or guilt
Impaired concentration, indecisiveness
Recurring thoughts of death or suicide

Further, one of the symptoms must be

either depressed mood or anhedonia.
The symptoms must be present nearly
every day for 2 weeks, and occur through
most of the day.
Symptoms must cause impairment of
functioning.

S
I
G
E
C
A
P
S

sleep
interest
guilt or worthlessness
energy
concentration
appetite
psychomotor changes
SI

Biobehavioral variables and mortality or

cardiac arrest in the Cardiac Arrhythmia Pilot
Study (CAPS)
502 pts with >10PVC/hr or >5 NSVT episodes
evaluated
Results indicated that higher levels of depression
and lower pulse rate reactivity were significant
risk factors for death or cardiac arrest, after
adjusting statistically for a set of known clinical
predictors of disease severity.

AJC 1990;66:59-62

Depression Following Myocardial

Infarction: Impact on 6-month Survival
To evaluate if MDD in patients hospitalized after
MI would have an independent impact on
mortality during 6month follow-up
Prospective evaluation of 222 patients with MI
using DIS
78% male. Ages 24-88. EF 12-76%. 82 pts with
previous MI.
Depression was a significant predictor of mortality
with HR 5.74, p=0.0006.
Controlling for LVEF, Killip class, previous MI, HR
4.29, p=0.013
JAMA 1993; 270(15) 1819-1825

Depression and 18-Month Prognosis After

Myocardial Infarction
18month follow-up showed that both DIS and BDI
scores consistent with depression were
significantly related to 18month cardiac mortality,
after controlling for other predictors of mortality
including Killip class, PVCs, previous MI. (OR 3.64,
p=0.012 and OR 7.82, p=0.0002 with adjusted
OR6.64, p=0.0026)
The deaths that occurred in 18month follow-up
were concentrated among depressed patients
with PVCs >10/hr.
Circ 1995; 91:999-1005.

n =10

n =56
n =16
n = 112

PVCs < 10/hour

PVCs 10/hour

Depression and Long-term Mortality

Risk in Patients with Coronary Artery
Disease
1250 patients with CAD assessed for
depression and followed for 15.2 years to
evaluate the long-term mortality risk.
Pts were enrolled at the time of LHC and
followed at 6 and 12 months then annually
with SDS.

Am J Cardiol 1996;78:613-617

 Higher depression scores were associated

with increased risk of subsequent cardiac
death (p=0.002) and total mortality
(p<0.001) after controlling for initial
disease severity and treatment.
Pts with moderate to severe depression
had a 69% greater odds of cardiac death
and a 78% greater odds of mortality from
all causes than nondepressed patients.
Pts with higher scores had a higher risk of
cardiac death >5 yrs later (p<0.005)

 Compared with nondepressed pts, those

with moderate to severe depression had
an 84% greater risk at 5-10yrs later and a
72% greater risk after >10yrs.

1.5

0.5

2-5

6-10

Years of Follow-up

11+

Effect of Depression on Late (8 years)

Mortality After Myocardial Infarction
Prospective observational study of 284 patients
hospitalized with MI
Any depression at the time of MI was not
associated with mortality at 8 years.
However, increased mortality was statistically
significant in the short term (4 months).

AJC 2008;101:602-606

100%
50%

Any Depression

0%

Percentage Surviving

No Depression

Years
Number at risk
Any Depression
No Depression

0
184
76
208

2
229
60
169

4
200
50
150

6
169
41
128

8
147
34
113

 Of note, this was a small observational

study of 284 hospitalized pts over age 63
with multiple comorbidities.

Usefulness of Persistent Symptoms of

Depression to Predict Physical Health Status
12 Months After an Acute Coronary
Syndrome

425 pts hospitalized for ACS completed the BDI

and SF-12 in hospital, 6- and 12 months later.

Only patients with persistent symptoms of

depression were at risk for poorer physical health.
Patients with newly developed depressive
symptoms after ACS had a trend toward worse
physical health, whereas patients with transient

depressive symptoms were not at increased risk .

