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Treatment-Resistant Depression in Patients with Coronary Heart Disease

Treatment-Resistant Depression in Patients with Coronary Heart Disease. Kenneth E. Freedland, Ph.D. Department of Psychiatry Washington University School of Medicine St. Louis, Missouri Tilburg University Symposium

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Treatment-Resistant Depression in Patients with Coronary Heart Disease

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  1. Treatment-Resistant Depression inPatients with Coronary Heart Disease Kenneth E. Freedland, Ph.D. Department of Psychiatry Washington University School of Medicine St. Louis, Missouri Tilburg University Symposium New Perspectives on Psychological Distress and Its Treatment in the Context of Coronary Heart Disease November 14, 2008

  2. Disclosure Statement • The speaker has no relevant financial interests to disclose. • Thanks to the global financial crisis, the speaker is lucky to have any financial interests.

  3. Then and Now

  4. Why Focus on Treatment-Resistant Depression in CHD? • Treatment-resistant patients may comprise a high-risk subgroup within the larger population of depressed cardiac patients. • We want to develop more effective interventions, especially for this subgroup.

  5. Depression as a Risk Factor After Acute Coronary Syndrome • Meta-analysis: major depression more than doubles the risk of mortality after an acute MI (van Melle, de Jonge, Spijkerman, et al., Psychosom Med 2004) • Risk may be even higher after hospital admission for unstable angina (Lespérance et al., Arch Intern Med 2004) • The risk is not uniform; there is growing interest in identifying high-risk subgroups.

  6. Treatment-Resistant Depression • Most common definition of Tx resistance: • Failure to respond to >2 established therapies (e.g., 2 drugs, drug + psychotherapy, etc.) • Other definitions are either more inclusive or more restrictive.

  7. Strategies for Overcoming Treatment Resistance • Sequential Intervention (switching) • Two different treatments for depression, in series, with differential effects • Combination • Two different treatments for depression, in parallel, with complementary effects • Augmentation • Depression therapy boosted with an effect multiplier, to increase the impact of the depression therapy • Innovation • Discover / develop more effective treatments

  8. STAR*D Trial • Sequenced Treatment Alternatives to Relieve Depression (STAR*D) • Aim: test strategies for refractory depression • Over 4,000 outpatients with unipolar depression, many with psychiatric and/or medical comorbidities. • Step 1 treatment with citalopram, at a higher dose (55 mg/day) for a longer duration (12 weeks) than is typical for primary care. Trivedi et al., Am J Psychiatry 2006

  9. STAR*D Trial • About 25% of citalopram nonresponders remitted after switching to a second antidepressant (Trivedi et al., NEJM 2006) • Slightly higher percentage remitted after combining citalopram with bupropion(Rush et al., NEJM 2006) or CBT(Thase et al., Am J Psychiatry 2007) • Thus, about 50% remitted, either during the Step 1 citalopram phase or the Step 2 switching / combination phase.

  10. STAR*D Trial • Over 30% did not fully remit even at Step 4. • Those who did respond to Step 3 or 4 treatments had high relapse rates (Rush et al., Am J Psychiatry 2006) • Thus, even with carefully managed, very aggressive treatment, about 1/3 of depressed patients do not achieve full remission. • Residual symptoms increase risk of relapse. • This is the current state of the art.

  11. Treatment Resistance andCardiac Events • Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial • Multicenter RCT to determine whether treating depression and low perceived social support (LPSS) reduces the risk of recurrent infarction and death after an acute MI • Participants had major or minor depression, and/or LPSS within 1 month after MI. • Randomized to treatment or usual care

  12. Treatment Resistance andCardiac Events • Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial • Treatment (Tx) participants received up to 6 months of cognitive behavior therapy (CBT) • Plus sertraline for up to 1 year for patients who were: • Severely depressed, and/or • Not responding well to CBT alone

  13. Treatment Resistance andCardiac Events • Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial • Among the depressed patients, 6-month mean BDI change scores were -8.6 ±9.2 and -5.8 ±8.1 in the Tx and UC arms, respectively. • There was no between-group difference in reinfarction-free survival during a median of 29 months of follow-up. Berkman et al., JAMA 2003

  14. Treatment Resistance • Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial • Late mortality analysis • 858 ENRICHD participants (409 UC, 449 Tx) • MD episode and BDI>10 at index and past Hx MD • Completed 6-month assessments. • Hypothesized that improvement in depression during the 1st 6 months is associated with better survival starting 6 months post-MI Carney et al., Psychosom Med 2004

