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ORIGINAL ARTICLES |
From the Department of Medical Psychology, Maastricht University, Maastricht, The Netherlands (A.A., G.v.d.P.); Department of Cardiology, Maastricht University, Maastricht, The Netherlands (F.B.); Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (R.E.); Department of Medical Psychology, University of Nijmegen, Nijmegen, The Netherlands (M.A.); Department of Medical Psychology, Erasmus Medical Center, Rotterdam, the Netherlands (W.T.); Department of Psychiatry, Maastricht University, Maastricht, The Netherlands (R.v.D.); Center for Breathing Therapy, Amersfoort, The Netherlands (J.v.D.); 8. Rush Institute for Healthy Aging, Rush-Presbyterian–St. Luke’s Medical Center, Chicago, IL.
Address correspondence and reprint requests to Ad Appels, Department of Medical Psychology, Maastricht University, Box 616, 6200 MD, Maastricht, The Netherlands. E-mail: Ad.Appels{at}MP.unimaas.nl
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ABSTRACT |
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Methods and Results: Seven hundred ten consecutive patients, ages 35 to 68 years, who felt exhausted after PCI were randomized into an intervention group and a usual-care group. The intervention was based on group therapy focusing on stressors leading to exhaustion, and on support for recovery by promoting rest and making rest more efficient. One month after PCI, 50% of the patients felt exhausted. The intervention reduced the odds of remaining exhausted at 18 months by 56% in those without a previous history of coronary artery disease (CAD) (OR = 0.44; 95% CI 0.29–0.66), but had no effect on exhaustion in those with a history of CAD (OR = 0.93; 95% CI 0.56–1.55; p = .78). The intervention did not reduce the risk of a new coronary event within 2 years (RR = 1.14; 95%CI 0.82–1.57). Post-hoc analyses suggest that the effect of the intervention was limited by a positive history of CAD, the presence of a chronic, painful condition (especially rheumatism), and by opposite effects on early and late cardiac events.
Conclusion: A behavioral intervention in PCI patients has a beneficial effect on feelings of exhaustion. It could not be demonstrated that the intervention reduces the risk of a new coronary event within 2 years.
Key Words: angioplasty • vital exhaustion • behavioral intervention • stress • trials
Abbreviations: PCI = percutaneous coronary intervention; CAD = coronary artery disease; MQ = Maastricht Questionnaire; MIVE = Maastricht Interview Vital Exhaustion; EXIT = Exhaustion Intervention Trial; CABG = coronary artery bypass graft; MI = myocardial infarction.
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INTRODUCTION |
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There are a number of reasons why exhaustion may increase the risk of cardiovascular endpoints. Psychophysiological studies have found that exhausted subjects are characterized by increased blood coagulability and decreased early morning fibrinolysis (8–10). Exhaustion has also been linked to factors activating immune-mediated inflammation (lower levels of the adrenocorticotropic hormone, lower levels of cortisol, reduced glucocorticoid sensitivity of monocytes) (11–15) and to serological markers of inflammation, that is, increased leukocyte adhesiveness/aggregation and increased levels of interleukin (IL-1ß, IL-6), tumor necrosis factor-
, and C-reactive protein (16,17). Finally, exhaustion has been linked to reactivation of microorganisms suspected of playing a role in the progression of atherosclerosis (Cytomegalovirus and Chlamydia pneumoniae) (16,18). These observations suggest that exhausted subjects are characterized by a decreased activity of the hypothalamic–pituitary–adrenocortical axis.
To the best of our knowledge, no study has examined whether treating exhaustion with counseling reduces exhaustion and cardiac risk in coronary patients. We therefore designed the EXhaustion Intervention Trial (EXIT), a multicenter, randomized, controlled trial to test the hypotheses that treating exhaustion after PCI reduces exhaustion and the risk of a new coronary event.
