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ORIGINAL ARTICLES |
From the Department of Medicine, Division of Cardiology, Emory University School of Medicine (V.V., J.L.A.), Atlanta, Georgia; and the Department of Epidemiology and Public Health, Yale University School of Medicine (M.D., S.V.K.), New Haven, Connecticut.
Address reprint requests to: Viola Vaccarino, MD, PhD, Emory University School of Medicine, Department of Medicine, Division of Cardiology, 1256 Briarcliff Road, Suite 1 North, Atlanta, GA 30306. Email: lvaccar{at}emory.edu
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ABSTRACT |
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METHODS: We analyzed data from the Third National Health and Nutrition Examination Survey, a representative sample of the US population from 1988 to 1994. Participants included a total of 6149 individuals aged 17 to 39 years who were free of cardiovascular diseases and chronic inflammatory conditions. The main predictor variable of interest was lifetime history of a major depressive episode as assessed by means of the Diagnostic Interview Schedule. The main outcome variable was the presence or absence of an elevated CRP level (
22 mg/dl).
RESULTS: Among men, history of a major depressive episode was associated with elevated CRP, particularly for recent episodes (up to 6 months before assessment). In multivariate analyses, men with a history of major depressive episode had 2.77 times higher odds of elevated CRP compared with never-depressed men (95% confidence interval, 1.43–5.26). The adjusted odds ratio was 3.81, 3.98, 1.51, and 1.52 for men who had their last major depressive episode less than 1 month before, 1 to 6 months before, 7 to 12 months before, and more than 12 months before assessment, respectively (p for trend = .004). In women, a comparable association between depression and CRP was quite weak and not significant.
CONCLUSIONS: A recent history of major depressive episode is strongly associated with elevated CRP in men aged 17 to 39. In this group, low-grade systemic inflammation could represent a mechanism linking depression to cardiovascular risk.
Key Words: depression, • inflammation, • epidemiology, • risk factors, • population studies.
Abbreviations: CHD = coronary heart disease;; CRP = C-reactive protein;; DIS = Diagnostic Interview Schedule;; DSM = Diagnostic and Statistical Manual of Mental Disorders;; HDL = high-density lipoprotein;; MEC = mobile examination center;; NHANES III = Third National Health and Nutrition Examination Survey.
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INTRODUCTION |
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Growing evidence suggests that atherosclerosis is fundamentally an inflammatory disease (25) and that inflammatory markers are powerful predictors of coronary heart disease (CHD) events (26–32). Therefore, it would be reasonable to argue that the link between depression and CHD might be mediated by inflammation. In support of this argument, some studies have reported that depression is associated with higher levels of C-reactive protein (CRP) (33–37), a marker of systemic inflammation that has been shown consistently to predict CHD risk (26–30). However, these previous studies of depression and CRP have been limited to selected clinical samples and/or have failed to control for important confounding factors. To clarify the association between depression and CRP, studies based on wider population samples with more extensive control of confounding factors are needed.
The primary objective of the present study was to investigate the association between history of major depressive episodes and the presence of a low-grade systemic inflammation as measured by serum CRP levels in a sample of 6149 persons who took part in the Third National Health and Nutrition Examination Survey (NHANES III). We hypothesized that after adjustment for confounding factors, individuals with a history of major depressive episodes would be more likely to have elevated CRP compared with individuals without such a history and that the more recent the last depressive episode, the higher the probability of elevated CRP. We also examined whether an association between depressive symptoms and CRP could be found in the absence of major depressive episodes.
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METHODS |
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Of the 7681 individuals aged 17 to 39 who received the DIS in NHANES III, we excluded pregnant women (N = 321, 4.2%), individuals whose interviews were coded as unreliable by the NHANES III file documentation (N = 9, 0.1%), and individuals with missing information on CRP (N = 458, 6.0%). Comparison of characteristics between subjects with and without missing data showed only minor differences. Persons with missing CRP tended to be more often white, more likely to have a normal body mass index (<25 kg/m2), and less often users of birth control pills. There were no significant differences in other risk factors or in previous history of major depressive episode. Individuals with diseases that are known to influence CRP (cardiovascular diseases, diabetes, and chronic inflammatory diseases) (40, 47–50) were also excluded (N = 744). Exclusion of persons with cardiovascular diseases was based on self-reported information of prior stroke, myocardial infarction, or angina using standard questions for population surveys, including the Rose Questionnaire (51). The latter has been shown to have a sensitivity of 82% and a specificity of 100% when compared with a diagnosis of angina pectoris performed by two independent physicians (52); it is a strong predictor of fatal and nonfatal CHD (53–55), and it is associated with standard CHD risk factors and carotid intima-media thickness measured by B-mode ultrasound (56). Exclusion of persons with diabetes mellitus was based on self-reported diabetes as well as on a fasting plasma glucose greater than or equal to 126 mg/dl (7.0 mmol/liter) (57). Exclusions resulting from chronic inflammatory disorders were based on self-reported recent diagnosis of one of the following: chronic bronchitis, asthma, emphysema, or rheumatoid arthritis. Finally, we excluded 49 persons with a history of bipolar disorder. After these exclusions, 6100 persons were included in this study.
