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Original Article |

Psychiatric Characteristics Associated With Long-term Mortality Among 361 Patients Having an Acute Coronary Syndrome and Major Depression:  Seven-Year Follow-up of SADHART Participants FREE

Alexander H. Glassman, MD; J. Thomas Bigger Jr, MD; Michael Gaffney, PhD
[+] Author Affiliations

Author Affiliations: Departments of Psychiatry (Dr Glassman) and Medicine (Dr Bigger), Columbia University College of Physicians and Surgeons; Department of Clinical Psychopharmacology, New York State Psychiatric Institute (Dr Glassman); and Pfizer Inc (Dr Gaffney), New York, New York.


Arch Gen Psychiatry. 2009;66(9):1022-1029. doi:10.1001/archgenpsychiatry.2009.121.
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Context  Major depressive disorder (MDD) after acute coronary syndrome (ACS) is associated with an increased mortality rate. We observed the participants of the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) to establish features of MDD associated with long-term mortality.

Objectives  To determine whether the following variables were associated with long-term mortality: baseline depression severity, previous MDD episodes, onset of MDD before or after the ACS event, 6 months of sertraline hydrochloride therapy, and mood improvement independent of treatment.

Design  SADHART was a double-blind, placebo-controlled, randomized trial comparing the safety and antidepressant efficacy of sertraline vs placebo in 369 patients with ACS who met criteria for MDD. The trial was completed in June 2000, and follow-up for vital status was completed in September 2007.

Setting  Academic research.

Participants  SADHART participants.

Main Outcome Measures  Vital status was determined in 361 participants (97.8%) during a median follow-up of 6.7 years.

Results  During the study, 75 participants (20.9%) died. Neither previous episodes of MDD, nor onset before or after the index ACS, nor an initial 6 months of sertraline treatment was associated with long-term mortality. Cox proportional hazards regression models showed that baseline MDD severity (hazard ratio, 2.30; 95% confidence interval, 1.28-4.14; P < .006) and failure of MDD to improve substantially during treatment with either sertraline or placebo (hazard ratio, 2.39; 95% confidence interval, 1.39-2.44; P < .001) were strongly and independently associated with long-term mortality. Marked improvement in depression (Clinical Global Impression–Improvement subscale score of 1) was associated with improved adherence to study medication.

Conclusions  Severity of MDD measured within a few weeks of hospitalization for ACS or failure of MDD to improve during the 6 months following ACS predicted more than a doubling of mortality over 6.7 years of follow-up. Because persistent depression increases mortality and decreases medication adherence, physicians need to aggressively treat depression and be diligent in promoting adherence to guideline cardiovascular drug therapy.

Figures in this Article

A 1993 study by Frasure-Smith et al1 reporting that major depressive disorder (MDD) increased 6-month mortality 3.5-fold in patients following an acute myocardial infarction (MI) raised the question whether antidepressant treatment would reduce that risk. At the time, it was unclear whether antidepressant drugs were safe soon after an MI. The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) tested the safety and antidepressant efficacy of sertraline hydrochloride, a selective serotonin reuptake inhibitor (SSRI), for the treatment of MDD after acute coronary syndrome (ACS).2 Sertraline gave no evidence of harm and trended toward a reduction in recurrent MI, rehospitalization for angina or heart failure, stroke, or deaths.2 Although the study did not specifically test safety, patients in the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial treated with an open-label SSRI had significantly fewer deaths or recurrent MI.3 Although neither study was definitive, both suggested that serious adverse cardiac events were decreased during SSRI treatment. Surprisingly, a small (n = 104) blinded placebo-controlled stroke study4 showed a persistent beneficial effect on mortality 9 years after 3 months of antidepressant treatment. This was the basis for our hypothesis that 6 months of sertraline treatment might show a long-term reduction in mortality rates.

Because mortality rates increase monotonically as the severity of post-MI depression increases from nondepressed, to depressive symptoms less than MDD, to a diagnosis of MDD57 and because it was previously observed that severity of depression during hospitalization for ACS was associated with treatment outcome,8 we tested whether, among SADHART participants, the severity of depression was associated with mortality during follow-up. Although not as extensively studied as severity, the literature at the time the SADHART follow-up was designed suggested that recurrent depression9 and failure of MDD to improve with antidepressant treatment10 were associated with increased mortality. In addition, it was reported that severity, prior episodes of MDD, and onset before or after the ACS event predicted improvement with sertraline therapy.8

To determine whether the same baseline characteristics that predict antidepressant success were associated with lower mortality rates, we determined the vital status of SADHART participants during almost 7 years of follow-up. Our principal objectives were to determine the long-term mortality effect of (1) baseline depression severity, (2) previous episodes of MDD, (3) onset of MDD before or after the index ACS, (4) six months of placebo-controlled sertraline treatment, and (5) mood improvement during 6 months of treatment with either sertraline or placebo.

