University of Groningen
Shades of a blue heart
Moreira da Rocha de Miranda Az, Ricardo
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Publication date: 2018
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Moreira da Rocha de Miranda Az, R. (2018). Shades of a blue heart: An epidemiological investigation of depressive symptom dimensions and the association with cardiovascular disease. University of Groningen.
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Chapter 1
9
GENERAL INTRODUCTION What is depression?
Depression is a syndrome mainly characterized by two core symptoms: sadness (i.e. depressed mood) and loss of interest/pleasure in activities that once were considered to be pleasant. Depression includes both “cognitive” symptoms like guilt or self-dislike, and “somatic” symptoms, like hypo/hypersomnia and fatigue1,2.
A common way to conceptualize depression, both for research and clinical purposes, is by expressing depression as a dichotomous variable, for example by diagnosing a depressive disorder1. This gives clinicians and
researchers the possibility to categorize patients in a more homogeneous way. However, unlike with most somatic diseases, where objective laboratory tests are available for this purpose, depression can only be diagnosed through clinical diagnostic interviews, administered by an interviewer1.
There are several systems providing criteria for diagnosing depression. The two predominant systems are the International Classification of Diseases (ICD), provided by the World Health Organization (WHO)3 and the Diagnostic and Statistical Manual of Mental Disorders
(DSM), provided by the American Psychiatric Association (APA)2. Only the
latter diagnostic criteria will be approached throughout the present dissertation. The DSM was first released in 19524,5, and its current 5th
edition came out in 20132. The DSM-V includes a category entitled “depressive disorders”, which encompasses the following disorders: major depressive disorder (MDD; including major depressive episode), persistent depressive disorder (dysthymia), disruptive mood deregulation disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. For the purpose of illustrating depression as a disorder, Box 1 displays the DSM-V criteria for MDD2. A large body of research used in the present dissertation followed the diagnostic criteria of the DSM-IV. Nonetheless, the diagnostic criteria for depressive disorders are the same in the DSM-V6.
9
GENERAL INTRODUCTION What is depression?
Depression is a syndrome mainly characterized by two core symptoms: sadness (i.e. depressed mood) and loss of interest/pleasure in activities that once were considered to be pleasant. Depression includes both “cognitive” symptoms like guilt or self-dislike, and “somatic” symptoms, like hypo/hypersomnia and fatigue1,2.
A common way to conceptualize depression, both for research and clinical purposes, is by expressing depression as a dichotomous variable, for example by diagnosing a depressive disorder1. This gives clinicians and
researchers the possibility to categorize patients in a more homogeneous way. However, unlike with most somatic diseases, where objective laboratory tests are available for this purpose, depression can only be diagnosed through clinical diagnostic interviews, administered by an interviewer1.
There are several systems providing criteria for diagnosing depression. The two predominant systems are the International Classification of Diseases (ICD), provided by the World Health Organization (WHO)3 and the Diagnostic and Statistical Manual of Mental Disorders
(DSM), provided by the American Psychiatric Association (APA)2. Only the
latter diagnostic criteria will be approached throughout the present dissertation. The DSM was first released in 19524,5, and its current 5th
edition came out in 20132. The DSM-V includes a category entitled “depressive disorders”, which encompasses the following disorders: major depressive disorder (MDD; including major depressive episode), persistent depressive disorder (dysthymia), disruptive mood deregulation disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. For the purpose of illustrating depression as a disorder, Box 1 displays the DSM-V criteria for MDD2. A large body of research used in the present dissertation followed the diagnostic criteria of the DSM-IV. Nonetheless, the diagnostic criteria for depressive disorders are the same in the DSM-V6.
11
Figure 1. Dimensional structure of the BDI, according to Beck and Steer20
10
Epidemiology of depression
The 12-month prevalence of MDD was 6.6% (≈ 15,700,000) in adults 18 years or older living in the United States of America (USA) in 20147. Adults aged between 18-25 years had the highest prevalence: 9.6%;
followed by adults aged 25-50 years: 7.2%; and adults older than 50 years: 5.2%. The prevalence was higher in women (8.3%) than in men (4.4%). The Netherlands has similar figures: the 12-month prevalence between the years 2007 and 2009 of a MDD in the general population was ≈ 6%, and women also had a higher prevalence (≈ 7.5%) as compared with men (≈ 4.8%)8. MDD is also considered to be among the top causes of burden of disease in developed countries such as the USA and the Netherlands, and is also considered to be the fourth cause of burden of disease worldwide9. It has been also predicted that by 2030 depression will be associated with the second highest burden of disease worldwide9.
11
Figure 1. Dimensional structure of the BDI, according to Beck and Steer20
10
Epidemiology of depression
The 12-month prevalence of MDD was 6.6% (≈ 15,700,000) in adults 18 years or older living in the United States of America (USA) in 20147. Adults aged between 18-25 years had the highest prevalence: 9.6%;
followed by adults aged 25-50 years: 7.2%; and adults older than 50 years: 5.2%. The prevalence was higher in women (8.3%) than in men (4.4%). The Netherlands has similar figures: the 12-month prevalence between the years 2007 and 2009 of a MDD in the general population was ≈ 6%, and women also had a higher prevalence (≈ 7.5%) as compared with men (≈ 4.8%)8. MDD is also considered to be among the top causes of burden of disease in developed countries such as the USA and the Netherlands, and is also considered to be the fourth cause of burden of disease worldwide9. It has been also predicted that by 2030 depression will be associated with the second highest burden of disease worldwide9.
