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Psychosomatics 48:418-425, September-October 2007
doi: 10.1176/appi.psy.48.5.418
© 2007 Academy of Psychosomatic Medicine
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Major Depressive Disorder and Comorbid Cardiac Disease: Is There a Depressive Subtype With Greater Cardiovascular Morbidity? Results From the STAR*D Study

Renerio Fraguas, Jr., M.D., Ph.D., Dan V. Iosifescu, M.D., Jonathan Alpert, M.D., Ph.D., Stephen R. Wisniewski, Ph.D., Jennifer L. Barkin, M.S., Madhukar H. Trivedi, M.D., A John Rush, M.D., and Maurizio Fava, M.D.

Received August 30, 2005; revised October 24, 2005; accepted April 30, 2006. From the Dept. of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA; the Dept. of Epidemiology, Univ. of Pittsburgh, Pittsburgh, PA; and the Dept. of Psychiatry, Univ. of Texas Southwestern Medical Center, Dallas, TX. Send correspondence and reprint requests to Renerio Fraguas Jr., M.D., Ph.D., 50 Staniford St., Suite 401, Depression Clinical and Research Program, Massachusetts General Hospital, Harvard University, Boston, MA 02114. e-mail: rfraguas{at}partners.org
© 2007 The Academy of Psychosomatic Medicine


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
The authors conducted exploratory analyses to determine whether specific symptoms of major depressive disorder (MDD) are associated with cardiac disease in 4,041 outpatients at baseline in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. MDD was diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; depressive symptoms were evaluated with the 30-item Inventory of Depressive Symptomatology, Clinician-Rated; and cardiac disease, with the Cumulative Illness Rating Scale. After adjustments for gender, age, ethnicity, education, and employment status, sympathetic arousal and early-morning insomnia were significantly associated with cardiac disease. Prospective studies are warranted to confirm these results.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Major depressive disorder (MDD), diagnosed by standard criteria, has been prospectively associated with myocardial infarction (MI),1 cardiac mortality,2 and associated rehospitalization.3 Depression, defined either by clinical criteria4 or a depression-severity scale threshold score, has been prospectively associated with increased incidence of angina,5 coronary heart disease (CHD),4 heart failure,6 MI,4 and mortality.7 Finally, depressive symptoms, regardless of the diagnosis of depression, have been associated with increased incidence of MI,8 cardiac events,9,10 CHD,11,12 and mortality.11,13 Despite these consistent associations, there has been little investigation of the relationship of cardiac disease with specific depressive symptoms of MDD. Depressive symptom presentation in MDD is quite heterogeneous and can vary greatly from patient to patient. For example, sleep-related symptoms in MDD include insomnia and/or hypersomnia. Researchers have subtyped depression on the basis of certain symptom clusters (e.g., melancholic, anxious, or atypical features). Neurophysiologic studies have consistently supported this approach.14 Therefore, it is reasonable to hypothesize that those with cardiac disease and MDD have a different depressive symptom presentation than those with MDD and no cardiac disease. Anxiety disorders frequently co-occur with depression and may contribute to the increased cardiac morbidity seen in depressed patients. Symptoms of anxiety have been associated with CHD16 and fatal CHD.17 Also, panic disorder has been associated with an increased mortality rate, particularly from cardiac causes.18 However, few studies have investigated the cardiac impact of a concurrent anxiety disorder in depressed patients.13 This study investigated differences in the sociodemographic and clinical characteristics of nonpsychotic MDD outpatients with and without cardiac disease enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.19,20


  METHOD

 
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 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 REFERENCES
 
Study Organization
The STAR*D study included 14 regional centers across the United States, each of which conducted the protocol at two to four clinical sites. Of the 41 clinical sites, 18 were primary-care settings, and the remainders were psychiatric-care settings. (Detailed study methods are available elsewhere.19) In brief, the STAR*D study investigated treatment alternatives for outpatients with nonpsychotic MDD with an unsatisfactory clinical response to initial treatment with a selective serotonin reuptake inhibitor (SSRI) or to subsequent treatments (if needed).

Participants
The authors included data from baseline (before starting the first treatment step) in 4,041 male and female outpatients, age 18–75 years, with nonpsychotic MDD, and a 17-item Hamilton Rating Scale for Depression (Ham-D–17)21 score ≥14 obtained by the Clinical Research Coordinator (CRC). All subjects in this report provided written informed consent for study participation.

