This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sheps, D. S. Articles by Rozanski, A. Search for Related Content PubMed Articles by Sheps, D. S. Articles by Rozanski, A. Related Collections Depression

From Feeling Blue to Clinical Depression: Exploring the Pathogenicity of Depressive Symptoms and Their Management in Cardiac Practice

From the Department of Medicine, Division of Cardiovascular Medicine, University of Florida, Malcom Randall VA Medical Center, Gainesville, Florida D.S.S.); and the Division of Cardiology, St. Luke's–Roosevelt Hospital Center, and the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY (A.R.).

Address correspondence and reprint requests to David S. Sheps, MD, MSPH, Department of Medicine, Division of Cardiovascular Medicine, University of Florida, Malcom Randall VA Medical Center, Gainesville, FL 32610-0277. E-mail: shepsds{at}medicine.ufl.edu

	INTRODUCTION

TOP INTRODUCTION EPIDEMIOLOGY PATHOPHYSIOLOGY THERAPEUTIC CONSIDERATIONS IN... BEHAVIORAL INTERVENTION IN... NOTES REFERENCES

 
This issue of Psychosomatic Medicine includes the first supplement for this journal in nearly 40 years. Why have we chosen to do one now? Evidence is growing that a variety of psychosocial factors are strongly linked to coronary artery disease (CAD), including such factors as depression, poor social support, low socioeconomic status, and various forms of chronic stress (1). Such data should be of interest to the community of internists and cardiologists who take care of patients at risk for heart disease. Mastering this literature, however, is difficult, because articles covering such topics appear in a large number and diverse array of journals: medical psychology journals such as our own, general internal medicine journals, and cardiology subspecialty journals, to name just a few categories.

We have chosen to focus on depression and heart disease because both are associated with substantial morbidity and mortality. Depression is observed quite commonly within cardiac populations, with a prevalence three to four times that of the general population. Moreover, our understanding of how depression is related to CAD is rapidly evolving.

The goal of this supplement is to summarize recent advances in the understanding of the pathogenicity of depressive symptoms and their management in cardiac practice. The articles in this supplement address four topics, including delineating the epidemiology that links depressive syndromes to coronary artery disease (CAD), defining the pathophysiology that mediates this association, evaluating the efficacy of treatment options for depression among cardiac patients, and reviewing potential ways in which cardiologists and other physicians can enhance behavioral intervention in clinical practice.

	EPIDEMIOLOGY

TOP INTRODUCTION EPIDEMIOLOGY PATHOPHYSIOLOGY THERAPEUTIC CONSIDERATIONS IN... BEHAVIORAL INTERVENTION IN... NOTES REFERENCES

 
The first two articles in this supplement offer an interesting contrast in the effort to define the spectrum of depressive disorders that are of potential importance. In their review, Davidson et al. focus on the distinctions between depressive disorders deserving of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) classifications, including major depressive disorder, dysthymia, adjustment disorders, and mood disorder resulting from a general medical condition (2). The DSM-IV also describes milder forms of major depression under its tentatively proposed syndrome of "minor" or "subsyndromal" depression. Davidson et al. observe that lesser depressive symptoms may be measured by self-report scales such as the Beck Depression Inventory (BDI) or the Center for Epidemiological Studies–Depression Subscale, but how these measures relate to major depressive disorders requires more attention according to these authors. To obtain comparative outcome data for each of these depressive states, the authors suggest that investigators should be encouraged to evaluate outcomes data in existing datasets that contain extensive information regarding psychiatric disorders.

