Coronary Heart Disease & Depression:

The Bi-Directional Relationship

Coronary Heart Disease & Depression:

The Bi-Directional Relationship

Madeleine Lloyd MS, RN, FNP, MHNPMadeleine Lloyd MS, RN, FNP, MHNP

Ana Mola MA, RN, ANPAna Mola MA, RN, ANP

Global Burden of DiseaseGlobal 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

CDC Data 1979-2002

400

420

440

460

480

500

520

'80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02

Dea

ths

in T

ho

usa

nd

s

WomenMen

CVD Mortality in US Women Is Not Declining

CVD Mortality in US Women Is Not Declining

AHA. Heart Disease and Stroke Statistics–2005 Update. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

NCEP ATP II NCEP ATP IIINCEP ATP I

434,000

494,000

Global Burden of DiseaseGlobal Burden of Disease

WHO 2002 MEN WOMEN

Hypothalamic-Pituitary-Adrenal (HPA) axis in depression

Hypothalamic-Pituitary-Adrenal (HPA) axis in depression

Endothelium-Teflon ResistantEndothelium-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.

LDL-small dense particlesLDL-small dense particles

LDLLDL

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

EndotheliumEndothelium

Vessel Lumen-Teflon ResistentVessel Lumen-Teflon ResistentMonocyteMonocyte

oxidized LDLoxidized LDL

Macrophages Macrophages engulf LDLengulf LDL

Adhesion Modules-Adhesion Modules-increase monocytes increase monocytes

adherenceadherence

CytokinesCytokines

Atherosclerosis is an Inflammatory DiseaseLDL pro-inflammatory & HDL anti-inflammatory

Foam Cell-increase Foam Cell-increase ANGIOTENSIN II, ANGIOTENSIN II,

PAI, -pro-PAI, -pro-thrombotic state & thrombotic state &

decrease NOdecrease NOHDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux

HDL InhibitHDL InhibitOxidationOxidation

of LDLof LDL

Libby, P. et al. Circulation 2005;111:3481-3488

Plaque Morphology and Ischemic Impact

Pathophysiology in MotionPathophysiology in Motion

Bi-Directional Biological Mechanisms

Bi-Directional Biological Mechanisms

Pro-arrhythmic mechanisms-low HRV is a strong predictor of SCD after MI strongly exists in depressed patients then non-depressed patients with CAD

Plasma catecholamines provoke arrhythmias, myocardial ischemia and SCD are elevated in depressed patients

Depression is associated with serotonin platelet activation and cytokines that may increase the risk of developing CAD or, in patients with established CAD, of myocardial infarction.

Grippo, A. Neuroscience and Beh Reviews 2002 26: 941-962Grippo, A. Neuroscience and Beh Reviews 2002 26: 941-962

Depression and the HeartDepression and the Heart

Recognized in language Recognized in language and literatureand literatureBut scientific evidence But scientific evidence lacking!lacking!First credible studies by First credible studies by Meyer Friedman & Ray Meyer Friedman & Ray Rosenman following Rosenman following WWIIWWIIHowever, by mid-1970’s However, by mid-1970’s type A’s effect vanishedtype A’s effect vanished

Stirling County StudyCardiovascular Deaths Stirling County Study

Cardiovascular Deaths

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Major Depression No major depression

P = 0.03

Mo

rtal

ity

Rat

e

Murphy 1987

1000 Community residents followed 16 yrs

0

5

10

15

20

25

30

0 1 2 3 4 5 6Months After Heart Attack

Mor

talit

y (%

)

183

Frasure-Smith N et al. JAMA. 1993;270:1819-1825.

Depressed (n = 35)Nondepressed (n = 187)

Depression Associated With Increased Mortality Post-Myocardial Infarction

80

85

90

95

100

0 100 200 300 400

Time After Discharge for MI (Days)

Su

rviv

al F

ree

of C

ard

iac

Mo

rta

lity,

Cu

mu

lativ

e (

%)

Not Depressed (BDI < 10)

Depressed (BDI ≥ 10)

Frasure-Smith N et al. Psychosom Med. 1999;61:18-20.

Depression and 1-Year Post-Myocardial Infarction (MI) Cardiac Mortality

Depression and 1-Year Post-Myocardial Infarction (MI) Cardiac Mortality

N = 896

Odds Ratio = 3.4 (1.8-6.7)

P < .001

60

70

80

90

100

100 365 730 1095 1460 1825

Time After Discharge for MI (Days)

Su

rviv

al F

ree

of C

ard

iac

Mo

rta

lity,

Cu

mu

lativ

e (

%)

BDI < 5

BDI 5-9

BDI 10-18

BDI ≥ 19

Lespérance,2000.

