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Ann Thorac Surg 2003;75:314-321
© 2003 The Society of Thoracic Surgeons

Review

Depression and anxiety and outcomes of coronary artery bypass surgery

Virginie Pignay-Demaria, MDa,c, François Lespérance, MDa,e, Roland G. Demaria, MD, PhDb,d, Nancy Frasure-Smith, PhDa,f, Louis P. Perrault, MD, PhDb*

a Department of Psychosomatic Medicine, Montreal Heart Institute, Montreal, Quebec, Canada
b Department of Surgery, Montreal Heart Institute, Montreal, Quebec, Canada
c Department of Medical Psychology and Psychiatry, Lapeyronie Hospital, Montpellier, France
d Department of Cardiovascular Surgery, Arnaud de Villeneuve Hospital, Montpellier Teaching Hospital, Montpellier, France
e Department of Psychiatry, University of Montreal Teaching Hospital, Montreal, Quebec, Canada
f Department of Psychiatry, McGill University, Montreal, Quebec, Canada

* Address reprint requests to Dr Perrault, Research Center, Montreal Heart Institute, 5000 Bélanger St, Montreal, QC H1T 1C8, Canada.
e-mail: lpperrau{at}icm.umontreal.ca


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Overview of epidemiology of...
 Depression and anxiety before...
 Pathophysiology
 Implications for clinical...
 Comment
 Acknowledgments
 References
 
Psychological and psychiatric disorders independently increase the risk of cardiovascular disease and worsen the prognosis in patients with established cardiovascular lesions. The objective of this literature review is to discuss recent data concerning the relationships between depression and anxiety and the outcomes of coronary artery bypass grafting. Pathophysiological hypotheses are put forward to explain observed links. We suggest recommendations aimed at improving the psychological evaluation and management of heart surgery candidates, as well as postbypass patients, in the hope of improving quality of life and cardiovascular outcomes in these patients.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Overview of epidemiology of...
 Depression and anxiety before...
 Pathophysiology
 Implications for clinical...
 Comment
 Acknowledgments
 References
 
Many studies have shown depression, anxiety, or a combination of the two to be linked to the risk of cardiovascular disease independently of classic risk factors, both in patients with established coronary artery disease (CAD) and in previously healthy individuals. There are several excellent reviews of this literature [1–6]. Somewhat surprisingly, given the increasing use of coronary artery bypass grafting (CABG) procedures, there has been relatively little specific consideration of the importance of these psychological factors in those undergoing CABG. Therefore, a review of published data on depression and anxiety in CAD was undertaken, paying special attention to issues concerning CABG patients. The aim of the present review is to describe the current state of knowledge about symptoms of depression and anxiety in CABG patients, and to provide practical suggestions about the pre- and postoperative treatment of psychological factors.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Overview of epidemiology of...
 Depression and anxiety before...
 Pathophysiology
 Implications for clinical...
 Comment
 Acknowledgments
 References
 
The identification of articles in English language peer-reviewed journals was obtained by using PubMed from 1980 to 2001 (www.ncbi.nlm.nih.gov/PubMed), with key words as follow: depression, anxiety, mood disorder, and coronary artery bypass graft surgery. The articles were also identified by searching on any author who had contributed one relevant article and by using the function "related articles" in PubMed.


   Overview of epidemiology of depression and anxiety in coronary artery disease
Top
 Abstract
 Introduction
 Material and methods
 Overview of epidemiology of...
Depression and anxiety before...
 Pathophysiology
 Implications for clinical...
 Comment
 Acknowledgments
 References
 
Many studies conducted over the last 10 years have documented that the prevalence of depression is increased among patients with various manifestations of CAD, including those recently hospitalized for an acute myocardial infarction (AMI) [7, 8], unstable angina [9], congestive heart failure [10], and coronary catheterization or angioplasty [11, 12]. There is also evidence of an increased prevalence in patients with stable coronary artery disease [13], and at 6 months and 1 year after an AMI [14]. Depending on the population studied and the instrument used, the prevalence of major depression, as defined by the American Psychiatric Association’s Diagnostic and Statistical Manual(DSM-IV) [15], has been estimated to be between 16% and 23%, and the prevalence of high levels of depressive symptoms between 31.5% and 60% [3, 4]. However, it is well understood that depressive symptoms and major depression are two aspects of the same psychopathology. These depression rates can be compared with those usually seen in community-based epidemiological studies, which typically find 1-month prevalence estimates of 2% to 3% and lifetime prevalences of 6% to 9% [16].

