Journal of Psychosomatic Research 74 (2013) 122–127
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Journal of Psychosomatic Research
Association of anxious and depressive symptoms with medication nonadherence in patients with stable coronary artery disease Christian Dempe a, 1, Jana Jünger a, 1, Sebastian Hoppe a, Marie-Louise Katzenberger a, Andreas Möltner a, Karl-Heinz Ladwig b, Wolfgang Herzog a, Jobst-Hendrik Schultz a,⁎ a b
Department of Psychosomatic and General Internal Medicine, University of Heidelberg, Medical Hospital, Heidelberg, Germany Department of Psychosomatic Medicine and Psychotherapy, Klinikum rechts der Isar München, Munich, Germany
a r t i c l e
i n f o
Article history: Received 13 July 2012 Received in revised form 28 November 2012 Accepted 4 December 2012 Keywords: Adherence Anxious symptoms Coronary artery disease Depressive symptoms Depressive–anxious co-morbidity
a b s t r a c t Objective: Depression and anxiety lead to increased morbidity and mortality in patients with coronary artery disease (CAD). Medication nonadherence is one possible pathway contributing to adverse outcome, but it is unknown how either depression or anxiety itself inﬂuences adherence compared to combined depressive– anxious comorbidity. The aim of the study was to evaluate the inﬂuence of simultaneous depressive and anxious symptoms on medication adherence in patients with stable CAD. Methods: Between 02/2009 and 06/2010 we examined the association between current depressive and anxious symptoms with medication nonadherence in a cross-sectional study of 606 inpatients with stable CAD. Symptoms were assessed by using the Hospital Anxiety and Depression Scale. Morisky Medical Adherence Scale measured medication adherence. Results: Depressive and anxious symptoms were weakly and independently associated with medication nonadherence (r = 0.28, p b 0.01 and r = 0.27, p b 0.01 respectively). Compared to non-depressed, patients with depressive symptoms had an up to 3.6-fold odds, those with anxious symptoms an up to 3.2-fold odds of nonadherence. The presence of combined anxiety and depressive symptoms was also weakly correlated with adherence (r = 0.30, p b 0.01). The risk for nonadherence in patients suffering from both anxiety and depression was up to 4.4 times higher compared to patients without symptoms. Conclusion: Apart from depressive symptoms, anxiety is a second important and independent marker for nonadherence in patients with coronary artery disease. The negative effect of anxiety on medication adherence increases in case of comorbid depressive symptoms. Future studies addressing medication adherence should focus more on anxious-depressive comorbidity than on singular depressive or anxious symptoms. © 2012 Elsevier Inc. All rights reserved.
Introduction Mental disorders, especially anxiety and depression, are common in patients with coronary artery disease [1–3]. Both are associated with a higher risk for increased morbidity and mortality: While the effect of depression on prognosis is established and well-known [4–8], the knowledge of the inﬂuence of anxiety is quiet new. A recent meta-analysis showed that anxious patients have a 26% increased risk of suffering from a coronary artery disease and a 48% increased risk of cardiac death . One of the suggested pathways linking mental disorders and decreased prognosis in patients with coronary artery disease is medication nonadherence [1,10]. A meta-analysis showed that in a population of
⁎ Corresponding author at: Heidelberg University Hospital, Department of Psychosomatic and General Internal Medicine, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Tel.: +49 6221 56 8654; fax: +49 6221 56 5330. E-mail address: [email protected]
(J.-H. Schultz). 1 Equal ﬁrst authors. 0022-3999/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpsychores.2012.12.003
patients with chronic diseases the odds of medication nonadherence are up to 3-times greater in depressed than in non-depressed patients [10,11]. The average effect of anxiety in the meta-analysis, however, was close to zero as a result of values deviating between −0.64 and 0.39 . Until now, the relationship between anxiety and medication nonadherence remains unclear. Recently, Bauer et al. reported an independent impact of depressive and anxious symptoms, respectively, on adherence in a sample of patients with cardiac diseases in general. However, they could not make any statements regarding the impact of depressive–anxious co-morbidity on adherence in these patients due to a limited number of participants (n = 134) . The present study examines the association between anxiety, depression, and medication adherence in a large sample of patients with stable coronary artery disease (CAD). The study also focuses on the association of comorbid anxious and depressive symptoms, and medication adherence, a constellation which to our knowledge has not been investigated up to now, neither in patients with CAD nor in those with chronic diseases in general.
