Depression and Heart Disease: Recent Developments

1
Depression and Heart DiseaseRecent Developments

• Kenneth E. Freedland, PhD
• Professor of Psychiatry
• Washington University School of Medicine
• St. Louis, Missouri
• Montana Cardiovascular Health Summit
• Missoula, Montana
• April 4, 2009

2
Disclosure

• The speaker has no relevant financial interests
  to disclose.
• The speakers research is funded by the National
  Institutes of Health.

3
Overview

• Screening for depression
• Effects of depression on heart disease
• The mechanistic puzzle and the search for
  high-risk subgroups
• Treatment trials
• Translating research into clinical practice

4
Screening for Depressionin Patients with Heart
Disease

• Steadily growing evidence over the past 25 years
  that
• Depression is a common comorbidity in patients
  with heart disease.
• It has a variety of harmful effects, including
  increased risk of morbidity and mortality.
• Yet most cardiologists have ignored this
  important risk factor, at least until recently.

5
New Guidelines

• In September 2008, the American Heart Association
  published a Science Advisory
• Depression and Coronary Heart Disease
  Recommendations for Screening, Referral, and
  Treatment
• The guidelines were also endorsed by the American
  Psychiatric Association.

6
New Guidelines

• Other medical societies in the U.S. and overseas
  have recognized the importance of depression in
  various patient groups, including those with
  heart disease.
• The new AHA guidelines represent the first time
  that this problem has been officially
  acknowledged by cardiologists in the United
  States.

7
New Guidelines

• Shortly after the guidelines were published in
  Circulation, two articles appeared in JAMA that
  challenge the authors recommendations.
• What do the guidelines recommend?
• What do the critiques claim?
• Where do they leave us?

8
Depression and Coronary Heart DiseaseRecommendati
ons 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 20081181768-1775

9
Patient Health Questionnaire

• Brief screen for depression.
• Widely used in research clinical practice.
• DSM-IV criteria for major or minor dep.
• Severity score.
• Public domain.

Kroenke K, Spitzer RL, Williams JB. The PHQ-9
validity of a brief depression severity measure.
J Gen Intern Med. 200116606613.
10
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. 200116606613.
11
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. 200116606613.
12
AHA Screening Guideline
13
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 20081181768-1775
14
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 20081181768-1775
15
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.
• (Be alert for hypomania too its relatively
  rare but very important to address.)

Lichtman et al., Circulation 20081181768-1775
16
AHA Recommendations

• Monitoring cardiovascular health may include, but
  is not limited to, more frequent office visits,
  ECGs, or assessment of blood levels of meds,
  based on the needs and circumstances of the
  patient.
• Coordination of care between healthcare providers
  is essential for patients with combined medical
  and mental health diagnoses.

Lichtman et al., Circulation 20081181768-1775
17
AHA Guidelines Challenge 1

• Tricoci P, Allen JM, Kramer JM, Califf RM, Smith
  SC. Scientific evidence underlying the ACC/AHA
  clinical practice guidelines. JAMA
  2009301(8)831-841.

18
AHA Guidelines Challenge 1

• The ACC/AHA practice guidelines are important
  documents for guiding cardiology practice and
  establishing benchmarks for quality of care.
• Purpose of review To describe the evolution of
  recommendations in ACC/AHA cardiovascular
  guidelines and the distribution of
  recommendations across classes of recommendations
  and levels of evidence.

Tricoci, P, et al. JAMA 2009301(8)831-841.
19
AHA Guidelines Challenge 1

• Procedure Data from all ACC/AHA practice
  guidelines issued from 1984 to September 2008
  were abstracted by personnel in the ACC Science
  and Quality Division.
• 53 guidelines on 22 topics, including a total of
  7196 recommendations, were abstracted.
• The distribution of classes of recommendation (I,
  II, and III) and levels of evidence (A, B, and C)
  were determined.

Tricoci, P, et al. JAMA 2009301(8)831-841.
20
AHA Guidelines Challenge 1

• Recommendation classes
• Class I conditions for which there is evidence
  and/or general agreement that a given procedure
  or treatment is useful and effective
• Class II conditions for which there is
  conflicting evidence and/or a divergence of
  opinion about the usefulness/ efficacy of a
  procedure or treatment
• Class IIa weight of evidence/opinion is in favor
  of usefulness/efficacy
• Class IIb usefulness/efficacy is less well
  established by evidence/opinion
• Class III conditions for which there is evidence
  and/or general agreement that the
  procedure/treatment is not useful/effective and
  in some cases may be harmful.

