Depression and cardiovascular disease

Depressed patients with CV disease often have high levels of biomarkers associated with atherosclerosis. They may also have neurohumoral dysfunction..
Abdelwahab Ward, BS Pharm, PharmD

Introduction

Depression is common in patients with cardiovascular (CV) disease. Symptoms of depression are seen in 65% of patients after an acute myocardial infarction (MI). Major depressive disorder is diagnosed in up to 20% of patients after an acute coronary syndrome. Depression is associated with a doubling in the risk of a cardiovascular event within one to two years after an acute MI. Patients with depression have behaviors that can promote and/or worsen heart disease (e.g., inactivity, smoking, poor diet, medication nonadherence, etc). Depressed patients with CV disease often have high levels of biomarkers associated with atherosclerosis. They may also have neurohumoral dysfunction, vascular dysfunction, and/or inflammatory processes that affect both depression and cardiovascular risk.

Management

Non-pharmacological therapy

Cognitive behavioral therapy can be used as an adjunct to pharmacotherapy in moderate or severe depression. It could also be an alternative to pharmacotherapy in patients who cannot tolerate medications or prefer a nondrug approach. Exercise was as effective as sertraline in depressed cardiac patients in a small study. Patients who are depressed may need extra encouragement to exercise, however. Cardiac rehabilitation is a program that combines exercise, education, and counselling to improve outcomes after an acute cardiovascular syndrome. In addition to improving mood, exercise and cardiac rehabilitation improve cardiovascular health. In a meta-analysis, depression and coronary heart disease events where both reduced with cardiac rehabilitation and mental health treatments. However, only cardiac rehabilitation had a reduction in total mortality.

Pharmacotherapy

Antidepressants

However, antidepressants do improve symptoms of depression, including improved mood and quality of life, in these patients. The ENRICHD trial found no difference in cardiac outcomes between the treatment group and the group who received usual care. However, a nonrandomized subanalysis of the ENRICHD trial suggested that antidepressants reduced the risk of death or recurrent MI. Consider a selective serotonin reuptake inhibitor (SSRI) first in most patients with depression and heart disease. Sertraline (Lustral) has the most safety and efficacy evidence in post-MI and chronic heart failure patients. Patients who have a history of tolerability and response to another antidepressant, with some exceptions noted below, could restart that agent following an MI or heart failure hospitalization, if there are no contraindications.

  • Avoid using citalopram (Cipram) after a recent MI due to concerns about QT prolongation and torsades de pointes.
    • When used by patients with heart disease, minimize risk with a maximum dose of 40 mg daily.
    • But don’t exceed 20 mg daily in patients older than 60 years of age, in patients with liver impairment, CYP2C19 poor metabolizers, and in patients taking CYP2C19 inhibitors (e.g., omeprazole, etc) or cimetidine.
    • U.S. labeling recommends against using citalopram in patients with long QT syndrome; taking other QT-prolonging drugs and in patients with bradycardia, recent MI, or uncompensated heart failure. Canadian labeling contraindicates citalopram in patients with QT prolongation.
    • Any at-risk patient who takes citalopram should receive ECG monitoring.
    • Use caution and consider avoiding the use of some SSRIs (e.g., fluvoxamine, citalopram) in combination with clopidogrel as the effectiveness of clopidogrel may be reduced.
      • Fluvoxamine and citalopram inhibit CYP2C19, which is needed to metabolize clopidogrel to its active metabolite.
  • Escitalopram (Cipralex) seems to carry a lower risk. Studies suggest a lower risk of QT prolongation when escitalopram is limited to 10 mg once daily in post-MI patients, compared to higher doses.
    • A maximum dose of escitalopram 10 mg once daily is also recommended for the elderly and those with hepatic impairment.
      • Canadian labeling also recommends a maximum daily dose of 10 mg for poor metabolizers of CYP2C19 and those on cimetidine or CYP2C19 inhibitors.
    • In Canada, escitalopram is contraindicated in patients with QT prolongation and its use is discouraged in patients taking QT-prolonging drugs or drugs that cause electrolyte depletion.
  • Consider mirtazapine or bupropion when an SSRI (e.g., sertraline, etc) can’t be used, or in addition to an SSRI in treatment-resistant depression.
    • Mirtazapine (Remeron) appeared to be safe and effective. Consider mirtazapine if insomnia or weight loss are a problem.
    • Bupropion appeared safe as a smoking cessation aid in a study of post-MI patients.
      • Bupropion tends to be activating and may be helpful in patients with fatigue.
      • But bupropion can increase blood pressure. Keep the dose as low as possible and monitor blood pressure.
      • Bupropion inhibits CYP2D6 and can increase the concentration of medications metabolized by CYP2D6, including beta-blockers (e.g., metoprolol).
  • Trazodone appeared safe in one study in a small number of patients with heart disease but has been associated with ventricular arrhythmias in case reports.
    • Trazodone can also cause orthostatic hypotension, especially in elderly patients with heart disease.
    • It could be used at a low dose (e.g., 25 mg at bedtime) as an adjunct to an SSRI in patients with insomnia.