In the next chapter, Kubzansky et al. examine the range of mild symptoms, well below the threshold of severe symptoms that define major clinical depression, which may also be associated with adverse cardiovascular outcomes (3). For example, the authors refer to recent studies of postinfarction patients in which BDI scores of only 5 to 9, a very mild range for depressive symptoms, were associated with an increased frequency of cardiac events (4,5). It remains to be determined if this threshold is a reproducible finding, particularly among initially healthy subjects. Nevertheless, other data reviewed by the authors suggest that the range of psychologic factors of interest may be far wider than previously conceived. The authors cite recent evidence linking pessimism, a potential cognitive precursor of depression, to adverse cardiac outcomes. They also review preliminary data that suggest that other negative cognitive states such as worry and rumination may also be associated with adverse cardiovascular effects.

The juxtaposition of these two articles has a practical clinical implication. Whereas psychiatrists are trained to focus on severe depressive symptoms, physicians in clinical practice are commonly exposed to a wide gamut of depressive symptoms, from mild to severe. Pending further study, the results cited in these articles may encourage physicians to pay closer attention to mild depressive symptoms in their patients. There is a spectrum of depressive symptoms, and even negative cognitive states, that may be associated with the development of CAD and thus worthy of our attention and clinical management.

Gender
Knowledge of gender differences in disease prevalence and presentation is important in cardiovascular practice. Ischemic symptoms, for example, often present differently in men and women. Some diagnostic tests such as exercise electrocardiography have different sensitivities and specificities in men and women. Gender may also play an important role in the link between depression and cardiovascular disease. As pointed by Naqvi et al. (6), depression is twice as common in females compared with males within cardiac populations, paralleling a higher incidence of depression in women in the general population. Although emphasizing that depression's potency as a CAD risk factor appears independent of gender, the authors speculate on potential reasons for this gender gap in the prevalence of depression. In light of sparse but suggestive data from treatment trials that is reviewed by the authors, they also suggest the need to develop and assess gender-specific approaches for treating depression among cardiac patients.

Methodologic Issues Regarding Epidemiology Studies of Depression
In the final article in our section on epidemiology, Frasure-Smith and Lespérance focus on methodologic issues related to proper epidemiologic investigation of depression (7). Many of the methodologic challenges cited by the authors pertain to cardiology in general and include such thorny issues as the reliance on death certificates and varying definitions of cardiovascular death based on different International Classification of Diseases (ICD) codes for assessing medical outcome data. The authors also cite a problem more specific to outcome studies regarding depression, that being the reporting of results from studies with insufficient statistical power to detect significant associations between depression and outcomes. The authors emphasize that among studies that have been adequately powered (although sometimes with other methodologic problems), a robust relationship has been noted between depression and cardiovascular outcomes. The authors provide strong grounds for reexamining current methods of adjusting the results of outcome studies for the presence of covariates of depression.

	PATHOPHYSIOLOGY

TOP INTRODUCTION EPIDEMIOLOGY PATHOPHYSIOLOGY THERAPEUTIC CONSIDERATIONS IN... BEHAVIORAL INTERVENTION IN... NOTES REFERENCES

 
Extensive progress has been made in understanding the pathophysiology by which depression causes cardiovascular disease. In part, this has been made possible through advances in understanding the pathobiology of atherosclerosis, which is now widely recognized to be an atheroinflammatory process. Important mediators of atherosclerosis that have been characterized in recent years include endothelial dysfunction, inflammation, and a spectrum of hematologic and metabolic abnormalities. Notably, there is now impressive evidence for the presence of all of these abnormalities in people with depression. Pathophysiological research has therefore shifted from a more superficial search for potential mediators to a more "mature" phase of research, which now seeks to identify how each of these mediators is activated and/or exacerbated by the presence of depression. This section of our supplement reflects this maturity.

One of the early important findings is that depression can be associated with hypercortisolemia. Accordingly, this section of our supplement begins with a brief summary of hypercortisolemia by Gillespie and Nemeroff (8). They note the common elevation of corticotropin-releasing factor (CRF) that occurs in the cerebrospinal fluid of depressed subjects. This stimulation leads to hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, high plasma cortisol levels, blunting of the ACTH response to CRF infusion, dexamethasone nonsuppression, and adrenal hypertrophy. The authors note that hypercortisolemia is not universal in depression, a finding that has also been emphasized by Gold and Chrousos (9), but among those depressed subjects with hypercortisolemia, these physiological abnormalities can disappear after successful clinical intervention. The authors conclude by noting experimental pharmacologic approaches that would attempt to treat depression based on the linkage of depression to dysregulation of the HPA axis.