Tricoci, P, et al. JAMA 2009301(8)831-841.
21
AHA Guidelines Challenge 1

• Levels of evidence
• Level A recommendation based on evidence from
  multiple randomized trials or meta-analyses
• Level B recommendation based on evidence from a
  single randomized trial or nonrandomized studies
• Level C recommendation based on expert opinion,
  case studies, or standards of care.

Tricoci, P, et al. JAMA 2009301(8)831-841.
22
AHA Guidelines Challenge 1

• Findings
• Among guidelines with at least one revision or
  update by September 2008, the number of
  recommendations increased from 1330 to 1973 (48)
  from the first to the current version.
• The largest increase was observed in the use of
  class II recommendations.

Tricoci, P, et al. JAMA 2009301(8)831-841.
23
AHA Guidelines Challenge 1

• Findings
• Of the 16 current guidelines reporting levels of
  evidence, only 314 recommendations out of 2711
  (median, 11) are level of evidence A.
• 1246 (median, 48) are level of evidence C.
• Level of evidence significantly varies across
  categories of guidelines (disease, intervention,
  or diagnostic) and across individual guidelines.

Tricoci, P, et al. JAMA 2009301(8)831-841.
24
AHA Guidelines Challenge 1

• Findings
• Recommendations with level of evidence A are
  mostly concentrated in class I.
• But only 245 of 1305 (median, 19) class I
  recommendations have level of evidence A.

Tricoci, P, et al. JAMA 2009301(8)831-841.
25
AHA Guidelines Challenge 1

• Conclusions
• Recommendations issued in current ACC/AHA
  clinical practice guidelines are mostly developed
  from lower levels of evidence or expert opinion.
• The proportion of recommendations for which there
  is no conclusive evidence is growing.
• Need to improve the process of writing guidelines
  and expand the evidence base from which clinical
  practice guidelines are derived.

Tricoci, P, et al. JAMA 2009301(8)831-841.
26
AHA Guidelines Challenge 2

• Thombs BD, de Jonge P, Coyne JC, et al.
  Depression screening and patient outcomes in
  cardiovascular care a systematic review. JAMA
  2008300(18)2161-2171.

27
AHA Guidelines Challenge 2

• Purpose of review To evaluate the potential
  benefits of depression screening in patients with
  cardiovascular disease by assessing
• the accuracy of depression screening instruments
• the effect of depression treatment on depression
  and cardiac outcomes
• the effect of screening on depression and cardiac
  outcomes in patients in cardiovascular care
  settings.

Thombs et al., JAMA 2008300(18)2161-2171
28
AHA Guidelines Challenge 2

• Data sources
• MEDLINE, PsycINFO, CINAHL, EMBASE, ISI, SCOPUS,
  Cochrane databases from inception to May 1, 2008
• Manual journal searches
• Reference lists
• Reviews
• Citation tracking of included articles

Thombs et al., JAMA 2008300(18)2161-2171
29
AHA Guidelines Challenge 2

• Study Selection Articles in any language about
  patients in cardiovascular care settings that
• compared a screening instrument to a valid major
  depressive disorder criterion standard
• compared depression treatment with placebo or
  usual care in a randomized controlled trial or
• assessed the effect of screening on depression
  identification and treatment rates, depression,
  or cardiac outcomes.

Thombs et al., JAMA 2008300(18)2161-2171
30
AHA Guidelines Challenge 2

• Research Questions
• What is the accuracy of screening instruments for
  depression in cardiovascular care populations?
• Is treatment of depression in cardiovascular care
  patients effective in improving
• depression?
• cardiac outcomes?
• Is systematic screening for depression more
  effective than usual care in
• identifying patients with depression?
• facilitating treatment of depression?
• reducing depressive symptoms?
• improving cardiac outcomes?

