US Pharm. 2018;43(2):HS2-HS6.

ABSTRACT: Depression is a strong predictor of survival after cardiovascular (CV) events, and this disorder may predict reduced 5-year survival in patients with an acute myocardial infarction or congestive heart failure compared with nondepressed peers with similar CV diseases (CVDs). Patients with CVD are more likely to experience depression, and those with depression are more likely to develop CVD eventually, with even higher mortality rates than in the general population. Those with depression are more likely to exhibit decreased adherence to medication therapy. For these reasons, patients with CVD and comorbid depression are more likely than those without depression to experience poorer outcomes.

Chronic disorders, including cardiovascular disease (CVD), have long been recognized to significantly affect patients’ mental health. Depression is a strong predictor of survival after CV events, and mortality is increased in patients with an acute myocardial infarction or congestive heart failure. The presence of depression may also predict reduced 5-year survival in these patients compared with nondepressed peers facing similar CV-associated medical challenges.1-5 These risks are notable even after adjustment for the nonmodifiable demographic risks of age and sex.

Depression and anxiety can result from the psychological burden of dealing with the challenges of a chronic disease and may contribute to worsening of the chronic disease. Criteria for diagnosing depression and anxiety are noted in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).6 These psychological conditions can also occur after acute medical events. Depressed mood, anhedonia, lack of motivation, decreased insight, and feelings of worthlessness may be associated with an acute coronary event or any illness or medical procedure perceived to be a threat to one’s life or well-being.

Although these disorders do not meet the diagnostic criteria for major depressive disorder (MDD), a transient adjustment disorder coupled with unaddressed anxiety may contribute to a long-term depressive disorder.7 In fact, the presence of anxiety soon after an acute cardiac event is often associated with—and actually may predict—later development of depression.8 These psychological factors, along with  the predictable lower-than-expected adherence rates for such patients (whether or not diagnosed with mental illness), worsen outcomes for both pharmacologic and nonpharmacologic interventions. The rate of medication nonadherence in depressed patients with comorbid CVD is estimated to be twice that of nondepressed patients.9

Physiological predisposing factors that pose an even higher risk of adverse CV outcomes in patients with mental-health conditions are being explored. Depression has been reported to occur in about 10% of Americans aged 18 years and older; however, the incidence is as high as 33% in those who have experienced myocardial infarction (MI).10 The prevalence of depression may vary with illness severity, as is the case with congestive heart failure (CHF). The more significant the functional-class impairment, the greater the likelihood of depression; the later stages represent worsening of the disease and are associated with a 40% incidence of comorbid depression.11

Physiological Factors That May Pose Increased CVD Risk

Compared with the general population, patients with MDD have up to twice the risk of CVD and increased mortality associated with acute coronary syndrome.1 Little evidence exists regarding the cause of this physiological and psychological phenomenon; however, commonly accepted hypotheses center on an imbalance between the sympathetic and parasympathetic nervous systems that results in suboptimal autonomic homeostasis in patients diagnosed with depression.12

Decreased autonomic tone and diminished capacity to react to changes in heart-rate (HR) variability are physiological sequelae reported in patients with depression.12 Acutely stressful events can trigger a domino effect of negative bodily reactions, including release of norepinephrine, which results in increased HR and blood pressure (BP). Increased release of stress hormones, higher levels of cortisol, and higher blood glucose levels are physiological changes commonly associated with CV stress and disease. Chronic stress is also responsible for alterations in arterial walls resulting from daily elevations in HR and BP. These stress-induced changes are not limited to CV effects, but also include physical discomforts—such as headache and gastrointestinal symptoms—and impaired immunity.13 Alterations in coagulopathic factors such as plasminogen activator inhibitor-1 and fibrinogen; proinflammatory cytokines; and changes in endothelial function, neurohormonal factors, and platelet receptors have been linked to depression and increased risk of CVD.14-18 In addition to the depression-associated noradrenergic-system hyperactivity resulting in increased sympathetic outflow and a higher concentration of urinary catecholamines, the hyperactive hypothalamic activity resulting in elevation of corticosteroids also increases the risk of hypercholesterolemia, atherosclerosis, and hypertension, which are common risk factors for CVDs such as ischemic heart disease (IHD).19,20

In addition to altered platelet function, another potential hypothesis for the pathogenesis of the increased CVD risk with depression involves an increased level of inflammatory markers. Higher levels of C-reactive protein (a nonspecific marker of inflammation) have been reported in patients with depression; this can lead to activation of coronary endothelium and accumulation of plaque, resulting in subsequent signs and symptoms of CVDs such as IHD.20 Patients with depression have also been reported to exhibit a higher sensitivity to thrombin activation, with subsequent clot formation and activated platelet aggregation.20

Many other CVDs besides acute MI and CHF have a connection to MDD. Atrial fibrillation (AF) and IHD are included in the higher-risk, worse-prognosis category. Patients with symptomatic AF are more likely than the general population to have depression and anxiety, with an occurrence rate of roughly 30% and 23%, respectively.21,22 These patients also have poorer quality of life compared with AF patients without these additional psychological disorders.22 Patients with depression who are hospitalized for unstable angina have an increased mortality rate compared with patients without depression.23 In an evaluation of the impact of depression and anxiety on patients diagnosed with AF, Thompson and colleagues found that increased level of anxiety or depression results in increased AF symptom severity (AFSS) even after potential confounding effects are addressed.24 AFSS reduction via pharmacotherapy or surgical ablation did not improve symptoms of either anxiety or depression.24 Suzuki and colleagues found that, in patients who received an implantable cardioverter defibrillator, more than 25% of them reported depressive symptoms 2 years after implantation and those with higher rates of shocks were significantly more likely to be depressed.25

Compared with the general population, patients with IHD are more likely than peers without IHD to have concomitant depression, at a reported rate of up to 45%.26 A recent prospective cohort study by Kim and colleagues examined the seemingly strong association between depression and recurrent chest pain regardless of whether the patient also had a diagnosis of IHD.27 Chest pain was more prevalent in patients with underlying anxiety and depression, and more severe depressive symptoms and worse depression scores were associated with more frequent episodes of chest pain (odds ratio, 2.11; 95% CI, 1.18-3.79).27

Antidepressant Use in Patients With CVD

Although some patients with mild depression can be treated with psychotherapy alone, antidepressants are generally indicated in patients with mild-to-moderate depression and certainly in those with severe MDD. Since antidepressants are considered equally effective between and within classes of medications when given at comparable optimal doses, the initial selection of an antidepressant should be based on the potential side effects and pharmacokinetic characteristics of the specific agent. Owing to their favorable profiles, the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been accepted as first-line agents for treatment of MDD. Bupropion is another alternative that may offer enhanced benefit for depressed patients who are planning smoking cessation to improve CV health.28

SSRIs and SNRIs are associated with side effects that require special consideration in patients with CVD. Given that these agents can induce malignant arrhythmia, their potential for causing QTc prolongation must be considered not only for their agent-specific risk, but also for their cumulative pharmacodynamic effect when combined with other medications that pose a similar risk. Clinicians must consider limiting or avoiding use of QTc-prolonging agents in patients already at risk for QTc prolongation. Such patients include—but are not limited to—older adults, females, and those with electrolyte imbalances.29

To ensure careful consideration of this QTc risk, the FDA made labeling changes in August 2011 and in March 2012 to include new warnings about the QTc risk associated with use of citalopram (Celexa) that also limited the maximum daily dose to 20 mg in patients aged older than 60 years (TABLE 1).30 Escitalopram (Lexapro) is the S-isomer of citalopram, which is a racemic mixture of R- and S-isomers. Although the antidepressant action of citalopram and escitalopram has been associated exclusively with the S-isomer, the QTc effects are less selective. Citalopram’s dose-dependent QT-interval prolongation was not observed with escitalopram use; therefore, the FDA stated that they did not plan to modify dose recommendations for escitalopram.31

The serotonin-reuptake effect on platelets has been considered a potentially positive consequence in patients who otherwise would benefit from reduced platelet activity such as that seen (although to lesser degree) with aspirin. However, an increased risk of bleeding has been noted in patients at risk for hemorrhage, including those who take antidepressants along with anticoagulants. Quinn and colleagues reported that, compared with patients not taking SSRIs, AF patients taking warfarin who also received SSRIs experienced a significantly increased risk of hemorrhage.32 These patients had major hemorrhage events even after adjustment for baseline bleeding risk and time in international normalized ratio range >3 (adjusted rate ratio, 1.41; 95% CI, 1.04-1.92). However, the researchers did not identify concomitant use of nonsteroidal anti-inflammatory drugs or aspirin, which are also known to increase bleeding risk. Hemorrhage rates were similar for fluoxetine, paroxetine, and sertraline.32

The increased bleeding risk with SSRIs and SNRIs is linked to the effects of reuptake inhibition on the platelets, impairing their ability to aggregate.29 Although other antidepressants, such as tricyclic antidepressants, also influence serotonin, their use is not associated with this increased bleeding risk.32 Another consideration for anticoagulation therapy in patients with comorbid depression is that, ideally, any potential relationship between the anticoagulants and subsequent improvement or worsening of depressed mood should be examined further. Turker and colleagues reported that, 6 months after a sample of patients were switched from warfarin to dabigatran (Pradaxa) and compared with an equal sample who continued warfarin, depression symptoms were higher in the warfarin group.33 In this study, Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A) scores were used to assess depression symptoms in warfarin and dabigatran patients (BDI, 15.6  7.8 vs. 11.5  4.8, P <.001; HAM-A, 16.8  10.4 vs. 12.6  8.1, P <.001).33 More research is needed to validate any possible association between depression and anticoagulation therapy; however, in the future, optimal selection of anticoagulants in depressed patients based on impact of depressive symptoms may be another consideration in the overall management of these patients.

MDD Treatment in Patients With CVD

Patients diagnosed with and treated for depression may need increasingly more aggressive interventions if the treatment response is suboptimal after a trial of two different antidepressants (from different classes) given for a sufficient duration and at an adequate dose. Controversy exists regarding the definition of treatment-resistant depression (TRD; also termed treatment-refractory depression); current literature contains at least 10 different definitions.34 Accordingly, the various definitions of the interventions studied and reported create an even greater disparity in how treatment approaches may be presented and applied clinically to patients in need of care.35 Although most cases of TRD are thought to result from inadequate therapy (relative resistance), many TRD patients fail to respond to treatment despite optimal dose and duration.28

There are numerous options for treating TRD, including concomitant use of lithium, thyroid hormone, and antipsychotic augmentation. Other options with much less evidence supporting efficacy include augmentation using an anticonvulsant, omega-3 fatty acids, folate, or a psychostimulant (including modafinil).28

Support for the use of second-generation antipsychotics (SGAs) as MDD augmentation has been shown, in part, by an increase in FDA approvals of SGAs for this purpose. Aripiprazole (Abilify), quetiapine (Seroquel), olanzapine (Zyprexa), and brexpiprazole (Rexulti) have been approved for augmentation in the treatment of MDD. Because augmentation requires continuation of the primary antidepressant, a key concern is not only increased QTc risk, but also the potential for the SGA to contribute to or cause cardiometabolic symptoms in patients with predisposed risk.29 Because antipsychotic agents carry varying degrees of cardiometabolic risk and it appears that certain people are more susceptible to these effects, it is often difficult to predict who will experience these metabolic events. Further, these events have not been associated with specific dose thresholds of the SGA; therefore, even the smaller doses approved for use as augmentation in TRD may pose a risk. Additionally, antipsychotic agents now carry a black box warning advising against use in dementia-related psychosis, including dementia resulting from stroke or cerebrovascular accidents. Patients with dementia-related psychosis who take antipsychotics have a greater risk of mortality. In studies, although the causes of death were different, most deaths were reported to have either CV (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) causes.36,37

The Pharmacist’s Role

Whether in ambulatory or institutional care, it has become increasingly clear that the pharmacist’s role in managing both the physical and mental health of patients as crucial priorities is essential to improved quality and length of life. Medications used for CVD may contribute to depression (i.e., beta-blockers, reserpine, clonidine), and medications used to treat depression may complicate CV treatment and outcomes (QTc and cardiometabolic symptoms). The American Heart Association has supplied evidence linking depression to coronary heart disease and offers recommendations for healthcare providers to prioritize the assessment, referral, and treatment of depression.38

Pharmacists also play a critical role in enhancing medication adherence through patient consultation that encourages self-reports of adverse drug reactions that pose barriers to uninterrupted treatment. In most cases, the failure of a patient with TRD to improve is likely the result of inadequate therapy. Pharmacists can encourage patients to be diligent in taking medications as prescribed, thereby preventing a false designation of treatment failure and subsequent unnecessary augmentation that carries additional risk. Also, pharmacists can ensure that adequate doses are used to appropriately treat depression in older adults by educating prescribers that lower dose limits do not apply to all antidepressants used in older adults.


The DSM-5 updates on depression, coupled with enhanced awareness of the importance of reporting depression symptoms, are expected to increase the number of people diagnosed with depression in the United States. The increasing number of depression diagnoses, along with the high volume of people with CVD, will require greater efforts by healthcare professionals handling medication management for CVD patients with comorbid depression. Treatment plans should be developed to foster both a sound mind and a sound body to ensure the best outcomes.


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