COPES October 2006

Depression and Cardiovascular Disease

Funded by the National Heart Lung and Blood Institute

Karina Davidson, PhD

2007 PMBC Summer Institute, Pittsburgh, PA

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•I have no financial conflicts of interest to declare

•I am indebted to all my colleagues and students for their many contributions towards our work

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FacultyFaculty

Thomas Pickering, MD Co-Director

Joseph Schwartz, PhD,Richard Sloan, PhD, Associated Faculty

Lynn Clemow, PhD

William Gerin, PhD Director of Research

Karina Davidson, PhD Co-Director

Daichi Shimbo, MD

Gbenga Ogedegbe, MD

Matthew M. Burg, PhD

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Anda et al., 1993, Fatal CAD

Anda et al., 1993, Nonfatal CAD

Aromaa et al., 1994, men

Aromaa et al., 1994, women

Vogt et al., 1994

Barefoot and Schroll, 1996

Pratt et al., 1996

Wassertheil-Smoller et al., 1996

Schwartz et al., 1998

Sesso et al., 1998

Mendes de Leon et al., 1998, men

Mendes de Leon et al., 1998, women

Pennix et al., 1998

Whooley and Browner, 1998

Ford et al., 2000

Ariyo et al., 2000

Ferketich et al., 2000, men

Ferketich et al., 2000, women

Yamanaka et al., 2005

Marzari et al., 2005, men*

Rowan et al., 2005*

Wulsin et al., 2005, dichotomous score*

Wulsin et al., 2005, continuous score*

Depression and CHD Morbidity and Mortality

* Indicates Hazard Ratio. All others are ORs.

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0 1 2 3 4 5 6 7

Barefoot et al., 1983 (OR)

Shekelle et al., 1983 (OR)

McCraine et al., 1985 (OR)

Hearn et al., 1988 (OR)

Koskenvuo et al., 1988 (RR)

Maruta et al., 1993 (OR)

Barefoot et al., 1995 (RR)

Everson et al., 1997, Fatal CVD (RH)

Everson et al., 1997, Incident MI (RH)

Todaro et al., 2005 (OR)

Hostility and CHD Morbidity and Mortality

Page 6COPES October 2006

4-Year Cardiac Death-Free Survival in Relation to Negative Emotions During Admission in Post-MI Patients (n=896)

146010957303650

100%

90%

80%146010957303650

100%

90%

80%

146010957303650

100%

90%

80%146010957303650

100%

90%

80%

Anger Anxiety

Social Support DepressionFrasure-Smith & Lesperance, Arch Gen Psychiatry 2003;60:627-636

Depressed: BDI>10

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Gaps in KnowledgeGaps in Knowledge We don’t know why post-ACS patients are depressed/distressed

We don’t know the mechanisms by which depressive symptoms confer independent risk

We don’t know what kind of depression/distress intervention will be either efficacious or acceptable

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Aims of C PES

Project 1: To test the applicability of psychological proximal causes of depression to dysphoric, post-ACS patients

Long-Term Follow-up of Project 1: All-Cause Mortality and Cardiac Event ascertainment, Dysphoria rates

Project 2: To explore patient acceptability, safety, and efficacy of depression interventions

Project 3: To test potential behavioral and physiological mediators in depression - ACS relation

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Project 1 and 3

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5692 Patients Screened

560 Patients Enrolled

4039 Excluded 1612 non-ACS 1235 Logistic barriers 390 Medical Reasons 147 BDI score 5-9 166 Physician refusal 489 Patient refusal

492 Completed 3 Month Follow-Up

88%

68 No 3-month Follow-up 15 Deceased 30 Missed 3-month visit 21 Dropped out of study 2 Missing 3-month BDI

Consort Diagram

3 month follow-up N=560

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Gender, ethnic and racial distribution (N=560)

Non-depressed (BDI 0-4; N=299)

Depressed (BDI >10; N=261)