Thombs et al., JAMA 2008300(18)2161-2171
31
AHA Guidelines Challenge 2

• Eligible Studies
• 11 studies about screening accuracy
• 6 depression treatment trials
• 0 studies of the effects of screening per se on
• depression or cardiovascular outcomes

Thombs et al., JAMA 2008300(18)2161-2171
32
AHA Guidelines Challenge 2

• Main Findings
• In studies that tested depression screening
  instruments using a priori defined cutoff scores
• sensitivity ranged from 39 to 100 (median, 84)
• specificity ranged from 58 to 94 (median, 79)
• Depression treatment with medication or cognitive
  behavior therapy yielded modest reductions in
  depressive symptoms (ES 0.20-0.38 r2 1-4).
• No evidence that treating depression improves
  cardiac morbidity or mortality.

Thombs et al., JAMA 2008300(18)2161-2171
33
AHA Guidelines Challenge 2

• Conclusions
• Depression treatment with medication or cognitive
  behavior therapy in patients with cardiovascular
  disease is associated with modest improvement in
  depressive symptoms but no improvement in cardiac
  outcomes.
• No clinical trials have assessed whether
  screening for depression improves depressive
  symptoms or cardiac outcomes in patients with
  cardiovascular disease.

Thombs et al., JAMA 2008300(18)2161-2171
34
Dilemma

• AHA/ACC clinical guidelines recommend routine
  screening and treatment of depression in patients
  with heart disease.
• But this is based on inadequate evidence.
• So, what should clinicians do?
• Stay tuned....

35
Its Time to Take a Step BackTo See the Bigger
Picture
36
Depression

• Affects over 120 million people worldwide.
• The leading cause of disability as measured by
  years lived with disability (YLDs)
• The 4th leading contributor to the global burden
  of disease as measured in disability-adjusted
  life years (DALYs) as of 2000.
• By 2020, it is projected to reach 2nd place of
  the ranking of DALYs calcuated for all ages and
  for both sexes second only to heart disease.
• Today, depression is already the 2nd cause of
  DALYs in the age category 15-44 years for both
  sexes combined.

Source World Health Organization
37
Major Depression

• Episodes can be brief or chronic.
• Relapses and recurrences are common.
• Severity ranges from mild to severe to psychotic
• Usually mild to moderate in patients with heart
  disease
• Often accompanied by anxiety
• Atypical subtype increased appetite, weight
  gain, hypersomnia, feelings of paralysis.

38
Key Risk Factors for Major Depression

• Family history heritability of liability .33
• Past history of major depressive episodes
• Female
• Major medical illness, especially if
• Chronic, debilitating, or painful
• Poor prognosis
• Patient is relatively young
• Exposure to multiple, stressful life events.
• Residual symptoms from prior episode(s)

39
Gene Environment Interaction in
DepressionSerotonin Transporter Gene
Polymorphism and Stress
Caspi et al. Science 2003301386-389.
40
Prevalence of Major Depression

• 16 of all US adults have had gt1 episode of major
  depression in their lifetime.
• In any given year, about 7 of all adults have a
  major depressive episode.
• 10 mild
• 39 moderate
• 38 severe
• 13 very severe

Kessler et al., JAMA 20032893095-3105.
41
Prevalence of Major Depression

• Prevalence is higher in medically ill than in
  healthy populations.
• About 15 of patients meet the criteria for MD
  during hospitalization for an acute coronary
  syndrome (ACS).
• Almost half are already depressed at the time of
  the ACS many have had prior episodes.
• About 10 of initially nondepressed patients will
  become depressed within a year after ACS.

42
Prevalence of Major Depression

• The prevalence of MD after coronary artery bypass
  graft (CABG) surgery is approximately 20.
• The overall prevalence in heart failure is about
  15, but it varies dramatically by age and
  functional status.

43
Freedland et al. Psychosom Med 200365119-28.
44
How Does Depression Affect Functional Status in
Cardiac Patients?

• Activity limitations due to symptoms such as
  sleep disturbance, fatigue, anhedonia, and social
  withdrawal.
• Heightened sensitivity to pain discomfort, and
  increased worry about symptoms.
• Discouragement, hopelessness, loss of
  self-confidence.
• The relationship between depression and
  functional impairment is reciprocal.