AJC 2008;101:15-19

What about patients

with no history of
heart disease?

Depression Is a Risk Factor for Coronary

Artery Disease in Men: The Precursors Study

Observational study of 1190 male medical students

enrolled from 1948 to 1964 followed for 40 years
Incidence of depression was 12%. In multivariate analyses,
these men were at greater risk for subsequent CAD (RR
2.12) and MI (RR 2.12).
The increased risk associated with depression was present
even for MIs occurring 10 yrs after the first MDE (RR 2.1)
The association did not change when time-dependent
smoking, EtOH, and coffee use were added to models, nor
when BMI, FH of MI, baseline cholesterol, and timedependent HL were added.
In a model with the strongest RF, the risk of CHD from
depression was still significant with RR of 1.7
Arch Int Med 1998;158:1422-1426

 Clinical depression was associated with a greater

risk of total mortality according to both
unadjusted and adjusted analyses.
Clinical depression was significantly related to
CVD mortality in unadjusted analyses, with a
trend toward increased CVD mortality in adjusted
analyses.
The association of clinical depression with CVD
mortality was stronger than the association of
clinical depression with other causes of death,
exclusive of suicide.

Depression as an Antecedent to Heart

Disease Among Women and Men in the
NHANES I Study
5006 women and 2888 men who completed
the CES-D were followed over 10 years.
17.5% of women were depressed and 9.7%
of men were depressed.
The mean poverty index was lower in
depressed patients.
Women had 187 nonfatal and 137 fatal
events. Men had 187 nonfatal and 129 fatal
events.
Arch Int Med 2000;160:1261-1268

 The RR of nonfatal CHD among

women with scores of 23 or higher on
CES-D was 2.09
Adjusted RR with final model taking
into consideration poverty, DM, HTN,
smoking, and BMI was 1.73.

 The adjusted RR for nonfatal CHD in

depressed men was 1.71.
Adjusted RR for CHD mortality was 2.34.
Adjusted all-cause mortality RR was 1.69.

What is the connection between

depression and cardiac events?
Pathophysiologic changes
Behavioral issues
Medication Adherence
Medication Side Effects

Candidate Mechanisms Linking

Depression To Cardiovascular Morbidity &
Mortality
Physiological pathways
Cardiovascular autonomic dysregulation
E.g., low heart rate variability (HRV)

Pro-inflammatory processes
E.g., elevated CRP, IL-6

Pro-coagulant processes
E.g., elevated fibrinogen, PF4, BTG

Shared genetic factors

E.g., TNFA, IL1B, 5-HTT, 5-HT2A, 5-HT2B

Hypothalamic-PituitaryAdrenal (HPA) axis in

depression

Endothelium-Teflon
Resistant
Tunica adventitia
Tunica media
Tunica intima
Endothelium
Subendothelial connective
tissue
Internal elastic membrane
Smooth muscle cells
Elastic/collagen fibers
External elastic membrane

Ross, R. Nature, 1993; 362: 801-809. 1993;362:801-809.

Atherosclerosis is an Inflammatory Disease

LDL pro-inflammatory & HDL anti-inflammatory
Vessel Lumen-Teflon Resistent

Monocyte

LDL-small dense particles

Endothelium

Adhesion Modulesincrease monocytes

adherence

LDL

Cytokines

oxidized LDL

Macrophages
engulf LDL

HDL Promote Cholesterol Efflux

Mackness MI et al. Biochem J 1993;294:829-834.

HDL Inhibit
Oxidation
of LDL
Foam Cell-increase
ANGIOTENSIN II,
PAI, -prothrombotic state &
decrease NO

Plaque Morphology and Ischemic

Impact

Libby, P. et al. Circulation

Pathophysiology in Motion

Autonomic dysregulation in depression

sympathetic; parasympathetic activity:
increased catecholamines (e.g. NE)
lower threshold for ischemia, ventricular
tachycardia, ventricular fibrillation, sudden death
in CHD pts and may contribute to endothelial
injury
resting heart rate; heart rate variability
baroreceptor sensitivity
QT interval/impaired repolarization, variable
repol

Psychosom Med 2005;67:S1:S29-33.

