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Depression has been associated with increased risk of cardiovascular disease (CVD). The inflammatory marker C-reactive protein (CRP) has also been identified as an independent predictor of short- and long-term CVD events. Inflammation may influence the relationship between depression and CVD.
The objective of this study was to investigate the association between symptoms of depression and high-sensitivity CRP (hs-CRP) in an obese clinical population. We also sought to determine whether this relationship was different in men and women, given prior reports of a gender effect.
Symptoms of depression and hs-CRP were measured in 390 participants enrolled in a weight loss intervention trial that was delivered in a primary care setting. Symptoms of depression were evaluated with the Patient Health Questionnaire-8 (PHQ-8), in which a score > 10 is consistent with major depression.
A total of 58 (15.2%) participants reported a PHQ-8 score ≥ 10. The median (interquartile range) hs-CRP concentration was significantly higher in participants with symptoms consistent with major depression [7.7 (4.2–13) mg/L] compared to those without depression [5.1 (3–9.7) mg/L; p<0.01]. Symptoms consistent with major depression were significantly associated with log-transformed hs-CRP concentrations in an analysis adjusted for age, gender, obesity class, and other metabolic variables (p=0.04). When interaction by gender was examined, this relationship remained significant in men (p<0.01) but not in women (p=0.32).
Symptoms consistent with major depression were significantly associated with hs-CRP in men only, even after adjusting for age, obesity class, metabolic variables, and medications known to affect inflammation. This finding suggests that there are biologic differences between men and women that may modify the relationship between hs-CRP and depression. Further studies are needed to elucidate the biologic basis for these findings.
Depression has been reported to be an independent risk factor for the development of coronary heart disease (CHD) in several large epidemiologic studies, after controlling for traditional cardiovascular risk factors such as hypertension, hyperlipidemia, increased body mass, smoking, and a previous history of cardiac disease.1–4 Although the specific mechanisms underlying this association remain unknown, increased plasma levels of the inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) have been reported in depressed individuals,5–7 suggesting that enhanced inflammatory-mediated atherogenesis may contribute to the increased cardiovascular risk observed in this population. However, obesity and depression frequently occur in tandem, and increased adiposity is also associated with an increased inflammatory state.8–10 Therefore, obesity may be an important confounder in the relationship between depression and cardiovascular disease.
C-reactive protein (CRP), an inflammatory marker that is produced in the liver in response to IL-6, has been identified as an independent predictor of both short- and long-term risk of cardiovascular events or stroke in both healthy11–13 and high-risk populations.14–16 The development of high-sensitivity CRP (hs-CRP) assays has markedly improved the ability to detect low levels of systemic inflammation that may potentiate cardiovascular risk in apparently healthy populations. Such assays can detect CRP levels as low as 0.007 mg/L, whereas the previous limit of detection of the conventional assay is 3 to 5 mg/L.17 Thus, hs-CRP has emerged as an important tool in cardiovascular risk stratification. Screening is recommended by the American Heart Association (AHA) and the Centers for Disease Control and Prevention (CDC) in individuals with an intermediate risk of cardiac disease.18 According to the AHA/CDC statement on cardiovascular risk stratification, hs-CRP levels < 1.0 mg/L indicate low risk, 1.0–3.0 mg/L indicates intermediate risk, and > 3.0 mg/L indicates the highest risk.18
Several studies have found that circulating CRP levels are increased in patients with diagnosed clinical depression19 and self-reported depressive symptomatology,20–23 even after adjusting for age, gender, race, smoking status, and body mass index (BMI). Gender may influence this relationship; two large population-based studies found that depression and elevated CRP concentrations were more strongly associated in men than women.20,23 In contrast to these findings, other studies have either failed to observe an association between depression and CRP concentrations24–27 or have observed an inverse relationship.28 Differences in study sample characteristics (clinical versus population-based), index of depression (clinical diagnosis or symptom report), and other variations in methodology or analysis (selection of covariates controlled) may account for some of the inconsistent findings.