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METHODS |
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Subjects consisted of consecutive patients aged 35 to 68, who felt exhausted after being successfully treated by PCI. PCI patients were chosen because of the high incidence of new coronary events. This makes a study more efficient. Successful treatment was defined as a reduction in stenosis of the responsible lesion >50%. A two-stage procedure was used to ascertain exhaustion. First, 2 weeks after PCI, patients were asked to complete the Maastricht Questionnaire (MQ), a standardized self-administered instrument designed to measure exhaustion (19). Two items asking about increased irritability were added to the scale. A MQ score of 
14, which corresponds with the presence of seven or more complaints, was used to select patients for the next stage, which consisted of an interview-based assessment of exhaustion. This interview, the Maastricht Interview for Vital Exhaustion (MIVE), is a previously validated assessment of exhaustion that has a higher predictive validity with regard to future coronary events compared with the self-administered questionnaire (20). This interview consists of 23 questions, such as "Do you sometimes feel as if your body is like a battery that is losing its power?," "Do you feel that you have no energy?," "Do you blow up more easily than you used to?" The interview has a high internal consistency (Cronbach = 0.90). In previous studies, a cut-off score of 8 was used to divide subjects into exhausted and nonexhausted groups. For the present study, the inclusion criterion for exhaustion was defined on the basis of 7 positive responses.
Exclusion criteria were a) severe somatic or mental comorbidity (eg, kidney insufficiency, a 3-year or longer history of major depression); b) somatization disorder, fibromyalgia or chronic fatigue; c) participation in a behavioral rehabilitation program other than EXIT; d) unsuccessful treatment for a recent depression or panic disorder; and e) inability to speak Dutch.
Once a block of 12 qualifying patients was formed, participants were randomized to the intervention group or the usual-care control group individually by a computerized random-number generator maintained in the EXIT coordination center (Maastricht). Treatment assignment was never unmasked by previous assignments to avoid selection bias that results from research staff being able to predict the next treatment assignment. In case less than 12 qualifying patients could be selected within 6 weeks, the computer allocated six patients to the intervention group and the remaining patients to the control group to prevent unwanted delays. Physicians were notified in writing that their patients were enrolled in the study. All subjects gave written informed consent.
Treatment
Guided by the neurohormonal characteristics of exhausted subjects mentioned in the introduction, the aim of the treatment was to reduce stressors leading to exhaustion and to support recovery by promoting rest and making rest more efficient. Group discussions were used to identify stressors in the family and work domain, and to assist patients in coping with these stressors. Recovery was promoted by discussing the minimum and maximum length of resting time, by doing relaxation exercises designed to make rest more efficient (21), by stimulating physical exercise, and by assigning homework. If, for example, two or more patients felt very tired at noon but were reluctant to slow down, these patients were invited to form a "siesta group" and to phone each other at night to discuss whether or not they had taken a nap.
Because of the idiosyncratic nature of the stressors experienced by the patients and the large interindividual differences in work conditions and family conditions, group discussions were used as the main basis of the EXIT intervention to ensure an optimal match between the needs and demands of the patients and the content of the program. Counselors acted mainly as facilitators of the group discussions.
The program included treatment of hostility, because aggressive coping with stressors is one of the causes of exhaustion. We used methods developed by Williams and Williams (22) and by Powell (23). All groups were offered the possibility to meet with a cardiologist, dietitian, and a health educator if they wanted to have more information about medical aspects, nutrition, and smoking cessation. These specialists did not lecture, but answered questions prepared by the patients. The treatment was pretested in a nonrandomized pilot study and was found to be able to reduce exhaustion and cardiac risk (24).
Exhaustion has some features that overlap with depression. However, we do not approach this state as a mood disorder because a sad mood and distorted cognitions, such as "I do not deserve to be loved," are usually absent in exhausted subjects (25). Depressive symptoms are observed to lose their predictive power when fatigue is controlled for (26–28). If a patient suffered from major depression and no improvement was observed during the intervention, the recommendation was given for the patient to consult his family physician about antidepressive medication. No individual treatment modalities were used outside of the group meetings.
All centers followed the same protocol that described the content and sequence of the activities.1 Counselors were allowed to adapt the sequence of activities to the needs and demands of each group, and to skip one or more of the educational sessions if the patients felt no need to receive specific information. The content of two weekly sessions and of the four monthly sessions was not prespecified, to give room for discussions about new issues believed to be important by the participants and/or the counselors and for rehearsals. Compliance to the protocol was monitored through regular meetings, site visits, and inspection of the records made about each session. The counselors were experienced psychotherapists or clinical psychologists. They were trained by one of the authors (J.v.D.) in the application of the relaxation exercises and by the first author in the application of the protocol.