Interestingly, the high prevalence of depression in CAD patients is not explained by cardiac disease severity or CAD-related functional impairments [7, 12]. Furthermore, not only is depression highly prevalent, but it also predicts subsequent major cardiac events [1, 3, 4, 7–9, 17–20]. In summary, of all the psychosocial risk factors reported to play a role in CAD, depression is therefore best supported by well-designed prospective epidemiological studies [3–5]. In fact, several studies also suggest that depression may be a major risk factor for the development and progression of CAD in initially disease-free individuals [21].

Although not as convincing, there are also research data to suggest that anxiety may influence the prognosis in patients with established CAD [1, 22, 23], and influence the development of cardiovascular lesions in previously healthy subjects [1, 22, 24]. For example, patients free of CAD and having phobic anxiety symptoms have been reported to have a four- to sixfold increase in the risk of fatal cardiac events [24].


   Depression and anxiety before and after bypass surgery
Top
 Abstract
 Introduction
 Material and methods
 Overview of epidemiology of...
 Depression and anxiety before...
Pathophysiology
 Implications for clinical...
 Comment
 Acknowledgments
 References
 
In contrast to the large number of studies documenting relationships between depression and anxiety and cardiovascular disease outcomes, relatively few studies have examined links between psychological symptoms and morbidity and mortality after CABG. Although there is some evidence that surgery may be associated with better psychological and social outcomes after AMI than nonsurgical treatment [25], symptoms of anxiety, depression, or reactive stress are commonly reported among patients with a history of CABG [26, 27].

Depression and anxiety before surgery
The prevalence of depression was estimated to be between 27% and 47% in patients scheduled for heart surgery, and 19% to 61% after heart surgery [28]. Preoperative anxiety or depression seems to reliably predict the occurrence of symptoms or psychopathology after surgery [29–31]. Although the levels of symptoms of anxiety or depression [28, 30] were significantly less marked after surgery than at baseline, the scores were far higher than in patients who were free of psychopathological disturbances before surgery [32].

Pirraglia and associates [28] identified a number of predictors of postoperative depression, including poor social support, at least one stressful life event during the last year, a low level of education, and moderate to severe dyspnea. Furthermore, they reported that spending more than 2 days in the intensive care unit or feeling that assistance was not available may be associated with a higher risk of postoperative depression.

Other psychological factors besides depression and anxiety have been reported to predict surgical outcome. For example, some character traits, including a take-charge attitude, denial, and optimism, and psychosocial factors, such as quality of social support, may predict a favorable postoperative outcome [29]. Thus, optimism has been reported to correlate with a lower readmission rate 6 months after CABG, independently from socio-demographic and medical variables [33]. Conversely, pessimistic tendencies predicted greater psychological distress (anxiety, depression), greater functional restriction, and ineffective coping strategies during a 20-month postoperative follow-up period [34].

Depression and anxiety and outcomes after CABG
The first clinical observations suggesting that symptoms of anxiety and depression may be associated with worse outcomes after cardiac surgery were published in the 1960s [35, 36]. More recent studies have confirmed these initial observations [18, 31, 33, 37]. To date, only one study has shown that patients with major depression are more likely to experience unfavorable outcomes after CABG [38] (Table 1).


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  		Table 1. Impact of Depression on Postoperative Outcomes

 
Depression and surgical outcomes
Saur and associates [31] studied 416 patients scheduled for CABG, and reported that presence of depressive symptoms before or after surgery was positively correlated with the rate of readmission for cardiac problems within 6 months after CABG. Similar results were obtained in an earlier study in 309 patients [33]. Other studies have suggested that preoperative symptoms of depression significantly predict postoperative cardiac events (unstable angina, AMI, repeat CABG, or angioplasty) or death [18, 33, 37]. In a recent study of 158 patients, the mortality rate after the first postoperative month was six times higher among the 24 patients with preoperative symptoms of depression than in the other 134 patients [37]. However, this marked effect requires confirmation in a larger number of patients.

