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THE GREAT DEBATE |
From the Department of Psychiatry and Behavioral Science, Duke University Medical Center, Durham, NC and the Behavioral Medicine Research Center, University of Miami, Coral Gables, FL
Address reprint requests to: Dr. Redford B. Williams, Duke University Medical Center, Department of Psychiatry & Behavioral Sciences, Box 3926, Durham, NC 27710. Email: redfordw{at}acpub.duke.edu
Abbreviations: BHAT = Beta-Blocker Heart Attack Trial;; CBSM = cognitive behavioral stress management;; CHD = coronary heart disease;; HIV = human immunodeficiency virus;; TM = Transcendental Meditation;; PMR = progressive muscle relaxation;; EC = lifestyle education;; MMPI =Minnesota Multiphasic Personality Inventory;; MI = myocardial infarction.
AFFIRMATIVE SPEAKER 1: Dr. Williams
Let me begin by thanking Dr. Markovitz for his splendid work in organizing this debate. On behalf of the American Psychosomatic Society, we extend a warm welcome to Dr. Angell and Dr. Relman and our thanks for joining us in what I am confident will be a constructive and enlightening debate. We also thank Dr. Lundberg, who we are confident will help all of us make sense of the arguments that will be presented.
The question before us is: "Resolved: Psychosocial Interventions Can Improve [Objective] Clinical Outcomes in Organic Disease." The term "Objective" was suggested by Dr. Relman in one of our conference calls to plan this debate. He was very emphatic that we should only consider studies in which "hard" end points—documented clinical events and/or mortality—were the "Clinical Outcomes" being studied. Although we believe that quality of life is an important outcome worthy of study, we agreed to limit the debate’s scope as proposed by Dr. Relman.
The affirmative case will be made by documenting the following three propositions:
The limited time available does not permit us to review in detail all the papers that we sent to our opponents, but, except where otherwise noted, all studies evaluating the impact of psychosocial risk factors on incidence or prognosis use a prospective longitudinal design with control for possible physical confounders. For the most part, these epidemiological studies documenting psychosocial risk factors involved large samples, ie, 1000 persons or more. All studies evaluating the impact of behavioral interventions used randomized clinical trials methodology with matching and/or control for possible baseline confounders. Time does not permit us to present evidence about the biological plausibility of the psychosocial risk factors identified. In general, however, the psychosocial risk factors have been associated with increased health risk behaviors such as caloric and fat intake, smoking, and alcohol consumption; increased physical risk factors such as body mass index, waist-hip ratio, total cholesterol/HDL ratio, LDL cholesterol; and biological characteristics including altered hypothalamic-pituitary-adrenal axis, cardiovascular, autonomic, and immune system function (1).
In our opening remarks, I shall review evidence from the cardiovascular area supporting our three core propositions, and Dr. Schneiderman will present supporting evidence from research on cancer and HIV/AIDS.
Hypertension
Evidence that psychosocial factors contribute to the development of hypertension comes from a study by Jonas et al. (2) of a U.S. population-based sample of nearly 3000 normotensive adults. Incident hypertension was increased by 82% (RR = 1.82) in whites aged 45 to 64 with high anxiety, and elevated depression was associated with an 80% increase in hypertension incidence. For treated hypertension, the relative risks among whites aged 45 to 64 were 2.36 and 1.89 for anxiety and depression, respectively. The impact of anxiety on incident (RR = 2.74) and treated (RR = 3.24) hypertension was even larger among blacks aged 25 to 64.
Will reducing negative emotions such as anxiety or depression have a beneficial effect on hypertension? In a randomized clinical trial comparing effects of TM, PMR, and EC on blood pressure in 111 older African Americans, Schneider et al. (3) found that TM resulted in blood pressure reductions that were larger by 10.7 mm for systolic blood pressure (p = .0002) and 6.4 mm for diastolic blood pressure (p < .0001) than those observed in the EC group. The PMR intervention was also credible. It had lesser effects than TM on blood pressure but still had significantly larger effects than those observed in the EC group; and TM was significantly better than PMR. Very interestingly, in terms of objective outcomes, a later study by this same group (4) found a significantly larger decrease in carotid intimal thickness in African Americans randomized to TM compared with those receiving usual care.
