Depression in Patients With Heart Failure: Prevalence, Pathophysiological Mechanisms, and Treatment

Detect depression in patients with heart failure using a symptom inventory and an interview to confirm the results.As treatment of cardiovascular diseases improves and the population ages, the incidence and prevalence of heart failure are increasing. More than 5 million patients in the United States are living with heart failure, and 550 000 new cases are diagnosed each year.1 The estimated prevalence of depression is 100 cases per 1000 persons in the population more than 65 years old.2 Strong evidence3–11 links depression to increased morbidity and mortality in patients with coronary heart disease, the underlying cause of half of the cases of heart failure. Depression is associated with mortality in outpatients,12–15 inpatients,16 and hospitalized patients who have heart failure.17,18 The association of depression with mortality in these patients is independent of anxiety and social isolation. In a sample of patients (N=153) enrolled in the Sudden Cardiac Death in Heart Failure Trial, depression (P=.02, hazard ratio=2.2) was an independent predictor of mortality after controls for significant demographic and clinical predictors of mortality, anxiety, social support, and treatment group.13 On the basis of analysis via the Cox proportional hazards model, patients with mild depression were 2.2 times as likely to die as those who were not depressed.13 Mortality due to all causes was 12% for patients with depression and 9% for others.13In this article, we describe a holistic model for cardiovascular health and apply it to depression in heart failure, summarize the pathophysiological changes in depression that may contribute to increased morbidity and mortality of patients with heart failure, and review the growing literature on the prevalence of depression in patients with heart failure. We also discuss assessment of depression in patients with heart failure and implications for nursing practice. Future research is proposed.Thomas et al11,19–22 have proposed a holistic model of cardiovascular health in which biological, psychological, and social realms interact within each person and are integrated into health (Figure 1). Health interacts with factors in each realm to affect all other realms. Acute and chronic shifts in each realm affect health status, and health status affects biological, social, and psychological factors. Psychosocial factors either promote health by moderating pathological processes or promote disease by enhancing the processes. In the psychological realm, depression, anxiety, and life stress diminish health.11,13 In the social realm, social support and pet ownership promote health.13,23–25 Social and psychological factors affect the biological factors. Depression alters levels of cortisol, catecholamines, and cytokines; autonomic neurocardiac regulation; and factors that influence cardiovascular functioning. The holistic model provides the basis for a dynamic interactive approach to the assessment and treatment of depression in patients with heart failure.Examination of the physiology of depression in patients with heart failure illustrates the integration of physiological and psychological factors in cardiovascular health. Depression causes physiological changes that are associated with increased morbidity and mortality in patients with heart failure.22 Four pathological patterns that occur in depressed patients correspond to the pathogenesis of heart failure: neurohormonal activation,26,27 hyper-coagulability,26,27 autonomic neurocardiac dysfunction,26,27 and cytokine release27 (Figure 2). These pathophysiological changes are thought to mediate the increased risk for cardiac events in people who are depressed and the subsequent poor prognosis if such events occur.27–29Endogenous neurohormones are activated in patients with heart failure as a result of increased left ventricular filling pressure that stimulates the activation of norepinephrine, renin-angiotensin-aldosterone, vasopressin, and endothelin 1. Activation of these systems results in both vasoconstriction and volume expansion.28,30,31Patients with depression experience increased activation of the nervous system via hyperreactivity of the hypothalamic-pituitary-adrenal axis, leading to increased release of cortisol into the bloodstream.26,27 Elevated levels of serum cortisol cause high blood pressure, high levels of blood lipids, insulin resistance, and abdominal obesity.26,27 Over time, these factors have a long-term deleterious effect.Hyperactivity of the hypothalamic-pituitary-adrenal axis also mediates hyperreactivity of the sympathetic nervous system as indicated by elevated plasma levels of norepinephrine and increased catecholamine response to orthostatic challenge.32,33 Evidence supports a relationship between mortality and increased levels of catecholamines, most likely a result of