ORIGINAL SADHART DESIGN

Details of the original trial have been published previously.2,8 All patients gave written informed consent for participation, and institutional review or ethics boards at each participating center approved the study. In brief, the study recruited patients who were hospitalized for ACS and found to have MDD by screening. The study tested the safety and antidepressant efficacy of sertraline in a 6-month randomized double-blind placebo-controlled trial. Randomization was stratified on left ventricular ejection fraction (<0.30 vs ≥0.30), depression severity using a Hamilton Depression Rating Scale (HAM-D) score of less than 18 vs 18 or higher, and the presence or absence of at least 2 previous episodes of depression. Change in MDD during treatment was quantified using the Clinical Global Impression–Improvement subscale (CGI-I).11 Remission refers to complete recovery, defined as a CGI-I score of 1 (very much improved) and is similar to a Ham-D score of 7 or less. Enrollment began in April 1997, and the last patient was randomized in December 1999.

SUBJECT SELECTION

Patients 18 years or older hospitalized for ACS were screened for MDD (exclusion criteria were previously published2). At the end of a 2-week single-blind placebo period, a psychiatrist administered the Depression Interview Schedule.12 Only patients satisfying DSM-IV criteria for MDD were randomized to 6 months of blinded treatment with placebo or sertraline.

FOLLOW-UP VITAL STATUS ASCERTAINMENT

The mortality follow-up protocol was approved by the Columbia University Institutional Review Board and by the Advisory Board of the National Death Index, Division of Vital Statistics, National Center for Health Statistics, US Department of Health and Human Services. The original safety and efficacy study was conducted at 44 outpatient centers in 7 countries; 81.0% of participants were recruited in the United States. Five years after the final patient completed the trial, researchers began to collect the vital status of SADHART participants. Site personnel were asked to provide evidence (office visit, laboratory testing, or documented telephone calls) of the last date on which each participant was known to be alive or the date of death if they knew the patient had died. If evidence that the patient was alive in the previous 18 months was unavailable, US sites were asked to send names and Social Security numbers to Columbia University College of Physicians and Surgeons, where they were combined with sex and birth date to create a database for submission to the National Death Index, Division of Vital Statistics, National Center for Health Statistics, US Department of Health and Human Services. The National Death Index sensitivity ranged from 87.0% to 97.9%, whereas the sensitivity of Social Security Administration files ranged from 83.0% to 83.6%.13

MEDICATION ADHERENCE

SADHART was conducted under Pfizer Inc's new drug application. Accordingly, the use of trial drugs was under strict supervision by protocol, sponsor monitoring, and auditing by the Food and Drug Administration. Drug use data were complete in 98.1% of participants. At each of 5 visits during treatment, SADHART supplied sufficient drug or placebo tablets to last until the patient's next scheduled visit plus 1 additional week's supply. Patients were instructed to return all unused medication at the next visit. The returned tablets were counted and subtracted from the number of tablets originally dispensed to obtain the nominal number of tablets ingested. Adherence was measured as the number of tablets presumed to be ingested divided by the number of tablets prescribed for the treatment interval.

STATISTICAL ANALYSIS

Differences in baseline characteristics between patients who responded and those who did not were evaluated by t test (continuous variables) or χ2 test (categorical variables). Cox proportional hazards regression models were used to analyze univariate and multivariate effects of risk factors on the time to death.14 The risk factors are (1) baseline severity (HAM-D score <18 vs ≥18), (2) a previous episode of major depression, (3) onset of depression before or after the index event, (4) treatment assignment at randomization (sertraline vs placebo), and (5) response to 6 months of therapy (judged by the CGl-I score). The effects of the risk factors are described by their Cox regression hazard ratios (HRs) and 95% confidence intervals (CIs). All Cox regression models included age and sex as covariates. Cumulative mortality curves were computed by the Kaplan-Meier method.

Collection of vital status information began in the spring of 2005, which was 5 years after the last patient completed treatment, and was finished in the summer of 2007. Vital status was obtained on 361 of the SADHART's 369 participants (97.8%); 75 (20.9%) died during a median follow-up of 6.7 years.

We first tested whether, among SADHART participants, the severity of depression was associated with the mortality rate during follow-up. Because the SADHART sample was stratified by severity of MDD at randomization using a HAM-D score of less than 18 or 18 or higher, this same dichotomy was used to evaluate the association of MDD severity with mortality during follow-up. We found that severity of depression during hospitalization for ACS was strongly and significantly associated with mortality during 6.7 years of follow-up (Figure 1).

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Figure 1.