  15. Treatment Resistance andCardiac Events • Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial • Among Tx patients, the nonresponders had a higher risk of late mortality (death occurring >6 months after the acute MI) compared to responders. • Patients whose depression worsened by >10 Beck Depression Inventory (BDI) points despite treatment were 1.6 times more likely to die than were those who merely failed to improve, and 2.5 times as likely to die as those who improved by >10 points on the BDI. Carney et al., Psychosom Med 2004

  16. Treatment Resistance andCardiac Events • Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial • Effects were independent of baseline BDI, antidepressant use, and established predictors of post-MI mortality, including LVEF, age, and prior history of MI. • Despite strong relationship between change in depression and late mortality in the Tx arm, the relationship was not significant in the UC arm. • Fewer subjects in Tx (15%) than UC (26%) arm failed to show any improvement in BDI from baseline to 6 months. • The mortality rate among non-improvers was higher in the Tx arm (21%) than in the UC arm (10%). Carney et al., Psychosom Med 2004

  17. ENRICHD: Covariate-Adjusted Effect of Change in BDI on Late Mortality, by Treatment Group Carney et al., Psychosom Med 2004

  18. Treatment Resistance andCardiac Events • Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial • Only about 15% of UC patients received any non-study treatment for depression. • Even fewer UC patients who failed to improve had received any depression treatment. • Some might not have remitted even if treated, but others might have responded very well. Carney et al., Psychosom Med 2004

  19. Treatment Resistance andCardiac Events • Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial • Stronger relationship between nonresponse and late mortality in Tx patients who received both sertraline and CBT than those who received only CBT. • UC patients on non-study antidepressants: two-fold difference in mortality for those with the best vs. worst treatment responses. • Suggests that exposure to intervention identified patients with a high-risk subtype of depression, i.e., depression that does not respond to standard antidepressant therapy. Carney et al., Psychosom Med 2004

  20. Treatment Resistance • Secondary analyses of other trials also support the Tx resistance hypothesis: • MIND-IT • 24 weeks of usual care vs mirtazapine vs placebo, followed by open-label citalopram for treatment nonresponders • Study interventions were not superior to UC for cardiac event-free survival over an average of 27 months of follow-up Van Melle, de Jonge, et al., Br J Psychiatry 2007

  21. Treatment Resistance • Secondary analyses of other trials also support the Tx resistance hypothesis: • MIND-IT • Tx patients classified as responders (>50% improvement on the HAM-D at 24 weeks) or nonresponders (<50%) • 18-month incidence of cardiac events: 26% in Tx nonresponders, 11% in untreated controls, 7% in responders (p<.001). de Jonge et al., Am J Psychiatry 2007

  22. Treatment Resistance • Secondary analyses of other trials also support the Tx resistance hypothesis: • MIND-IT • Finding very similar to ENRICHD. • Like ENRICHD, fidning not explained by severity of CHD or severity of comorbidities. de Jonge et al., Am J Psychiatry 2007

  23. Treatment Resistance • Secondary analyses of other trials also support the Tx resistance hypothesis: • SADHART • Sertraline vs. placebo for CHD patients with MDD. • Primary: No difference in depression outcomes. • Secondary: Significant (but modest) efficacy in subgroup with severe, recurrent MDD. Glassman et al., JAMA 2002

  24. Treatment Resistance • Secondary analyses of other trials also support the Tx resistance hypothesis: • SADHART • 6.6 year median follow-up • Depression improvement during the 24 weeks of treatment predicted survival in both the sertraline and placebo arms, even after adjusting for mortality risk factors Glassman, personal communication, 2008

  25. SADHART Glassman, personal communication, 2008

  26. Treatment Resistance • Unsuccessful treatment of depression after hospitalization for ACS unmasks patients at high risk for mortality. • Untreated-unimproved subgroups combine low-risk and masked high-risk subsets. • May help to explain failure of ENRICHD and other trials to improve survival.

  27. Treatment Resistance • 1st MD episodes seem less Tx-responsive than recurrent episodes after MI • SADHART • MIND-IT • CREATE • After ACS, 1st episodes may also be riskier than recurrent episodes vis-a-vis mortality.

  28. Treatment Resistance • Some of the best biological predictors of Tx resistance in psychiatric depression are also cardiac risk markers, e.g., • ANS and HPA dysfunction • Proinflammatory & procoagulant markers • Low omega-3 FFAs • Obstructive sleep apnea/hypopnea syndrome

  29. Implications • After ACS, nonresponders to aggressive depression Tx should receive aggressive cardiological care. • Need to clarify mechanisms. • Need to develop more efficacious treatments for these patients. • Need to determine whether these treatments improve prognosis.