Connerney and coworkers [38] evaluated the impact of major depression and depressive symptoms in 309 CABG patients. Of the 63 patients who met modified DSM criteria for a major depressive episode at hospital discharge, 27% experienced a cardiac-related event, usually ischemia related, within the first year after surgery, as compared with 10.2% of patients without depression. This study provides compelling evidence that major depression significantly increases the incidence of nonfatal cardiac events, independently from classic risk factors, and that its effect on postsurgical outcomes is similar in magnitude to that of a low ejection fraction (< 35%) or female gender. However, in contrast to the results for major depression, marked depressive symptoms were not significantly correlated with postsurgical cardiac events. Similar results were obtained earlier by Pirraglia and associates [28] in 218 patients who underwent CABG. The apparent discrepancy between these results and those described above, which found an impact of depressive symptoms, may be related to differences in assessment methods (diagnostic tools, subjectivity of replies to self-administered questionnaires) and to the short duration of follow-up.

Perski and associates [18] monitored 171 CABG patients for 3 years. Among the 33 subjects with a high level of emotional distress before surgery (symptoms of anxiety, depression, asthenia), 16% experienced cardiac events during follow-up, as compared with 5% in the patients with no evidence of psychological distress. In addition, these symptoms had a significant negative relationship with the quality of life 1 year after surgery, particularly in patients older than 65 years of age. Studies in elderly patients have shown that CABG improves outcomes, including quality of life [39]. Thus, emotional distress, but also loss of basic activities of daily living and lack of participation in social activities, and even absence of religion, may increase the risk of postoperative death after cardiac surgery, and should be considered as prognostic factors in these patients [31, 40].

Anxiety and surgical outcomes
The relationship between symptoms of anxiety and outcomes after coronary surgery seems less straightforward [41]. The small size of the studies and the differences in the type of disturbance evaluated (anxiety disorder, symptoms, or trait anxiety) may explain the discrepancies across studies. The links with outcomes may vary according to the type of disturbance. For instance, in a study that evaluated state and trait anxiety in 94 patients 24 to 48 hours before cardiac surgery, acute preoperative anxiety was significantly associated with adverse outcomes, acting as an independent risk factor for postoperative morbidity and mortality, whereas trait anxiety was not [41]. Larger studies are needed to confirm and expand these preliminary data.


   Pathophysiology
Top
 Abstract
 Introduction
 Material and methods
 Overview of epidemiology of...
 Depression and anxiety before...
 Pathophysiology
Implications for clinical...
 Comment
 Acknowledgments
 References
 
The factors that link major depression or depressive symptoms, and possibly anxiety, to an increased risk of postsurgical morbidity and mortality remain unclear. In addition to the pathophysiological disturbances postulated to underlie relationships between depression and anxiety and prognosis in CAD patients, several factors specific to cardiac surgery may be involved in CABG patients.

According to several reviews of the current data, symptoms of depression, and to some extent anxiety, may promote the development of cardiovascular lesions through multiple pathophysiological pathways, including a direct influence on health-related behaviors (such as smoking, poor diet, poor compliance with treatment, or an inactive lifestyle) [1, 42], as well as effects on myocardial perfusion, autonomic nervous system regulation, platelet activation, hypothalamo-pituitary-adrenal axis activity, and inflammatory processes [1, 3, 6].

Acute stress has been shown to increase systolic and diastolic blood pressure and myocardial oxygen consumption and to decrease relative coronary perfusion, thereby potentially promoting myocardial ischemia [43]. Hyperventilation, which is common during acute anxiety such as panic attacks, can promote coronary artery spasm or arrhythmia, which can trigger fatal cardiac events both in patients with CAD and in apparently healthy individuals [44]. Ongoing research suggests that induction of panic attacks in the laboratory by inhalation of CO2 can cause cardiac ischemia detectable by myocardial perfusion scintigraphy [45].