The serotonin norepinephrine reuptake inhibitors (SNRIs) venlafaxine (Effexor), desvenlafaxine (Pristiq), and duloxetine (Cymbalta) can increase heart rate and blood pressure by varying degrees. However, increases in blood pressure are dose related. The risk of increased blood pressure is more common with doses of venlafaxine greater than 225 mg/day compared to lower doses. As well, the risk is greater with venlafaxine doses above 150 mg/day than with duloxetine 60 to 120 mg/day. Case reports suggest venlafaxine and duloxetine may exacerbate heart failure. For a patient with neuropathic pain, an SNRI may be a safer choice than a TCA. SNRI doses should be kept as low as possible, and heart rate and blood pressure should be monitored. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors should be avoided in cardiac patients due to their adverse cardiac effects (e.g., conduction abnormalities and hypertension, respectively). Furthermore, TCAs seem to increase the risk of MI. Get our note "Address depression in patients after a heart attack 'summary note'".

Bleeding risk with antidepressants

SSRI and SNRI antiplatelet effects are an important consideration in cardiac patients. When Antidepressants added to other antiplatelet medications, the risk of bleeding can increase. Treatment with sertraline caused further reductions in platelet activation, when used with antiplatelet drugs such as aspirin and clopidogrel (Plavix, generics). Sertraline also inhibited platelet function in congestive heart failure patients taking aspirin 325 mg daily. SSRIs, venlafaxine, and mirtazapine also seem to modestly increase the odds of hospitalization due to GI bleeding in patients taking warfarin.

Summary

There is currently little evidence that depression screening or treatment in cardiac patients improves cardiovascular outcomes. However, screening is advised because of the association between depression and increased morbidity and mortality in this population. When treatment of depression is needed, SSRIs are the antidepressants of choice in cardiac patients due to their safety and efficacy in this population. Several other antidepressants could be used based on response, but TCAs and monoamine oxidase inhibitors should be avoided. However, SSRIs and SNRIs may pose a modest, but clinically significant, bleeding risk in patients taking antiplatelets and anticoagulants. Consider gastroprotection (e.g., proton pump inhibitor [PPI]) in patients at high risk for a GI bleed (e.g., prior GI bleed, also on dual antiplatelet therapy, etc).

References

  1. Carney RM, Freedland KE. Depression and heart rate variability in patients with coronary heart disease. Cleve Clin J Med 2009;76(Suppl 2):S13-7
  2. Lichtman JH, Bigger JT Jr, Blumenthal JA, et al. Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Psychiatric Association. Circulation 2008;118:1768-75
  3. Nieuwsma JA, Williams JW Jr, Namdari N, et al. Diagnostic accuracy of screening tests and treatment for post-acute coronary syndrome depression. Ann Intern Med 2017;167:725-35
  4. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288:701-9
  5. O’Connor CM, Jiang W, Kuchibhatla M, et al. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart disease in Chronic Heart Failure) trial. J Am Coll Cardiol 2010;56:692-9
  6. Pizzi C, Rutjes AW, Costa GM, et al. Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease. Am J Cardiol 2011;107:972-9
  7. Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among SSRIs. Ann Pharmacother 2013;47:1330-41
  8. Serebruany VL, Glassman AH, Malinin AI, et al. Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 2003;108:939-44
  9. Serebruany VL, Glassman AH, Malinin AI, et al. Selective serotonin reuptake inhibitors yield additional antiplatelet protection in patients with congestive heart failure treated with antecedent aspirin. Eur J Heart Fail 2003;5:517-21
  10. Labos C, Dasgupta K, Nedjar H, et al. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ 2011;183:1835-43
  11. Schelleman H, Brensinger CM, Bilker WB, Hennessy S. Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. PLoS One 2011;6:e21447
  12. Laporte S, Chapelle C, Caillet P, et al. Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res 2017;118:19-32
Abdelwahab Ward, BS Pharm, PharmD