Cumulative mortality among 360 participants with an acute coronary syndrome and major depressive disorder. The severity of depression at baseline was stratified by Hamilton Depression Rating Scale (HAM-D) score and was adjusted for age and sex. The thicker line represents participants with a baseline HAM-D score of 18 or higher (severe depression), and the thinner line represents participants with a baseline HAM-D score of less than 18. The numbers of participants who are at risk at the beginning of each year after randomization are listed under the x-axis. The shaded area between curves represents the 6-month period when participants were treated with blinded Sertraline Antidepressant Heart Attack Randomized Trial medication. CI indicates confidence interval; HR, hazard ratio.

Graphic Jump Location

Next, we determined the association of recurrent vs first-episode MDD with long-term mortality. Previous episodes of depression were not associated with increased mortality. Mortality was also not influenced by whether a first episode of MDD began before or after hospitalization (Table 1).

Table Graphic Jump LocationTable 1. Time of Depression Onset, History of MDD, and Mortality Rate

Because patients following stroke who received 12 weeks of antidepressant treatment had significantly decreased mortality rates during 9 years of follow-up,4 we tested the hypothesis that 24 weeks of sertraline treatment in patients having ACS with MDD would show a similar persistent benefit on mortality. However, we found no evidence to support this hypothesis. A Kaplan-Meier plot (Figure 2) revealed no long-term mortality difference by treatment assignment (HR, 0.99; 95% CI, 0.63-1.56; P = .42). Therefore, the data supported only 1 of our first 4 hypotheses.

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Figure 2.

Cumulative mortality by treatment assignment to sertraline hydrochloride (thinner line) or placebo (thicker line) among 361 participants with an acute coronary syndrome and major depressive disorder, adjusted for age and sex. See the legend to Figure 1 for additional information.

Graphic Jump Location

Our final objective was to test the hypothesis that mood improvement in MDD after ACS, independent of treatment, was associated with a long-term decrease in mortality. The post hoc subgroup analysis from the ENRICHD trial suggested that patients after an MI with MDD who improved while receiving treatment had lower 30-month mortality than patients whose depression persisted.10 However, this result was puzzling because it was seen only in the group randomized to cognitive behavioral therapy and not in the usual care group.

SADHART participants whose depression improved substantially (CGI-I score 1-2 at 6 months) regardless of randomized treatment assignment (placebo or sertraline) had significantly lower mortality during 6.7 years of follow-up (Figure 3); 15.6% (33 of 211) of participants who were judged very much or much improved died compared with 28.4% (42 of 148) of patients whose depression showed little or no improvement (age- and sex-adjusted Cox regression model HR, 2.39; 95% CI, 1.50-3.81; P < .001). Because patients who improved substantially and those who did not might differ at baseline in characteristics that are associated with mortality, we compared baseline characteristics for these 2 groups (Table 2). The left ventricular ejection fraction (LVEF) and a history of hypertension differed significantly between patients who improved substantially and those who did not. Patients whose depression did not improve had a lower LVEF and were more likely to have a history of hypertension, both of which are risk factors for mortality. Controlling for hypertension in a multivariate Cox regression analysis reduced the HR for response from 2.39 to 2.27 (95% CI, 1.42-3.65), while controlling for the LVEF reduced the HR to 1.92 (95% CI, 1.15-3.20; P = .01). Controlling for both hypertension and LVEF, the HR was 1.76 (95% CI, 1.04-2.97; P = .04).

Place holder to copy figure label and caption
Figure 3.

Cumulative mortality by response of depression (improved or not improved) to blinded therapy with sertraline hydrochloride or placebo, adjusted for age and sex. The thinner line represents participants who were very much or much improved (Clinical Global Impression–Improvement subscale [CGI-I] score 1-2), and the thicker line represents participants who were not improved (CGI-I score 3-7). I (improved) and NI (not improved) represent the numbers of participants who are at risk at the beginning of each year after randomization. See the legend to Figure 1 for additional information.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Baseline Characteristics by CGI-I Scores

To determine whether the degree of improvement in depression was associated with lower mortality, CGI-I score categories were tabulated (Table 3). A Cox regression model showed that lower CGI-I scores were associated with decreased mortality (P < .001) during a median follow-up of 6.7 years and that the reduction in mortality was primarily associated with complete remission (CGI-I score of 1). In the ENRICHD trial, failure of depression to improve was associated with increased mortality but only in the active treatment arm10; we found that lack of improvement in depression was associated with increased mortality in both the sertraline and placebo arms of SADHART (Table 4).