45
Cardiac Morbidity and Mortality

• Depression has been shown to predict cardiac
  morbidity and mortality
• In patients with stable CAD
• After acute coronary syndromes
• After revascularization, esp. CABG surgery
• In patients with heart failure
• In patients with arrhythmias

46
Depression and Five-Year Survival After ACS
Carney, Freedland, et al., Journal of Affective
Disorders (2008)109133138
47
Depression and All-Cause Mortality in
CHDMeta-Analysis
Adjusted RR1.6 (1.3-1.9) Based on 6362
events 146,538 patients 54 studies
Nicholson et al., European Heart Journal
20062727632774
48
Depression and Mortality in Heart
FailureMeta-Analysis
Adjusted RR2.10 (1.7-2.6)
Rutledge et al., J Am Coll Cardiol
2006481527-1537
49
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

50
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

51
Treatment

• Evidence that two SSRI antidepressants are safe
  and moderately efficacious for comorbid
  depression in patients with CHD
• Sertraline (Zoloft)
• Citalopram (Celexa)
• Cognitive behavior therapy (CBT) is also safe and
  moderately efficacious
• Alone or in combination with an SSRI

52
ENRICHD

• Enhancing Recovery
• in Coronary Heart Disease
• Multicenter, Randomized Clinical Trial
• Sponsored by
• National Heart, Blood, and Lung Institute

53
ENRICHD Study Design

• Randomized, parallel-group clinical trial to
  compare the efficacy of a psychosocial
  intervention vs. usual care
• 2,481 patients with major or minor depression
  and/or low social support
• Recruited within 1 month of acute MI
• Primary outcome paper Berkman et al., JAMA
  2003289(23)3106-16.

54
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

55
ENRICHD Overall Effects onDepression 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.
56
The Efficacy of the ENRICHD Intervention Depended
on Initial Severity of Depression
RL1.35 plt0.006
RL1.80 plt0.0008
RL2.58 plt0.0015
(N346)
(N313)
(N200)
Relative Likelihood of Remission
57
The ENRICHD Intervention Did NotImprove
Reinfarction-Free Survival
58
The ENRICHD Intervention Did Improve Late
Survival (gt6 Months)
Late survival depended on whether
depression improved over the course of
the intervention.
Carney et al., Psychosom Med 200466(4)466-474.
59
Sertraline Antidepressant Heart Attack Randomized
Trial (SADHART)

• 1st multicenter, placebo-controlled RCT of safety
  and efficacy of sertraline in patients
  hospitalized for an acute coronary syndrome.
• Glassman et al. JAMA 2002288701-709
• Carney Jaffe. JAMA 2002288750-751 (editorial)

60
SADHART Methods

• Randomized, double-blind, placebo-controlled
  trial conducted at 40 centers on 3 continents
• N369, enrolled within 30 days of MI or UA.
• Current major depressive episode.
• 2-week single-blind placebo run-in.
• Flexible dosages of 50 to 200 mg/d.
• 24-week treatment phase.

61
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)

62
SADHART Deaths CVD Hospitalizations
63
SADHART Efficacy
HAM-D Hamilton Rating Scale for Depression ?2
prior episodes plus HAM-D score ?18.
64
CREATE

• Canadian Cardiac Randomized Evaluation of
  Antidepressant and Psychotherapy Efficacy
• Multicenter, randomized, controlled, 12-week, 2X2
  factorial trial
• N284 with established CAD MD HAMD gt20
• Hypothesis 1
• Clinical Management Interpersonal Psychotherapy
  (IPT), vs.
• Clinical Management
• Hypothesis 2
• Citalopram 20 to 40 mg/d, vs.
• Placebo

65
CREATE Results

• Citalopram gt Placebo
• ?HAMD3.3 (95 CI, 0.80 to 5.85), p.005
• Response 53 vs 40, p.03
• Remission 36 vs 23, p.01
• More side effects on citalopram (dizziness,
  diarrhea, somnolence, sweating, palpitations,
  sexual difficulties)
• No difference in cardiovascular SAEs
• More non-CVD SAEs on citalopram, but mostly
  unrelated to drug
• Clinical Mgt gt Clinical Mgt IPT
• ?HAMD-2.26 (95 CI, -4.78 to 0.27), p.06

Lespérance et al., JAMA 2007297367-379
66
Washington UniversityPost-CABG Depression Trial

• 123 depressed patients enrolled between six weeks
  and one year after surgery
• 50 female
• 20 minority
• Mean age 6010 years
• 66 DSM-IV major depression at enrollment
• 34 minor

Freedland et al., Archives of General Psychiatry,
in press
67
Washington UniversityPost-CABG Depression Trial

• Cognitive Behavior Therapy (CBT)
• Efficacious for depression in medically well pts.
• Modestly effective for post-MI depression in the
  ENRICHD clinical trial.
• Supportive Stress Management (SSM)
• Reduces distress and improves HQOL after acute MI
  or CABG surgery.
• Promising results in previous trials (Murphy et
  al., 1995 Trzcieniecka-Green Steptoe, 1996).