An increased activity of the sympathetic nervous system, and conversely, decreased parasympathetic activity, have also been long postulated as important mechanisms linking various manifestations of stress and coronary artery disease. Assessment of the sympathetic nervous system in clinical research has relied primarily on two techniques: evaluation of plasma concentrations of norepinephrine and assessment of heart rate variability. Heart rate variability, denoting decreased parasympathetic activity or increased sympathetic activity, has been reported in patients with major depression, severe anxiety, or hostility [6, 44, 46]. There is substantial evidence that decreased heart rate variability has negative prognostic implications after AMI [47], as well as among CAD patients in general. This abnormality may promote the occurrence of ventricular arrhythmias or sudden death in patients with both CAD and anxiety or depression [2]. Preliminary studies suggest that cognitive behavioral therapy may significantly improve heart rate variability in patients with severe depression [48] and reduce premature ventricular complexes in patients who received counseling for their hostility and time urgency [44]. However, there is no evidence from large studies that antidepressants improve heart rate variability [49].

Elevation of plasma norepinephrine and norepinephrine metabolites, as well as increased norepinephrine secretion, have been documented in patients with major depression not suffering from cardiac disease [50]. This may contribute to the development of cardiovascular disease by a direct effect of catecholamines on myocardial excitatory activity [1, 2] and by effects on platelets, vascular reactivity [1, 51], and hemodynamic factors (increased shear stress). This may promote cardiac rhythm disorders, activate platelet aggregation, and modify vasoactivity and vessel permeability, thereby increasing the risk of ischemic and arrhythmic cardiac events [1, 3]. However, an increase in norepinephrine plasma levels has not yet been confirmed among depressed CAD patients [52].

Platelets play a pivotal role in the occurrence of acute coronary events by interacting with the subendothelial components of the vessel wall and with plasma coagulation factors. Several studies have documented heightened platelet activity among patients with depression, with or without comorbid CAD. In patients with depression, the circulating catecholamine levels increase, triggering aggregation of platelets and release of various pro-aggregant factors involved in several processes, including inflammation and vasomotricity. It has been suggested that these effects contribute to the development of thrombi, vessel wall damage, and arteriosclerosis [53, 54]. Furthermore, serotonin released by platelets facilitates platelet aggregation and coronary vasoconstriction by an effect on 5HT2 receptors and serotonin reuptake sites [55], thus potentially inducing thrombotic and ischemic events. It has been suggested that the impact of depression may be mediated through modifications in the regulation of platelet serotonin receptor [56] and reuptake sites [57]. Emotional stress (hostility, anger) could also promote atherogenesis by different mechanisms: correlation with adverse lipid profile and hypertension, vasoconstriction induced by stress-related-neurotransmitters, and influence of cytokines increasing platelet activity [44].

Finally, hyperactivity of the hypothalamo-pituitary-adrenocortical axis has been demonstrated in patients with untreated depression and no evidence of CAD [3]. High plasma cortisol levels have been shown to promote the development of atherosclerotic lesions, and administration of supraphysiological dosages of corticosteroids to modify serum lipids, to increase the risk of arterial hypertension, and to induce endothelial damage [51, 58]. Furthermore, hyperactivity of hypothalamic neurons that produce corticotropin-releasing hormone (CRH) may indirectly stimulate various autonomic nervous centers involved in regulating sympathetic activity [59].

In patients with anxiety or depression, the effects of the direct vascular trauma associated with cardiovascular surgery [60, 61] occur against a background of preexisting physiologic alterations, including vascular endothelial dysfunction, neurohormonal changes, and instability of myocardial excitatory properties, thus posing an additional threat to the circulatory and homeostatic balance. In fact, one recent study found that acute preoperative stress was associated with hemostatic disturbances, and also dyslipoproteinemia, serum lipid elevation, and changes in the cellular antioxidant system during surgery, as well as with evidence of coronary artery insufficiency or arrhythmia by Holter recording 24 hours after surgery [62].

Cognitive disorders are common after bypass surgery. Interestingly, symptoms of depression and anxiety may precede or follow acute cognitive disorders. Indeed, a low level of education, preoperative cognitive impairments, and symptoms of depression or anxiety may be risk factors for the development or worsening of cognitive impairments after surgery [63, 64]. Awareness of cognitive impairment is a frequent source of anxiety or depression in surgical patients during the postoperative period [27, 64]. Moreover, neurocognitive impairment can also be manifested as symptoms of anxiety or depression, raising challenging diagnostic problems.

