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Depression and coronary heart disease: Observations and questions
Journal of Psychosomatic Research, Vol. 43, No. 5. pp. 443452, 1997 Copyright © 1997 Elsevier Science lnc. All rights reserved. 0022-3999/97 $17.00 + .00
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EDITORIAL D E P R E S S I O N A N D C O R O N A R Y H E A R T DISEASE: OBSERVATIONS AND QUESTIONS A. A P P E L S evidence that depressive symptomatologyprecedes the onset of the acute coronary syndromes and influencesthe course of disease after their manifestation is accumulating. However, we still are far short of proof that depression has a causal role in the etiologyand pathogenesisof coronary heart disease (CHD). Some unsolved questions concern the causes and the nature of the depression preceding a first or recurrent cardiac event, the biologicalmechanisms relating depression and CHD, the time window of the exposure-disease association, and the power of therapy programs for depression to reduce the risk of a first or recurrent cardiac event. © 1997 Elsevier Science Inc. Abstract--The
Keywords: Coronary heart disease; Depression; Vital exhaustion.
INTRODUCTION In 1987, Booth Kewley and Friedman published a meta-analysis of all studies published between 1945 and 1985 on the psychological predictors of heart disease. Their conclusion was that depression is reliably associated with coronary heart disease ( C H D ) and that, of all personality factors, depression had the highest risk [1]. Several studies published since that date supported this conclusion. Barefoot and Schroll observed that a subset of obvious depressive symptoms, derived from the MMPI, predicted acute myocardial infarction (AMI) over a 27-year period [2]. Feelings of hopelessness were found to precede C H D morbidity and mortality in the Kuopio Ischemic Heart Disease Study and in the N H A N E S study [3, 4]. About 16-18% of patients hospitalized because of MI suffer from major depression according to DSM criteria [5, 6]. Frasure-Smith et al. observed that this subgroup has over four times the death rate of nondepressed patients during the first 6 months of follow-up. Further follow-up to 18 months showed that major depression ceased to predict survival after 6 months. However, the Beck Depression Inventory (BDI) continued to predict survival in later phases of follow-up [7]. Similar findings have been reported by Barefoot, Silverstone, Denollet, and Ladwig. It was first observed that patients with moderate to severe depression, according to their scores on the Zung scale, had a 72% greater risk of cardiac mortality over a period of 19 years [8]. Silverstone observed that patients who felt depressed immediately after hospitalization, according to their scores on the Montgomery-Asberg rating scale, had a poorer outcome (cardiac death or arrest or recurrent MI) than those with low Department of Medical Psychology, Maastricht University, MaastrichL The Netherlands. Address reprint requests to: A. Appels, Department of Medical Psychology, Maastricht University, Box 616, 6200 MD, Maastricht, The Netherlands. Tel.: -043-3881481; Fax: -043-3670952; E-mail: ad. [email protected]
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ratings of depression [9]. Denollet et al. observed that patients with documented CHD, who scored above the median of the depression scale of the Millon Behavioral Health Inventory, had an increased risk of dying within a 6-10-year follow-up period [10]. Ladwig observed that MI patients with elevated scores on a combination of symptoms of manifest depression, emotional isolation, and vulnerability (fatigue; vulnerability to criticism) had an elevated risk of cardiac death within a 6-month follow-up period [11]. Depressive symptomatology was also found to influence the course of the disease in other groups of cardiac patients. The presence of major depression or POMSdefined fatigue at the time of coronary angiography in patients with CHD more than doubles the risk that a major cardiac event will occur within 1 year [12, 13]. Generalized fatigue has been found to be the most important predictor of survival after pace-maker implantation and to increase the risk of mortality in patients with ventricular arrhythmias [14, 15]. In the CAPS study of patients with nonsustained tachycardia after MI it was observed that patients with elevated BDI scores and low scores on the vigor scale of the POMS had an increased risk of cardiac death or cardiac arrest [16, 17]. The evidence that a depressive symptomatology precedes the onset of several manifestations of coronary heart disease and influences the course of the disease after its manifestation is mounting. Therefore, research on the association between depression and CHD is a priority area of psychosomatic medicine. However, we are still far short of proof that depression has a causal role in the etiology or pathogenesis of CHD. Many questions are unanswered. Is the depression in coronary patients essentially the same disorder as depression in non-medical populations? Why are so many patients depressed after MI? Is depression equally associated with several manifestations of coronary heart disease such as MI and sudden cardiac death? Is depression equally associated with CHD in men and women? What biological mechanisms explain the association between depressive symptomatology and coronary events? Does a successful intervention to reduce depression reduce the risk of a first or recurrent cardiac event? Three of these questions will be discussed in the following paragraphs. Insufficient data are available to discuss gender differences in the association between depression and CHD and the association between depression and different manifestations of CHD.
