Psychiatry and Medical Illness
Depression and Cardiovascular Disease
What Is the Correlation?
By Julie Schulman, MD and Peter A. Shapiro, MD
August 1, 2008
Dr Schulman is assistant clinical professor and Dr Shapiro is associate clinical professor in the department of psychiatry at Columbia University in New York City. The authors report no conflicts of interest concerning the subject matter of this article.
Treating Depression Comorbid with Cardiovascular Disease
Depression can be safely treated in patients with coronary artery disease. One common mistake that physicians make is to undertreat patients who have mild congestive heart failure. Patients with severe congestive heart failure have reduced cardiac output, hepatic congestion, and renal impairment, which affects absorption, metabolism, and elimination of medications. However, allowing for necessary adjustments, the psychiatrist should use therapeutically effective doses of antidepressants, while keeping in mind other factors such as concurrent medications, age, and so forth.
Tricyclic antidepressants are not recommended as a first-line treatment option, even though they are as effective as SSRIs for treating depression. They cause orthostatic hypotension and delayed cardiac conduction, and can trigger ventricular arrhythmias when overdosed. Orthostatic hypotension can pose a significant risk for falls in elderly patients, and patients with heart disease often take medications (eg, diuretics, vasodilators) that can increase this risk. Tricyclic antidepressants are type 1A antiarrhythmic agents that prolong atrial and ventricular depolarization and widen P-R, QRS, and QT intervals. Studies have shown that QTc intervals of more than 440 milliseconds, and especially more than 500 milliseconds, are associated with an increased risk of sudden death.43
Type 1A antiarrhythmic agents have also been shown to increase mortality in patients who had had a myocardial infarction with premature ventricular contractions.43
Two small open-label trials initially demonstrated the safety but also relatively low efficacy of fluoxetine(Drug information on fluoxetine)
A trial that compared paroxetine with nortriptyline(Drug information on nortriptyline)
in patients with left ventricular dysfunction found that both medications were effective but that the patients in the paroxetine(Drug information on paroxetine)
group had significantly fewer adverse cardiac effects.46
Strik and colleagues47
published a randomized double-blind study that compared fluoxetine with placebo in patients who had had a myocardial infarction. Fluoxetine had no significant cardiac effects, although it was significantly more effective than placebo for patients with mild depression.
There have been 2 large double-blind studies of SSRIs in cardiac patients. In the Sertraline(Drug information on sertraline)
Antidepressant Heart Attack Randomized Trial (SADHART), 369 patients who had had a recent acute coronary syndrome (acute myocardial infarction or unstable angina) were randomized within 30 days of the coronary event to receive either sertraline or placebo.48,49
Sertraline at dosages of 50 to 200 mg daily was associated with a modest improvement in mood that was significant in patients with a history of at least 1 depressive episode or more severe depression, and there was no difference from placebo in heart rate, blood pressure, cardiac conduction, or left ventricular ejection fraction.
One study, the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE), looked at 284 patients with stable, documented coronary artery disease, a major depressive episode of at least 4 weeks, and a Hamilton depression rating (HAM-D) score of 20 or more. Patients were randomized to receive citalopram(Drug information on citalopram)
or placebo, as well as clinical management supplemented by interpersonal psychotherapy compared with clinical management alone.50
Citalopram for 12 weeks at a mean dosage of 33.1 mg daily was more efficacious than placebo and did not cause any adverse cardiovascular effects. Interpersonal psychotherapy conferred no significant benefit.
There has been 1 other large randomized controlled trial of antidepressants in patients with cardiac disease. In the Myocardial Infarction and Depression–Intervention Trial (MIND-IT), 2177 patients who were hospitalized for an acute myocardial infarction were evaluated for depression as defined by the International Classification of Diseases (ICD-10).51
The patients who met criteria and were eligible for the study were randomized to receive either care as usual (n = 122) or intervention (n = 209). A subset of participants in the intervention arm were randomized to mirtazapine(Drug information on mirtazapine)
, 30 to 45 mg daily, or placebo. Mirtazapine treatment was superior to placebo for some depression measures at 8 and 24 weeks.52
The remainder of the patients in the intervention arm received a variety of interventions for 6 months of treatment. At the 18-month follow-up, there were no significant differences between the intervention and control groups in Beck Depression Inventory (BDI) scores or presence of ICD-10–defined depression.
