TreatmentResistant Depression in Patients with Coronary Heart Disease

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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

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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.

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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.

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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.

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Treatment-Resistant Depression

• Most common definition of Tx resistance
• Failure to respond to gt2 established therapies
  (e.g., 2 drugs, drug psychotherapy, etc.)
• Other definitions are either more inclusive or
  more restrictive.

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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

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STARD Trial

• Sequenced Treatment Alternatives to Relieve
  Depression (STARD)
• 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
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STARD 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.

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STARD 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.

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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

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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

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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
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Treatment Resistance

• Enhancing Recovery in Coronary Heart Disease
  (ENRICHD) clinical trial
• Late mortality analysis
• 858 ENRICHD participants (409 UC, 449 Tx)
• MD episode and BDIgt10 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
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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 gt6 months
  after the acute MI) compared to responders.
• Patients whose depression worsened by gt10 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
  gt10 points on the BDI.

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

• Secondary analyses of other trials also support
  the Tx resistance hypothesis
• MIND-IT
• Tx patients classified as responders (gt50
  improvement on the HAM-D at 24 weeks) or
  nonresponders (lt50)
• 18-month incidence of cardiac events 26 in Tx
  nonresponders, 11 in untreated controls, 7 in
  responders (plt.001).

de Jonge et al., Am J Psychiatry 2007
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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
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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
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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
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SADHART
Glassman, personal communication, 2008
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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.

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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.

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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

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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.

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Congratulationstoprof. dr. de Jonge
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Discussion
Maletic et al. Int J Clin Practice 2007 Kendler
et al. Am J Psychiatry 2001.
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Potential Risk Modifiers

• Lifetime Course of Depression
• Temporal Relationship to MI
• Treatment Resistance
• Depression
• Severity
• Subtype
• Chronicity

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Lifetime Course of Depression

• Onset of Major Depressive Disorder (MDD) usually
  occurs in teens or 20s.
• Sometimes earlier.
• Sometimes later.
• Sometimes much later.
• Sometimes before ACS.
• Sometimes after.

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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

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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

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

• de Jonge et al., J Am Coll Cardiol 2006
• Univariate hazard ratios
• First vs nondep log-rank 4.30 p0.04
• Recurrent vs nondep log-rank0.13 p0.72
• 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

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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

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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
• Tukeyadjusted log rank tests
• First vs. nondepressed, plt0.0001
• Recurrent vs. nondepressed, p0.004
• First vs. recurrent, p0.04

Carney, Freedland, et al., under review
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First Episode vs. Recurrent MDD
Adjusted HRs F vs N 4.0, plt.0001 R vs N 2.6,
plt.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
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First Episode vs. Recurrent MDD

• Secondary analyses
• 6-month remission (BDIlt7)
• Intervention arm
• First episode 57 Recurrent 41 p0.004
• Usual Care arm
• First episode 40 Recurrent 20 p0.0001

Carney, Freedland, et al., under review
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First Episode vs. Recurrent MDD

• Secondary analyses
• BDI at baseline
• First 19.48.2 Recurrent 22.28.4 plt0.0001
• 6-month mean Tx-UC change difference
• First episode 3.3 Recurrent 3.9 p0.67
• Thus, remission difference due to difference in
  baseline severity, not in amount on change

Carney, Freedland, et al., under review
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First Episode vs. Recurrent MDD

• Secondary analyses
• Age
• First 6112 Recurrent 5812 p0.01
• Systolic BP
• First 12720 Recurrent 12320 p0.01
• BMI
• First 286 Recurrent 296 p0.02
• Current smoking
• First 29 Recurrent 38 p0.02

Carney, Freedland, et al., under review
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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
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Temporal Relationship to MI

• Dickens et al., Psychosom Med 2008
• N558 assessed 3.62.1 days post-MI
• HADS at index patients asked to reflect their
  mental state during the week prior to the MI.
• N440 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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Temporal Relationship to MI

• Dickens et al., Psychosom Med 2008
• Late cardiac mortality in 12-month survivors
• New onset vs pre-MI, p.003 (log rank)
• New onset vs nondep, p.06
• Cox regression analysis
• Pre-MI dep, adj. HR0.31, p.12
• New onset dep, adj. HR2.3, p.05

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Temporal Relationship to MI
Dickens et al., Psychosom Med 2008
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Treatment Resistance

• Carney et al., Psychosom Med 2004
• Depression and late mortality after MI
• 858 ENRICHD participants (409 UC, 449 Tx)
• MD episode and BDIgt10 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

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Treatment Resistance
Tx Adjusted HR, 1.05 1.01, 1.08, p.007 UC
Adjusted HR, 0.99 0.95, 1.03, p.76
Carney et al., Psychosom Med 2004
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Treatment Resistance
Tx w/ SSRI HR, 1.08 1.011.47, p.02)
Carney et al., Psychosom Med 2004
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Treatment Resistance

• Secondary analyses of other trials also support
  the Tx resistance hypothesis
• MIND-IT (de Jonge et al., Am J Psychiatry 2007)
• MHART (Frasure-Smith, personal communication)
• Carney et al. planning a prospective test.

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Treatment Resistance

• 1st MD episodes seem less Tx-responsive than
  recurrent episodes after MI
• SADHART (Glassman et al., 2002)
• CREATE (Lespérance et al., 2007)

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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
• OSAHS

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Discussion

• In post-MI patients, 1st episodes of MD seem to
  be riskier than recurrent episodes.
• Counterintuitive recurrent MDD more exposure
  to depression over years / decades.
• But stress may play greater role in 1st episodes.

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

• Thus, post-MI patients with first episodes might
  be under more recent life stress.
• Need to investigate this.
• New onset of depression during year after MI may
  be riskier than pre-MI depression.
• Limited evidence more needed.
• Also need better data on relationship between
  lifetime courses of MDD and CHD.

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Discussion

• MD that does not respond to aggressive Tx seems
  to be riskier than Tx-responsive depression.
• Less aggressive Tx (typical UC) may fail to
  uncover the truly Tx-resistant cases.
• Antidepressants are less efficacious than
  published trials suggest, due to selective
  publication (Turner et al., N Engl J Med 2008 Jan
  17358(3)252-60.)

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Discussion

• STARD trial showed that many patients who fail
  to respond to citalopram do respond to switching
  or augmentation with other agents or CBT.
• It also showed that many other patients fail to
  respond to second- or even third-step treatment.

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Conclusions

• First episode MD may be risker than recurrent MD
  in post-MI patients, but we need
• more evidence
• better understanding of differences between 1st
  and recurrent episodes
• better charactization of lifetime exposure
• Tx-resistant depression may be a high-risk group
• More efficacious treatments are needed for them
• More Tx development work
• More clinical trials

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Collaborators

• Robert Carney PhD
• James Blumenthal PhD
• Matthew Burg PhD
• Carol Cornell PhD
• Susan Czajkowski PhD
• Peter de Jonge PhD
• Karina Davidson PhD

• Allan Jaffe MD
• Peter Kaufmann PhD
• Patrice Saab PhD
• Brian Steinmeyer MS
• Richard Veith MD
• Marston Youngblood MA
• ENRICHD Investigators