THE NATURE OF THE DEPRESSION BEFORE AND AFTER MYOCARDIAL INFARCTION
Is what we call depression in coronary patients essentially the same disorder as depression in nonmedical populations? The observation that DSM-III-defined depression has a shorter predictive power than BDI defined depression makes many investigators rather cautious in their labeling of the mood state of coronary patients. Some prefer "depressive symptomatology" over "depression," whereas others are of the opinion that the mental state of coronary patients may be better thought of as a general negative affect, because of the substantial and consistent correlation of measures of depression, hostility, anxiety, and fatigue [18]. Doubts with regard to the best term to label the depressive symptoms do not refute the empirical findings. Rather they reflect some uncertainty in the development
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and composition of the symptomatology, the determinants of the post-MI depression, and the homogeneity of depressed coronary patients with regard to the origin of their depression. We have described the mental state before MI as "vital exhaustion" (VE), a state characterized by feelings of unusual tiredness and lack of energy, increased irritability, and feelings of demoralization. This state was found to be a strong, short-term precursor of MI in apparently healthy males [19] and a risk factor for a new cardiac event in angioplasty patients [20]. VE shares a substantial amount of variance with depression. The magnitude of the common variance ranges between 25% and 50%, depending on the methods used to assess both constructs [21]. The label "vital exhaustion" was chosen because many coronary patients indicate that loss of energy and unusual tiredness is their core feeling and that they feel depressed because of that loss of energy. Frequently used expressions are: "I feel hopeless because of my lack of energy"; "I want, but I can't"; "I have the wish but not the power"; "I feel blue because it is hard to accept that I do not have what it takes anymore." These expressions indicate that the sad mood reflects a secondary condition, a condition which is superimposed upon a state of fatigue. In an attempt to check whether there is a sequential order in the depressive symptomatology we reanalyzed the databases of the cohort study of healthy males and of the prospective study of angioplasty patients. Results showed that the items reflecting a negative mood state lost their predictive power when controlled for items asking for exhaustion and loss of energy. This observation does not prove that mood disturbances preceding a cardiac event are a secondary condition. However, they strengthen the need for further investigation to test the hypothesis that, in many coronary patients, a negative mood state is superimposed upon a state of exhaustion. A difference in the constituent elements of depression in MI patients and depression in psychiatric populations seems to be formed by the relative absence of a deprecatory image of the self and of guilt feelings in depressed coronary patients. Psychiatric patients often show a negative image of the self and assume a primary responsibility for a loss, leading to the conclusion that there is no expectation that anyone else can provide a solution. These distorted cognitions are relatively rare in coronary patients. This statement is based on clinical experience and may reflect the fact that the concept of "self-esteem" has a broader connotation in the English language than it has in several other languages. Detailed studies are needed to compare the prevalence of distorted cognitions in mental and cardiac patients and to compare both groups on relevant components or dimensions of depression. Detailed studies are also needed to answer the question of how often a post-MI depression can be labeled as a reactive depression, originating in the need to reorganize one's life, or in the loss of existential goals, and why a minority only is depressed after MI. What are the determinants of major or minor depression after MI? Which factors explain why some patients are depressed after MI and others are not? The available data suggest that 8-16% of all patients were depressed before MI [22, 23] and that 36-50% were exhausted before MI [21, 24, 25]. Ladwig et al. observed that high levels of exhaustion and fatigue in the prehospital phase were significantly related to subsequent high levels of depression [26].
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Lifetime depression also increases the chance that a cardiac patient will be depressed after hospitalization. Lesperance et al. observed that 28% of post-MI patients had at least one episode of major depression at some point in their lives before their admission [22]. Freedland et al. observed that, of 39 patients with recently diagnosed CAD who met DSM-III-R criteria for major depression, 44% had a prior history of MD [6]. These findings correspond with an observation, made by Mayou, that previous psychological vulnerability (liability in the past to develop psychological symptoms under stress) was highly predictive of the mental state in hospital and at 2 and 12 months thereafter [27]. Together the available observations indicate that previous depression is a risk factor for depression in the hospital following MI. Its prognostic impact on the course of the disease might be even larger than the impact of depression following MI [28, 29]. Hardly any information is available about other psychosocial, medical, and somatic factors, which increase the risk of depression after MI. Studies investigating the risk associated with life events, family and marital problems, job conditions and personality factors (such as hostility, anxiety, and ways of coping) are badly needed. The difference in the prevalence of depression and VE before MI is suggestive of different "roots" of post-MI depression. According to DSM-IV, the essential feature of a major depressive episode is a period of at least 2 weeks, during which there is either depressed mood o r the loss of interest or pleasure in nearly all activities. This double "entry" to the same set of phenomena may correspond with a difference in the cause of depression in coronary patients. In some, the depression is related to grief or a loss of self-esteem, for example, after the loss of a job. In other patients the depression seems to be related to deficiencies in the ability to raise energy. It is, for example, manifested by the need to take a long rest after the completion of a job, because one feels completely worn-out. This deficiency is often related to prolonged overwork [30, 31], and may result in the avoidance of daily activities to save energy, an avoidance or withdrawal behavior which is experienced as a loss of interest and pleasure. No empirical studies are available which give support to this postulated distinction between two groups of depressed coronary patients. The experience that so many otherwise happy coronary patients complain about a loss of energy, and that in cardiac rehabilitation some patients have to be advised to do more and many patients to do less, suggest that a distinction between two groups of coronary patients presenting the same depressive symptoms might make sense.