Exclusion Criteria
Exclusionary diagnoses were schizophrenia, schizo-affective disorder, bipolar disorder, anorexia nervosa or primary diagnosis of an eating disorder, or obsessive-compulsive disorder (OCD). Individuals with current substance abuse or dependence were study-eligible, provided inpatient detoxification was not required clinically. Individuals were also excluded if they had a well-documented history of nonresponse to, or clear intolerance to, adequate doses of an SSRI or one of the other medications utilized in the first two protocol treatment steps during the current major depressive episode. Participants were also excluded if they were receiving a specific psychotherapy for depression. Other exclusion criteria were severe, unstable concurrent psychiatric conditions that would likely require hospitalization within 6 months (e.g., severe alcohol dependence with recent detoxification admissions), and concurrent medical or psychiatric conditions contraindicating the use of protocol treatment options within the first two protocol treatment steps.19 Concomitant use of nonpsychotropic medications or anxiolytics and sedative-hypnotics, were not exclusionary, provided the patients’ clinicians determined that protocol-specified antidepressants would still represent safe and appropriate treatments. Finally, participants who were pregnant or who were trying to become pregnant were also excluded.

Data Collection
After obtaining written informed consent, the CRCs collected clinical and demographic data, previous course of illness, current and past substance abuse, earlier suicide attempts, family history of mood disorders, current general-medical illnesses (GMCs), and previous history of treatment (both medication and psychotherapy) during the current major depressive episode. The CRCs also confirmed the clinician’s diagnosis of MDD, using a checklist of DSM–IV criteria.

Concurrent Psychiatric Disorders
Participants completed a modified version of the Psychiatric Diagnosis Screening Questionnaire (PDSQ) to assess concurrent psychiatric symptoms.22,23 This measure was used to identify 11 DSM–IV Axis I diagnoses on the basis of a 90% specificity threshold.24

Depressive Symptoms
Trained Research Outcome Assessors (ROAs) conducted telephone interviews within 72 hours of the baseline visit, and completed the Ham-D–17 and the 30-item Inventory of Depressive Symptomatology–Clinician-Rated (IDS–C30), using a semistructured interview.25 Participants also completed the 16-item Self-Rated Quick Inventory of Depressive Symptomatology (QIDS-SR–16).26

Cardiac Disease
Cardiac disease and other current general-medical conditions (GMCs) were assessed with the 14-item Cumulative Illness Rating Scale (CIRS),27 completed by the CRCs using a scoring manual. The CIRS scores the severity/morbidity of GMCs for each of 14 organ systems from 0 to 4 and has a good validity and interrater reliability (intraclass correlations of 0.78 and 0.88).28,29 The cardiac disease severity scores were determined in accordance with the following CIRS criteria: 0) no heart problem; 1) current mild problem or past significant problem, which includes any current cardiac problem that causes mild discomfort or disability or has occasional exacerbations that have an overall minor impact on morbidity; remote myocardial infarction (>5 years ago); occasional angina treated with primary-line medications; or a detectable murmur that indicates valvular pathology without activity restriction; 2) moderate disability or morbidity; requires "first-line" therapy; includes cardiac heart failure compensated with medications; daily anti-angina medications; left-ventricular hypertrophy, atrial fibrillations, bundle-branch block, and daily antiarrhythmic drugs; 3) chronic conditions that are not controlled with "first-line" therapy, with the presence of a constant significant disability, however, many less-strenuous activities are possible; includes previous MI within 5 years, abnormal stress test, and post-percutaneous coronary angioplasty or coronary artery bypass graft surgery; 4) extremely severe; immediate treatment required, organ failure, severe impairment in functioning; includes the late stages of disease or disability within a category; failure to arrest the disease process, with resulting disability, pain, or restricted activities of daily living, and any acute condition that requires immediate treatment.