CHD Incidence and All-Cause Mortality
In a prospective study of 2832 healthy people, Anda et al. (5) found that depressed affect or severe hopelessness were associated with 50% and 110% increases, respectively, in risk of ischemic heart disease These results remained the same following control for physical risk factors, and they remained the same when the first 2 years of follow-up were excluded to remove any confounding from comorbid depression and disease at the start of the study.
Several studies have documented the impact of hostility and anger on coronary heart disease incidence and all-cause mortality in healthy samples. Shekelle et al. (6) followed up more than 1800 middle-aged men who had completed the MMPI over 15 years earlier. Based on earlier research among angiography patients, Shekelle predicted that those with a hostility score greater than 10 would experience a higher incidence of CHD over a 10-year follow-up period, a prediction that was confirmed when they found a 50% higher CHD rate among those with a hostility score more than 10. After adjustment for physical risk factors, the hostility score showed an even more statistically robust, monotonic, positive association with all-cause mortality such that those men with hostility scores in the top quintile had a 42% increase in all-cause mortality over 20-year follow-up period. In a study of coronary artery calcification using electron beam computed tomography (EBCT) in a subset of 374 younger people from the CARDIA study (7), high hostility scores were associated with a number of physical risk factors. Comparing those with hostility scores at or above the median with those with scores below the median, the odds ratio of having a calcium score greater than zero on EBCT was 2.5, and those with high hostility scores were nearly 10 times more likely to have a calcium score greater than 20 (indicative of more severe atherosclerosis). Controlling for potential confounders had little effect, and these effects were present in men and women, blacks and whites. In a 4 1/2-year follow-up study of 12,986 participants in the ARIC Study (8), those with high trait anger scores experienced 75% more hard clinical events than those with lower scores. There was a significant interaction with blood pressure status, such that the risk was increased monotonically with increase in trait anger only among the normotensive individuals, and no effects of anger were found among the hypertensives.
With respect to prognosis in patients with established coronary heart disease, Frasure-Smith et al. (9) evaluated 222 post-MI patients and found that 16% met modified criteria for major depression. There was a robust five- to six-fold increase in mortality at 6 months as a function of this depression. The impact of depression on mortality was about the same as Killip class and previous MI, which were the other two best independent predictors from the physical realm. Social isolation has been shown to have an adverse impact on prognosis in established coronary disease. In a study of 1368 CHD patients, Williams et al. (10) found a three-fold higher 5-year mortality among those who were socially isolated, an effect that was unchanged following control for ejection fraction and other known physical prognostic factors.
As the evidence just reviewed indicates, a good case can be made that psychosocial risk factors increase the risk of CHD and all-cause mortality in healthy populations and confer an adverse prognosis in patients with established CHD. There is also encouraging, albeit limited, evidence that behavioral interventions can decrease levels of psychosocial risk factors, with corresponding improvements in clinical outcomes.
The Recurrent Coronary Prevention Project randomized 862 post-MI patients to either type A counseling plus cardiac counseling or cardiac counseling alone (11). The type A counseling group showed a larger decrease in type A behavior over a 3-year period than the cardiac counseling group. The average annual recurrence rate of 2.96 in the type A counseling group was 44% lower than the 5% recurrence rate in the cardiac counseling group over 4 1/2 years. Subsequent follow-up study showed that the reduced cardiac recurrence rate was maintained over the 4 years after the treatment ended (12). Type A counseling also resulted in improved hostility, anger, depression, self-efficacy, and well being (13), so we cannot be sure which aspect of the change was responsible for the benefits, but there was a benefit nevertheless. Blumenthal et al. (14) assigned 107 CHD patients to usual care, exercise, or stress management in small groups. This study was flawed in that the usual care group consisted of people who live at a distance from the treatment center and could not be randomized to come back for exercise or stress management, but they were not different from the other two groups in terms of distance from a medical center that could take care of them. Compared with usual care, there was a 74% decrease in coronary recurrence rates in the stress management group, and this was still significant after adjusting for physical risk factors. Stress management training affected one biological process that could account for the observed benefits. Patients with more severe wall motion abnormalities to mental or exercise stress at baseline showed less severe abnormalities after stress management training.