13 Box 1. Diagnostic criteria for MDD in the DSM-V A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.) 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.) 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The episode is not attributable to the physiological effects of a substance or to another medical condition. D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. E. There has never been a manic episode or a hypomanic episode. *Criteria extracted from the DSM-V2 12 How is depression assessed?
Clinical diagnostic interviews are used for the purpose of diagnosing MDD. The DSM-V diagnosis made by a health professional is regarded as the gold standard in clinical practice. Another widely used diagnostic interview, primarily used for research purposes, is the structured clinical interview for the DSM criteria (SCID)10. Examples of other diagnostic interviews used for diagnosing depression are the Diagnostic Interview Schedule (DIS)11, the Composite International Diagnostic Interview (CIDI)12, and the Mini-International Neuropsychiatric
Interview (M.I.N.I.)13.
Depressive symptoms are also often assessed through self-report questionnaires14. These instruments have phrases describing depressive
symptoms, and respondents can indicate the presence/absence and the intensity of a certain symptom. A score can be calculated by summing up the responses. The score is used to indicate the severity of the depressive symptomatology. In some cases, certain cutoff levels can be used to indicate substantially increased symptomatology, however, self-report scales cannot be used for making clinically valid diagnoses14. Examples of self-report depressive symptoms scales are the Beck Depression Inventory (BDI and BDI-II)15,16, the Patient Health Questionnaire (PHQ-9)17, the
Inventory of Depressive Symptomatology Self-Report (IDS-SR)18, and many
others.
The BDI is the most used questionnaire in patients with cardiovascular disease19. The BDI is a 21-item self-report measure that assesses the presence and severity of symptoms of depression. The items are assessed on a 4-point Likert scale, with sum scores ranging from 0 to 6315. Due to the heterogeneity of the items (i.e. some items are
mental/cognitive, while other items are physical/somatic), Beck and Steer proposed that the BDI measures two symptom dimensions, namely cognitive and somatic symptom dimensions20. Figure 1 illustrates the
items and the dimensionality of the BDI according to Beck and Steer20. 13 Box 1. Diagnostic criteria for MDD in the DSM-V A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.) 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.) 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The episode is not attributable to the physiological effects of a substance or to another medical condition. D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. E. There has never been a manic episode or a hypomanic episode. *Criteria extracted from the DSM-V2
13 Box 1. Diagnostic criteria for MDD in the DSM-V A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.) 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.) 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The episode is not attributable to the physiological effects of a substance or to another medical condition. D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. E. There has never been a manic episode or a hypomanic episode. *Criteria extracted from the DSM-V2 12 How is depression assessed?
Clinical diagnostic interviews are used for the purpose of diagnosing MDD. The DSM-V diagnosis made by a health professional is regarded as the gold standard in clinical practice. Another widely used diagnostic interview, primarily used for research purposes, is the structured clinical interview for the DSM criteria (SCID)10. Examples of other diagnostic interviews used for diagnosing depression are the Diagnostic Interview Schedule (DIS)11, the Composite International Diagnostic Interview (CIDI)12, and the Mini-International Neuropsychiatric
Interview (M.I.N.I.)13.
Depressive symptoms are also often assessed through self-report questionnaires14. These instruments have phrases describing depressive
symptoms, and respondents can indicate the presence/absence and the intensity of a certain symptom. A score can be calculated by summing up the responses. The score is used to indicate the severity of the depressive symptomatology. In some cases, certain cutoff levels can be used to indicate substantially increased symptomatology, however, self-report scales cannot be used for making clinically valid diagnoses14. Examples of self-report depressive symptoms scales are the Beck Depression Inventory (BDI and BDI-II)15,16, the Patient Health Questionnaire (PHQ-9)17, the
Inventory of Depressive Symptomatology Self-Report (IDS-SR)18, and many
others.
The BDI is the most used questionnaire in patients with cardiovascular disease19. The BDI is a 21-item self-report measure that assesses the presence and severity of symptoms of depression. The items are assessed on a 4-point Likert scale, with sum scores ranging from 0 to 6315. Due to the heterogeneity of the items (i.e. some items are
mental/cognitive, while other items are physical/somatic), Beck and Steer proposed that the BDI measures two symptom dimensions, namely cognitive and somatic symptom dimensions20. Figure 1 illustrates the
items and the dimensionality of the BDI according to Beck and Steer20. 13 Box 1. Diagnostic criteria for MDD in the DSM-V A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.) 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.) 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The episode is not attributable to the physiological effects of a substance or to another medical condition. D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. E. There has never been a manic episode or a hypomanic episode. *Criteria extracted from the DSM-V2
15 Figure 2. Atherosclerosis in the coronary artery Epidemiology of CHD CHD is the leading cause of death worldwide1. In the year of 2013, more than 8.14 million deaths were attributed to cardiovascular disease, representing 16.8% of deaths21. The most common form of CHD is MI28.