P

Age, mean (yrs) 63 59 .001

% Female 35.1 44.8 .01

% Hispanic or Latino 4.0 13.0 .001

% White 81.9 79.3

% Black 11.4 12.6

% Other 6.7 8.0 .72

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Depression at baseline

Depression at 1 month

Depression at 3 months

Adherence week 3-4

Adherence month 2-3

-.32*

.75** .80**

.57**Adherence week 1-2

-.30**

.41**

Figure 1

Cross-lagged ModelNote: Only significant standardized coefficients are displayed. Dashed paths were insignificant; *P < 0.05 ** P < 0.01

Adjusted Odds RatiosVariables: age, gender, race, ethnicity, employment, living alone, Charlson index, depressive status

0

18

0 1 2Odds Ratio

■ Remittent depressed

Quit smoking

Took meds

Cardiac rehab

Exercised

Modified diet

Overall

■ Persistent depressed

0

10

20

30

40

50

60

70

80

90

100

16.7

83.3

47.1

52.9

63.2

36.8

CRP-Levels 3 months after ACS

persistently depressed

remittent depressed

persistently non-depressed

% p

atie

nts

3mo CRP <= 3

3mo CRP > 3

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COGNITIVE: DAS Dysfunctional Attitudes Scale (24-items)

BEHAVIORAL:PES Pleasant Events Schedule for the Elderly

Frequency rating of 20 pleasant activities

INTERPERSONAL:Role Transition Occurrence of 6 major role transitions

during the past year

Dyadic Distress Dyadic Adjustment Scale

Depression Vulnerabilities Measures

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*We used pre-existing cut-offs or > 1SD above mean

Percent Patients with elevated vulnerability scores*

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Percentage of patients with 0, 1, or more elevated vulnerabilities

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Conclusions

Gradient relation between presence of vulnerability and depression severity

A significant proportion of depressed patients (25% of mildly depressed and 14% of moderately to severely depressed) had NO vulnerability

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46.951.6

1.5

0

10

20

30

40

50

60

Therapy Preference

Take Medications

Go to Counseling

Both Checked (notan option)

Would you rather take medication or get counseling?

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Would you rather take medication or get counseling?

50.6

46.9

1.2

40.4

59.6

00

10

20

30

40

50

60

Men Women

TakeMedicationsGo toCounselingBoth Checked

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40

6055

43

5450

0

10

20

30

40

50

60

70

80

90

100

BDI 0-4 BDI 10-16 BDI >16

TakeMedications

Go tocounseling

Would you rather take medication or get counseling?

Note: sometimes people check both options, thus total is > 100%

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Conclusions Thus Far:

Improvements in depression precede improvements in adherence, but not vice versa Persistently depressed report fewer protective behaviors, less medication

adherence, and lower CRP after 3 months There isn’t one type of psychosocial vulnerability that characterizes post-ACS

depression Many vulnerabilities are present (leading to different depression intervention

possibilities)

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A next trial needs to consider:

A run-in period to rule out those with remittent depression Patients have differing psychosocial reasons for their depressive

symptoms Medical patients are have strong preferences for, and against, both

psychotherapy and medication to treat their depressive symptoms

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Project 2--Phase I RCT

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Project 2

Aim: To explore patient acceptability, safety, and efficacy of a stepped care, patient preference Phase-II Randomized Controlled Trial (RCT)

Treatment: Problem-Solving Therapy or Antidepressant Medication or both Opened in May 2005 Recruitment thus far: N=327 Enrolled in RCT: N=84

(persistent depressed from baseline to 3 month)

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0

Design

3 mo: screening

3 mo: randomization to Stepped Care or Usual Care and pre-RCT assessment

RCT

1 mo phone call

5 mo: interim depression and safety assessment decision to “step-up”

7 mo: interim depression and safety assessment decision to “step-up”

9 mo: post-RCT assessment

21 mo: long-term FU assessment

Step-up?

Step-up?