Table Graphic Jump LocationTable 3. Clinical Global Impression–Improvement Subscale (CGI-I) Score Categories, Proportions, and Mortality Ratesa
Table Graphic Jump LocationTable 4. Association of Depression Improvement With Mortality by Treatment Assignment

Because severity of MDD also was associated with mortality, we tested whether the association of baseline severity (HAM-D score ≥18) with long-term mortality was independent of the association of failure of MDD to improve (CGI-I score ≥3) with long-term mortality. In a multivariate Cox regression model, baseline depression severity and failure to improve were significantly associated with long-term mortality (Table 5). A CGI-I score of 1 (very much improved) had a stronger association with long-term mortality, and like patients with a CGI-I score of 2 or lower, the association with mortality among 130 participants who had a CGI-I score of 1 remained independent of baseline depression severity compared with 228 participants who had a CGI-I score of 3 or higher, adjusting for the HAM-D score (<18 vs ≥18). In a Cox regression model for participants with a CGI-I score of 3 or higher, the adjusted HR was 2.92 (95% CI, 1.63-5.22; P < .001), and the HR was 2.30 (95% CI, 1.28-4.14; P < .006) for a HAM-D score of 18 or higher.

Table Graphic Jump LocationTable 5. Relationships of Baseline Depression Severity (HAM-D Score), CGI-I Score, and Crude Mortality Rate During a Median Follow-up of 6.7 Years

A recent study15 documents that improvement in depressive symptoms improves adherence to aspirin therapy after ACS. Adherence to cardiovascular medications after ACS reduces mortality16 and could mediate the relationship between failure of MDD to improve substantially and long-term mortality. SADHART did not measure adherence to cardiovascular medications but performed pill counts for sertraline and placebo, which could be a surrogate for adherence to cardiovascular medications. Participants whose depression improved had significantly greater medication adherence. The mean (SD) percentage of prescribed tablets taken by 187 patients whose depression improved substantially (CGI-I score 1-2) after they attained a clinical response was 77.4% (22.1%). For 146 patients with a CGI-I score of 3 to 7, the mean (SD) percentage over the entire treatment period was 68.6% (22.6%). This 8.8% higher adherence is statistically significant (P = .002) but could result from adherent patients' being more likely to respond rather than responding patients' becoming more adherent. To determine this, we compared responders' medication adherence before and after improvement in MDD. Medication adherence increased among 128 of 187 participants (68.4%) who remitted (CGI-I score of 1) following remission. This is significantly greater than would be expected by chance (P < .001).

The literature indicates that depression is associated with increased mortality and that the risk increases from nondepressed, to depressive symptoms less than MDD, to a diagnosis of MDD.57 Even in this truncated sample in which all patients met criteria for MDD, severity strongly predicts long-term mortality. When this study was designed, a published study9 supported (and we expected) that patients with previous MDD episodes would also have greater mortality. Our rationale was that previous episodes reflected chronic depression and would be associated with higher mortality, while a first MDD episode during a coronary event was more likely to be a reaction to ACS and to be associated with less mortality. Contrary to our expectation and the early data by Lesperance et al,9 SADHART participants with no previous episodes, those with only 1 previous episode, and those with 2 or more previous episodes had similar long-term mortality. Onset of MDD before or after the index coronary event also had no significant association with long-term mortality. These issues have recently become a point of controversy in the literature.17 Our evidence indicates that a first episode of post-MI MDD carries at least as much risk for long-term mortality as recurrent MDD.

Similar to the suggestion by Carney et al,10 failure of depression to improve substantially during 6 months of treatment (sertraline or placebo) was associated herein with increased long-term mortality rates. Two recent studies18,19 also indicate that cardiovascular events are associated with depression response. Although it remains uncertain whether treating MDD reduces mortality rates, patients whose post-ACS depression does not improve have twice the risk of dying as those who improve. When patients with MDD after ACS do not respond to antidepressant treatment, a special effort should be made to promote lifestyle improvements and cardiovascular medication adherence. Lack of adherence to guideline cardiovascular drug therapy increases mortality after an MI,16,20,21 and depression reduces medication adherence.2224 Recently, improvement in depression was shown to improve aspirin adherence,15 and the SADHART pill counts support this observation and suggest that medication adherence improves primarily with complete remission.

A striking observation in SADHART is that 2 psychological characteristics, severity of MDD soon after admission for ACS and failure of depression to improve substantially when treated for 6 months with sertraline or placebo, are independently associated with more than a doubling of the 7-year mortality rate. The association of recovery from depression with lower mortality rates could be partially explained by medication adherence, but this does not explain the effect of severity. Adherence improves when depression remits, while baseline severity is associated with mortality independent of the 6-month outcome. Among consecutive patients with an MI, the risk of dying increases with greater depressive severity, and this association is independent of the usual post-MI risk factors.5,7,25 Depression26,27 and cardiovascular disease28 are associated with increased serum levels of inflammatory markers, and these markers are not usually included when examining post-ACS risk factors. Traditionally, the inflammatory state associated with depression is thought to accelerate atherosclerosis and to increase the risk of cardiac death.2931 However, inflammatory activity may also be a risk factor for depression.32 Interferon alfa increases inflammation and is associated with augmented onset of MDD,33 while treatment with drugs that decrease inflammatory markers have been noted to decrease depression.34,35