In 2012, a total of 20,025 men and 9,653 women living in the Netherlands were hospitalized as a consequence of a MI29. The overall incidence of MI has decreased by 32% in women and by 38% in men in the last decade. Since 1980, mortality related to MI has decreased more than 70%29. In the year of 2012, a total of 2,681 women and 3,541 men died
after having a MI29. CHD-related mortality represented 31% of the deaths
in men, and 19% in women (25% in both)29.
In terms of burden of disease, CHD is considered to have the highest burden of disease worldwide in terms of disability-adjusted life years (DALYs)30. The occurrence of non-fatal CHD leads to impairment to work, which is a growing problem in developing countries31. There was
also an increase in years lived with disability in the period between 1990-201032 as a result of CHD. The increase of years lived with disability as a
14
What is CHD?
Coronary heart disease (CHD) is the most prevalent disease category among the cardiovascular diseases21. This category includes for
example, myocardial infarction (MI), sudden coronary death, and stable/unstable angina22. CHD is a consequence of ischemic heart disease (IHD), also known as coronary artery disease (CAD), although in practice, the terms CHD and CAD are used interchangeably. CAD is caused by the obstruction of the blood flow to the heart, which leads to the starvation of the myocardial cells due to oxygen depletion22. This process is known as
ischemia. Ischemia occurs primarily due to atherosclerosis in the carotid artery, which is the accumulation of white blood cells and propagation of intimal-smooth-muscle cell in the artery. This accumulation leads to the creation of a fatty plaque deposit and the loss of elasticity (stiffness) in the carotid artery. Figure 2 illustrates atherosclerosis of the coronary artery.
The typical symptoms of CHD are angina (chest pain) that often irradiates into the back, the shoulders and the arms; less often dyspnea (shortness of breath) or acid indigestion (heartburn). These symptoms last for a short period and frequently occur following stressful situations or situations of enhanced physical activity22.
Several risk factors have been reported in the literature23: namely diabetes, high blood pressure, smoking, alcohol consumption, unhealthy eating, lack of physical activity, etc. Treatment of CHD consists mainly of cardiovascular risk factors modification, achieved by smoking cessation, following a healthy diet and engaging in physical activity24. Surgical
procedures are also used in patients with increased disease severity, such as coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI)25. Moreover, pharmaceutical treatment is also commonly used, by the administration of anti-platelets drugs, such nitroglycerin, aspirin and beta-blockers26 and statins27.
15 Figure 2. Atherosclerosis in the coronary artery Epidemiology of CHD CHD is the leading cause of death worldwide1. In the year of 2013, more than 8.14 million deaths were attributed to cardiovascular disease, representing 16.8% of deaths21. The most common form of CHD is MI28.
In 2012, a total of 20,025 men and 9,653 women living in the Netherlands were hospitalized as a consequence of a MI29. The overall incidence of MI has decreased by 32% in women and by 38% in men in the last decade. Since 1980, mortality related to MI has decreased more than 70%29. In the year of 2012, a total of 2,681 women and 3,541 men died
after having a MI29. CHD-related mortality represented 31% of the deaths
in men, and 19% in women (25% in both)29.
In terms of burden of disease, CHD is considered to have the highest burden of disease worldwide in terms of disability-adjusted life years (DALYs)30. The occurrence of non-fatal CHD leads to impairment to work, which is a growing problem in developing countries31. There was
also an increase in years lived with disability in the period between 1990-201032 as a result of CHD. The increase of years lived with disability as a
14
What is CHD?
Coronary heart disease (CHD) is the most prevalent disease category among the cardiovascular diseases21. This category includes for
example, myocardial infarction (MI), sudden coronary death, and stable/unstable angina22. CHD is a consequence of ischemic heart disease (IHD), also known as coronary artery disease (CAD), although in practice, the terms CHD and CAD are used interchangeably. CAD is caused by the obstruction of the blood flow to the heart, which leads to the starvation of the myocardial cells due to oxygen depletion22. This process is known as
ischemia. Ischemia occurs primarily due to atherosclerosis in the carotid artery, which is the accumulation of white blood cells and propagation of intimal-smooth-muscle cell in the artery. This accumulation leads to the creation of a fatty plaque deposit and the loss of elasticity (stiffness) in the carotid artery. Figure 2 illustrates atherosclerosis of the coronary artery.
The typical symptoms of CHD are angina (chest pain) that often irradiates into the back, the shoulders and the arms; less often dyspnea (shortness of breath) or acid indigestion (heartburn). These symptoms last for a short period and frequently occur following stressful situations or situations of enhanced physical activity22.
Several risk factors have been reported in the literature23: namely diabetes, high blood pressure, smoking, alcohol consumption, unhealthy eating, lack of physical activity, etc. Treatment of CHD consists mainly of cardiovascular risk factors modification, achieved by smoking cessation, following a healthy diet and engaging in physical activity24. Surgical
procedures are also used in patients with increased disease severity, such as coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI)25. Moreover, pharmaceutical treatment is also commonly used, by the administration of anti-platelets drugs, such nitroglycerin, aspirin and beta-blockers26 and statins27.
17 deviation in a depression scale is associated with an increased risk of 28% for all-cause mortality, and an increased risk of 25% for having recurrent cardiovascular events44.