The groups comprised six patients. Partners were encouraged to attend the meetings. Sessions lasted 2 hours. As a rule the meetings started with group discussions and ended by doing one or two relaxation exercises. However, patients were allowed to skip the relaxation exercises if they did not want to stop a discussion. Groups met weekly during the first 10 weeks and once a month during the following 4 months.
Usual care consisted of the care regularly given in the four centers. It included routine check-ups in all centers and referral to a physical rehabilitation program in one center (Rotterdam).
Assessments
At baseline, data on demographics, medical history, and current medication were recorded. Somatic comorbidity was registered by asking the patients if they had visited a medical specialist in the year before PCI and, if so, for what reason. Comorbidity was classified in three categories: diseases meeting the exclusion criteria, chronic painful conditions causing unusual tiredness (eg, rheumatism), and no comorbidity. Major depression and somatization disorders were assessed according to DSM IV criteria. Anxiety was assessed by the State-Trait Anxiety Inventory (STAI) (29). Information about previous cardiac events, indication for PCI, degree and location of stenoses before and after PCI, and number of areas dilated was obtained from the medical records.
Assessments at 6 months, that is, immediately after the intervention, included anxiety and exhaustion (via the questionnaire). Assessments at 18 months included exhaustion (via the interview) and depression. Other psychosocial assessments made during the trial will be described elsewhere.
Endpoint Follow-up and Masking
The primary outcomes were interview-defined exhaustion at 18 months, new cardiac events and "de novo" lesions. Occurrence of new coronary events (defined as re-PCI, coronary artery bypass graft (CABG), MI, or cardiac death) was assessed by inspection of the medical records by a research assistant blinded to treatment allocation of the patient. The assistant was trained by the first two authors.
No reangiographies were performed as part of the study. Therefore, it was unknown whether a new cardiac event was related to "scars" caused by the treatment of the responsible lesion or to the growth of atherosclerosis elsewhere in the coronary system. Many new events are unrelated to the damage caused by the treatment of the culprit lesion. By definition the occurrence of "de novo lesions"—that is, lesions in a coronary vessel that was open at the index PCI—is not related to the damage of a coronary vessel caused by PCI. Therefore, "de novo lesions" were included as a separate outcome, because of the certainty with which they reflect the growth of atherosclerosis.
To ensure that no deaths were missed, the family physicians received a letter asking whether a patient was still alive and, if not, what had been the cause of death.
A treatment-masked adjudication committee evaluated possible incorrect inclusions, as well as outcome events with incomplete or conflicting information regarding the primary outcomes.
Statistical Analyses
Primary Analyses
Based on the results of a pilot study and an estimated 25% incidence of new coronary events within 18 months in usual care, the projected sample size of both treatment arms was 335 patients, to give the study a 90% power to detect a difference in incidence of 40% between the intervention group and the control group (24).
Logistic regression analysis was used to investigate the effect of the intervention on exhaustion and depression at 18 months. The Cox regression model was used to analyze time elapsed to the coronary events, and log-rank statistics were used to compare survival curves for the intervention and usual care arms. Age and gender were included as covariates in the Cox regression model. Separate analyses were done for each endpoint with the exception of cardiac death. Because of the small number of cardiac deaths (N = 9), fatal and nonfatal MIs were combined. All treatment-group comparisons were based on intention-to-treat-approach principles. All subjects allocated to the intervention group were included in the analyses, irrespective of their compliance. Missing values at 6 and 18 months were replaced by the last observed value.
Secondary Analyses
To test the hypothesis that reduction of exhaustion reduces the risk of new cardiac events, an exploratory analysis was done to see whether those whose exhaustion symptoms improved at 6 months, regardless of treatment condition, had lower event rates thereafter. Improvement was defined as a MQ score <14 or a reduction of the MQ score by 50% or more.
New coronary events after PCI can be divided into "early events" and "late events" (30). "Early events," that is, events occurring within 6 months after PCI, are mainly caused by inadequate intervention, recoil of the vessel wall, and neointimal hyperplasia (an effect of the vascular damage due to PCI). "Late events," that is, events occurring after 6 months, are usually not related to the responsible lesion but to new lesions elsewhere in the coronary system. Because early and late events may have a different pathological basis, we explored the effect of the intervention on early and late events separately.