BIOLOGICAL MECHANISMS LINKING DEPRESSIVE SYMPTOMATOLOGY AND CORONARY HEART DISEASE The literature offers a broad spectrum of potential mechanisms linking depression with cardiac events, These include: increased sympathetic and decreased vagal tone; increased platelet aggregability without a corresponding increase in fibrinolytic activity; decreased heart rate variability; impaired slow-wave sleep; decreased fibrillation threshold; poor adherence to medical treatment regimens; and difficulties in stopping smoking [32-41]. It is not unlikely that the list of potential mechanisms has to be extended by psychoneuroimmunological (PNI) factors. This statement requires a brief description
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of the current view of pathologists on the pathogenesis of acute coronary syndromes. In normal circumstances, atherosclerosis is a protective response to insults to the wall of an artery. It consists of the formation of fibrofatty and fibrous lesions, preceded and accompanied by inflammation. The presence of numerous macrophages and T lymphocytes in the coronary lesion indicates that not only is there an inflammatory reaction to tissue damage but also a true immunological reaction. The activated macrophages play a role in the healing fibroproliferative process by their capacity to form platelet-derived growth factor (PDGF). They also secrete the cytokines interleukin-1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-t~). These cytokines can induce smooth muscle cell proliferation and migration by stimulating other growth factors. In case the healing response becomes excessive and prolonged (and the intended protection threatens to become a disease entity in itself) high doses of IL-1 and TNF-~ can inhibit the proliferative effect of growth factors by downregulating PDGF receptors [42, 43]. The cytokines are tailored to function as an "SOS signal for tissue damage. This information is relayed to other parts of the body, including the brain, where they evoke feelings of lack of well-being, general malaise, sickness, and tiredness [44, 45]. The feelings of exhaustion before the occurrence of an acute coronary event may form part of a homeostatic reaction to an excessive inflammation and, thus, be an adaptive response. The main forms of insult to the vessel wall are oxidized low-density lipoprotein, blood flow shear, oxygen-derived free radicals, vasoactive amines, cigarette smoke, and immune complexes. Recent investigations indicate that infections by cytomegalovirus (CMV) and/or Chlamydiapneumoniae also belong to these factors [46]. For example, it was observed in the Helsinki Heart Study that Chlamydiapneumoniae infection, as indicated by the presence of elevated IgA titer and lipopolysaccharide complexes 3-6 months before MI, form an independent risk factor for the development of CAD [47, 48]. More than half of all adults have antibodies against these agents, indicating that in normal conditions the infections remain latent. When activated, a virus may impair the normal healing through multiple cellular mechanisms, including inactivation of the tumor suppression gene p53. This inhibits programmed cell death or apoptosis, which contributes to the proliferation of smooth muscle cells [49]. If the inflammation of a coronary artery preceding a cardiac event is caused by activation of a latent infection, the question remains as to the factor(s) that determine this reactivation. It is well known that depression or prolonged stress may weaken immunocompetence. This may set the stage for viral reactivation [50]. It is also known that prolonged exposure to mental or physical stress may result in a decreased activation of the hypothalamic-pituitary-adrenal (HPA) axis, which evokes many behavioral effects including fatigue, irritability, dysthymia, and atypical depression. A defective HPAoaxis also causes increased susceptibility to autoimmune or inflammatory disease, which strengthen the feelings of general malaise through the release of cytokines [51]. No data are yet available which support the hypothesis that inflammation-derived cytokines cause or strengthen depressive symptomatology before or after MI. Yet, this hypothesis deserves attention for two reasons.
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Depressive symptomatology in coronary patients, and especially the dominant complaints of fatigue and lack of energy, have long been thought to reflect the severity of coronary heart disease (CHD) or low left ventricular ejection fraction. Recent studies showed that depression and fatigue are not, or only modestly, related to the severity of cardiac disorder, to the extent of atherosclerosis, or to left ventricular ejection fraction [5, 28, 52-54]. These observations may lead to the conclusion that depressive symptomatology is not a marker of (sub)clinical heart disease. However, it is possible that they are fully or partially caused by the functional (inflammatory) status of the coronary arteries. The inflammation model of CHD includes several positive and negative loops of the involved factors. Similar cyclic processes--with depression as a facilitator of viral reactivation and symptoms of fatigue, somnolence, and listlessness as part of the negative feedback to inflammation--may apply to the mental state preceding a coronary event. Therefore, psychological factors may play a different role at various stages of the disease process. Depression seems to harbor a lifetime risk for cardiac mortality. In contrast, vital exhaustion is a strong short-term precursor of cardiac events [2, 19, 55]. These observations suggest that the timeframes of the exposuredisease relation are unequal for different psychosocial factors. The conceptualization and operationalization of time windows of exposure and the identification of different bodily reactions in several stages of the stress-disease relation, forms a major challenge for study designs, exposure assessment, and data analysis, especially so because fatigue, angina pectoris, and depression are mutually reinforcing factors which may have a spiral instead of a linear association.