a decrease in the number of β1-adrenergic receptor sites, decreased sensitivity to adrenergic stimulation, inadequate myocardial remodeling, myocardial toxic effects, and increased tendency for ventricular arrhythmias.27,28,30,31 Additional research is needed to determine if catecholamine levels are elevated in patients with heart failure who are depressed.Both hypercortisolism and increased norepinephrine levels increase blood coagulation. Hyper-cortisolism causes increases in the levels of factor VIII and von Willebrand factor and a decrease in fibrinolysis. Elevated norepinephrine levels are associated with increased coagulation and fibrinolysis.34Increased platelet aggregation in cardiac patients who are depressed increases their vulnerability to thrombus formation, myocardial infarction, and stroke.28 Evidence of the effects of coagulation abnormalities in patients with heart failure is inconclusive. Abnormalities in platelet function in patients with untreated depression may cause platelet aggregation, leading to thrombus formation.35 Patients with depression have increases in the number of platelet receptors for serotonin 5-HT2A.36,37 Even though the relationship between these receptors and platelet activation is not known, platelet reactivity is reduced in patients treated with selective serotonin reuptake inhibitors (SSRIs), one type of antidepressant.38 Additional research is needed to determine the relationship between depression, platelets, and outcomes for patients with heart failure.27Changes in autonomic neurocardiac regulation occur both in patients with depression and in patients with heart failure. In heart failure and depression, patients experience increased sympathetic activity as well as decreased parasympathetic activity. In the healthy heart, the parasympathetic nervous system works as a homeostatic mechanism to balance sympathetic cardiac stimulation. Because of decreased parasympathetic activity in depression and heart failure, patients with these conditions are more likely to experience cardiac arrhythmias than are patients with other abnormalities. Heart rate variability, a measure of beat-to-beat alterations in heart rate, is used to measure autonomic neurocardiac dysfunction.39 The time domain measure of heart rate variability,40 which is the standard deviation of all normal-to-normal R-to-R intervals in a 24-hour period, strongly reflects circadian rhythms, as well as neuroendocrine rhythms, activity, and other factors.41 The normal standard deviation is greater than 100 milliseconds.42 Reduced heart rate variability correlates with reduced parasympathetic activity or decreased vagal tone and with increased mortality.41,43–46 Depression is associated with reduced heart rate variability in patients with heart failure.47,48Cytokines are low-molecular-weight proteins that function as chemical communicators within and between cells. Although all of the mechanisms of actions of cytokines are not yet conclusively established, evidence indicates that these proteins are critical components in the immune response.49 According to their role in the immune response and inflammation, cytokines are categorized as proinflammatory or anti-inflammatory.50 The unique receptors for cytokines promote or inhibit the activities of these proteins. Cytokine inhibitors decrease potential tissue injuries by limiting a prolonged inflammatory response. Proinflammatory cytokines include interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α). Levels of IL-1, IL-6, and TNF-α are elevated in patients with heart failure.Three mechanisms are proposed to explain the actions of proinflammatory cytokines in heart failure. The first possibility is that cytokines are activated in response to the myocardial injury that triggers heart failure.50 The second possibility is that the heart is the source of TNF-α. This increase in TNF-α triggers a secondary activation of the immune system by triggering the hypothalamic-pituitary-adrenal axis and thereby increasing levels of corticosteroids.51 The third possibility is that the decreased cardiac output in heart failure causes underperfusion of systemic tissues and leads to the elaboration of TNF-α. Edema of the gut wall allows translocation of endotoxin, which in turn induces cytokine production.52Serum levels of IL-1, IL-6, and TNF-α are elevated in patients with major depression.53 Elevation in cytokines produces inflammation. The end result of the inflammation is left ventricular remodeling, contractile dysfunction, and uncoupling of myocardial β-adrenergic receptors. TNF-α increases pulmonary vascular permeability and pulmonary edema and produces myocardial necrosis.54The overlapping signs and symptoms of depression and heart failure make the diagnosis of depression in patients with heart failure challenging.55–57 It is often unclear whether a patient’s signs and symptoms indicate heart failure or heart failure with