0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Articles   |    
Depressive Symptoms, Health Behaviors, and Subsequent Inflammation in Patients With Coronary Heart Disease: Prospective Findings From the Heart and Soul Study
Hester E. Duivis, M.Sc.; Peter de Jonge, Ph.D.; Brenda W. Penninx, Ph.D.; Bee Ya Na, M.P.H.; Beth E. Cohen, M.D., M.A.S.; Mary A. Whooley, M.D.
Am J Psychiatry 2011;168:913-920. doi:10.1176/appi.ajp.2011.10081163
View Author and Article Information

Received Aug. 16, 2010; revisions received Dec. 20, 2010, and March 26, 2011; accepted April 25, 2011.

All authors report no financial relationships with commercial interests.

The Heart and Soul Study was funded by the Department of Veterans Affairs; the National Heart, Lung, and Blood Institute (grant R01 HL-079235); the American Federation for Aging Research (Paul Beeson Scholars Program); the Robert Wood Johnson Foundation (Generalist Physician Faculty Scholars Program); and the Ischemia Research and Education Foundation. Dr. de Jonge was supported by a Vidi grant from the Dutch Medical Research Council (grant 016.086.397). Dr. Cohen was supported by NCRR/OD UCSF-CTSI grant KL2 RR-024130 from the NIH Division of Research Resources. The funding organizations had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

From the Center of Research on Psychology in Somatic Diseases, Tilburg University, Tilburg, the Netherlands; the Department of Psychiatry, University Medical Center, University of Groningen, Groningen, the Netherlands; the Department of Psychiatry/EMGO Institute, University Medical Center, Vrije Universiteit, Amsterdam; the Section of General Internal Medicine, VA Medical Center, San Francisco; and the Department of Medicine, University of California, San Francisco.

Address correspondence to Ms. Duivis (h.e.duivis@uvt.nl).

Received August 16, 2010; Revised December 20, 2010; Revised March 26, 2011; Accepted April 25, 2011.

Copyright © American Psychiatric Association

Abstract

Objective:  Depression has been associated with inflammation in patients with coronary heart disease. However, it is uncertain whether depressive symptoms lead to inflammation or vice versa.

Method:  The authors evaluated 667 outpatients with established coronary heart disease from the Heart and Soul Study. Depressive symptoms were assessed annually with the 9-item Patient Health Questionnaire. Participants were categorized as having no significant depressive symptoms (score below 10 at all interviews), depressive symptoms (score of 10 or higher) at one interview, or depressive symptoms at two or more interviews. At baseline and 5-year follow-up, fasting blood samples were collected to measure three inflammatory biomarkers: fibrinogen, interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP).

Results:  Of the 667 participants, 443 had no depressive symptoms, 86 had depressive symptoms at one assessment, and 138 had depressive symptoms at two or more annual assessments. Across the three groups, greater depressive symptoms were associated with higher subsequent log-transformed levels of IL-6 and hsCRP, and the association with higher fibrinogen levels approached significance. Baseline inflammation did not predict subsequent depressive symptoms. The association of depressive symptoms with subsequent inflammation levels was eliminated after adjustment for health behaviors associated with depression—physical inactivity, smoking, and higher body mass index.

Conclusions:  Depressive symptoms predicted higher IL-6 and hsCRP levels among outpatients with coronary heart disease, but higher inflammation levels did not predict subsequent depressive symptoms. The association between depressive symptoms and inflammation was no longer significant after adjustment for health behaviors, which suggests these behaviors may mediate depressive effects.

Abstract Teaser
Figures in this Article

Depression is common in patients with cardiac disease, with prevalence rates nearly three times as high as in the general population (1, 2). Depression is also associated with worse cardiac prognosis and greater mortality (3). However, there is still considerable debate regarding how depression might contribute to a worse cardiac prognosis or mortality (4). Inflammation is associated with both cardiac disease and depression and is a plausible physiological link between depression and coronary heart disease. Cross-sectional studies have demonstrated an association between depression and inflammation in healthy subjects (59) and in cardiac patients (10, 11), but relatively little is known about the directionality of the association (i.e., whether depression causes inflammation or vice versa).

Previous studies on the direction of the association between depression and inflammation have yielded conflicting results. Stewart and colleagues (12) examined the directionality of the relationship in otherwise healthy subjects. They found that depressive symptoms as measured with the Beck Depression Inventory-II significantly predicted interleukin-6 (IL-6) levels after 6 years of follow-up, whereas inflammation did not predict depressive symptom scores at follow-up, suggesting that depression leads to an up-regulation of IL-6 levels. However, the Whitehall study came to the opposite conclusion. In over 3,000 British civil servants followed for almost 12 years, Gimeno and colleagues found that inflammation preceded depressive symptoms, whereas depressive symptoms did not predict inflammation (13).

To our knowledge, whether depressive symptoms are the cause or result of inflammation has not been evaluated in patients with cardiovascular disease. We therefore set out to evaluate the prospective association between depressive symptoms and inflammation using repeated measurements of depressive symptoms and inflammation in patients with stable coronary heart disease. We evaluated whether depressive symptoms (assessed annually for 6 years) were associated with higher levels of subsequent inflammation and vice versa. In addition, we evaluated the role of health behaviors in mediating the association between depression and inflammation.