N = 896

Long-Term Survival Impact of Increasing Levels of Post-MI Depression

Long-Term Survival Impact of Increasing Levels of Post-MI Depression

N = 896

Lower Social Support Depression

14600 365 730 1095

100%

90%

80%14600 365 730 1095

100%

90%

80%

Time After Discharge for MI (Days) Time After Discharge for MI (Days)

Sur

viva

l Fre

e of

Car

dia

c M

orta

lity,

Cu

mul

ativ

e (%

)

Anxiety Anger

14600 365 730 1095

100%

90%

80%14600 365 730 1095

100%

90%

80%

Sur

viva

l Fre

e of

Car

dia

c M

orta

lity,

Cu

mul

ativ

e (%

)

Time After Discharge for MI (Days) Time After Discharge for MI (Days)

The Prognostic Impact of Depression The Prognostic Impact of Depression

N = 896

N = 896 N = 896

BDI < 10Depressed BDI>10

SADHART: Objectives

PrimaryPrimary To evaluate the safety and To evaluate the safety and

efficacy of Sertraline as a efficacy of Sertraline as a treatment of depression in treatment of depression in patients with AMI or patients with AMI or unstable anginaunstable angina

SecondarySecondary Antidepressant response in Antidepressant response in

“more severe” subset of “more severe” subset of patients (baseline HAM-D patients (baseline HAM-D > 18, 2 prior episodes of > 18, 2 prior episodes of major depression) major depression)

Improvement in quality of Improvement in quality of life and functional status life and functional status with Sertralinewith Sertraline

Efficacy in Post-MI Depression:Week-24 Responder Rates for

Sertraline vs Placebo

78%72%

59%

45%51

55%

0

20

40

60

80

100

No Prior Episode Any RecurrentDepression

2 Prior Episodes andHAM-D ≥ 18

Res

pon

der

Rat

es (

%)

SertralinePlacebo

90 93 96

P ≤ .058

90

P ≤ .003

50

P ≤ .001

40

.

ENRICHD TRIAL ENRICHD TRIAL 2481 MI patients (33,780 screened)2481 MI patients (33,780 screened) 1084 Women 1397 Men 8 centers1084 Women 1397 Men 8 centers

Objective Effect of CBT vs. treatment as usual on all-cause mortality and

nonfatal reinfarction in pt with an AMI and/or low perceived social support

Results Antidepressant drug use was associated with a lower risk of

death and non-fatal MI (H.R. 0.67) Improvement in psychosocial risk factors with intervention but

no improvement in medical outcome (death, reinfarction) Difference between the two groups were modest and small

Berkman, L.F., et al. JAMA 2003 289 (23):3171-3Berkman, L.F., et al. JAMA 2003 289 (23):3171-3

ENRICHD-sub studies:Impact of PE on MDD and LSS

ENRICHD-sub studies:Impact of PE on MDD and LSS

982 pt (47%) reported they exercise regularly 6 months 982 pt (47%) reported they exercise regularly 6 months after AMIafter AMI

Pt who did not exercise tended to be less well educated Pt who did not exercise tended to be less well educated and lower household income and more severe CADand lower household income and more severe CAD

Exercise was associated with lower levels of depression, Exercise was associated with lower levels of depression, reduced depressive symptoms and increased survivalreduced depressive symptoms and increased survival

Despite failure of CBT to reduced mortality risk in this Despite failure of CBT to reduced mortality risk in this population, exercise maybe a valuable additionpopulation, exercise maybe a valuable addition

Blumenthal: 2004 Am. College of Sports medicine36:746-755

Myocardial Infarction and Depression-Intervention Trial (MIND-IT)

Myocardial Infarction and Depression-Intervention Trial (MIND-IT)

Mirtazapine/Placebo for BDI > 10 (n=190) or care as usual (n=130)

Citalopram as an alternative if nonresponsive after 8wks or refusal

CAU pt not aware of research Dx 27months with primary end point of new events and

secondary end point of cardiac function 1 yr after MI, the course of post MI MDD and quality of life

No treatment for first 3 months after AMI to allow for natural recovery of a transient reactive MDD

MIND IT: Sub-studiesMIND IT: Sub-studies

Explored the relationship between LV function and depression in the first year post MI

1989 pts monitored LVEF Strong associated between lower

LVEF and higher depression rates MI pts younger than 60yr had a 2

fold increased risk for developing MDD

2 strong predictors of post MI depression are young age and low LEVF

CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and

Psychotherapy Efficacy)

CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and

Psychotherapy Efficacy) IPT and Citalopram alone or in

combination in the treatment of MDD in 280 stable CAD pts.