Depression is also associated with stimulation of the sympathetic nervous system, which, as noted by Carney et al., is associated with elevated levels of circulating plasma norepinephrine levels (10). Such stimulation is associated with resultant dysfunction of the autonomic nervous system. The authors note that depressed subjects generally manifest increases in resting heart rates compared with nondepressed controls and decreased heart rate variability in some cohorts with depression. They also review preliminary data regarding baroreflex dysfunction and increased QT variability in depressed subjects.

Depression is also associated with complex platelet abnormalities such as increased concentrations of functional glycoprotein IIb/IIIa receptors (11) and hyperactivity of the 5-hydroxytryptamine (5-HT) transporter_2A receptor signal transduction system (12). Bruce and Musselman provide a detailed list of recent studies regarding abnormalities of platelet activation, secretion, and aggregation among patients with depression or related negative emotional states (11). In addition, they review recent data regarding the potential antiplatelet effects that may result from the use of selective serotonin reuptake inhibitors and discuss potential clinical implications that may be derived from these findings.

Kop and Gottdiener describe new research into the evolving understanding of how depression can promote inflammation (13). They begin their review with an overview of the link between inflammation and atherosclerosis. They next review the relationship between depression and a range of immune abnormalities, including increased production of cytokines and acute-phase proteins such as C-reactive protein. In addition, they discuss the potential bidirectional relationship that may exist between depression and atherosclerosis, citing, for example, data indicating an increase in depressive symptoms after the experimental administration of tumor necrosis factor- (TNF-).

Besides direct pathophysiological effects, depression may contribute to CAD by its recognized association with various coronary-prone behaviors such as smoking, physical inactivity, and poor diets. Moreover, depression may promote lifestyle and medication nonadherence, an important issue in the treatment of cardiac patients.

The relationship between depression and behavior as they relate to the pathogenesis of CAD is complex, as illustrated in a scholarly review of depression and smoking behavior by Freedland et al. (14). They review many aspects of the depression-smoking link such as whether depression and smoking behavior are causally linked to each other (or related to each other by a "third party" such as genetics) and whether smoking plays a direct mediating role in the relationship between depression and CAD.

Overall, the pathophysiological links between depression and CAD are impressive, both for the strength and number of mechanisms involved. These data indicate that depression can be viewed as a disease with broad systemic effects involving potential activation of essentially all of the important mediators of atherosclerosis. The studies exploring the pathophysiological mechanisms of depression can lay the groundwork for such studies of other psychosocial risk factors as well.

Positive Psychologic Factors
If negative psychologic factors are associated with CAD, are positive factors associated with better health outcomes? Recent data, although limited, suggest this may be the case (15). The next article explores this through a paradigm of "flexibility" (16). This paradigm proposes that "vitality," a potentially health-promoting state of positive energy and enthusiasm, is promoted by the ability to exert emotional and coping flexibility. Conversely, inflexibility, including the inflexibility represented by depression and other negative emotional states, diminishes vitality. Prospective evaluation of this idea is required, but preliminary evidence links a wide variety of inflexible life conditions to adverse cardiovascular outcomes.