+

Design and Participants

The Heart and Soul Study is an ongoing prospective cohort study of psychosocial factors and health outcomes in patients with coronary heart disease. Its methods have been described previously (14). Briefly, 1,024 outpatients with stable coronary heart disease were recruited and completed a baseline examination between September 2000 and December 2002. Following the baseline examination, patients received annual telephone calls for assessment of depressive symptoms. Between September 2005 and December 2007, 667 participants (80% of the 829 survivors) completed a 5-year follow-up examination that included measures of inflammation. The study protocol was approved by the appropriate institutional review boards, and all participants provided written informed consent.

+

Depressive Symptoms

Depressive symptoms were assessed annually for 6 years by using the 9-item Patient Health Questionnaire, a self-report instrument that measures the frequency of depressive symptoms corresponding to the nine DSM-IV criteria for depression (15). A paper-and-pencil version of the questionnaire was administered at the baseline examination (year 0), telephone versions were administered after 1, 2, 3, and 4 years of follow-up, and a paper-and-pencil version was again administered after 5 years of follow-up. Of the 667 participants who were examined at 5 years, 640 completed five or more interviews, 23 (3.4%) completed four interviews, three (0.4%) completed three interviews, and one (0.1%) completed two interviews.

At each assessment, participants were asked to indicate the frequency of experiencing each depressive symptom during the last 2 weeks. Each of the nine symptoms was scored as 0 (not at all), 1 (on several days), 2 (more than half the days), or 3 (nearly every day), with total scores ranging from 0 to 27 (16). The Patient Health Questionnaire has demonstrated excellent validity when compared with a mental health interview for depression in patients with coronary heart disease (17, 18). Telephone and in-person assessments yield similar results (19). As a summary measure of depressive symptoms, we calculated the mean score for each participant as the sum of the annual questionnaire scores divided by the number of interviews completed. We also created a categorical variable by defining “depressive symptoms” as a score of 10 or higher on the Patient Health Questionnaire. We used this to group the participants into three categories: depressive symptoms at two or more interviews, depressive symptoms at one interview, or no depressive symptoms. We chose these groups for analysis because further divisions would have yielded too few participants in each category.

+

Inflammatory Biomarkers

Fasting blood samples were obtained at baseline and after 5 years of follow-up. Levels of high-sensitivity C-reactive protein (hsCRP), IL-6, and fibrinogen were determined from plasma and serum samples. The laboratory technicians were blinded to the depression status of the participants.

A highly sensitive CRP assay was performed with a BN II nephelometer (Dade-Behring, Newark, Del.). Interassay coefficients of variation were 1.66%–5.32%. IL-6 was measured by using the Millipore Milliplex Map kit (Millipore, Billerica, Mass.), with interassay coefficients of variation from 6.3% to 11.6%. Concentrations of serum fibrinogen were determined by the Clauss assay with coefficients of variation less than 3%. We log-transformed the hsCRP and IL-6 levels because they were not normally distributed, and we verified that the transformation resulted in normal distributions. We also created three separate dichotomous variables for IL-6, hsCRP, and fibrinogen, defining a priori a high level as one in the highest quartile. For IL-6 a high level was defined as above 5.40 pg/ml, for hsCRP a high level was one above 3.48 mg/liter, and a high fibrinogen level was defined as above 420 mg/dl.

+

Other Assessments

We recorded self-reported age, gender, ethnicity, education, and medical history at baseline and at the 5-year examination. In addition, we assessed health behaviors known to be associated with inflammation, such as smoking status, physical activity, and body mass index (BMI) (20, 21). To assess physical activity, we asked, “Which of the following statements best describes how physically active you have been during the last month, that is, done activities such as 15–20 minutes of brisk walking, swimming, general conditioning, or recreational sports?” Participants responded by choosing one of the six following categories: not at all active, a little active (one or two times per month), fairly active (three or four times per month), quite active (one or two times per week), very active (three or four times per week), or extremely active (five or more times per week). Self-report of physical activity has been shown to be valid, accurate, and reliable (2225). Physical inactivity was defined as “not at all active” or “a little active.” Height and weight were measured and used to calculate BMI (weight in kilograms divided by the square of height in meters). Alcohol consumption was measured with the AUDIT-C self-report questionnaire (26). Left ventricular ejection fraction was assessed by means of two-dimensional echocardiography. High-density lipoprotein (HDL) levels were measured from fasting venous blood samples, and non-HDL cholesterol was calculated as total cholesterol minus HDL cholesterol. Participants were asked to bring all of their medication bottles to the study appointment, and all current medications were recorded. Medications were categorized by using Epocrates Rx (Epocrates, San Mateo, Calif.).

+

Statistical Analyses

The goal of this study was to determine the directionality of the depression-inflammation relationship. We used general linear models to compare mean levels of each marker across three groups: participants who were not depressed at any interview (having a score below 10 on the Patient Health Questionnaire at all interviews), participants who reported depressive symptoms (a score of 10 or higher) at one interview, and those who reported significant depressive symptoms at two or more interviews.

To further evaluate the association between Patient Health Questionnaire score and levels of inflammation, we used multivariate analysis of variance adjusted for other patient characteristics associated with depressive symptoms (age, gender, education, race, aspirin use, history of diabetes, myocardial infarction, and congestive heart failure) and health behaviors (physical activity, smoking, and BMI). In addition, we evaluated change in inflammation over 5 years across the three subgroups. Finally, we used multivariate analysis of covariance (MANCOVA) to evaluate the effect of depressive symptoms on all three measures of inflammation as a single dependent variable, adjusted for the baseline level of inflammation. We also used MANCOVA to evaluate the effect of inflammation on subsequent depressive symptoms (as a single dependent variable), adjusted for the baseline level of depressive symptoms. Analyses were performed by using SAS 9.2 (SAS Institute, Cary, N.C.).