C. Dempe et al. / Journal of Psychosomatic Research 74 (2013) 122–127
We hypothesize that in our sample depressive and anxious symptoms are independently associated with medication nonadherence. The strongest association is expected in patients with comorbid anxious and depressive symptoms.
from 0 points (optimum of adherence) to 4 points (maximum of nonadherence). Following the classiﬁcation of former studies having used the MMAS in patients with CAD we categorized 0–1 point as having good medication adherence, 2–4 points as having poor medication adherence .
Methods Study design and participants
Other parameters assessed
The study was performed as a cross-sectional study in agreement with the Ethics Committee of the faculty of clinical medicine of the University of Heidelberg, based on the Declaration of Helsinki of 1964 (Ethics Committee vote S-293/2008). Between February 2009 and June 2010 patients were screened on three internal medicine inpatients wards of the University Hospital Heidelberg. Patients were considered for inclusion if they were between 18 and 75 years old, German-speaking, if they had a CAD conﬁrmed by a recent coronary angiogram (within 3 months) and gave written informed consent. Criteria for CAD were deﬁned as having an actual stenosis of at least 50% in one or more major coronary arteries or having a history of myocardial infarction, coronary artery bypass surgery or angioplasty. Patients with severe heart failure (NYHA IV), acute life-threatening conditions (as progressive cancer disease or history of organ transplantation), severe chronic inﬂammatory disease (as borreliosis, HIV-infection or chronic hepatitis), inﬂammatory bowel diseases and severe obstructive lung diseases were excluded. Patients with current severe depressive disorder, psychosis, delirium or dementia were also not been considered. The data of our study were collected parallel to those of the SPIRR-CAD-Study , a randomised, controlled, multi-centre clinical trial which evaluates the effect of a stepwise psychotherapy intervention for reducing risk in patients with CAD. It has to be mentioned that the patients were ﬁrst informed about the course of SPIRR-CAD after having been screened for mental disorders. So, participants of our study completed the handed questionnaires without being inﬂuenced by another trial.
Besides measuring psychic symptoms and medication adherence we registered age and gender of all patients.
Statistical analysis Assessed data were fed into 2 copies of the same access data base by two different persons. After electronic comparison the data were corrected manually in case of deviation. The analysis did not consider MMAS scores, if one single item was missing. In case of the HADS we tolerated up to 2 missing values of each subscale replacing it with the mean of the remaining 5 items. Subscales with more than 2 missing values were excluded. Differences in characteristics between participants were compared using a 2-sample t-test. We correlated the scores of the anxiety subscale and the depression subscale as independent variable with the MMAS score as dependent variable linearly in order to describe the association between depressive symptoms, anxious symptoms and medication adherence. Multiple regression models were used to prove independence of the found correlations. Afterwards, we divided anxious and depressive symptoms in categories of different severity and medication adherence in groups of adherent and nonadherent participants. To exemplify the associations found between psychic symptoms and medication nonadherence we calculated the corresponding relative risks using the categorized data. Finally age and gender were correlated with the summary score of MMAS to describe the inﬂuence of socio-demographic data. All analyses were performed using statistical analysis software (SAS Version 9.2).
Measurement of depressive and anxious symptoms Results
Depressive and anxious symptoms were assessed by using the Hospital Anxiety and Depression Scale (HADS), a self-rating instrument developed by Zigmond and Snaith in 1983 to measure severity of anxiety and depressive symptoms in physically ill patients . In a large sample of studies the HADS has shown good internal consistency  and satisﬁable test–retest reliability over short intervals as well as good sensitivity to changes of affective symptoms . The German Version used in this study has initially been validated in cardiological patients and has been recommended as a routine screening tool for affective disorders in this group by the test authors . The questionnaire contains 14 items split into 2 different subscales (depression and anxiety). Compared to other established rating-scales for depression and anxiety both subscales have shown high correlations . The scores of each subscale range from 0 points (no symptoms) to 21 points (maximum of symptoms). With regard to the recommended classiﬁcation of the test authors we categorized participants as having no symptoms (HADS score of 0–7), mild symptoms (HADS score 8–10) and severe symptoms (HADS score 11–21) .