	THERAPEUTIC CONSIDERATIONS IN PATIENTS WITH KNOWN CORONARY ARTERY DISEASE

TOP INTRODUCTION EPIDEMIOLOGY PATHOPHYSIOLOGY THERAPEUTIC CONSIDERATIONS IN... BEHAVIORAL INTERVENTION IN... NOTES REFERENCES

 
In contrast to the mounting epidemiologic data and rich pathophysiological evidence that links depression to CAD, studies evaluating the benefit of treating depression among patients with CAD are relatively recent and sparse. Three articles review the treatment of depression among patients with CAD. One article examines the relative safety of using selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants in patients with CAD (17); one evaluates nonpharmacologic forms of treating depression in patients with CAD (18), and one reviews lessons learned from the recently conducted clinical trials in patients with CAD with depression, including the ENRICHD and SADHART trials (19). Together, these studies suggest promising opportunities but provide sparse evidence for supporting specific therapies. For example, the potential use of SSRIs for treating depression among known patients with CAD is emphasized by a combination of findings within these reviews, beginning with data indicating these medications have a favorable safety profile in patients with known CAD and preliminary data suggesting that SSRIs may favorably affect various mediators of adverse outcomes such as platelet abnormalities. Lett et al. also note favorable data on the use of exercise as a therapy for reducing both depressive symptoms and adverse event rates among depressed cardiac patients (18). There is, however, a pressing need for further studies that evaluate the impact that various therapies, perhaps alone or in combination, can exert on outcomes among patients with CAD presenting with depression.

	BEHAVIORAL INTERVENTION IN CARDIAC PRACTICE

TOP INTRODUCTION EPIDEMIOLOGY PATHOPHYSIOLOGY THERAPEUTIC CONSIDERATIONS IN... BEHAVIORAL INTERVENTION IN... NOTES REFERENCES

 
Whereas the considerations stated here address the treatment of people with relatively severe depressive symptoms, physicians in clinical practice commonly see patients with milder symptoms and a variety of other psychosocial risk factors that may be associated with CAD. Even if cardiologists are not naturally inclined to consider these psychosocial risk factors, they do commonly ask patients to adhere to specific behavioral suggestions (e.g., change diet, exercise), often with poor results. Psychologic factors, both negative and positive motivational ones, can promote or interfere with patient adherence to physician recommendations. Accordingly, what do physicians need to know to optimize behavioral management in clinical practice? This question is addressed, in part, by the final article in our supplement (20), which summarizes aspects of a recent but rich medical literature concerning motivation. Three potential approaches to optimizing patient adherence are reviewed in light of this literature.

This supplement is dedicated not only to the loyal readership of our journal, but also to the larger medical community we are aiming to reach with this issue. Our hope is that this exposure will lead to greater efforts to evaluate and improve the management of depression and other psychosocial risk factors in cardiac practice.

	NOTES

TOP INTRODUCTION EPIDEMIOLOGY PATHOPHYSIOLOGY THERAPEUTIC CONSIDERATIONS IN... BEHAVIORAL INTERVENTION IN... NOTES REFERENCES

 

In accordance with CME accreditation guidelines, author David S. Sheps disclosed that he has served on the speakers' bureau for Pfizer. Alan Rozanski disclosed no real or potential conflicts of interest.

DOI:10.1097/01.psy.0000164251.27403.d9

	REFERENCES

TOP INTRODUCTION EPIDEMIOLOGY PATHOPHYSIOLOGY THERAPEUTIC CONSIDERATIONS IN... BEHAVIORAL INTERVENTION IN... NOTES REFERENCES

 

