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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
COPES October 2006 Page 2
•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
COPES October 2006 Page 3
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
COPES October 2006 Page 40 1 2 3 4 5 6 7
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.
COPES October 2006 Page 5
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
COPES October 2006 Page 7
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
COPES October 2006 Page 8
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
COPES October 2006 Page 9
Project 1 and 3
COPES October 2006 Page 10
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
COPES October 2006 Page 11
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
COPES October 2006 Page 12
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
COPES October 2006 Page 15
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
COPES October 2006 Page 16
*We used pre-existing cut-offs or > 1SD above mean
Percent Patients with elevated vulnerability scores*
COPES October 2006 Page 17
Percentage of patients with 0, 1, or more elevated vulnerabilities
COPES October 2006 Page 18
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
COPES October 2006 Page 19
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?
COPES October 2006 Page 20
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
COPES October 2006 Page 21
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%
COPES October 2006 Page 22
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)
COPES October 2006 Page 23
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
COPES October 2006 Page 24
Project 2--Phase I RCT
COPES October 2006 Page 25
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)
COPES October 2006 Page 26
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
COPES October 2006 Page 27
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
COPES October 2006 Page 28
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
COPES October 2006 Page 29
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)
COPES October 2006 Page 30
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
COPES October 2006 Page 31
“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
COPES October 2006 Page 32
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
COPES October 2006 Page 33
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
COPES October 2006 Page 34
Project 1 Longterm Follow-up
COPES October 2006 Page 35
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
COPES October 2006 Page 36
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
COPES October 2006 Page 37
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
COPES October 2006 Page 38
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.
COPES October 2006 Page 39
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
COPES October 2006 Page 40
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
COPES October 2006 Page 41
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
COPES October 2006 Page 42
Kaplan-Meier Curves by Anhedonia Strata
* P < 0.0001
COPES October 2006 Page 43
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
COPES October 2006 Page 45
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?
COPES October 2006 Page 46
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?
COPES October 2006 Page 47
COPES October 2006 Page 48
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
COPES October 2006 Page 49
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