The present study sought to determine the association between hs-CRP and symptoms of depression in a sample of obese individuals drawn from a primary care setting. We hypothesized that increased symptoms of depression would be associated with increased hs-CRP concentrations, after controlling for BMI and other obesity-related conditions. Given previous findings of a different relationship between depression and hs-CRP in men and women, we also examined the effect of gender and other co-morbid conditions associated with increased inflammation on this relationship.
Three hundred and ninety obese individuals were recruited from six primary care practices within the University of Pennsylvania Health System between January 2008 and February 2009 to participate in the Practice-based Opportunities for Weight Reduction (POWER) trial, a 2-year primary care-based weight reduction intervention.29 Eligible participants were aged 21 yr and older, had a BMI of 30–50 kg/m2, an elevated waist circumference (≥ 102 cm for men; ≥ 88 cm for women), and at least one other criterion for the metabolic syndrome.30 Exclusion criteria included having uncontrolled blood pressure, recent cardiovascular events, weight change ≥ 5% over the preceding 6 months, active participation in a weight loss program, prior or planned use of bariatric surgery, serious co-morbid conditions (e.g., severe psychiatric illness, end-stage renal disease), use of medications known to cause significant (≥ 5%) long-term changes in weight, or pregnancy. The study was approved by the Institutional Review Board at the University of Pennsylvania, and all participants provided written informed consent. The questionnaires used in this analysis were collected at the randomization visit before participants received any intervention.
Hs-CRP was measured following a ≥ 9-hour fast. Prior to October 1, 2008, hs-CRP was measured by particle-enhanced turbidimetric immunoassay (Roche Diagnostics P-Module, Roche Diagnostics, Indianapolis, IN), which has a measurement range of 0.1–20 mg/L. The inter-assay variability for low- and high-concentration internal standards was 2.5% and 6%, respectively. After October 1, 2008, hs-CRP was measured by ultra high-sensitivity latex turibimetric immunoassay (Beckman Coulter Unicel DXC 800, Beckman Coulter, Fullerton, CA), which has a measurement range of 0.2–380 mg/L. The inter-assay coefficient of variation is approximately 13.0% and 1.2% for low- and high-concentration internal standards, respectively. A Deming regression31 was used to standardize the scale of the two laboratory assays that were used to measure hs-CRP during the baseline data collection. As per the ADA/CDC joint statement on cardiovascular risk stratification, hs-CRP was considered elevated if the concentration exceeded 3.0 mg/L.18
Symptoms of depression were assessed with the Patient Health Questionnaire-8 (PHQ-8), a validated eight-item depression scale.32 The PHQ-8 includes eight of the nine criteria for depression according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),33 but excludes the question about suicidal ideation contained in the PHQ-9.34 The PHQ-8 asks the number of days over the past 2 weeks that the respondent has experienced a particular symptom of depression. The scores for each item are summed to produce a total score ranging from 0 to 24 points. Scores of 0 to 4 indicate no depressive symptoms, 5 to 9 represent mild depressive symptoms, 10 to 14 indicate moderate depression, and ≥ 15 are indicative of severe depression.32 A score of ≥ 10 is consistent with a DSM-IV diagnosis of major depressive disorder.32 The PHQ-8 and PHQ-9 scores are highly correlated and have nearly identical operating characteristics.32,34
Demographic data including gender, age, race/ethnicity, educational level, and income level were collected by a self-report questionnaire at baseline, prior to any intervention. Self-reported smoking status and the number of alcoholic beverages consumed weekly were also ascertained at baseline by an additional self-administered questionnaire. Body mass index was calculated from measured height and weight. Anthropometric and metabolic data were obtaining using measures described previously.29 Participants were classified according to the BMI categories adopted by the World Health Organization:35 class I (BMI, 30–34.9 kg/m2); class II (BMI, 35–39.9 kg/m2); and class III (BMI ≥ 40 kg/m2).
All analyses were conducted using hs-CRP as a continuous outcome, which was log-transformed to normalize the data. The main exposure variable was the presence or absence of symptoms consistent with major depression, which was defined as a PHQ-8 score ≥ 10 or < 10, respectively.