Procoagulant effects of depression

Elevated catecholamines may also promote
procoagulant processes by potentiating platelet
activation through agonist effects, by increasing
hemodynamic stress on vascular walls, or by
inhibiting vascular eicosanoid synthesis.

Psychosom Med 2005;67:S1:S34-36.

Immunologic response
Cytokines may lead to sickness-behavior (lethargia,
anorexia, paresthesia, irritability, social withdrawal,
impaired concentration, sleep problems, decreased libido;
particularly TNF-alfa and IL-6 may induce depression,
anxiety and memory impairment)

In non-melancholic depression elevated levels of

-IL-6 (mediates activation of the HPA axis),

-NK cells (acute stage)
-leucocytes/lymphocytes (acute stage)

In melancholic depression:
- decreased (in vitro) production of IL-2; IFN-g; IL-10 (acute
stage), but normal cell counts
Schwarz . Dialogues in Clin
Neurosciences 2003; 5: 139-153

The relationship between central nervous system correlates of depression and

immune system parameters is bidirectional, mediated by neurohormonal and
parasympathetic pathways. Depressive symptoms primarily affect the transition
from stable CAD to acute coronary syndromes via plaque activation and
prothrombotic processes (solid line) and may adversely affect the initial response
to injury at early stages of coronary atherosclerosis (dashed line).

Kop: Psychosom Med 2005; 67 [Suppl

1]: s37-s41

SSRI therapy in patients with

ischemic heart disease
SSRIs reduce platelet activity. SSRI
(sertraline) was associated with
substantially less release of
platelet/endothelial biomarkers: PF4,
TG, platelet/endothelial cell adhesion
molecule 1, P selectin, thromboxane
B2, 6-keto prostaglandin F1a, vascular
cell adhesion molecule 1, and E
selectin.
Jiang W, Davidson JRT. Am Heart J
2005; 150: 871-881

Sympathetic activity in
major depressive disorder

SSRI therapy abolished the excessive

sympathetic activation, with whole
body noradrenaline spillover falling from
518 +/- 83 to 290 +/- 41 ng/min (P =
0.008).

Barton et al. J Hypertens. 2007

Oct;25(10):2117-2124.

Heart rate variability (HRV) recovery following myocardial infarction in the Sertraline
Antidepressant Heart Attack Randomized Trial (SADHART) and studies by Jokinen et al and
McFarlane et al

Jokinen et al
SADHART
McFarlane et al

n=416

n=11

B
n=125

n=12
n=133

Patients Without
Depression

Prescribed
Sertraline

Given
Placebo

Patients With Depression

Glassman, A. H. et al. Arch Gen Psychiatry 2007;64:1025-1031.
Copyright restrictions may apply.

n=15

Candidate Mechanisms Linking

Depression To Cardiovascular Morbidity &
Mortality
Behavioral pathways
Smoking
High prevalence of smoking in depression & vice versa
Depression decreases smoking cessation rates.

Physical inactivity
Depression is inversely associated with exercise,
participation in cardiac rehabilitation

Poor diet and obesity

Nonadherence to prescribed medications

Depression and Medication Adherence in

Outpatients With Coronary Heart Disease
Findings From the Heart and Soul Study
14% of depressed pts vs 9% of nondepressed pts
reported not taking their medications as
prescribed (OR 2.8, p<0.001)
Twice as many depressed pts as nondepressed
pts reported forgetting to take their medications
(OR2.4, p<0.001)
9% depressed pts and 4% nondepressed pts
reported deciding to skip their medications (OR
2.2 p=0.009)
Archives 2005;165:2508-2513

Course of Depressive Symptoms and

Medication Adherence After Acute Coronary
Syndromes
Depression was associated with medication
nonadherence in a gradient fashion.
15% of nondepressed pts, 29% of mildly
depressed pts, and 37% of mod-severely
depressed pts took ASA <80% of the time.
Change in depressive symptoms over the
study period were linearly related to changes
in adherence.
JACC 2006;48:2218-22

Beta-Blockers and Depression After

Myocardial Infarction
381 pts, 127 without BB and 254
matched pts with BB at discharge
after MI
There were no significant differences
in BDI at baseline, 3, 6, or 12 months
after MI.