There is one additional small study worth considering here that was done with rigorous clinical trials methodology, in which post-MI patients were randomized to either hostility reduction training or usual care (15). Patients in the hostility reduction group showed larger decreases in both self-reported and behaviorally assessed (blinded raters) hostility than patients randomized to usual care. Patients randomized to hostility control training also showed significant decreases in diastolic blood pressure, with a mean decrease of 8 mm Hg at 2 months after the end of the intervention, vs. an increase of 6 mm Hg in the usual care group; and there was a dose-response effect, with larger decreases in self-reported hostility from pre- to posttraining associated with larger decreases in blood pressure at 2 months follow-up.
In summary, there is strong evidence from large-scale prospective studies that psychosocial risk factors increase the risk of CHD and all-cause mortality in healthy populations followed over periods of several years. Similar strong evidence from studies of clinical samples indicates a robust effect of psychosocial risk factors on prognosis among patients with established coronary heart disease. The evidence showing improved objective clinical outcomes from randomized clinical trials of behavioral interventions in CHD patients is much more limited than the evidence showing the impact of psychosocial risk factors on disease incidence and prognosis. Nevertheless, the evidence that is available, although not definitive, does make a good case that behavioral interventions have the potential to improve prognosis, and that more definitive, larger scale studies are warranted.
Dr. Schneiderman will now continue the Affirmative case by reviewing evidence from research on cancer, HIV, and other disorders.
AFFIRMATIVE SPEAKER 2: Dr. Schneiderman
I, too, would like to welcome Drs. Angell, Relman, and Lundberg. Dr. Williams provided evidence that behavioral interventions can improve clinical outcomes in essential hypertension and CHD; I shall provide similar evidence for HIV and cancer. I intend to show that psychosocial factors influence the course of organic disease by biologically plausible mechanisms, that behavioral interventions can modify the psychosocial factors that influence the course of these diseases, and that behavioral interventions can influence the course of organic diseases in terms of objective clinical outcomes.
HIV/AIDS
Do psychosocial factors influence the course of HIV? Mayne et al. (16) followed 402 HIV-positive gay men for up to 6 years with depressive affect measured at each 6-month assessment period. Depressive affect was positively associated with significantly greater mortality (adjusted RR 1.67; 95% CI, 1.01–2.78). Leserman et al. (17) followed 82 HIV-positive gay men every 6 months for up to 7.5 years. Faster progression to AIDS was associated with stressful life events (p < .004), denial coping (p < .02), low satisfaction with social support (p < .05), and elevated serum cortisol (p < .01). In terms of biological plausibility, Markham and colleagues (18) have shown that HIV infection of normal human lymphocytes is enhanced by supplementing the cell culture with cortisol; and Nair and Schwartz (19) have shown that cortisol inhibits natural killer cell cytotoxicity, which is a plausible subclinical marker.
Do behavioral interventions modify the psychosocial factors that influence the course of HIV? Lutgendorf et al. (20) randomized 40 HIV-positive gay men into either group-based cognitive behavioral stress management (CBSM) or a control condition. Subjects who received CBSM, when compared with controls, showed significantly greater increases in cognitive coping (p < .05) and perceived social support (p < .05). This, in turn, led to decreased depressed affect (p < .05), distress (p < .05), and total mood disturbances (p < .05). After the methodology of Baron and Kenney (21), regression analysis indicated that decreases in total mood disturbances in the intervention condition were in large part mediated by increases in cognitive coping and social support. Thus, behavioral intervention can modify the psychosocial factors that influence the course of HIV.
Do behavioral interventions influence the course of HIV? I would next like to describe the article by Karl Goodkin et al. (22), which appeared only last week in the Journal of Human Virology. Consequently, I apologize to Dr. Angell and Dr. Relman because they may not have yet had the opportunity to read it. However, it is a relevant published article, which merits our consideration in this debate. Basically, HIV-positive gay men were randomly assigned either to a control condition or to 10 weekly group-based bereavement counseling sessions. Being in the intervention, as opposed to the control group, significantly buffered against an increase in HIV viral load that was observed after the 10-week period, controlling for prophylactic and antiretroviral therapy (t = 2.58, p < .02). Viral HIV burden is known to be the single most powerful predictor of HIV progression. The difference observed in this study, which was half a log unit, is clinically significant and the criterion usually used to make decisions about medications.