+

Characteristics of Participants

As compared with the 162 patients who were alive and did not complete the 5-year follow-up examination, the 667 participants who completed the exam were older (mean age=66 years, SD=10, versus mean=64 years, SD=12; t=–2.09, df=827, p=0.04) and had fewer baseline depressive symptoms as indicated by scores on the Patient Health Questionnaire (mean=4.75, SD=5.26, versus mean=6.77, SD=5.84; t=4.29, df=827, p<0.01). Participants who completed the exam also had lower log-transformed baseline hsCRP levels (mg/liter) than those who did not complete the 5-year exam (mean=0.57, SD=1.29, versus mean=0.85, SD=1.32; t=2.48, df=795, p=0.01). Baseline levels of IL-6 and fibrinogen were similar in the patients who did and did not complete the 5-year examination (p>0.10 in both cases).

Of the 667 participants who completed the 5-year examination, 138 (21%) had depressive symptoms (i.e., a score of 10 or higher on the Patient Health Questionnaire) at two or more interviews, 86 (13%) had depressive symptoms at one interview, and 443 (66%) had no significant depressive symptoms (a score less than 10 on the Patient Health Questionnaire at all interviews). As compared to participants without significant depressive symptoms, those with depressive symptoms at any interview were younger and less likely to be male, to be white, or to have graduated from high school (Table 1). They were more likely to have a history of diabetes, myocardial infarction, or congestive heart failure and had higher BMI values. Participants with depressive symptoms were less likely to use aspirin and more likely to smoke and to be physically inactive. The three groups had similar levels of hypertension, cardiac disease severity, cardiac risk factors, and use of cardioprotective medications.

 
Anchor for Jump
TABLE 1.

Baseline Characteristics of 667 Patients With Coronary Heart Disease, by Depressive Symptoms Over 5 Yearsa

Table Footer Note

a Depressive symptoms were assessed at baseline and annually for the next 5 years.

Table Footer Note

b Total number varied because data on some variables were not available for all participants.

+

Presence of Depressive Symptoms as Predictor of Subsequent Inflammation

MANCOVAs evaluating the effect of depression on subsequent inflammation showed that depressive symptoms predicted subsequent inflammation in an unadjusted analysis (F=2.56, df=6, 1304, p=0.02) and after adjustment for age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, aspirin use, and baseline levels of inflammatory markers (F=2.15, df=6, 1182, p<0.05). This association was no longer significant after adjustment for health behaviors (F=1.74, df=6, 1128, p=0.11).

Across the three groups, greater depressive symptoms were associated with higher subsequent log-transformed levels of IL-6 and hsCRP, and they were nonsignificantly associated with higher levels of fibrinogen (Table 2). Depressive symptoms remained associated with subsequent levels of IL-6 and were marginally related to levels of fibrinogen but were not associated with hsCRP, after adjustment for age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, and aspirin use (Table 2). However, after further adjustment for health behaviors (physical activity, smoking, and BMI), depressive symptoms were no longer associated with any inflammation index. When we evaluated the multivariable-adjusted mean change in levels of inflammatory markers, depressive symptoms did not predict statistically significant changes in IL-6, hsCRP, or fibrinogen (Table 3).

 
Anchor for Jump
TABLE 2.

Levels of Inflammatory Markers at 5-Year Follow-Up in Patients With Coronary Heart Disease, by Depressive Symptoms Over 5 Yearsa

Table Footer Note

a Depressive symptoms were assessed at baseline and annually for the next 5 years.

Table Footer Note

b Model 1: adjusted for age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, and aspirin use. Model 2: adjusted for all of the preceding variables plus physical activity, current smoking, and body mass index.

Table Footer Note

c Unadjusted values use SD, and adjusted values use SE.

 
Anchor for Jump
TABLE 3.

Change in Inflammatory Marker Levels Over 5 Years in Patients With Coronary Heart Disease, by Depressive Symptoms Over 5 Yearsa

Table Footer Note

a Depressive symptoms were assessed at baseline and annually for the next 5 years.

Table Footer Note

b Model 1: adjusted for age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, and aspirin use. Model 2: adjusted for all of the preceding variables plus physical activity, current smoking, and body mass index.

Table Footer Note

c Unadjusted values use SD, and adjusted values use SE.

When we analyzed depressive symptoms as a continuous variable, the average score on the Patient Health Questionnaire across the annual assessments predicted subsequent log-transformed levels of IL-6 (β=0.102, p=0.009) and hsCRP (β=0.121, p=0.002) but not the level of fibrinogen (β=0.058, p=0.13). Again, this association was no longer significant after adjustment for health behaviors (log IL-6: β=0.038, p=0.36; hsCRP: β=0.018, p=0.67; fibrinogen: β=0.018, p=0.68).

When inflammation was evaluated as a dichotomous variable, the proportions of participants with levels of inflammatory markers in the highest quartile were 22% to 24% in those without depression at any interview, 23% to 28% in those with depressive symptoms at one interview, and 30% to 35% in patients with depressive symptoms at two or more interviews (Figure 1).

 
Anchor for JumpAnchor for Jump
FIGURE 1.

Proportion of Patients With Coronary Heart Disease Who Had High Levels of Inflammatory Markers at 5-Year Follow-Up, by Depressive Symptoms Over 5 Yearsa

a Inflammatory markers were measured at baseline and at the 5-year follow-up assessment. Depressive symptoms were assessed with the nine-item Patient Health Questionnaire at baseline and annually for the next 5 years.

b Significant difference among groups (χ2=8.45, df=2, p=0.01).

c Significant difference among groups (χ2=5.96, df=2, p=0.05).