It has been hypothesized that the type of depression in patients with heart disease is not the same as in the general psychiatric population46. An integrative model, consisting of two prototypical forms of depression was proposed by Ormel and de Jonge46. These prototypical forms of depression differ in terms of etiology and prognosis: a cognitive/affective subtype, marked by psychosocial vulnerability (e.g. avoidant coping, neuroticism, stress vulnerability), and a somatic/affective subtype, characterized by vascular disease (e.g. atherosclerosis, inflammation markers, sickness behavior, and deregulation of the hypothalamic-pituitary-adrenal [HPA] axis). This model has been supported by a number of prospective longitudinal studies that investigated specific dimensions of depressive symptoms and their association with cardiovascular prognosis47-52.
Objectives of the present dissertation
The prospective association between depression and CHD has been studied for decades, and despite the fact that much research has been conducted, there are still many questions yet to be answered53.
Depression is a pleomorphic syndrome, and due to its heterogeneity in symptom profiles, investigating the pathways linking it to CHD is an arduous task, therefore the main objective of the present dissertation is to provide a comprehensive investigation on the association between depression and CHD, taking into account the heterogeneity of depressive symptoms. The present dissertation is structured in two sections, comprising five chapters that approach unresolved issues in the literature of the association between depression and CHD. Section 1 approaches the pathway of depressive symptoms as a prognostic marker for medical prognosis in CHD. Section 2 approaches the pathway of depressive symptoms as a consequence of CHD and subclinical cardiovascular disease. The structure of the present dissertation is illustrated at Figure 3. 16 result of CHD in low/middle income areas ranges between 13-100%, while in high income areas the increase ranges between 15-33%32. Depression and CHD
The association between depression and CHD has been steadily demonstrated through several pathways. A summary of these pathways is presented below:
(1) Depression is an etiologic risk marker for CHD.
In a meta-analysis of 21 studies, authors reported that individuals with depression have a 80% higher risk of developing CHD as compared with individuals without depression33, with its oldest study dating more than 30 years ago34. Several potential mechanisms have been suggested to explain
the link between depression and the increased risk for CHD. Some examples are proinflammatory cytokines, fibrinogen and plasminogen activator inhibitor-1 (i.e. coagulopathic factors)35; platelet receptors36 and
heart rate variability (i.e. autonomic nervous function)37. (2) CHD leads to increased levels of depression.
MDD is present in approximately 15% of the patients with cardiovascular disease38, which is approximately two to three times higher when
compared with individuals in the general population39,40. It has also been hypothesized that the increased prevalence of depression occurs due to the psychological burden of receiving a diagnosis of CHD41. Nonetheless, biological mechanisms explaining the increased prevalence of depression in patients with CHD have been suggested and therefore the possibility of a biological link cannot be ruled out42.
(3) Depression as a prognostic marker in CHD.
There is compelling evidence linking depression to adverse medical prognosis in patients with CHD33,43-45. Findings from a meta-analysis of
17 deviation in a depression scale is associated with an increased risk of 28% for all-cause mortality, and an increased risk of 25% for having recurrent cardiovascular events44.
It has been hypothesized that the type of depression in patients with heart disease is not the same as in the general psychiatric population46. An integrative model, consisting of two prototypical forms of depression was proposed by Ormel and de Jonge46. These prototypical forms of depression differ in terms of etiology and prognosis: a cognitive/affective subtype, marked by psychosocial vulnerability (e.g. avoidant coping, neuroticism, stress vulnerability), and a somatic/affective subtype, characterized by vascular disease (e.g. atherosclerosis, inflammation markers, sickness behavior, and deregulation of the hypothalamic-pituitary-adrenal [HPA] axis). This model has been supported by a number of prospective longitudinal studies that investigated specific dimensions of depressive symptoms and their association with cardiovascular prognosis47-52.
Objectives of the present dissertation
The prospective association between depression and CHD has been studied for decades, and despite the fact that much research has been conducted, there are still many questions yet to be answered53.
Depression is a pleomorphic syndrome, and due to its heterogeneity in symptom profiles, investigating the pathways linking it to CHD is an arduous task, therefore the main objective of the present dissertation is to provide a comprehensive investigation on the association between depression and CHD, taking into account the heterogeneity of depressive symptoms. The present dissertation is structured in two sections, comprising five chapters that approach unresolved issues in the literature of the association between depression and CHD. Section 1 approaches the pathway of depressive symptoms as a prognostic marker for medical prognosis in CHD. Section 2 approaches the pathway of depressive symptoms as a consequence of CHD and subclinical cardiovascular disease. The structure of the present dissertation is illustrated at Figure 3. 16 result of CHD in low/middle income areas ranges between 13-100%, while in high income areas the increase ranges between 15-33%32. Depression and CHD
The association between depression and CHD has been steadily demonstrated through several pathways. A summary of these pathways is presented below:
(1) Depression is an etiologic risk marker for CHD.
In a meta-analysis of 21 studies, authors reported that individuals with depression have a 80% higher risk of developing CHD as compared with individuals without depression33, with its oldest study dating more than 30 years ago34. Several potential mechanisms have been suggested to explain
the link between depression and the increased risk for CHD. Some examples are proinflammatory cytokines, fibrinogen and plasminogen activator inhibitor-1 (i.e. coagulopathic factors)35; platelet receptors36 and
heart rate variability (i.e. autonomic nervous function)37. (2) CHD leads to increased levels of depression.