Statistical Analysis
For purposes of statistical analysis, the authors considered a score of "0" in the CIRS as absence of cardiac disease and any score ≥1 as presence of cardiac disease. Comparisons between patients with and without cardiac disease were conducted for clinical, psychosocial, and demographic characteristics (N=4,041), psychiatric comorbidities (N=3,993), and for each IDS–C30 symptom (N=3,745). The sample size varied across comparisons because of missing data. Continuous measures by the presence of cardiac disease were carried out with the Student t-test (two-tailed) for normally distributed data and with the Mann-Whitney U test if data were not normally distributed. A chi-square test was used to compare discrete variables between patients with and without cardiac disease. To investigate the association of cardiac disease with depressive symptoms and psychiatric comorbidities, logistic-regression models were constructed, and the results were adjusted for gender, age, ethnicity, education, and employment status. Significance was set at ≤0.05. These analyses are exploratory in nature, so no post-hoc adjustment in p values for multiple comparisons was used; results must be interpreted accordingly.


  RESULTS

 
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 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 3,463 MDD subjects (85.7%) did not have cardiac disease as measured by the CIRS (score: 0); 333 subjects (8.4%) had current mild or past cardiac problem (score: 1); 191 (4.7%) had moderate cardiac disability/morbidity (score: 2); 49 (1.2%) had severe constant cardiac disability (score: 3), and 3 (0.1%) had extremely severe cardiac disease (score: 4). Subjects with cardiac disease were significantly more likely to be treated in primary-care settings than those without cardiac disease (adjusted for gender, age, ethnicity, education, and employment status; Table 1). Subjects with cardiac disease were significantly more likely to have a positive family history of depression and a lower numbers of depressive episodes, than those without cardiac disease. Depression severity (by Ham-D–17 and IDS–C30) was significantly but minimally greater in subjects with as opposed to without cardiac disease (Table 1).


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TABLE 1. Psychosocial, Demographic, and Clinical (Course of Illness and Disease Severity) Characteristics by Presence or Absence of Cardiac Disease, N (%)



The presence of cardiac disease was associated with symptoms of sympathetic nervous system arousal (i.e., palpitations, tremors, blurred vision, tinnitus, or increased sweating, dyspnea, hot and cold flashes, and chest pain) and early-morning insomnia, as assessed with the IDS–C30 (Table 2) after adjusting for gender, age, education, ethnicity, and employment status. Subjects with cardiac disease also had a higher rate of panic disorder (Table 3). There were no significant differences in rates of other comorbid Axis I disorders or depressive symptomatology between patients with and without cardiac disease.


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TABLE 2. Prevalence of IDS–C30 Symptoms by Presence or Absence of Cardiac Disease, N (%)




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TABLE 3. Psychiatric Comorbidities (Psychiatric Diagnosis Screening Questionnaire [PDSQ]) by Presence or Absence of Cardiac Disease, N (%)




  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
REFERENCES
 
In this baseline STAR*D study investigation with 4,041 MDD outpatients, cardiac disease was associated with symptoms of sympathetic arousal and early-morning insomnia after adjustments for gender, age, ethnicity, employment status, and education. To our knowledge, this is the first time these symptoms have been identified as potential clinical features of MDD with increased association with cardiac disease. The authors also found an association of cardiac disease with increased rates of concurrent panic disorder and a positive family history of depression, after adjustments for gender, age, ethnicity, education, and employment status. The association between sympathetic arousal and cardiac disease in our depressed outpatients is consistent with earlier evidence of increased sympathetic (or decreased parasympathetic) CNS activity as a potential mechanism by which depression exerts increased cardiac morbidity.30 Sympathetic hyperreactivity, generally defined as a dispositional tendency to exaggerated heart-rate and blood-pressure responses in the face of challenging or aversive events, has been associated with more rapid progression of carotid atherosclerosis.31 Insomnia has been prospectively associated with an increased risk of MI32 and cardiac mortality.33 Insomnia in MDD has been associated with increased levels of excreted norepinephrine, epinephrine, and dopamine.34 Thus, it is possible that an increased sympathetic tone is responsible for the increased cardiac morbidity and mortality associated with insomnia, which is consistent with our findings of an association between cardiac disease and both increased sympathetic arousal and early-morning insomnia. The finding of an association between concurrent panic disorder in MDD patients and cardiac disease also suggests the relevance of increased sympathetic arousal, given that patients with panic disorder have been reported to have increased sympathetic activation.35 Although less extensively studied than depression, panic disorder has also been associated with cardiac morbidity and mortality.18 High anxiety scores have previously been associated with cardiovascular risk factors.36 However, given that a prospective study did not find an association of trait-anxiety or state-anxiety and cardiac mortality,13 it is probably relevant to make the distinction between a chronic and moderate-intensity anxiety, as seen in generalized anxiety disorder, and an episodic, high-intensity anxiety, as seen in panic disorder, when the objective is to evaluate the cardiovascular impact of anxiety, as previously recommended.15 Of note, our depressed patients with cardiac disease had a higher rate of family history of depression than those patients without cardiac disease, further strengthening the hypothesis of a possible common genetic factor for both depression and cardiac disease. Using genetic models, it has been found that the occurrence of depression and cardiac disease in twins was partly explained by common genetic risk factors.37 Also, the allelic combination that has been reported to increase the risk of MI38 was also found to increase the vulnerability for depressive disorder.39