+

Inflammation as Predictor of Subsequent Depressive Symptoms

MANCOVAs revealed no effect of inflammation on subsequent depression in unadjusted analyses (F=1.37, df=6, 1256, p=0.22) or after adjustment for age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, aspirin use, and baseline depressive symptoms (F=0.65, df=6, 1224, p=0.69). In addition, baseline levels of inflammatory markers were not associated with subsequent depressive symptoms (Table 4). As compared with participants who had significant depressive symptoms at two or more annual assessments, those without depressive symptoms had similar baseline levels of log IL-6, log hsCRP, and fibrinogen.

 
Anchor for Jump
TABLE 4.

Baseline Levels of Inflammatory Markers in Patients With Coronary Heart Disease, by Depressive Symptoms Over 5 Yearsa

Table Footer Note

a Depressive symptoms were assessed at baseline and annually for the next 5 years.

Table Footer Note

b Model 1: adjusted for baseline age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, and aspirin use. Model 2: adjusted for all of the preceding variables plus baseline physical activity, current smoking, and body mass index.

Table Footer Note

c Unadjusted values use SD, and adjusted values use SE.

The aim of this study was to examine the directionality of the depression-inflammation relationship in a group of patients with stable coronary heart disease. The rate of depressive symptoms was consistent with the rate in a previous study (27): 34% of the participants had a score of 10 or higher on the Patient Health Questionnaire at one or more time points. We found that depressive symptoms were associated with higher subsequent levels of inflammation, whereas baseline levels of inflammation did not predict subsequent depressive symptoms. The association between depressive symptoms and subsequent inflammation was eliminated after adjustment for health behaviors associated with inflammation—physical inactivity, smoking, and higher BMI. Taken together, these findings suggest that depression may lead to inflammation through poor health behaviors, but inflammation does not lead to depression in patients with coronary heart disease.

There have been only a few studies regarding the directionality of the depression-inflammation relationship, and to our knowledge, this is the first study on this subject in a cardiac population. We also believe this to be the first study evaluating the association of depressive symptoms over time with subsequent inflammation. Our results extend the findings of Stewart and colleagues (12), who found that depression predicted high levels of IL-6, whereas high levels of IL-6 did not predict depression. However, our results differ from those of Gimeno and colleagues, who reported that CRP and IL-6 levels were predictive of subsequent depressive symptoms, but not vice versa, in the Whitehall II study (13).

One possible explanation for this discrepancy is that the Whitehall II study used a different measure of depressive symptoms. Their assessment was based on four items from the General Health Questionnaire (thinking of yourself as a worthless person, feeling that life is entirely hopeless, feeling that life is not worth living, and finding times when you could not do anything because your nerves were too bad) and did not include measures of sleep, appetite, concentration, energy, suicidal thoughts, or depressed mood. In contrast, we administered the Patient Health Questionnaire, which was specifically designed to assess the nine symptoms of depression. Another possible explanation for the difference in findings is the difference between study populations. The association between depressive symptoms and inflammation in the general population may differ from the relationship in patients with established coronary heart disease.

It is interesting that our results show that depressive symptoms predicted high levels of hsCRP and IL-6 but not fibrinogen. A possible explanation could be that hsCRP and IL-6 are more specific for the underlying inflammation process in stable patients with coronary heart disease. In contrast to hsCRP and IL-6, which are both markers of inflammation, fibrinogen not only reflects inflammation but also is a blood coagulation factor (28), which could explain why we did not find a prospective association between depression and fibrinogen.

We also found that patients with depressive symptoms at two or more interviews had higher levels of inflammation at follow-up than patients with depressive symptoms at one interview. To the extent that depressive symptoms at two or more interviews represented chronic or recurrent depression, our findings suggest that persistent depression may have greater effects on inflammation than a single episode of depression. Consistent with these findings are the results of Hamer and colleagues (29), who found that in a group of 3,609 aging subjects, participants with depressive symptoms at two time points had higher levels of CRP and fibrinogen than those with depressive symptoms at one time point. In addition, Kaptein and colleagues (30) showed that patients with chronic depressive symptoms following myocardial infarction were at higher risk for having new cardiovascular events than those whose depressive symptoms resolved. Taken together, the findings suggest that the duration of depressive symptoms may influence cardiac health.

The prospective association of depression with inflammation was no longer significant after adjustment for health behaviors (physical inactivity, BMI, and smoking). Although our results cannot determine the direction of the association between depression and health behaviors, this raises the possibility that helping depressed cardiac patients improve these behaviors could potentially reduce inflammation. These findings are further supported by a longitudinal community-based study in which Matthews and colleagues (31) investigated the directionality of the depression-inflammation relationship among 1,781 premenopausal and early perimenopausal women who were free of cardiac disease at baseline. They found that depression, as measured with the Center for Epidemiologic Studies Depression Scale, was associated with higher CRP levels at follow-up. Similar to our results, this association was no longer significant after adjustment for a range of covariates including health behaviors. In addition, Hamer and colleagues (29) found that weight change, waist circumference, current smoking, alcohol use, and especially physical activity were significant mediators in the depression-inflammation relationship. Finally, Dod and colleagues (32) showed in a group of nonsmoking patients with stable coronary heart disease that a combination of intensive exercise and dietary changes significantly lowered levels of IL-6 and CRP, suggesting that physical inactivity and BMI may influence inflammation levels.