Freedland et al., Archives of General Psychiatry,
in press
68
Washington UniversityPost-CABG Depression Trial
Freedland et al., manuscript submitted for
publication
69
University of PittsburghPost-CABG Depression
Trial

• Collaborative care model
• Primary outcome QOL
• Secondary outcome Depression
• Intervention was efficacious
• Manuscript under review (Rollman et al.)

70
Washington UniversityCBT for Depression in Heart
Failure

• 23 depressed patients enrolled
• 9 female, 5 racial minority
• age 5510 years,
• 15 with major and 8 with minor depression
• NYHA classes I (n2), II (n23), III (n12), IV
  (excluded)
• LVEF 42.6 15.6
• Randomly assigned to 6 months of individual CBT
  vs. usual care (UC)
• 8 UC and 11 CBT patients took non-study
  antidepressants during the trial.
• Analyses Mixed models, adjusted for
  antidepressant use

Freedland et al., submitted for publication
71
Washington UniversityCBT for Depression in Heart
Failure
Type III Tests of Fixed Effects Group .003
Time lt.0001 Group X Time .0009 Antidep .28
Type III Tests of Fixed Effects Group .04
Time lt.0001 Group X Time .02 Antidep .08
72
Washington UniversityCBT for Depression in Heart
Failure
Type III Tests of Fixed Effects Group .08
Time .0001 Group X Time .0003 Antidep .06
Type III Tests of Fixed Effects Group .26
Time .20 Group X Time .48 Antidep .47
73
Washington UniversityCBT for Depression in Heart
Failure
Type III Tests of Fixed Effects Group .11
Time .0004 Group X Time .003 Antidep .65
Type III Tests of Fixed Effects Group .40
Time .23 Group X Time .31 Antidep .70
74
Washington UniversityNew Heart Failure Trial

• 5-year RCT comparing cognitive behavior therapy
  (CBT) to supportive clinical mgt (SCM) for
  depression in patients with HF.
• All patients also receive a heart failure
  self-care intervention.
• In start-up phase.

75
Duke UniversityHeart Failure Trial

• SADHART-CHF (Jiang et al.)
• Sertraline vs. placebo for depression in patients
  with heart failure.
• Primary results reported at recent cardiology
  conference.
• Negative findings.
• Manuscript under review.

76
Treatment RecommendationsBased on Existing
Evidence

• Choose citalopram or sertraline as first-line
  treatment for major depression in patients with
  CAD, if the patient accepts and tolerates
  antidepressant therapy.
• Nonresponse and partial response rates are high
  follow up to assess need for switching,
  augmentation, referral.
• Cognitive behavior therapy (CBT), alone or
  combined with an antidepressant, is safe and
  efficacious for depression in cardiac patients.
• Results depend on therapists training, skill,
  and experience

77
Translating Research Into Clinical Practice

• Strong evidence that depression has adverse
  effects on the course outcome of coronary
  disease and heart failure.
• Growing evidence that certain treatments for
  depression can be safely used or adapted for
  patients with heart disease.
• However, existing treatments have only modest
  efficacy for depression.

78
Translating Research Into Clinical Practice

• Limited evidence that treatment of depression can
  improve cardiac outcomes
• No evidence that routine screening per se,
  without a systematic intervention plan or
  program, is beneficial.
• Not surprising true of almost any type of
  medical or psychiatric screening.

79
Translating Research Into Clinical Practice

• The strength of evidence supporting AHA
  depression recommendations for cardiac patients
  is no weaker than the evidence for many of their
  other recommendations.
• Major depression, especially if its relatively
  severe, is non-ignorable, whether or not the
  patient also has heart disease.

80
Translating Research Into Clinical Practice

• Depressed patients need treatment to decrease
  emotional distress, improve functioning, and
  improve quality of life
• Effective treatment may decrease the risk of
  adverse medical outcomes, but we should not
  expect or promise that it will.
• The decision to treat depends on the first point,
  not on the second.