depression.55–57The essential feature required for the diagnosis of depression, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), the most recently published criteria for the diagnosis of psychiatric disorders, is a period of at least 2 weeks with depressed mood or a loss of interest in pleasurable activities58 (Table 1). A person with heart failure often has both of these symptoms because of the decreased cardiac output49 that accompanies heart failure. Decreased cardiac output leads to poor physical functioning. Poor physical function is associated with depressed mood and loss of interest, particularly in younger patients.57 Once this criterion is met, the diagnosis of clinical depression depends on the presence of 7 additional signs and symptoms. The presence of any 4 of them is required for a diagnosis of major depression and any 3 of them for a diagnosis of minor depression. Lack of appetite and weight loss in patients with heart failure may be a consequence of decreased mesenteric circulation and diminished ability to absorb nutrients.49 Weight gain is a consequence of water retention in heart failure.49 Hypersomnia, or sleeping for prolonged periods during the day, may also occur in patients with heart failure as a consequence of compromised cardiac output and low energy levels.49 Fatigue or loss of energy is a core symptom of both depression55,56 and heart failure.49 Patients with heart failure often report restlessness or insomnia at night caused by shortness of breath, orthopnea (degree of shortness of breath when lying flat), and paroxysmal nocturnal dyspnea (being awakened from sleep by shortness of breath).49 In a study by Redeker,55 when demographics, comorbid conditions, and physical function were controlled for, differences in depression between patients with heart failure and a control group of members of the community were explained by sleep disturbances, fatigue, and excessive daytime sleepiness. Feelings of worthlessness, trouble concentrating, and thoughts of dying can be caused by the poor general quality of life that often accompanies progressive heart failure.59,60The 2 major challenges in evaluating depression in patients with heart failure are the setting in which the assessment is conducted and the variety of methods and tools used to measure depression.Depression in patients with heart failure is assessed in either the hospital or the outpatient setting. When patients with heart failure are hospitalized, the purpose is to address acute exacerbations of the signs and symptoms of heart failure. The pathological changes that occur as a result of the episodes that lead to hospitalization can increase the signs and symptoms of depression.22 Once the heart failure is under control, the depressive signs and symptoms may abate. Assessment of depression in patients with heart failure is more reliable in outpatients whose signs and symptoms of heart failure are more stable.Two basic methods are used to assess depression: structured diagnostic interviews conducted by trained clinicians and symptom inventory self-reports by patients. Diagnostic interviews are designed to categorize individuals as meeting or not meeting the DSM-IV criteria for major and minor depression. Diagnostic interviews must be conducted by trained mental health professionals, including nurses with appropriate training, who are unfamiliar to the patient. In face-to-face interviews, the level of depression may be underestimated because patients are reluctant to admit to symptoms of depression.61,62 Structured diagnostic interviews are time and personnel intensive.61,62The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)63 and the Diagnostic Interview Schedule (DIS)64,65 are the 2 interviews used most often to detect major depression. The SCID-I is a semistructured interview designed to assess an individual’s experience, either lifetime or current, of categorically defined DSM-IV Axis I psychiatric disorders, including mood and anxiety disorders.63 The SCID-I takes 45 to 90 minutes to complete. The interrater reliability and test-retest reliability (κ statistic) for major depressive disorder were 0.80 and 0.61, respectively, for the patients’ edition.66 The DIS is the fully structured questionnaire designed to provide reliable and valid detection of psychiatric disorders on the basis of the DSM-IV.64,65 The DIS takes 90 to 120 minutes to administer. With the SCID-I as a clinical standard, the sensitivity and specificity were 0.25 and 0.98, respectively.67 Interrater reliabilities (κ statistic) of SCID-I for major depressive episode, suicidal ideation, and suicide attempts were 0.67, 0.76, and 0.80, respectively.68Self-report symptom inventories provide quantification of the number and severity of depressive symptoms a person is experiencing during a specified time in relation to the continuum of possible symptom experience. 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