Study Variables
Serum CRP was measured with a latex-enhanced Behring Nephelometer Analyzer System. The coefficient of variation was between 3.2% and 16.1% throughout the period of data collection. This system was able to detect a minimal CRP concentration of 0.22 mg/dl. Because most persons had values less than this minimum detectable concentration, CRP was treated as a categorical rather than a continuous variable and dichotomized into either undetectable (<0.22 mg/dl) or elevated (0.22 mg/dl) consistent with previous work (58). Because only 5% of the women and 2% of the men had clinically raised CRP according to the conventional clinical cutoff point for inflammation (>1.00 mg/dl), this level was not considered as a separate category. Therefore, elevated levels of CRP (0.22 mg/dl) in this study are mostly indicative of a subtle and persistent increase in systemic inflammation, a response that has been linked to cardiovascular risk (27, 30, 59, 60).
Depression was assessed by means of the DIS (40), which yields clinical diagnoses of major depression and major depressive episodes based on DSM-III-R (41).
Race-ethnicity was self-reported as non-Hispanic white, non-Hispanic black, or Mexican American, representing the three major ethnic groups in NHANES III. People outside these categories were classified as "other." Body mass index was computed as weight in kilograms divided by the square of standing height in meters (kg/m2) and was categorized as normal (<25 kg/m2), overweight (25 to <30 kg/m2), or obese (30 kg/m2 or above) (61). Participants were classified into current, former, and never smokers based on self-reported information on smoking patterns. Irrespective of self-report, individuals with a serum cotinine concentration greater than 57 nmol/liter (62) were classified as current smokers. A small proportion of individuals (4.9%) who classified themselves as nonsmokers were, in fact, smokers according to cotinine values. Education was categorized into less than high school (<12 years of education), high school degree (12 years), and at least some college (>12 years). Women were classified as being contraception users if they reported current use of birth control pills or contraceptive implant and as hormone replacement users if they reported current use of estrogens or other female hormone treatment. The presence of acute infection or inflammation was based on a positive answer to the question, "In the past few days have you had a cough, cold, or other acute illness?" or on the examining physicians’ diagnosis of a possible active infection. Use of antidepressants in the past month was self-reported. Total serum cholesterol was categorized as <200 mg/dl, 200 to 239 mg/dl, and 240 mg/dl. High-density lipoprotein cholesterol was categorized as <35 mg/dl, 35 to 60 mg/dl, and >60 mg/dl (63). Hypertension was defined as a systolic blood pressure of 140 mm Hg, a diastolic blood pressure of 90 mm Hg, or the current use of antihypertensive medication.
Statistical Analyses
The first step in the analysis was to calculate the proportion of individuals with elevated CRP according to depression and other important sample characteristics. Differences in proportions were tested with chi-square statistics, and Mantel tests for trend were performed for ordinal variables with more than two levels. Two-sided p values were always generated. Consistent with previous studies of depression and CHD (18), our main predictor was lifetime history of major depressive episode. In our main analyses, this definition included a small number of individuals in whom a major depressive episode was related to bereavement (N = 58). We examined the association between depression and CRP with depression as a dichotomous variable (ever had major depressive episode vs. never had major depressive episode). Additionally, to investigate whether the presence of elevated CRP levels depended on how recently the last major depressive episode had occurred, we constructed a series of dummy variables indicating the time since the last major depressive episode (<1 month, 1–6 months, 7–12 months, >12 months, and never had one). A Mantel test for trend was performed to determine whether the prevalence of elevated CRP differed according to the levels of this variable. The percentages were weighted to represent the total civilian, noninstitutionalized US population and, therefore, are population prevalence estimates.
The multivariate association between a major depressive episode and elevated CRP was examined by means of logistic regression models, which were adjusted for all the variables listed in Table 1. Odds ratios and 95% confidence intervals (CIs) were calculated with the never-depressed individuals used as the reference category. Because the prevalence of elevated CRP was above 10%, odds ratios do not approximate risk ratios and should not be interpreted as risk ratios in this study. The use of antidepressant medications was included among the adjustment factors because both positive (64, 65) and negative (66–68) effects have been described with the use of these drugs in relation to cardiovascular disease and because antidepressant use can reduce CRP levels irrespective of response to therapy (69). However, because of a concern of overadjustment, we repeated the analyses after excluding this variable from the multivariable models. These analyses, however, yielded very similar results and therefore are omitted from this report.