JACC 2006;48:2209-14

 Does treatment of depression, then,

improve outcomes in patients with
CAD?

Sertraline Treatment of Major Depression in

Patients With Acute MI or Unstable Angina
SADHART
369 pts with MDD randomized to sertraline
(50-200mg/day) or placebo for 24 weeks
Pts were hospitalized with ACS in the past 30
days and met DSM-IV criteria for MDD.
The study involved 7 countries from 04/199704/2001.
Primary outcome was change from baseline
EF.
Secondary measures included cardiovascular
adverse events, HAM-D scores, CGI-I scores
JAMA 2002;288(6) 701-709

SADHART: Safety Outcomes

No difference between drug and placebo
in:
LVEF
Blood pressure
Resting ECG (HR, QRS, QT)
24-Hour Holter ECG
VPCs
HRV (time & frequency domain)

SADHART: Efficacy
All Randomized Patients
Sertraline
(n=186)
-8.4 (0.4)

Outcome
HAM-D, mean (SD)

Placebo
(n=183)
-7.6 (0.4)

p
.14

Severe Recurrent MDD Subgroup*

Outcome
HAM-D, mean (SD)

Sertraline
(n=50)
-12.3 (0.9)

HAM-D: Hamilton Rating Scale for Depression

* 2 prior episodes plus HAM-D score 18.

Placebo
(n=40)
-8.9 (1.0)

p
.01

SADHART
Sertraline had no significant effect on mean
LVEF, incidence of PVCs, or QTc interval.
The incidence of severe CV adverse events was
14.5% with sertraline and 22.4% with placebo.
CGI-I but not HAM-D favored sertraline.
In the groups with preexisting depression, both
CGI-I and HAM-D measures were significantly
better in those assigned to sertraline.

SADHART
Sertraline appears to be a safe medication
for use following ACS.
In patients with recurrent depression and
CAD, sertraline was efficacious in the
treatment of depression.

Effects of Treating Depression and Low

Perceived Social Support on Clinical
Events After Myocardial Infarction
ENRICHD
2481 MI patients at 8 centers enrolled from
10/1996 to 04/2001.
Pts had major or minor depression by DSM IV
criteria.
Randomized to usual medical care or CBT
based therapy with primary endpoints of
death or nonfatal MI.
JAMA 2003;289(23) 3106-3116.

ENRICHD: Intervention
Cognitive behavior therapy
Behavioral activation, cognitive restructuring, social
skills training, social network.
Up to 6 months of CBT with trained therapist

Sertraline added for severely depressed

patients and for those who did not respond
sufficiently to CBT within 6 weeks

ENRICHD: Overall Effects on

Depression and Social Support

ENRICHD Social Support Instrument (ESSI) scores reported for patients with low social
support only; Hamilton depression scores reported for depressed patients only.

The Efficacy of the ENRICHD

Intervention Depended on Initial
Severity of Depression
RL*=1.35
p<0.006
RL=1.80
p<0.0008

RL=2.58
p<0.0015

(N=346)

(N=313)

*Relative Likelihood of Remission

(N=200)

The ENRICHD Intervention Did Not

Improve Reinfarction-Free Survival

The ENRICHD Intervention Did

Improve Late Survival (>6 Months)

Late survival
depended on
whether depression
improved over the
course of the
intervention.

Carney et al., Psychosom Med 2004;66(4):466-474.