T H E T R E A T M E N T O F D E P R E S S I O N IN C O R O N A R Y P A T I E N T S
The belief that depression has a causal role in the etiology or pathogenesis of CHD requires a confirmation of the hypothesis that a decrease of depression results in a decreased risk of a first or recurrent MI. Evidence supporting this hypothesis still is lacking, and therefore badly needed. The need for intervention studies raises three questions. Which type of intervention should be chosen? To whom should the intervention be offered? Should a therapy for depression form part of a comprehensive program that also includes an intervention for other behavioral risk factors, or not? The main options for the treatment of depression are formed by cognitive behavioral therapy (CBT) and by medication. CBT might be an appropriate choice if the feelings of sadness, hopelessness, and negative thinking about one's future extend beyond the illness situation, and cognitions about the self and others are really distorted. However, feeling depressed may be an appropriate and realistic response in a patient who has a poor prognosis because of his age, the severity of the disease, or adverse life conditions. Feelings of hopelessness make sense if a disabling fatigue prevents a patient from doing their usual work ("I want, but I can't"). A depressed affect is not always the result of distorted cognitions. Therefore, careful screening and selection of patients to whom CBT is offered is needed, to prevent the possibility that challenging negative cognitions would be experienced as a lack of understanding or as being disrespectful. Drug therapy might be an appropriate choice if cardiac safety of the drug is guar-
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anteed. Again, prescription of antidepressive drugs might be perceived by coronary patients as a suggestion that they have a mental problem, or as a lack of understanding, especially so if the drug therapy does not form part of more comprehensive treatment. This may explain the clinical experience that many coronary patients refuse to take antidepressive drugs. Relaxation therapy might be a reasonable choice for those in whom the depression after MI is superimposed upon a state of exhaustion. Suppression of or insensitivity to fatigue is a known characteristic of type A behavior [56, 57]. Relaxation therapy, and especially the breathing relaxation technique developed by van Dixhoorn, is a powerful technique to increase bodily awareness and to recognize somatic stress reactions. This training in psychophysiological self-regulation helps patients to become aware of tension, to understand that fatigue or sleepiness may form a cry for rest, which should be respected. Furthermore, it provides subjects with tools to handle stress in different situations, van Dixhoorn has shown that breathing relaxation results in an increased feeling of well-being, less silent ischemia, lower resting heart rate, and a decrease of new cardiac events during a 2-3 year follow-up period [58-60]. However, it is unknown whether this intervention reduces depression in coronary patients. The question as to whom treatment of depression should be offered is still open. Are the cardiac risks that are attributable to depression confined to certain severity levels or subtypes? We do not know whether it is only major depression that affects the course and outcomes of CHD, or whether minor or subclinical depression, grief reactions, or even transient demoralization do so as well. Given the fact that elevated BDI scores predict survival over a follow-up period of 18 months [7], it is likely that those with minor depression may also profit from a behavioral intervention. A related question is whether an intervention upon depression should also be offered to those in whom the depressive symptomatology should mainly be understood as a transient adjustment reaction, because the symptoms of depression disappear after 4 weeks. We do not know whether those who mentally recover within 1 month have the same risk of future CHD as those who remain depressed. A major question is whether or not therapy for depression should form part of a comprehensive program, which includes health education about lifestyle factors, physical exercise, and intervention for other psychosocial risk factors (such as hostility or lack of social support). The results of a multicenter, randomized, controlled trial, based on psychological therapy, counseling, relaxation training, and stress management independent of possible contamination by exercise training or risk factor modification, proved negative with regard to reduction of clinical complications, clinical sequelae, or mortality [61]. However, the interventions used in this multicenter trial did not result in a decrease of depression and anxiety. Therefore, the main message from this study is that an unsuccessful treatment of depression and anxiety is also unsuccessful in reducing the risk of CHD. A recent meta-analysis of 23 randomized, controlled trials that evaluated the additional impact of psychosocial treatment of rehabilitation for documented coronary artery disease showed that this addition resulted in a 46% reduction in 2 years of follow-up and a 39% reduction for longer follow-up. The nature of the psychosocial interventions was found to be diverse in terms of length, target behavior, and
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the type of person delivering them. Yet the effect was almost uniformly positive. Therefore, the positive effect is attributable to shared nonspecific therapy factors like emotional support, establishment of hope, and a sense of control [62]. Given the observation that nonspecific therapy factors result in an impressive reduction in the risk of a new coronary event, it remains to be demonstrated that the addition of a specific therapy for depression will result in an increase of these already impressive percentages. The inclusion of a specific therapy for depression in a comprehensive program has the obvious disadvantage that it will be hard to disentangle the effects of the depression therapy on the outcome variables. Inclusion in a comprehensive rehabilitation program also has some distinct advantages. Post infarction patients are generally somewhat skeptical of psychotherapy. Offering support and help for emotional problems as part of a physical rehabilitation program may improve adherence. If the outcomes are positive, it will be easier to implement the intervention after the study. Finally, inclusion in a comprehensive program will give more insight into the interactions between several behavioral changes on the risk of a new coronary event, and thus contribute to finding an answer to the question of why a reduction of depression eventually decreases cardiovascular risks. The identification of depression and exhaustion as risk indicators of cardiac events also has consequences for the evaluation of cardiac rehabilitation programs. Many scales used to assess improvement of the quality of life after rehabilitation contain questions about exhaustion and depression. If the latter should be considered as determinants and not as the consequence of the disease, they would be better excluded from quality-of-life assessment.