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Analyses were conducted in SUDAAN (74), which incorporates sampling weights to account for oversampling and nonresponse. Variance estimation in SUDAAN allowed for the complex sampling design of NHANES III (75). All analyses were conducted separately by gender, given the important gender differences in the prevalence of depression (76) and elevated CRP (58) as well as gender differences in the strength of the association between depression and CHD (16, 19, 77).
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RESULTS |
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0.22 mg/dl) were found in 13.29% of men (N = 474) and 24.5% of women (N = 925). As expected, higher body mass index and acute inflammatory conditions were associated with a higher prevalence of elevated CRP in both men and women. Older age and smoking status were associated with CRP levels in men (Table 1). Race-ethnicity was also associated with the prevalence of elevated CRP, with non-Hispanic whites having the lowest prevalence and African Americans the highest prevalence. Hypertension and lower levels of HDL cholesterol tended to be associated with a higher likelihood of elevated CRP. History of a major depressive episode was present in 134 men (5.2%) and 324 women (10.6%). Men with a history of a major depressive episode were about twice as likely to have elevated CRP compared with men without a history of depression: 24.0% vs. 12.6% (unadjusted odds ratio, 2.17; 95% CI, 1.81–4.00). No association between history of a major depressive episode and elevated CRP, however, was found in women (Tables 1 and 2).
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0.20. In men, the prevalence of elevated CRP was related to the time of the occurrence of the last major depressive episode (Table 3 and Fig. 1). About one third of the men who reported a major depressive episode within the past month or between 1 and 6 months had an elevated CRP. If the major depressive episode occurred more than 6 months before, however, the prevalence of elevated CRP was considerably lower and close to the levels of men with no history of depression. These associations were not weakened in multivariable analyses that adjusted for all the variables listed in Table 1 (Table 3). The overall adjusted odds ratio was 2.77 comparing men with a history of major depressive episode to those who had never been depressed (95% CI, 1.43–5.26).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Previous studies investigating the association between depression and CRP were conducted mostly in clinical populations (33–37). Many of these studies have suggested that depression promotes systemic inflammation and increases plasma levels of inflammatory cytokines such as interleukin-6 (IL-6) (34, 36, 37, 78) as well as a number of acute-phase proteins such as CRP (34–36). Reported results, however, have not been entirely consistent. Rothermundt et al. (79) found that 
2-macroglobulin and monocyte counts, but not CRP, were increased in patients with nonmelancholic depression compared with control subjects and that none of these inflammatory markers was elevated in patients with melancholic depression. Most of the patients studied (86%), however, were receiving pharmacological treatment for depression. Lanquillon et al. (69) found that although pretreatment CRP levels were significantly elevated in patients with major depressive disorder compared with control subjects, antidepressive treatment decreased these values to levels similar to those of control subjects irrespective of response to treatment.
Many of these previous reports were limited by small sample sizes, selected samples, and/or failure to control for important confounding variables. By using a broad, population-based sample and by controlling extensively for potential confounding factors, the present study provides the strongest evidence to date of an association between depression and an increase in systemic inflammation. A particular strength of our study is the fact that our population was composed of young individuals, aged 17 to 39 years. In this group, the prevalence of clinical and subclinical disease can be expected to be very low; therefore, confounding by unmeasured disease status should be minimal in our results.
Depression might promote an inflammatory response by activating the immune response (80). Alternatively, the effects of depression on inflammation might be due to its links to psychological stress (81–83). The latter has also been associated with excessive production of IL-6 (36, 78, 80, 84). IL-6 and IL-1ß synergistically induce a systemic immune response. IL-6 is also the main proinflammatory cytokine inducing synthesis of type 1 acute-phase proteins such as CRP. Psychological stress has been shown to increase oxidative state (85–89), which in turn, through modified lipids and lipoproteins, is thought to initiate an inflammatory response in the artery wall (85, 86) . It may also be that depression leads to higher CRP levels, but that it does so through some indirect, nonbiological mechanism such as a health behavior. For example, depression may lead to higher smoking levels, which in turn would lead to higher CRP levels. Our finding in men was adjusted for smoking, so it seems unlikely that smoking could explain the association we observed, but we cannot rule out that it was due to some other intervening factor.
