Depression and Cardiovascular Disease
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.
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
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
18
16
% Mortality
14
Depressed (n=35)
12
10
8
6
Nondepressed (n=187)
4
2
0
0
1
2
3
4
Months Post-MI
5
6
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
70%
% Cardiac Mortality
60%
50%
40%
30%
n =56
20%
n =16
n = 112
10%
0%
PVCs ≥ 10/hour
PVCs < 10/hour
BDI < 10
BDI ≥ 10
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 longterm 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.
Mild
Moderate/Severe
Relative Risk
21
1.5
0.5
10
0.5
-0.5
1
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 SF12 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 time-dependent 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.
5
Men
Relative Risk of Fatal Event
4.5
Women
4
3.5
3
2.5
2
1.5
1
0.5
0
0
5
10
15
CES-D Score
20
25
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
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 TNFalfa 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, βTG,
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
A
40
Change in HRV, %
30
20
n=416
n=11
B
10
n=125
0
n=12
n=133
n=15
-10
-20
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.
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
Depressed (n=204)
Not Depressed (n=736)
20
Percentage of Participants
18
16
14
12
10
8
6
4
2
0
Not as Prescribed
(P <.001)
Forgot to Take
(P <.001)
Reason for Nonadherence
Decided to Skip
(P <.01)
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 (50200mg/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
Outcome
HAM-D, mean (SD)
Sertraline
(n=186)
Placebo
(n=183)
p
-8.4 (0.4)
-7.6 (0.4)
.14
Severe Recurrent MDD Subgroup*
Outcome
HAM-D, mean (SD)
Sertraline
(n=50)
Placebo
(n=40)
p
-12.3 (0.9)
-8.9 (1.0)
.01
HAM-D: Hamilton Rating Scale for Depression
* 2 prior episodes plus HAM-D score 18.
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
10
5.1
5
3.4
0
Intervention
Usual care
-5
-10
-8.4
-10.1
-15
ESSI score
Hamilton depression
score
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
% Remission of Depression
80
70
60
RL*=1.35
Usual Care
Intervention
p<0.006
RL=1.80
50
p<0.0008
40
RL=2.58
p<0.0015
30
20
10
0
BDI 10-15
BDI 16-23
BDI 24+
(N=346)
(N=313)
(N=200)
*Relative Likelihood of Remission
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
Prevalence
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
Cumulative Hazard
0.35
0.30
Depressed
0.25
0.20
0.15
0.10
0.05
Nondepressed
0
0
1
2
3
Time (Years)
Milani RV, Am J Med 2007
4
5
Psychological Distress is Common
Prevalence of Depression Before and After Cardiac Rehab
Before
30
After
Prevalence (%)
23%
19%
20
10
6%
4%
0
Young
Elderly
Lavie CF, Arch Int Med, 2006
What are the treatment recommendations
regarding depression in patients with
CHD?
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, Lespérance
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, physician’s 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;16:606–613.
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;16:606–613.
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
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
Depression & Anxiety, 2006
http://www.ca.uky.edu/hes/?p=6
Mental Health Shortage Area, 2000
http://www.ca.uky.edu/hes/?p=6
Primary Care Shortage Area, 2000
http://www.ca.uky.edu/hes/?p=6
Population Uninsured, 2000
http://www.ca.uky.edu/hes/?p=6
Psychological Distress is Common
Prevalence of Hostility Before and After Cardiac Rehab
Before
30
Prevalence (%)
After
20
13%
6%
10
5%
2%
0
Young
Elderly
Lavie CF, Arch Int Med, 2006
Psychosocial influences on mortality after
myocardial infarction
W Ruberman, et al
2320 men from the Beta blocker heart attack trial
With other important prognostic factors controlled for, the
patients classified as being socially isolated and having a
high degree of life stress had more than four times the
risk of death of the men with low levels of stress and
isolation.
An inverse association of education with mortality in this
population was noted.
NEJM 1984; 311:552-559
588 pts evaluated for the time prior to MI and at 12
months with HADS and followed for 8 years.
Multivariate predictors of death included age, previous
MI, Killip class, medications prescribed on dc.
Depression was not associated with cardiac mortality
whether detected imediately before MI (p=0.48), 12
months after (p=0.27), or at both times (p=0.97).
Mean systolic blood pressure (mmHg) in men
over a working day according to overcommitment
and occupational position (N=105)
140
overcommitment +,
occup. position -
mmHg
135
overcommitment +,
occup. position +
130
125
overcommitment -,
occup. position +
120
ng
i
n
or
m
n
n
o
o
rn
e
t
af
n
o
o
ng
i
en
v
e
overcommitment -,
occup. position -
Source: A. Steptoe et al. (2004), Psychosomatic Medicine, 66: 323-329.
The Nature and Course of Depression Following
Myocardial Infarction
282 post MI patients interviewed in hospital and at 3-4 months
3-4 months after infarction, 33% of patients met criteria
for depression. The large majority of patients who initially
met criteria for major but not minor depression showed
evidence of depression at 3 months and most patients
with major depression had not returned to work by 3
months.
Treatment of major depressive syndromes after
myocardial infarction may reduce chronicity and
disability, while minor depressive syndromes may be
similar to normal grief and tend to be self-limited.
Arch Intern Med. 1989;149(8):17851789.
• Elevated values were observed in patients
with co-morbid panic disorder (P = 0.006).
• Consistent with a defect in noradrenaline
reuptake, the cardiac extraction of tritiated
noradrenaline (0.80 +/- 0.01 versus 0.56 +/0.04%, P < 0.001) and cardiac
dihydroxyphenylglycol overflow (109 +/- 8
versus 73 +/- 11, P = 0.01) were reduced in
patients with MDD.
Barton et al. J Hypertens. 2007
Oct;25(10):2117-2124.