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EDITORIAL D E P R E S S I O N A N D C O R O N A R Y H E A R T DISEASE: OBSERVATIONS AND QUESTIONS A. A P P E L S evidence that depressive symptomatologyprecedes the onset of the acute coronary syndromes and influencesthe course of disease after their manifestation is accumulating. However, we still are far short of proof that depression has a causal role in the etiologyand pathogenesisof coronary heart disease (CHD). Some unsolved questions concern the causes and the nature of the depression preceding a first or recurrent cardiac event, the biologicalmechanisms relating depression and CHD, the time window of the exposure-disease association, and the power of therapy programs for depression to reduce the risk of a first or recurrent cardiac event. © 1997 Elsevier Science Inc. Abstract--The
Keywords: Coronary heart disease; Depression; Vital exhaustion.
INTRODUCTION In 1987, Booth Kewley and Friedman published a meta-analysis of all studies published between 1945 and 1985 on the psychological predictors of heart disease. Their conclusion was that depression is reliably associated with coronary heart disease ( C H D ) and that, of all personality factors, depression had the highest risk [1]. Several studies published since that date supported this conclusion. Barefoot and Schroll observed that a subset of obvious depressive symptoms, derived from the MMPI, predicted acute myocardial infarction (AMI) over a 27-year period [2]. Feelings of hopelessness were found to precede C H D morbidity and mortality in the Kuopio Ischemic Heart Disease Study and in the N H A N E S study [3, 4]. About 16-18% of patients hospitalized because of MI suffer from major depression according to DSM criteria [5, 6]. Frasure-Smith et al. observed that this subgroup has over four times the death rate of nondepressed patients during the first 6 months of follow-up. Further follow-up to 18 months showed that major depression ceased to predict survival after 6 months. However, the Beck Depression Inventory (BDI) continued to predict survival in later phases of follow-up [7]. Similar findings have been reported by Barefoot, Silverstone, Denollet, and Ladwig. It was first observed that patients with moderate to severe depression, according to their scores on the Zung scale, had a 72% greater risk of cardiac mortality over a period of 19 years [8]. Silverstone observed that patients who felt depressed immediately after hospitalization, according to their scores on the Montgomery-Asberg rating scale, had a poorer outcome (cardiac death or arrest or recurrent MI) than those with low Department of Medical Psychology, Maastricht University, MaastrichL The Netherlands. Address reprint requests to: A. Appels, Department of Medical Psychology, Maastricht University, Box 616, 6200 MD, Maastricht, The Netherlands. Tel.: -043-3881481; Fax: -043-3670952; E-mail: ad. [email protected]
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ratings of depression [9]. Denollet et al. observed that patients with documented CHD, who scored above the median of the depression scale of the Millon Behavioral Health Inventory, had an increased risk of dying within a 6-10-year follow-up period [10]. Ladwig observed that MI patients with elevated scores on a combination of symptoms of manifest depression, emotional isolation, and vulnerability (fatigue; vulnerability to criticism) had an elevated risk of cardiac death within a 6-month follow-up period [11]. Depressive symptomatology was also found to influence the course of the disease in other groups of cardiac patients. The presence of major depression or POMSdefined fatigue at the time of coronary angiography in patients with CHD more than doubles the risk that a major cardiac event will occur within 1 year [12, 13]. Generalized fatigue has been found to be the most important predictor of survival after pace-maker implantation and to increase the risk of mortality in patients with ventricular arrhythmias [14, 15]. In the CAPS study of patients with nonsustained tachycardia after MI it was observed that patients with elevated BDI scores and low scores on the vigor scale of the POMS had an increased risk of cardiac death or cardiac arrest [16, 17]. The evidence that a depressive symptomatology precedes the onset of several manifestations of coronary heart disease and influences the course of the disease after its manifestation is mounting. Therefore, research on the association between depression and CHD is a priority area of psychosomatic medicine. However, we are still far short of proof that depression has a causal role in the etiology or pathogenesis of CHD. Many questions are unanswered. Is the depression in coronary patients essentially the same disorder as depression in non-medical populations? Why are so many patients depressed after MI? Is depression equally associated with several manifestations of coronary heart disease such as MI and sudden cardiac death? Is depression equally associated with CHD in men and women? What biological mechanisms explain the association between depressive symptomatology and coronary events? Does a successful intervention to reduce depression reduce the risk of a first or recurrent cardiac event? Three of these questions will be discussed in the following paragraphs. Insufficient data are available to discuss gender differences in the association between depression and CHD and the association between depression and different manifestations of CHD.