Several strengths can be attributed to this study. First, the annual assessments of depressive symptoms and medical health status presented us with the opportunity to assess the direction of this association. In addition, biological and behavioral mediators were carefully assessed at baseline and after 5 years of follow-up. However, there are also several limitations. This study focused on outpatients with stable coronary heart disease. Our results may therefore not apply to healthy participants or to patients with acute coronary syndromes. Furthermore, the study group mostly consisted of older men, so these results may not be generalizable to either women or younger men. Finally, 20% (162 of 829) of the surviving participants did not complete the 5-year follow-up examination. However, these participants were younger and had worse depression scores than those who completed the examination, so including them would probably have strengthened the association between depression and inflammation.

In conclusion, we found no evidence of a bidirectional relationship between depression and inflammation. Depression was prospectively associated with IL-6 and hsCRP, but not vice versa. This prospective association was no longer significant after adjustment for physical inactivity, BMI, and smoking. These findings raise the possibility that helping depressed cardiac patients improve health behaviors could reduce inflammation.

Thombs  BD;  Bass  EB;  Ford  DE;  Stewart  KJ;  Tsilidis  KK;  Patel  U;  Fauerbach  JA;  Bush  DE;  Ziegelstein  RC:  Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 2006; 21:30–38
[PubMed]
[CrossRef]
 
Wells  KB;  Rogers  W;  Burnam  MA;  Camp  P:  Course of depression in patients with hypertension, myocardial infarction, or insulin-dependent diabetes. Am J Psychiatry 1993; 150:632–638
[PubMed]
 
van Melle  JP;  de Jonge  P;  Spijkerman  TA;  Tijssen  JG;  Ormel  J;  van Veldhuisen  DJ;  van den Brink  RH;  van den Berg  MP:  Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 2004; 66:814–822
[PubMed]
[CrossRef]
 
de Jonge  P;  Rosmalen  JG;  Kema  IP;  Doornbos  B;  van Melle  JP;  Pouwer  F;  Kupper  N:  Psychophysiological biomarkers explaining the association between depression and prognosis in coronary artery patients: a critical review of the literature. Neurosci Biobehav Rev 2010; 35:84–90
[PubMed]
[CrossRef]
 
Danner  M;  Kasl  SV;  Abramson  JL;  Vaccarino  V:  Association between depression and elevated C-reactive protein. Psychosom Med 2003; 65:347–356
[PubMed]
[CrossRef]
 
Dowlati  Y;  Herrmann  N;  Swardfager  W;  Liu  H;  Sham  L;  Reim  EK;  Lanctot  KL:  A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67:446–457
[PubMed]
[CrossRef]
 
Elovainio  M;  Aalto  AM;  Kivimaki  M;  Pirkola  S;  Sundvall  J;  Lonnqvist  J;  Reunanen  A:  Depression and C-reactive protein: population-based Health 2000 Study. Psychosom Med 2009; 71:423–430
[PubMed]
[CrossRef]
 
Ford  DE;  Erlinger  TP:  Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2004; 164:1010–1014
[PubMed]
[CrossRef]
 
Penninx  BW;  Kritchevsky  SB;  Yaffe  K;  Newman  AB;  Simonsick  EM;  Rubin  S;  Ferrucci  L;  Harris  T;  Pahor  M:  Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition Study. Biol Psychiatry 2003; 54:566–572
[PubMed]
[CrossRef]
 
Bankier  B;  Barajas  J;  Martinez-Rumayor  A;  Januzzi  JL:  Association between major depressive disorder and C-reactive protein levels in stable coronary heart disease patients. J Psychosom Res 2009; 66:189–194
[PubMed]
[CrossRef]
 
Howren  MB;  Lamkin  DM;  Suls  J:  Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71:171–186
[PubMed]
[CrossRef]
 
Stewart  JC;  Rand  KL;  Muldoon  MF;  Kamarck  TW:  A prospective evaluation of the directionality of the depression-inflammation relationship. Brain Behav Immun 2009; 23:936–944
[PubMed]
[CrossRef]
 
Gimeno  D;  Kivimaki  M;  Brunner  EJ;  Elovainio  M;  De Vogli  R;  Steptoe  A;  Kumari  M;  Lowe  GD;  Rumley  A;  Marmot  MG;  Ferrie  JE:  Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med 2009; 39:413–423
[PubMed]
[CrossRef]
 
Whooley  MA;  de Jonge  P;  Vittinghoff  E;  Otte  C;  Moos  R;  Carney  RM;  Ali  S;  Dowray  S;  Na  B;  Feldman  MD;  Schiller  NB;  Browner  WS:  Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA 2008; 300:2379–2388
[PubMed]
[CrossRef]
 
Spitzer  RL;  Kroenke  K;  Williams  JB:  Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study: Primary Care Evaluation of Mental Disorders Patient Health Questionnaire. JAMA 1999; 282:1737–1744
[PubMed]
[CrossRef]
 
Kroenke  K;  Spitzer  RL;  Williams  JB:  The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606–613
[PubMed]
[CrossRef]
 
Stafford  L;  Berk  M;  Jackson  HJ:  Validity of the Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9 to screen for depression in patients with coronary artery disease. Gen Hosp Psychiatry 2007; 29:417–424
[PubMed]
[CrossRef]
 
Thombs  BD;  Ziegelstein  RC;  Whooley  MA:  Optimizing detection of major depression among patients with coronary artery disease using the Patient Health Questionnaire: data from the Heart and Soul Study. J Gen Intern Med 2008; 23:2014–2017
[PubMed]
[CrossRef]
 