1. Rozanski A, Blumenthal JA, Davidson KW, Saab PG, Kubzansky L. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005;45:637–51.[Abstract/Free Full Text]
2. Davidson KW, Rieckmann N, Rapp MA. Definitions and distinctions among depressive syndromes and symptoms: implications for a better understanding of the depression—cardiovascular disease association. Psychosom Med 2005;67(Suppl 1):S6–9.[Abstract/Free Full Text]
3. Kubzansky LD, Davidson KW, Rozanski A. The clinical impact of negative psychological states: expanding the spectrum of risk for coronary artery disease. Psychosom Med 2005;67(Suppl 1):S10–14.[Abstract/Free Full Text]
4. Lesperance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002;105:1049–53.[Abstract/Free Full Text]
5. Bush DR, Zieglestein RC, Tayback M, Richter D, Stevens S, Zahalsky H, Fauerbach JA. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001;5:337–41.
6. Naqvi TZ, Naqvi S. Bairey-Merz CN. Gender differences in the link between depression and cardiovascular disease. Psychosom Med 2005;67(Suppl 1):S15–8.[Abstract/Free Full Text]
7. Frasure-Smith N, Lespérance F. Reflections on depression as a cardiac risk factor. Psychosom Med 2005;67(Suppl 1):S19–25.[Abstract/Free Full Text]
8. Gillespie CF, Nemeroff CB. Hypercortisolemia and depression. Psychosom Med 2005;67(Suppl 1):S26–8.[Abstract/Free Full Text]
9. Gold PW, Chrousos GP. The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc Assoc Am Physicians 1998;111:22–34
10. Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med 2005;67(Suppl 1):S29–33.[Abstract/Free Full Text]
11. Bruce EC, Musselman DL. Depression, alterations in platelet function, and ischemic heart disease. Psychosom Med 2005;67(Suppl 1):S34–6.[Abstract/Free Full Text]
12. Schins A, Honig A, Crijns H, Baur L, Hamulyak K. Increased coronary events in depressed cardiovascular patients: 5-HT_2A receptor as missing link? Psychosom Med 2003;65:729–37.[Abstract/Free Full Text]
13. Kop WJ, Gottdiener JS. The role of immune system parameters in the relationship between depression and coronary artery disease. Psychosom Med 2005;67(Suppl 1):S37–41.[Abstract/Free Full Text]
14. Freedland KE, Carney RM, Skala JA. Depression and smoking in coronary heart disease. Psychosom Med 2005;67(Suppl 1):S42–6.[Abstract/Free Full Text]
15. Salovey P, Rothman AJ, Detweiler JB, Steward WT. Emotional states and physical health. Am Psychol 2000;55:110–21.[CrossRef][Medline]
16. Rozanski A, Kubzansky LD. Psychologic functioning and physical health: a paradigm of flexibility. Psychosom Med 2005;67(Suppl 1):S47–53.[Abstract/Free Full Text]
17. Roose SP, Miyazaki M. Pharmacologic treatment of depression in patients with heart disease. Psychosom Med 2005;67(Suppl 1):S54–7.[Abstract/Free Full Text]
18. Lett HS, Davidson J, Blumenthal JA. Nonpharmacologic treatments for depression in patients with coronary heart disease. Psychosom Med 2005; 67(Suppl 1):S58–62.[Abstract/Free Full Text]
19. Joynt KE, O'Connor CM. Lessons from SADHART, ENRICHD, and other trials. Psychosom Med 2005;67(Suppl 1):S63–6.[Abstract/Free Full Text]
20. Rozanski A. Integrating psychologic approaches into the behavioral management of cardiac patients. Psychosom Med 2005;67(Suppl 1):S67–73.[Abstract/Free Full Text]

This article has been cited by other articles:

				P. P. Roy-Byrne, K. W. Davidson, R. C. Kessler, G. J.G. Asmundson, R. D. Goodwin, L. Kubzansky, R. B. Lydiard, M. J. Massie, W. Katon, S. K. Laden, et al. Anxiety Disorders and Comorbid Medical Illness Focus, October 1, 2008; 6(4): 467 - 485. [Abstract] [Full Text] [PDF]

				J. Bunde and R. Martin Depression and Prehospital Delay in the Context of Myocardial Infarction Psychosom Med, January 1, 2006; 68(1): 51 - 57. [Abstract] [Full Text] [PDF]

				A. Levin Depression, Heart Disease: Links Remain Elusive Psychiatr News, August 5, 2005; 40(15): 33 - 41. [Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sheps, D. S. Articles by Rozanski, A. Search for Related Content PubMed Articles by Sheps, D. S. Articles by Rozanski, A. Related Collections Depression