THE NATURE OF THE DEPRESSION BEFORE AND AFTER MYOCARDIAL INFARCTION
Is what we call depression in coronary patients essentially the same disorder as depression in nonmedical populations? The observation that DSM-III-defined depression has a shorter predictive power than BDI defined depression makes many investigators rather cautious in their labeling of the mood state of coronary patients. Some prefer "depressive symptomatology" over "depression," whereas others are of the opinion that the mental state of coronary patients may be better thought of as a general negative affect, because of the substantial and consistent correlation of measures of depression, hostility, anxiety, and fatigue [18]. Doubts with regard to the best term to label the depressive symptoms do not refute the empirical findings. Rather they reflect some uncertainty in the development
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and composition of the symptomatology, the determinants of the post-MI depression, and the homogeneity of depressed coronary patients with regard to the origin of their depression. We have described the mental state before MI as "vital exhaustion" (VE), a state characterized by feelings of unusual tiredness and lack of energy, increased irritability, and feelings of demoralization. This state was found to be a strong, short-term precursor of MI in apparently healthy males [19] and a risk factor for a new cardiac event in angioplasty patients [20]. VE shares a substantial amount of variance with depression. The magnitude of the common variance ranges between 25% and 50%, depending on the methods used to assess both constructs [21]. The label "vital exhaustion" was chosen because many coronary patients indicate that loss of energy and unusual tiredness is their core feeling and that they feel depressed because of that loss of energy. Frequently used expressions are: "I feel hopeless because of my lack of energy"; "I want, but I can't"; "I have the wish but not the power"; "I feel blue because it is hard to accept that I do not have what it takes anymore." These expressions indicate that the sad mood reflects a secondary condition, a condition which is superimposed upon a state of fatigue. In an attempt to check whether there is a sequential order in the depressive symptomatology we reanalyzed the databases of the cohort study of healthy males and of the prospective study of angioplasty patients. Results showed that the items reflecting a negative mood state lost their predictive power when controlled for items asking for exhaustion and loss of energy. This observation does not prove that mood disturbances preceding a cardiac event are a secondary condition. However, they strengthen the need for further investigation to test the hypothesis that, in many coronary patients, a negative mood state is superimposed upon a state of exhaustion. A difference in the constituent elements of depression in MI patients and depression in psychiatric populations seems to be formed by the relative absence of a deprecatory image of the self and of guilt feelings in depressed coronary patients. Psychiatric patients often show a negative image of the self and assume a primary responsibility for a loss, leading to the conclusion that there is no expectation that anyone else can provide a solution. These distorted cognitions are relatively rare in coronary patients. This statement is based on clinical experience and may reflect the fact that the concept of "self-esteem" has a broader connotation in the English language than it has in several other languages. Detailed studies are needed to compare the prevalence of distorted cognitions in mental and cardiac patients and to compare both groups on relevant components or dimensions of depression. Detailed studies are also needed to answer the question of how often a post-MI depression can be labeled as a reactive depression, originating in the need to reorganize one's life, or in the loss of existential goals, and why a minority only is depressed after MI. What are the determinants of major or minor depression after MI? Which factors explain why some patients are depressed after MI and others are not? The available data suggest that 8-16% of all patients were depressed before MI [22, 23] and that 36-50% were exhausted before MI [21, 24, 25]. Ladwig et al. observed that high levels of exhaustion and fatigue in the prehospital phase were significantly related to subsequent high levels of depression [26].
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Lifetime depression also increases the chance that a cardiac patient will be depressed after hospitalization. Lesperance et al. observed that 28% of post-MI patients had at least one episode of major depression at some point in their lives before their admission [22]. Freedland et al. observed that, of 39 patients with recently diagnosed CAD who met DSM-III-R criteria for major depression, 44% had a prior history of MD [6]. These findings correspond with an observation, made by Mayou, that previous psychological vulnerability (liability in the past to develop psychological symptoms under stress) was highly predictive of the mental state in hospital and at 2 and 12 months thereafter [27]. Together the available observations indicate that previous depression is a risk factor for depression in the hospital following MI. Its prognostic impact on the course of the disease might be even larger than the impact of depression following MI [28, 29]. Hardly any information is available about other psychosocial, medical, and somatic factors, which increase the risk of depression after MI. Studies investigating the risk associated with life events, family and marital problems, job conditions and personality factors (such as hostility, anxiety, and ways of coping) are badly needed. The difference in the prevalence of depression and VE before MI is suggestive of different "roots" of post-MI depression. According to DSM-IV, the essential feature of a major depressive episode is a period of at least 2 weeks, during which there is either depressed mood o r the loss of interest or pleasure in nearly all activities. This double "entry" to the same set of phenomena may correspond with a difference in the cause of depression in coronary patients. In some, the depression is related to grief or a loss of self-esteem, for example, after the loss of a job. In other patients the depression seems to be related to deficiencies in the ability to raise energy. It is, for example, manifested by the need to take a long rest after the completion of a job, because one feels completely worn-out. This deficiency is often related to prolonged overwork [30, 31], and may result in the avoidance of daily activities to save energy, an avoidance or withdrawal behavior which is experienced as a loss of interest and pleasure. No empirical studies are available which give support to this postulated distinction between two groups of depressed coronary patients. The experience that so many otherwise happy coronary patients complain about a loss of energy, and that in cardiac rehabilitation some patients have to be advised to do more and many patients to do less, suggest that a distinction between two groups of coronary patients presenting the same depressive symptoms might make sense.