The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial compared a cognitive-based psychosocial intervention—aimed at improving depression and increasing social supports—with usual medical care; 2481 patients with an acute myocardial infarction and either depression or poor social support were enrolled. Participants in the active treatment group attended a median of 11 individual sessions in 6 months, plus group therapy when feasible, and were referred to psychiatrists for possible antidepressant treatment if their HAM-D score was higher than 24 or they had less than a 50% reduction in their BDI scores after 5 weeks. The trial found that there was a statistically significant diminution in depressive symptoms and social isolation in the active intervention arm compared with the usual-care group. However, both groups showed substantial improvement at the 6-month follow-up; HAM-D scores improved by 10 points in the cognitive behavioral therapy group and by almost 9 points in the usual-care group.53 Does Depression Treatment Reduce the Risk of Cardiac Events?
There is no clear evidence that treatment of depression reduces the risk of having a cardiac event. However, a large retrospective case-control study by Sauer and colleagues54
compared patients who were smokers and had been hospitalized with a first myocardial infarction with controls. After adjusting for numerous confounding variables, the OR for myocardial infarction among current SSRI users compared with nonusers was 0.35 (95% CI, 0.18 to 0.68; P
In a larger study of patients who had been hospitalized with a first myocardial infarction (both smokers and nonsmokers) compared with community controls, SSRI use overall was not associated with a significant reduction in risk of myocardial infarction. However, use of SSRIs that have a high affinity for the serotonin transporter—paroxetine, fluoxetine, and sertraline—was associated with a reduced risk of myocardial infarction. Users of other SSRIs or tricyclics did not have any significant difference in risk compared with nonusers, but overall there was a significant trend (P
< .01) toward increased protective effect with an increased degree of affinity for the serotonin transporter.55
These 4 prospective, randomized, clinical studies—ENRICHD, SADHART, CREATE, and MIND-IT—have failed to show statistically significant cardiovascular benefits of treatment for depression. In the ENRICHD trial, there was no difference in recurrent myocardial infarction or mortality between the active and control groups. Patients taking antidepressants, particularly SSRIs, did have a significantly lower risk of both outcomes, but the use of antidepressants was not randomized.56
The SADHART study was designed to test the safety of sertraline in patients with heart disease—not to detect differences in cardiac outcomes.48,49
However, results of the study show a clear trend towards improved outcomes in the group treated with sertraline, with an RR of 0.77 for cardiac events (32 events in the sertraline arm and 41 events in the placebo arm). However, because of the low total number of cardiac events in the subject groups, this result is statistically nonsignificant.
As with SADHART, CREATE was underpowered to show any significant difference in cardiac outcomes.50
However, unlike SADHART, there was no trend toward improved cardiac outcomes with citalopram; there were 6 cardiovascular events in the citalopram arm and 6 events in the placebo arm. Of note, study participants started treatment an average of 18 months after their index event, unlike the participants in SADHART and ENRICHD, who usually began treatment in the first month.
In MIND-IT, there was no significant difference between the active intervention and usual-care groups in the number of cardiac events—myocardial infarction, cardiac death, revascularization, heart failure, myocardial ischemia, or ventricular arrhythmias—at 18 months.52
There was also no significant difference between those in the active group who received treatment with mirtazapine, citalopram, or other antidepressants (n
= 90), and the usual-care group. Conclusion
Modern treatment of depression is reasonably safe and effective for patients with cardiac disease, but treatment that has greater effectiveness than has been demonstrated so far would be highly desirable. Although depression treatment has not yet been shown to improve cardiac outcomes in depressed patients with heart disease, it is likely that it improves quality of life and functional status in cardiac patients.57
1. Fergusson DM, Goodwin RD, Horwood LJ. Major depression and cigarette smoking: results of a 21-year longitudinal study. Psychol Med. 2003;33:1357-1367.
2. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160:2101-2107.
3. Bunde J, Martin R. Depression and prehospital delay in the context of myocardial infarction. Psychosom Med. 2006;68:51-57.
4. Wong CK, Tang EW, Herbison P, et al. Pre-existent depression in the 2 weeks before an acute coronary syndrome can be associated with delayed presentation of the heart attack. QJM. 2008;101:137-144.