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RESULTS |
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14. All were invited for an interview, and 1,254 (56%) accepted. "No interest" and "feeling too ill" were the main reasons for refusal. The mean interval between PCI and the intake interview was 37 days (SD 19.3). Of those interviewed, 298 patients were excluded because they did not feel exhausted, 84 patients because of comorbidity, and 62 patients for other reasons; 83 patients did not want to participate. The mean time between the interview and the start of the intervention was 29 days (SD 21.4). After completion of the intervention, a list of 19 possible false inclusions was presented to the adjudication committee. The committee accepted the exclusion of 17 patients. Main reasons for exclusion were: missing informed consent; comorbidity meeting the exclusion criteria; age <35 years; scheduled for a new coronary intervention before intake; attending physician disallowed participation. Thus, 710 patients were included in the study (Table 1). The slightly larger number of patients included in the intervention group (366 vs. 344) is caused by the policy to avoid unwanted delays when starting a new intervention group.
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Data on the occurrence of a new coronary event were available for all patients (100%). Ninety-three percent of the general practitioners responded to the questionnaire. Only one noncardiac death had been missed.
Baseline demographic and clinical characteristics of the trial groups are shown in Table 2. The groups were balanced in terms of all medical, demographic, and psychological characteristics except gender. Relatively more women were included in the control group. Therefore, gender was included in all multivariate analyses.
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Dropout Rate and Missing Values
Eleven patients (1.5%) never attended any session. Twenty-seven (3.8%) patients attended less than four meetings. A total of 298 (81%) patients attended at least nine meetings. Rehospitalization and feeling ill were the main reasons for noncompliance. Exhaustion at entrance was not associated with compliance. Thirty-eight (10%) patients of the intervention group and 37 (11%) patients of the control group did not participate in the 18-month interview. The mean exhaustion score at entrance of those who did not attend the 18-month interview was higher compared with the mean exhaustion scores of those who were interviewed at 18 months (t = 4.17; p < .00). Attendance of the interview was not associated with age, gender, education, marital status, or the experience of a new cardiac event.
Treatment Effects on Exhaustion
At 18 months, 48% of the intervention group and 58% of the control group still felt exhausted (
2 = 8.02; p = .005). Bivariate analyses showed that the effect of the intervention was modified by the presence of a previous cardiac history (PCI, MI, or CABG before the index PCI). A positive effect of the behavioral intervention was observed in those without a history of coronary artery disease (CAD), and no effect at all in those with a history of CAD (Table 3).
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Multivariate analyses (including age, gender, and level of exhaustion at intake assessed as a continuous variable) showed that the intervention reduced the odds of exhaustion at 18 months by 55% (OR = 0.45; 95% CI: 0.30–0.68; p < .00) in those without a history of CAD. However, the absolute effect size was modest, Cohen’s d being 0.37. The intervention had no effect on exhaustion in those with a history of CAD (OR = 0.93; 95% CI: 0.56–1.55; p = .78).
Of all the patients, 85 (12%) suffered from a chronic, painful condition that caused extreme tiredness. The presence of this condition doubled the risk of continued exhaustion (2 = 9.05; p = .003). Inclusion of this variable in the multivariate model hardly affected the results (OR = 0.44; 95% CI: 0.29–0.66; p = .00; OR = 0.91; 95% CI: 0.54–1.53; p = .72, in those with or without a history of CAD, respectively).
At intake, 58 patients (16%) of the intervention group and 43 patients (12%) of the control group were depressed (2 = 1.63; p = .20). At 18 months, 21 patients (6%) of the intervention group and 29 patients (8%) of the control group were depressed (2 = 1.96; p = .16). The effect of the intervention on depression was not modified by a positive history of CAD. The intervention reduced the odds of being depressed at 18 months by 50%, controlling for age, gender, and depression at intake (OR = 0.50; 95% CI 0.26–0.95; p = .04). Additional analysis controlling for use of antidepressive medication at intake did not change this result.
Treatment Effects on New Coronary Events
Primary Endpoints
Inspection of the medical records was completed in September 2002. Mean follow-up time for cardiac events was 24.4 months (SD 13.0) in the intervention group and 25.9 months (SD 12.7) in the control group. The survival curve showed no significant difference between treatments in the recurrence of a cardiac event (log rank = 0.68; p = .41). This null effect was consistent for all separate endpoints and did not change when age and gender were included as covariates (Table 4; Figure 1).