The use of cardiopulmonary bypass (CPB) has been incriminated in the genesis of neurocognitive deficiencies, with potential mechanisms involved being hypoperfusion and multiple microemboli of gas or atheromatous material [65]. The recently introduced beating-heart surgery could potentially be less likely to affect cognitive function than surgery with CPB [66], particularly in elderly patients. However, recent data suggest that patients who received their first CABG surgery without CPB had improved cognitive outcomes 3 months after the procedure, but the effects were limited and became negligible at 12 months [67].


   Implications for clinical practice
Top
 Abstract
 Introduction
 Material and methods
 Overview of epidemiology of...
 Depression and anxiety before...
 Pathophysiology
 Implications for clinical...
Comment
 Acknowledgments
 References
 
Interventions before surgery
Evaluation and psychological support specifically designed to reduce the apprehension and emotional tension experienced by CAD patients before cardiac surgery may prevent adverse effects, thus facilitating postoperative recovery and reducing the cost of care [64]. Given that symptoms of anxiety and depression are common in patients scheduled for CABG [26] and can influence the outcome of the procedure, detection of these symptoms during the preoperative evaluation is essential. Structured interviews or self-administered questionnaires may be used for diagnostic orientation and, if needed, pharmacological or psychotherapeutic interventions can be instituted.

Among antidepressants, tricyclic agents and monoamine oxidase inhibitors have adverse cardiovascular effects that contraindicate their use in patients with CAD [17]. Selective serotonin reuptake inhibitors (SSRIs) are, at present, the most widely prescribed antidepressant drugs because of their good safety profile, particularly regarding the cardiovascular system [49]. However, some SSRIs may interact with some cardiovascular drugs, in particular by inhibiting isoenzymes of the cytochrome P450 complex. Among currently available SSRIs, citalopram may have the lowest risk of interactions with other drugs, followed by sertraline [17, 68]. Nevertheless, because the beneficial effects of SSRIs become apparent only after a minimum of 2 weeks on average, they cannot be expected to improve symptoms of depression during the preoperative hospital stay. In some patients in line for elective surgery, it may be desirable to postpone surgery until the depressive symptoms respond to treatment, if the stability of the patient’s medical condition permits.

However, no studies to date have provided compelling evidence that pharmacological treatment of depressive symptoms in CAD patients improves cardiac outcomes. Several biochemical and neurophysiological factors may be involved in the development of depressive symptoms in CAD patients (inflammatory process, multiple neurovascular lesions) [69], and therefore, antidepressant drugs may not be as efficacious in these patients as in depressed patients without comorbid physical conditions. The Sertraline Anti-Depressant Heart Attack Randomized Trial (SADHART), which was preceded by an open-label trial [70], can be expected to provide answers about the pharmacological management of patients with depression and unstable angina or a recent AMI. In contrast, acute preoperative anxiety can be brought under control easily and rapidly by a short course of benzodiazepine therapy.

Psychotherapy has been shown to be effective in improving anxiety and depression in patients without CAD. Benefits in patients with CAD have not yet been demonstrated. A small prospective study in 32 patients admitted for CABG evaluated the potential benefits of self-hypnosis–based relaxation taught before surgery. Subjects in the self-hypnosis group were more relaxed and required smaller analgesic doses postoperatively compared with the control group [71]. These findings expand those of earlier studies [72, 73], in which psychological interventions significantly reduced pain, mean hospital length of stay, and postsurgical morbidity. These data support the possibility that pre- and postoperative psychological support may improve quality of life in cardiac surgical patients.

Although the benefits of short-term preoperative intervention have not been established by large-scale randomized trials, clinical experience suggests that routine evaluation and effective treatment of preoperative psychological distress in patients scheduled for coronary revascularization may facilitate postoperative recovery, which may translate into a better cardiovascular prognosis [18, 73]. Preoperative symptoms of anxiety ("afraid to die") or depression ("physically and psychologically depleted," "no reason to go on living") should direct the psychological management toward careful listening, identification of misconceptions about the surgical procedure and postoperative care, and towards rational explanations, comforting, and encouragement to move about.