Summary statistics for all variables, both continuous and categorical, were examined for range and to assess plausibility of values. Continuous variables were reported as means [standard deviations (SD)] when normally distributed or as medians [interquartile range (IQR)] when the distribution was not normal. Categorical variables were reported as frequencies. Differences in weight and other characteristics between participants with and without symptoms consistent with major depression were compared using t-tests (or the Wilcoxon rank sum test when appropriate) for continuous variables and chi square tests for categorical variables.
We first examined the overall graphical relationship of hs-CRP values with PHQ-8 scores. We also examined this relationship separately for men and women, given prior findings that gender may modify this relationship.21,24,36 The goal of our adjusted analysis was to determine the relationship between symptoms consistent with major depression and log-transformed hs-CRP, after adjusting for confounding factors. Previous studies have reported that the relationship between depression and CRP may be different in men and women,20,23,37 so we also examined effect modification by gender. We started with the unadjusted association between a binary depression variable (symptoms consistent with and without major depression) and log-transformed hs-CRP. Potential confounding variables including race, weight, waist circumference, obesity class, presence of other comorbidities (diabetes, hyperlipidemia, and hypertension), smoking status, alcohol use, and medications known to influence CRP concentrations (statins, anti-inflammatory agents, etc.) were evaluated in a multivariable linear regression model based on unadjusted associations with elevated hs-CRP (p<0.15) for inclusion in the next model. Variables remained in the adjusted model based on their ability to confound the association between symptoms consistent with major depression and log-transformed hs-CRP, defined as a p-value < 0.15. We decided to include age, gender, and obesity class in the adjusted model a priori because these variables are known to influence hs-CRP concentrations. Finally, an interaction term between gender and depression was included in the model to examine whether the adjusted association of major depression and log-transformed hs-CRP was different between men and women.
In secondary analyses, we examined the association between continuous PHQ-8 scores and log-transformed hs-CRP scores in a multivariable linear regression model. All analyses were conducted using Stata, Version 10.1 for Windows (Stata Corporation, College Station, TX). Two-sided hypothesis testing was used for all analyses, and a pre-determined level of p<0.05 was considered statistically significant for the final model.
Of 390 participants, baseline PHQ-8 scores and hs-CRP measurements were available for 382 (97.9%) and 385 (98.7%), respectively. Overall, participants had a mean (±SD) BMI of 38.5 (4.7) kg/m2 and were predominantly women (79.7%), who were white (59.0%), middle-aged [mean age of 52.1 (11) yr], and well-educated (53.4% completed college or more). When participants were stratified by a PHQ-8 cutpoint of ≥ 10 (see Table 1), those with symptoms consistent with major depression had a significantly higher BMI and waist circumference (p<0.01 for both variables) than those without major depression. Significantly more participants with symptoms consistent with major depression also smoked (p<0.01).
The median PHQ-8 score for the total sample was 4 (IQR 2–8). Men and women reported a median score of 4 (IQR=2 to 8) and 5 (IQR=2 to 8), respectively, which did not significantly differ (p=0.39). A total of 45 participants (11.8%) of participants reported a PHQ-8 score of 10 or greater, which is consistent with clinically significant depression. Thirteen of these participants (3.4% of the total study population) had a PHQ-8 score in a range consistent with severe depression range (≥ 15).
The median hs-CRP concentration was 5.6 mg/L (IQR=3.1 to 10.2 mg/L), and 293 (76.1%) participants had an hs-CRP concentration classified as high cardiovascular risk (> 3.0 mg/L). Hs-CRP levels were significantly higher in participants with symptoms consistent with major depression [median 7.7 mg/L (IQR=4.2–13)] compared to those without depression [5.1 mg/L (IQR=3–9.7); p<0.01].
When the data were examined graphically (see Figure 1), we observed a linear relationship between symptoms of depression and hs-CRP that was weakly correlated (Spearman’s rho=0.101; p=0.05). However, in an unadjusted analysis, symptoms consistent with major depression were significantly associated with log-transformed hs-CRP (p<0.01).