Low-grade systemic inflammation may play a role in the initiation and progression of atherosclerosis, plaque destabilization, or thrombosis (59, 90). Atherosclerosis itself is now recognized to be predominantly an inflammatory process (25). Consistent with this view, in recent epidemiological studies serum markers of inflammation have come to the fore as important indicators of cardiovascular risk in both individuals with established coronary heart disease (31, 32, 91) and in individuals initially free of the disease (26, 27, 29). CRP, in particular, has been proposed as a potential candidate for coronary risk screening (92, 93).
In general, there is little doubt that the link between CRP and CHD is a chronic inflammatory state that predisposes to atherosclerosis and to plaque rupture (93). For example, recent studies have shown that CRP predicts coronary events only among patients not pretreated with aspirin (94); conversely, aspirin reduces coronary event rates only among individuals with CRP in the highest quartile (27). However, the exact role of CRP in the pathogenesis of atherosclerosis is not clear. CRP could be only a marker of inflammation with no direct role in the pathogenesis of atherosclerosis. A direct proinflammatory effect of CRP on the endothelium, however, has been described (90), as has an ability of CRP to induce the production of tissue factor, a potent procoagulant, in monocytes (95). Whatever the exact role of CRP in inflammation, the results of our study suggest that in men, the link between depression and higher CHD risk may be mediated by a depression-induced increase in inflammation (1–6).
An intriguing finding of our study is that an association between depressive episodes and CRP was found in men but not in women. One possible explanation is that women, particularly if premenopausal, are protected from the pathophysiological consequences of psychological stress because of their estrogen levels (96, 97). However, estrogen has complex effects on inflammation, including both antiinflammatory and proinflammatory effects (98). The proinflammatory properties of estrogen may explain the higher prevalence of elevated CRP in women than in men even in the absence of depression.
Another explanation for the sex-based difference in the effect of depression on CRP is that because women have relatively high levels of CRP even in absence of depression, it may be more difficult to detect an effect of depression on CRP in this group. Whatever the reason for this sex-based difference, if inflammation is truly an important mechanism linking depression to CHD risk, depression should be more strongly related to cardiovascular disease in men than in women. In general, this does seem to be the case (16, 19, 24, 77).
Our study has a number of limitations. First, it was based on observational data; thus we cannot rule out unmeasured confounding factors. For example, there might be unmeasured medical conditions that might explain the association between depression and CRP. However, given the young age of our sample, and the fact that we are dealing with a presumably healthy community sample as opposed to a clinical population, this potential confounding may be less of an issue in our analysis than in other observational studies.
Second, our finding was based on cross-sectional data; therefore, the temporal ordering of the association between depression and CRP cannot be definitively established. It is possible that instead of depression leading to inflammation, inflammation leads to depression. Indeed, IL-6 may induce production of corticotropin-releasing hormone, resulting in hypercortisolemia (1, 2, 36, 80, 84, 99), which in turn might contribute to depression. The latter might also represent a vicious cycle ultimately leading to an exacerbation of depression, immunosuppression, and inflammation.
Third, the CRP assay used in NHANES III was not a high-sensitivity assay and was not able to detect CRP concentrations less than 0.22 mg/dl. Because of this assay limitation, and because of the small proportion of persons in the category of clinically elevated CRP (CRP >1.00 mg/dl), we were unable to examine more than one cutoff point of the CRP values. For example, we were unable to verify that a history of major depression would be related also to clinically raised CRP according to the conventional clinical cutoff point of >1.00 mg/dl. This limitation, however, should not diminish the importance of our results because recent epidemiological studies have shown an increased cardiovascular risk for CRP levels of 0.2 mg and higher, corresponding to a low-grade inflammation (27, 30, 59, 60).
Finally, in our study, depression was measured by means of the DIS, an interview instrument designed to provide psychiatric diagnoses according to the DSM-III-R in epidemiological studies (40). Although a clinician-administered structured psychiatric interview might have been the ideal method, such an approach is unfeasible in large community-based studies. In these settings the DIS has been shown to provide accurate diagnoses of major depression, and it is the tool used in most large psychiatric epidemiology studies (43–46).
In conclusion, our study demonstrated for the first time in a large representative US sample of younger adults a strong association between recent major depressive episodes and CRP, a marker of systemic inflammation and a strong risk factor for atherosclerotic heart disease. This association was noted in men only. Because of the young age of our study population, subclinical disease is unlikely to explain our findings. These results may have important implications in explaining the pathophysiological mechanisms linking depression to cardiovascular disease in men. Future studies should link depression and systemic inflammation with higher risk of cardiovascular events using a longitudinal design.
Received for publication August 1, 2001.
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