12 weeks of Tx is more effective in reducing MDD symptoms in CAD pts.

Tolerability and safety of each treatment in comparison to control.

RESULTS THIS SUMMER

Frassure-Smith, Psychosomatic Medicine 68:87-93 (2006)

Evidence for Depression as an Independent Risk factor for CAD

Evidence for Depression as an Independent Risk factor for CAD

GOODGOOD

1.1. Strength of AssociationStrength of Association

2.2. PredictionPrediction

3.3. ConsistencyConsistency

4.4. Dose-response Effect Dose-response Effect

FAIRFAIR

5.5. SpecificitySpecificity

6.6. Biological PlausibilityBiological Plausibility

INSUFFICIENT EVIDENCEINSUFFICIENT EVIDENCE

7.7. Cardiac risk reduction in Cardiac risk reduction in response to treatmentresponse to treatment for for depression.depression.

Wulsin, L.R; Harv Rev Psychiatry. March/April 2004Wulsin, L.R; Harv Rev Psychiatry. March/April 2004

Criteria for Major DepressionCriteria for Major Depression

Depressed moodDepressed mood Diminished interest or pleasureDiminished interest or pleasure

5 or more of the following Sx present for > 2 weeks:5 or more of the following Sx present for > 2 weeks: Fatigue or loss of energyFatigue or loss of energy Diminished ability to concentrateDiminished ability to concentrate Insomnia or hypersomniaInsomnia or hypersomnia Weight loss or weight gainWeight loss or weight gain Feelings of worthlessness or excessive guiltFeelings of worthlessness or excessive guilt Psychomotor agitation or retardationPsychomotor agitation or retardation Recurrent thoughts of death or suicidal ideation Recurrent thoughts of death or suicidal ideation

or attemptor attempt

One or the other required

When to suspect depression in cardiac ptsWhen to suspect depression in cardiac pts

Symptoms:Symptoms: chronic tiredness, wt loss, chronic tiredness, wt loss, insomnia, recent onset of irritability or angerinsomnia, recent onset of irritability or anger

Impairment:Impairment: reduced social contact, poor reduced social contact, poor ADLs, reduced interest, difficulty coping with ADLs, reduced interest, difficulty coping with recent losses and stressesrecent losses and stresses

Medical Management Problems: Medical Management Problems: chronic chronic anxiety, poor medication compliance or risk anxiety, poor medication compliance or risk factor modificationfactor modification

Tools for Assessment of Depression in Clinical Practice

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)

Meta-Analysis of the Adverse Effect of Depression on Patient

Adherence

Meta-Analysis of the Adverse Effect of Depression on Patient

Adherence

Compared to Compared to nondepressed patients, nondepressed patients, the odds are 3 times the odds are 3 times greater that depressed greater that depressed patients would be patients would be nonadherent with medical nonadherent with medical treatment treatment recommendationsrecommendations

DiMatteo MR, et al. Arch Intern Med. 2000;160(14):2101-2107.

Depression Is AssociatedWith ↑% Smoking

Depression Is AssociatedWith ↑% Smoking

0

5

10

15

20

None Minor Major

Depression Group

% S

mok

ing

p<0.001; Major>Nonep<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

Bi-Directional ConclusionsBi-Directional Conclusions

PSYCHIATRYPSYCHIATRY

Depression is associated with Depression is associated with an increase in cardiac riskan increase in cardiac risk

Recurrent depression worsens Recurrent depression worsens cardiac outcomescardiac outcomes

CBT improves mood but does CBT improves mood but does not improve cardiovascular not improve cardiovascular outcomes in depressed outcomes in depressed cardiac patientscardiac patients

SSRIs improves mood and SSRIs improves mood and appears safe in the cardiac appears safe in the cardiac patientpatient

CARDIOLOGY/PRIMARY CARDIOLOGY/PRIMARY CARECARE

20% of patients post MI 20% of patients post MI will have symptoms of will have symptoms of depression depression

Understand the potential Understand the potential mechanisms of how mechanisms of how depression may increase depression may increase the risk for CHD eventsthe risk for CHD events

Treatment of depression Treatment of depression leads to better clinical leads to better clinical outcomes after a cardiac outcomes after a cardiac eventevent

Wulsin, L.R; Harv Rev Psychiatry. March/April 2004Wulsin, L.R; Harv Rev Psychiatry. March/April 2004

MDD is an independent predictor of all cause mortality and CV death after AMI complicated by heart failure

““Insanity: Insanity:

Doing the same thingDoing the same thing over and over again over and over again

and expecting different resultsand expecting different results.”.”

Albert Einstein