MDD is present in approximately 15% of the patients with cardiovascular disease38, which is approximately two to three times higher when
compared with individuals in the general population39,40. It has also been hypothesized that the increased prevalence of depression occurs due to the psychological burden of receiving a diagnosis of CHD41. Nonetheless, biological mechanisms explaining the increased prevalence of depression in patients with CHD have been suggested and therefore the possibility of a biological link cannot be ruled out42.
(3) Depression as a prognostic marker in CHD.
There is compelling evidence linking depression to adverse medical prognosis in patients with CHD33,43-45. Findings from a meta-analysis of
19 artery bypass graft (CABG) surgery reported an association of cognitive/affective but not somatic/affective symptoms of depression with cardiovascular mortality47 and recurrent cardiovascular events58. In
chapter 2, a meta-analysis of prognostic studies was conducted as an attempt to aggregate these studies reporting mixed findings and to answer the following question: are cognitive/affective and somatic/affective symptoms of depression differentially associated with medical prognosis in patients with CHD?
One criticism of using symptom dimensions of depression is that these dimensions are still indicative of a general depression factor, and that they are not different constructs59. A possible solution to address this
issue is by using bifactor factor analysis to estimate scores of depressive symptom severity60-63. In chapter 3, the following research questions were
attempted to be answered: (1) does the BDI fits a bifactor structure consisting of a general depression factor, a general depression-free cognitive/affective factor and a general depression-free somatic/affective factor in patients with MI? (2) is the general depression factor associated with adverse medical prognosis independent of general depression-free cognitive/affective and general depression-free somatic/affective symptoms? (3) are the general depression-free cognitive/affective and the general depression-free somatic/affective factors associated with adverse medical prognosis? For this purpose, we used data of the MINDMAPS, an individual patient database of studies assessing the association between depression and cardiac prognosis in patients with MI across several countries44. IPD meta-analysis offers several advantages as compared to a
regular meta-analysis, including standardization of the analyses64.
Although using symptom dimensions partially addresses the issue of the heterogeneity of depression symptomatology, the picture gets even more complex when looking at individual symptom profiles. A study conducted in clinically depressed participants found 1,030 different symptoms profiles while assessing the symptoms included in the DSM-V criteria65. A solution researchers found for addressing this issue is
individual item-level analysis, which basically consists of assessing the prognostic value for each symptom of a depression scale66. 18 Table 1. Structure of the dissertation
Part I
Part II
“Depressive symptoms as a prognostic marker for medical prognosis in cardiovascular disease.” “Depressive symptoms as a consequence of cardiovascular disease.” Chapter 2 Chapter 5 Chapter 3 Chapter 6 Chapter 4 Depressive symptoms as a prognostic risk marker of medical prognosis in CHD It has been demonstrated in several meta-analyses that post-CHD depression is associated with adverse medical prognosis33,43-45. However,sum scores of depressive symptoms are potentially inflated by the influence of somatic illness on somatic items54. The use of symptom
dimensions of depression, namely cognitive/affective (e.g. pessimism, guilt and self-dislike) and somatic/affective (e.g. insomnia, fatigue and work difficulty), in opposition to total scores was a solution researchers found to address this problem50,55. A significant association between somatic/affective symptoms of depression and cardiovascular mortality among MI patients was reported, even after adjustment for somatic health status56. By contrast, cognitive/affective depressive symptoms were not
predictive of adverse outcomes. The same pattern of findings was reported in other studies in MI patients and patients with acute coronary syndrome49,57. However, two studies in patients undergoing coronary
19 artery bypass graft (CABG) surgery reported an association of cognitive/affective but not somatic/affective symptoms of depression with cardiovascular mortality47 and recurrent cardiovascular events58. In
chapter 2, a meta-analysis of prognostic studies was conducted as an attempt to aggregate these studies reporting mixed findings and to answer the following question: are cognitive/affective and somatic/affective symptoms of depression differentially associated with medical prognosis in patients with CHD?
One criticism of using symptom dimensions of depression is that these dimensions are still indicative of a general depression factor, and that they are not different constructs59. A possible solution to address this
issue is by using bifactor factor analysis to estimate scores of depressive symptom severity60-63. In chapter 3, the following research questions were
attempted to be answered: (1) does the BDI fits a bifactor structure consisting of a general depression factor, a general depression-free cognitive/affective factor and a general depression-free somatic/affective factor in patients with MI? (2) is the general depression factor associated with adverse medical prognosis independent of general depression-free cognitive/affective and general depression-free somatic/affective symptoms? (3) are the general depression-free cognitive/affective and the general depression-free somatic/affective factors associated with adverse medical prognosis? For this purpose, we used data of the MINDMAPS, an individual patient database of studies assessing the association between depression and cardiac prognosis in patients with MI across several countries44. IPD meta-analysis offers several advantages as compared to a
regular meta-analysis, including standardization of the analyses64.
