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SPECIAL ISSUE: COMORBIDITY STUDIES |
From the Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, New York.
Address reprint requests to: Hillel W. Cohen, DrPH, Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Room 1302 Belfer, 1300 Morris Park Ave., Bronx, NY 10461. Email: hicohen{at}aecom.yu.edu
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ABSTRACT |
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METHODS: Participants (5564) in a union-sponsored, hypertension control program in New York City, who entered the program during 1981–1994 without a history of cardiovascular disease and who were asked whether they had been treated for depression, were followed in a prospective cohort study. The primary outcome of interest was hospitalization or death due to myocardial infarction.
RESULTS: At entry, 3.5% of men and 6.4% of women reported a history of treatment for depression. During 4.9 years (average) of follow-up, 112 fatal and nonfatal myocardial infarctions were recorded. The sex-adjusted relative risk of myocardial infarction was 2.24 (confidence interval = 1.13–4.45). Controlling for known cardiovascular risk factors with multivariate proportional hazards models, history of treatment for depression was significantly associated with subsequent myocardial infarction (hazard ratio = 2.10, confidence interval = 1.04–4.23).
CONCLUSIONS: A self-reported history of treatment for depression is independently associated with subsequent myocardial infarction in treated hypertensive patients without prior cardiovascular disease. Whether additional or different treatment for depression will be cardioprotective is unknown and merits further study.
Key Words: depression • myocardial infarction • hypertension.
Abbreviations: CI = confidence interval; CVD = cardiovascular disease; DSM = Diagnostic and Statistical Manual of Mental Disorders; MI = myocardial infarction; RR = relative risk.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Recent studies have found depression, measured with survey or interview scales, to be associated with cardiac events (9–11), other CVD events (12–15), and atherosclerosis (16). The results have been generally consistent despite the use of different measures of depression among various populations. However, in one study that compared patients in the lowest (most depressed) and highest terciles based on depression scores, investigators did not observe a significant association between depression and mortality due to ischemic heart disease, although they did report an association of depression with all-cause mortality among men (17). In that study, however, the measure of depression may not have been sufficiently specific, because 33% of the population was categorized as exposed, whereas exposure in other studies typically ranged from 2% to 24% (9–14).
In a study of a hypertensive population, investigators observed that baseline depression did not predict subsequent CVD events. The investigators did report an association of change in depression with stroke but not MI (15). All participants in that study were 60 years old or older.
Several studies have examined CVD outcomes associated with use of pharmacological antidepressants (18–20). One of these found an association with ischemic heart disease events, although there were few events among the exposed group and a 90% confidence interval was used (18). Swedish investigators studied a considerably larger number of patients using antidepressants and reported an association with subsequent all-cause mortality among subjects >65 years old. An association was also observed for CVD mortality, but only for those with evidence of ischemic heart disease at baseline (19). Investigators in a recent study of a much larger working-age population reported that prior antidepressant use predicted subsequent MI (20).
None of these studies examined the association of treated depression within an exclusively hypertensive population. Although hypertension and treated depression have both been individually associated with increased risk of CVD, it has not been established whether among hypertensives, treated depression conveys additional excess risk of CVD events in general or the risk of MI in particular. We conducted a prospective study of hypertensive patients without a history of CVD and found that a self-reported history of treatment for depression is positively and independently associated with subsequent MI and other cardiac events.
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METHODS |
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160 mm Hg or a diastolic blood pressure 95 mm Hg and those taking antihypertensive medication at the time of screening were eligible to enroll in the program. The entry blood pressure threshold was changed to 140/90 mm Hg in 1993 after a revision in the recommendations of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (24). In 1981 a new entry form that included a medical history question on treatment for depression was introduced. Subjects in the current study were those who entered the program between January 1981 and 1994 and had provided information on the medical history question on depression. Of the 6837 patients who met these criteria, 55 responded "uncertain" to the medical history question on depression and 1218 had a history of CVD at entry. These patients were excluded, and the remaining 5564 formed the study cohort. Baseline information included demographic data, personal medical history, cigarette smoking status, physical examination by a nurse and physician, electrocardiographic findings, routine clinical blood chemistry values, and blood pressure. Patients came in for revisits and were seen by a project nurse several times during the year. Blood pressure was measured at these revisits, and prescriptions for antihypertensive medication were renewed or reevaluated. At the annual reexaminations, patients were asked if they had been hospitalized during the previous year. All outcome data were obtained without knowledge of depression status. The study was performed according to a protocol approved by the institutional review committee.