ENRICHD
Improvements in psychosocial outcomes
favored treatment at 6 months.
There was no difference in event-free
survival.
Of note, treatment with anti-depressants
was 4.8% to 20.6% in the usual care group
and 9.1% to 28% in the treatment arm.

Effects of Citalopram and Interpersonal

Psychotherapy on Depression in Patients
With Coronary Artery Disease
CREATE

284 patients with CAD and DSM-IV

criteria for MDD with HAM-D scores >20.
Pts randomized to (1) 12 weekly
sessions of interpersonal psychotherapy
plus clinical mgmt vs clinical mgmt only
and (2) 12 weeks citalopram or
matching placebo
JAMA 2007;297(4) 367-379

CREATE
Citalopram was superior to placebo in
reducing 12 week HAM-D scores (p=0.005)
No benefit was seen of IPT over clinical
mgmt (p=0.06)
Similar to the results of SADHART,
response to SSRI was more pronounced in
pts with a history of recurrent depression.

Impact of Cardiac Rehabilitation on

Depression and Its Associated
Mortality
522 patients enrolled in cardiac rehab and
a control group not enrolled evaluated
over 4 years

AJM 2007;120:799-806

Cardiac Rehab Improves

Depression
Effect of Cardiac Rehab on Depression in 552 patients
17%

20%

Before
After

15%

10%

6%
5%

0
Before

After

Milani RV, Am J Med 2007

Depression is Associated with Decreased

Survival
Actuarial cumulative hazard plot for survival time
based on depression status upon completion of cardiac rehabilitation
0.35
0.30

Depressed

0.25
0.20
0.15
0.10
0.05

Nondepressed

0
0

Time (Years)
Milani RV, Am J Med 2007

Psychological Distress is Common

Prevalence of Depression Before and After Cardiac Rehab
Before
30

After

23%
19%

20

10

6%

4%
0
Young

Elderly
Lavie CF, Arch Int Med, 2006

Evidence for Depression as

an Independent Risk factor
for CAD
GOOD
1. Strength of
Association
2. Prediction
3. Consistency
4. Dose-response Effect
FAIR
5. Specificity
6. Biological Plausibility
Wulsin, L.R; Harv Rev Psychiatry. March/April 2004

INSUFFICIENT EVIDENCE
7. Cardiac risk reduction in
response to
treatment for
depression.

Criteria for Major

Depression
One or the
Depressed mood
other required
Diminished interest or pleasure
5 or more of the following Sx present for > 2
weeks:
Fatigue or loss of energy
Diminished ability to concentrate
Insomnia or hypersomnia
Weight loss or weight gain
Feelings of worthlessness or excessive
guilt
Psychomotor agitation or retardation
Recurrent thoughts of death or suicidal
ideation or attempt

When to suspect depression in

cardiac pts
Symptoms: chronic tiredness, wt loss,
insomnia, recent onset of irritability or
anger
Impairment: reduced social contact,
poor ADLs, reduced interest, difficulty
coping with recent losses and stresses
Medical Management Problems:
chronic anxiety, poor medication
compliance or risk factor modification

What are the

treatment
recommendations
regarding depression
in patients with CHD?

Tools for Assessment of

Depression in Clinical
Practice
Patient Health Questionnaire
(PHQ-9) and (PHQ-2)
Beck Depression Inventory
(Self-report)
Zung Self-rating Depression
Scale (self report)
Center for Epidemiologic
Studies-Depression (self
report)
Hamilton Depression Scale
(Administered)

Depression and Coronary Heart

Disease
Recommendations for Screening,
Referral, and Treatment: A Science
Advisory From the American Heart
Association
Lichtman JH, Bigger JT, Blumenthal JA,
Frasure-Smith N, Kaufmann PG,
Lesprance F, Mark DB, Sheps DS,
Taylor CB, Froelicher ES.
Circulation 2008;118;1768-1775

AHA Recommendations
Routine screening for depression in
patients with CHD in various settings,
including the hospital, physicians office,
clinic, and cardiac rehabilitation center.
The opportunity to screen for and treat
depression in cardiac patients should
not be missed, as effective depression
treatment may improve health
outcomes.
Lichtman et al., Circulation 2008;118;1768-1775

Patient Health Questionnaire

(PHQ-2)
Over the past 2 weeks, how often have you been bothered
by any of the following problems?
(1) Little interest or pleasure in doing things.
(2) Feeling down, depressed, or hopeless.
Positive screen = yes to either question.

Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression
severity measure. J Gen Intern Med. 2001;16:606613.

Patient Health Questionnaire

(PHQ-9)
Over the past 2 weeks, how often have you been bothered by any of the
following problems?
(1) Little interest or pleasure in doing things.
(2) Feeling down, depressed, or hopeless.
(3) Trouble falling asleep, staying asleep, or sleeping too much.
(4) Feeling tired or having little energy.
(5) Poor appetite or overeating.
(6) Feeling bad about yourself, feeling that you are a failure, or feeling
that you have let yourself or your family down.
(7) Trouble concentrating on things such as reading the newspaper or
watching television.
(8) Moving or speaking so slowly that other people could have noticed.
Or being so fidgety or restless that you have been moving around a
lot more than usual.
(9) Thinking that you would be better off dead or that you want to hurt
yourself in some way.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression
severity measure. J Gen Intern Med. 2001;16:606613.

AHA Recommendations
Patients with positive screens should be
evaluated by a professional qualified in
the diagnosis and management of
depression.
Patients with cardiac disease who are
under treatment for depression should
be carefully monitored for adherence to
their medical care, drug efficacy, and
safety with respect to their
cardiovascular as well as mental health.
Lichtman et al., Circulation 2008;118;1768-1775

AHA Recommendations
Monitoring mental health may
include, but is not limited to, the
assessment of patients receiving
antidepressants for possible
worsening of depression or
suicidality, especially during initial
treatment when doses may be
adjusted, changed, or discontinued.

Lichtman et al., Circulation 2008;118;1768-1775

AHA Screening Guideline

Meta-Analysis of the
Adverse Effect of
Depression on Patient
Adherence
Compared to
nondepressed
patients, the odds are
3 times greater that
depressed patients
would be
nonadherent with
medical treatment
recommendations
DiMatteo MR, et al. Arch Intern Med. 2000;160(14):2101-2107.

Depression Is Associated
With % Smoking
p<0.001; Major>None
p<0.01; Minor>None
N=4225

Adjusted for demographics, medical comorbidity, diabetes severity,diabetes type and duration, treatment type,
HbA1c and clinic.
Katon et al, Diabetes Care, 2004

Summary
MDD occurs in 15-23% of patients with coronary
disease and is an independent RF for morbidity and
mortality.
RCTs in the 1990s and 2000s show RR of MI and CV
mortality of 1.5-2 in pts with preexisting depression.
In persons with established IHD, depression is
associated with a 3-4 fold increase in the risk of
subsequent CV morbidity and mortality.
Treatment of depression in patients with CAD is safe
and somewhat efficacious
Rehabilitation is associated with a 50% decrease in
depressive symptoms in pts with CHD

Bi-Directional Conclusions
PSYCHIATRY
Depression is associated
with an increase in cardiac
risk
Recurrent depression
worsens cardiac outcomes
CBT improves mood but
does not improve
cardiovascular outcomes in
depressed cardiac patients
SSRIs improves mood and
appears safe in the cardiac
patient

CARDIOLOGY/PRIMARY CARE
20% of patients post MI
will have symptoms of
depression
Understand the potential
mechanisms of how
depression may increase
the risk for CHD events
Treatment of depression
leads to better clinical
outcomes after a cardiac
event

MDD is an independent predictor of

all cause mortality and CV death after
AMI complicated by heart failure
Wulsin, L.R; Harv Rev Psychiatry. March/April 2004

Insanity:
Doing the same thing
over and over again
and expecting different
results.
Albert Einstein