Descriptive data In total, 606 persons participated in the study. Their mean age was 62.5 ± 9.1 years, with a range of 25–75 years. 76.6% of participants were male. Women were signiﬁcant older than men (64.60 ± 8.69 years vs. 61.88 ± 9.11 years, p b 0.01). Due to exclusion criteria more than 40% (760/1765) of the screened patients were ruled out. 399 persons did not give informed consent and were excluded, too (Fig. 1). Compared to patients included the part of male patients excluded was higher (76.6% and 75.8%, respectively, p = 0.73). However, mean age does not differ signiﬁcantly between both groups (62.5 ± 9.1 years and 64.3 ± 8.5 years, respectively, p b 0.01). Table 1 provides an overview of mean HADS and MMAS score separated by age and gender of participants. In total, 137 of 606 participants (22.6%) did not take their medications as prescribed. Overall, 253 of 606 participants (41.7%) reported having at least mild or severe symptoms of the screened mental disorders. A total of 24.4% (148/606) showed current depressive symptoms and 35.5% (215/606) showed current anxious symptoms. 18.2% (110 of 606) suffered from depressive and anxious symptoms simultaneously. Depressive symptoms were 3 times more frequently in combination with anxious symptoms than alone (74.3% versus 25.6%).
Depressive symptoms and medication adherence
Measurement of medication adherence Medication adherence was measured by using the Morisky Medical Adherence Scale (MMAS). The self-rating scale was developed and validated by Morisky et al. in 1986 to predict whether patients adhere to their medications or not . It has been used in a wide sample of chronic diseases, especially in cardiovascular patients [18–21]. The questionnaire contains in total 4 items. The summary score range
Medication nonadherence increases with the severity of depressive symptoms (Table 2). A total of 15.3% (70/458) of patients with no symptoms (HADS-D b 8) reported not to take their medication compared with 39.6% (36/91) of patients with mild (8 ≤ HADS D ≤ 10) and 54.5% (31/57) with severe depressive symptoms (HADS-D ≥ 11) (Fig. 2). Compared to patients who reported having no symptoms, those with severe symptoms had a 3.6 times higher risk of being nonadherent to prescribed medication. Statistical analysis showed a weak negative correlation of depressive symptoms and medication adherence (r = −0.28, p b 0.01).
C. Dempe et al. / Journal of Psychosomatic Research 74 (2013) 122–127
1765 Patients screened
1005 Patients without exclusion criteria
760 Patients with exclusion criteria
606 Patients with informed consent
399 Patients without informed consent
606 Patients included Fig. 1. Flow diagram for study enrolment.
Anxious symptoms and medication adherence Similar to depressive symptoms, medication nonadherence increases with severity of anxious symptoms, too (Table 2). 27.1% (38/140) of the patients with mild (8 ≤HADS ≤10) and 50.7% (38/75) of those with severe anxious symptoms (HADS-A ≥ 11) reported not taking their medication compared to 15.6% (61/391) of those without anxious symptoms (HADS-A b 8) corresponding an up to 3.2 times higher risk of medication nonadherence in patients with anxious symptoms (Fig. 3). Comparable to depressive symptoms, statistical analysis showed a weak negative correlation of anxious symptoms and medication adherence (r = −0.27, p b 0.01). Both associations remained signiﬁcant after implementing multiple regression models. So, in our study population, increasing anxious and depressive symptoms go along independently with a higher level of medication nonadherence. Comorbid anxious and depressive symptoms and medication adherence A weak negative association exists between the presence of comorbid anxious and depressive symptoms and medication adherence (r = −0.30, p b 0.01). Their risk of medication nonadherence was up to 4.4 times higher than in patients without these psychic symptoms. Fig. 4 shows distribution of medication nonadherence in the subpopulation. A total of 14.2% (50/353) of the participants with no affective symptoms (total HADS b 8) reported not being adherent compared to 42.1% (16/38) of those with mild (8 ≤ total HADS ≤ 10) and 62.5% (20/32) of patients with severe symptoms (total HADS ≥ 11). Sociodemographic data and medication adherence Younger age was weakly associated with medication nonadherence (r = 0.14, p b 0.01). The younger the patients the higher was their risk of not taking their
medications as prescribed. Gender, however, showed no signiﬁcant inﬂuence on medication adherence. The part of nonadherence among men and women was nearly the same (22.6% versus 22.5%, p = 0.89). All associations remained signiﬁcant after adjustment for age as a potential confounding variable (r = −0.26, p b 0.01, r = −0.25, p b 0.01 and r = −0.31, p b 0.01, respectively, regarding the association of medication adherence with depressive symptoms, anxiety symptoms and depressive–anxious co-morbidity, respectively).