Major depression remained significantly correlated with log-transformed hs-CRP levels (p=0.04) in a multivariable linear regression model that included age, gender, education, obesity class, LDL cholesterol, log-transformed HOMA, heart rate, hormone replacement therapy, and oral contraceptives. However, when an interaction term between gender and levels of depressive symptoms was included (see Table 2), we observed that this association was significant in men (p<0.01) but not in women (p=0.32).
We also examined the association between PHQ-8 scores as a continuous variable and log-transformed hs-CRP levels. Increasing PHQ-8 scores were significantly correlated with log-transformed hs-CRP levels (p<0.01) in a multivariable linear regression model that included age, gender, obesity class, education, LDL cholesterol, log-transformed HOMA, heart rate, hormone replacement therapy, and oral contraceptives. When an interaction term between gender and PHQ-8 scores was included (see Table 3), we observed that this association still remained significant in men (p=0.02) but not in women (p=0.42).
Clear differences were observed in the relationship between depression and hs-CRP in men and women in the present study. Depression was significantly correlated with log-transformed hs-CRP concentrations in men, but not in women, in both primary and secondary analyses. Few studies have reported results separately for men and women, and results have been discrepant.20,23,36 Depression and elevated CRP concentrations were found to be more strongly associated in men than women in two large population-based studies.20,23 In a study of 6,914 US adults who participated in the Third National Health and Nutrition Survey (NHANES III), Ford et al. found that major depression was strongly associated with increased CRP levels in men after controlling for obesity, but not in women.20 Similarly, this relationship was also observed in a study of 6,005 Finnish men and women in which the Beck Depression Inventory (BDI) and the Composite International Diagnostic Interview (CIDI) were used to assess a range of symptoms of depression and clinical depression, respectively.23 In contrast to our findings and others, Ma et al. found that depression was associated with hs-CRP only in women, in a population-based study of 508 healthy adults living in Massachusetts.37 However, the authors failed to control for important confounding variables such as estrogen therapy and oral contraceptive use that may influence this relationship.
The mechanisms for sex-specific differences in the relationship between hs-CRP and depression are likely multifactorial, but it has been hypothesized that CRP levels may vary by hormonal environment.20 In women, menopausal status and estrogen replacement have been shown to impact adiposity38 and inflammation,36 which could potentially confound the relationship. Few women in the present study took hormone replacement therapy or oral contraceptive pills. Even when this subset was excluded, no relationship between depression and hs-CRP was observed in women. Gender may also influence CRP-related genetic variation, which has been found to moderate the association between depressive symptomatology and circulating CRP levels.39 Thus, it is possible that symptoms of depression might interact with genetic variation to predict the inflammatory marker differently in men and women.
The present investigation has several strengths. First, we performed a robust analysis that included important factors known to affect hs-CRP concentrations, including medications such as statins and anti-inflammatory therapies, estrogen use, and conditions associated with increased inflammation (such as diabetes and metabolic syndrome). Previous studies have failed to adjust for many of these confounding variables,37,40 which may explain why our findings differed from others. Second, our study population is generally representative of patients seen in the primary care setting and may be more generalizable than studies performed in specific clinical populations. For example, Dixon et al. reported a positive association between depression and CRP in obese individuals with a BMI range of 31 to 91 kg/m2, who presented for bariatric surgery.41 However, these individuals had a higher BMI and greater adiposity than obese individuals in the general population, which has significant effects on inflammation.8–10
This study also had several limitations. First, relatively few men participated in the study, compared to women. Despite the small number of males, the relationship between symptoms of depression and increasing hs-CRP remained significant in men. Second, our findings were based on cross-sectional data. Thus, the temporal relationship between hs-CRP and depression cannot be definitively established. Furthermore, CRP is an acute phase reactant and can vary considerably depending on the underlying inflammatory state at the time of measurement (i.e., infections, acute attack of gout). Thus, serial measurement of hs-CRP over time provides more clinically useful information than a single measurement and may have yielded a stronger relationship between hs-CRP and symptoms of depression. Finally, diagnoses of depression were made based on an 8-item questionnaire rather than by using a structured clinical interview (for the DSM-IV), the preferred method.