Although using symptom dimensions partially addresses the issue of the heterogeneity of depression symptomatology, the picture gets even more complex when looking at individual symptom profiles. A study conducted in clinically depressed participants found 1,030 different symptoms profiles while assessing the symptoms included in the DSM-V criteria65. A solution researchers found for addressing this issue is
individual item-level analysis, which basically consists of assessing the prognostic value for each symptom of a depression scale66. 18 Table 1. Structure of the dissertation
Part I
Part II
“Depressive symptoms as a prognostic marker for medical prognosis in cardiovascular disease.” “Depressive symptoms as a consequence of cardiovascular disease.” Chapter 2 Chapter 5 Chapter 3 Chapter 6 Chapter 4 Depressive symptoms as a prognostic risk marker of medical prognosis in CHD It has been demonstrated in several meta-analyses that post-CHD depression is associated with adverse medical prognosis33,43-45. However,sum scores of depressive symptoms are potentially inflated by the influence of somatic illness on somatic items54. The use of symptom
dimensions of depression, namely cognitive/affective (e.g. pessimism, guilt and self-dislike) and somatic/affective (e.g. insomnia, fatigue and work difficulty), in opposition to total scores was a solution researchers found to address this problem50,55. A significant association between somatic/affective symptoms of depression and cardiovascular mortality among MI patients was reported, even after adjustment for somatic health status56. By contrast, cognitive/affective depressive symptoms were not
predictive of adverse outcomes. The same pattern of findings was reported in other studies in MI patients and patients with acute coronary syndrome49,57. However, two studies in patients undergoing coronary
21
Depressive symptoms as a consequence of subclinical cardiovascular disease and CHD
It is already well established that depression in patients with CHD is 2 to 3 times higher than in the general population39,40. One could argue
that this is an obvious link; receiving a diagnosis of one of the world’s leading causes of death should be very saddening, which could explain this increased prevalence. Being diagnosed with CHD implies making substantial life changes, such as eating healthier and the daily use of medications. Nonetheless, researchers have also made efforts to investigate whether the link between cardiovascular health and increased levels of depression also occurs regardless of getting a diagnosis of CHD. Some potential biological mechanisms are increased platelet activation, inflammatory biomarkers, such as Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP)35, autonomic nervous function (i.e. heart rate variability)37,76 and endothelial function42.
Several studies investigated whether subclinical cardiovascular disease is associated with depression and findings were mixed. Some studies reported an association between subclinical cardiovascular disease and depression77-79, while others did not80,81. In these studies, subclinical cardiovascular disease was usually assessed through carotid intima-media thickness (CIMT)77 or arterial stiffness82. Both CIMT83-85 and arterial
stiffness86-88 are associated with the onset of CHD. The use of markers of
subclinical cardiovascular disease poses as an interesting way to study the etiology of depression in patients with CHD, as in this case patients are not aware of their condition, and therefore there is not a confounding effect of the psychological burden being diagnosed with a severe disease. Studying the link between depression and CHD in a group that is not severely ill can help to identify whether underlying disease mechanisms are linked to depression. A previous study reported that CIMT is associated with the progression of depressive symptoms in a large sample of elderly French participants 89. However, another study performed in a sample of
Dutch elderly participants has found no association between CIMT and progression of depressive symptoms90. A main limitation of these studies is the use of sum scores of depressive symptoms. Sum scores of depressive symptoms in participants with potential somatic comorbidities run into the 20 Patients with MI are also very heterogeneous. Older patients tend to have a worsened clinical profile in terms of cardiomyocyte renewal capacity, cardiac dysfunction, history of previous MI, left-ventricular ejection fraction (LVEF) ≤ 40, and Killip class >1 as compared to younger patients66,67. Nonetheless, older patients tend to follow a healthier lifestyle
in terms of smoking68 or substance misuse69 as compared to younger
patients70. Sex is also a potential effect modifier in the association between depression and medical prognosis in patients with MI71. Men and women have important differences in terms of age of onset, cardiac-related symptomatology, comorbidities, time of hospitalization and risk of mortality72-74.
Chapter 4 attempts to address the issue of the heterogeneity of individual symptoms of depression and its prognostic value in patients with MI, taking into account the heterogeneity of patients from different age and sex groups. For this purpose, we used the MINDMAPS database, and conducted individual-item level analysis of the BDI10, a short version of the BDI designed to assess 10 symptoms in cardiac patients across three dimensions of depression75: core symptoms (sadness and hopelessness);
negative self-view (sense of failure, self-dislike, suicidal ideas and negative
body-image change), and lack of satisfaction/energy (dissatisfaction, indecisiveness, work inhibition and fatigue). Therefore, in chapter 4, the following research question was attempted to be answered: are there interaction effects between age, sex and individual depressive symptoms in the association with all-cause mortality following MI.
21
Depressive symptoms as a consequence of subclinical cardiovascular disease and CHD
It is already well established that depression in patients with CHD is 2 to 3 times higher than in the general population39,40. One could argue
that this is an obvious link; receiving a diagnosis of one of the world’s leading causes of death should be very saddening, which could explain this increased prevalence. Being diagnosed with CHD implies making substantial life changes, such as eating healthier and the daily use of medications. Nonetheless, researchers have also made efforts to investigate whether the link between cardiovascular health and increased levels of depression also occurs regardless of getting a diagnosis of CHD. Some potential biological mechanisms are increased platelet activation, inflammatory biomarkers, such as Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP)35, autonomic nervous function (i.e. heart rate variability)37,76 and endothelial function42.