Interventions after surgery
Whereas brief sessions of psychological support or a prescription of an anxiolytic drug may be all there is time for before surgery when the procedure is urgent, there is general agreement that early intervention should be offered to patients with evidence of psychological distress after surgery [17, 34, 74]. This intervention can consist of antidepressant therapy complying with the above-mentioned recommendations, psychotherapy, or psychosocial management, according to the clinical presentation and to the patient’s wishes and needs. Particular caution must be taken about the early postoperative prescription of benzodiazepine, which may increase the risk of delirium [75].

Preliminary results have shown that early psychological management may be associated with a reduction of hospital length of stay, analgesic use, and postsurgical morbidity [71, 72, 74, 76], and may also help patients adopt more effective coping strategies in their everyday lives [27, 77]. However, there have been few large-scale studies demonstrating the efficacy of early intervention after CABG. In a study of 100 patients with AMI, in whom 50 received nonsurgical treatment and 50 underwent CABG, a stress-management program (based on relaxation) offered 3 months after the AMI or CABG procedure improved most study outcomes, including emotional well-being, daily activities, the ability to participate in social activities, and the quality of social interactions [78]. Furthermore, stress management has been suggested as a component of cardiac rehabilitation programs [79], but again, few studies have been performed to investigate the potential benefits of these programs on outcomes after CABG.

Management
Until scientific data on the practical management of CAD patients with depression or anxiety become available, a reasonable approach is to provide postoperative support based on active mobilization and stimulation of the patient’s physical and psychological capabilities. The goal is to ensure that loss of energy, lack of motivation, or reactions to stress do not cancel out the benefits of cardiac and physical rehabilitation therapy during the first few days after the operation or prevent the patient from returning to his or her usual activities later on. Some patients with depression have a passive attitude that can prolong the duration of bed rest and hospitalization, thereby increasing the risk of immobility-related respiratory and thromboembolic complications. Furthermore, the alterations in immune and inflammatory responses reported in patients with depression [80, 81] can potentially increase the risk of postoperative infectious complications (sternal infection, mediastinitis) [33].

Denial or blunting are common reactions in the immediate postoperative period. These reactions are associated with decreases in anxiety scores, indicating that they serve as coping mechanisms. They seem to predict better psychological outcomes up to 6 months after surgery [82]. Furthermore, early emotional reactions (insomnia, mood swings, irritability, nervous tension) may reflect transient difficulty in adjusting to the physical and psychological stress associated with surgery. Similarly, complaints of atypical, diffuse somatic symptoms persisting in the absence of objective evidence of an underlying organic abnormality may indicate latent anxiety and depression, requiring a detailed psychiatric assessment and specific support. Conversely, persistence of symptoms of anxiety or depression for longer than 3 months after surgery may, as mentioned above, have a negative impact on medical, surgical, and psychosocial outcomes.

Finally, beyond the patient’s psychological stress, a somatic cause should be systematically sought and excluded. Symptoms of acute anxiety or loss of energy can herald a medical complication. Close cooperation between the psychiatrist and the medical and surgical team can assure establishment of the correct diagnosis in this situation and institution of the appropriate treatment.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Overview of epidemiology of...
 Depression and anxiety before...
 Pathophysiology
 Implications for clinical...
 Comment
Acknowledgments
 References
 
Depression and anxiety are well-recognized cardiovascular risk factors, similar in importance to smoking and hypertension, and must be detected and treated. These psychological disorders can affect the outcomes of cardiovascular disease by numerous pathophysiological mechanisms.

Furthermore, recent studies have confirmed that symptoms of depression or anxiety are associated with worse outcomes after CABG, often with a marked alteration in quality of life. Careful routine evaluation of these symptoms as part of the preoperative workup may allow identification of these high-risk patients, who may benefit from psychological support tailored to their specific needs and aimed at improving their long-term medical and surgical prognosis and their quality of life.

These observations are an invitation to treat psychological distress in patients undergoing CABG and to enhance cooperation between surgeons, cardiologists, and psychiatrists.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Overview of epidemiology of...
 Depression and anxiety before...
 Pathophysiology
 Implications for clinical...
 Comment
 Acknowledgments
References
 
We are greatly thankful to Luce Bégin for the preparation of the manuscript.


   References
Top
 Abstract
 Introduction
 Material and methods
 Overview of epidemiology of...
 Depression and anxiety before...
 Pathophysiology
 Implications for clinical...
 Comment
 Acknowledgments
 References
 

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