Cancer
Psychosocial factors can also influence the development and course of cancer. Everson et al. (23) followed 2428 men for up to 6 years. Men who perceived themselves as being moderately or highly hopeless showed a dose-response relationship both to all-cause and cause-specific mortality. Moderate and high hopelessness scores predicted incident cancer (adjusted RR, 1.80; 95%, CI, 1.11–2.92). In another study, Watson and colleagues (24) followed 578 women with early-stage breast cancer for 5 years. They found a significant increase in all-cause mortality in women scoring high on depression and a reliable increase in risk of relapse or death in women with high helplessness, hopelessness scores. High depression scores were associated with increased mortality (adjusted RR, 3.59; 95% CI, 1.39–9.24). Thus, it is clear that depression and feelings of hopelessness can influence the development and course of cancer.
Again, as in the case for HIV, we can show that behavioral interventions can modify the psychosocial factors that influence the course of disease. Antoni et al. (25) randomized 53 women into a control and 47 women into a 10-week group-based cognitive behavioral stress management (CBSM) condition 6 to 8 weeks after breast cancer surgery. The intervention significantly reduced moderate depression and significantly increased generalized optimism in the CBSM relative to the control condition (F = 5.13, p < .01). Consequently, we can conclude that a psychosocial intervention can significantly increase optimism, which is the opposite of hopelessness.
Fawzy et al. (26) randomized 28 stages I and II malignant melanoma patients into a control condition, and 38 similar patients into a 6-week group-based CBSM condition shortly after surgery. At 6-month follow-up, the CBSM subjects showed significantly less total mood disturbances (p < .006), increased adaptive behavioral (p < .003) and cognitive coping (p < .03). In a companion study conducted on the same cohort, Fawzy et al. (27) found that the interferon-alpha augmented natural killer cell response was significantly increased (p < .03) in the intervention group compared with the controls when measured at the 6-month follow-up. This argues for biological plausibility.
Behavioral interventions can also directly influence objective clinical outcomes in cancer. Spiegel et al. (28) randomized 86 women into a group-based weekly 1-year support intervention (N = 50) or a control condition (N = 36). At 10-year follow-up, mean survival time from randomization was 36.6 months in the intervention group, compared with 18.9 months in the control group (p < .0001). At 6-year follow-up, Fawzy et al. (29) were able to analyze data on recurrence and death on 34 psychosocial intervention and 34 control patients with malignant melanoma. A log-rank test showed the number of deaths was significantly less in the intervention than the control condition (p = .03).
In conclusion, the evidence that the Affirmative side has presented indicates that psychosocial factors unequivocally influence the course of organic disease by biologically plausible mechanisms. Furthermore, behavioral interventions can modify these psychosocial factors, which influence the courses of disease. The preponderance of evidence also indicates that psychosocial interventions can influence subclinical markers of disease as well as clinical outcomes in organic disorders. However, as I indicated in an Annual Review of Psychology article this year (30), only large-scale clinical trials will establish the robustness and generality of these effects. From the Affirmative side’s perspective, the issue in this debate is whether there currently is sufficient evidence to justify large-scale clinical trials examining relationships between psychosocial interventions and hard endpoints for at least some organic disorders. The argument that Dr. Williams and I are making is that current evidence supports the need for undertaking rigorous psychosocial clinical intervention trials in the areas of CHD, HIV/AIDS, and cancer.
ACKNOWLEDGMENTS
The preparation of this manuscript was supported in part by Grants (Dr. Williams) P01-HL36587 and R01-HL44998 from the National Heart, Lung, and Blood Institute; Grants 5P60-AG11268, P02-AG12058, and R01-AG19605 from the National Institute on Aging; Grant K01-MH70482 from the National Institute of Mental Health; the Duke Clinical Research Unit Grant M01-RR30; and research support from the Fetzer Institute; and Grants (Dr. Schneiderman) P01-HL36588 and N01 HL55143 from the National Heart, Lung, and Blood Institute; P01-MH49548 from the National Institute of Mental Health; and P50-CA84944 from the National Cancer Institute.
Received for publication September 10, 2001.
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