Pinto-Meza  A;  Serrano-Blanco  A;  Penarrubia  MT;  Blanco  E;  Haro  JM:  Assessing depression in primary care with the PHQ-9: can it be carried out over the telephone? J Gen Intern Med 2005; 20:738–742
[PubMed]
[CrossRef]
 
O'Connor  M-F;  Bower  JE;  Cho  HJ;  Creswell  JD;  Dimitrov  S;  Hamby  ME;  Hoyt  MA;  Martin  JL;  Robles  TF;  Sloan  EK;  Thomas  KS;  Irwin  MR:  To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun 2009; 23:887–897
[PubMed]
[CrossRef]
 
Frost-Pineda  K;  Liang  Q;  Liu  J;  Rimmer  L;  Jin  Y;  Feng  S;  Kapur  S;  Mendes  P;  Roethig  H;  Sarkar  M:  Biomarkers of potential harm among adult smokers and nonsmokers in the Total Exposure Study. Nicotine Tob Res 2011; 13:182–193
[PubMed]
[CrossRef]
 
Aadahl  M;  Kjaer  M;  Kristensen  JH;  Mollerup  B;  Jorgensen  T:  Self-reported physical activity compared with maximal oxygen uptake in adults. Eur J Cardiovasc Prev Rehabil 2007; 14:422–428
[PubMed]
[CrossRef]
 
Ainsworth  BE;  Jacobs  DR  Jr;  Leon  AS:  Validity and reliability of self-reported physical activity status: the Lipid Research Clinics questionnaire. Med Sci Sports Exerc 1993; 25:92–98
[PubMed]
[CrossRef]
 
Bowles  HR;  FitzGerald  SJ;  Morrow  JR  Jr;  Jackson  AW;  Blair  SN:  Construct validity of self-reported historical physical activity. Am J Epidemiol 2004; 160:279–286
[PubMed]
[CrossRef]
 
Kurtze  N;  Rangul  V;  Hustvedt  BE;  Flanders  WD:  Reliability and validity of self-reported physical activity in the Nord-Trondelag Health Study: HUNT 1. Scand J Public Health 2008; 36:52–61
[PubMed]
[CrossRef]
 
Bush  K;  Kivlahan  DR;  McDonell  MB;  Fihn  SD;  Bradley  KA:  The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking: Ambulatory Care Quality Improvement Project (ACQUIP) Alcohol Use Disorders Identification Test. Arch Intern Med 1998; 158:1789–1795
[PubMed]
[CrossRef]
 
Blumenthal  JA:  Depression and coronary heart disease: association and implications for treatment. Cleve Clin J Med 2008; 75(suppl 2):S48–S53
[PubMed]
[CrossRef]
 
Ridker  PM;  Genest  J;  Libby  P:  Risk factors for atherosclerotic disease, in  Heart Disease: A Textbook of Cardiovascular Medicine , 6th ed. Edited by Braunwald  E;  Zipes  DP;  Libby  P.  Philadelphia,  WB Saunders, 2001, pp 1010–1039
 
Hamer  M;  Molloy  GJ;  de Oliveira  C;  Demakakos  P:  Persistent depressive symptomatology and inflammation: to what extent do health behaviours and weight control mediate this relationship? Brain Behav Immun 2009; 23:413–418
[PubMed]
[CrossRef]
 
Kaptein  KI;  de Jonge  P;  van den Brink  RH;  Korf  J:  Course of depressive symptoms after myocardial infarction and cardiac prognosis: a latent class analysis. Psychosom Med 2006; 68:662–668
[PubMed]
[CrossRef]
 
Matthews  KA;  Schott  LL;  Bromberger  JT;  Cyranowski  JM;  Everson-Rose  SA;  Sowers  M:  Are there bi-directional associations between depressive symptoms and C-reactive protein in mid-life women? Brain Behav Immun 2010; 24:96–101
[PubMed]
[CrossRef]
 
Dod  HS;  Bhardwaj  R;  Sajja  V;  Weidner  G;  Hobbs  GR;  Konat  GW;  Manivannan  S;  Gharib  W;  Warden  BE;  Nanda  NC;  Beto  RJ;  Ornish  D;  Jain  AC:  Effect of intensive lifestyle changes on endothelial function and on inflammatory markers of atherosclerosis. Am J Cardiol 2010; 105:362–367
[PubMed]
[CrossRef]
 
References Container

FIGURE 1. 

Proportion of Patients With Coronary Heart Disease Who Had High Levels of Inflammatory Markers at 5-Year Follow-Up, by Depressive Symptoms Over 5 Yearsa

a Inflammatory markers were measured at baseline and at the 5-year follow-up assessment. Depressive symptoms were assessed with the nine-item Patient Health Questionnaire at baseline and annually for the next 5 years.

b Significant difference among groups (χ2=8.45, df=2, p=0.01).

c Significant difference among groups (χ2=5.96, df=2, p=0.05).

Anchor for Jump
TABLE 1.

Baseline Characteristics of 667 Patients With Coronary Heart Disease, by Depressive Symptoms Over 5 Yearsa

Table Footer Note

a Depressive symptoms were assessed at baseline and annually for the next 5 years.

Table Footer Note

b Total number varied because data on some variables were not available for all participants.

Anchor for Jump
TABLE 2.