Our study has several limitations. First, the cross-sectional design does not allow inferences about causality. Another limitation is the diagnosis of cardiac disease, which was defined by using the CIRS. Although the CIRS uses objective definitions of scores and has been considered a valid and reliable method for measuring clinical comorbidity in research,28,29 the use of data obtained from a patient interview as the only procedure for diagnosing cardiac disease is clearly a limitation. However, other large studies have also based cardiac endpoints on self-report data.1,4 and this procedure seems to have acceptable reliability.1 Under the variable for cardiac disease, the authors included disorders with different pathophysiologies that could reduce the usefulness of this concept as a dependent variable. However, depression has been associated with several cardiac disorders and with dysfunction such as cardiac arrhythmia,44,45 heart failure,46,47 coronary heart disease, and with myocardial revascularization.48,49 Diverse cardiac risk factors50 and markers of cardiac morbidity50 suggest that the association may, in fact, be mediated by several pathophysiologic mechanisms. Consequently, it is reasonable to investigate the existence of a depressive subtype linked with cardiac pathology. The authors did not evaluate negative affectivity, distressed personality, hostility, and anger, which is a limitation, since such psychological/psychiatric factors may mediate the potential cardiac impact in individuals with MDD.51 Also, although the depressive symptoms were scored only if not better explained by a physical disorder, it is possible that symptoms of sympathetic arousal were at least in part due to the cardiac disease itself. The association of cardiac disease with panic disorder may also be questioned, given the absence of an association between cardiac disease and panic symptoms. However, since patients with panic disorder do not necessarily present with panic symptoms (given its episodic nature) at study entry, there may be a true association of cardiac disease with panic disorder. Panic disorder is better defined as a long-term condition, as compared with the mere presence of panic symptoms; the long-term effect may explain an association with cardiac disease. Another study limitation is the low prevalence of some psychiatric disorders, which yields low statistical power to detect an association. For example, only 14 subjects received the diagnosis of somatization disorder, which diminishes the power to detect its association with cardiac disease, increasing the probability of a Type II error. Last, our investigation was exploratory, and the authors tested the association of cardiac disease with 30 depressive symptoms and 11 psychiatric disorders, increasing the probability of a chance p value <0.05 (Type I error). If the Bonferroni correction were used, because the authors performed 41 tests, only p values <0.0012 would be considered significant. Thus, the association of cardiac disease with early-morning insomnia and sympathetic arousal would still be significant in the unadjusted model (p<0.0001 for both), but not after adjusting for gender, age, education, employment status, and ethnicity (Table 2).

Our study is unique in determining, in a large, representative outpatient sample with MDD, that cardiac morbidity was associated with increases in sympathetic arousal and insomnia. If confirmed by prospective studies, a possible implication of these findings is that treatments best suited for depressed patients with cardiac disease should also resolve symptoms of sympathetic arousal and insomnia in addition to those symptoms typically associated with depression symptoms. Consequently, special attention to these symptoms will be essential in treatment programs and research focusing on depression and cardiac disease.

This study was funded by the National Institute of Mental Health (NIMH) under Contract N01-MH-90003 to UT Southwestern Medical Center (A.J. Rush, P.I.). The content of this publication does not necessarily reflect the views or policies of the Dept. of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Dr. Fraguas is supported by the National Council for Scientific and Technological Development, CNPq–Brazil, Grant 200776/2003-7E.


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 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 

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