In 1981 treatment generally began with a diuretic or a ß-blocker. By the mid-1980s, 
- and/or ß-adrenergic blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors were also used.
Depression Ascertainment
During the initial physical examination at entry (which was conducted by a nurse), each subject was asked a simple medical history question, "Are you now, or have you ever been, treated for any of the following conditions?," in which depression was one of the listed conditions. A "yes" answer for depression defined the exposed group. Throughout the rest of this article, whenever depression is used to refer to the exposure in this study, it means a self-reported history of treatment for depression. No further corroboration of the history of treatment for depression was made, nor was any additional information (eg, on onset, duration, severity, or treatment) collected.
Follow-Up and Outcomes
Patients had an average of five clinic visits per year. Follow-up time was calculated in years from the date of entry to the last revisit or to the first outcome event for those who had one. At each clinic visit, patients were asked if they had been hospitalized since their last visit. Subjects who missed their scheduled appointments were telephoned and sent letters to determine why the appointments were missed. When subjects could not be reached, inquiries were made of family members when possible. If there was any indication of hospitalization of a subject, hospital charts were requested. Hospital charts were reviewed by project physicians to assess the cause of hospitalization without consulting the clinic chart, in which the depression status was indicated. If there were multiple causes, the primary discharge diagnosis was used. If the subject had died, death certificates were obtained and the primary cause of death was recorded. For cases in which charts or death certificates could not be obtained to confirm the cause of an event, physicians outside the program, family members, friends, or union records were consulted.
Morbid and mortal events were hospitalizations and deaths classified according to the International Classification of Disease, 9th revision, Clinical Modification, 1997 (Context Software Systems, Inc., Burr Ridge, IL). MI was defined as code 410, and cardiac events were defined as either code 410 or procedure code 36 (angioplasty, revascularization, and coronary bypass). Ischemic heart disease events were defined by adding codes 411 through 414 to the cardiac events. Non-CVD events were all hospitalizations or deaths for all causes other than codes 390 through 459. For those with more than one event, the first event was used.
Other Measures
The medical history question also elicited information about heart attack, stroke, angina, other heart trouble (CVD other than heart attack, stroke, and angina), diabetes, kidney failure, asthma, lung disease, and gout. The first four events, alone or in combination, were grouped as history of prior CVD. Responses of uncertain to the other CVD conditions were grouped with yes responses for the purpose of exclusion so that the study group unambiguously had no history of prior CVD.
All blood pressure measurements were made by a registered nurse using a standard sphygmomanometer. An average of the second and third seated readings in a set of three was the blood pressure for the day. The blood pressure at screening was considered the baseline value.
Cholesterol and blood glucose values were determined by a commercial laboratory, and left ventricular hypertrophy was determined by a program physician who interpreted a standard 12-lead electrocardiogram (25). Body mass index was calculated from height and weight, which were recorded at entry along with current smoking status and history of hypertension treatment. Subjects who responded that they or their family considered the subject’s drinking a problem were considered to have an alcohol problem. For purposes of analysis, categorical variables were dichotomized into indicator variables as follows: race, white or nonwhite; education, <12 or 12 years completed; marital status, married or unmarried (which combined single, divorced, and widowed).
Statistical Analysis
Baseline characteristics were assessed according to sex and depression status. Cause-specific event rates (per 1000 person-years) were computed by depression status for each sex and were sex-adjusted for the total population. The RR and 95% CI between the depression group and the nondepression group were determined for the incidence of MI and, for comparison, non-CVD events.