Levels of Inflammatory Markers at 5-Year Follow-Up in Patients With Coronary Heart Disease, by Depressive Symptoms Over 5 Yearsa

Table Footer Note

a Depressive symptoms were assessed at baseline and annually for the next 5 years.

Table Footer Note

b Model 1: adjusted for age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, and aspirin use. Model 2: adjusted for all of the preceding variables plus physical activity, current smoking, and body mass index.

Table Footer Note

c Unadjusted values use SD, and adjusted values use SE.

Anchor for Jump
TABLE 3.

Change in Inflammatory Marker Levels Over 5 Years in Patients With Coronary Heart Disease, by Depressive Symptoms Over 5 Yearsa

Table Footer Note

a Depressive symptoms were assessed at baseline and annually for the next 5 years.

Table Footer Note

b Model 1: adjusted for age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, and aspirin use. Model 2: adjusted for all of the preceding variables plus physical activity, current smoking, and body mass index.

Table Footer Note

c Unadjusted values use SD, and adjusted values use SE.

Anchor for Jump
TABLE 4.

Baseline Levels of Inflammatory Markers in Patients With Coronary Heart Disease, by Depressive Symptoms Over 5 Yearsa

Table Footer Note

a Depressive symptoms were assessed at baseline and annually for the next 5 years.

Table Footer Note

b Model 1: adjusted for baseline age, gender, education, race, history of diabetes, myocardial infarction, congestive heart failure, and aspirin use. Model 2: adjusted for all of the preceding variables plus baseline physical activity, current smoking, and body mass index.

Table Footer Note

c Unadjusted values use SD, and adjusted values use SE.

+

References

Thombs  BD;  Bass  EB;  Ford  DE;  Stewart  KJ;  Tsilidis  KK;  Patel  U;  Fauerbach  JA;  Bush  DE;  Ziegelstein  RC:  Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 2006; 21:30–38
[PubMed]
[CrossRef]
 
Wells  KB;  Rogers  W;  Burnam  MA;  Camp  P:  Course of depression in patients with hypertension, myocardial infarction, or insulin-dependent diabetes. Am J Psychiatry 1993; 150:632–638
[PubMed]
 
van Melle  JP;  de Jonge  P;  Spijkerman  TA;  Tijssen  JG;  Ormel  J;  van Veldhuisen  DJ;  van den Brink  RH;  van den Berg  MP:  Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 2004; 66:814–822
[PubMed]
[CrossRef]
 
de Jonge  P;  Rosmalen  JG;  Kema  IP;  Doornbos  B;  van Melle  JP;  Pouwer  F;  Kupper  N:  Psychophysiological biomarkers explaining the association between depression and prognosis in coronary artery patients: a critical review of the literature. Neurosci Biobehav Rev 2010; 35:84–90
[PubMed]
[CrossRef]
 
Danner  M;  Kasl  SV;  Abramson  JL;  Vaccarino  V:  Association between depression and elevated C-reactive protein. Psychosom Med 2003; 65:347–356
[PubMed]
[CrossRef]
 
Dowlati  Y;  Herrmann  N;  Swardfager  W;  Liu  H;  Sham  L;  Reim  EK;  Lanctot  KL:  A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67:446–457
[PubMed]
[CrossRef]
 
Elovainio  M;  Aalto  AM;  Kivimaki  M;  Pirkola  S;  Sundvall  J;  Lonnqvist  J;  Reunanen  A:  Depression and C-reactive protein: population-based Health 2000 Study. Psychosom Med 2009; 71:423–430
[PubMed]
[CrossRef]
 
Ford  DE;  Erlinger  TP:  Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2004; 164:1010–1014
[PubMed]
[CrossRef]
 
Penninx  BW;  Kritchevsky  SB;  Yaffe  K;  Newman  AB;  Simonsick  EM;  Rubin  S;  Ferrucci  L;  Harris  T;  Pahor  M:  Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition Study. Biol Psychiatry 2003; 54:566–572
[PubMed]
[CrossRef]
 
Bankier  B;  Barajas  J;  Martinez-Rumayor  A;  Januzzi  JL:  Association between major depressive disorder and C-reactive protein levels in stable coronary heart disease patients. J Psychosom Res 2009; 66:189–194
[PubMed]
[CrossRef]
 
Howren  MB;  Lamkin  DM;  Suls  J:  Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71:171–186
[PubMed]
[CrossRef]
 
Stewart  JC;  Rand  KL;  Muldoon  MF;  Kamarck  TW:  A prospective evaluation of the directionality of the depression-inflammation relationship. Brain Behav Immun 2009; 23:936–944
[PubMed]
[CrossRef]
 
Gimeno  D;  Kivimaki  M;  Brunner  EJ;  Elovainio  M;  De Vogli  R;  Steptoe  A;  Kumari  M;  Lowe  GD;  Rumley  A;  Marmot  MG;  Ferrie  JE:  Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med 2009; 39:413–423
[PubMed]
[CrossRef]
 
Whooley  MA;  de Jonge  P;  Vittinghoff  E;  Otte  C;  Moos  R;  Carney  RM;  Ali  S;  Dowray  S;  Na  B;  Feldman  MD;  Schiller  NB;  Browner  WS:  Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA 2008; 300:2379–2388
[PubMed]
[CrossRef]
 
Spitzer  RL;  Kroenke  K;  Williams  JB:  Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study: Primary Care Evaluation of Mental Disorders Patient Health Questionnaire. JAMA 1999; 282:1737–1744
[PubMed]
[CrossRef]
 
Kroenke  K;  Spitzer  RL;  Williams  JB:  The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606–613
[PubMed]
[CrossRef]
 