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During follow-up, 15 patients were treated for a "de novo lesion": 4 in the intervention group and 11 in the control group. Univariate analyses showed that the incidence of "de novo" lesions was positively associated with comorbidity (2 = 3.14; p = .08). Results showed that the intervention reduced the risk of a "de novo" lesion by 66% (RR = 0.34; 95% CI: 0.11–1.07; p = .07), controlling for age, gender, and comorbidity.
Compliance was not significantly associated with the effect of the intervention on exhaustion or on coronary endpoints. There did not appear to be any significant difference between centers of the effect of the intervention on exhaustion and on the occurrence of a new cardiac event. No adverse side effects of the intervention were seen.
Secondary Analyses
At 6 months, 134 (37%) patients of the intervention group and 95 (28%) patients of the control group had improved (2 = 6.58; p = .01). The effect of improvement of exhaustion on the risk of new cardiac events was modified by "previous history of CAD" (RR improved x history = 2.64; 96% CI: 0.91 –7.69; p = .07). No effect of improvement on new cardiac events was observed in those with a previous history of CAD. In those without a history of CAD, improvement of exhaustion reduced the odds of a new cardiac event by 60% (RR = 0.40; 95% CI: 0.16–0.97; p = .04), controlling for age, gender, and comorbidity. This observation gives partial support to the theory that a state of exhaustion increases the risk of a new cardiac event.
Forty-five percent of all events occurred within 6 months. Eight events (five in the intervention group and three in the control group) occurred within 1 month after intake and before the start of the intervention. Because the date of intake was taken as the start of the follow-up, these events were included in the analyses. The intervention increased the risk of early events (RR = 1.78; 95% CI: 1.08–2.92; p = .02), and decreased (nonsignificantly) the risk of a late event (RR = 0.79; 95% CI: 0.64–1.23; p = .29), controlling for age and gender.
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DISCUSSION |
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The behavioral intervention did not reduce the risk of a new cardiac event. Thus, the hypothesis that treatment of exhaustion reduces the risk of a new cardiac event after PCI could not be confirmed.
The intervention reduced the odds of "de novo lesions" by 64%. Because of the small number of patients, the confidence interval of this estimate is rather broad and the corresponding p value is slightly larger than the conventional value of 0.05. Therefore, this result does not prove the hypothesis that intervening on exhaustion reduces the risk of "de novo lesions," especially because silent restenosis may have been missed. However, together with the observation that the reduction of exhaustion reduces the risk of a late event in those without a previous history of CAD, this result gives a hint that intervening on exhaustion may influence the growth of atherosclerosis.
The four participating centers perform about 80% of all angioplasties in the southern half of the Netherlands. The results of the EXIT study can be generalized to all Dutch cardiologic centers. However, the external validity of the EXIT study decreases over time because of the rapid improvement of cardiologic intervention techniques. No significant differences in any of the outcome variables were observed between centers. Therefore, it is unlikely that the internal validity was limited by the fact that the participants were referred to a physical rehabilitation program in one center.
The internal validity may have been limited by the fact that those who conducted the interview at 18 months were aware of patients’ randomization status. However, essentially the same results were observed when the self-rating of exhaustion by the MQ was used to evaluate the effect of the intervention on exhaustion.
Three factors were found to limit the effect of the intervention on new cardiac events: the presence of a "history of CAD," the necessity to combine all cardiac events in one group despite their pathological differences, and "comorbidity."
"History of CAD" modified the effect of the intervention on exhaustion. The intervention reduced exhaustion in those without a previous history of CAD, and had no effect on exhaustion in those with a previous history of CAD. Exploratory analyses suggest that the lack of effect occurred mainly in those with a long history of CAD. Sixty-nine patients (10%) had experienced two or more cardiac events before the index PCI. This subgroup was not only more exhausted at entry, they also had felt exhausted during a longer period of time. Thirty-five percent of those without a cardiac event before PCI or with a single event had felt exhausted for more than 1 year before PCI. Forty-eight percent of those with two or more cardiac events had felt exhausted for more than 1 year (2 = 4.16; p = .04). Changes in mean exhaustion scores were significantly lower in those who had felt exhausted for more than 1 year. Therefore, it is not unlikely that the effect modification by "history of CAD" has to be partially attributed to the presence of a subgroup with a very serious history of CAD. This group was also characterized by a higher prevalence of a poor left ventricular ejection fraction (2 = 3.43; p = .06).