Cox proportional hazards regression models (26) were used to determine the association of depression with outcome while controlling for potential confounders and other covariates. Categorical variables, including depression status, were coded 1 for yes or present and 0 for no or absent. In the calculation of event rates and in the Cox models, follow-up time was calculated from entry in the program until the first outcome event. For subjects with no outcome events who were still active in the program as of June 30, 1997, follow-up time was calculated from entry to that cutoff date. Those without outcome events who left the program before that date were censored at the date of the last visit. All clinical chemistry measures were converted to SI units using appropriate conversion factors. All statistical analyses were performed with SPSS for Windows software (27).
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RESULTS |
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Sex-adjusted incidence rates ( Table 2) for MI per 1000 person-years were 8.7 for those with depression and 3.9 for those without depression (RR = 2.24, 95% CI = 1.13–4.45). The corresponding rates for non-CVD events were 15.0 and 15.5 for the depression and nondepression groups, respectively (RR = 1.06, 95% CI = 0.67–1.68).
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The association of depression with MI for women (RR = 2.14, 95% CI = 0.64–7.21) was similar to men in magnitude but was not statistically significant. The associations of depression with non-CVD events for women was positive (RR = 1.29, 95% CI = 0.72–2.33) but smaller than the association with MI and not significant (p = .40).
When these analyses were repeated separately for cardiac events and ischemic heart disease events, the results were similar. Excluding subjects with less than 6 months of follow-up did not substantially change the results.
Multivariate Analysis
In a Cox regression model with MI as the dependent variable and depression as an independent variable along with other known risk factors ( Table 3), depression had a hazard ratio of 2.10 (95% CI = 1.04–4.23). Age, total cholesterol, white race, history of diabetes, male sex, smoking, and left ventricular hypertrophy were also found to be independently and significantly associated with MI. When the models were stratified by sex, the associations of MI with depression were similar in size for both men and women for the group as a whole but were not statistically significant.
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DISCUSSION |
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This study is among the largest prospective studies to date, with regard to number of subjects and patient-years of observation, linking depression to subsequent CVD events. It is the only such study that has examined a cohort of working-age, treated hypertensive patients. The results are consistent with those of earlier studies that examined different populations and used different measures of depression, including the Center for Epidemiological Studies Depression Scale (15), the Diagnostic Interview Schedule (9, 11), other scales (10, 12, 13), and self-reports (14). The results are also consistent with those of studies in which treatment for depression was the exposure (18–20), except that in those studies the treatment was use of antidepressants at baseline whereas in this study neither the time nor method of treatment was known. The depression measure used in this study most closely resembles the self-report of clinical depression used in a previous study of predominantly white, male medical students (14). Although that population differed from the current study population of hypertensive service workers of mixed ethnicity, the results were remarkably similar.
Because only a self-reported history of treatment for depression was used in this study, there was no way to test the reliability and validity of the exposure measure. However, unconfirmed medical history questions on major events and on chronic illness have been found to be useful in identifying risk of subsequent health outcomes (28, 29). Medical history questions with much the same format as that used in our study have been used routinely to identify history of CVD and other selection or control conditions for all the cited studies.
Although there were no data to test the sensitivity or specificity of the medical history question on depression, the responses showed a sex ratio similar to what has been found with validated instruments. In particular, the proportions of men and women reporting a history of treatment for depression in this study, 6.4% for women and 3.5% for men, reflected the 2-to-1 sex ratio observed in many depression studies in the United States and Western Europe (30–32).
It is likely that measuring treatment for depression provided an underestimation of the prevalence of depression, because not everyone with depressive symptoms will seek treatment, and of those that do, some might not report such a history, given that psychological ailments still convey a stigma (32). Conversely, some of those who reported treatment for depression may have seen a clinician for depressive symptoms that would not meet DSM criteria for a diagnosis of depression (33). Also, without a quantitative scale or a specific diagnosis, the severity of depression could not be ascertained. However, measuring treatment for depression rather than simply depressive symptoms might better reflect a level of severity comparable to a diagnosis of major depression or major depressive episodes as defined by DSM criteria. Data were not available in this study to examine this issue.