Screening Phase

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Team

Depression Diagnosis (DISH) over phone

Blinded Interviewers

Blinded Interviewer trained in psychiatric

interviewing

ASSESSMENT Monitoring

DSMB

Data Management Core

Training Core

Clinical Psychologist / Licensed Clinical Social

Worker

Team Psychiatrist

Cardiologist,Primary Care Provider

CARE

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Primary Outcome: Patient Satisfaction

“Over the last 2 months, how would you rate the quality of care you have received for your distress from your medical specialist?”

“Over the last 2 months, how would you rate the overall quality of care you have received from your medical specialist?”

Answer options: Poor, fair, good, very good, excellent (no PC visits, DK, no visits for distress)

OUTCOME: % satisfied = % very good or excellent ratings

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Stepped Care

Choice of

Problem Solving:

– weekly sessions, frequency of visits can be increased or decreased as needed

Antidepressant

– Sertraline, Escitalopram, or buproprion or Mirtazapine (either history of no response to SSRI OR insufficient response to chosen SSRI in Step 1)

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Usual Cardiology Care

Usual cardiology care (UCC) is individually defined as the care a patient receives by their treating physician(s) after notification of depression status

We will document what depression treatments prescribed and received

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“Step-Up”

Patient Chooses Pharmacotherapy at 1st Step: If no or insufficient improvement is seen, augment with psychotherapy.

If patient declines psychotherapy, switch medication or augment dosage

Patient Chooses therapy at 1st StepIf no improvement is seen, augment with pharmacotherapy according to patient medication history

If patient declines medication, then increase intensity of psychotherapy

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Successful Treatment

PHQ-9 < 3 for 2 consecutive weeks.

If this occurs during PST, then the patient moves to a monitoring phase. This entails weekly phone contact for 2 weeks, then every 2 weeks for 4 weeks, then monthly. If PHQ-9 remains < 4, then this is maintained. If PHQ-9 score is > 4 during these phone contacts, treatment is reinitiated.

Patients on medication will continue until end of study and then be referred to continuous psychiatric care

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Random Allocation SequencePermuted block design (with block sizes of 4 and 6)

Stratification by center, sex, and ethnicity (Hispanic)

Expect 40% female, 22% minority

Staff calls Data coordinating center for assignment when eligible patient has consented

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Project 1 Longterm Follow-up

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Measures

Baseline (index ACS event): MDD status based on a structured clinical interview Beck Depression Inventory-I (BDI) Grace risk score Charlson comorbidity index Demographics

Outcome: All-cause mortality during the 18 months following

hospitalization for ACS

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Cox Prop Haz Regression Analysis*

rh (95% CI) p

Major Depression Dx minor dep major dep

1.23 (0.27-5.54)5.39 (1.79-16.2)

.79 .003

* Controlling for sex, race, ethnicity, Grace score & Charlson index

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Cox Prop Haz Regression Analyses*

rh (95% CI) p

Major Depression Dx minor dep major dep

1.23 (0.27-5.54)5.39 (1.79-16.2)

.79 .003

BDI (per 10 points) 2.15 (1.38-3.33) .0007

* Controlling for sex, race, ethnicity, Grace Score & Charlson

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Key Criteria for DepressionDepressed MoodQ1 A. I do not feel sad.

B. I feel sad.C. I am sad all the time and I can't snap out of it.D. I am so sad or unhappy that I can't stand it.

Q10 A. I don't cry anymore than usual.B. I cry more now than I used to.C. I cry all the time now.D. I used to be able to cry, but now I can't cry even though I want to

AnhedoniaQ4 A. I get as much satisfaction out of things as I used to.

B. I don't enjoy things the way I used to.C. I don't get real satisfaction out of anything anymore.D. I am dissatisfied or bored with everything.

Q12. A. I have not lost interest in other people.B. I am less interested in other people than I used to be.C. I have lost most of my interest in other people.D. I have lost all of my interest in other people.