  30. Congratulationstoprof. dr. de Jonge

  31. Discussion Maletic et al. Int J Clin Practice 2007; Kendler et al. Am J Psychiatry 2001.

  32. Potential Risk Modifiers • Lifetime Course of Depression • Temporal Relationship to MI • Treatment Resistance • Depression • Severity • Subtype • Chronicity

  33. Onset of Major Depressive Disorder (MDD) usually occurs in teens or 20’s. Sometimes earlier. Sometimes later. Sometimes much later. Sometimes before ACS. Sometimes after. Lifetime Course of Depression

  34. First Episode vs. Recurrent MDD • Lespérance et al., Psychosom Med 1996 • 222 acute MI patients, followed for 18 months. • 35 (16%) met MD criteria in hospital • 61 (28%) had a prior hx of MD • More likely to be depressed in hospital • 18-month mortality if depressed in hospital: • 10% if first episode • 40% if recurrent episode • P=.04

  35. First Episode vs. Recurrent MDD • de Jonge et al., J Am Coll Cardiol 2006 • 468 patients assessed for MD within 1 yr of an acute MI • 119 (25%) met criteria for MD on the CIDI • 53 (45%) first episodes • 66 (55%) recurrent episodes • 349 not depressed during the year • 22 (6%) of them had a pre-MI history of depression

  36. First Episode vs. Recurrent MDD de Jonge et al., J Am Coll Cardiol 2006

  37. First Episode vs. Recurrent MDD • de Jonge et al., J Am Coll Cardiol 2006 • Univariate hazard ratios: • First vs nondep: log-rank = 4.30; p=0.04 • Recurrent vs nondep: log-rank=0.13; p=0.72 • Covariate-adjusted hazard ratios: • First vs nondep: 1.76 [95% CI 1.06 to 2.65] • Recurrent vs nondep: 1.39 [95% CI 0.74 to 2.61]

  38. First Episode vs. Recurrent MDD • Carney, Freedland, et al., under review • Sample • 929 patients with MDD from ENRICHD • 373 (40%) first episode • 550 (60%) recurrent episode • 408 never-depressed controls • Assessed within 1 month of acute MI

  39. First Episode vs. Recurrent MDD • Median follow-up, 29 months • Mortality • 03.4% of nondepressed controls • 11.8% of patients with recurrent MDD • 18.4% of patients with first episode of MDD • Tukey–adjusted log rank tests • First vs. nondepressed, p<0.0001 • Recurrent vs. nondepressed, p=0.004 • First vs. recurrent, p=0.04 Carney, Freedland, et al., under review

  40. First Episode vs. Recurrent MDD *Adjusted HRs: F vs N: 4.0, p<.0001 R vs N: 2.6, p<.0001 R vs F: 0.7, p=.056 *Adjusted for ENRICHD all-cause mortality risk score (Jaffe et al., 2006) Carney, Freedland, et al., under review

  41. First Episode vs. Recurrent MDD • Secondary analyses • 6-month remission (BDI<7) • Intervention arm • First episode: 57%; Recurrent: 41%; p=0.004 • Usual Care arm • First episode: 40%; Recurrent: 20%; p=0.0001 Carney, Freedland, et al., under review

  42. First Episode vs. Recurrent MDD • Secondary analyses • BDI at baseline • First: 19.4+8.2; Recurrent: 22.2+8.4; p<0.0001 • 6-month mean Tx-UC change difference • First episode: 3.3; Recurrent: 3.9; p=0.67 • Thus, remission difference due to difference in baseline severity, not in amount on change Carney, Freedland, et al., under review

  43. First Episode vs. Recurrent MDD • Secondary analyses • Age • First: 61+12; Recurrent: 58+12; p=0.01 • Systolic BP • First: 127+20; Recurrent: 123+20; p=0.01 • BMI • First: 28+6; Recurrent: 29+6; p=0.02 • Current smoking • First: 29%; Recurrent: 38%; p=0.02 Carney, Freedland, et al., under review

  44. First Episode vs. Recurrent MDD • Secondary analyses • Not consistent with vascular depression. • “ “ “ worse CHD. • “ “ “ worse comorbidities • Higher proportion of first episode patients received thrombolytic therapy (rural / urban?) • But thrombolytic therapy did not affect survival Carney, Freedland, et al., under review

  45. Temporal Relationship to MI • Dickens et al., Psychosom Med 2008 • N=558 assessed 3.6+2.1 days post-MI • HADS at index – patients asked to reflect their mental state during the week prior to the MI. • N=440 completed HADS at 12 mos • 273 (62%) not depressed at either point • 96 (22%) depressed prior to MI • 71 (16%) depressed at 12 but not pre-MI

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