5. Jackson JL, Passamonti M, Kroenke K. Outcome and impact of mental disorders in primary care at 5 years. Psychosom Med. 2007;69:270-276.
6. Lesperance F, Frasure-Smith N, Talajic M. Major depression before and after myocardial infarction: its nature and consequences. Psychosom Med. 1996;58: 99-110.
7. Luutonen S, Holm H, Salminen JK, et al. Inadequate treatment of depression after myocardial infarction. Acta Psychiatr Scand. 2002;106:434-439.
8. Rugulies R. Depression as a predictor for coronary heart disease: a review and meta-analysis. Am J Prev Med. 2002;23:51-61.
9. Yusuf S, Hawken S, Ounpuu S, et al; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937-952.
10. Surtees PG, Wainwright NW, Luben RN, et al. Depression and ischemic heart disease mortality: evidence from the EPIC-Norfolk United Kingdom prospective cohort study. Am J Psychiatry. 2008;165: 515-523.
11. Frasure-Smith N, Lespérance F, Talajic M. Depression and 18-month prognosis after myocardial infarction [published correction appears in Circulation. 1998;97:708]. Circulation. 1995;91:999-1005.
12. Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001;58:221-227.
13. Lespérance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation. 2002;105:1049-1053.
14. Blumenthal JA, Lett HS, Babyak MA, et al; NORG Investigators. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet. 2003; 362:604-609.
15. Burg MM, Benedetto MC, Soufer R. Depressive symptoms and mortality two years after coronary artery bypass graft surgery (CABG) in men. Psychosom Med. 2003;65:508-510.
16. Borowicz L Jr, Royall R, Grega M, et al. Depression and cardiac morbidity 5 years after coronary artery bypass surgery. Psychosomatics. 2002;43:464-471.
17. Murberg TA, Bru E, Svebak S, et al. Depressed mood and subjective health symptoms as predictors of mortality in patients with congestive heart failure: a two-year follow-up study. Int J Psychiatry Med. 1999;29:311-326.
18. Jiang W, Alexander J, Christopher E, et al. Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure. Arch Intern Med. 2001;161:1849-1856.
19. De Clerck F. Effects of serotonin on platelets and blood vessels. J Cardiovasc Pharmacol. 1991;17 (suppl 5):S1-S5.
20. Weyrich AS, Solis GA, Li KS, et al. Platelet amplification of vasospasm. Am J Physiol. 1992;263(2, pt 2):H349-H358.
21. Arora RC, Meltzer HY. Increased serotonin2 (5-HT2) receptor binding as measured by 3H-lysergic acid diethylamide (3H-LSD) in the blood platelets of depressed patients. Life Sci. 1989;44:725-734.
22. Sheline YI, Bardgett ME, Jackson JL, et al. Platelet serotonin markers and depressive symptomatology. Biol Psychiatry. 1995;37:442-447.
23. Musselman DL, Marzec UM, Manatunga A, et al. Platelet reactivity in depressed patients treated with paroxetine: preliminary findings. Arch Gen Psychiatry. 2000;57:875-882.
24. Atar D, Malinin A, Takserman A, et al. Escitalopram, but not its major metabolites, exhibits antiplatelet activity in humans. J Clin Psychopharmacol. 2006;26: 172-177.
25. Maes M, Bosmans E, Meltzer HY, et al. Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? Am J Psychiatry. 1993;150:1189-1193.
26. Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord. 1995;34:301-309.
27. Mikova O, Yakimova R, Bosmans E, et al. Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol. 2001;11:203-208.
28. Miller GE, Stetler CA, Carney RM, et al. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol. 2002;90:1279-1283.
29. Bremmer MA, Beekman AT, Deeg DJ, et al. Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord. 2008; 106:249-255.
30. Blum A, Miller H. Pathophysiological role of cytokines in congestive heart failure. Annu Rev Med. 2001;52:15-27.
31. Alonso-Martínez JL, Llorente-Diez B, Echegaray-Agara M, et al. C-reactive protein as a predictor of improvement and readmission in heart failure. Eur J Heart Fail. 2002;4:331-336.