BIOLOGICAL MECHANISMS LINKING DEPRESSIVE SYMPTOMATOLOGY AND CORONARY HEART DISEASE The literature offers a broad spectrum of potential mechanisms linking depression with cardiac events, These include: increased sympathetic and decreased vagal tone; increased platelet aggregability without a corresponding increase in fibrinolytic activity; decreased heart rate variability; impaired slow-wave sleep; decreased fibrillation threshold; poor adherence to medical treatment regimens; and difficulties in stopping smoking [32-41]. It is not unlikely that the list of potential mechanisms has to be extended by psychoneuroimmunological (PNI) factors. This statement requires a brief description
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of the current view of pathologists on the pathogenesis of acute coronary syndromes. In normal circumstances, atherosclerosis is a protective response to insults to the wall of an artery. It consists of the formation of fibrofatty and fibrous lesions, preceded and accompanied by inflammation. The presence of numerous macrophages and T lymphocytes in the coronary lesion indicates that not only is there an inflammatory reaction to tissue damage but also a true immunological reaction. The activated macrophages play a role in the healing fibroproliferative process by their capacity to form platelet-derived growth factor (PDGF). They also secrete the cytokines interleukin-1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-t~). These cytokines can induce smooth muscle cell proliferation and migration by stimulating other growth factors. In case the healing response becomes excessive and prolonged (and the intended protection threatens to become a disease entity in itself) high doses of IL-1 and TNF-~ can inhibit the proliferative effect of growth factors by downregulating PDGF receptors [42, 43]. The cytokines are tailored to function as an "SOS signal for tissue damage. This information is relayed to other parts of the body, including the brain, where they evoke feelings of lack of well-being, general malaise, sickness, and tiredness [44, 45]. The feelings of exhaustion before the occurrence of an acute coronary event may form part of a homeostatic reaction to an excessive inflammation and, thus, be an adaptive response. The main forms of insult to the vessel wall are oxidized low-density lipoprotein, blood flow shear, oxygen-derived free radicals, vasoactive amines, cigarette smoke, and immune complexes. Recent investigations indicate that infections by cytomegalovirus (CMV) and/or Chlamydiapneumoniae also belong to these factors [46]. For example, it was observed in the Helsinki Heart Study that Chlamydiapneumoniae infection, as indicated by the presence of elevated IgA titer and lipopolysaccharide complexes 3-6 months before MI, form an independent risk factor for the development of CAD [47, 48]. More than half of all adults have antibodies against these agents, indicating that in normal conditions the infections remain latent. When activated, a virus may impair the normal healing through multiple cellular mechanisms, including inactivation of the tumor suppression gene p53. This inhibits programmed cell death or apoptosis, which contributes to the proliferation of smooth muscle cells [49]. If the inflammation of a coronary artery preceding a cardiac event is caused by activation of a latent infection, the question remains as to the factor(s) that determine this reactivation. It is well known that depression or prolonged stress may weaken immunocompetence. This may set the stage for viral reactivation [50]. It is also known that prolonged exposure to mental or physical stress may result in a decreased activation of the hypothalamic-pituitary-adrenal (HPA) axis, which evokes many behavioral effects including fatigue, irritability, dysthymia, and atypical depression. A defective HPAoaxis also causes increased susceptibility to autoimmune or inflammatory disease, which strengthen the feelings of general malaise through the release of cytokines [51]. No data are yet available which support the hypothesis that inflammation-derived cytokines cause or strengthen depressive symptomatology before or after MI. Yet, this hypothesis deserves attention for two reasons.
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Depressive symptomatology in coronary patients, and especially the dominant complaints of fatigue and lack of energy, have long been thought to reflect the severity of coronary heart disease (CHD) or low left ventricular ejection fraction. Recent studies showed that depression and fatigue are not, or only modestly, related to the severity of cardiac disorder, to the extent of atherosclerosis, or to left ventricular ejection fraction [5, 28, 52-54]. These observations may lead to the conclusion that depressive symptomatology is not a marker of (sub)clinical heart disease. However, it is possible that they are fully or partially caused by the functional (inflammatory) status of the coronary arteries. The inflammation model of CHD includes several positive and negative loops of the involved factors. Similar cyclic processes--with depression as a facilitator of viral reactivation and symptoms of fatigue, somnolence, and listlessness as part of the negative feedback to inflammation--may apply to the mental state preceding a coronary event. Therefore, psychological factors may play a different role at various stages of the disease process. Depression seems to harbor a lifetime risk for cardiac mortality. In contrast, vital exhaustion is a strong short-term precursor of cardiac events [2, 19, 55]. These observations suggest that the timeframes of the exposuredisease relation are unequal for different psychosocial factors. The conceptualization and operationalization of time windows of exposure and the identification of different bodily reactions in several stages of the stress-disease relation, forms a major challenge for study designs, exposure assessment, and data analysis, especially so because fatigue, angina pectoris, and depression are mutually reinforcing factors which may have a spiral instead of a linear association.