Several studies investigated whether subclinical cardiovascular disease is associated with depression and findings were mixed. Some studies reported an association between subclinical cardiovascular disease and depression77-79, while others did not80,81. In these studies, subclinical cardiovascular disease was usually assessed through carotid intima-media thickness (CIMT)77 or arterial stiffness82. Both CIMT83-85 and arterial
stiffness86-88 are associated with the onset of CHD. The use of markers of
subclinical cardiovascular disease poses as an interesting way to study the etiology of depression in patients with CHD, as in this case patients are not aware of their condition, and therefore there is not a confounding effect of the psychological burden being diagnosed with a severe disease. Studying the link between depression and CHD in a group that is not severely ill can help to identify whether underlying disease mechanisms are linked to depression. A previous study reported that CIMT is associated with the progression of depressive symptoms in a large sample of elderly French participants 89. However, another study performed in a sample of
Dutch elderly participants has found no association between CIMT and progression of depressive symptoms90. A main limitation of these studies is the use of sum scores of depressive symptoms. Sum scores of depressive symptoms in participants with potential somatic comorbidities run into the 20 Patients with MI are also very heterogeneous. Older patients tend to have a worsened clinical profile in terms of cardiomyocyte renewal capacity, cardiac dysfunction, history of previous MI, left-ventricular ejection fraction (LVEF) ≤ 40, and Killip class >1 as compared to younger patients66,67. Nonetheless, older patients tend to follow a healthier lifestyle
in terms of smoking68 or substance misuse69 as compared to younger
patients70. Sex is also a potential effect modifier in the association between depression and medical prognosis in patients with MI71. Men and women have important differences in terms of age of onset, cardiac-related symptomatology, comorbidities, time of hospitalization and risk of mortality72-74.
Chapter 4 attempts to address the issue of the heterogeneity of individual symptoms of depression and its prognostic value in patients with MI, taking into account the heterogeneity of patients from different age and sex groups. For this purpose, we used the MINDMAPS database, and conducted individual-item level analysis of the BDI10, a short version of the BDI designed to assess 10 symptoms in cardiac patients across three dimensions of depression75: core symptoms (sadness and hopelessness);
negative self-view (sense of failure, self-dislike, suicidal ideas and negative
body-image change), and lack of satisfaction/energy (dissatisfaction, indecisiveness, work inhibition and fatigue). Therefore, in chapter 4, the following research question was attempted to be answered: are there interaction effects between age, sex and individual depressive symptoms in the association with all-cause mortality following MI.
23 For this purpose, data from the Lifelines study was used96 . A cross-sectional design was used for this investigation, which does not leave room for inferring on the causality of this association. Nonetheless, conducting such an investigation could help obtaining a better comprehension of whether the association between CHD and depression is dependent on the psychological burden of having a diagnosis of MI.
Lastly, in chapter 7 a summary of the main findings of each of the investigations conducted throughout this dissertation will be presented. Further a discussion on translational implications for clinical practice, methodological issues and recommendations for future research will be reported.
22
risk of overestimating the scores due to inflation caused by somatic/affective symptoms54,56. Therefore, the following question was
attempted to be answered in chapter 5: are markers of subclinical cardiovascular disease, namely CIMT and arterial stiffness, associated with the progression of mood/cognition and anxiety/somatic symptom dimensions of depression? For this purpose, a longitudinal study using repeated measures of depressive symptoms was conducted in a sub sample of the Netherlands Study of Depression and Anxiety (NESDA)91. The NESDA study includes Dutch participants with and without depressive/anxiety disorders, followed up through several measurement waves. Another possible way to investigate whether the increased prevalence of depression in patients with CHD occurs due to awareness of its somatic condition is by assessing the risk of having depression in individuals with unrecognized CHD. Mostly, a MI is experienced in an acute way, including symptoms like sweating, nausea and chest pain92. Nonetheless, a MI can
also be asymptomatic or accompanied by minor and atypical symptoms93,94. Due to this absence of symptoms, the MI remains clinically undetected until routine electrocardiogram (ECG) examinations are performed95. This phenomenon is known as “silent MI” or “unrecognized MI”.
The risk for depression in individuals with recognized and unrecognized MI has been investigated in older participants and findings suggested that only men with recognized MI are at a higher risk of depression41. These findings suggest that the awareness of having a severe disease such as MI explains the increased prevalence of depression in patients with CHD. Nonetheless, this study has several limitations, namely: (1) the association was only investigated in older participants; (2) the confounding effect of somatic/affective symptoms of depression has not been accounted for.
In chapter 6, the following research question was attempted to be answered: (1) Is the risk of having depressive/anxiety disorders significantly higher for individuals with recognized MI as compared with individuals with unrecognized MI and without MI.
23 For this purpose, data from the Lifelines study was used96 . A cross-sectional design was used for this investigation, which does not leave room for inferring on the causality of this association. Nonetheless, conducting such an investigation could help obtaining a better comprehension of whether the association between CHD and depression is dependent on the psychological burden of having a diagnosis of MI.
Lastly, in chapter 7 a summary of the main findings of each of the investigations conducted throughout this dissertation will be presented. Further a discussion on translational implications for clinical practice, methodological issues and recommendations for future research will be reported.