Stafford  L;  Berk  M;  Jackson  HJ:  Validity of the Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9 to screen for depression in patients with coronary artery disease. Gen Hosp Psychiatry 2007; 29:417–424
[PubMed]
[CrossRef]
 
Thombs  BD;  Ziegelstein  RC;  Whooley  MA:  Optimizing detection of major depression among patients with coronary artery disease using the Patient Health Questionnaire: data from the Heart and Soul Study. J Gen Intern Med 2008; 23:2014–2017
[PubMed]
[CrossRef]
 
Pinto-Meza  A;  Serrano-Blanco  A;  Penarrubia  MT;  Blanco  E;  Haro  JM:  Assessing depression in primary care with the PHQ-9: can it be carried out over the telephone? J Gen Intern Med 2005; 20:738–742
[PubMed]
[CrossRef]
 
O'Connor  M-F;  Bower  JE;  Cho  HJ;  Creswell  JD;  Dimitrov  S;  Hamby  ME;  Hoyt  MA;  Martin  JL;  Robles  TF;  Sloan  EK;  Thomas  KS;  Irwin  MR:  To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun 2009; 23:887–897
[PubMed]
[CrossRef]
 
Frost-Pineda  K;  Liang  Q;  Liu  J;  Rimmer  L;  Jin  Y;  Feng  S;  Kapur  S;  Mendes  P;  Roethig  H;  Sarkar  M:  Biomarkers of potential harm among adult smokers and nonsmokers in the Total Exposure Study. Nicotine Tob Res 2011; 13:182–193
[PubMed]
[CrossRef]
 
Aadahl  M;  Kjaer  M;  Kristensen  JH;  Mollerup  B;  Jorgensen  T:  Self-reported physical activity compared with maximal oxygen uptake in adults. Eur J Cardiovasc Prev Rehabil 2007; 14:422–428
[PubMed]
[CrossRef]
 
Ainsworth  BE;  Jacobs  DR  Jr;  Leon  AS:  Validity and reliability of self-reported physical activity status: the Lipid Research Clinics questionnaire. Med Sci Sports Exerc 1993; 25:92–98
[PubMed]
[CrossRef]
 
Bowles  HR;  FitzGerald  SJ;  Morrow  JR  Jr;  Jackson  AW;  Blair  SN:  Construct validity of self-reported historical physical activity. Am J Epidemiol 2004; 160:279–286
[PubMed]
[CrossRef]
 
Kurtze  N;  Rangul  V;  Hustvedt  BE;  Flanders  WD:  Reliability and validity of self-reported physical activity in the Nord-Trondelag Health Study: HUNT 1. Scand J Public Health 2008; 36:52–61
[PubMed]
[CrossRef]
 
Bush  K;  Kivlahan  DR;  McDonell  MB;  Fihn  SD;  Bradley  KA:  The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking: Ambulatory Care Quality Improvement Project (ACQUIP) Alcohol Use Disorders Identification Test. Arch Intern Med 1998; 158:1789–1795
[PubMed]
[CrossRef]
 
Blumenthal  JA:  Depression and coronary heart disease: association and implications for treatment. Cleve Clin J Med 2008; 75(suppl 2):S48–S53
[PubMed]
[CrossRef]
 
Ridker  PM;  Genest  J;  Libby  P:  Risk factors for atherosclerotic disease, in  Heart Disease: A Textbook of Cardiovascular Medicine , 6th ed. Edited by Braunwald  E;  Zipes  DP;  Libby  P.  Philadelphia,  WB Saunders, 2001, pp 1010–1039
 
Hamer  M;  Molloy  GJ;  de Oliveira  C;  Demakakos  P:  Persistent depressive symptomatology and inflammation: to what extent do health behaviours and weight control mediate this relationship? Brain Behav Immun 2009; 23:413–418
[PubMed]
[CrossRef]
 
Kaptein  KI;  de Jonge  P;  van den Brink  RH;  Korf  J:  Course of depressive symptoms after myocardial infarction and cardiac prognosis: a latent class analysis. Psychosom Med 2006; 68:662–668
[PubMed]
[CrossRef]
 
Matthews  KA;  Schott  LL;  Bromberger  JT;  Cyranowski  JM;  Everson-Rose  SA;  Sowers  M:  Are there bi-directional associations between depressive symptoms and C-reactive protein in mid-life women? Brain Behav Immun 2010; 24:96–101
[PubMed]
[CrossRef]
 
Dod  HS;  Bhardwaj  R;  Sajja  V;  Weidner  G;  Hobbs  GR;  Konat  GW;  Manivannan  S;  Gharib  W;  Warden  BE;  Nanda  NC;  Beto  RJ;  Ornish  D;  Jain  AC:  Effect of intensive lifestyle changes on endothelial function and on inflammatory markers of atherosclerosis. Am J Cardiol 2010; 105:362–367
[PubMed]
[CrossRef]
 
References Container
+
+

Self-Assessment Quiz - Expired

Did you know? You can add a subscription now to earn CME Credits!

1.
What did the investigators find about the bidirectional relationship between depression and inflammation?
2.
What health behaviors appeared to explain the association between depressive symptoms and inflammation?
3.
In this study, the results showed that depressive symptoms predicted high levels of which of the following marker(s)?
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 39

Related Content
Articles
Books
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 45.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 9.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 9.  >
The American Psychiatric Publishing Textbook of Geriatric Psychiatry, 4th Edition > Chapter 7.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 9.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles