The 12-month prevalence of the mental disorders in the general European population is between 27% and 38%. All mental disorders are associated with the development of cardiovascular disease and with a decreased life expectancy for both genders(1). The 12-month prevalence of mental disorders in patients with cardiovascular disease (CVD) is 40%. The prognosis is worse(1).
The most common psychiatric problems in patients with heart disease are adjustment disorders, anxiety disorders, depressive disorders, neurocognitive disorders (delirium and dementia) and posttraumatic stress disorder(2).
Patients who undergo long-term treatment with antipsychotic medications are at risk for heart disease due to metabolic side effects. Nicotine dependence, substance use disorders and sexual disfunction may be also issues that require intervention(2).
Several studies have demonstrated that one in three patients with cardiovascular disease suffers from depression, and depression increases the likelihood for cardiac morbidity and mortality in the CVD population by 2-3-fold, independently of traditional risk factors or gender(4).
Major depression is a highly prevalent condition, affecting approximately 10% of the population(3). It is also a growing global issue(2) and it has been consistently associated with an increased risk of coronary heart disease (CHD)(3). It is therefore not surprising that depression is highly comorbid with CHD, being two to three times more common among patients with coronary heart disease than in the general population. The prevalence of depression is 15-30% in patients with CHD(4), and is approximately twice as high in women than men, especially affecting young women in the aftermath of acute myocardial infarction (MI)(3). Depression as a risk factor for CHD has been characterized from mild depressive symptoms to a clinical diagnosis of major depression(3).
In CHD patients, depression is also associated with the severity of functional impairment, with a lower adherence to therapy and with a lower participation in cardiac rehabilitation(3).
The literature provides evidence for an association between clinical depression (or depressive symptoms) and coronary heart disease. This link is seen in individuals initially free of CHD and in a variety of CHD patient populations, including patients with acute coronary syndromes (ACS), heart failure, stable CHD, and post-coronary bypass surgery(3).
However, individual studies have produced heterogeneous risk estimates and have varied in their ability to adjust for other factors such as smoking, physical inactivity, other risk factors and the severity of CHD. Indeed, depression is associated with several CHD risk factors and health behaviors as described above. In statistical models that adjust for these risk factors, depression usually remains an independent risk factor for coronary heart disease, suggesting a biological relationship between these two disease states that remains in part unexplained by an increase in the traditional risk factors or lifestyle behaviors(3).
In one of the relatively recent meta-analyses, which included 30 prospective cohort studies of individuals initially free of CHD, depression was associated with a 30% increased risk of future coronary events. The association remained significant in the group of studies that adjusted for sociodemographic factors and lifestyle behaviors. In community samples and in general practice clinics, the rate of depression is about 10%, but it goes up to about 15-30% in patients with coronary heart disease(3).
Studies have also suggested that specific subtypes of depression may be more strongly associated with CHD risk than others. For instance, patients with a new onset of depression after ACS, with treatment resistant depression, or with somatic depressive symptoms as opposed to cognitive symptoms, are all at an increased risk of developing adverse CHD outcomes.
Among women, depression is approximately twice as prevalent as in men, and has shown some of the most robust associations with coronary heart disease. Depression in women is also, on average, more severe than in men and has an earlier age of onset. Women with CHD similarly have twice the rates of depression as men with CHD. The condition is especially common in young women who have survived a myocardial infarction; about half of women younger than 60 years old with a previous myocardial infarction have a history of major depression. Of note, young women are more likely to die from myocardial infarction than men. Depression is linked to early life adversities and psychological trauma, which tend to be more common in girls than boys, and may result in chronic dysregulation of neurohormonal stress systems. This may begin at an early age, setting the stage for an increase in cardiovascular risk in women many years before CHD becomes manifest.
Among women, depression increases their risk for coronary heart disease between 30% and two-fold, depending on depression measures and on CHD endpoints.
In the Third National Health and Nutrition Examination Survey (NHANES III), a history of major depression or suicide attempt was associated with an almost 15-fold increased risk of ischemic heart disease among women and with a 3.5-fold increase in men. In the prospective Community Mental Health Epidemiology Study of Washington County, women younger than 40 years old with depression had a six-fold increased risk of coronary heart disease compared with women of the same age without depression, while depression was not associated with CHD in men or older individuals. Even among patients referred for coronary angiography, depression is more predictive of adverse cardiovascular outcomes in young women than in other groups.
After an acute myocardial infarction, however, depression seems to affect prognosis to a similar extent in women and men. Overall, the evidence suggests that depression is more closely associated with coronary heart disease for women than for men, with the strongest effects for younger women.
Clinical and prognostic considerations(3)
Depression as a prognostic factor in acute coronary syndromes
Despite some heterogeneity of findings, the bulk of the evidence supports the notion that depression after acute coronary syndromes is a risk factor for all-cause and cardiac mortality, as well as for composite outcomes, including mortality or non-fatal cardiac events(4). Among patients hospitalized for ACS, the increased risk occurs regardless of whether depression predated the ACS event or it developed subsequently, although some evidence suggests that that depressive episodes which develop soon after an acute coronary syndrome may carry a higher risk than episodes that begin before the event. Depression is also a major determinant of unplanned rehospitalizations within 30 days after a hospital discharge for MI.
Depressive episodes that do not respond to standard treatments have also been identified as high-risk subtypes. However, evidence suggests that the recognition and treatment of depression improve prognosis. In a previous study, patients with depression that was recognized or treated during a myocardial infarction hospitalization or at discharge had similar one-year mortality than those without depression, while a higher mortality was confined to patients with untreated depression. These data are important since depression in ACS patients is frequently underrecognized and untreated.
During the first year after myocardial infarction, the presence of depression is associated with approximately 40% higher healthcare costs, including outpatient care and hospital readmissions.
For all the aforementioned reasons, major depression has been proposed as a risk factor for adverse medical outcomes in patients with ACS(4). The application of collaborative care interventions for depression in CHD populations has emerged as a promising healthcare model to reduce the societal impact of this common comorbidity.
Depression and quality of life
In the setting of coronary heart disease, depression is the strongest predictor of quality of life (QoL). Depression has a higher impact on QoL than symptoms related to the severity of cardiac disease, such as functional impairment or dyspnea in patients with heart failure, and angina or exercise capacity in patients with stable coronary heart disease.
Depression, atrial fibrillation and ventricular arrhythmias
Atrial fibrillation (AF) can profoundly affect patients’ QoL and long-term outcome, and depression, which has been associated with AF, may worsen the symptoms and clinical course of this condition
Depression has been associated with an almost three-fold increase in the odds of the reoccurrence of atrial fibrillation after successful electric cardioversion, and negative emotions have been shown to trigger AF episodes in persons with paroxysmal AF. Furthermore, negative life events, like the death of a partner, have been associated with transiently increased risk of atrial fibrillation. The opposite pathway may also be true, however, as atrial fibrillation can have a substantial impact on the risk or worsening of depression. Thus, atrial fibrillation can cause depression and anxiety in patients, and depression and anxiety, in turn, may create an environment that is conducive for the initiation and perpetuation of atrial fibrillation.
Individuals with depression, as well as those exposed to various forms of chronic and acute psychological distress, have also an increased risk of developing ventricular arrhythmias and sudden cardiac arrest, a finding reported both in initially CHD-free populations and in patients with coronary heart disease.
Evaluation of depression in CHD patients
Recognition and screening(3)
The recognition of depression is an important part of the management of patients with coronary heart disease. Depressive symptoms are highly prevalent in this population and can affect patients’ well-being and QoL. They can also influence treatment adherence, including fidelity to taking medications as prescribed, cooperating with follow-up care, and making risk factor and lifestyle changes needed to enhance recovery. In spite of these, depression is often unrecognized and untreated in CHD patients. Barriers to recognition of depression include lack of mental health expertise and training in cardiology practices, and the perception that this is not part of the treatment mission. Additionally, many symptoms of psychological distress are easily confused with physical disease – for example, fatigue, weight loss, poor appetite or trouble sleeping.
Psychological interventions, such as stress management, individual or group counselling, and support for self-care and pharmacotherapy, are recommended for patients with CHD and comorbid depression. This is because these interventions can help promote modifications in standard risk factors, encourage lifestyle changes, and mitigate distress when added to standard cardiac rehabilitation or as part of a coordinated care management approach(3).
Current clinical guidelines in the USA only mention depression as a psychosocial factor that is reasonable for the non-mental health clinician to recognize if patients have access to adequate care support systems (class of recommendation IIa, level of evidence B). These guidelines further state that the treatment of depression may be reasonable for its clinical benefits other than improving CHD outcomes (class IIb, level of evidence C). In contrast, the European guidelines, while noting limitations for depression screening, recognize the importance of a comprehensive approach for the detection of psychosocial risk factors, using at least a preliminary assessment with a short series of Yes/No questions, and recommend a multimodal behavioral intervention approach integrating health education, physical activity and psychological therapy (class Ia, level of evidence A). In the case of clinically significant symptoms of depression or other psychosocial factors, the European guidelines recommend considering interventions such as psychotherapy, medication or collaborative care(3).
Assessment of depression
Several reliable and valid instruments have been developed for the assessment of depression. The standard for research in the field, at least in the USA, is the Structured Clinical Interview for the DSM-5 (SCID) interview. This interview requires training and must be administered by someone with clinical experience or with close supervision by a mental health professional. It permits diagnosis based on DSM-5 criteria of major depression and related disorders, including dysthymia and bipolar disorder. The assessment of the severity of depressive symptoms can be performed with the Hamilton Depression Scale (Ham-D), a reliable and valid measure of depressive symptoms based on a clinician interview. A score higher than 9 is indicative of moderate to severe depression. Both of these instruments, however, rely on a mental health clinician to administer, which is not usually practical in busy cardiology clinics. An alternative that can be self-administered by patients with CHD is the Beck Depression Inventory. This is a reliable and valid assessment that can be used to screen for the presence of depression, although it does not provide a diagnosis. If suicidal ideation is a concern, the Sheehan Suicidality Tracking Index is another self-report instrument that can be employed. A score above 0 indicates the need for further timely follow-up by a mental health clinician(3).
Antidepressants – treatment of depression in heart disease(2)
Initial investigations of tricyclic antidepressants (TCAs) demonstrated their significant cardiovascular side-effect profile, which was particularly pronounced in patients with heart disease: increased heart rate, orthostatic hypotension and cardiac conductions disturbances with heart block. In overdose, TCAs can cause lethal ventricular arrhythmias. They are associated with increased mortality in patients with ischemic heart disease, leading to myocardial infarction, compared with non-antidepressants users and with users of selective serotonin reuptake inhibitors (SSRI).
SSRI may reduce heart rate and may prolong the QT interval to a variable extent. Sinus bradycardia and syncope have been reported. FDA requires a warning about QT interval prolongation and risk of torsades de pointes in the manufacturer’s package insert for citalopram and (to a lesser degree) for escitalopram. The Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) enrolled 369 patients within 30 days of an acute coronary syndrome. Sertraline was dosed in a range from 50 to 200 mg/day. Sertraline was more effective than placebo overall, as measured by the Clinical Global Impressions Improvement Scale. Sertraline treatment did not have a significant effect on heart rate, blood pressure, cardiac conduction intervals, left ventricular ejection fraction, or on arrhythmias. The results were similar for patients with left ventricular ejection fraction above and below 35%. The treatment with sertraline was associated with reduced major adverse cardiac events and reduced mortality.
The Korean study EsDEPACS enrolled 300 patients treated with 5-20 mg/day escitalopram for depression in a post-hospitalization status for an acute coronary syndrome. The effects of citalopram on Ham-D ratings was significant, and no adverse cardiovascular effects were found more common in escitalopram-treated subjects, except for dizziness.
Bleeding risk is a theoretical concern when using SSRI in patients taking warfarin or antiplatelet therapy because SSRIs themselves increase gastrointestinal bleeding and inhibit platelet activation by reducing platelet serotonin. A retrospective case-control comparison study in patients hospitalized for acute coronary syndromes found a reduction of in-hospital recurrent ischemic events, heart failure and asymptomatic cardiac enzyme elevation in patients taking SSRI during the hospital stay. SSRIs were associated with an increase in minor bleeding complications, but with no effect on either major cardiac event rates or major bleeding complications. Almost all of the patients in this study were also taking aspirin or antiplatelet therapy. Bleeding complications were no more likely in patients who had undergone cardiac artery bypass surgery and were exposed to SSRIs than in those exposed to other antidepressants. Other studies have found an increased incidence of bleeding events in longer-term follow-up of patients treated concurrently with SSRIs and warfarin, anti-platelet therapy, or antiplatelet therapy plus aspirin, with hazard ratios in the range of 1.5-3.
In patients with heart failure, depression is common and is associated with a lower quality of life, with a more rapid decline in functional status and with increased mortality.
Orthostatic hypotension is a well-known side effect of mirtazapine in patients who do not have heart disease. Mirtazapine dosing ranged from 30 to 45 mg per day. Mirtazapine was well tolerated.
Limited data are available about other antidepressant for the treatment of patients with heart disease. Hypertension sufficient to cause treatment discontinuation occurred in 2 of 40 patients in an open-label study of bupropion in patients with heart disease. Hypertension is also a known adverse effect of venlafaxine. An open-label study in patients older than 60 years old found significant rates of increased blood pressure and orthostatic hypotension and several cases of palpitations, dizziness or QT prolongation. Duloxetine has not been studied in patients with significant heart disease.
Trazodone was without significant adverse cardiac effects, except for postural hypotension. Numerous case reports have described QT prolongation and ventricular arrhythmias after trazodone overdose.
Hierarchy of drug choice(2)
On the basis of available evidence, escitalopram, citalopram and sertraline appear to be the first-line pharmacotherapy treatment options for depression in patients with coronary artery disease, with very limited data to suggest a preferential role of paroxetine in congestive heart failure. The relative absence of CYP interactions associated with citalopram and escitalopram (and with lower-dose sertraline) is an advantage in patients taking other medications. Citalopram requires vigilance with respect to the QT interval and arrhythmia risk.
Patients who cannot tolerate or have failed to respond to these agents might logically be offered a second-line treatment with mirtazapine, bupropion, venlafaxine or duloxetine, with special attention to blood pressure response during treatment. TCSs remain the gold standard of antidepressant efficacy, but they carry an increased mortality risk in patients with ischemic heart disease.
Medication should be started at a low dose, possibly below the lowest therapeutic dose, and the subjective tolerability and relevant EKG effects, vital signs, physical examination and laboratory parameters should be reassessed before the dose is increased. Dosage increases should be followed by the reassessment for adverse effects. For patients with heart failure who also have hepatic or renal dysfunction, the target dosages may need to be reduced to lower than normal levels because of prolonged metabolism. However, if a patient is tolerating medication well, but not responding adequately, it is worthwhile to consider a dosage increase.
Desirable secondary effects
Antihistaminic agents (trazodone, mirtazapine) may increase appetite and promote wight gain in patients with cachexia, and the sedating effect may help patients with insomnia. Bupropion is associated with wight loss and, therefore, it may help patients who need to lose weight as part of their cardiac treatment program(2).
When you become a heart patient, one of the most important journeys of your life begins. When you get home from hospital, you suddenly feel “left alone”, says Dan Foldager, Chair of the European Society of Cardiology (ESC) Patient Forum(5). “This is the part of the journey where you experience new things in your daily life, and it is also the part where doubts and anxiety tend to take over. Questions and concerns about family, work, sports, sex, friends, plans, medication, and much more pile up and become a burden that you must carry. You must find solutions and make changes, often on your own.”
There is general agreement that the physical treatment, management and rehabilitation of cardiovascular disease has progressed significantly in recent years. Most patients receive high quality physical care, but the quality of life and the positive outcomes do not solely rely on looking after the body. While there is some acknowledgement of the psychological stresses associated with cardiovascular diseases, particularly anxiety and depression, more research and guidance are needed to address patients’ mental and emotional well-being.
In a worrying number of cases, the psychological impact of cardiovascular diseases extends to relatives. Partners of myocardial infarction survivors face many years of concern, anxiety and, possibly, post-traumatic stress disorder (PTSD), despite being physically healthy themselves. Parents are also affected, as one Forum member notes: “When parents-to-be learn that their child will be born with a congenital heart condition, their uncertainty about the child’s future is often accompanied by guilt. If these psychological issues are not tackled, it may have consequence for the child”(5).
Conflict of interest: none declared
Financial support: none declared
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