Discussion Summary of main results In our study population depressive and anxious symptoms had a high prevalence. Forty-two percent of the participants reported suffering from at least one of both symptoms. Depressive symptoms were three times more frequently in combination with anxious symptoms than without. We found that depressive symptoms as well as anxious symptoms were independently and comparably associated with medication nonadherence. This effect increased with severity of symptoms. In addition, a weak, but somewhat stronger, relationship however was seen in patients who suffered from both symptoms simultaneously. Their risk for medication nonadherence was up to 4.4 times higher compared to patients without anxious and without depressive symptoms.
Table 1 Mean HADS and MMAS score by age and gender* Age
HADS_A HADS_D MMAS HADS_A HADS_D MMAS HADS_A HADS_D MMAS HADS_A HADS_D MMAS HADS_A HADS_D MMAS HADS_A HADS_D MMAS
Mean ± SD
Mean ± SD
3 3 3 40 40 40 128 128 128 169 169 169 124 124 124 464 464 464
8.67 ± 4.16 4.33 ± 5.77 1.33 ± 0.58 7.34 ± 3.71 6.45 ± 4.41 1.03 ± 1.17 7.19 ± 3.94 6.16 ± 4.06 1.03 ± 1.19 5.42 ± 3.31 4.48 ± 3.16 0.72 ± 0.96 5.74 ± 3.22 4.67 ± 3.03 0.57 ± 0.88 6.18 ± 3.59 5.16 ± 3.61 0.80 ± 1.04
26.00 13.00 4.00 293.68 258.00 41.00 919.68 788.61 131.97 915.14 756.95 122.02 712.01 578.96 70.06 2866.51 2395.52 369.05
1 1 1 8 8 8 24 24 24 56 56 56 53 53 53 142 142 142
9 9 2 9.42 ± 4.86 7.38 ± 4.60 0.63 ± 0.92 7.22 ± 4.42 5.35 ± 3.65 0.83 ± 1.20 7.64 ± 3.38 5.54 ± 3.39 0.77 ± 1.06 6.17 ± 3.87 5.38 ± 3.58 0.77 ± 1.14 7.13 ± 3.89 5.76 ± 3.57 0.78 ± 1.10
9 9 2 75.34 59.00 5.00 173.17 128.33 19.99 427.67 310.02 43.01 327.17 285.35 41.02 1012.35 791.70 111.02
C. Dempe et al. / Journal of Psychosomatic Research 74 (2013) 122–127 Table 2 Medication adherence of participants by severity of psychic symptoms⁎ Severity of symptoms
Mean MMAS score ± SD
HADS_D b 8 HADS_D 8–10 HADS_D ≥11 HADS_A b 8 HADS_A 8–10 HADS_A ≥11 HADS_D + A b 8 HADS_D + A 8–10 HADS_D + A ≥11
458 91 57 391 140 75 353 38 32
0.63 ± 0.93 1.19 ± 1.26 1.47 ± 1.20 0.60 ± 0.89 0.94 ± 1.11 1.55 ± 1.32 0.56 ± 0.87 1.29 ± 1.29 1.66 ± 1.26
⁎ The MMAS score indicates the rate of medication adherence. Scale ranges from 0 point (optimum of adherence) to 4 points (maximum of nonadherence). HADS_D represents the depression subscale of the HADS, HADS_A the anxiety subscale, HADS_D+A the co-morbidity of anxious and depressive symptoms.
diagnosis of CAD . Gehi et al. conﬁrmed these results in a large sample of 940 outpatients with stable CAD. Moreover they could demonstrate that severe depressive symptoms are associated with greater medication nonadherence than mild depressive symptoms . The third study published so far is a recent survey of May et al. Their study supported the former results as well, but was also the ﬁrst one evaluating a stable, negative effect of a clinical diagnosis of depression on medication adherence over a long-term period of 2 years . Our ﬁndings also support the observation of Gehi et al. that severe depressive symptoms are correlated with greater medication nonadherence . In addition, however, we could demonstrate that the quantitative extent of the found correlation is obviously larger than supposed so far [27,28]. So, medication nonadherence as a pathway linking depression and decreased prognosis in patients with CAD gains in importance by our results.
Representativeness of results
Anxiety and medication adherence
Prevalence assessed in our study are consistent with those published so far regarding medication adherence , depression [1,3] and anxiety [2,23,24]. Our study showed almost similar distribution of prevalence of anxious and depressive symptoms compared with a survey performed on wards for internal medicine of the same hospital 9 years before . So, in contrast to the authors of former studies investigating the association between depression and medication adherence in patients with CAD [26–29] we assume that our survey does not select motivated and health-conscious patients . Moreover, our study controls the inﬂuence of many chronic illnesses and handicaps due to the large amount of exclusion criteria. Former investigations did not continuously exclude these patients [27,28]. So, it ﬁnally remains unclear if reported associations are mainly due to the inﬂuence of depression or if they might be the result of other chronic diseases like dementia. Therefore we consider the results of our study as being representative for patients with stable CAD, although men were slightly more likely to be included than women. In contrast to gender, there was no difference between the mean age of participants and patients excluded. So our study did not select younger patients unconsciously.
