Depression and Cardiovascular Disease

1. Depression and Cardiovascular Disease Karina Davidson, PhD Funded by the National Heart Lung and Blood Institute 2007 PMBC Summer Institute, Pittsburgh, PA COPES October 2006

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

3. Faculty Thomas Pickering, MD Co-Director Karina Davidson, PhD Co-Director William Gerin, PhD Director of Research Matthew M. Burg, PhD Lynn Clemow, PhD Gbenga Ogedegbe, MD Daichi Shimbo, MD Joseph Schwartz, PhD, Richard Sloan, PhD, Associated Faculty COPES October 2006

4. Depression and CHD Morbidity and Mortality 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* 0 1 2 3 4 5 6 7 COPES October 2006 * Indicates Hazard Ratio. All others are ORs.

5. Hostility and CHD Morbidity and Mortality 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) 0 1 2 3 4 5 6 7 COPES October 2006

6. 4-Year Cardiac Death-Free Survival in Relation to Negative Emotions During Admission in Post-MI Patients (n=896) Depressed: BDI>10 Anger Anxiety Social Support Depression COPES October 2006 Frasure-Smith & Lesperance, Arch Gen Psychiatry 2003;60:627-636

7. Gaps 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

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

9. Project 1 and 3 COPES October 2006

10. 5692 Patients Screened • 4039 Excluded • 1612 non-ACS • 1235 Logistic barriers • 390 Medical Reasons • 147 BDI score 5-9 • 166 Physician refusal • 489 Patient refusal Consort Diagram 3 month follow-up N=560 560 Patients Enrolled • 68 No 3-month Follow-up • 15 Deceased • 30 Missed 3-month visit • 21 Dropped out of study • 2 Missing 3-month BDI 492 Completed 3 Month Follow-Up 88% COPES October 2006

11. Gender, ethnic and racial distribution (N=560) COPES October 2006

12. Depression at 1 month .80** .75** Depression at baseline Depression at 3 months -.32* -.30** .57** Adherence week 1-2 .41** Adherence week 3-4 Adherence month 2-3 Figure 1 Cross-lagged ModelNote: Only significant standardized coefficients are displayed. Dashed paths were insignificant; *P < 0.05 ** P < 0.01 COPES October 2006

13. Adjusted Odds RatiosVariables: age, gender, race, ethnicity, employment, living alone, Charlson index, depressive status ■Persistent depressed ■ Remittent depressed Quit smoking Took meds Cardiac rehab Exercised Modified diet Overall

14. 3mo CRP > 3 100 3mo CRP <= 3 90 36.8 80 52.9 70 60 83.3 50 40 63.2 30 47.1 20 10 16.7 0 CRP-Levels 3 months after ACS % patients remittent depressed persistently non-depressed persistently depressed

15. Depression Vulnerabilities Measures COGNITIVE: DAS Dysfunctional Attitudes Scale (24-items) BEHAVIORAL: PES Frequency rating of 20 pleasant activities Pleasant Events Schedule for the Elderly INTERPERSONAL: Role Transition Occurrence of 6 major role transitions during the past year Dyadic Distress Dyadic Adjustment Scale COPES October 2006

16. Percent Patients with elevated vulnerability scores* *We used pre-existing cut-offs or > 1SD above mean COPES October 2006

17. Percentage of patients with 0, 1, or more elevated vulnerabilities COPES October 2006

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

19. Would you rather take medication or get counseling? COPES October 2006

20. Would you rather take medication or get counseling? COPES October 2006

21. Would you rather take medication or get counseling? Note: sometimes people check both options, thus total is > 100% COPES October 2006

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

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

24. Project 2--Phase I RCT COPES October 2006

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

26. Design Screening Phase 0 1 mo phone call 3 mo: screening RCT 3 mo: randomization to Stepped Care or Usual Care and pre-RCT assessment Step-up? 5 mo: interim depression and safety assessment  decision to “step-up” Step-up? 7 mo: interim depression and safety assessment  decision to “step-up” 9 mo: post-RCT assessment 21 mo: long-term FU assessment COPES October 2006

27. ASSESSMENT CARE Monitoring Clinical Psychologist / Licensed Clinical Social Worker Blinded Interviewers DSMB Team Psychiatrist Training Core Blinded Interviewer trained in psychiatric interviewing Cardiologist,Primary Care Provider Data Management Core Depression Diagnosis (DISH) over phone Team COPES October 2006

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

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

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

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 Step If no improvement is seen, augment with pharmacotherapy according to patient medication history If patient declines medication, then increase intensity of psychotherapy COPES October 2006

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

33. Random Allocation Sequence • Permuted 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

34. Project 1 Longterm Follow-up COPES October 2006

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

36. Cox Prop Haz Regression Analysis* * Controlling for sex, race, ethnicity, Grace score & Charlson index COPES October 2006

37. Cox Prop Haz Regression Analyses* * Controlling for sex, race, ethnicity, Grace Score & Charlson COPES October 2006

38. Key Criteria for Depression • Depressed Mood • Q1 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 • Anhedonia • Q4 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

39. Cox Prop Haz Regression Analyses* * Controlling for sex, race, ethnicity, Grace Score & Charlson COPES October 2006

40. Cox Prop Haz Regression Analyses* * Controlling for sex, race, ethnicity, Grace Score & Charlson COPES October 2006

41. Cox Prop Haz Regression Analyses* * Controlling for sex, race, ethnicity, Grace Score & Charlson COPES October 2006

42. Kaplan-Meier Curves by Anhedonia Strata * P < 0.0001 COPES October 2006

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

44. Psychological Endophenotypes and CHD Recurrence Karina W. Davidson COPES October 2006

45. Gene Environment Definitions • Phenotype: 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 E CHD Cholesterol LDL? HDL? COPES October 2006

46. Gene Environment Definitions • Phenotype: 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 E CHD Cholesterol LDL? HDL? COPES October 2006

47. COPES October 2006

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

49. Depression Impaired executive cognitive function Impaired learning and memory Increased stress sensitivity Psychomotor change Anhedonia Depressed mood REM sleep abnormalities Stress Stress Stress Serotonergic dysfunction (5-HT1AR, SERT, tryptophan depletion) CRH system and HPA axis dysfunction Catecholaminergic dysfunction (catecholamine depletion) CREB MAO-A CHRM2 TPH2 5-HT1AR GR DBH 5-HT2AR MR COMT 5-HTTLPR CRH1-R COPES October 2006