If an inflammatory state associated with ACS provokes depression, it could explain the extraordinary frequency of depression after acute coronary events. The rate of MDD observed in the first few weeks after an infarction is regularly reported to approach 20%.3,36,37 In the US general population, the 1-year MDD prevalence is 7%, and the lifetime prevalence is 16%.38 Thus, the rate of MDD during the first few weeks after a coronary event is more than the lifetime prevalence in the general population, even though MDD occurs primarily among women while patients with ACS are predominantly men. The rate of MDD associated with ACS is often attributed to the stress of the acute cardiac event, but recent studies8,39 show that most MDD episodes observed during ACS begin before the coronary event. However, if inflammatory activity in ACS provokes depression, this might explain the high frequency of depression associated with ACS and our observation that a first episode of MDD related to ACS has the same or, as others have reported,4042 even greater morbidity and mortality than recurrent MDD.9 Some first episodes of MDD beginning after ACS are probably reactive and improve spontaneously. However, others may be provoked by vascular disease with high levels of inflammation, show little improvement, and carry a high risk of dying.43 Although some studies26,27,44 have found that inflammatory markers are increased in depression, other recent findings suggest that inflammatory markers associated with depression contribute only modestly to new coronary events.45,46 To our knowledge, there are no published studies testing whether inflammatory markers in ACS are associated with new episodes of major depression. Establishing inflammation as a causal factor in depression associated with ACS could provide a rationale for the use of anti-inflammatory drugs in post-ACS depression.47,48

A limitation of all studies of psychosocial risk factors in coronary syndromes is that many patients refuse to be interviewed,5,18,42 especially older women.5,42 Participation is further limited in placebo-controlled trials like SADHART because ethical concerns preclude randomization of patients already taking antidepressants for fear of causing relapse. Exclusion of these subjects could confound conclusions about variation between the sexes, as well as differences between first-episode and recurrent MDD. Almost 15% of patients otherwise eligible for SADHART were excluded because they were already taking antidepressants. Usual treatment trials also exclude patients with a HAM-D severity score of less than 18 to increase the chance of finding drug-placebo differences. The primary objective of SADHART was to determine safety (not efficacy), and patients with mild MDD were not excluded. This resulted in a high placebo response rate and reduced the overall drug-placebo difference. Some authors have perceived the efficacy in SADHART as modest or even unconvincing.49 Nevertheless, our group believes that the modest overall drug effect was due to the high placebo response rate among participants with milder depression.8 In any case, inclusion of very mild MDD had the advantage of a more representative range of post-ACS depression than usual treatment studies.

Extensive evidence indicates that medically healthy individuals experiencing depression are at increased risk to develop coronary events,50 and the association between depression and adverse cardiac events is stronger in patients with ACS.51 How much the presence of depression increases cardiac risk compared with the extent that cardiac disease increases the risk for depression is unclear. Depression is a syndrome with multiple pathways to a similar clinical picture.52 In patients with active coronary heart disease, it seems likely that the association with depression is a 2-way street, and each can aggravate the other. Regardless of whether the inflammatory state is contributing to the onset of depression, depression impairs quality of life and needs to be treated. Even without definitive evidence that they reduce mortality,53 SSRIs (especially in more severe depression) are efficacious8 and safe2,3,39 and improve the quality of a patient's life.54 More severe baseline depression or lack of response should be red flags warning the clinician of more malignant cardiovascular disease and a greater likelihood of nonadherence with guideline cardiovascular drug therapy. Additional evaluation is needed to determine whether anti-inflammatory therapy will reduce depression and whether treatment of depression improves adherence to cardiovascular guideline therapy.

Correspondence: Alexander H. Glassman, MD, Department of Clinical Psychopharmacology, New York State Psychiatric Institute, 1051 Riverside Dr, New York, NY 100322 (ahg1@columbia.edu).

Submitted for Publication: September 9, 2008; final revision received February 20, 2009; accepted February 23, 2009.

Author Contributions: Drs Glassman and Gaffney had full access to all the study data and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: Dr Glassman reported having received grant funding from Pfizer Inc. Dr Gaffney is an employee of Pfizer Inc.

Funding/Support: This research was funded by grant R01-HL081131 from the National Heart, Lung, and Blood Institute of the National Institutes of Health; by the National Alliance for Research in Schizophrenia and Depression; by the Suzanne C. Murphy Foundation; and by the Thomas and Caroline Royster Research Fund.

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Ladwig  KHMarten-Mittag  BLöwel  HDöring  AKoenig  WMONICA-KORA Augsburg Cohort Study 1984-1998, C-reactive protein, depressed mood, and the prediction of coronary heart disease in initially healthy men: results from the MONICA-KORA Augsburg Cohort Study 1984-1998. Eur Heart J 2005;26 (23) 2537- 2542
PubMed
Willerson  JTRidker  PM Inflammation as a cardiovascular risk factor. Circulation 2004;109 (21) ((suppl 1)) II2- II10
PubMed
Carney  RMFreedland  KEMiller  GEJaffe  AS Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res 2002;53 (4) 897- 902
PubMed
Lett  HSBlumenthal  JABabyak  MASherwood  AStrauman  TRobins  CNewman  MF Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med 2004;66 (3) 305- 315
PubMed
Frasure-Smith  NLespérance  F Depression and coronary artery disease. Herz 2006;31 ((suppl 3)) 64- 68
PubMed
Raison  CLCapuron  LMiller  AH Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006;27 (1) 24- 31
PubMed
Capuron  LMiller  AH Cytokines and psychopathology: lessons from interferon-α. Biol Psychiatry 2004;56 (11) 819- 824
PubMed
Tyring  SGottlieb  APapp  KGordon  KLeonardi  CWang  ALalla  DWoolley  MJahreis  AZitnik  RCella  DKrishnan  R Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006;367 (9504) 29- 35
PubMed
Uguz  FAkman  CKucuksarac  STufekci  O Anti-tumor necrosis factor-α therapy is associated with less frequent mood and anxiety disorders in patients with rheumatoid arthritis. Psychiatry Clin Neurosci 2009;63 (1) 50- 55
PubMed
Thombs  BDBass  EBFord  DEStewart  KJTsilidis  KKPatel  UFauerbach  JABush  DEZiegelstein  RC Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 2006;21 (1) 30- 38
PubMed
Lett  HAli  SWhooley  M Depression and cardiac function in patients with stable coronary heart disease: findings from the Heart and Soul Study. Psychosom Med 2008;70 (4) 444- 449
PubMed
Kessler  RCMerikangas  KRWang  PS Prevalence, comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first century. Annu Rev Clin Psychol 2007;3137- 158
PubMed
Lespérance  FFrasure-Smith  NKoszycki  DLaliberté  MAvan Zyl  LTBaker  BSwenson  JRGhatavi  KAbramson  BLDorian  PGuertin  MCCREATE Investigators, Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial [published correction appears in JAMA. 2007;298(1):40]. JAMA 2007;297 (4) 367- 379
PubMed
Grace  SLAbbey  SEKapral  MKFang  JNolan  RPStewart  DE Effect of depression on five-year mortality after an acute coronary syndrome. Am J Cardiol 2005;96 (9) 1179- 1185
PubMed
de Jonge  Pvan den Brink  RHSpijkerman  TAOrmel  J Only incident depressive episodes after myocardial infarction are associated with new cardiovascular events. J Am Coll Cardiol 2006;48 (11) 2204- 2208
PubMed
Parker  GBHilton  TMWalsh  WFOwen  CAHeruc  GAOlley  ABrotchie  HHadzi-Pavlovic  D Timing is everything: the onset of depression and acute coronary syndrome outcome [published correction appears in Biol Psychiatry. 2009;65(5):449]. Biol Psychiatry 2008;64 (8) 660- 666
PubMed
Alexopoulos  GSMurphy  CFGunning-Dixon  FMLatoussakis  VKanellopoulos  DKlimstra  SLim  KOHoptman  MJ Microstructural white matter abnormalities and remission of geriatric depression. Am J Psychiatry 2008;165 (2) 238- 244
PubMed
Vaccarino  VBrennan  MLMiller  AHBremner  JDRitchie  JCLindau  FVeledar  ESu  SMurrah  NVJones  LJawed  FDai  JGoldberg  JHazen  SL Association of major depressive disorder with serum myeloperoxidase and other markers of inflammation: a twin study. Biol Psychiatry 2008;64 (6) 476- 483
PubMed
Vaccarino  VJohnson  BDSheps  DSReis  SEKelsey  SFBittner  VRutledge  TShaw  LJSopko  GBairey Merz  CNational Heart, Lung, and Blood Institute, Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute–sponsored WISE study. J Am Coll Cardiol 2007;50 (21) 2044- 2050
PubMed
Frasure-Smith  NLespérance  FIrwin  MRSauvé  CLespérance  JThéroux  P Depression, C-reactive protein and two-year major adverse cardiac events in men after acute coronary syndromes. Biol Psychiatry 2007;62 (4) 302- 308
PubMed
