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EDITORIAL COMMENT |
University of Montreal and Montreal Heart Institute
McGill University and Montreal Heart Institute
Depression is common in the general community and affects significant proportions of patients with medical illness (1). It results in substantial disability and reduces quality of life for both depressed individuals and their family members (2, 3). Most physicians encounter depression in their daily practice, but many fail to recognize it as a serious condition. Although there is ample evidence that, at least in the absence of medical illness, depression is treatable with medications and/or psychotherapy (4), it remains both underrecognized and undertreated. Why? It is partly because of the stigma and mystery of mental illness. There is also the idea that lowered mood is something that people can control, if they only try. However, as clearly demonstrated in the review by Wulsin and colleagues in this issue of Psychosomatic Medicine (5), the impact of depression can be even more profound. Even since the most recent article cited in the review was published in 1996, evidence has continued to accumulate rapidly that depression increases the risk of mortality in diverse populations (6–8). Prevention of mortality has always been one of the most important factors in determining the allocation of funding for research and clinical activities. Therefore, it is not surprising that these findings have rekindled the hope from the early days of Type A behavior research that psychiatrists and psychologists might have the opportunity to play in the major league of medicine by influencing mortality.
With the idea of influencing mortality by treating depression as a goal, it seems prudent to take some time to sit back, think, and critically examine the evidence as Wulsin and colleagues have done. They present us with a global narrative review of the evidence on the association between depression and death in different populations including patients needing psychiatric care, patients with postmyocardial infarction (MI) and cancer, and other groups that are medically ill. Although they clearly describe their approach to finding relevant studies, searches of computerized databases are notoriously bad at picking up all relevant material. It has been reported that without additional hand searches and consultation of bibliographies only about 50% of relevant studies are obtained. The current review is no exception. For example, at least in the cardiac area, we are aware of three studies meeting their selection criteria that were omitted (10–12). None found a statistically significant relationship between depression and mortality, although the study by Carney et al., one of the earliest classics in the field, did find a relationship between depression and combined cardiac events. If these three studies had been included in the review, the degree of inconsistency reported would have been somewhat greater, but the global conclusions probably would not have been affected because of the rating scheme used for comparing the methodological quality of the included studies.
The authors rated studies according to their sample sizes, the nature of their comparison groups, their measures of depression, and whether they included statistical control for the confounding effects of age, sex, smoking, alcohol, physical illness, and suicide. Although we agree that sample size is important, the relevant issue is whether the sample was large enough to have the power to detect a statistically significant difference given the overall death rate in the population studied. Obviously, the number of previously healthy subjects needed to detect a mortality difference associated with depression would considerably exceed the number of post-MI patients needed to draw the same conclusion. We also have doubts that controlling for smoking, alcohol abuse, and suicide is necessary for all populations. For example, in our studies in Montreal we have followed some 2000 coronary artery disease (CAD) patients for at least 1 year with virtually complete tracking of survival status and causes of death. We are aware of only one suicide. In contrast, in psychiatric samples in which suicide and parasuicide are major causes of mortality, control for suicide is imperative.
The issue of controlling for smoking in patients with established CAD is also complex. In our article on gender differences in post-MI depression in this issue of Psychosomatic Medicine (13), we found that women smokers had lower mortality than those who were nonsmokers at the time of the infarct. However, additional analyses revealed that the smokers were also younger, less likely to have had a previous MI, less likely to be diabetic, and less likely to have been treated for hypertension. In contrast, in previously healthy subjects followed for long periods of time, smoking is one of the clearest risk factors for mortality. Beyond all this, there are very real and complex issues surrounding the measurement of smoking as well as alcohol use and abuse, which are clearly beyond the scope of this type of review, but nonetheless constitute limits to the methodological rating system of Wulsin et al.
In all fairness, any attempt at combining this literature would have been plagued by difficulties and open to criticism. Despite problems, the authors have provided a methodologically honest and replicable review and are to be congratulated for their efforts. Their conclusions are appropriate. Clearly, there is evidence that the impact of depression on mortality is substantial, especially for cardiovascular disorders, but the relationship is not proven. Estimation of the true effect size and the potential confounding effects of smoking, alcohol, suicide, and physical disease warrant additional study. Finally, it is reasonable to argue that studies on the pathophysiology of depression and the impact of treatment for depression should be the next steps. Patients with cardiovascular disease are the most promising research target.