32. Lespérance F, Frasure-Smith N, Théroux P, Irwin M. The association between major depression and levels of soluble intercellular adhesion molecule 1, interleukin-6, and C-reactive protein in patients with recent acute coronary syndromes. Am J Psychiatry. 2004;161:271-277.
33. Schins A, Tulner D, Lousberg R, et al. Inflammatory markers in depressed post-myocardial infarction patients. J Psychiatr Res. 2005;39:137-144.
34. Heit S, Owens MJ, Plotsky PM, Nemeroff CB. Corticotropin-releasing factor, stress, and depression. Neuroscientist. 1997;3:186-194.
35. Otte C, Marmar CR, Pipkin SS, et al. Depression and 24-hour urinary cortisol in medical outpatients with coronary heart disease: The Heart and Soul Study. Biol Psychiatry. 2004;56:241-247.
36. Pepper GS, Lee RW. Sympathetic activation in heart failure and its treatment with beta-blockade. Arch Intern Med. 1999;159:225-234.
37. Benedict CR, Shelton B, Johnstone DE, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators. Circulation. 1996;94:690-697.
38. Carney RM, Blumenthal JA, Stein PK, et al. Depression, heart rate variability, and acute myocardial infarction. Circulation. 2001;104:2024-2028.
39. Agelink MW, Boz C, Ullrich H, Andrich J. Relationship between major depression and heart rate variability. Clinical consequences and implications for antidepressive treatment. Psychiatry Res. 2002;113: 139-149.
40. Jiang W, Hathaway WR, McNulty S, et al. Ability of heart rate variability to predict prognosis in patients with advanced congestive heart failure. Am J Cardiol. 1997;80:808-811.
41. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005;111:363-368.
42. Rybakowski JK, Wykretowicz A, Heymann-Szlachcinska A, Wysocki H. Impairment of endothelial function in unipolar and bipolar depression. Biol Psychiatry. 2006;60:889-891.
43. Glassman AH, Roose SP, Bigger JT Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA. 1993;269:2673-2675.
44. Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry. 1994;151:1735-1739.
45. Roose SP, Glassman AH, Attia E, et al. Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry. 1998;155:660-665.
46. Roose SP, Laghrissi-Thode F, Kennedy JS, et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA. 1998;279:287-291.
47. Strik JJ, Honig A, Lousberg R, et al. Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial. Psychosom Med. 2000;62:783-789.
48. Glassman AH, O’Connor CM, Califf RM, et al; Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288:701-709.
49. Glassman AH, Bigger JT, Gaffney M, et al. Onset of major depression associated with acute coronary syndromes: relationship of onset, major depressive disorder history, and episode severity to sertraline benefit. Arch Gen Psychiatry. 2006;63:283-288.
50. Lesperance F, Frasure-Smith N, Koszycki D, et al; CREATE Investigators. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA. 2007; 297: 367-379.
51. van Melle JP, de Jonge P, Honig A, et al; MIND-IT investigators. Effects of antidepressant treatment following myocardial infarction. Br J Psychiatry. 2007; 190:460-466.
52. Honig A, Kuyper AM, Schene AH, et al; MIND-IT investigators. Treatment of post-myocardial infarction depressive disorder: a randomized, placebo-controlled trial with mirtazapine. Psychosom Med. 2007; 69:606-613.
53. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. JAMA. 2003;289:3106-3116.
54. Sauer WH, Berlin JA, Kimmel SE. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation. 2001;104:1894-1898.
55. Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation. 2003;108:32-36.
56. Taylor CB, Youngblood ME, Catellier D, et al; ENRICHD Investigators. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry. 2005;62:792-798.
57. Swenson JR, O’Connor CM, Barton D, et al; Sertraline Antidepressant Heart Atttack Randomized Trial (SADHART) Group. Influence of depression and effect of treatment with sertraline on quality of life after hospitalization for acute coronary syndrome. Am J Cardiol. 2003;92:1271-1276.
Lespérance F, Frasure-Smith N, Koszycki D, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA. 2007;297:367-379.
van Melle JP, de Jonge P, Honig A, et al; MIND-IT investigators. Effects of antidepressant treatment following myocardial infarction. Br J Psychiatry. 2007; 190:460-466.
SearchMedica SEARCH RESULT
Find peer-reviewed literature and websites for practicing medical professionals