22
risk of overestimating the scores due to inflation caused by somatic/affective symptoms54,56. Therefore, the following question was
attempted to be answered in chapter 5: are markers of subclinical cardiovascular disease, namely CIMT and arterial stiffness, associated with the progression of mood/cognition and anxiety/somatic symptom dimensions of depression? For this purpose, a longitudinal study using repeated measures of depressive symptoms was conducted in a sub sample of the Netherlands Study of Depression and Anxiety (NESDA)91. The NESDA study includes Dutch participants with and without depressive/anxiety disorders, followed up through several measurement waves. Another possible way to investigate whether the increased prevalence of depression in patients with CHD occurs due to awareness of its somatic condition is by assessing the risk of having depression in individuals with unrecognized CHD. Mostly, a MI is experienced in an acute way, including symptoms like sweating, nausea and chest pain92. Nonetheless, a MI can
also be asymptomatic or accompanied by minor and atypical symptoms93,94. Due to this absence of symptoms, the MI remains clinically undetected until routine electrocardiogram (ECG) examinations are performed95. This phenomenon is known as “silent MI” or “unrecognized MI”.
The risk for depression in individuals with recognized and unrecognized MI has been investigated in older participants and findings suggested that only men with recognized MI are at a higher risk of depression41. These findings suggest that the awareness of having a severe disease such as MI explains the increased prevalence of depression in patients with CHD. Nonetheless, this study has several limitations, namely: (1) the association was only investigated in older participants; (2) the confounding effect of somatic/affective symptoms of depression has not been accounted for.
In chapter 6, the following research question was attempted to be answered: (1) Is the risk of having depressive/anxiety disorders significantly higher for individuals with recognized MI as compared with individuals with unrecognized MI and without MI.
25 11. Robins L, Helzer J, Croughan J, Ratcliff K. National-institute-of-mental-health diagnostic interview schedule - its history, characteristics, and validity. Arch Gen Psychiatry. 1981;38(4):381-389. 12. ROBINS L, WING J, WITTCHEN H, et al. The composite international diagnostic interview - an epidemiologic instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry. 1988;45(12):1069-1077. 13. Sheehan D, Lecrubier Y, Sheehan K, et al. The mini-international neuropsychiatric interview (MINI): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59:22-33. 14. Sharp LK, Lipsky MS. Screening for depression across the lifespan: A review of measures for use in primary care settings. Am Fam Physician. 2002;66(6):1001-1008. 15. Beck AT, Steer RA. Beck depression inventory: Manual. New York: Psychological Corporation; 1987. 16. Beck, AT. Steer, RA. Brown, GK. Manual for the beck depression inventory-II. San Antonio, TX.: Psychological Corporation.; 1996. 17. Kroenke K, Spitzer R, Williams J. The PHQ-9 - validity of a brief depression severity measure. Journal of General Internal Medicine. 2001;16(9):606-613. 18. Rush A, Gullion C, Basco M, Jarrett R, Trivedi M. The inventory of depressive symptomatology (IDS): Psychometric properties. Psychol Med. 1996;26(3):477-486. 19. de Miranda Azevedo R, Roest AM, Hoen PW, de Jonge P. Cognitive/affective and somatic/affective symptoms of depression in patients with heart disease and their association with cardiovascular prognosis: A meta-analysis. Psychol Med. 2014:1-15. 20. Beck AT, Steer RA, Carbin MG. Psychometric properties of the beck depression inventory: Twenty-five years of evaluation. Clin Psychol Rev. 1988;8(1):77-100. 24 REFERENCES 1.Hare DL, Toukhsati SR, Johansson P, Jaarsma T. Depression and cardiovascular disease: A clinical review. Eur Heart J. 2014;35(21):1365-1372. doi: 10.1093/eurheartj/eht462. 2.American Psychiatric Association., American Psychiatric Association.,DSM-5 Task Force.,. Diagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C.: American Psychiatric Association; 2013. 3.World Health Organisation. ICD-10 classifications of mental and behavioural disorder: Clinical descriptions and diagnostic guidelines. Geneva.: World Health Organisation.; 1992. 4.Houts AC. Fifty years of psychiatric nomenclature: Reflections on the 1943 war department technical bulletin, medical 203. J Clin Psychol. 2000;56(7):935-967. 5.American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 1st ed. Washington, DC: American Psychiatric Association; 1952. 6.Highlights of changes from DSM-IV to DSM-5. In: American Psychiatric Association; 2013. http://dx.doi.org/10.1176/appi.books.9780890425596.changes. doi:10.1176/appi.books.9780890425596.changes. 7.Center for Behavioral Health Statistics and Quality. Behavioral health trends in the united states: Results from the 2014 national survey on drug use and health. http://www.samhsa.gov/data/. Updated 2015. Accessed 04/03, 2016. 8.de Graaf R, ten Have M, van Gool C, van Dorsselaer S. Prevalence of mental disorders and trends from 1996 to 2009. results from the netherlands mental health survey and incidence study-2. Soc Psychiatry Psychiatr Epidemiol. 2012;47(2):203-213. 9.Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442. 10. First, MB. Spitzer, RL. Gibbon, M. Williams, JB. Structured clinical interview for DSM-IV axis I disorders-patient edition (SCID-I/P, version 2.0).. New York, NY: New York State.: Psychiatric Institute.; 1995.
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