In summary, symptoms consistent with major depression were significantly associated with hs-CRP in men only, even after adjusting for age, obesity class, metabolic variables, and medications known to affect inflammation. This finding suggests that there are biologic differences between men and women that may modify the relationship between hs-CRP and depression. Further studies are needed to elucidate the biologic basis for these findings.
Funding: Supported by grants from the National Heart, Lung, and Blood Institute (U01-HL087072) and the National Institute of Diabetes and Digestive and Kidney Diseases (K24-DK065018).
POWER-UP ClinicalTrials.gov number NCT00826774
We thank Jesse Chittams, M.S. and Jeffrey Lavenberg, M.S. for their assistance with the statistical analysis.
Academic investigators at the Perelman School of Medicine at the University of Pennsylvania were Thomas A. Wadden, Ph.D. (principal investigator), David B. Sarwer, Ph.D. (co-principal investigator), Robert I. Berkowitz, M.D., Jesse Chittams, M.S., Lisa Diewald, M.S., R.D., Shiriki Kumanyika, Ph.D., Renee Moore, Ph.D., Kathryn Schmitz, Ph.D., Adam G. Tsai, M.D., MSCE, Marion Vetter, M.D., and Sheri Volger, M.S., R.D.
Research coordinators at the University of Pennsylvania were Caroline H. Moran, B.A., Jeffrey Derbas, B.S., Megan Dougherty, B.S., Zahra Khan, B.A., Jeffrey Lavenberg, M.A., Eva Panigrahi, M.A., Joanna Evans, B.A., Ilana Schriftman, B.A, Dana Tioxon, Victoria Webb, B.A., and Catherine Williams-Smith, B.S.
PennCare - Bala Cynwyd Medical Associates: Ronald Barg, M.D., Nelima Kute, M.D., David Lush, M.D., Celeste Mruk, M.D., Charles Orellana, M.D., and Gail Rudnitsky, M.D. (primary care providers); Angela Monroe (lifestyle coach); Lisa Anderson (practice administrator).
PennCare - Internal Medicine Associates of Delaware County: David E. Eberly, M.D., Albert H. Fink Jr., M.D., Kathleen Malone, C.R.N.P., Peter B. Nonack, M.D., Daniel Soffer, M.D., John N. Thurman, M.D., and Marc J. Wertheimer, M.D. (primary care providers); Barbara Jean Shovlin, Lanisha Johnson (lifestyle coaches); Jill Esrey (practice administrator).
PennCare - Internal Medicine Mayfair: Jeffrey Heit, M.D., Barbara C. Joebstl, M.D., and Oana Vlad, M.D. (primary care providers); Rose Schneider, Tammi Brandley (lifestyle coaches); Linda Jelinski (practice administrator).
Penn Presbyterian Medical Associates: Joel Griska, M.D., Karen J. Nichols, M.D., Edward G. Reis, M.D., James W. Shepard, M.D., and Doris Davis-Whitely, P.A. (primary care providers); Dana Tioxon (lifestyle coach); Charin Sturgis (practice administrator).
PennCare - University City Family Medicine: Katherine Fleming, C.R.N.P., Dana B. Greenblatt, M.D., Lisa Schaffer, D.O., Tamara Welch, M.D., and Melissa Rosato, M.D. (primary care providers); Eugonda Butts, Marta Ortiz, Marysa Nieves, and Alethea White (lifestyle coach); Cassandra Bullard (practice administrator).
PennCare - West Chester Family Practice: Jennifer DiMedio, C.R.N.P., Melanie Ice, D.O., Brandt Loev, D.O., John S. Potts, D.O., and Christine Tressel, D.O. (primary care providers); Iris Perez, Penny Rancy, and Dianne Rittenhouse (lifestyle coaches); Joanne Colligan (practice administrator).
Conflict of Interest
Thomas Wadden serves on the advisory boards of Novo Nordisk and Orexigen Therapeutics, which are developing weight loss medications, as well as of Alere and the Cardiometabolic Support Network, both of which provide behavioral weight loss programs. David Sarwer discloses relationships with the following companies: Allergan, BaroNova, Enteromedics, Ethicon Endo-Surgery, and Galderma. The other authors declare no conflicts of interest.