As reported above, the mean time between PCI and intake was 37 days. Therefore, it is unlikely that very early events, caused by inadequate intervention or recoil of the vessel wall, were counted as events. With regard to all other new cardiac events, except "de novo" lesions, insufficient information was available to decide whether the new event was related to neointimal hyperplasia or not.
The higher incidence of early events in the intervention group should raise serious concerns. Did the intervention do more harm than good? Secondary analyses showed remarkable differences in the predictors of early and late events. Determinants of early events were number of areas dilated, multivessel disease after PCI, nonsmoking, and a higher level of education. The determinants of late events were previous history of CAD and comorbidity. A lower incidence of target lesion revascularization among smokers has also been observed by Cohen et al. (31). This could be explained by a reduced sensitivity to restenosis on the part of smokers and by the greater reluctance of smokers to seek medical assistance despite recurrent angina. We checked for differences in anxiety and exhaustion between the intervention group and the control group and observed a significantly greater decline of trait anxiety and exhaustion between the start of the intervention and 6 months in the intervention group compared with the control group (data not shown). Therefore, we do not believe that the intervention resulted in some form of anxiety or distress that fostered restenosis. We assume that a higher level of education, nonsmoking, and participation in the intervention do not cause early events, but rather lower the threshold to present complaints. A similar effect may have influenced the results of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. The 4-year survival curves presenting the effect of the ENRICHD intervention on cardiac death and myocardial infarction are suggestive of a negative effect of the intervention during the beginning of the follow-up (35).
The presence of a noncardiac chronic, painful condition ("comorbidity") limited the effect of the intervention on exhaustion. "Comorbidity" was also found to increase the risk of a late event. Most patients classified as suffering from comorbidity suffered from rheumatism of hard or soft tissue. Rheumatism is an inflammatory disease known to increase the risk of CAD (32). Rheumatism may also evoke feelings of tiredness through the release of proinflammatory cytokines.
The inability of the intervention to reduce the risk of new cardiac events may also be caused by other factors such as inadequate treatment. To investigate that question, we computed the effect of the intervention on the occurrence of late events in those without a previous history of CAD and comorbidity (24 events and 342 no-events). The result of this post hoc analysis showed that the intervention reduced the risk of a late event by 55% (RR = 0.45; 95% CI: 0.19–1.06; p = .07) in this selected group of patients. This observation gives some support to the belief that the three factors described above constituted the major factors limiting the effect of the intervention on new cardiac events.
During the last decade, three large-scale randomized controlled trials, which attempted to determine whether mortality and recurrent infarction are reduced by treatment of depression or distress, reported negative results (33–35). The EXIT study has to be added to this list because we could not demonstrate that intervening on exhaustion reduces the risk of a new coronary event. Because of differences in treatment, patient selection, and endpoints, these studies are difficult to compare.
These negative outcomes do not refute the strong predictive power of depressive symptomatology or exhaustion observed in many studies, nor do they refute the biological plausibility of this association. Rather, they help to detect the obstacles preventing success in intervention studies. The major suggestions that EXIT has to offer to future behavioral intervention studies in coronary patients are to consider carefully whether patients with a very serious history of CAD should be included, to extend and refine the exclusion criteria for somatic comorbidity, and to control for changes in the reluctance to present new cardiac complaints.
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APPENDIX |
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Steering Committee
A. Appels (principal investigator), F.Bär (study co-chair).
Clinical Sites
Maastricht University and Academic Hospital Maastricht; A. Appels, F. Bär, J. Lasker, and L. Bögemann.
Erasmus Medical Centre, Rotterdam; P. van Andel, R.A.M. Erdman, A van ’t Spijker, W. Trijsburg, and M. J. B. M. Van den Brand.
Academic Hospital Nijmegen; M. Assmann, A. Jacobs, and F. Kraaimaat.
Catharina Hospital, Eindhoven; A. Jacobs, A. Appels, H. Adriaans, I. Luchtenberg, H. Bonnier, and W. Fontijn.
Coordination and technical staff: G. van der Pol (supervisor), A. Brink, R. Vink, M. Palmans, N. Rutten, and N. van de Steeg.
Adjudication Committee: G. Dinant, P. Falger, and H. de Swart.
Methodological and statistical advice: F. Kessels and C. Mendes de Leon
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NOTES |
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Received for publication April 13, 2004; revision received July 2, 2004.
DOI:10.1097/01.psy.0000151485.38411.36
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