In our study anxious symptoms had a similar effect on medication adherence like depressive symptoms. As the statistical analysis shows, the found association was independent from depressive symptoms. To our knowledge our study is the ﬁrst survey demonstrating this association in a large population of patients with CAD. Just one small study was reported so far, which assessed anxiety and medication nonadherence in those patients, too: In a side issue Carney et al. could demonstrate an opposite effect of state and trait anxiety on medication adherence in patients with CAD. Whereas state anxiety was associated with medication nonadherence, trait anxiety seems to have a protective effect on adherence . As the anxiety subscale of the HADS correlates strongly with the state subscale of the State-Trait-Inventory  used by Carney et al. results of both studies substantiate the suspicion that state anxiety seems to be associated with a higher level of medication nonadherence in patients with CAD.
Depression and medication adherence
Percentage of Participants
Our ﬁndings conﬁrm those of former studies showing an elevated risk of medication nonadherence in patients with CAD and depression [26–28]. Carney et al. were the ﬁrst one reporting an association of major depression with nonadherence to prescribed aspirin after the
Comorbid anxiety and deoression, and medication adherence The strongest association with medication nonadherence however has been seen in patients who reported suffering from both anxious and depressive symptoms simultaneously. To our knowledge the effect of anxious-depressive comorbidity on medication adherence has not been studied so far. Our study demonstrates that it might be important to focus more on comorbidity of depression and anxiety than on singular depression or anxiety. Nevertheless, further studies are needed to conﬁrm our results and to investigate if the effect of
100 90 80 70 60 50 40 30 20 10 0
HADS_D < 8 (n = 458)
HADS_D 8-10 (n = 91)
HADS_D ≥ 11 (n = 57)
Depression Severity Score Fig. 2. Proportion of participants who were medication nonadherent according to the depression severity score on the Hamilton Anxiety and Depression Scale (HADS_D). Error bars represent conﬁdence interval of 95%.
C. Dempe et al. / Journal of Psychosomatic Research 74 (2013) 122–127
Percentage of Participants
100 90 80 70 60 50 40 30 20 10 0
HADS_A < 8 (n = 391)
HADS_A ≥ 11 (n = 75)
HADS_A 8-10 (n = 140)
Anxiety Severity Score Fig. 3. Proportion of participants who were medication nonadherent according to the anxiety severity score on the Hamilton Anxiety and Depression Scale (HADS_A). Error bars represent conﬁdence interval of 95%.
in order to evaluate reasons for the adverse effect of anxiety on medication adherence in patients with CAD.
Reasons for medication nonadherence
Limitations and strengths of the study
The analysis of the former studies provides several reasons why depression has a negative effect on medication adherence: hopelessness [27,28], missing social support , increased sensitivity to medication adverse effects [27,30,31] as well as physical limitations like lack of energy, motivation or concentration [27,28]. The question why state anxiety affects medication adherence in patients with CAD, however, has not been answered so far. We suppose that anxiety goes along with excessive demands in case of being a state, but not a fundamental trait of the patients. In this connection state anxiety might cause poor medication adherence in situations considered as being threatening (like suffering from coronary heart disease). By contrast, anxiety defends people from nonadherence in case of being a fundamental trait: Because of the consistent fear of complications people are probably more adherent to prescribed medication regimen compared to those without anxiety. Finally, the common occurrence of excessive demands on the one hand and a lack of motivation on the other could explain why state anxiety increases the individual risk of medication nonadherence in depressed patients in case of anxiety-depressive co-morbidity. Nevertheless these explanations are just assumptions. Further studies investigating patients with state and trait anxiety are needed
Several limitations have to be considered in interpreting our results. First, our survey was performed as a cross-sectional study. Therefore we could not make any statements regarding causality of our ﬁndings. If depressive and anxious symptoms affect medication adherence or vice versa remains unclear. Because of the typical psychopathological behaviour of depression and anxiety, however, we agree with the opinion of several expert groups who suppose the ﬁrst pathway [1,10]. Nevertheless large, randomised, controlled trials are needed to clarify certainly the direction of found correlations. Second, we excluded patients with current severe depressive disorder. This limitation was due to the exclusion criteria of SPIRR-CAD. However severity of depression was only known in single cases. If documents just list diagnose of depression patients were always considered for inclusion in case of absence of other exclusion criteria. Third, we did not collect other socio-demographic data beside age and gender of the participants. Therefore we could not make any statements if these data may have confound our ﬁndings. Of the studies underlying our survey [26–29], only Gehi et al. collected additional socio-demographic data (e.g. high school graduate, marital status, annual income, social support) . After adjustment for these potential confounding variables the association between depression and adherence found by Gehi et al. kept
Percentage of Participants
anxious-depressive co-morbidity on medication adherence can be transferred to other risk modifying behaviours too.