A limitation of this study is that data were not available to identify a group with untreated depression. However, the hazard ratios found in this study are consistent with those found in studies in which depression measured by symptoms rather than treatment was linked to cardiac events (9–11) or other CVD events (12–14). The consistency of the results of the current study with results from these other studies suggests that the treatment for depression measured as the exposure reflected an underlying depression and that the observed association was not simply an artifact of the treatment experience.
It has been reported that depression is a common result and complication of MI (34–36) and other serious illness (37), raising the possibility that depression in this hypertensive population was simply a marker of preexisting CVD. The findings, however, suggest that depression was not merely a comorbid condition or complication of prior MI or other CVD events because those with indications of prior CVD were excluded from these analyses.
The consistency of the results for MI alone with those for cardiac events and all ischemic heart disease events suggests that the results did not simply reflect that subjects in the depression group were more likely to seek medical attention and thus increase the chance of having cardiac procedures.
Several plausible mechanisms have been advanced to link depression with MI and other cardiac events (38, 39). For example, people with depression may have poorer diets, smoke or abuse alcohol more, exercise less, or be less able to comply with their hypertension treatment regimen. However, in this study the association persisted even after adjusting for smoking, problem drinking, cholesterol, and body mass index. Because achieved blood pressure control did not differ between depressed and nondepressed subjects, variation in hypertension control cannot account for the results. Depression may be associated with other, unmeasured poor health behaviors or poorer health in general. However, if either poor health behaviors or generally poor health were major factors underlying the observed association, then one might expect that the rate of non-CVD events would also be higher for the depression group. This was not the case.
Other mechanisms that have been suggested but that could not be tested for lack of data include effects of sympathetic nervous system activity and levels of catecholamines, impaired heart rate variability, platelet dysfunction, and deleterious effects on plasma lipids and plaque formation (37–41). Other factors, such as the role of steroidal hormones, that might be associated with both depression and CVD should be investigated in future studies (42, 43).
The association between depression and MI might be explained in part by any factor that contributed to an increased risk of both. For example, a lower socioeconomic status might be a common antecedent of both depression (44) and CVD (45). Although this relationship could be an important one for a general population, it is less likely to be a major explanation for the observed associations in this population, which was relatively homogeneous in occupation and income and which had uniform access to health care. We were also able to control for differences in ethnicity and education.
The question of whether treatment for depression will affect cardiovascular risk may be very important. Although a number of studies have shown consistent associations between different measures of depression and subsequent CVD, few have had sufficient numbers of subjects with evidence of treatment to indicate whether treatment for depression provides cardioprotection. In the current study, unfortunately, no data were available to identify those with a history of untreated depression, so comparison of treated and untreated groups was not possible. Similarly, the lack of precise data on the onset, duration, and method of treatment prevented examination of specific treatment effects.
It is possible that different types of treatment might have different results. Although the data in this study did not allow us to examine this question, a recent study that involved two of the current authors found that in a general working population without a history of CVD, use of tricyclic antidepressants was associated with subsequent MI with a hazard ratio of 2.3 (95% CI = 1.2–4.5), similar to that reported here (20). In the same study, however, use of selective serotonin reuptake inhibitors was not associated with subsequent MI. If those findings are replicated, they could indicate that tricyclics are in some way cardiotoxic, that selective serotonin reuptake inhibitors are in some way protective, or both. It would be helpful if clinical trials of antidepressant treatment could include examination of long-term CVD outcomes as well as short-term changes in depressive symptoms and behavior.
CVD remains the leading cause of death in the United States, and MI is the largest component of CVD with regard to hospitalizations and deaths (46). At the same time, depression is recognized as a major health problem worldwide (47) and is the most prevalent psychological disorder (48). Because much remains unknown about both of these conditions, further assessment of the association between the two could lead to a better understanding of the etiology of both and possibly new preventive interventions.
In conclusion, these data demonstrate that among hypertensive patients without prior CVD, a history of treatment for depression can identify those at higher risk of MI and cardiac events. Whether more vigorous treatment for depression or changes in the type of antidepressant therapy would provide cardioprotection is a provocative question worthy of further investigation.
Received for publication October 6, 1999.
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