T H E T R E A T M E N T O F D E P R E S S I O N IN C O R O N A R Y P A T I E N T S
The belief that depression has a causal role in the etiology or pathogenesis of CHD requires a confirmation of the hypothesis that a decrease of depression results in a decreased risk of a first or recurrent MI. Evidence supporting this hypothesis still is lacking, and therefore badly needed. The need for intervention studies raises three questions. Which type of intervention should be chosen? To whom should the intervention be offered? Should a therapy for depression form part of a comprehensive program that also includes an intervention for other behavioral risk factors, or not? The main options for the treatment of depression are formed by cognitive behavioral therapy (CBT) and by medication. CBT might be an appropriate choice if the feelings of sadness, hopelessness, and negative thinking about one's future extend beyond the illness situation, and cognitions about the self and others are really distorted. However, feeling depressed may be an appropriate and realistic response in a patient who has a poor prognosis because of his age, the severity of the disease, or adverse life conditions. Feelings of hopelessness make sense if a disabling fatigue prevents a patient from doing their usual work ("I want, but I can't"). A depressed affect is not always the result of distorted cognitions. Therefore, careful screening and selection of patients to whom CBT is offered is needed, to prevent the possibility that challenging negative cognitions would be experienced as a lack of understanding or as being disrespectful. Drug therapy might be an appropriate choice if cardiac safety of the drug is guar-
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anteed. Again, prescription of antidepressive drugs might be perceived by coronary patients as a suggestion that they have a mental problem, or as a lack of understanding, especially so if the drug therapy does not form part of more comprehensive treatment. This may explain the clinical experience that many coronary patients refuse to take antidepressive drugs. Relaxation therapy might be a reasonable choice for those in whom the depression after MI is superimposed upon a state of exhaustion. Suppression of or insensitivity to fatigue is a known characteristic of type A behavior [56, 57]. Relaxation therapy, and especially the breathing relaxation technique developed by van Dixhoorn, is a powerful technique to increase bodily awareness and to recognize somatic stress reactions. This training in psychophysiological self-regulation helps patients to become aware of tension, to understand that fatigue or sleepiness may form a cry for rest, which should be respected. Furthermore, it provides subjects with tools to handle stress in different situations, van Dixhoorn has shown that breathing relaxation results in an increased feeling of well-being, less silent ischemia, lower resting heart rate, and a decrease of new cardiac events during a 2-3 year follow-up period [58-60]. However, it is unknown whether this intervention reduces depression in coronary patients. The question as to whom treatment of depression should be offered is still open. Are the cardiac risks that are attributable to depression confined to certain severity levels or subtypes? We do not know whether it is only major depression that affects the course and outcomes of CHD, or whether minor or subclinical depression, grief reactions, or even transient demoralization do so as well. Given the fact that elevated BDI scores predict survival over a follow-up period of 18 months [7], it is likely that those with minor depression may also profit from a behavioral intervention. A related question is whether an intervention upon depression should also be offered to those in whom the depressive symptomatology should mainly be understood as a transient adjustment reaction, because the symptoms of depression disappear after 4 weeks. We do not know whether those who mentally recover within 1 month have the same risk of future CHD as those who remain depressed. A major question is whether or not therapy for depression should form part of a comprehensive program, which includes health education about lifestyle factors, physical exercise, and intervention for other psychosocial risk factors (such as hostility or lack of social support). The results of a multicenter, randomized, controlled trial, based on psychological therapy, counseling, relaxation training, and stress management independent of possible contamination by exercise training or risk factor modification, proved negative with regard to reduction of clinical complications, clinical sequelae, or mortality [61]. However, the interventions used in this multicenter trial did not result in a decrease of depression and anxiety. Therefore, the main message from this study is that an unsuccessful treatment of depression and anxiety is also unsuccessful in reducing the risk of CHD. A recent meta-analysis of 23 randomized, controlled trials that evaluated the additional impact of psychosocial treatment of rehabilitation for documented coronary artery disease showed that this addition resulted in a 46% reduction in 2 years of follow-up and a 39% reduction for longer follow-up. The nature of the psychosocial interventions was found to be diverse in terms of length, target behavior, and
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the type of person delivering them. Yet the effect was almost uniformly positive. Therefore, the positive effect is attributable to shared nonspecific therapy factors like emotional support, establishment of hope, and a sense of control [62]. Given the observation that nonspecific therapy factors result in an impressive reduction in the risk of a new coronary event, it remains to be demonstrated that the addition of a specific therapy for depression will result in an increase of these already impressive percentages. The inclusion of a specific therapy for depression in a comprehensive program has the obvious disadvantage that it will be hard to disentangle the effects of the depression therapy on the outcome variables. Inclusion in a comprehensive rehabilitation program also has some distinct advantages. Post infarction patients are generally somewhat skeptical of psychotherapy. Offering support and help for emotional problems as part of a physical rehabilitation program may improve adherence. If the outcomes are positive, it will be easier to implement the intervention after the study. Finally, inclusion in a comprehensive program will give more insight into the interactions between several behavioral changes on the risk of a new coronary event, and thus contribute to finding an answer to the question of why a reduction of depression eventually decreases cardiovascular risks. The identification of depression and exhaustion as risk indicators of cardiac events also has consequences for the evaluation of cardiac rehabilitation programs. Many scales used to assess improvement of the quality of life after rehabilitation contain questions about exhaustion and depression. If the latter should be considered as determinants and not as the consequence of the disease, they would be better excluded from quality-of-life assessment.
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