Ormiston  TWolkowitz  OMReus  VIManfredi  F Behavioral implications of lowering cholesterol levels: a double-blind pilot study. Psychosomatics 2003;44 (5) 412- 414
PubMed
Young-Xu  YChan  KALiao  JKRavid  SBlatt  CM Long-term statin use and psychological well-being. J Am Coll Cardiol 2003;42 (4) 690- 697
PubMed
Thombs  BDde Jonge  PCoyne  JCWhooley  MAFrasure-Smith  NMitchell  AJZuidersma  MEze-Nliam  CLima  BBSmith  CGSoderlund  KZiegelstein  RC Depression screening and patient outcomes in cardiovascular care: a systematic review. JAMA 2008;300 (18) 2161- 2171
PubMed
Wulsin  LRSingal  BM Do depressive symptoms increase the risk for the onset of coronary disease? a systematic quantitative review. Psychosom Med 2003;65 (2) 201- 210
PubMed
Bush  DEZiegelstein  RCPatel  UVThombs  BDFord  DEFauerbach  JA McCann  UDStewart  KJTsilidis  KKPatel  ALFeuerstein  CJBass  EB Post–Myocardial Infarction Depression: Evidence Report/Technology Assessment 123.  Rockville, MD Agency for Healthcare Research and Quality2005;1- 8AHRQ publication 05-E018-2
Kendler  KSGardner  COPrescott  CA Toward a comprehensive developmental model for major depression in men. Am J Psychiatry 2006;163 (1) 115- 124
PubMed
Glassman  AH Does treating post-myocardial infarction depression reduce medical mortality? Arch Gen Psychiatry 2005;62 (7) 711- 712
PubMed
Swenson  JRO’Connor  CMBarton  Dvan Zyl  LTSwedberg  KForman  LMGaffney  MGlassman  AHSertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group, Influence of depression and effect of treatment with sertraline on quality of life after hospitalization for acute coronary syndrome. Am J Cardiol 2003;92 (11) 1271- 1276
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Cumulative mortality among 360 participants with an acute coronary syndrome and major depressive disorder. The severity of depression at baseline was stratified by Hamilton Depression Rating Scale (HAM-D) score and was adjusted for age and sex. The thicker line represents participants with a baseline HAM-D score of 18 or higher (severe depression), and the thinner line represents participants with a baseline HAM-D score of less than 18. The numbers of participants who are at risk at the beginning of each year after randomization are listed under the x-axis. The shaded area between curves represents the 6-month period when participants were treated with blinded Sertraline Antidepressant Heart Attack Randomized Trial medication. CI indicates confidence interval; HR, hazard ratio.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Cumulative mortality by treatment assignment to sertraline hydrochloride (thinner line) or placebo (thicker line) among 361 participants with an acute coronary syndrome and major depressive disorder, adjusted for age and sex. See the legend to Figure 1 for additional information.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Cumulative mortality by response of depression (improved or not improved) to blinded therapy with sertraline hydrochloride or placebo, adjusted for age and sex. The thinner line represents participants who were very much or much improved (Clinical Global Impression–Improvement subscale [CGI-I] score 1-2), and the thicker line represents participants who were not improved (CGI-I score 3-7). I (improved) and NI (not improved) represent the numbers of participants who are at risk at the beginning of each year after randomization. See the legend to Figure 1 for additional information.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Time of Depression Onset, History of MDD, and Mortality Rate
Table Graphic Jump LocationTable 2. Baseline Characteristics by CGI-I Scores
Table Graphic Jump LocationTable 3. Clinical Global Impression–Improvement Subscale (CGI-I) Score Categories, Proportions, and Mortality Ratesa
Table Graphic Jump LocationTable 4. Association of Depression Improvement With Mortality by Treatment Assignment
Table Graphic Jump LocationTable 5. Relationships of Baseline Depression Severity (HAM-D Score), CGI-I Score, and Crude Mortality Rate During a Median Follow-up of 6.7 Years