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Cox Prop Haz Regression Analyses*

rh (95% CI) p

Major Depression Dx minor dep major dep

1.23 (0.27-5.54)5.39 (1.79-16.2)

.79 .003

BDI (0-63) 1.08 (1.03-1.13) .0007

Depressed Mood 1.21 (0.89-1.63) .22

* Controlling for sex, race, ethnicity, Grace Score & Charlson

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Cox Prop Haz Regression Analyses*

rh (95% CI) p

Major Depression Dx minor dep major dep

1.23 (0.27-5.54)5.39 (1.79-16.2)

.79 .003

BDI (0-63) 1.08 (1.03-1.13) .0007

Depressed Mood 1.21 (0.89-1.63) .22

Anhedonia 1.85 (1.31-2.63) .0006

* Controlling for sex, race, ethnicity, Grace Score & Charlson

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Cox Prop Haz Regression Analyses*

rh (95% CI) p

Anhedonia Depressed Mood

1.94 (1.32-2.86)0.91 (0.64-1.29)

.0008.59

AnhedoniaMajor Depression Dx minor dep major dep

1.88 (1.18-2.99)

0.75 (0.16-3.52)1.72 (0.41-7.21)

.008

.14

.55

* Controlling for sex, race, ethnicity, Grace Score & Charlson

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Kaplan-Meier Curves by Anhedonia Strata

* P < 0.0001

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Conclusions Both a diagnosis of major depression (MDD) or BDI

> 10 predict 18-month all-cause mortality following hospitalization for an acute cardiac event

Of the two psychological components of depression, anhedonia (but not depressed mood) predicts mortality risk

Anhedonia can account for all of the effects of MDD and total BDI score on mortality risk

A score of 4 or above on anhedonia (0-6) predicts a VERY high risk of mortality

COPES October 2006

Psychological Endophenotypes and CHD RecurrenceKarina W. Davidson

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DefinitionsPhenotype: Multiple, observable characteristics of

an organism produced by the interaction of the organism’s genotype and its environment (e.g., psychiatric syndrome)

Endophenotype: Single components of a phenotype that lie along the pathway from disease to distal genotype. They are heritable, are present in the absence of disease/syndrome manifestation, and occur in unaffected relatives

Represent better clues to the genetic and environmental underpinnings of CHD risk than a broad phenotype

Gottesman & Gould, Am J Psychiatry 2003

EnvironmentGene

Cholesterol CHDE

LDL?HDL?

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DefinitionsPhenotype: Multiple, observable characteristics of

an organism produced by the interaction of the organism’s genotype and its environment (e.g., psychiatric syndrome)

Endophenotype: Single components of a phenotype that lie along the pathway from disease to distal genotype. They are heritable, are present in the absence of disease/syndrome manifestation, and occur in unaffected relatives

Represent better clues to the genetic and environmental underpinnings of CHD risk than a broad phenotype

Gottesman & Gould, Am J Psychiatry 2003

EnvironmentGene

Cholesterol CHDE

LDL?HDL?

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Research Agenda

Establish which phenotypes confer CHD/Mortality risk => eg, depression

Identify stable psychological endophenotypes that are associated with CHD/Mortality risk

THEN go on to find candidate genes for endophenotypes conferring CHD risk

Test interventions tailored to those at genetic risk, informed by psychological, biological and environments that exacerbate this risk

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Increased stress sensitivity

AnhedoniaDepressed

mood

Depression

Serotonergicdysfunction

(5-HT1AR, SERT, tryptophandepletion)

CRH system and HPA axisdysfunction

Catecholaminergicdysfunction

(catecholaminedepletion)

REM sleepabnormalities

Stress

Stress Stress

5-HT1AR TPH2 GR

5-HTTLPRMR

CRH1-R

DBH

MAO-A

COMT

CHRM2

CREB

5-HT2AR

Impaired executivecognitive function

Impaired learning and

memory

Psychomotorchange