100 90 80 70 60 50 40 30 20 10 0
adherent non adherent
HADS_D+A < 8 (n = 353)
HADS_D+A ≥ 11
(n = 38)
(n = 32)
Depression-Anxiety Severity Score Fig. 4. Proportion of participants who were medication nonadherent according to the depression–anxiety severity score on the Hamilton Anxiety and Depression Scale (HADS_D + A). Error bars represent conﬁdence interval of 95%.
C. Dempe et al. / Journal of Psychosomatic Research 74 (2013) 122–127
strong, but the odds of not taking medications as prescribed decreased from 3.1-fold to 2.2-fold . Therefore the relative risks of medication nonadherence in case of current mental disorders reported in our study might be overestimated. Last, we used a self-rating scale for assessment of anxiety and depression. Strictly speaking, HADS does not deﬁne a depression or an anxiety disorder. Instead, it aims to measure the extent of depressive and anxious symptoms that a patient is experiencing. The strengths of our survey include its large sample size, the use of validated instruments for measuring affective disorders and medication adherence as well as the large amount of exclusion criteria that allowed us to expect that our ﬁndings can be transferred to patients with stable CAD in general. Conclusion Our ﬁndings underline the importance of the effect of depressive symptoms on medication adherence in patients with CAD. Moreover, they demonstrate that the quantitative extent of medication nonadherence in those patients is larger than supposed so far. Apart from depression, state anxiety plays an important role in medication non-adherence as well. The association with medication nonadherence seems even to be stronger in case of their comorbid occurrence. All found associations, however, remain weak with a range of r = −0.27 to r = −0.30 indicating that CAD is a multi-factorial illness which cannot be explained by single risk-factors or behaviours and which needs a holistic treatment. Therefore efforts to screen for medication nonadherence in patients with known or suspected depression and anxiety gain in importance. In case of positive screening targeted clinical therapy could help to modify medication adherence of patients. According to the healthy-adherer effect  this intervention could be an approach improving prognosis of patients with CAD and comorbid anxious and depressive symptoms. Conﬂict of interest Source of Funding: The study was supported by DFG (Deutsche Forschungsgemeinschaft). Financial Disclosure Information: None. There is no further relationship with industry or ﬁnancial associations that might pose a conﬂict of interest except the non-commercial support from DFG. References  Khawaja IS, Westermeyer JJ, Gajwani P, Feinstein RE. Depression and coronary artery disease: the association, mechanisms, and therapeutic implications. Psychiatry (Edgmont) 2009;6:38–51 [Epub 2009/09/03].  Todaro JF, Shen BJ, Raffa SD, Tilkemeier PL, Niaura R. Prevalence of anxiety disorders in men and women with established coronary heart disease. J Cardiopulm Rehabil Prev 2007;27:86–91 [Epub 2007/06/15].  Zellweger MJ, Osterwalder RH, Langewitz W, Pﬁsterer ME. Coronary artery disease and depression. Eur Heart J 2004;25:3–9 [Epub 2003/12/20].  Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med 2004;66:802–13 [Epub 2004/11/27].  Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995;91:999–1005 [Epub 1995/02/15].  Lesperance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002;105:1049–53 [Epub 2002/03/06].  Blumenthal JA, Lett HS, Babyak MA, White W, Smith PK, Mark DB, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003;362:604–9 [Epub 2003/08/29].  Bush DE, Ziegelstein RC, Tayback M, Richter D, Stevens S, Zahalsky H, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001;88:337–41 [Epub 2001/09/08].  Roest AM, Martens EJ, de Jonge P, Denollet J. Anxiety and risk of incident coronary heart disease: a meta-analysis. Journal of the American College of Cardiology 2010 Jun 29;56(1):38–46 [Epub 2010/07/14].
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