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PubMed
Willerson  JTRidker  PM Inflammation as a cardiovascular risk factor. Circulation 2004;109 (21) ((suppl 1)) II2- II10
PubMed
Carney  RMFreedland  KEMiller  GEJaffe  AS Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res 2002;53 (4) 897- 902
PubMed
Lett  HSBlumenthal  JABabyak  MASherwood  AStrauman  TRobins  CNewman  MF Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med 2004;66 (3) 305- 315
PubMed
Frasure-Smith  NLespérance  F Depression and coronary artery disease. Herz 2006;31 ((suppl 3)) 64- 68
PubMed
Raison  CLCapuron  LMiller  AH Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006;27 (1) 24- 31
PubMed
Capuron  LMiller  AH Cytokines and psychopathology: lessons from interferon-α. Biol Psychiatry 2004;56 (11) 819- 824
PubMed
Tyring  SGottlieb  APapp  KGordon  KLeonardi  CWang  ALalla  DWoolley  MJahreis  AZitnik  RCella  DKrishnan  R Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006;367 (9504) 29- 35
PubMed
Uguz  FAkman  CKucuksarac  STufekci  O Anti-tumor necrosis factor-α therapy is associated with less frequent mood and anxiety disorders in patients with rheumatoid arthritis. Psychiatry Clin Neurosci 2009;63 (1) 50- 55
PubMed
Thombs  BDBass  EBFord  DEStewart  KJTsilidis  KKPatel  UFauerbach  JABush  DEZiegelstein  RC Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 2006;21 (1) 30- 38
PubMed
Lett  HAli  SWhooley  M Depression and cardiac function in patients with stable coronary heart disease: findings from the Heart and Soul Study. Psychosom Med 2008;70 (4) 444- 449
PubMed
Kessler  RCMerikangas  KRWang  PS Prevalence, comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first century. Annu Rev Clin Psychol 2007;3137- 158
PubMed
Lespérance  FFrasure-Smith  NKoszycki  DLaliberté  MAvan Zyl  LTBaker  BSwenson  JRGhatavi  KAbramson  BLDorian  PGuertin  MCCREATE Investigators, Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial [published correction appears in JAMA. 2007;298(1):40]. JAMA 2007;297 (4) 367- 379
PubMed
Grace  SLAbbey  SEKapral  MKFang  JNolan  RPStewart  DE Effect of depression on five-year mortality after an acute coronary syndrome. Am J Cardiol 2005;96 (9) 1179- 1185
PubMed
de Jonge  Pvan den Brink  RHSpijkerman  TAOrmel  J Only incident depressive episodes after myocardial infarction are associated with new cardiovascular events. J Am Coll Cardiol 2006;48 (11) 2204- 2208
PubMed
Parker  GBHilton  TMWalsh  WFOwen  CAHeruc  GAOlley  ABrotchie  HHadzi-Pavlovic  D Timing is everything: the onset of depression and acute coronary syndrome outcome [published correction appears in Biol Psychiatry. 2009;65(5):449]. Biol Psychiatry 2008;64 (8) 660- 666
PubMed
Alexopoulos  GSMurphy  CFGunning-Dixon  FMLatoussakis  VKanellopoulos  DKlimstra  SLim  KOHoptman  MJ Microstructural white matter abnormalities and remission of geriatric depression. Am J Psychiatry 2008;165 (2) 238- 244
PubMed
Vaccarino  VBrennan  MLMiller  AHBremner  JDRitchie  JCLindau  FVeledar  ESu  SMurrah  NVJones  LJawed  FDai  JGoldberg  JHazen  SL Association of major depressive disorder with serum myeloperoxidase and other markers of inflammation: a twin study. Biol Psychiatry 2008;64 (6) 476- 483
PubMed
Vaccarino  VJohnson  BDSheps  DSReis  SEKelsey  SFBittner  VRutledge  TShaw  LJSopko  GBairey Merz  CNational Heart, Lung, and Blood Institute, Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute–sponsored WISE study. J Am Coll Cardiol 2007;50 (21) 2044- 2050
PubMed
Frasure-Smith  NLespérance  FIrwin  MRSauvé  CLespérance  JThéroux  P Depression, C-reactive protein and two-year major adverse cardiac events in men after acute coronary syndromes. Biol Psychiatry 2007;62 (4) 302- 308
PubMed
Ormiston  TWolkowitz  OMReus  VIManfredi  F Behavioral implications of lowering cholesterol levels: a double-blind pilot study. Psychosomatics 2003;44 (5) 412- 414
PubMed
Young-Xu  YChan  KALiao  JKRavid  SBlatt  CM Long-term statin use and psychological well-being. J Am Coll Cardiol 2003;42 (4) 690- 697
PubMed
Thombs  BDde Jonge  PCoyne  JCWhooley  MAFrasure-Smith  NMitchell  AJZuidersma  MEze-Nliam  CLima  BBSmith  CGSoderlund  KZiegelstein  RC Depression screening and patient outcomes in cardiovascular care: a systematic review. JAMA 2008;300 (18) 2161- 2171
PubMed
Wulsin  LRSingal  BM Do depressive symptoms increase the risk for the onset of coronary disease? a systematic quantitative review. Psychosom Med 2003;65 (2) 201- 210
PubMed
Bush  DEZiegelstein  RCPatel  UVThombs  BDFord  DEFauerbach  JA McCann  UDStewart  KJTsilidis  KKPatel  ALFeuerstein  CJBass  EB Post–Myocardial Infarction Depression: Evidence Report/Technology Assessment 123.  Rockville, MD Agency for Healthcare Research and Quality2005;1- 8AHRQ publication 05-E018-2
Kendler  KSGardner  COPrescott  CA Toward a comprehensive developmental model for major depression in men. Am J Psychiatry 2006;163 (1) 115- 124
PubMed
Glassman  AH Does treating post-myocardial infarction depression reduce medical mortality? Arch Gen Psychiatry 2005;62 (7) 711- 712
PubMed
Swenson  JRO’Connor  CMBarton  Dvan Zyl  LTSwedberg  KForman  LMGaffney  MGlassman  AHSertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group, Influence of depression and effect of treatment with sertraline on quality of life after hospitalization for acute coronary syndrome. Am J Cardiol 2003;92 (11) 1271- 1276
PubMed

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