We think that three major issues need to be considered in undertaking these next research steps: the definition/diagnosis of depression, the generation of alternative hypotheses, and the consideration of outcomes. We know that many depressions in patients (14) who are medically ill are of the milder type. In fact, a recent study in hospitalized medically ill patients (7), as well as our own work with cardiac patients (15), suggests that patients do not need to have a full-blown major depression at the time of their assessment to be at increased risk. Is it because most patients with milder forms of depression go on to develop major depressions, which eventually predispose them to death, or is there also a risk associated with milder or subthreshold forms of chronic depression? Until we know more about the specific aspects of depressive conditions that increase the risk of mortality, the best measures of depression are probably those that tap the full depressive spectrum ranging from subthreshold symptomatology to major depression and dysthymia.
Although several plausible behavioral and pathophysiological mechanisms have been proposed to explain the link between depression and cardiovascular mortality (16), we also need to explore alternative hypotheses. It is possible that depression is not causally related to cardiovascular disorders. The two may co-occur frequently in the same individuals because of a common pathophysiological mechanism. Perhaps a genetic defect in serotonin receptor regulation in some region of the brain increases the risk of depression, and the same defect in serotonin receptors in platelets increases the risk of cardiovascular events. In other words, the regulatory state of the brain’s receptors may have no direct influence on the regulation of the platelet receptors. Also, we know that without exposure to environmental cofactors, most genetic predispositions are not sufficient to produce disease. It takes time and the appropriate environmental demands before the biological mechanisms compensating for genetic defects are no longer sufficient to prevent disease. Genetically susceptible brain serotonin receptors challenged by factors such as stress, sleep deprivation, or loneliness may produce the state of depression, whereas genetically dysregulated platelet receptors combined with high lipid levels or tobacco by-products promote the atherosclerotic process. Therefore, what we may have is one genetic defect, but two independent phenotypic expressions, frequently occurring in the same individuals. Obviously, this theory is purely speculative and a gross oversimplification of the processes involved, but illustrates that it is by no means certain that reducing depressive symptoms will change the pathophysiological mechanisms responsible for cardiac events. Some of the links between depression and mortality may respond to treatment: others may not.
Finally, there is the issue of choice of outcome. Although the prevention of death is a powerful tool to influence many of our medical colleagues who use it to justify the allocation of resources, death is not everything. In fact, because of improvements in medical treatment of cardiovascular disease, cardiology itself is beginning to focus on outcomes other than mortality. Recent trials have required randomization of as many as 14,000 patients to be able to demonstrate that a new drug or device is able to improve survival significantly over current treatment. At some point, we have to ask whether gains in survival continue to be clinically relevant. When we begin to see improved survival as the gold standard for judging the value of psychological and psychiatric treatments, we have missed the point both practically and philosophically. As new cardiovascular medications are developed, the link between depression and death may be reduced, but the impact of depression on individual and family quality of life will remain.
Our primary clinical goal should continue to be improving psychological well-being. If we are fortunate enough to show that reducing the symptoms and impairment of depressed patients also improves their survival, the theoretical and clinical implications will be enormous. However, we should not lose sight of the fact that an intervention that improves well-being, but fails to change survival, is still a very valuable treatment.
REFERENCES
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  J. M. McCaffery, N. Frasure-Smith, M.-P. Dube, P. Theroux, G. A. Rouleau, Q. Duan, and F. Lesperance Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin. Psychosom Med, March 1, 2006; 68(2): 187 - 200. [Abstract] [Full Text] [PDF]
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N. R. Benazon, M. M. Mamdani, and J. C. Coyne Trends in the Prescribing of Antidepressants Following Acute Myocardial Infarction, 1993-2002 Psychosom Med, November 1, 2005; 67(6): 916 - 920. [Abstract] [Full Text] [PDF]
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K. Z. Bambauer, O. Aupont, P. H. Stone, S. E. Locke, M. G. Mullan, J. Colagiovanni, and T. J. McLaughlin The Effect of a Telephone Counseling Intervention on Self-Rated Health of Cardiac Patients Psychosom Med, July 1, 2005; 67(4): 539 - 545. [Abstract] [Full Text] [PDF]
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K. W. Davidson, N. Rieckmann, and F. Lesperance Psychological Theories of Depression: Potential Application for the Prevention of Acute Coronary Syndrome Recurrence Psychosom Med, March 1, 2004; 66(2): 165 - 173. [Abstract] [Full Text] [PDF]
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D. Lane, D. Carroll, C. Ring, D. G. Beevers, and G. Y. H. Lip Mortality and Quality of Life 12 Months After Myocardial Infarction: Effects of Depression and Anxiety Psychosom Med, March 1, 2001; 63(2): 221 - 230. [Abstract] [Full Text] [PDF]
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